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NEUROSCIENCE




SCIENCE OF THE BRAIN
AN INTRODUCTION FOR YOUNG STUDENTS




British Neuroscience Association
European Dana Alliance for the Brain
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Neuroscience: the Science of the Brain
1 The Nervous System P2


2 Neurons and the
Action Potential P4


3 Chemical Messengers P7


4 Drugs and the Brain P9


5 Touch and Pain P11


6 Vision P14


Inside our heads, weighing about 1.5 kg, is an astonishing living organ consisting of
7 Movement P19
billions of tiny cells. It enables us to sense the world around us, to think and to talk.
The human brain is the most complex organ of the body, and arguably the most
8 The Developing P22 complex thing on earth. This booklet is an introduction for young students.
Nervous System
In this booklet, we describe what we know about how the brain works and how much
9 Dyslexia P25 there still is to learn. Its study involves scientists and medical doctors from many
disciplines, ranging from molecular biology through to experimental psychology, as
well as the disciplines of anatomy, physiology and pharmacology. Their shared
10 Plasticity P27
interest has led to a new discipline called neuroscience - the science of the brain.

11 Learning and Memory P30 The brain described in our booklet can do a lot but not everything. It has nerve cells
- its building blocks - and these are connected together in networks. These
12 Stress P35 networks are in a constant state of electrical and chemical activity. The brain we
describe can see and feel. It can sense pain and its chemical tricks help control the
uncomfortable effects of pain. It has several areas devoted to co-ordinating our
13 The Immune System P37
movements to carry out sophisticated actions. A brain that can do these and many
other things doesn’t come fully formed: it develops gradually and we describe some
14 Sleep P39 of the key genes involved. When one or more of these genes goes wrong, various
conditions develop, such as dyslexia. There are similarities between how the brain
15 Brain Imaging P41 develops and the mechanisms responsible for altering the connections between
nerve cells later on - a process called neuronal plasticity. Plasticity is thought to
underlie learning and remembering. Our booklet’s brain can remember telephone
16 Artificial Brains and P44
numbers and what you did last Christmas. Regrettably, particularly for a brain
Neural Networks that remembers family holidays, it doesn’t eat or drink. So it’s all a bit limited.
But it does get stressed, as we all do, and we touch on some of the hormonal and
17 When things go wrong P47 molecular mechanisms that can lead to extreme anxiety - such as many of us feel in
the run-up to examinations. That’s a time when sleep is important, so we let it have
18 Neuroethics P52 the rest it needs. Sadly, it can also become diseased and injured.

New techniques, such as special electrodes that can touch the surface of cells,
19 Training and Careers P54
optical imaging, human brain scanning machines, and silicon chips containing
artificial brain circuits are all changing the face of modern neuroscience.
20 Further Reading and P56 We introduce these to you and touch on some of the ethical issues and social
Acknowledgements implications emerging from brain research.


The Neuroscience Community
at the University of Edinburgh
The European
Dana Alliance
for the Brain




To order additional copies: Online ordering: www.bna.org.uk/publications
Postal: The British Neuroscience Association, c/o: The Sherrington Buildings, Ashton Street, Liverpool L68 3GE
Telephone: 44 (0) 151 794 4943/5449 Fax: 44 (0) 794 5516/5517
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This booklet was prepared and edited on behalf of the British Neuroscience Association and the European Dana Alliance for
the Brain by Richard Morris (University of Edinburgh) and Marianne Fillenz (University of Oxford). The graphic design was by
Jane Grainger (Grainger Dunsmore Design Studio, Edinburgh). We are grateful for contributions from our colleagues in the
Division of Neuroscience, particularly Victoria Gill, and others in the neuroscience community in Edinburgh. We also thank
members of the University Department of Physiology in Oxford, particularly Colin Blakemore, and helpful colleagues in other
institutions. Their names are listed on the back page.

The British Neuroscience Association (BNA) is the professional body in the United Kingdom that represents
neuroscientists and is dedicated towards a better understanding of the nervous system in health and disease.
Its members range from established scientists holding positions in Universities and Research Institutes through to
postgraduate students. The BNA’s annual meetings, generally held in the spring, provide a forum for the presentation of the
latest research. Numerous local groups around the country hold frequent seminars and these groups often organise
activities with the general public such as school visits and exhibitions in local museums. See http://www.bna.org.uk/ for
further information.

The goal of The European Dana Alliance for the Brain (EDAB) is to inform the general public and decision makers about the
importance of brain research. EDAB aims to advance knowledge about the personal and public benefits of neuroscience and
to disseminate information on the brain, in health and disease, in an accessible and relevant way. Neurological and
psychiatric disorders affect millions of people of all ages and make a severe impact on the national economy. To help
overcome these problems, in 1997, 70 leading European neuroscientists signed a Declaration of Achievable Research Goals
and made a commitment to increase awareness of brain disorders and of the importance of neuroscience. Since then, many
others have been elected, representing 24 European countries. EDAB has more than 125 members.
See http://www.edab.net/ for further information.

Published by The British Neuroscience Association
The Sherrington Buildings
Ashton Street
Liverpool
L69 3GE
UK
Copyright British Neuroscience Association 2003

This book is in copyright. Subject to statutory
exception and the provisions of relevant collective
licensing agreements, no reproduction of any part
may take place without the written permission of
The British Neuroscience Association

First Published 2003
ISBN: 0-9545204--0-8




The images on this page are of neurons of the cerebral cortex visualised using special dyes inserted into the adjacent cells.
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The Nervous
System

Neurons have an architecture that consists of a cell body
and two sets of additional compartments called
‘processes’. One of these sets are called axons; their job is
to transmit information from the neuron on to others to
which it is connected. The other set are called dendrites -
their job is to receive the information being transmitted by
the axons of other neurons. Both of these processes
participate in the specialised contacts called synapses
(see the Chapters 2&3 on Action Potential and Chemical
Messengers). Neurons are organised into complex chains
and networks that are the pathways through which
information in the nervous system is transmitted.

The brain and spinal cord are connected to sensory
receptors and muscles through long axons that
make up the peripheral nerves. The spinal cord has two
functions: it is the seat of simple reflexes such as the knee
jerk and the rapid withdrawal of a limb from a hot object or a
pinprick, as well as more complex reflexes, and it forms a
highway between the body and the brain for information
Human central nervous system showing the brain and travelling in both directions.
spinal cord
These basic structures of the nervous system are the same
Basic structure in all vertebrates. What distinguishes the human brain is its
large size in relation to body size. This is due to an enormous
The nervous system consists of the brain, spinal cord and increase in the number of interneurons over the course of
peripheral nerves. It is made up of nerve cells, called evolution, providing humans with an immeasurably wide choice
neurons, and supporting cells called glial cells. of reactions to the environment.

There are three main kinds of neurons. Sensory neurons are
coupled to receptors specialised to detect and
respond to different attributes of the internal and external
Anatomy of the Brain
environment. The receptors sensitive to changes in light,
The brain consists of the brain stem and the cerebral
sound, mechanical and chemical stimuli subserve the sensory
hemispheres.
modalities of vision, hearing, touch, smell and taste.
When mechanical, thermal or chemical stimuli to the skin
The brain stem is divided into hind-brain, mid-brain and a
exceed a certain intensity, they can cause tissue damage
‘between-brain’ called the diencephalon. The hind-brain is an
and a special set of receptors called nociceptors are
extension of the spinal cord. It contains networks of
activated; these give rise both to protective reflexes and to
neurons that constitute centres for the control of vital
the sensation of pain (see chapter 5 on Touch and Pain).
functions such as breathing and blood pressure. Within
Motor neurons, which control the activity of muscles, are
these are networks of neurons whose activity controls these
responsible for all forms of behaviour including speech.
functions. Arising from the roof of the hind-brain is the
Interposed between sensory and motor neurons are
cerebellum, which plays an absolutely central role in the
Interneurones. These are by far the most numerous (in the
control and timing of movements (See Chapters on
human brain). Interneurons mediate simple reflexes as well
Movement and Dyslexia).
as being responsible for the highest functions of
the brain. Glial cells, long thought to have a purely
The midbrain contains groups of neurons, each of which seem
supporting function to the neurons, are now known to make
to use predominantly a particular type of chemical
an important contribution to the development of the
messenger, but all of which project up to cerebral
nervous system and to its function in the adult brain.
hemispheres. It is thought that these can modulate the
While much more numerous, they do not transmit
activity of neurons in the higher centres of the brain
information in the way that neurons do.




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The human brain seen from above, below and the side. Side view of the brain
showing division between
the cerebral hemisphere
and brain stem, an
to mediate such functions as sleep, attention or reward. extension of which is the
The diencephalon is divided into two very different areas cerebellum
called the thalamus and the hypothalamus: The thalamus
Cerebral Hemisphere
relays impulses from all sensory systems to the cerebral Cerebellum
cortex, which in turn sends messages back to the thalamus. Brain Stem
This back-and-forward aspect of connectivity in the brain is
intriguing - information doesn’t just travel one way.
The hypothalamus controls functions such as eating and
drinking, and it also regulates the release of hormones Cross section through
involved in sexual functions. the brain showing the
thalamus and
hypothalamus
The cerebral hemispheres consist of a core, the basal
ganglia, and an extensive but thin surrounding sheet of Thalamus
neurons making up the grey matter of the cerebral cortex. Hypothalamus
The basal ganglia play a central role in the initiation and
control of movement. (See Chapter 7 on Movement).
Packed into the limited space of the skull, the cerebral cortex
is thrown into folds that weave in and out to enable a much
larger surface area for the sheet of neurons than would
otherwise be possible. This cortical tissue is the most highly
developed area of the brain in humans - four times bigger Cross section through
the brain showing the
than in gorillas. It is divided into a large number of discrete basal ganglia and corpus
areas, each distinguishable in terms of its layers and callosum
connections. The functions of many of these areas are
known - such as the visual, auditory, and olfactory areas, the Cerebral Hemisphere
sensory areas receiving from the skin (called the Corpus Callosum
Basai Ganglia
somaesthetic areas) and various motor areas.
The pathways from the sensory receptors to the cortex and
from cortex to the muscles cross over from one side to the
other. Thus movements of the right side of the body are
controlled by the left side of the cortex (and vice versa).
Similarly, the left half of the body sends sensory signals to
The father of modern
the right hemisphere such that, for example, sounds in the neuroscience, Ramon y
left ear mainly reach the right cortex. However, the two Cajal, at his microscope
halves of the brain do not work in isolation - for the left and in 1890.
right cerebral cortex are connected by a large fibre tract
called the corpus callosum.

The cerebral cortex is required for voluntary actions,
language, speech and higher functions such as thinking and
remembering. Many of these functions are carried out by
both sides of the brain, but some are largely lateralised to
one cerebral hemisphere or the other. Areas concerned with Cajal’s first pictures
some of these higher functions, such as speech (which is of neurons and their
dendrites.
lateralised in the left hemisphere in most people), have been
identified. However there is much still to be learned,
particularly about such fascinating issues as consciousness, Cajal’s exquisite
and so the study of the functions of the cerebral cortex is neuron drawings -
one of the most exciting and active areas of research these are of the
in Neuroscience. cerebellum.
g




Internet Links: http://science.howstuffworks.com/brain.htm
http://faculty.washington.edu/chudler/neurok.html http://psych.hanover.edu/Krantz/neurotut.html
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Neurons and the
Action Potential

Whether neurons are sensory or motor, big or small, they Spinal motor neuron Pyramidal cell Purkinje cell of cerebellum
all have in common that their activity is both electrical and
chemical. Neurons both cooperate and compete with each
other in regulating the overall state of the nervous
system, rather in the same way that individuals in a
society cooperate and compete in decision-making
processes. Chemical signals received in the dendrites from
the axons that contact them are transformed into
electrical signals, which add to or subtract from electrical
signals from all the other synapses, thus making a decision Cell Body
about whether to pass on the signal elsewhere. Electrical Cell Body
potentials then travel down axons to synapses on the Cell Body
Axon
dendrites of the next neuron and the process repeats. Axon Axon

The dynamic neuron
3 different types of Neurons
As we described in the last chapter, a neuron consists of
dendrites, a cell body, an axon and synaptic terminals. Inside neurons are many inner compartments. These
This structure reflects its functional subdivision into consist of proteins, mostly manufactured in the cell body,
receiving, integrating and transmitting compartments. that are transported along the cytoskeleton. Tiny
Roughly speaking, the dendrite receives, the cell-body protuberances that stick out from the dendrites called
integrates and the axons transmit - a concept called dendritic spines. These are where incoming axons make
polarization because the information they process most of their connections. Proteins transported to the
supposedly goes in only one direction. spines are important for creating and maintaining neuronal
connectivity. These proteins are constantly turning over,
Dendrites Cell Body Axon Synapse being replaced by new ones when they’ve done their job.
All this activity needs fuel and there are energy factories
(mitochondria) inside the cell that keep it all working. The
end-points of the axons also respond to molecules called
growth factors. These factors are taken up inside and then
transported to the cell body where they influence the
expression of neuronal genes and hence the manufacture of
new proteins. These enable the neuron to grow longer
dendrites or make yet other dynamic changes to its shape
Receiving Integrating Transmitting or function. Information, nutrients and messengers flow to
and from the cell body all the time.
The key concepts of a neuron

Like any structure, it has to hold together. The outer
membranes of neurons, made of fatty substances, are
draped around a cytoskeleton that is built up of rods of
tubular and filamentous proteins that extend out into
dendrites and axons alike. The structure is a bit like a canvas
stretched over the tubular skeleton of a frame tent.
The different parts of a neuron are in constant motion, a
process of rearrangement that reflects its own activity and
that of its neighbours. The dendrites change shape,
sprouting new connections and withdrawing others, and the
axons grow new endings as the neuron struggles to talk a bit Dendritic spines are the tiny green protuberances sticking
more loudly, or a bit more softly, to others. out from the green dendrites of a neuron. This is where
synapses are located.




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Receiving and deciding The action-potential
On the receiving side of the cell, the dendrites have close To communicate from one neuron to another, the neuronal
contacts with incoming axons of other cells, each of which is signal has first to travel along the axon. How do neurons
separated by a miniscule gap of about 20 billionths of metre. do this?
A dendrite may receive contacts from one, a few, or even
thousands of other neurons. These junctional spots are The answer hinges on harnessing energy locked in physical
named synapses, from classical Greek words that mean “to and chemical gradients, and coupling together these forces
clasp together”. Most of the synapses on cells in the in an efficient way. The axons of neurons transmit electrical




cerebral cortex are located on the dendritic spines that pulses called action potentials. These travel along nerve
stick out like little microphones searching for faint signals. fibres rather like a wave travelling down a skipping rope.
Communication between nerve cells at these contact points This works because the axonal membrane contains ion-
is referred to as synaptic transmission and it involves a channels, that can open and close to let through electrically
chemical process that we will describe in the next Chapter. charged ions. Some channels let through sodium ions (Na+),
When the dendrite receives one of the chemical messengers while others let through potassium ions (K+). When channels
that has been fired across the gap separating it from the open, the Na+ or K+ ions flow down opposing chemical and
sending axon, miniature electrical currents are set up inside electrical gradients, in and out of the cell, in response to
the receiving dendritic spine. These are usually currents electrical depolarisation of the membrane.
that come into the cell, called excitation, or they may be
currents that move out of the cell, called inhibition. All these
positive and negative waves of current are accumulated in
the dendrites and they spread down to the cell body. If they
don’t add up to very much activity, the currents soon die
down and nothing further happens. However, if the currents
add up to a value that crosses a threshold, the neuron will
send a message on to other neurons.

So a neuron is kind of miniature calculator - constantly
adding and subtracting. What it adds and subtracts are the
messages it receives from other neurons. Some
synapses produce excitation, others inhibition. How these
signals constitute the basis of sensation, thought and
movement depends very much on the network in which the
neurons are embedded.


The action potential




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When an action potential starts at the cell body, the first
channels to open are Na+ channels. A pulse of sodium ions Research Frontiers
flashes into the cell and a new equilibrium is established
within a millisecond. In a trice, the transmembrane voltage
switches by about 100 mV. It flips from an inside membrane
voltage that is negative (about -70 mV) to one that is
positive (about +30 mV). This switch opens K+ channels,
triggering a pulse of potassium ions to flow out of the cell,
almost as rapidly as the Na+ ions that flowed inwards, and
this in turn causes the membrane potential to swing back
again to its original negative value on the inside. The action-
potential is over within less time than it takes to flick a
domestic light switch on and immediately off again.
Remarkably few ions traverse the cell membrane to do this,
and the concentrations of Na+ and K+ ions within the
cytoplasm do not change significantly during an action
potential. However, in the long run, these ions are kept in
balance by ion pumps whose job is to bale out excess sodium The nerve fibres above (the purple shows the axons) are
ions. This happens in much the same way that a small leak in wrapped in Schwann cells (red) that insulate the electrical
transmission of the nerve from its surroundings.
the hull of a sailing boat can be coped with by baling out
The colours are fluorescing chemicals showing a newly
water with a bucket, without impairing the overall ability of discovered protein complex. Disruption of this protein
the hull to withstand the pressure of the water upon which complex causes an inherited disease that leads to muscle-
the boat floats. wasting.

The action potential is an electrical event, albeit a complex
one. Nerve fibres behave like electrical conductors (although New research is telling us about the proteins that make up
they are much less efficient than insulated wires), and so an this myelin sheath. This blanket prevents the ionic currents
action potential generated at one point creates another from leaking out in the wrong place but, every so often the
gradient of voltage between the active and resting glial cells helpfully leave a little gap. Here the axon
membranes adjacent to it. In this way, the action potential concentrates its Na+ and K+ ion channels. These clusters of
is actively propelled in a wave of depolarisation that spreads ion channels function as amplifiers that boost and maintain
from one end of the nerve fibre to the other. the action potential as it literally skips along the nerve.
This can be very fast. In fact, in myelinated neurons,
An analogy that might help you think about the conduction action-potentials can race along at 100 metres per second!
of action potentials is the movement of energy along a
firework sparkler after it is lit at one end. The first ignition Action potentials have the distinctive characteristic of being
triggers very rapid local sparks of activity (equivalent to the all-or-nothing: they don’t vary in size, only in how often they
ions flowing in and out of the axon at the location of the occur. Thus, the only way that the strength or duration of a
action potential), but the overall progression of the sparkling stimulus can be encoded in a single cell is by variation of the
wave spreads much more slowly. The marvellous feature of frequency of action potentials. The most efficient axons can
nerve fibres is that after a very brief period of silence (the conduct action potentials at frequencies up to 1000 times
refractory period) the spent membrane recovers its per second.
explosive capability, readying the axon membrane for the next
action potential.

Much of this has been known for 50 years based on
wonderful experiments conducted using the very large Alan Hodgkin and Andrew
neurons and their axons that exist in certain Huxley won the Nobel Prize
sea-creatures. The large size of these axons enabled for discovering the
scientists to place tiny electrodes inside to measure the mechanism of transmission
changing electrical voltages. Nowadays, a modern electrical of the nerve impulse.
recording technique called patch-clamping is enabling They used the "giant axon"
neuroscientists to study the movement of ions through of the squid in studies
individual ion-channels in all sorts of neurons, and so make at the Plymouth Marine
very accurate measurements of these currents in brains Biology Laboratory
much more like our own.

Insulating the axons
In many axons, action-potentials move along reasonably well,
but not very fast. In others, action potentials really do skip
along the nerve. This happens because long stretches of the
axon are wrapped around with a fatty, insulating blanket,
made out of the stretched out glial cell membranes, called a
myelin sheath.
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Internet Links: http://psych.hanover.edu/Krantz/neurotut.html
6 http://www.neuro.wustl.edu/neuromuscular/
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Chemical
Messengers

Action potentials are transmitted along axons to around the synaptic cleft. Some of these have miniature
specialised regions called synapses, where the axons vacuum cleaners at the ready, called transporters, whose
contact the dendrites of other neurons. These consist of job is to suck up the transmitter in the cleft. This clears the
a presynaptic nerve ending, separated by a small gap from chemical messengers out of the way before the next action
the postsynaptic component which is often located on a potential comes. But nothing is wasted - these glial cells
dendritic spine. The electrical currents responsible for the then process the transmitter and send it back to be stored
propagation of the action potential along axons cannot in the storage vesicles of the nerve endings for future use.
bridge the synaptic gap. Transmission across this gap is Glial-cell housekeeping is not the only means by which
accomplished by chemical messengers called neurotransmitters are cleared from the synapse.
neurotransmitters. Sometimes the nerve cells pump the transmitter molecules
back directly into their nerve endings. In other cases, the
transmitter is broken down by other chemicals in the
synaptic cleft.

Messengers that open ion channels
The interaction of neurotransmitters with receptors
resembles that of a lock and key. The attachment of the
transmitter (the key) to the receptors (the lock) generally
causes the opening of an ion channel; these receptors are
called ionotropic receptors (see Figure). If the ion channel
Chemical transmitter packed in allows positive ions (Na+ or Ca++) to enter, the inflow of
spherical bags is available for release positive current leads to excitation. This produces a swing
across synaptic junctions in the membrane potential called an excitatory post-synap-
tic potential (epsp). Typically, a large number of synapses
converge on a neuron and, at any one moment, some are
active and some are not. If the sum of these epsps reaches
Storage and Release the threshold for firing an impulse, a new action potential is
set up and signals are passed down the axon of the receiving
Neurotransmitters are stored in tiny spherical bags called neuron, as explained in the previous chapter.
synaptic vesicles in the endings of axons. There are vesicles
for storage and vesicles closer to nerve endings that are
ready to be released. The arrival of an action potential leads
to the opening of ion-channels that let in calcium (Ca++).
This activates enzymes that act on a range of presynaptic Transmitter Receptor Transmitter
proteins given exotic names like “snare”, “tagmin” and “brevin” (ligand) Receptor G-protein
- really good names for the characters of a recent scientific
Extracellular
adventure story. Neuroscientists have only just discovered
Plasma Membrane
that these presynaptic proteins race around tagging and
Intracellular
trapping others, causing the releasable synaptic vesicles to
fuse with the membrane, burst open, and release the
chemical messenger out of the nerve ending. Second Messenger
Effector
This messenger then diffuses across the 20 nanometre gap
called the synaptic cleft. Synaptic vesicles reform when
their membranes are swallowed back up into the nerve ending
where they become refilled with neurotransmitter, for
subsequent regurgitation in a continuous recycling process. Ionotropic receptors (left) have a channel through which
Once it gets to the other side, which happens amazingly ions pass (such as Na+ and K+). The channel is made up of
quickly â€" in less than a millisecond - it interacts with five sub-units arranged in a circle. Metabotropic receptors
specialised molecular structures, called receptors, in the (right) do not have channels, but are coupled to G-proteins
membrane of the next neuron. Glial cells are also lurking all inside the cell-membrane that can pass on the message.




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The main excitatory neurotransmitter in the brain is ions in the membrane, as ionotropic receptors do, but
glutamate. The great precision of nervous activity requires instead kick-starts intracellular second messengers into
that excitation of some neurons is accompanied by action, engaging a sequence of biochemical events (see
suppression of activity in other neurons. This is brought Figure). The metabolic engine of the neuron then revs up and
about by inhibition. At inhibitory synapses, activation of gets going. The effects of neuromodulation include changes
receptors leads to the opening of ion channels that allow the in ion channels, receptors, transporters and even the expres-
inflow of negatively charged ions giving rise to a change in sion of genes. These changes are slower in onset and more
membrane potential called an inhibitory post-synaptic long-lasting than those triggered by the
potential (ipsp) (see Figure). This opposes membrane excitatory and inhibitory transmitters and their effects
depolarisation and therefore the initiation of an action extend well beyond the synapse. Although they do not
potential at the cell body of the receiving neuron. There are initiate action potentials, they have profound effects on the
two inhibitory neurotransmitters â€" GABA and glycine. impulse traffic through neural networks.

Synaptic transmission is a very rapid process: the time Identifying the messengers
taken from the arrival of an action potential at a synapse to
the generation of an epsp in the next neuron is very rapid - Among the many messengers acting on G-protein coupled
1/1000 of a second. Different neurons have to time their receptors are acetylcholine, dopamine and noradrenaline.
delivery of glutamate on to others within a short window of Neurons that release these transmitters not only have a
opportunity if the epsps in the receiving neuron are going to diverse effect on cells, but their anatomical organisation is
add up to trigger a new impulse; and inhibition also has to also remarkable because they are relatively few in number but
operate within the same interval to be effective in shutting their axons project widely through the brain (see Figure).
things down. There are only 1600 noradrenaline neurons in the human
brain, but they send axons to all parts of the brain and spinal
cord. These neuromodulatory transmitters do not send out
precise sensory information, but fine-tune dispersed
neuronal assemblies to optimise their performance.

Noradrenaline is released in response to various forms of
novelty and stress and helps to organise the complex
response of the individual to these challenges. Lots of
networks may need to “know” that the organism is under
stress. Dopamine makes certain situations rewarding for
the animal, by acting on brain centres associated with
positive emotional features (see Chapter 4). Acetylcholine,
by contrast, likes to have it both ways. It acts on both
The excitatory synaptic potential (epsp) is a shift in ionotropic and metabotropic receptors. The first
membrane potential from -70 mV to a value closer to 0 mV. neurotransmitter to be discovered, it uses ionic mechanisms
An inhibitory synaptic potential (ipsp) has the opposite to signal across the neuromuscular junction from motor
effect. neurons to striated muscle fibres. It can also function as a
neuromodulator. It does this, for example, when you want to
focus attention on something - fine-tuning neurons in the
brain to the task of taking in only relevant information.
Messengers that modulate
The hunt for the identity of the excitatory and inhibitory
neurotransmitters also revealed the existence of a large
number of other chemical agents released from neurons.
Many of these affect neuronal mechanisms by interacting
with a very different set of proteins in the membranes of
neurons called metabotropic receptors. These receptors
don’t contain ion channels, are not always localised in the
region of the synapse and, most importantly, do not lead to
the initiation of action potentials. We now think of these
receptors as adjusting or modulating the vast array of
chemical processes going on inside neurons, and thus the
action of metabotropic receptors is called neuromodulation.

Metabotropic receptors are usually found in complex
particles linking the outside of the cell to enzymes inside the
cell that affect cell metabolism. When a neurotransmitter is
recognised and bound by a metabotropic receptor, bridging Noradrenaline cells are located in the locus coeruleus (LC).
molecules called G-proteins, and other membrane-bound Axons from these cells are distributed throughout the
enzymes are collectively triggered. Binding of the midbrain such as the hypothalamus (Hyp), the cerebellum (C)
transmitter to a metabotropic recognition site can and cerebral cortex.
be compared to an ignition key. It doesn’t open a door for
g




An excellent web site about synapses is at: http://synapses.mcg.edu/index.asp
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Drugs and the Brain


Many people seem to have a constant desire to alter their dependence the body and brain slowly adapt to the repeated
state of consciousness using drugs. They use stimulant presence of the drug, but exactly what changes go on in the
drugs to help them stay awake and dance the night away. brain remain mysteries. Although the primary sites of action
Others use sedatives to calm their nerves. Or even of heroin, amphetamines, nicotine, cocaine and cannabis are
substances that enable them to experience new forms of all different, these drugs share an ability to promote the
consciousness and to forget the troubles of everyday life. release of the chemical messenger dopamine in certain brain
All of these drugs interact in different ways with regions. Although this is not necessarily akin to triggering a
neurotransmitter and other chemical messenger systems “pleasure” mechanism, it is thought that the drug-induced
in the brain. In many cases, the drugs hijack natural brain release of dopamine may be an important final common
systems that have to do with pleasure and reward - pathway of “pleasure” in the brain. It represents the signal
psychological processes that are important in eating, that prompts a person to carry on taking the drug.
drinking, sex and even learning and memory.
Individual Drugs - How they work and
The Path to Addiction and Dependence the hazards of taking them.
Drugs that act on the brain or the blood supply of the brain Alcohol
can be invaluable - such as those that relieve pain.
Recreational drug use has a very different purpose, and the Alcohol acts on neurotransmitter systems in the brain to
problem with it is that it can lead to abuse. The user can, all dampen down excitatory messages and promote inhibition of
too easily, become dependent or even addicted. He or she neural activity. Alcohol’s action proceeds through stages of
will then suffer very unpleasant physical and psychological relaxation and good humour, after one drink, through to
withdrawal symptoms when they interrupt their drug habit. sleepiness and loss of consciousness. That is why the police
This state of dependence can lead a user to crave the drug, are so strict about drinking and driving, and why there is so
even though doing so is clearly damaging to their work, health much public support for this strict attitude. Some people
and family. In extreme cases the user may be drawn into become very aggressive and even violent when they drink, and
crime in order to pay for the drug. about one in ten of regular drinkers will become dependent
alcoholics. Long-term alcohol use damages the body,
Fortunately not everyone who takes a recreational drug especially the liver, and can cause permanent damage to the
becomes dependent on it. Drugs differ in their dependence brain. Pregnant mothers who drink run the risk of having
liability - ranging from high risk in the case of cocaine, heroin babies with damaged brains and low IQ’s. More than 30,000
and nicotine to lower risk in the case of alcohol, cannabis, people die every year in Britain from alcohol-related diseases.
ecstasy and amphetamines. During the development of drug




76% Tobacco 32%

92% Alcohol 15%
46% Marijuana 9%
Tranquilizers &
13% Prescription Drugs 9%

16% Cocaine 17%

2% Heroin 23%
Percentage of people who have ever used the drug Percentage of users who became dependent




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Cannabis smokers tend to develop lung diseases and they
run the risk of developing lung cancer - although this has not
yet been proved. About one in ten users may become
dependent, which people who sell the drug are well aware of.
Repeated heavy use is incompatible with the skill of driving
and with intellectually demanding work; experiments have
established that people intoxicated with cannabis are unable
to carry out complex mental tasks. Although not yet proven,
there is some evidence that heavy use by young people might
trigger the mental illness schizophrenia (see p.51) in
susceptible individuals.

Amphetamines
Amphetamines are man-made chemicals that include
“Dexedrine”, “Speed”, and the methamphetamine derivative
called “Ecstasy”. These drugs act in the brain by causing the
release two naturally occurring neurotransmitters. One is
dopamine - which probably explains the strong arousal and
pleasurable effects of amphetamines. The other is serotonin
- which is thought to account for their ability to cause a
sense of well-being and a dream-like state that can include
“Skull with a burning cigerette” by Vincent Van Gogh 1885. hallucinations. Dexedrine and Speed promote mainly
dopamine release, Ecstasy more serotonin. The even more
powerful hallucinogen d-LSD also acts on serotonin
mechanisms in the brain. Amphetamines are powerful
Nicotine psychostimulants and they can be dangerous - especially in
overdose. Animal experiments have shown that Ecstasy can
Nicotine is the active ingredient in all tobacco products. cause a prolonged, perhaps permanent reduction of
Nicotine acts on brain receptors that normally recognise the serotonin cells. This might account for the “mid-week blues”
neurotransmitter acetylcholine; it tends to activate natural suffered by weekend ecstasy users. Every year, dozens of
alerting mechanisms in the brain. Given this, it’s not young people die after taking it. Frightening schizophrenia-
surprising that smokers say that cigarettes help them like psychosis can happen after Dexedrine and Speed. You
concentrate and have a soothing effect. The trouble is that might be lured into thinking that Speed could help you in an
nicotine is highly addictive and many inveterate smokers exam - but don’t. It won’t.
continue to smoke for no better reason than to avoid the
unpleasant signs of withdrawal if they stop. The pleasure Heroin
has long gone. While there appears to be no deleterious
effect on the brain, tobacco smoke is extremely damaging Heroin is a man-made chemical derivative of the plant
to the lungs and long-term exposure can lead to lung cancer product morphine. Like cannabis, heroin hijacks a system in
and also to other lung and heart diseases. More than the brain that employs naturally occurring neurotransmit-
100,000 people die every year in Britain from smoking- ters known as endorphins. These are important in pain
related diseases. control - and so drugs that copy their actions are very
valuable in medicine. Heroin is injected or smoked whereupon
Cannabis it causes an immediate pleasurable sensation - possibly due
to an effect of endorphins on reward mechanisms. It is highly
Cannabis presents us with a puzzle, for it acts on an addictive, but, as dependence develops, these pleasurable
important natural system in the brain that uses neurotrans- sensations quickly subside to be replaced by an incessant
mitters that are chemically very like cannabis. This system “craving”. It is a very dangerous drug that can kill in even
has to do with the control of muscles and regulating pain modest overdose (it suppresses breathing reflexes). Heroin
sensitivity. Used wisely, and in a medical context, cannabis has ruined many people’s lives.
can be a very useful drug. Cannabis is an intoxicant which can
be pleasurable and relaxing, and it can cause a dream-like Cocaine
state in which one’s perception of sounds, colours and time
is subtly altered. No-one seems to have died from an over- Cocaine is another plant-derived chemical which can cause
dose, although some users may experience unpleasant panic intensely pleasurable sensations as well as acting as a
attacks after large doses. Cannabis has been used at least powerful psychostimulant. Like the amphetamines, cocaine
once by nearly half the population of Britain under the age of makes more dopamine and serotonin available in the brain.
30. Some people believe it should be legalised - and doing so However, like heroin, cocaine is a very dangerous drug. People
could cut the link between supply of the drug and that of intoxicated with it, especially the smoked form called “crack”,
other much more dangerous drugs. Unfortunately, as with can readily become violent and aggressive, and there is a life-
nicotine, smoking is the most effective way of delivering it to threatening risk of overdose. The dependence liability is high,
the body. Cannabis smoke contains much the same mixture and the costs of maintaining a cocaine habit draw many
of poisons as cigerettes (and is often smoked with tobacco). users into crime.
g




Related Internet Sites: www.knowthescore.info, www.nida.nih.gov/Infofax/ecstasy.html,
10 www.nida.nih.gov/MarijBroch/Marijteens.html
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Touch & Pain


Touch is special - a handshake, a kiss, a baptism. adapt quickly and so respond best to rapidly changing inden-
It provides our first contact with the world. Arrays of tations (sense of vibration and flutter), Merkel’s disk
receptors throughout our bodies are tuned to different responds well to a sustained indentation of the skin (sense
aspects of the somatosensory world â€" touch, temperature of pressure), while Ruffini endings respond to slowly changing
and body position - with yet others for the sensations of indentations.
pain. The power of discrimination varies across the body
surface, being exquisitely sensitive at places such as the An important concept about somatosensory receptors is
tips of our fingers. Active exploration is important as well, that of the receptive field. This is the area of skin over which
pointing to important interactions with the motor each individual receptor responds. Pacinian corpuscles have
system. Pain serves to inform and to warn us of damage to much larger receptive fields than Meissner’s corpuscles.
our bodies. It has a strong emotional impact, and is Together, these and the other receptors ensure that you can
subject to powerful controls within the body and brain. feel things over your entire body surface. Once they detect a
stimulus, the receptors in turn send impulses along the sen-
sory nerves that enter the dorsal roots of the spinal cord.
The axons connecting touch receptors to the spinal cord are
large myelinated fibres that convey information from the
periphery towards the cerebral cortex extremely rapidly.
Cold, warmth and pain are detected by thin axons with
“naked” endings, which transmit more slowly. Temperature
Meissner’s receptors also show adaptation (see Experiment Box). There
corpuscle are relay stations for touch in the medulla and the thalamus,
before projection on to the primary sensory area in
Axons the cortex called the somatosensory cortex. The nerves
Merkel’s cross the midline so that the right side of the body is
disc represented in the left hemisphere and the left in the right.

Sweat gland
Ruffini end organ



t
An Experiment on Temperature
A variety of very small Adaptation
sensory receptors are
embedded in the surface
of your skin. Pacinian corpuscle
This experiment is very simple. You need a metal
rod about a metre long, such as a towel rail, and two
buckets of water. One bucket should contain fairly
hot water, the other with water as cold as possible.
Put your left hand in one bucket and your right hand
It begins in the skin in the other, and keep them there for at least a
minute. Now take your hands out, dry them very
Embedded in the dermal layers of the skin, beneath the
quickly and hold the metal rod. The two ends of the
surface, are several types of tiny receptors. Named after the
rod will feel as though they are at different
scientists who first identified them in the microscope,
temperatures. Why?
Pacinian and Meissner corpuscles, Merkel’s disks and Ruffini
endings sense different aspects of touch. All these
receptors have ion channels that open in response to
mechanical deformation, triggering action potentials that can The input from the body is systematically “mapped” across
be recorded experimentally by fine electrodes. Some amazing the somatosensory cortex to form a representation of the
experiments were conducted some years ago by body surface. Some parts of the body, such as the tips of
scientists who experimented on themselves, by inserting your fingers and mouth, have a high density of receptors and
electrodes into their own skin to record from single sensory a correspondingly higher number of sensory nerves.
nerves. From these and similar experiments in anaesthetised Areas such as our back have far fewer receptors and nerves.
animals, we now know that the first two types of receptor However, in the somatosensory cortex, the packing density




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of neurons is uniform. Consequently, the ‘map’ of the body including proprioceptive feedback on to motor neurons, and it
surface in the cortex is very distorted. Sometimes called continues at all levels of the somatosensory system.
the sensory homunculus, this would be a curiously distorted The primary sensory and motor cortices are right beside
person if it actually existed with its complement of touch each other in the brain.
receptors spread at a uniform density across the body
surface. Active exploration is crucial for the sense of touch. Imagine
that you are discriminating fine differences in texture, such
You can test this differential sensitivity across the body as between different fabrics or grades of sandpaper. Which
with the two-point discrimination test. Bend some paper of the following conditions do you think generates the finest
clips into a U-shape, some with the tips 2-3 cm apart, discriminations:
others much closer. Then, with a blindfold on, get a friend to
touch various parts of your body with the tips of the paper • Placing your finger-tips on the samples?
clips. Do you feel one tip or two? Do you sometimes feel one • Running your finger-tips over the samples?
tip when you are actually being touched by two? Why? • Having a machine run the samples over your finger-tips?

The outcome of such behavioural experiments leads to
questions about where in the brain the relevant sensory
information is analysed. Functional brain imaging suggests
that the identification of textures or of objects by touch
involves different regions of cortex. Brain imaging is also
starting to produce insights about cortical plasticity by
revealing that the map of the body in the somatosensory
area can vary with experience. For example, blind Braille
readers have an increased cortical representation for the
index finger used in reading, and string players an enlarged
cortical representation of the fingers of the left hand.


Pain
Although often classed with touch as another skin sense,
pain is actually a system with very different functions and a
very different anatomical organisation. Its main attributes
are that it is unpleasant, that it varies greatly between
individuals and, surprisingly, that the information conveyed
by pain receptors provides little information about the
nature of the stimulus (there is little difference between the
The homunculus. The image of a person is drawn across the pain due an abrasion and a nettle sting). The ancient Greeks
surface of the somatosensory cortex in proportion to the regarded pain as an emotion not a sensation.
number of receptors coming from that part of the body.
They have a most distorted shape. Recording from single sensory fibres in animals reveals
responses to stimuli that cause or merely threaten tissue
damage - intense mechanical stimuli (such as pinch), intense
heat, and a variety of chemical stimuli. But such experi-
The exquisite power of discrimination ments tell us nothing directly about subjective experience.

The ability to perceive fine detail varies greatly across Molecular biological techniques have now revealed the
different parts of the body and is most highly developed in structure and characteristics of a number of nociceptors.
the tips of the fingers and lips. Skin is sensitive enough to They include receptors that respond to heat above 460 C,
measure a raised dot that is less than 1/100th of a to tissue acidity and - again a surprise - to the active
millimetre high â€" provided you stroke it as in a blind person ingredient of chilli peppers. The genes for receptors
reading Braille. One active area of research asks how the responding to intense mechanical stimulation have not yet
different types of receptor contribute to different tasks been identified, but they must be there. Two classes of
such as discriminating between textures or identifying the peripheral afferent fibres respond to noxious stimuli:
shape of an object. relatively fast myelinated fibres, called Î'δ fibres, and very
fine, slow, non-myelinated C fibres. Both sets of nerves
Touch is not just a passive sense that responds only to what enter the spinal cord, where they synapse with a series of
it receives. It is also involved in the active control of neurons that project up to the cerebral cortex. They do so
movement. Neurons in the motor cortex controlling the through parallel ascending pathways, one dealing with the
muscles in your arm that move your fingers get sensory localisation of pain (similar to the pathway for touch), the
input from touch receptors in the finger tips. How better to other responsible for the emotional aspect of pain.
detect an object that is starting to slip out of your hand
than via rapid communication between the sensory and
motor systems? Cross-talk between sensory and motor
systems begins at the first relays in the spinal cord,




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Morphine Met-enkaphalin

A number of chemical transmitters are involved including
endogenous opioids such as met-enkaphalin. The pain-killer
morphine acts on the same receptors at which some of the
endogenous opioids act.

The converse phenomenon of enhanced pain is called
hyperalgesia. There is a lowering of the pain threshold, an
Ascending pathways for pain from a region of the spinal increase in the intensity of pain, and sometimes both a
cord (bottom) up to several areas in the brainstem and broadening of the area over which pain is felt or even pain in
cortex including ACC (anterior cingulate) and the insular. the absence of noxious stimulation. This can be a major
clinical problem. Hyperalgesia involves sensitisation of the
peripheral receptors as well as complex phenomena at
This second pathway projects to quite different areas than
various levels of the ascending pain pathways. These include
the somatosensory cortex, including the anterior cingulate
the interaction of chemically mediated excitation and
cortex and the insular cortex. In brain-imaging experiments
inhibition. The hyperalgesia observed in chronic pain states
using hyponosis, it has been possible to separate mere pain
results from the enhancement of excitation and depression
sensation from the ‘unpleasantness’ of pain.
of inhibition. Much of this is due to changes in the
responsiveness of the neurons that process sensory
Subjects immersed their hands in painfully hot water and
information. Important changes occur in the receptor
were then subjected to hypnotic suggestion of increased or
molecules that mediate the action of the relevant
decreased pain intensity or pain unpleasantness.
neurotransmitters. In spite of the great advances in our
Using positron emission tomography (PET), it was found
understanding of the cellular mechanisms of hyperalgesia,
that during changes in experienced pain intensity there was
the clinical treatment of chronic pain is still sadly
activation of the somatosensory cortex, whereas the
inadequate.
experience of pain unpleasantness was accompanied by
activation of the anterior cingulate cortex.

A life without pain? Research Frontiers
Given our desire to avoid sources of pain, such as the
dentist, you might imagine that a life without pain would be
good. Not so. For one of the key functions of pain is to
enable us to learn to avoid situations that give rise to pain.
Action potentials in the nociceptive nerves entering the
spinal cord initiate automatic protective reflexes, such as
the withdrawal reflex. They also provide the very information
that guides learning to avoid dangerous or threatening
situations. Traditional Chinese Medicine uses a procedure called
"acupuncture" for the relief of pain. This involves fine
Another key function of pain is the inhibition of activity - needles, inserted into the skin at particular positions in the
the rest that allows healing to occur after tissue damage. body along what are called meridians, which are then rotated
or vibrated by the person treating the patient. They
Of course, in some situations, it is important that activity certainly relieve pain but, until recently, no one was very
and escape reactions are not inhibited. To help cope in these sure why.
situations, physiological mechanisms have evolved that can
either suppress or enhance pain. The first such modulatory Forty years ago, a research laboratory was set up in China to
mechanism to be discovered was the release of endogenous find out how it works. Its findings reveal that electrical
analgesics. Under conditions of likely injury, such as soldiers stimulation at one frequency of vibration triggers the
in battle, pain sensation is suppressed to a surprising degree release of endogenous opoiods called endorphins, such as
â€" presumably because these substances are released. met-enkephalin, while stimulation at another frequency
Animal experiments have revealed that electrical stimulation activates a system sensitive to dynorphins. This work has
of brain areas such as the aqueductal gray matter causes a led to the development of an inexpensive electrical acupunc-
ture machine (left) that can be used for pain relief instead of
marked elevation in the pain threshold and that this is drugs. A pair of electrodes are placed at the "Heku" points
mediated by a descending pathway from the midbrain to the on the hand (right), another at the site of pain.
spinal cord.
g




Want to read more about acupuncture?
Try this web site.... http://acupuncture.com/Acup/AcuInd.htm
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Vision


Humans are highly visual animals constantly using their brain, “seeing” this next image would then need another
eyes to make decisions about the world. With forward person to look at it - a person inside the brain! To avoid an
facing eyes like other primates, we use vision to sense infinite regression, with nothing really explained along the
those many aspects of the environment that are remote way, we confront the really big problem that the visual brain
from our bodies. Light is a form of electromagnetic energy has to solve - how it uses coded messages from the eyes to
that enters our eyes where it acts on photoreceptors in interpret and make decisions about the visual world.
the retina. This triggers processes by which neural
impulses are generated and then travel through the Once focused on the retina, the 125 million photoreceptors
pathways and networks of the visual brain. Separate arranged across the surface of the retina respond to the
pathways to the midbrain and the cerebral cortex mediate light that hits them by generating tiny electrical potentials.
different visual functions - detecting and representing These signals pass, via synapes through a network of cells in
motion, shape, colour and other distinctive features the retina, in turn activating retinal ganglion cells whose
of the visual world. Some but not all are accessible to axons collect together to form the optic nerve. These enter
consciousness. In the cortex, neurons in a large number of the brain where they transmit action potentials to different
distinctive visual areas are specialised for making different visual regions with distinct functions.
kinds of visual decisions.

Light on the eye
Ganglion cell
Light enters the eye through the pupil and is focused, by the Bipolar cell
cornea and the lens, on to the retina at the back of the eye. Horizontal cell
The pupil is surrounded by a pigmented iris that can expand Rods
or copntract, making the pupil larger or smaller as light levels Cones
vary. It is natural to suppose that the eye acts like a
camera, forming an ‘image’ of the world, but this is a mislead-
ing metaphor in several respects. First, there is never a Light
static image because the eyes are always moving. Second,
even if an image on the retina were to send an image into the

Pupil
Iris Cornea
Optic nerve
Retina Amacrine cell

Lens

The retina. Light passes through the fibres of the optic
nerve and a network of cells (eg. bipolar cells) to land on the
Retina rods and cones at the back of the retina.

Much has been learned about this earliest stage of visual
Fovea processing. The most numerous photoreceptors, called rods,
are about 1000 times more sensitive to light than the other,
Blind spot less numerous category called cones. Roughly speaking, you
see at night with your rods but by day with your cones.
Optic nerve There are three types of cones, sensitive to different wave-
lengths of light. It is oversimplification to say it is the cones
The human eye. Light entering the eye is focused by the lens simply produce colour vision - but they are vital for it. If over-
onto the retina located at the back. Receptors there exposed to one colour of light, the pigments in the cones
detect the energy and by a process of transduction initiate adapt and then make a lesser contribution to our perception
action-potentials that travel in the optic nerve.
of colour for a short while thereafter (see Experiment Box).




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Over the past 25 years, important discoveries have been
made about the process of phototransduction (the conver-
sion of light into electrical signals in the rods and cones), the
genetic basis of colour blindness which is due to the absence
of certain visual pigments, the function of the retinal
network and the presence of two different types of ganglion
cells. About 90% of these cells are very small, while another
5% are large M-type or magnocellular cells. We shall see
later that abnormalities in the M-Type cells may underlie
certain cases of dyslexia (Chapter 9).




t
An Experiment on Colour Adaptation




Focus on the small fixation cross (+) between the two
large circles for at least 30 sec. Now transfer your
gaze to the lower fixation cross. The two “yellow” The pathways from eye to brain.
circles will now appear to be different colours. Can you
think out why this might have happened?
The visual cortex consists of a number of areas, dealing with
the various aspects of the visual world such as shape, colour,
movement, distance etc. These cells are arranged in columns.
An important concept about visually responsive cells is that
of the receptive field - the region of retina over which the cell
will respond to the prefered kind of image. In V1, the first
stage of cortical processing, the neurons respond best to
lines or edges in a particular orientation. An important
discovery was that all the neurons in any one column of cells
fire to lines or edges of the same orientation, and the
neighbouring column of cells fires best to a slightly different
orientation, and so on across the surface of V1. This means
cortical visual cells have an intrinsic organisation for
interpreting the world, but it is not an organisation that is
immutable. The extent to which an individual cell can be
driven by activity in the left or right eye is modified by
experience. As with all sensory systems the visual cortex
displays what we call plasticity.

David
Hubel



The next steps in visual processing Torsten
Wiesel
The optic nerve of each eye projects to the brain. The fibres
of each nerve meet at a structure called the optic chiasm; Electrical recordings made from cells
half of them “cross” to the other side where they join the in the visual cortex (left) by David
other half from the other optic nerve that have stayed Hubel and Torsten Wiesel (above) have
“uncrossed”. Together these bundles of fibres form the optic revealed some amazing properties.
tracts, now containing fibres from both eyes, which now These include orientation selectivity,
the beautiful columnar organisation of
project (via a synaptic relay in a structure called the lateral
such cells (below) and the plasticity
geniculate nucleus) to the cerebral cortex. It is here that of the system. These discoveries led
internal “representations” of visual space around us are to the award of the Nobel Prize.
created. In a similar way to touch (previous Chapter), the
left-hand side of the visual world is in the right-hemisphere
and the right-hand side in the left-hemisphere. This neural
representation has inputs from each eye and so the cells in
the visual areas at the back of the brain (called area V1, V2
etc.) can fire in response to an image in either eye. This is
called binocularity.




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Research Frontiers Just black and white
dots? It is at first hard
Can you see if you are blind? Surely not. However, the to identify to edges or
discovery of multiple visual areas in the brain has shown surfaces of the image.
that some visual abilities occur without conscious But once you know it is a
awareness. Certain people who have sustained damage to Dalmation dog, the image
the primary visual cortex (V1) report being unable to see “pops out”. The visual
things in their field of view but, when asked to reach for the brain uses internal
things they claim they cannot see, they do so with knowledge to interpret
remarkable accuracy. This curious but fascinating the sensory scene.
phenomenon is known as “blindsight”. This is probably
mediated by parallel connections from the eyes to other
parts of the cortex.

Being unaware of things one sees is an everyday others can be simple and automatic. Even the simplest
phenomenon in normal people too. If you chat with a decisions involve an interplay between sensory input and
passenger whilst driving your car, your conscious
awareness may be directed entirely to the conversation -
existing knowledge.
yet you drive effectively, stopping at lights and avoiding
obstacles. This ability reflects a kind of functional One way to try to understand the neural basis of decision-
blindsight. making would be to let an individual go about their normal
daily activity and record the activity of neurons as they do
various things. We might imagine being able to record, with
The intricate circuitry of the visual cortex is one of the great millisecond precision, the activity of every single one of the
puzzles that has preoccupied neuroscientists. Different 1011 neurons of the brain. We would then have not only a lot
types of neurons are arranged across the six cortical layers, of data, but also a formidable task in processing it all. We
connected together in very precise local circuits that we are would have an even greater problem in interpreting it. To
only now starting to understand. Some of their connections understand why, think for a moment about the different
are excitatory and some inhibitory. Certain neuroscientists reasons why people do things. A person we see walking to a
have suggested there is a canonical cortical microcircuit - railway station may be going there to catch a train, to meet
like chips in a computer. Not everyone agrees. We now think someone off a train, or even to go “train-spotting”. Without
the circuitry in one visual area has many similarities to that knowing what their intentions are, it might prove very
in another, but there could be subtle differences that reflect difficult to interpret the correlations between any patterns
the different ways in which each bit of the visual brain inter- of activation in their brain and their behaviour.
prets different aspects of the visual world. Study of visual
illusions has also given us insight into the kind of processing Experimental neuroscientists like, therefore, to bring
that may be going on at different stages of visual analysis. behavioural situations under precise experimental control.
This can be achieved by setting a specific task, ensuring that
the human subjects are doing it to the best of their ability
after extensive practice, and then monitoring their
performance. The best kind of task is one that is sufficiently
complex to be interesting, yet sufficiently simple to offer a
chance of being able to analyse what is going on. A good
example is the process of making a visual decision about the
appearance of stimuli - often no more than two stimuli - with
the response being a simple choice (e.g. which spot of light is
bigger, or brighter?). Although such a task is simple, it does
The tiles of this famous café wall in Bristol (left) are
incorporate a complete cycle of decision-making. Sensory
actually rectangular - but they don’t look it. The tiling
arrangement creates an illusion caused by complex information is acquired and analysed; there are correct and
excitatory and inhibitory interactions amongst neurons incorrect answers for the decision made; and rewards can be
processing lines and edges. The Kanizsa Triangle (right) assigned according to whether performance was correct or
doesn’t really exist - but this doesn’t stop you seeing it! not. This sort of research is a kind of “physics of vision”.
Your visual system “decides” that a white triangle is on top
of the other objects in the scene. Decisions about motion and colour
A subject of great current interest is how neurons are
Decision and Indecision involved in making decisions about visual motion. Whether or
not an object is moving, and in which direction, are critically
A key function of the cerebral cortex is its ability to form and important judgements for humans and other animals.
act upon sensory information received from many sources. Relative movement generally indicates that an object is
Decision making is a critical part of this capability. This is different from other nearby objects. The regions of the
the thinking, knowledge-based, or “cognitive” part of the visual brain involved in processing motion information can be
process. Available sensory evidence must be weighed up and identified as distinct anatomical regions by examining the
choices made (such as to act or refrain from acting) on the patterns of connections between brain areas, by using
best evidence that can be obtained at that time. Some human brain imaging techniques (Chapter 14), and by record-
decisions are complex and require extended thinking while ing the activity of individual neurons in non-human animals.




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A B




C D




Motion sensitivity. A. A side-view of the a monkey’s brain with the primary visual cortex (V1) at the left and an
area called MT (sometimes called V5) in which motion-sensitive neurons are found. B. A motion-sensitive
neuron in which action potentials (vertical red lines) occur frequently in response to motion in the northwest
direction, but rarely in the opposite direction. Different columns of cells in MT (or V5) code for different
directions of movement. C. A circular TV screen used in experiments on motion sensitivity in which dots move
about in random directions (0% coherence) or all in one direction (100% coherence). D. The monkey’s indication
of the likely direction of the dots increases as their coherence increases (yellow line). Electrical microstimula-
tion of the columns of different orientations shifts the estimate of preferred direction (blue line).


Neurons in one of these areas, area MT or V5, have been
recorded in a monkey, while it makes a simple visual decision
about a pattern of moving dots. Most of the dots are made
to move randomly in different directions but a small fraction
of them are moving consistently in a single direction - up,
down, left or right. The observer has to judge the overall
direction of movement of the pattern. The task can be made
very easy by arranging for a large percentage of the dots to
be moving consistently in one direction, as opposed to
randomly, or harder by decreasing the proportion of dots
that move consistently. It turns out that activity of cells in
V5 accurately reflects the strength of the movement signal.
Neurons here respond selectivity to particular directions of
movement, increasing their activity systematically and
accurately when the proportion of dots moving in their
preferred motion direction increases.

Amazingly, some individual neurons perform just as well at
detecting the movement of dots as is an observer, whether
a monkey or a human, at making a behavioural judgement.
Microstimulation of such neurons through the recording
electrode can even bias the judgement of relative movement
that the monkey is making. This is remarkable given that The Necker cube is constantly reversing perceptually.
The retinal image doesn’t change, but we see the cube first
very large numbers of neurons are sensitive to visual motion with the top left corner nearer to us and then as if it is
and one might have expected decisions to be based on the receding. Rarely, it is even seen as a set of intersecting
activity of many neurons rather than just a few. Decisions lines on a flat surface. There are many types of reversible
about colour proceed in a similar way (see Research figure, some of which have been used to explore the neural
Frontiers Box - above). signals involved when the visual brain makes decisions
about which configuration is dominant at any one time.




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Research Frontiers
Colour sensitive cells. Certain neurons show different patterns of activity to different wavelengths of light.
Some respond best to long wavelengths, others to short. You might think this would be enough to perceive colour,
but this may not be so. Compare the cell firing on the left to that on the right. Can you tell the difference?




Left. Clever design of a coloured patchwork called a Right. A true colour-sensitive cell in V4 fires to an
Mondrian (after the artist Piet Mondrian). This is illu- area of the Mondrian that we see as red, but much
minated with different combinations of long, middle less to other areas. This differential response occurs
and short wavelength light so that each panel in turn even though the same triplet of wave energies was
reflects exactly the same mixture of light, even reflected from each. V4 may therefore be the area of
though we always perceive them as being different the brain that enables us to perceive colour, though
colours because of the presence of the surrounding some neuroscientists suspect it is not the only area
patches. The cell on the left, recorded in V1, fires involved.
about the same extent in all cases. It does not
"perceive" colour, it simply responds to the identical
wavelength mixture reflected from each patch.

Believing is seeing Our visual world is an astonishing place. Light entering the
eyes enables us to appreciate the world around us ranging
Area V5 does more than just register the motion of visual from the simplest of objects through to works of art that
stimuli, it registers perceived motion. If visual tricks are dazzle and beguile us. Millions and millions of neurons are
played such that an area of dots are perceived as moving in involved, with their duties ranging from the job of a retinal
one direction or another only by virtue of the motion of photoreceptor responding to a speck of light through to a
surrounding dots, i.e. an illusion of movement, the neurons neuron in area V5 that decides whether something in the
corresponding to the area of the illusion will fire differently to visual world is moving. All of this happens apparently effort-
rightwards or leftwards perceived movement. If the move- lessly within our brains. We don’t understand it all, but
ment is completely random, neurons that normally prefer neuroscientists are making great strides.
rightwards movement fire slightly more on trials when the
observer reports that the random motion signal is moving Colin Blakemore has contributed to
“rightwards” (and vice versa). The difference between neu- understanding how the visual system
ronal decisions of “rightwards” or “leftwards” reflects what develops. This includes pioneering
the observer judges about the appearance of motion, not the studies using cell-culture to study
absolute nature of the moving stimulus. interactions between different parts of
a pathway in the embryonic brain (left).
Other examples of visual decision and indecision include On the right, we see axons (stained
reactions to perceptual targets that are genuinely green) growing down from the develop-
ambiguous, such as the so-called Necker cube (Figure). ing cortex to meet other fibres (stained
With this type of stimulus the observer is placed in a state orange) that perform a “handshake”
of indecision, constantly fluctuating from one interpretation before growing up to the cortex.
to another. A similar rivalry is experienced if the left eye sees
a pattern of vertical lines while the right eye sees a pattern
of horizontal lines. The resulting percept is termed binocular
rivalry, as the observer reports first that the vertical lines
dominate, then the horizontal lines and then back again to
vertical. Once again, neurons in many different areas of the
visual cortex reflect when the observer’s perception switch-
es from horizontal to vertical.
g




Internet Links: faculty.washington.edu/chudler/chvision.html
18 http://www.ncl.ac.uk/biol/research/psychology/nsg.
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Movement


Think about catching a ball. Easy? It may seem so, but to
perform even this simple movement, your brain has to do
some remarkable things. We take it all for granted, yet
there is the planning: Is the ball light or heavy? From what
direction is it coming and how fast will it be going? There is
the coordination: How does one automatically coordinate
one’s limbs for catching and what way would be best? And
there is the execution: Does your arm get to the right
place and do your fingers close at the right time?
Neuroscientists now know that there are many areas of
the brain that get involved. Neural activity in these areas
combines to form a loose chain of command â€" a motor hier-
archy - from the cerebral cortex and basal ganglia to the
cerebellum and spinal cord.
Recordings of the electrical activity associated with
muscles (electro-myographic activity).

The neuromuscular junction The electrical events in the muscles of the arm can be
At the lowest extreme of the motor hierarchy, in the spinal recorded with an amplifier, even through the skin, and these
cord, hundreds of specialised nerve cells called motor electro-myographic recordings (EMGs) can be used to
neurons increase their rate of firing. The axons of these measure the level of activity in each muscle (see Fig. above).
neurons project out to the muscles where they activate
contractile muscle fibres. The terminal branches of the The spinal cord plays an important part in the control of the
axons of each motor neuron form specialised neuromuscular muscles through several different reflex pathways. Among
junctions on to a limited number of muscle fibres within one these are the withdrawal reflexes that protect you from
muscle (see Figure below). Each action potential in a motor sharp or hot objects, and the stretch reflexes that have a
neuron causes the release of neurotransmitter from nerve role in posture. The well-known ‘knee-jerk’ reflex is an example
endings and generates a corresponding action potential in of a stretch reflex that is rather special because it involves
the muscle fibres. This causes Ca2+ ions to be released from only two types of nerve cell - sensory neurons that signal
intracellular stores inside each muscle fibre. This in turn muscle length, connected through synapses to motor
triggers contraction of the muscle fibres, producing force neurons that cause the movement. These reflexes combine
and movement. together with more complex ones, in spinal circuits that
organise more or less complete behaviours, such as the
rhythmic movement of the limbs when walking or running.
These involve coordinated excitation and inhibition of
motor neurons.

Motor neurons are the final common path to the muscles
that move your bones. However, the brain has a major
problem controlling the activity of these cells. Which muscles
should it move to achieve any particular action, by how much,
and in what order?

The top of the hierarchy -
To make muscles contract, the nerves form specialized
contacts with individual muscle fibres at the the motor cortex
neuromuscular junction. As they develop, multiple nerve
fibres go to each muscle fibre but, due to competition At the opposite end of the motor hierarchy, in the cerebral
between neurons, all but one is eliminated. The final cortex, a bewildering number of calculations have to be made
successful nerve is then left to release its
neurotransmitter acetylcholine on to specialised molecular by many tens of thousands of cells for each element of
detectors at the “motor endplate” (stained red). movement. These calculations ensure that movements are
This image was made using a confocal microscope. carried out smoothly and skilfully. In between the cerebral




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t
An Experiment on Movement




Who moves me? Try this experiment with a friend.
Pick up a fairly heavy book on the palm of your right
hand. Now lift the book from your right hand with
your left. Your task is to keep your right hand still!
You should find this easy. Now try again, keeping
your hand absolutely still while your friend lifts the
book off your hand. Few people can do that. Don’t
worry; it takes very many trials to be able to get
even close to the performance you found easy when
you did it yourself.

This experiment illustrates that the sensorimotor
The several regions of the brain involved in controlling areas of your brain have more knowledge about
movements. what you do entirely yourself than it receives when
you watch others give the trigger for your actions.
cortex and motor neurons of the spinal cord, critical areas in
the brain stem combine information about the limbs and
muscles ascending from the spinal cord with descending
information from the cerebral cortex.

The motor cortex is a thin strip of tissue running across the
surface of the brain, directly in front of the somatosensory
cortex (see p.12). Here is a complete map of the body: nerve
cells that cause movements in different limbs (via connec-
tions onto the motor neurons in the spinal cord) are
topographically arranged. By using a recording electrode,
neurons may be found in any part of this map that are active
about 100 milliseconds before activity in the appropriate
muscles. Quite what is coded in the motor cortex was the
subject of a long debate - do the cells in the cortex code for
actions that a person wants to perform or for the individual
muscles that must be contracted to perform it. The answer
to this question turned out to be somewhat different â€"
individual neurons do not code for either. Instead a
population code is used in which actions are specified by the
firing of an ensemble of neurons.

Just in front of the motor cortex lie important pre-motor
areas that are involved in planning actions, in preparing spinal
circuits for movement, and in processes that establish links after a stroke, can cause misreaching for objects or even
between seeing movements and understanding gestures. neglect or denial of parts of the world around us. Patients
Striking new findings include the discovery of mirror neurons with so-called parietal neglect fail to notice objects (often
in monkeys that respond both when the monkey sees a hand on their left side) and some even ignore the left side of their
movement and when the animal performs that same move- own body.
ment. Mirror neurons are likely to be important in imitating
and understanding actions. Behind the motor cortex, in the
parietal cortex, a number of different cortical areas are
The basal ganglia
concerned with the spatial representation of the body and of
The basal ganglia are a cluster of interconnected areas
visual and auditory targets around us. They seem to hold a
located beneath the cortex in the depths of the cerebral
map of where our limbs are, and where interesting targets
hemispheres. They are crucial in the initiation of movements,
are with respect to us. Damage to these areas, for example


“…mirror neurons will do for psychology what DNA did for biology: they will provide a
unifying framework and help explain a host of mental abilities that have hitherto
remained mysterious and inaccessible to experiments. They are the great leap
forward of primate brain evolution”. V.S.Ramachandran




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though quite how they do this is far from clear. The basal target, programming the movements of your limbs, and
ganglia seem to act rather like a complex filter, selecting adjusting the postural reflexes of your arm. At all stages,
information from amongst the enormous numbers of diverse you would need to integrate sensory information into the
inputs they receive from the anterior half of the cortex (the stream of signals leading to your muscles.
sensory, motor, prefrontal and limbic regions). The output of
the basal ganglia feeds back to the motor cortical areas.

A common human motor disorder, Parkinson’s disease, is
characterised by tremor and difficulty in initiating move-
ments. It is as if the selective filter in the basal ganglia is
blocked. The problem is the degeneration of neurons in an
area of the brain called the substantia nigra (so-called
because it is black in appearance) whose long, projecting
axons release the neurotransmitter dopamine into the basal
ganglia (see Research Frontiers box below). The precise
arrangement of the dopamine axons onto their target
neurons in the basal ganglia is very intricate, suggesting an
important interaction between different neurotransmitters.
Treatment with the drug L-Dopa, which is converted into
dopamine in the brain, restores dopamine levels and restores
movement (see Chapter 16).

The basal ganglia are also thought to
be important in learning, allowing the
selection of actions that lead to A Purkinje cell of the cerebellum showing the extensive
rewards. ‘arborisation’ of its dendritic tree. This serves to receive
the myriad of inputs required for the precise timing of
skilled movements that we learn.
The cerebellum
The cerebellum is crucial for skilful
smooth movements.
It is a beautiful neuronal machine Research Frontiers
whose intricate cellular architecture
has been mapped out in great detail. Basal ganglia
Like the basal ganglia, it is extensively cortical
afferents
interconnected with the cortical 10,000
Caudate
areas concerned with motor control, cortical
and also with brainstem structures. terminals
Damage to the cerebellum leads to Putamen 1000 dopamine
synapses on
poorly coordinated movements, loss dendritic spines
dopamine
of balance, slurred speech, and also a afferent
number of cognitive difficulties. striatal
Sounds familiar? Alcohol has a SN neuron
powerful effect on the cerebellum. Substantia
Nigra (SN)
The cerebellum is also vital for motor
learning and adaptation. Almost all voluntary actions rely on
An unexpected story about dopamine
fine control of motor circuits, and the cerebellum is
important in their optimal adjustment - for example with The chemistry underlying actions and habits involves the
respect to timing. It has a very regular cortical arrangement neurotransmitter dopamine that is released on to
and seems to have evolved to bring together vast amounts neurons in the basal ganglia where it acts at
of information from the sensory systems, the cortical motor metabotropic receptors (Chapter 3). There it serves as
areas, the spinal cord and the brainstem. The acquisition of both an incentive to act and as a reward signal for acting
skilled movements depends on a cellular learning mechanism appropriately. An intriguing new discovery is that the
called long-term depression (LTD), which reduces the release of dopamine is highest when the reward is
strength of some synaptic connections (see chapter on unexpected. That is, the dopamine neurons fire most
Plasticity). There are a number of theories of cerebellar strongly at a stage of learning when it really helps to give a
strong reinforcement to the motor system for having
function; many involve the idea that it generates a “model” of
produced the right output. Movements can then be
how the motor systems work â€" a kind of virtual reality strung together in a sequence through the release of
simulator of your own body, inside your head. It builds this successive bursts of dopamine. Later on, particularly if
model using the synaptic plasticity that is embedded into complex movements become habitual, the system
its intricate network. So, catch that ball again, and realise free-runs without the dopamine reward. At this point,
that almost all levels of your motor hierarchy are involved - particularly if movements have to be accurately timed,
from planning the action in relation to the moving visual the cerebellum starts to play a role.
g




Learn a bit about the history of how neuroscientists found out about the control of movement at:
http://www.pbs.org/wgbh/aso/tryit/brain/
21
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The Developing
Nervous System

The basic plan of the brain is virtually identical from person
to person and recognisably similar across all mammals.
It is largely genetically determined, but fine details of the
networks are influenced by the electrical activity of the A
brain, especially during early life. Such is its complexity, we
are still far from a complete understanding of how the
brain develops, but clear insights have emerged in recent
years by virtue of the genetic revolution.

Take one fertilised egg, and then follow B
the instructions
The human body and brain develop from a single cell - the
fertilized egg. But how? The governing principle of
developmental biology is that the genome is a set of
instructions for making an organ of the body, not a blueprint.
The genome is the 40,000 or so genes that orchestrate the
process. Carrying out these instructions is a bit like the
Chinese art of paper folding - a limited set such as fold, bend
and unfold produces a structure that would take many draw-
ings to describe as a blueprint. Beginning with the embryo, a
comparatively small set of genetic instructions is able to
C
generate the huge diversity of cells and connections of the
brain during development.

Amazingly, many of our genes are shared with the fruit fly,
D
Drosophila. Indeed, thanks to studies of the fruit fly, the
majority of the genes known to be important in human
E
nervous system development were first identified. F
Neuroscientists studying brain development examine a wide
variety of animals - zebrafish, frog, chick and mouse â€" each
having advantages for examining particular molecular or
cellular events. The zebrafish embryo is transparent -
allowing each cell to be watched under the microscope as it
develops. The mouse breeds rapidly - its genome has been
mapped and almost completely sequenced. Chicks and frogs
are less amenable to genetic studies, but their large embryos
allow microsurgical manipulations - such as examining what
happens when cells are moved to abnormal positions.

First steps…
The first step in brain development is cell division. Another The neural plate folds into the neural tube. A. A human
key step is cell differentiation in which individual cells stop embryo at 3 weeks after conception. B. The neural plate
dividing and take on specific characteristics - such as those forming the top (dorsal) surface of the embryo. C. A few
of neurons or glial cells. Differentiation orders things days later, the embryo develops enlarged head folds at the
spatially. Different kinds of neurons migrate to various front (anterior) end. The neural plate remains open at both
locations in a process is called pattern formation. head and tail ends but has closed in between. D, E, F.
Different levels of the axis from head to tail showing
The first major event of pattern formation takes place in the various stages in neural tube closure.
third week of human gestation when the embryo is just two




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connected sheets of dividing cells. A small patch of cells on
the upper surface of the bilayer is instructed to make the
entire brain and spinal cord. These cells form a tennis racket-
shaped structure called the neural plate, the front of which
is destined to form the brain, the rear to be the spinal cord.
Signals directing the destiny of these cells come from the
layer beneath that goes on to form the midline skeleton and
muscles of the embryo. Various regions of the early nervous
system express different subsets of genes, presaging the
emergence of brain areas - forebrain, midbrain and hindbrain -
with distinct cellular architecture and function. A
26 Days
Rolling around
A week later, the neural plate rolls up, closes into a tube and
sinks into the embryo, where it becomes enveloped by the
future epidermis. Further profound changes happen in the
next few weeks, including changes in cell shape, division and
migration, and cell-cell adhesion. For example, the neural tube
flexes such that the head region is bent at right angles to
the trunk region. This patterning progresses to finer and


neural groove
B
28 Days
neural crest


B



C
D 35 Days




E
D
49 Days



The morphogenesis of the human brain between (a)
4 weeks, and (d) 7 weeks after conception. Different
F regions expand and there are various flexures along the
head-tail axis.




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finer levels of resolution, ultimately conferring individual
identity on to young neurons. Things can go wrong. Failure of
the neural tube to close results in spina bifida, a condition
that is usually confined to the lower spinal cord. While
distressing, it is not lifethreatening. By contrast, failure of
closure at the head end can result in the complete absence
of an organised brain, a condition known as anencephaly.

Know your position in life
The underlying principle of patterning is that cells get to
know their position relative to the principal axes of the
nervous system - front to back and top to bottom. In effect,
each cell measures its position with respect to these
orthogonal coordinates much as a map-reader figures out Various types of guidance cues encountered by neurons
his or her position by measuring distance from defined (blue) as they extend their axons and growth cones (spikes
points. The way this works at the molecular level is that the at the front end). Both local and distant cues can be
embryo sets up a number of localised polarizing regions in attractive to the growth cone (+) or repulsive (-). Some
the neural tube that secrete signal molecules. In each case, examples are given of specific molecular guidance cues.
the molecule diffuses away from its source to form a
gradient of concentration with distance. An example of this
position-sensing mechanism is the top to bottom point mapping between neurons in the eye and the brain,
(dorsoventral) axis of the spinal cord. The bottom part of absolutely required for sharp vision, is achieved in part
the neural tube expresses a secreted protein with a through the influence patterned electrical activity in the
wonderful name - Sonic hedgehog. Sonic hedgehog diffuses retina. Also, an initial exuberant set of connections is
away from the floor plate and affects cells on the sculpted during a critical period, after which the basic
dorsoventral axis according to their distance from the floor pattern of the visual system is complete, at around eight
plate. When close, Sonic hedgehog induces the expression of weeks of age in monkeys, perhaps a year in humans.
a gene that makes a particular type of interneuron. Further An intriguing question is whether such early developmental
away, the now lower concentration of Sonic hedgehog programs can ever be re-activated in cases of pathological
induces expression of another gene making motor neurons. neuronal loss (such as in Alzheimer and Parkinson’s diseases)
or of spinal cord damage that results in paralysis. In the
latter, axons can be encouraged to re-grow following injury
Staying put or knowing where but whether they can be made to re-connect appropriately
you are going remains an area of intense investigation.

Once a neuron acquires its individual identity and stops The genomic revolution
dividing, it extends its axon with an enlarged tip known as a
growth cone. A bit like a nimble mountain guide, the growth We are rapidly acquiring a complete catalogue of the genes
cone is specialized for moving through tissue, using its skills needed to build a brain. Thanks to the prodigious power of
to select a favourable path. As it does so, it plays out the molecular biological methods, we can test the function of
axon behind it, rather like a dog on an extending leash. Once genes by modulating their expression wherever and whenever
its target has been reached the growth cone loses its power we want during development. The major task now is to work
of movement and forms a synapse. Axonal guidance is a out the hierarchy of genetic control that converts a sheet of
supreme navigational feat, accurate over short and long cells into a working brain. It is one of the grand challenges of
distances. It is also a very single-minded process for not neuroscience.
only is the target cell selected with high precision but, to get
there, the growth cone may have to cross over other growth
cones heading for different places. Along the path, guidance Research Frontiers
cues that attract (+) or repel (-) the growth cones help
them find their way, although the molecular mechanisms Stem cells are cells of the body with the potential to
change into all sorts of different kinds of other cells.
responsible for regulating the expression of these cues Some, called embryonic stem cells, proliferate very early in
remain poorly understood. development. Others are found in bone marrow and in the
umbilical cord that connects a mother to her newborn baby.
Sculpting by electrical activity Neuroscientists are trying to
find out if stem cells can be
Although a high degree of precision in both the spatial used to repair damaged
arrangement of neurons and their connectivity is achieved neurons in the adult brain.
from the outset, the wiring of some parts of the nervous Most of the work at the
system is later subject to activity-dependent moment is being done with
animals, but the hope is that
refinement, such as the pruning of axons and the death of we may eventually be able to
neurons. These losses may appear wasteful, but it is not repair areas of the brain
always possible or desirable to make a complete and perfect damaged by diseases such as
brain by construction alone. Evolution has been said to be Parkinson’s Disease.
“a tinkerer” - but it is also a sculptor. For example, point-to-
g




250,000 cells get added to your brain every minute at certain stages of its development.
24 Read more about it at: http://faculty.washington.edu/chudler/dev.html
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Dyslexia




KLO
ABCDEF GH
O IKJ MN




UQ
T Z




R

P
X




W
Y
S
Do you remember how difficult it was to learn to read? The ability to sequence letters and sounds accurately
Unlike speaking, whose evolutionary origins are very old, depends on both visual and auditory mechanisms.
reading and writing are relatively recent human inventions. For unfamiliar words, and all are unfamiliar to the beginning
It may only have been a thousand years ago that reader, each letter has to be identified and then to be put in
communities in scattered parts of the world realised that the right order. This process is not as easy as it sounds,
the thousands of spoken words are made up of a smaller because the eyes make small movements flicking from one
number of separate sounds (44 phonemes in English) and letter to the next. The letters are identified during each
that these can be represented by an even smaller number fixation of the eye but their order is given by where the eye
of visual symbols. Learning these symbols takes time and was pointing when each letter was seen. What the eyes see
some children experience exceptional difficulties. This is has to be integrated with motor signals from the eye
not through any lack of intelligence but because their movement system; and it is with this visuomotor integration
brains find the particular requirements of reading difficult that many dyslexics have problems.
to master. As many as 1 in 10 of us may have had this
condition, now known by its neurological name,
developmental dyslexia.

Dyslexia is very common. As children who have it cannot
understand why they find reading so difficult when they know
they are as intelligent as friends who find it easy, dyslexia is
a real cause of misery. Many children lose confidence, and
this can lead to a downward spiral of frustration, rebellion, Eye movements during reading. Up and down movements
aggression and even delinquency. Yet many dyslexics go on to of the pen recorder correspond to left and right.
display great talents in other spheres - sport, science,
computing, commerce or the arts â€" provided their early Visual control of the eye movement system is dominated by
problems with reading have not caused them to lose all hope a network of large neurons known as the magnocellular
and self- esteem. Hence understanding the biological basis system. It gets this name because the neurons (cells) are
of dyslexia is not only important in itself, but also a very large (magno). This network can be traced right from
contribution to preventing a burden of misery. Understanding the retina, through the pathway to the cerebral cortex and
the process of reading better may lead us to a way of cerebellum, to the motor neurons of the eye-muscles. It is
overcoming or treating the problem. specialised to respond particularly well to moving stimuli and
it is therefore important for tracking moving targets. An
Learning to read important feature of this system is that it generates
motion signals, during reading, when the eyes move off
Reading depends on being able to recognise alphabetic visual letters they are meant to be fixating. This motion error
symbols in their right order - the orthography of whatever signal is fed back to the eye-movement system to bring the
language a child is learning - and to hear the separate eyes back on target. The magnocellular system plays a
sounds in words in their right order. This involves extracting crucial part in helping to point the eyes steadily at each
what is called the phonemic structure, so that the symbols letter in turn, and hence in determining their order.
can be translated into the correct sounds. Unfortunately
most dyslexics are slow and inaccurate at analysing both
the orthographic and phonological features of words.
parvocellular
layers

magnocellular
layers
100 µm
Control Dyslexic
Histological stain of the lateral geniculate nucleus show-
ing well organized parvo and magnocellular cells in a normal
person and disorganization in some kinds of dyslexia.




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Neuroscientists have found that the visual magnocellular their handwriting is often very poor. Neuroimaging (see p.41)
system is mildly impaired in many dyslexics. Looking at brain and metabolic studies of the cerebellum have indicated that
tissue directly is one way to reveal this (Figure) but, in its function can be impaired in dyslexics and this may be at
addition, the sensitivity to visual motion of dyslexics is the root of their difficulties with handwriting. Some neuro-
poorer than that of normal readers and their brain wave scientists believe the cerebellum is involved in much more
responses to moving stimuli are abnormal. Brain imaging has than the execution of movements such as writing and
also revealed altered patterns of functional activation in speaking, even including aspects of cognitive planning.
regions sensitive to visual motion (see Chapter 15 on Brain If correct, deficits in cerebellar function could add to
Imaging). The control of the eye in dyslexics is less steady; problems with learning to read, write and spell.
hence they often complain that letters seem to move around
and change places when they are trying to read. These visual What can be done?
confusions are probably the result of the visual magnocellular
system failing to stabilise their eyes as well as it does in There are a number of treatments for dyslexia, each
good readers. indicated by the different hypotheses about its underlying
cause. Sum focus on the magnocellular hypothesis, but
Putting sounds into the right order other accounts distinguish different forms of the acquired
condition, known as surface and deep dyslexia, which may
Many dyslexics also have problems putting the sounds of require different kinds of treatment. All treatments rely on
words in the right order so that they tend to mispronounce early diagnosis.
words (such as pronouncing lollypop as pollylop) and they
are very bad at tongue twisters. When they come to reading, Scientists do not always agree on things and the best
they are slower and more inaccurate at translating letters treatment for dyslexia is one such area of disagreement.
into the sounds they stand for. Like their visual problems, It has been suggested recently that problems in sound
this phonological deficiency is probably rooted in a mild processing result in some dyslexics going down the wrong
deficiency of basic auditory skills. path for learning about sounds using the brain’s normal
mechanisms of plasticity. The idea is that children can get
We distinguish letter sounds, called phonemes, by detecting back on the ‘straight and narrow’ if they are encouraged to
the subtle differences in the sound frequency and intensity play computer games in which they hear sounds that have
changes that characterise them. Detecting these acoustic been slowed down to the point where phonemic boundaries
modulations is carried out by a system of large auditory are much clearer. The sounds are then gradually speeded up.
neurons that track changes in sound frequency and It is claimed that this works very well, but independent tests
intensity. There is growing evidence that these neurons fail are still being done. What is scientifically interesting about
to develop as well in dyslexics as in good readers and that the idea is that perfectly normal brain processes interact
the categorical boundaries between similar sounds, such as with an early genetic abnormality to produce an exaggerated
‘b’ and ‘d’, are harder for them to hear (see Figure). effect. It’s a striking example of how genes and the
environment can interact.
Many dyslexics show evidence of impaired development of
brain cells, extending beyond the visual and auditory It is important to stress that dyslexics may be slightly
problems they have with reading. These are problems in better than even good readers at some perceptual
neurons that form networks throughout the brain that seem judgements such as colour distinctions and global, rather
to be specialised for tracking temporal changes. The cells all than local, shape discriminations. This hints at a possible
have the same surface molecules by which they recognise explanation of why many dyslexics may be superior in seeing
and form contacts with each other, but which may make long-range associations, unexpected associations and at
them vulnerable to antibody attack. ‘holistic’ thinking in general. Remember that Leonardo da
Vinci, Hans Christian Andersen, Edison and Einstein and
The magnocellular system provides a particularly large input many other creative artists and inventors were dyslexic.
to the cerebellum (see Chapter 7 on Movement).
Interestingly, some dyslexics are remarkably clumsy and
g




Related Internet Sites about dyslexia and learning difficulties:
http://www.sfn.org/content/Publications/BrainBriefings/dyslexia.html
26 http://www.learningdisabilities.com/programs.shtml
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Plasticity

Throughout our lives our brains constantly change. A flavour of how it all works
This ability of the brain to change is called plasticity - by
analogy with plasticine model whose internal components Glutamate is a common amino acid used throughout our
can be constantly re-shaped. Not the brain as a whole, but bodies to build proteins. You may have come across it as the
the individual neurons can be modified for different reasons flavour enhancer called mono-sodium glutamate. It is the
- during development when we are young, in response to neurotransmitter that functions at the most plastic
brain injury, and during learning. There are various synapses of our brains - those that exhibit LTP and LTD.
mechanisms of plasticity, of which the most important is Glutamate receptors, which are mainly on the receiving side
synaptic plasticity â€" the science of how neurons alter their of the synapse, come in four varieties: three are ionotropic
ability to communicate with one another. receptors and have been given the names AMPA, NMDA and
kainate. The fourth type is metabotropic and is called
Moulding our futures mGluR. Although all the types of glutamate receptors
respond to the same neurotransmitter, they perform very
As we saw in the last chapter, the connections between different functions. The ionotropic glutamate receptors use
neurons early in life require fine-tuning. As we interact with their ion channels to generate an excitatory post-synaptic
our environment, these synaptic connections start to potential (epsp) while the metabotropic glutamate
change â€" with new ones being made, useful connections receptors, like the neuromodulatory actions we described
becoming stronger, and connections that are infrequently earlier (p. 8), modulate the size and nature of this response.
used becoming weaker or even lost for good. Synapses that All types are important for synaptic plasticity, but it is the
are active and those that are actively changing are kept while AMPA and NMDA receptors about which we know the most
the rest are pruned. This is a kind of use it or lose it and that are often thought of as memory molecules. Much
principle by which we mould the future of our brains. of this knowledge has come about because of pioneering work
developing new drugs that act on these receptors to modify
Synaptic transmission involves the release of a chemical their activity (see box p. 29).
neurotransmitter that then activates specific protein
molecules called receptors. The normal electrical response AMPA receptors are fastest into the act. Once glutamate
to neurotransmitter release is a measure of synaptic is bound to these receptors, they rapidly open their ion
strength. This can vary and the change may last for a channels to produce a transient excitatory postsynaptic
few seconds, a few minutes or even for a lifetime. potential (epsps are described in Chapter 3). The glutamate
Neuroscientists are particularly interested in long-lasting is only bound to AMPA receptors for a fraction of a second
changes in synaptic strength that can be produced by brief and, once it leaves and is removed from the synapse, the ion
periods of neuronal activity, notably in two processes called channels close and the electrical potential reverts to its
long-term potentiation (LTP), which enhances their resting state. This is what happens when neurons in the
strength, and long-term depression (LTD), which brain send information to each other quickly.
depresses them.



Glutamate is
released from
synaptic
terminals,
crosses the
synaptic cleft,
and binds to the
different kinds of
glutamate
receptors -
AMPA, NMDA and
mGLUR.
Some glutamate
synapses also
have kainate
receptors.




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NMDA receptors (red) are the molecular machinery for NMDA receptors: molecular machines
learning. Transmitter is released during both baseline
activity and the induction of LTP (top left). The site where
for triggering plasticity.
Mg2+ (small black circle, top right) blocks the Ca2+ channel
is inside the cell membrane and it is displaced by intense Glutamate also binds to NMDA receptors on the
depolarization (next diagram down). This happens when postsynaptic neuron. These are the critical molecular
neurons need to change their connectivity with other machines that trigger synaptic plasticity. If the synapse is
neurons. LTP can be expressed as either a larger number of activated quite slowly, the NMDA receptors play little or no
AMPA receptors (yellow receptors, bottom left) or as more role. This is because as soon as NMDA receptors open their
efficient AMPA receptors (bottom right). ion channels these channels become plugged by another ion
present in the synapse â€" magnesium (Mg2+). But, when
synapses are activated by several pulses very quickly to a
set of inputs on to a neuron, the NMDA receptors
immediately sense this excitement. This greater synaptic
activity causes a large depolarisation in the postsynaptic
neuron and this dispels the Mg2+ from the NMDA ion
channels by a process of electrical repulsion. NMDA
receptors are then immediately able to partake in the




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synaptic communication. They do this in two ways: first, and Exercising the brain
just like AMPA receptors, they conduct Na+ and K+ which
adds to the depolarisation; second, they allow calcium (Ca2+) Changes in the functioning of AMPA receptors are not the
to enter the neuron. In other words, NMDA receptors sense whole story. As memories become more permanent,
strong neuronal activity and send a signal to the neuron in structural alterations occur in the brain. Synapses with
the form of a surge of Ca2+. This Ca2+ surge is also brief, more AMPA receptors inserted following the induction of LTP
lasting for no more than about a second while glutamate is change their shape and may grow bigger, or new synapses
bound to NMDA receptors. However, Ca2+ is a crucial may sprout out from the dendrite so that the job of one
molecule as it also signals to the neuron when NMDA synapse can now be done by two. Conversely, synapses that
receptors have been activated. lose AMPA receptors following the induction of LTD may
wither and die. The physical substance of our brains is
altering in response to brain activity. Brains like exercise â€"
mental exercise of course! Just as our muscles grow
stronger when we engage in physical exercise, so it now
seems that our synaptic connections become more
numerous and better organised when we use them a lot.


Mind over memory
How well we learn is greatly influenced by our emotional state
- we tend to remember events associated with particularly
happy, sad or painful experiences. We also learn better when
we pay attention! These states of mind involve the release of
neuromodulators, such as acetylcholine (during heightened
attention), dopamine, noradrenaline and steroid hormones
such as cortisol (during novelty, stress and anxiety).
Modulators have multiple actions on neurons, several of
Apparatus used for monitoring the tiny electrical voltages
that occur at synapses. which act via changes in the functioning of NMDA receptors.
Other actions include the activation of special genes
specifically associated with learning. The proteins that they
Once inside the neuron, the Ca2+ binds to proteins located make help to stabilise LTP and make it last longer.
extremely close to the synapses where the NMDA receptors
were activated. Many of these proteins are physically
connected to the NMDA receptors in what constitutes a
The doctor within
molecular machine. Some are enzymes that are activated by
Synaptic plasticity plays another critical function in our
Ca2+ and this lead to chemical modifications of other
brains â€" it can help the brain recover from injury. For example,
proteins within or close to the synapse. These chemical
if the neurons that control particular movements are
modifications are the first stages of the formation of the
destroyed, as happens during a stroke or serious head injury,
memories.
all is not necessarily lost. Under most circumstances, the
neurons themselves do not grow back. Instead other
AMPA receptors: our molecular neurons adapt and can sometimes take on similar
machines for storing memories. functional roles to the lost neurons, forming another
network that is similar. It is a process of re-learning and
If NMDA receptor activation triggers plastic changes in the highlights certain recuperative abilities of the brain.
connectivity of neurons, what expresses the change in
strength? It could be that more chemical transmitter is
released. This can occur, but we are fairly certain that one
set of mechanisms involves AMPA receptors on the Jeffery Watkins
post-synaptic side of the synapse. There are various ways a medicinal chemist who transformed the
of doing this. One way might be to enable AMPA receptors study of excitatory transmission in the
brain by developing drugs like AP5 (below)
to work more efficiently, such as to pass more current into
that act on specific glutamate receptors.
the neuron upon activation. A second way would be to enable
more AMPA receptors to be inserted into the synapse. In
both cases this leads to a larger epsp - the phenomenon of
LTP. The opposite change, a reduction in the efficiency or
number of AMPA receptors can result in LTD. The beauty of
this mechanism for inducing LTP or LTD is its elegance yet
relative simplicity â€" it can all occur within a single dendritic
spine and thereby alter synaptic strength in a highly
localised manner. It is the stuff that memories might
actually be made of - an issue to which we return in the
next chapter.
g




Related Internet Sites: http://www.cf.ac.uk/plasticity/index.html
http://www.bris.ac.uk/synaptic/public/brainbasic.html
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Learning & Memory HER
calculus
FACE
AME
MY N
R ESS
ADD
Shoppin
g AGE
List




Memories are central to our individuality. What each of us of information very accurately. We use it to remember
remember is different from what others remember, even of speech for long enough to interpret the flow of conversation,
situations we have been in together. Yet, in our distinct for doing mental arithmetic, and for remembering where and
ways, all of us remember events, facts, emotional feelings when we put our keys down a moment ago. Fidelity is central
and skills - some for a short time, others for a lifetime. to the system - a feature that comes at the cost of limited
The brain has multiple memory systems with different capacity and persistence. It is often said that you can
characteristics and mediated by different neuronal remember 7 ± 2 items in working memory; this is why so
networks. The formation of new memories is now widely many telephone numbers are no longer than 7 or 8 digits.
thought to depend on synaptic plasticity, as described in But remembering these accurately is essential. You can
the last chapter, but we are still uncertain about the demonstrate the capacity and limited persistence of
neural mechanisms of information retrieval. While we all working memory in a simple experiment you can do with
complain about our memories, they are in the most part your friends.
pretty good, only starting to fail in old age or certain
neurological diseases. It might be good to try to improve
our memory, but doing so could be at the cost of
remembering many things that it is as well to forget.

The organisation of memory
There is no single brain area to which all the information we
t An Experiment on Short-Term Memory




A simple test of short-term or working memory is
ever learn is shuttled for storage. Working-memory holds called “letter-span”. You need a minimum of 2
information in your mind for a short time in an active people, although it works better with the whole
conscious state. The much larger, more passive storehouse class. Privately, one of you writes down a series of
of information is called long-term memory. letters beginning with as few as 2, taking care they
do not spell out a word (e.g. XT). This person then
Inner Scribe produces further letter strings, one letter longer
at a time (e.g. a 5-letter string such as QVHKZ and
a 10-letter string such as DWCUKQBPSZ).
The experiment begins after these are prepared.
Visuo-Spatial Sketch Pad
The other person (or class) listens to each letter
string in turn and, after about 5 seconds, tries to
write down the letters in the correct order from
memory. Starting with the easy 2-letter string,
Central Executive System the memory test moves on to longer ones. Most
people can do it perfectly up to about 7 or 8 letters
- and then errors creep in. Very few can do 10 let-
ters correctly. The capacity of short-term memory
has been described as “the magical number 7 plus or
Auditory Short Term Store minus 2”.


A central executive system controls the flow of information,
Silent Rehearsal Loop supported by two additional memory stores. There is a
phonological store alongside a silent rehearsal loop - the bit
of your brain that you use to say things to yourself. Even if
The short-term working-memory system of the brain you read words or numbers visually, the information will be
transcribed into a phonological code and stored for a short
while in this two-part system. There is also a visual
sketchpad that can hold on to images of objects for long
Working Memory enough for you to manipulate them in your mind’s eye.

Like a pad on a desk for jotting down names or telephone Working memory is largely located in the frontal and parietal
numbers that we need to remember only briefly, the brain has lobes. Brain imaging studies (see p. 41) using PET and fMRI
a system for holding on to and working with small amounts brain imaging indicate that the auditory parts of working-




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memory are generally lateralised to the left frontal and pari- that DNA encodes genetic information as a sequence of base
etal lobes where they interact with neuronal networks involved pairs, and so on. The critical property is that facts are
in speech, planning and decision-making. These are activities organised into categories. This is vital for memory retrieval as
for which a good working-memory is essential. The visual the search process can then shuttle through tree diagrams in
sketchpad is in the right hemisphere (see Box at end of this storehouse to find things efficiently. If semantic memory
chapter). were organised in the way that many people organise things in
the attic of their houses - pretty randomly - we would have
How did working-memory evolve? Animals, even most terrible trouble remembering anything. Fortunately, the brain
mammals, probably do not have quite the same sort of sorts the information that we encode into categories, though
short-term memory system as we have, and it clearly didn’t it helps to have a skilled teacher for the complex things we
evolve to help early hominids remember telephone numbers! learn at school. Indeed, gifted teachers build these
Studies with young children point to a critical role for working- structures in their pupils effortlessly.
memory in learning language, suggesting that this memory
system may have co-evolved with speech. The precision Objects
required for keeping track of words and their order in a
sentence is critical for accurately working out the correct
meaning. Inanimate Animate

Long-term memory Mammals Birds

Long-term memory is also sub-divided into different Flying birds Flightless birds
systems located in widely dispersed networks of the brain.
The different networks do very different jobs. Broadly
Sing birds Other birds
speaking, information enters sensory systems and then
passes down pathways that provide increasingly specialised
processing. For example, information entering the visual Canaries Penguins
system passes down a so-called ventral pathway from the
striate cortex to the medial temporal lobe through a
The facts we know about animals are organized in a
cascade of networks that work out shape, colour, object
tree-structure. We do not yet know how the networks of
dentity, whether the object is familiar or not, until finally,
the brain do this.
some kind of memory is formed of this particular object and
when and where it has been seen.
We also learn skills and acquire emotional feelings about
things. Knowing that a piano is a piano is one thing: being able
to play it is another. Knowing how to ride a bicycle is useful,
but being aware that certain situations on the road can be
dangerous is no less important. Skills are learned through
deliberate and extensive practice, whereas emotional learning
tends to be much more rapid. Often it has to be fast,
particularly for the things we learn to be afraid of. Both are
types of learning called conditioning. Specialised brain areas
are involved - the basal ganglia and cerebellum being very
important for skill learning, and the amygdala for emotional
learning. Many animals learn skills - it is very important for
their survival.




The cascade of brain areas through which visual information
is first processed perceptually and then for the purpose
of memory.

There are several ways of thinking about this cascade of
analysis. First, there are areas in the cortex that extract a
perceptual representation of what we are looking at.
This is used to store and later recognise things around us.
Our ability to identify familiar people in newspaper cartoons,
such as politicians, reflects this system. Very closely
related is a system called semantic memory - the vast Chimpanzees have learned the skill of fishing for termites
storehouse of factual knowledge that we have all accumulated using a stick. Young chimpanzees learn this by watching
about the world. We know that Paris is the capital of France, their parents.




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Memory failure and the localisation of Amazingly, amnesic patients can learn some things that they
cannot consciously remember! They can be taught motor
episodic memory in the brain skills or to read backwards very quickly.

The last type of memory system in the brain is called Training to read backwards quickly takes a while
episodic memory. It is what you use to keep track of person- This is true for amnesics no less than for us, but whereas
al experience. Remembering events is different from learning we would remember being taught to do this, they do not.
facts in one very important respect - events happen only This is a fascinating dissociation in their conscious
once. If you forget what you ate at breakfast today (unlike- awareness. Amnesics are certainly conscious when they
ly), or what happened last Christmas (possibly), or all the learn, but are later unaware of having learned. They cannot
things that happened on your very first day at school recover conscious awareness from the past.
(probably), you cannot re-run any of these events like an The damage that causes this distressing condition can occur
extra lesson in class. This system learns quickly because it in a number of brain circuits. Areas of the midbrain called
has to. mamillary bodies and the thalamus seem to be critical for
normal memory, as is a structure in the medial temporal lobe
We have learned a lot about what episodic memory is by called the hippocampus. Damage in these regions seems
studying neurological patients who, following a stroke, brain particularly to affect the formation of episodic and
tumours or viral infections such as herpes encephalitis, semantic memories.
sometimes have very specific deficits in this type of memory.
Studying such patients carefully has been the major way to
work out the anatomical organization of this and other
memory systems.


“It is not so much the injury that captures our
attention as how, through injury or disease, normal
function is laid bare.”
(Sir Henry Head - 20th C Neurologist).
People affected by a condition known as amnesia cannot
remember meeting other people only half an hour earlier.
They cannot remember whether they have recently eaten a
meal or ought to have one, and even such simple necessities
of life as where things have recently been put down around
the house. Shown a complex drawing - such as the one in the
inset - they can copy it accurately but they cannot draw it
as well as most of us could do from memory as little as 30
minutes later. Often, they cannot remember things that
happened before they became ill. This is called retrograde
amnesia.

Such a life lacks all structure in time and place and has been
described by one extensively studied amnesic patient as like
continually “waking from a dream”. Yet this same person
retains his command of
language and the meaning
of words, and enough
NC working-memory to carry on
a sensible conversation. It
Copy Delayed Recall is not until one has exactly
the same conversation with
him a few minutes later
A
that the devastating
isolation of his existence
is revealed.

Amnesics (A) can see just fine and copy complex drawings Two structures are very important for episodic memory -
like this one quite accurately, but they cannot remember the perirhinal cortex (PRH) which mediates the sense of
them for very long compared to normal control familiarity about the past and the hippocampus (HIPPO)
subjects (NC). which encodes events and places.




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Other memory systems where this learning process takes place in the young chick’s
brain and the chemical transmitters that are released to act
Damage elsewhere in the brain affects other memory on receptors involved in storing some kind of an ‘image’ of the
systems. Degenerative conditions, such as certain types of mother. This image is quite precise, such that the young
semantic dementia (a type of Alzheimer’s Disease), can chick will follow its mother but not another. Young animals
cause fascinating patterns of breakdown of semantic also need to know what foods are safe to eat by tasting
memory. Early on, patients will be quite capable of telling you small amounts of food at a time, and learning those that
that the pictures they are being shown in an experiment are taste bad. This cannot be left to genetic predispositions
of a cat, or a dog, or of a car, or a train. Later on in the alone - developmentally tuned learning mechanisms are at
disease, they may hesitate to call a picture of a mouse a work. Downstream of the receptors activated during
mouse, saying instead that it is a dog. What this confirms is imprinting or the tasting of food, a cascade of second-
that factual information is organised categorically, with messenger chemicals transmit signals to the nucleus of
animate information stored together in one place well away brain cells where genes are activated to make special
from inanimate information. proteins that can literally fix the memory.

The neurobiology of memory Place cells are another important discovery. These are
neurons in the hippocampus that fire action-potentials only
Studying neurological patients carefully helps us to discover when an animal explores a familiar place. Different cells code
where memory functions are in the brain, but finding out how for different parts of the environment such that a
They work in terms of neurons and chemical transmitters population of cells is involved in mapping a whole area. Other
involves carefully conducted research using laboratory cells in a nearby brain area code for the direction the animal
animals. is moving in. The two areas working together - the map of
space and the sense of direction - help the animal learn to
Neuroscientists now believe that many aspects of the find its way around the world. This is clearly very important
fine-tuning of neural connections in the developing brain are for animals, because finding food and water and then their
also used during early learning. The attachment that way back to the burrow, nest, or other home is vital for their
develops between an infant and its mother has been studied survival. This navigational learning system relates to both
in young chicks in a process called imprinting. We now know semantic and episodic memory. Animals form a stable
representation of where things are in their territory - just
like the factual knowledge we acquire about our world. And
this map of space provides a memory framework in which to
The Hippocampus remember events - such as where a predator was last seen.
This Golgi stain shows a Place cells may code more than just place - they may help
subset of neurons animals to remember where events have happened.
in black




Four recording wires near cells in the hippocampus reveal
nerve impulses on two of the wires (1 and 2, occasionally 4)
that represent neurons firing at a particular place (red hot
spot in the circular enclosure). Expanding the time scale
(red circle) shows the shape of the spikes in the brain.


How are these maps and other memory traces formed?
One emerging view is that synaptic plasticity based on
NMDA receptors is involved. In the last chapter, we
described how activating synaptic plasticity changes the
strength of the connections in a network of neurons and
that this is a way of storing information. Learning about
places is impaired when a drug that blocks NMDA receptors




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is applied to the hippocampus. For example, rats and mice
can be trained to swim in a pool of water to find an escape Research Frontiers
platform hidden at one place underneath the water surface.
They use their place cells and head-direction cells to help find
their way, and they encode the correct location of the
platform into memory using plasticity triggered by NMDA
receptors. Also gene knockout animals have been engineered
in which NMDA receptors have been deleted in the
hippocampus. These animals are also bad at learning and
they also have very inaccurate place cells. In the last
chapter, we explained that changes in synaptic weights are
expressed through alterations in excitatory AMPA
receptors. We still don’t know if that is true of memory - it is
a topic of intense research just now.




London taxi drivers have to know the city very well before
they are allowed to ply the city for fares. When researchers
put experienced taxi drivers in a brain scanner and asked
them to imagine a trip from Marble Arch to Elephant and
Castle, they saw greater activation in the right
parahippocampal cortex (red areas). Structural MRI scans
of taxi drivers show changes in the relative size of different
parts of their hippocampus that may be related to how
The rat has swum in the pool to the hidden platform on much of the city they are able to remember - although there
which it is standing. could be other factors as well.



Can we improve memory? drugs, but it is no less important. The idea is to take
advantage of what has been learned about how information
We all think that it would be good to improve the capacity or is encoded, stored, consolidated (the ‘fixing’ process) and
persistence of our memory. Older people often complain then retrieved. Paying attention, spacing out learning
about their memory. However, improving memory would sessions, and getting frequent reminders to help the ‘fixing’
almost certainly come at a price. This is because a good process are all examples. Some elderly patients with
memory is a balance between remembering and forgetting. memory problems are finding a paging system called
If we were we to improve it, we might then have difficulty “NeuroPage” quite helpful - it reminds them of what they
forgetting all the trivial things that happened during the day should be doing next and so helps them structure their day
that there is no need to remember. The ‘yin and yang’ of a in a manner that they might otherwise forget to do.
good memory is one that remembers and organises the right Recognising the different operating principles of episodic
things in the brain, but forgets things that seem less memory and skill learning is also essential - you will never
important. It seems unlikely that we shall ever have a pill learn a skill by merely hearing about it, although this works
that will act like a magic bullet to improve memory, at least in fine for episodic memory. Anyone trying to learn a skill must
normal people. Evolution has ensured that the system is practice often, as the pupils of any music teacher are
optimally balanced. always reminded.

Having said that, really serious forgetfulness might be Alan Baddeley
alleviated by drugs that make NMDA or AMPA receptors who developed the idea
work better, or drugs to stimulate the cascade of second- of working memory, which consists of
messenger signals that studies of learning in young animals a number of different interacting systems.
have identified. It would be helpful also to find some way of
stemming the course of neurodegenerative diseases such as
Alzheimer’s Disease that affect memory early on. One of the
exciting adventures in neuroscience today, for scientists in
universities, research institutes and pharmaceutical The phonological store, visuospatial sketch pad and
companies, is working on projects of this kind. With the central executive are located in various parts of the brain.
population demography of virtually all developed countries
veering towards a greater preponderance of older people,
treatments that could help them lead independent lives for
longer would be greatly valued.

However, some scientists believe that cognitive engineering
will be needed alongside drugs. You do not hear so much
about cognitive engineering in the newspapers as about new
g




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Stress


Stress affects even the most seemingly tranquil lives. Fight or Flight?
We all experience it - during exams, competing in sports, or
when falling out with friends and enemies alike. Why does it The easiest response to recognise is the immediate
occur and what causes its unpleasant sensations? Is it activation of what is - endearingly - called the sympathetic
good for anything? What happens when it goes wrong? nervous system. After receiving a stressful challenge and
Neuroscientists are beginning to understand how the brain computing the right response, the brain rapidly activates
generates a coordinated chemical response to stress. nerves originating from control centres in the brainstem.
These cause the release of noradrenaline in a variety of
What is stress and why do we need it? structures and of adrenaline from the adrenal glands
(situated just above the kidney). Their release underpins the
Stress is tricky to pin down. It isn’t just being under fight or flight response - the classical, immediate reaction
pressure - for this is not always stressful - but some kind of that has to be made in response to danger. We all recognise
mismatch between what the body and brain anticipate and the initial tingling sensation, sweating, heightened
what challenges we actually experience or feel. awareness, rapid pulse rate, higher blood pressure and
Many challenges that we face are psychological - reflecting general feelings of fear that we all feel in the moments
the difficulties of interacting with others as we work immediately after a stressful challenge.These changes
towards academic success, compete for a place in the school happen because of receptors that are found on blood
team or, later in life, for a job. Other stresses are physical vessels, causing them to constrict and so our blood pressure
such as an acute illness or a broken leg in a car accident. to shoot up, and in the heart, causing it to accelerate and
Most stressors are mixed: the pain and other physical produce the pounding sensation in the chest known as
afflictions of an illness are coupled with worry and concern. palpitations. There are also receptors in the skin causing
hairs to erect (goosebumps) and in the gut causing those
Stress is a fundamental process. It affects all organisms, disconcerting abdominal sensations that we all sense as
from the simplest bacterium and protozoan, to complex stress. These changes are there to prepare us to fight or to
eukaryotes such as mammals. In single-celled organisms and flee - and to concentrate blood flow to vital organs, the
in the individual cells of our bodies, molecules have evolved muscles and the brain.
which provide a series of emergency systems that protect
key cellular functions from unexpected external challenges
and their internal consequences. For example, special The hypothalamic-pituitary-adrenal
molecules called heat-shock proteins guide damaged (HPA) axis
proteins to where they can be repaired or harmlessly
degraded, thus protecting cells from toxicity or dysfunction.
In complex organisms such as ourselves, stress systems
have evolved as highly sophisticated processes to help deal
with out-of-the-ordinary challenges that may afflict us.
These use the cellular protection mechanisms as building
blocks in a larger network of stress protection.

Stress and the brain
Stress is perceived and the response co-ordinated by the
brain. Our cognitive appraisal of a situation in the brain
interacts with bodily signals in the blood stream such as
hormones, nutrients, and inflammatory molecules, and with
information from peripheral nerves monitoring vital organs
and sensations. The brain integrates these to produce a
series of specific and graded responses. Our understanding
of how it does this has come from the study of
neuroendocrinology. Circulating hormones in the blood are The HPA Axis. The hypothalamus at the centre controls the
monitored by the brain to enable the body to cope release of hormones from the pituitary that act on the
adrenal glands. Negative feedback of the hormonal release
with stress. is provided at various levels of the axis.




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The second major neuroendocrine response to stress is
activation of a circuit linking the body and brain called the
HPA axis. This links together the hypothalamus, pituitary
gland, adrenal cortex and hippocampus by a bloodstream
highway carrying specialised hormones.

The hypothalamus is the key brain area regulating many of
our hormones. It has strong inputs from areas of the brain
processing emotional information, including the amygdala,
and from regions of the brainstem controlling sympathetic
nervous responses. It integrates these to produce a
co-ordinated hormonal output that stimulates the next part
of the circuit - the pituitary gland. In turn, this releases a The bell-shaped curve for stress. A little bit of stress can
make things better, but too much makes things worse.
hormone called adrenocorticotrophin (ACTH) into the blood.
ACTH then stimulates a part of the adrenal gland to
secrete cortisol.
Depression and stress-system
Cortisol is a steroid hormone that is the key to overactivity
understanding the next phase of the stress response.
It raises blood sugar and other metabolic fuels such as fatty An excess of cortisol in the blood is seen in some chronic
acids. This often occurs at the expense of proteins that are brain diseases. In particular, in severe depression cortisol is
broken down into fuels required immediately - instant over-produced and recent work suggests that the
‘chocolate bars’ for the muscles and brain. Cortisol also hippocampus also shrinks in this condition. Such findings
helps adrenaline to raise blood pressure and, in the short have led psychiatrists to think of severe depression as
term, makes you feel good. Faced with the challenge of severe long-term stress. It is not at all certain that the
singing a solo at the school concert, the last thing you want increased cortisol is the primary cause of this illness rather
to do is dwell on worrying things. You just want to do it right than it being simply a consequence of severe psychological
with as little self-consciousness as possible. Cortisol also upset and its attendant stress. However, patients can be
turns off growth, digestion, inflammation, and even wound- markedly helped by blocking the production or action of
healing - clearly things that can be better done later on. cortisol, particularly those in whom classical anti-
It also turns off sex. The last step of the circuit is cortisol depressant drug treatments do not work. Anti-depressant
feedback to the brain. The highest density of cortisol drugs often help to normalise the overactive HPA axis. One
receptors is in the hippocampus, a key structure for learning idea is that they do so, in part, by adjusting the density of
and memory, but cortisol also acts on the amygdala, which MR and GR receptors in the brain, particularly in the
processes fear and anxiety. The net effect is to turn on the hippocampus. Neuroscientists working on this hope to
amygdala - to allow learning of fear-related information; and develop more effective treatments for stress disorders that
to turn off the hippocampus - to ensure that resources are work by resetting the feedback control system and reducing
not wasted on more complex but unnecessary aspects of excessive hormonal stress responses.
learning. Cortisol is focus juice.
Stress and ageing
STRESS IS INEVITABLE, SOMETHING WE ALL Ageing of the brain is accompanied by a general decline in
EXPERIENCE. IT MAY BE PSYCHOLOGICAL, function, but a decline that varies a great deal between
PHYSICAL OR (USUALLY) BOTH. individuals. Some individuals maintain good cognitive abilities
with age (successful ageing), whilst others do not do so well
(unsuccessful ageing). Can we get a molecular understand-
A tale of two cortisol receptors and the ing of this? Cortisol levels are higher in unsuccessful than in
successful ageing. This rise precedes the fall in mental
shrinking hippocampus abilities and the associated decline in the size of the
hippocampus seen in brain scans. Experiments in rats and
The hippocampus has high levels of the two receptors for
mice have shown that keeping stress hormone levels low from
cortisol - let’s call them the low MR and the high GR
birth, or even from middle age onwards, prevents the
receptor. The low MR receptor is activated by the normally
emergence of memory defects otherwise seen in untreated
circulating levels of cortisol in the bloodstream highway of
populations. So it appears that individuals with excessive
the HPA axis. This keeps our general metabolism and brain
hormone responses to stress - not necessarily those who
processing ticking over nicely. However, as cortisol
had most stress, but those who make the greatest
levels begin to rise, particularly in the morning, the high GR
responses to stressors - are those who get more memory
receptor becomes progressively more occupied. When we
loss and other cognitive disorders with advancing years.
become stressed, cortisol levels become very high indeed,
If this is true in humans as well, we may able to reduce the
activation of this receptor is sustained and the
burden of such effects, perhaps by exploiting antidepressant
hippocampus is then shut down by a genetically controlled
drugs that keep the HPA stress system under control.
program. Put all this together and you have what is called a
Stress is a major feature of modern life - and there is more
bell-shaped curve. This is the classical curve relating stress
to the story. But to describe this, we will have to bring in the
to brain function - a little bit is good for you, a bit more is
immune system.
better, but too much is bad!
g




Related Internet Site: http://www.brainsource.com/stress_&_health.htm
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The Immune System


Until just a few years ago, the brain was thought to be an immune system triggers cells called leucocytes and
“immune privileged organ” because it was not affected by macrophages, and acute phase proteins that travel to the
immune responses or inflammation. It is certainly site of attack, to identify, kill and then remove invading
protected to some extent from external events by the pathogens. In addition, the acute phase response generates
“blood brain barrier”. This is not really a barrier, but the symptoms we have all felt (fever, aches and pains,
specialised endothelial cells in the brain blood vessels that sleepiness, loss of appetite, disinterest). Each of these
are relatively resistant to the passage of large molecules responses helps to combat infection, conserve energy and
or immune cells from the blood into the brain. However, this aid repair, but when activated too much or for too long they
view of the brain as privileged has changed dramatically can be very damaging. So they need to be carefully
over the last decade as the result of research on controlled.
brain-immune system interactions. Neuroimmunology
is now a very active area of research. The brain and defence responses
Body defences The view of the brain an immunologically privileged organ has
now given way to a very different conception of its
The immune system is our first line of defence against relationship to the immune system. This is because it is now
malicious invaders. These invaders, viruses, bacteria and known that the brain can, and does, respond to signals from
yeast, range from common and mild, such as the all too the immune system and from damaged tissues. The old
familiar cold, to severe and life threatening, e.g. HIV, orthodoxy has been overthrown. Experiments have revealed
meningitis or tuberculosis. that the brain exhibits an array of local immune and
inflammatory responses, and indeed is an important
Our defences work in many ways. The first is locally within controller of the immune system and of the acute phase
the tissue that is infected, injured or inflamed, causing response. Many responses to disease, such as fever (body
swelling, pain, changes in blood flow and release of local temperature), sleep, and appetite, are regulated primarily by
inflammatory molecules. More generally, activation of the the hypothalamus.

The brain receives signals from injured or infected tissues
STRESS, SOCIAL FACTORS that may be neural in origin (via sensory nerves) or humoral
(via circulating molecules). Neural signals seem to be via C-
fibres (which also communicate pain â€" see Chapter 5) and via
Brain the vagus nerve from the liver â€" a key site for production of
acute phase proteins. The nature of the main circulating
Hypothalamus signals to the brain are not fully understood, but are believed
to include prostaglandins (which are inhibited by aspirin),
and complement proteins (a cascade of proteins important
in killing invader cells). But perhaps the most important
Humoral CRP
& neural signals are a group of proteins which came to light only in the
afferents last 20 years â€" known as cytokines.
Sympathetic Pituitary

Infection
Nervous System Cytokines as defence molecules
Injury ACTH
Cytokines are the body’s retaliators. There are now well over
Inflammation
100 of them - and more are being discovered all the time.
Adrenal These proteins are normally produced in the body at very low
levels, but are switched on quickly in response to disease or
Local efferents Glucocorticolds injury. They include interferons, interleukins, tumour
Immune & Endocrine necrosis factors and chemokines. Many are produced
Systems locally within damaged tissues and act on cells nearby, but
some enter the blood stream where they send signals to
distant organs including the brain. It is cytokines that cause
Many brain mechanisms come together to coordinate the most of the responses to disease and infection.
brain and the immune system.




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The triggers for cytokine production include bacterial or viral inhibit our defence responses, such as excessive work or
products, damage to cells or threats to cell survival such as major tragedies. The precise mechanisms responsible for the
toxins or low levels of oxygen. Another important regulator link between stress and the immune system are not fully
of cytokine production is the brain that, through neural worked out, but we do know that an important feature is
signals to tissues (mainly via the sympathetic nervous activation of the hypothalamic-pituitary-adrenal axis.
system) or hormones (such as cortisol from the adrenal One of the main responses to stress in the brain is increased
gland), can switch cytokines on or off. production of a protein in the hypothalamus called
corticotrophin releasing factor (CRF). CRF travels the
Cytokines are protein molecules with many actions, short distance from the hypothalamus to the pituitary
particularly on the immune system. Most stimulate the gland to release another hormone, adrenocotrophin
immune system and the key components of inflammation releasing factor (ACTH). This hormone travels via the
such as swelling, local changes in blood flow, and the release circulation to the adrenal gland to release steroid hormones
of a second wave of inflammatory molecules. They act on (cortisol in humans), which are some of the most potent
almost all physiological systems, including the liver where suppressors of immune function and inflammation. But the
they stimulate the acute phase proteins. However, although story seems to be more complex than this because there are
cytokines share many actions, they also vary significantly. other hormonal and neural elements, and we also know that
Some are anti-inflammatory and inhibit pro-inflammatory some forms of mild stress can actively improve our immune
process; most act locally on cells close to where they are function.
produced, while others are released into the circulation,
like hormones. Immune and inflammatory responses
Stress and immune system within the brain
Recent research has shown that many of the defence
We have all heard that stress and worry can lower our
molecules such as cytokines are also active contributors to
defences and can make us ill. We are now starting to
brain diseases such as multiple sclerosis, stroke and
understand not only how stress can affect the brain directly
Alzheimer’s. It seems that over production of such
by activating the HPA axis (described in the previous
molecules within the brain itself can damage neurons -
chapter), but also how it can influence the immune system â€"
particularly certain cytokines. Various new treatment
not surprisingly by an indirect route that is also through the
strategies for brain disease are now being developed with the
brain. Stress can influence the immune system and
idea of inhibiting immune and inflammatory molecules.
susceptibility to disease, but it depends on the type of
So neuroimmunology â€" a newcomer to the field of
stress and how we respond - some people clearly thrive on it.
neuroscience may provide some clues and possible
It is the sorts of stress that we cannot cope with that can
treatments for major brain diseases.
g




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Sleep Z Z
Z Z




Every night we retire to our bedroom, climb into bed, and The stages of sleep
drift off into the unconscious state of sleep. Most of us
sleep for about 8 hours, which means we spend roughly a Sleep is not quite the passive process it seems. If a person is
third of our lives unconscious - part of it dreaming. If you wired up with electrodes to their scalp in a sleep laboratory
try to avoid sleep to use this precious time for other (which has beds not benches!), the brain’s
activities, such as late night parties or burning the electroencephalogram (EEG) passes through several
midnight oil cramming for exams, your body and brain will discrete stages. When awake, our brains show low-amplitude
soon tell you that you shouldn’t. We can stave it off for a electrical activity. As we fall asleep, the EEG becomes flatter
while but never for long. The sleep/wake cycle is one of a at first but then, gradually, it shows increases in amplitude
number of rhythmical activities of the body and brain. Why and decreases in frequency as we move through a series of
do they exist, what parts of the brain are involved and how discrete stages of sleep. These stages are called slow-wave
do they work? sleep (SWS). The reasons for these changes in electrical
activity are still not fully understood. However, it is believed
A rhythm to life that as neurons in the brain become unresponsive to their
normal inputs, they gradually become synchronised with each
The sleep-wake cycle is an endogenous rhythm that other. You lose muscle tone as the neurons controlling skele-
gradually becomes locked to the day-night cycle through the tal muscle movements are actively inhibited but,
first years of life. It is what is called a circadian rhythm - thankfully, the ones controlling respiration and heart rate
so called because ‘circa’ is Latin for around, and ‘dies’ for day. carry on working normally!
It is important throughout life: babies sleep for short periods
during both the day and the night, young children often take Throughout the night, we cycle back and forth between these
a nap after lunch, while adults generally sleep only at night. different stages of sleep. In one of them, the EEG becomes
Sleep is good for you - Winston Churchill, the Prime Minister like the waking state again and our eyes jerk back and forth
during World War II, was said to be partial to short naps of beneath our closed eyelids. This is the so-called rapid eye
five minutes or so - sometimes during cabinet meetings! movement (REM) stage of sleep when we are more likely to
dream. If people are woken during REM sleep, they almost
The normal pattern locking in sleep and wakefulness to the invariably report dreaming - even those who habitually claim
day-night cycle is partly controlled by a small group of cells in that they never dream (try it as an experiment on a member
the hypothalamus just above the optic chiasm called the of your family!). In fact, most of us will have about 4 to 6
suprachiasmatic nucleus. The neurons here, which are short episodes of REM sleep each night. Babies have a bit
unusual in having lots of synapses between their dendrites more REM sleep and even animals show REM sleep.
to synchronise their firing together, are part of the brain’s
biological clock. In humans, it ticks away at a rate just a bit
Awake
slower than a day, but is normally kept in register by inputs
REM
from the eye telling it when it is day-time or night-time. We
Stage 1
know this because people who have participated in sleep
experiments by living in deep caves for long Stage 2

periods of time, away from all clues as to the true time of Stage 3

day, adopt patterns of activity that free-run to a sleep- Stage 4

waking cycle of about 25 hours.
0 1 2 3 4 5 6 7 8
of Sleep
Hours of
Hours Sleep

A normal night’s sleep of 8 hours consists of a pattern of
different sleep stages, with short bursts of REM sleep
(red areas) occurring about 4 times each night


Sleep Deprivation
SCN active in daylight SCN quiescent at night
Some years ago, an American teenager called Randy Gardner
resolved to try and win his place in the Guinness book of
The suprachiasmatic nucleus is the brain’s own Records by going without sleep for the longest period ever
personal clock. recorded. His ambition was to last 264 hours without sleep -
and he did it! It was a carefully controlled experiment




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supervised by doctors in the American Navy - not one we
recommend you repeat! Amazingly, he survived very well.
The main difficulties he had (apart from feeling very sleepy)
were difficulties with speech, an inability to concentrate,
lapses of memory and hallucinatory daydreaming. But his
body remained in excellent physical condition and he never
became psychotic or lost contact with reality. After the
experiment was over, he showed a small rebound, sleeping for
nearly fifteen hours the first night and short extra periods
on succeeding nights. This and many other similar
experiments have convinced sleep researchers that it is
primarily the brain and not the body that really gains from
sleep. Similar conclusions have come from other studies,
including carefully controlled animal experiments.

Why do we sleep?
Many issues in neuroscience remain an enigma and sleep is adenosine, in a kind of molecular chain reaction that takes
one of them. Some people have argued that sleep is just a us through the various sleep stages. Synchronisation
convenient way for animals to be kept immobile and so out of mechanisms enable networks to pass from one sleep state
danger. But there must be more to it than that. The sleep to another.
deprivation experiments lead us to think that REM sleep and
certain phases of SWS enable the brain to recover. We have A big leap forward has come from neurogenetics. Various
this kind of sleep during the first 4 hours of the night. genes have been identified that, like the cog-wheels and
Perhaps it helps to reset things in the brain and that a good escapement of a clock, are the molecular components of
time to do this necessary task is, by analogy with a ship in rhythmical pacemakers. Much of this work has been done in
dry dock, when the brain is not processing sensory Drosophila (fruit flies) where it has been found that two
information, or being vigilant and attentive, or having to genes - per and tim - produce proteins that interact
control our actions. Research also suggests that sleep is together to regulate their own synthesis. mRNA and protein
the time when we consolidate what we have learned the day synthesis begins early in the day, the proteins accumulate,
before - an essential process in memory. link up together and this linkage then stops their own
synthesis. Daylight helps to degrade the proteins whose
How do rhythms work? level eventually drops to a point where the genes that make
PER and TIM protein get going again. This cycle goes round
A great deal has been learned about the neural mechanisms and round, and will even carry on if the neurons are kept alive
of rhythmical activities such as sleep by recording the in a dish. The clock in mammals such as ourselves operates in
activity of neurons in various brain areas during the a remarkably similar way to the one in flies. As circadian
transitions between different sleep stages. These have rhythms are very old in evolutionary terms, it is perhaps no
revealed a brain-stem activating system involving various surprise that the same types of molecules drive the clock in
neuromodulatory transmitters, including one called such different organisms.



Research Frontiers
Light Dark Light Dark Light Dark Light Dark
10

20
Days




30

Normal Mice show "jet-lag"
40 Mutant mice "clock-shift" immediately

Mice who don’t show jet-lag!

To try to understand the molecular mechanisms of circadian rhythms better, neuroscientists have genetically engineered mice
in which genes expressed in the suprachiasmatic nucleus are “knocked out”. These VIPR2 mice live fine and show changes in
activity patterns between night and day just like normal mice. The black dots of the pattern above show when the mice are
active - a daily rhythm with activity at night (grey areas). However, when the time that the lights are turned out is suddenly
shifted forward by 8 hr (around day 25), normal mice show “jet-lag” by taking a few days to shift their activity patterns.
The knock-out mice shift immediately. These kinds of studies should help us learn about the molecular mechanisms by which
light entrains circadian pacemaker genes.
g




Related Internet Sites: http://www.hhmi.org/lectures/2000/
40 http://www.cbt.virginia.edu, http://science.howstuffworks.com/sleep.htm
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Brain Imaging

Phrenologists thought they could understand the brain by How it all works
examining the bumps on the surface of the skull. If this
seems far-fetched now, their ambition to understand the Electrophysiological techniques for monitoring neuronal
brain by looking at it from outside the skull has fascinated activity are based on changes in the membrane potential of
many throughout the ages. Now we really can do this â€" activated neurons. Brain scanning techniques work by
through the advent of modern brain imaging techniques. monitoring changes in energy metabolism required by
Modern scanners use a variety of means to give us activate neurons.
wonderful images of neuronal and fibre pathway structure,
of blood flow and energy metabolism in the brain, and of the The electrochemical gradients that move charged ions in and
changes in neural activity that occur when we do out of neurons (that underlie synaptic and action
different things. potentials) require energy for their operation. The source of
this energy is oxidation of glucose. Glucose and oxygen are
The walkway to modern techniques delivered to the brain by the cerebral circulation. By virtue of
the neurovascular link, there is a local increase in cerebral
In attempts to relate structure to function, a great deal has blood flow in active areas. This occurs very quickly. Modern
been learned by neurologists and neuropsychologists who neuroimaging devices measure these changes in local
correlate any oddities of mind or behaviour with cerebral blood flow and use them as an index of
measurements of brain structure at postmortem. It was in neural activity.
this way that the speech areas of the brain were identified
by Broca. This approach has had many successes, but it also The first functional technique to be developed was called
has limitations. One cannot make the simple assumption Positron Emission Tomography (PET). This procedure
that the loss of a function due to damage to a region of the involves the injection, into the humansubjects, of radioactive
brain represents the normal function of that region. tracers that are attached to compounds of biological
For instance, a deficit might occur because that region is interest (such as drugs that bind to neurotransmitter
cut-off or disconnected from other regions with which it receptors). Rings of detectors around the subject’s head
normally communicates. It is also possible that brain areas record the timing and position of gamma particles emitted
that are undamaged may take over some functions that are by the nuclear isotope as it traverses the brain and decays.
performed by the damaged area under normal PET can be used to produce maps of changes in local cerebral
circumstances; this is known as plasticity. Finally, very few blood flow (CBF). Such measurements have led to the
pathological lesions are confined to a precise functional area. localisation in the human brain of sensory, motor and
And there may be long delay between the study of a patient cognitive brain functions. There are several disadvantages of
when they are alive and the later analysis of their brain. PET, the major one being that it requires the injection of
radioactive tracers. This means that many people cannot
Structural brain imaging techniques began to be developed have a PET scan, such as children and women of child-bearing
about 30 years ago. The recent development of functional age, and the number of measures taken during a scan
imaging methods by medical physicists has attracted are limited.
particular attention. These enable us â€" literally - to see
inside the skull and so peer into the human brain - as it A different technique, called Magnetic Resonance Imaging
thinks, learns or dreams. (MRI), was developed that is non-invasive and does not




Left: The profits made by E.M.I. from the sale of records by ‘The Beatles’ helped to pay for the development of the first brain
scanners. These and later machines have enabled neuroscientists to look into the brain in new ways.
Right: A modern MRI scanner. The subject lies on a table that is moved into the ring of magnets for the scan that may take
anything from 30 min to 1 hour.




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require radioactive substances. This allows people of any age
to be scanned. MRI can be used to provide very fine-grained
images of brain structure, and a recent development called
diffusion tensor imaging (DTI) permits detailed images of
the white matter tracts of fibres that connect brain regions.

One of the most exciting applications of MRI technology
provides images of brain function: this is called functional
Magnetic Resonance Imaging (fMRI). This technique is
based on the difference in magnetic properties of
oxyhaemoglobin and deoxygenated haemoglobin in blood
(hence the signal in fMRI is called the Blood-Oxygenation-
Level-Dependent signal â€" BOLD). As increased neuronal
activity leads to movements of ions that activate
energy-requiring ion pumps, there is an increase in energy
metabolism and oxygen consumption. This leads to an
increase in deoxygenated haemoglobin and a decrease of the
Images of blood vessels in the brain. Changes in blood flow magnetic signal. However increased oxygen consumption is
can be detected and serve as an index of neural activity. followed within seconds by an increase in local cerebral blood
flow. The increase in cerebral blood flow exceeds the increase
in oxygen consumption; there is therefore a relative increase
in oxyhaemoglobin and the size of the signal. The exact
mechanism of the increased cerebral blood flow is still
unclear, but neurotransmitterâ€"related signalling is now
thought to be responsible.

Putting it to use
You’re probably pretty good at subtracting numbers. But
have you ever tried subtracting brains? No wonder the boy
looks confused (cartoon). Subtracting brain images in 2- and
3 - dimensions turns out to be critical for the data analysis.
Most fMRI studies involve measuring the BOLD signal while
people are engaged in carefully controlled tasks. During a
scan, subjects lie within the bore of a magnet, and their
behavioural responses to stimuli are monitored. A wide range
With computer technology, the images obtained by PET and of stimuli can be presented, either visually, projected onto a
MRI scanners show exactly where the changes in blood flow
occur within the brain. screen for the subject to view, or in the auditory domain via
headphones. It is possible to examine covert phenomena




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such as perception, learning, remembering, thinking or
planning. Often two very similar tasks are designed with one
to be done immediately after the other. The idea is that the
first task should involve the brain process an
experimenter is interested in whereas the other should not.
The succession of brain images obtained are then subtracted
from each other to yield a pixellated 2D image of what
changes in activity are specifically associated with
performing the critical brain process. These images are
stacked up by the computer to yield an effective subtraction
of the image in 3 dimensions (see cartoon previous page).
Recent developments mean that even very brief thoughts or
brain events (as little as one or two seconds in duration) can
be measured. This is known as event-related fMRI.
Activation of area V5 reflects the perception of motion.
Sophisticated methods of data analysis are used to test This area’s inputs come from V2 of the cortex and the
whether changes in the signal during performance of a task pulvinar (Pul) that is deeper in the brain. The posterior
are statistically reliable. One widely-used analysis package parietal cortex (PPC) controls the flow of information.
Effective connectivity analyses enable the relative
contributions of these to be worked out.

see the medial temporal lobe lighting up routinely in long term
memory tasks. However, newer testing paradigms â€" some
including virtual reality - are now revealing its activity in
memory processing along with other areas such as the
prefrontal cortex and precuneous. Coupled with new
neuropsycholgical and other imaging findings, this diversity
of brain areas involved has led to a revision of our
understanding of the memory systems of the brain.
New mathematical techniques are also being developed to
look at how the neural activity of different brain regions
interacts and correlates during complex tasks - known as
effective connectivity). This measure allows us to
appreciate how brain areas work as a team and not merely as
isolated functional hot spots. The hope is that these new
techniques, with magnets of high field strength providing
A person in the scanner might be shown a variety of visual
images. All of these would ‘light up’ the primary areas of even more precise images, will tell us about the dynamics of
the visual cortex, V1 and V2. Use of clever subtraction networks of neurons talking to each other in the seamless
techniques has revealed that colour processing (left) is in control of perception, thought and action.
area V4, while motion processing (of random dots moving
about on a screen â€" right) activates V5.


that has standardized the processing of imaging data is Research Frontiers
called statistical parametric mapping (SPM). SPM maps are
often given colours, with a fiery yellow used for the ‘hottest’
areas of activity through to blue and black for ‘cooler’ areas.

Brain imaging scientists speak of areas ‘lighting up’ when
certain functions are carried out. If a person watches a
constantly changing checkerboard pattern, substantial
activation is observed in the primary visual cortex. The use
of moving and coloured colour patterns and other clever
stimuli designed to activate different areas of the visual
system has given us a great deal of new information about
the organisation of the human visual system. Similar Nikos Logothetis is a young researcher making a major
studies have been conducted for other sensory modalities. contribution to understanding the relationship between
the activity of neurons in the brain and the signals seen in
This localisational way of thinking has also helped to identify
brain-imaging experiments.
the brain areas involved in distinct components of reading â€"
such as transforming visual words into a phonological code, Recent experiments in which electrical recording is
the grouping of phonemes into whole words, the process of combined with fMRI have shown a much closer correlation
extracting the meaning of words, and so on. Learning tasks between synaptic activity and the BOLD signal than action
have also been studied, including work dissociating the brain potential discharge. The BOLD signal is therefore a more
areas involved in anticipating and perceiving pain. reliable index of synaptic processing within a brain region
than its action-potential output. This has important
However, as research has proceeded, various surprises have implications for the interpretation of the BOLD signal in
emerged. One early example was the unexpected failure to terms of localisation of function.
g




Related Internet Sites: http://www.dcn.ed.ac.uk/bic/
http://www.fil.ion.ucl.ac.uk/
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Neural Networks &
Artifical Brains

The real brain is squishy stuff. Its neurons, blood vessels Building brain circuits in silicon
and fluid- filled ventricles are made of lipid membranes,
proteins and a great deal of water. You can poke the brain The energy cost of signaling - from one neuron to another -
with your finger, cut it on a microtome, insert electrodes has probably been a major factor in the evolution of brains.
into its neurons and watch the blood pulsing through it. About 50-80% of the total energy consumption of the brain
The study of the brain seems firmly anchored in biology and is consumed in the conduction of action potentials along
medicine. However, there’s another way of thinking about it nerve fibres and in synaptic transmission. The rest is taken in
that has attracted the attention of mathematicians,
physicists, engineers and computer scientists. They think
manufacturing and maintenance. This is as true for the brain
of a bee as it is for ours. However, compared to the speed of
3
about the brain by writing equations, making computer digital computers, the speed of nerve impulses is very
models and even hardware devices that mimic the real slow - only a few metres per second. In a serial processor like
neurons inside our heads. a digital computer, this would make life impossible. Biological 1
brains, however, are constructed as highly parallel networks.
Real brains are highly adaptable. They are able to do things Most neurons connect directly to many thousands of
like read handwriting that we have never seen before and to
understand the speech of complete strangers. And they can
others. To do this, the brain exploits its three-dimensional
volume to pack everything in - bending the sheets of cells 2
tolerate things going wrong. They function reasonably well into folds and weaving the connections closely together into
for a life-time even though cells are dying and, even in old age, bundles. By contrast, making connections between even
brains are still capable of learning new tricks. Todays’ robots modest numbers of silicon neurons is limited by the
are very good at doing the restricted range of tasks for two-dimensional nature of chips and circuit boards. So unlike
which they have been designed, like building a bit of a car, but the brain, direct communication between silicon neurons is
much less tolerant when things go wrong. severely restricted. However, by exploiting the very high
speed of conventional electronics, the impulses from many
All real brains consist of highly interconnected neuronal silicon neurons can be ‘multiplexed’ - a process of carrying
networks. Their neurons need energy and the networks need many different messages along the same wire. In this way,
space. Our brain contains roughly 100 billion nerve cells, 3.2 silicon engineers can begin to emulate the connectivity of
million kilometers of ‘wires’, a million-billion connections, all biological networks.
packed into a volume of 1.5 litres, but weighing only 1.5 kg and
consuming a mere 10 watts. If we tried to build such a brain To reduce power but increase speed, neurally-inspired
using silicon chips, it would consume about 10 megawatts, i.e. engineers have adopted the biological strategy of using
enough electricity to power a town. To make matters worse, analogue rather than digital coding. Carver Mead, one of the
the heat produced by such a silicon brain would cause it to ‘gurus’ of silicon valley in California, coined the description
melt! The challenge is to discover how brains operate so ‘neuromorphic engineering’ to describe the translation of
efficiently and economically, and to use similar principles to neurobiology into technology. Instead of coding digitally in
build brain-like machines. 0’s and 1’s, analogue circuits code in continuous changes in
voltages, as do neurons in their sub-threshold state
(Chapter 3). Calculations can then be done in fewer steps
Your brain is 100,000,000,000 cells and because the basic physics of the silicon devices is exploited.
3,200,000 kilometres of wires, with Analogue computation easily provides the primitives of a cal-
culus: addition, subtraction, exponentials and integration, all
1,000,000,000,000,000 synaptic of which are complicated operations in digital machines.
connections, all packed into 1.5 litres and When neurons - whether biological or silicon - compute and
weighing 1.5 kg. Yet it consumes only make ‘decisions’ they transmit impulses down axons to
about the same amount of electric power communicate the answer to target neurons. Because spike
coding is energetically costly, efficient coding maximizes the
as a night-light!



t
amount of information represented in a pattern of spikes by
reducing what is called redundancy. Energy efficiency is also
increased by using as small a number of active neurons as
possible. This is called sparse coding and it provides another
important design principle for engineers building artificial
neural networks.


offcenter



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A silicon retina Artificial Neural Networks
One simple artificial version of a biological network has been Artificial neural networks (ANNs) are often used to study
built consisting of a silicon retina that captures light and learning and memory. Usually they software on a
adapts its output automatically to changes in conventional digital computer, they consist of a number of
overall lighting conditions. It connects to two silicon neurons simple processing units that are highly interconnected in a
that, like real neurons in the visual cortex, have the job of network. The simplest form of ANN is a feedforward
extracting information about the angles of lines and associator, which has layers of interconnected input and
contrast boundaries in the retinal image. output units. An associative memory is encoded by
modifying the strengths of the connections between the
The neurons in this prototype are called integrate-and-fire layers so that, when an input pattern is presented, the
neurons and neuromorphic engineers use them a lot. stored pattern associated with that pattern is retrieved
They get this name because they ‘add up’ the weighted (See Mathematical Puzzle Box on the next page). A more
inputs, coded as voltages that are arriving at their complex ANN is a recurrent neural net. This consists of a
synapses, and only ‘fire’ an action potential if the voltage single layer where every unit is interconnected and all the
reaches a set threshold. The silicon neurons themselves are units act as input and output. It sounds a bit strange, but
built of transistors, but instead of using the transistors as this design enables the net to store patterns rather than
switches and driving the voltages to saturation as in merely pairs of items. Decoding this kind of autoassociative
conventional digital systems, the transistors are operated network is achieved by a recursive search for a stored
in their subthreshold range. In this range, they act more like pattern. It has been shown that for a network of 1000
the cell membranes of real neurons. Additional transistors units, about 150 patterns can be retrieved before errors in
provide active conductances to emulate the voltage- and the retrieval patterns become too large.
time-dependent current flows of real ion channels. This small
visual system is a prototype for much more elaborate The similarity of ANNs to brains lies in the way they store
artificial visual systems that are under development, but and process information. The ‘knowledge’ that they process
even it illustrates how a very noisy real-world input can be resides in the network itself. They have no separate memory
processed rapidly to produce a simple decision. It can do location like the digital computer, for which the arithmetic
what it is designed to do - tell the orientation of a line in a processor and memory addresses are separate. Instead,
scene - and neuroscientists are already using this simple they have content-addressable storage. In an ANN,
silicon visual system to test equipment and train students. information is stored in the weights of the connections, the
The most important things about artificial networks is that same way that synapses change their strength during
they operate in the real world, in real time and use very learning. Nor are ANNs programmed to perform any given
little power. procedure. Each ‘neuron’ inside is ‘dumb’ and simply responds
according to the sum of its weighted inputs. Still, they can
be trained to clever things. The learning rules that train
networks do so by modifying the strength of the
connections between the neurons, a common one being a rule
that takes the output of the network to a given input
pattern and compares it with the desired pattern. Any ‘error’
in the comparison is then used to adjust the weights of the
connections to achieve a closer output to the desired one.
The network gradually reduces the error signal to a minimum.
This works - but only slowly.


Mistakes turn out to be important - no learning is possible if
the network cannot make mistakes. This is a feature of
learning that can get overlooked. Over-trained networks
that made no errors would end up responding only to one
type of input. Such networks are metaphorically called
grandmothered - a reference to mythical ‘grandmother cells’
in the human brain that might respond only when one’s
grandmother comes into view and must never make a
mistake! This is not very useful in real world applications
because everything we had to learn would require a separate
network. On the contrary, the neat thing about ANNs lies in
their ability to generalize to input patterns they have never
been exposed to in training. They see relationships, capture
associations and discover regularities in patterns. And they
are fault - tolerant just like real brains. They can still retrieve
a stored pattern even when the input pattern is noisy or
incomplete. These are very important properties for biological
brains and ANNs can do these things too.
A camera lens is located in front of the silicon retina.




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The paradox of modern
computing technology
The paradox of present-day ANNs is that they are simulated
mathematically on digital computers. This makes their use in
real - world situations much more limited, because the
k Mathematical Puzzle Box



A Content-Addressable Distributed Memory
simulation takes time and so the ANNs cannot operate in
real time. ANNs might seem well-suited to drive an Imagine a set of wires running horizontally, intersecting
automobile, or fly an aircraft, because they are robust in the with 4 running vertically, with “switches” at their point
face of noise and keep going when some units in the network of intersection (panel A). This matrix is to be a memory.
cease to work. However, the expert systems that are Information is presented to it in the form of binary
generally used in automatic pilots are digital computers numbers, such as 0011 and 1010, and we arrange for the
programmed with conventional deterministic software and, switches to turn on whenever a 1 meets a 1 (B shown in
blue). These store the pairing of these two numbers.
for safety, this always require a backup. If things ever go The matrix can store other numbers on top of the first
badly wrong with the aircraft, such expert systems cannot pair as well, such as 1010 and 0110. The final state of
cope. The human pilot must take over. Present-day training the matrix should have 7 switches on as shown in C. If
algorithms for ANNs are too slow for such emergencies. you now present the first number again - 0011 - to the
If silicon neurons could learn, which so far they can’t, then final state of the matrix and arrange for current to be
many of these problems would fall away. As we learn more induced in the vertical wires wherever a switch is on (D),
about the way in which brains work, we will be able to build you’ll end up with current coming out of the vertical
more sophisticated neural networks that will provide real wires at the bottom proportional to the number 2120.
brain-like performance. This isn’t the number that 0011 was first paired with.
But, if you divide 2120 by the total number of 1s in the
number used as a recall cue (0+0+1+1 which equals 2)
using integer division (the type where you forget about
the remainder), you end up with 1010. So the matrix has
“remembered” that 0011 goes with 1010 even though
another message has been stored on top of the first
one. You can check this works with the second pair of
numbers as well.



1 0 1 0

0
0
1
1


0 1 1 0

1 0
0 0
1 1
0 1

2 2 1 2 0
NOMAD is a fidgety yet thoughtful progenitor of thinking
machines to come. It stands 2-feet tall with a Integer Division by 2 1 0 1 0
cylindrically-shaped torso, it has “eyes”, “ears”, gripper
“arms” and other sensors to help it navigate. What makes
NOMAD different from most robots is that it operates
without coded instructions or rules. Instead, it has a This is the kind of memory we think the brain has.
computer-simulated brain with 10,000 simulated brain It doesn’t store information at specific locations - like in
cells and more than a million connections among them to a PC. Information is distributed across the network,
perceive and react to its environment. It can handle novel stored as changes in synaptic weight, and so can be
situations and learn from its mistakes, as it wanders retrieved with reference to its content. A problem is
around in a pen scattered with small painted cubes. that this kind of memory gets saturated very quickly,
Some of the cubes are striped and electrically conductive, particularly when there are only 4 wires. However, with
making them “tasty”. Other cubes are spotted and don’t 1000 pairs of wires, a matrix could store a lot of
conduct electricity so well, making them less tasty. By
looking for cubes and “tasting” them with the electrical overlapping pairs of messages without too much
sensors on its gripper, NOMAD learns to pass over the interference.
spotted cubes and go for the tasty striped ones.
g




Related Internet Sites: www.artificialbrains.com
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The brain is a delicate organ. Accidents can cause head Neuroscience research has made two major contributions to
injury and the brain can become diseased and stop working improving the lives of people with epilepsy. First, through our
normally. Diseases of the brain can produce an astonishing developing understanding of excitatory transmission, we can
range of symptoms and understanding these can be now design drugs that dampen down abnormal seizure
difficult. The assessment of brain disorders requires the activity without damping down normal brain activity.
clinical skills of the neurologist or psychiatrist at the Older drugs tended to act as generalised sedatives, whereas
bedside as well as sophisticated biomedical assays and modern ones are much more selective. Second, improve-
brain imaging. Research about brain disorders requires an ments in the quality of brain imaging means that for some
even wider range of expertise. Some disorders, such as people with severe disabling seizures, it is possible to localise
epilepsy and depression, are quite common - even in the source of their seizures quite accurately. It is then
children and teenagers. Others are less common, such as sometimes possible for a neurosurgeon to cut out this
Schizophrenia, or only common in old-age, such as diseased brain tissue with a resulting decrease in seizure
Alzheimer’s Disease, but they are no less disabling. frequency and a reduced risk of it spreading to brain tissue
Some have a strong genetic component, raising difficult that is still unaffected. The surgical management of epilepsy
questions about whether each of us would want to know if is sometimes thought to be a bit drastic, but it is remarkable
we had relevant mutations predisposing us to such how often it works.
conditions.
Headache and Migraine
Disorganised signalling â€" Epilepsy
Most people experience headache at some time. Usually this
During a seizure (an epileptic fit), the person loses is caused by muscle tension and is nothing serious to worry
consciousness and may fall to the ground, become stiff and about. Very occasionally - especially if the headache comes
shake. When they come round, they may find that they have on very quickly, or is associated with a skin rash or with
bitten their tongue or wet themselves. They may be vomiting â€" there can be a serious underlying cause. In these
confused or sleepy afterwards. Many children are affected, conditions the pain comes not from the brain itself, but from
but they may go on to have very few attacks later in their irritation or stretching of
life. For some, unfortunately, these can be every week or even the meninges - the lining of
every day. the brain.

So what is going wrong? During seizures, there is an increase A more common cause of
in the firing of action potentials by neurons followed by a headache is migraine. As
period of reduced excitability. This cyclical process is well as a sore head (often
modulated by inhibitory (GABA) and excitatory (glutamate) on one side), people feel
neurotransmitters. When the reduction in excitability is sick, find bright lights or
incomplete, seizures may be triggered by the uncontrolled loud noises discomforting,
recruitment of neighbouring neurons. This recruitment may and experience a
be localised (causing a partial seizure), or may spread to the migrainous aura consisting
entire cortex (a generalized seizure). During a generalised of flashing lights or jagged
seizure, the normal alpha rhythym of the lines. The aura generally
electroencephalogram (EEG) is replaced by large, slow, precedes the headache.
synchronous waves of electrical activity in both
cerebral hemispheres (see backdrop). It now seems likely that
migraine starts in the part
Isolated seizures are fairly common, but recurring seizures â€" of the brain that processes pain sensations coming from
epilepsy - is both less frequent and more troublesome. cerebral blood vessels. Brain imaging reveals increased
Its immediate causes are still unclear. In people with epilepsy, activity in these regions at the start of a migraine. In
attacks may be provoked by tiredness, missed meals, low response, there is a brief increase in local blood supply (which
blood sugar, alcohol, or flickering television screens. brings on symptoms like flashing lights), immediately followed
Those afflicted have to be careful. by reduced blood flow (reflected in temporary weakness).

The last decade has seen a revolution in the treatment of
Backdrop shows the EEG during an epileptic fit migraine attacks following advances in our understanding of




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serotonin (5-HT) receptors. A new class of drugs was In what is called a transient ischaemic attack (TIA), the
discovered which activated a particular subgroup of blood supply to a part of the brain fails and the supply of ATP
serotonin receptors. These drugs â€" triptans - are very is interrupted. Neurons cannot recharge their ionic
effective at stopping a migraine headache in its tracks. gradients and so can no longer conduct action potentials.
This is one of a number of ways in which neuroscience If, for example, the blood supply to the motor cortex of the
research has made a huge contribution to improving the lives left hemisphere were to be cut off, the right arm and leg
of millions of people around the world. would become paralysed. If the obstruction passes quickly,
neurons can again make ATP, recharge their membranes and
Not enough fuel â€" Stroke normal function will resume. Fortunately, no permanent
damage occurs in TIA.
When people suddenly develop a weakness down one side of
the body, this is usually due to a stroke affecting the
opposite side of the brain. Balance, sensation or language A stroke is more serious. If the blood supply is cut off for a
and speech may also be affected. Sometimes these prolonged period, irreversible damage can occur. In the
abnormalities get better with time, even to the point of absence of ATP, cells cannot maintain homeostasis and they
apparent normality, but stroke is still a very common cause may swell up and burst. Neurons may also spontaneously
of death and disability. Strokes come in different shapes depolarise, releasing potentially toxic neurotransmitters
and sizes, and the consequences depend very much on the such as glutamate. And glial cells, that normally mop up
part of the brain that is affected. excess glutamate through an ATP-dependent pump, also
stop working. In the absence of energy, the life of a brain cell
What has gone wrong has to do with interruption of the becomes very precarious.
energy supply that the brain needs to function. Neurons
and glia need fuel to work and to survive. That fuel is Through careful study of what happens during a stroke,
delivered through the four major blood vessels that supply neuroscientists have been able to develop new treatments.
the brain. The most important fuels are oxygen, and Most strokes are caused by blood clots blocking vessels and
carbohydrate in the form of glucose; together these provide treatment with a “clot-busting” drug called tissue
the raw materials to make ATP - the energy currency of cells. plasminogen activator (TPA) can break up the clot and
This energy (see Chapters 2 and 3) is necessary for driving restore blood flow. Given quickly enough, TPA can have a
the flow of charged ions that underlie the electrical activity dramatic effect on the outcome. Unfortunately, getting
of neurons. About two thirds of a neuron’s energy is used to such a drug to a stroke patient quickly isn’t easy as it may
fuel an enzyme called Sodium/ Potassium ATPase which not be obvious to a victim’s family what is happening.
recharges the ionic gradients of sodium and potassium after
an action potential has occurred. Another new treatment is a class of drugs that block
neurotransmitters including glutamate that accumulate to
toxic levels during a stroke. These drugs can either block
glutamate receptors themselves or the intracellular
signalling pathways that are turned on by glutamate.
Many such drugs are in development. Sadly, none has yet
had an impact on stroke.



Genetic Diseases
Doctors have long recognised and diagnosed brain disease
according to the region affected. For many diseases, the
name is a description of what appears to be wrong and the
part of the brain involved, often dressed up in Latin or Greek,
such as “parietal apraxia”. The explosion of genetic
information in the last ten years has changed things
completely. For many inherited diseases, the problem
lies elsewhere.

Some people inherit a problem with the fine control of
movements that makes them increasingly unsteady on their
feet as the years go by. Called spinocerebellar ataxia - a
name that reflects the classical history in the naming of
diseases â€" we now know the precise gene defects that
cause it. Many other conditions can now be classified
according to their cause and diagnostic genetic testing is
now routine for patients suspected of spinocerebellar ataxia
or other genetic conditions. The diagnosis can be made more
quickly and with much greater certainty than before.
Drawing showing brain damage in a stroke and the
penumbral region around that is at risk of damage.




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Learning Disability
Schizophrenia




Inflammation â€" Multiple Sclerosis
Multiple sclerosis is a disease of young adults. It is
characterised by repeated episodes of weakness, numbness,
double vision or poor balance, that last for a few weeks
before recovery - apparently back to normal. The cycle
between periods of illness and remission is a feature of
the disease.

Multiple sclerosis is caused by inflammation in the nervous
system that flares up and then settles down again.
Our immune system is designed to fight infections caused by
bacteria or viruses. Sometimes it gets confused and starts
attacking parts of us instead. We call such conditions
autoimmune diseases and they can affect almost any
tissue. If the immune system attacks the myelin that wraps
around neurons, there will be a local area of inflammation
A family tree showing the generations of a family prone to that causes demyelination. In time, the inflammation usually
learning disability and schizophrenia. Notice how these settles down, the myelin is repaired, and things return to
afflictions can sometimes skip a generation. normal. Quite what sparks off the inflammation in the first
place is not clear, and many people with demyelination only
Huntington’s disease is a neurodegenerative disease ever have one brief episode. However, some people seem to
associated with abnormal involuntary movements of the have a tendency to have recurrent bouts affecting different
body - in this case named after the doctor who first parts of the brain.
described the condition. It is entirely due to a repeat
mutation in one of the largest genes in the human genome Because we do not yet know what triggers inflammation in
called huntingtin. Some early onset forms of Parkinson’s multiple sclerosis, we cannot completely stop it. However, we
disease (a disease causing slowness, stiffness, tremor and now do know that the attacks can be made shorter using
unsteadiness) are due to problems in genes coding for Parkin. drugs such as steroids that dampen down the immune
As well as helping with diagnosis, genetic testing can be used system. For patients with severe MS, some doctors believe
to advise other family members about their risks of develop- that permanently dampening down certain parts of the
ing diseases, or passing it on to their children. immune system with drugs like azathioprine or ß-interferon
can be beneficial. There is still considerable uncertainty
However, much as the genetics revolution has changed the about their use.
way that doctors deal with diseases of the nervous system,
it is only the start of a long voyage of discovery. The same The immune system can also attack the junctions where
gene defect can cause different diseases in different people, nerves connect with muscles, causing a disease called
and different gene defects can cause very similar diseases. myasthenia gravis, or the nerves as they emerge from the
Understanding what it is that defines these differences, and spinal cord, resulting in a condition called Guillain
how your genetic makeup interacts with the world in which Barré syndrome.
you live and which you build around you, is one of the next
great challenges for the genomic era in which we live. Jacqueline du Pré â€" a well
known musician who
suffered from multiple
Discussion Point sclerosis
If you discovered you were at risk for developing a
genetic disease, would you want to know for sure?
Would it be right to identify the gene prior to birth
and abort those who would develop the disease?
What about all the useful and productive years lived
by sufferers before the disease develops?




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Neurodegeneration â€" genetically altered laboratory animals have been bred that
show features of the disease. Research on these has to be
Alzheimer’s disease interpreted very carefully, and not over-interpreted, but they
can help us get a grasp on the biology of the
It is our brains that make us who we are: how we react in disease process.
different situations, with whom we fall in love, what we fear,
what we remember. This fundamental aspect of human Treatments that stem the progression of Alzheimer’s
nature is laid bare when our brains fail in the progressive Disease still do not exist, although they are eagerly sought -
disorder known as Alzheimer’s Disease. Alzheimer’s disease and this is where the animal research is so valuable. It is
is a form of dementia â€" a global loss of faculties that known that nerves cells utilising the chemical transmitter
affects approximately 5% of 65 years olds and 25% of those acetylcholine are particularly vulnerable to attack in the
aged 85 or older. This is a heartbreaking illness: the condition. Drugs that boost the action of the remaining
condition usually starts with memory failure, and progresses acetylcholine by blocking the effect of enzymes that normally
to a loss of normal personhood and ultimately death. destroy this neurotransmitter have a modest treatment
To watch loved ones lose themselves in this fashion is an effect in both animal models and some clinical cases.
exceptionally difficult experience for relatives. Ultimately, However, these drugs do nothing to slow the progression of
sufferers may be unable to recognise those closest to them this still incurable disease. Drawing together genetic clues,
and will require help with everyday activities such as understanding relationships between brain chemistry and
dressing, eating, bathing and toileting. Consequently, their psychological function, and learning more about the
carer’s life is changed dramatically also. mechanisms by which cells are damaged seems to be the way
forward in ultimately defeating the disorder.
“ Dad doesn’t know who I am these days. He just
doesn’t seem to recognise me any more. He gets Depressive Disorder
angry and frightened at the least thing - I don’t think
he understands what is going on around him. At first, It may come as a surprise to learn that depression and
he just seemed to be forgetful, always losing things. neurodegeneration can be bedfellows â€" but we now know that
Then it got worse. He wouldn’t go to bed, didn’t seem severely depressed patients can lose brain cells.
to know what time it was or even where he was.
Now he’s lost control of his bowels and needs help to A depressive illness is very
eat and dress. I can’t cope.” different from the low
feelings we all experience
from time to time. We are
What is going wrong? As Alzheimer’s disease develops, brain dealing with a truly serious
cells die: the cortex thins and the ventricles (the fluid filled medical condition when low
spaces in the brain) enlarge. The diagnosis is usually made in mood becomes prolonged
life on the basis of the characteristic clinical features, but for weeks and months. It
can only be confirmed definitively at a post-mortem when then begins to take over
microscopic examination of the brain reveals the cell loss, everything â€" to the extent
and the widespread abnormal deposition of an amyloid that sufferers want to die
protein in scattered small degenerating amyloid plaques and and may try to kill themselves. Sufferers display other
a tangled mess of rod-like proteins that are normal characteristic symptoms: disturbed sleep, lowered appetite,
constituents of brain cells - fibrillary tangles. Current failing concentration and memory, and a loss of interest in
research projects are trying to improve diagnosis in life with life. Fortunately, it is eminently treatable. Antidepressant
new neuropsychological testing procedures focused on drugs, which enhance the effects of neuromodulatory
distinguishing the mental changes in the earliest stages of transmitters such as serotonin and noradrenaline can
Alzheimer’s from those in, for example, depression. rapidly (within weeks) treat
the illness. Specialised
Staining of the brain shows talking treatments are also
amyloid plaques (e.g. in the effective, and a
rectangle) and the darkly combination of chemical
stained tangles (arrow). and psychological
treatments can be
especially helpful.
Again, genetics has provided a handle to get us started in The condition is surprisingly
understanding the disease â€" pointing to mutations in genes common â€" 1 in 5 may suffer
that encode amyloid precursor protein (from which amyloid at some time in their lives
is made) and the presenilins (which encode enzymes that from some degree of
break the precursor protein down). Inheritance of a depressive
particular variation of the apolipoprotein E (apoE) gene disorder.
designated apoE-4 is also a major risk factor in the disease.
However, genetic factors do not tell the whole story: Being severely and
environmental factors, such as toxins and other insults such
Vincent Van Gogh â€" chronically depressed has
the impressionist painter â€" an unbalancing effect on
as traumatic brain injury, may also play an important role. suffered from severe
But genetic factors are sufficiently important that depression
the control of stress




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hormones, such as cortisol, that are beneficially released Drugs that block dopamine receptors are helpful in reducing
acutely during stressful situations (Chapter 12). However, the frequency and impact of symptoms, but they do not
when chronically activated, stress hormones may actually cure the condition. The latest research suggests that, when
damage brain cells, particularly in the frontal and temporal activated experimentally using drugs such as amphetamine,
lobes of the brain. It has recently been found that it is possible to detect abnormalities in the release of
antidepressant drugs promote the integrity of brain cells dopamine in people with schizophrenia. There is much more
and increase the rate at which new neurons are produced in to be discovered about the disorder: post-mortem studies
the hippocampus. In this way, they may go some way to suggest that the way that neurons have connected up
protect against and even reverse the toxic effects of stress during development may be abnormal, and that other
on the brain. neurotransmitter systems, such as glutamate, may be
malfunctioning.
Schizophrenia
Our efforts to understand the nature of mental disorders
Another psychiatric disorder that draws together represents the last great frontier for medical neuroscience.
abnormalities of brain chemistry and brain structure is Organisations such as the Medical Research Council and the
schizophrenia. This is a progressive and potentially very Wellcome Trust have put mental health high on their agenda
disabling condition that affects 1 in 100. The condition often for research over the next decade. One important current
starts in early adulthood and is said to blight more lives project is capitalising on both genetic knowledge and brain
than cancer. scanning equipment to study the disease prospectively - in
families at risk (see Box). Bridging the gaps from “molecules
The core symptoms of schizophrenia are delusions to bedside” remains one of the most challenging research
(abnormal beliefs â€" commonly bizarre ideas which are often endeavours.
persecutory in nature) and hallucinations (disorders of
perception where sufferers experience abnormal sensory
impressions, such as hearing voices when there is no one Research Frontiers
there). There is often a progressive decline in cognitive
ability, social interaction and ability to work.
Result
The condition is much misunderstood: it has nothing to do
with “split personality” with which it is often confused, nor as
a rule are sufferers in any way violent. Indeed, most people
with schizophrenia are fearful rather than dangerous. There
are clearly genetic factors at work in the genesis of the Investigators
illness, but as with other conditions, environment and stress
are also important. Nonetheless, for all the obvious
psychological changes, the condition is primarily a brain
disease. It has long been known that the ventricles of the
brain enlarge in the condition, and that the activity of the Psychiatrists
frontal lobes becomes impaired.

GP’s
“At first, we didn’t know what was happening to our
daughter, Sue. She had started well at University and
coped easily with the exams in her first year. Then she
began to change - she became quiet and withdrawn Subjects
when she was at home, quite unlike her former
outgoing self. She stopped seeing friends - later we
found she hadn’t been going to classes either and was High Risk
staying in bed all day. Then one day she told us she had Families
received a special message from the television set
saying that she had special powers, and that
satellites were controlling her thoughts by telepathy.
She laughed for no reason, and then she would cry. A prospective study of Schizophrenia
Obviously something was very wrong. She said that
she could hear voices all around her who spoke about Most studies of neurological and psychiatric disease
everything she did. It turned out that she was are on people who already have the condition.
suffering from schizophrenia. Researchers in Scotland are using genetic information
She was in hospital the first time for about two to study members of families that are at risk of
months. Now she takes regular medication. Although developing the condition. Brain scanning and careful
she has been much better recently - she doesn’t have tests of mental function and physical features are being
strange ideas about satellites any more - she still done at regular intervals to see if markers of the
doesn’t take much interest in things. She had to stop incipient development of the disease can be identified.
her studies at University and though she worked for a This information could prove very useful in developing
while in a local shop, she had to go into hospital again new treatments.
for a couple of weeks and lost her job. She just isn’t
the same person. “
g




Related Internet Sites: Brain and spine foundation: http://www.bbsf.org.uk
British epilepsy association: http://www.epilepsy.org.uk Stroke: http://www.strokecenter.org
National Institute of Neurological disorders and stroke: http://www.ninds.nih.gov 51
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Neuroethics


Once upon a time, a very long time ago (as the fairy-tale so The social context
often begins), there was a clear distinction between
science and technology. Scientists pursued an unbridled While some neuroscientists believe that their concepts are
path in search of truth, wherever that might lead, for no divorced from social reality, this is rarely so. In the 17th C,
more reward than the “the pleasure of finding out”. Descartes used a hydraulic metaphor to explain how the
Engineers and technologists applied the fruits of scientific “humours” of the brain moved the muscles - a metaphor
endeavour to change the world in which we live. However borrowed from the water engineering he saw in the gardens
beguiling this sharp distinction may seem, it is and always of French chateaux. At the turn of the 20th C, reflecting
has been a fairy-tale. Nowadays, scientists are ever more the industrial age, neurophysiologists described the
aware of the social context in which they work, and how intricate wiring of the brain as “an enchanted loom” or later
that context can affect what they study. as a giant “telephone exchange”. Now, at the start of the
21st C, computational metaphors abound, such as the
Questions relating to the impact of neuroscience on society fanciful speculation that “the cerebral cortex operates not
are collected under the general heading of neuroethics - the unlike a private world wide web”. These are partly shorthand
intersection of neuroscience, philosophy and ethics. to help convey complex ideas, but also concepts that are
This includes how discoveries about the brain affect our actually built into sophisticated brain theories.
sense of ourselves as human beings (such as the neural basis
of morality). It is about the implications for social policy Neuroscientists can and do engage in thinking about
(such as a child’s educational potential) and how research is scientific problems divorced from the everyday world.
itself conducted (such as the ethics of animal Often this escape is into an abstract, jargon-filled world in
experimentation or the use of deception with human which something quite close to a monastic search for truth
subjects). And it is about how neuroscientists should best really is underway. Whether it is working out the ionic
engage with the public in communicating what they do and currents that underlie the propagation of the action-
sharing idea about what they should be doing. potential, how chemical messengers are released and act, or
how cell-firing in the visual cortex represents aspects of the
visual world - many problems in neuroscience can be cast in
an isolated but tractable manner.

But the real world is never far away. Once we know how
chemical transmitters work, it is natural to think about
smart drugs that may help us remember better. Some
might think about designing neurotoxins (nerve agents) that
disrupt this critical process, such as enzyme inhibitors that
are but a step from the agents of biological warfare.




If a drug were available that could help you pass
examinations, would you take it? Is there any difference
between this and an athlete using steroids to improve their
performance or a person taking an anti-depressant?

“THINKING ABOUT THE BRAIN TOUCHES US ALL, Less fanciful ethical dilemmas surround the future of
IT IS LITERALLY HEADY STUFF” brain-imaging. For example, brain-imaging techniques may
soon make it feasible, with appropriate testing procedures,
Zach Hall, University of California to distinguish a person’s real memories from their false ones.




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The variability in response is too big just now, but courts may in such a research project, it would be to their long-term
one day have brain-scanning technology at their disposal - a detriment and that of later patients. Relatives also may not
kind of “cerebral fingerprinting” that could help establish the be in a state of mind where it is easy for them to make a
veracity of witnesses. This raises interesting issues about judgement of consent in the time available. Dare we abandon
what one might call cognitive privacy. informed consent and introduce waivers, for the greater
good? Or is that a slippery slope?
New findings about the brain are all the time revising our
sense of ourselves. Influential ideas about the evolution of Another important aspect of neuroethics relates to animal
the brain include many related to social cognition. There is experiments. Animals are not in a position to offer consent
an emerging awareness that morality and conscience are for invasive experiments to be conducted on their brains.
closely coupled to the emotional brain that processes sig- To some people, the prospect of such work is disturbing.
nals of reward and punishment â€" a possibility that some have To others, the opportunity it offers for advancing our
argued under the rubric of evolutionary ethics. Learning understanding of the nervous system in health and disease
more about these could be an immense force for good, helping is such that not to pursue it is irrational. These are not easy
us to be more aware of each other’s feelings. Building these issues to debate dispassionately, but it is important that
ideas into our presently primitive concepts of neuronal plas- we do - and that we do so respectfully.
ticity could yet have an impact on education beyond the
immediate academic goals that are so often the only focus In most European countries, animal experiments are
of discussion. regulated in an extremely strict manner. Researchers must
attend courses and pass examinations that test their
It is also important to appreciate that neuroscientists do knowledge of the law and their competence in ensuring that
not agree about the future directions of their subject. unnecessary animal suffering does not occur. There is a
For some molecular neurobiologists, ultimate truth lies widespread acceptance that three Rs - reduction,
embedded in the molecular constituents of the nervous refinement and replacement - are good principles for
system - with new DNA and proteomic technologies biomedical scientists to comply with. They do so willingly,
promising fuller explanations of the brain that will finesse the within a framework of law, and so command widespread if
problems faced by other neuroscientists. This is the reduc- not unanimous public acceptance. Many new findings in
tionist agenda, whose full philosophical and neuroscience are emerging from replacement techniques,
technological flowering is so often celebrated in media such as tissue culture and computational modelling.
accounts. But is such a reductionist confidence justified? But these cannot replace all studies of the living brain from
Or are there higher-level explanations of brain and mind that which many new findings and treatments for neurological and
are not reducible in this way? Are there emergent psychiatric diseases are coming. For instance, the use of
properties arising from the brain’s organization? L-DOPA to treat Parkinson’s disease emerged from Nobel
Interactionist neuroscientists firmly believe in a different Prize winning work on the rat brain. And new techniques offer
agenda. They argue for a more eclectic approach to modern new opportunities to help sick people and sick animals.
neuroscience, an approach that explores its interaction with
the social sciences as well. These are not issues easily Only communicate…
discussed in a public forum, but questions about what sorts
of research should be undertaken are matters about which It is a puzzling truth that countries in which scientists do
society should be consulted. After all, people’s taxes help most to communicate to the general public tend to be those
to pay for it. in which there are lower levels of trust in scientists. But cor-
relation is not the same as cause, and it is unlikely that this
Neuroethics - some concrete examples responsible effort to engage the public in discussing the
impact of science on society - and the growing sense of duty
Certain issues in neuroethics yield to little more than to do so - is the cause of this growing distrust. Rather it is
common-sense. Suppose a brain scan of a volunteer subject that the interested public is getting more sophisticated,
in an experiment was unexpectedly to reveal a cerebral properly more sceptical of new “miracle drugs”, and more
abnormality - such as brain tumour. Or imagine that a aware of the slow and sometimes uncertain progress of
subject in a human neurogenetics screen was found to have a science. Reducing distrust is no reason to favour a return to
mutation that rendered them susceptible to a blind ignorance.
neurodegenerative disease. In each of these cases - should
the subject be told? Common sense suggests that One reason to engage with young people and the interested
responsibility should be passed to the volunteer who, in public about neuroscience is that neuroscientists still
advance, would be asked to offer or decline their consent disagree about many of the central tenets of their field.
that any relevant medical information discovered in the Instead of focusing on isolated discoveries, the media would
course of the scan be passed on. do well to think more about science as a process. A process
riddled with uncertainty and debate.
However, informed consent is a funny business. Suppose a
brain researcher was conducting a trial of a new treatment Neuroethics is a new field. There is curious irony that it was
for stroke in which either the drug or a placebo had, in a blind Richard Feynman, a theoretical physicist, who described his
fashion, to be given within a few hours of the stroke. reason for doing science as being for “the pleasure of finding
There are sound scientific reasons for such a randomised out”. Ironic - because it was Feynman who threw himself
protocol. But we cannot anticipate who will suffer a stroke headlong into working out why one of the American Space
and it may be impossible for the person affected to give Shuttles, Challenger, exploded soon after take-off.
informed consent. If this prevents the patient participating The impact of science on society creeps up on us all.
g




Related Internet Sites: http://www.stanford.edu/dept/news/report/news/may22/neuroethics.html
http://www.dana.org/books/press/neuroethics/
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Training & Careers


When many young students think of a career in science, it
can conjure up images of white coats and laboratories.
Hopefully, this booklet will have gone some way to showing Rosamund Langston,
that there are many different aspects to neuroscience Neuroscience PhD
and that research on the brain will touch peoples’ lives in student at Edinburgh University
many ways. From the laboratory to the hospital to many
other walks of life, there is a diverse range of exciting “I studie d scie nces and English at
A-level and the n we nt on to study
opportunities within the field.

University Neuroscience Courses biological scie nces in Edinburgh.
I spe cialise d in Ne uroscie nce in my
Many universities now offer undergraduate degrees in final ye ar and re ally found my niche.
I was luck y e nough to be offe re d
neuroscience. Often the subject is taken as a specialisation
after earlier years training in such subjects as biology,
physiology, pharmacology and psychology. A knowledge of a position as a rese arch assistant in
genetics and molecular biology can also be valuable. the Cognitive Ne uroscie nce depart-
me nt of Edinburgh Unive rsity and this
However, you do not necessarily have to be doing only
science subjects in the sixth form to get into some of eve ntually le ad to a PhD.
these courses. Find out about neuroscience courses and
their entry requirements by looking at the UCAS pages on
the internet. You can look through these by subject or in
relation to the universities to which you may be interested
in applying.
Thomas Petty,
Medicine Medical student
at Edinburgh University
Medicine in Britain is an undergraduate degree. Many
universities have Medical Schools and there has recently
been an expansion in the number of students being trained “I have be e n set on me dicine as a
through the creation of several new Medical Schools. care e r eve r since school and I
Specialization in subject areas such as neurology,
neurosurgery, psychiatry and radiology comes in the later applie d to Edinburgh be cause of its
years of training, but there are often opportunities to work good reputation. In third ye ar I
in neuroscience research laboratories during summer was give n the opportunity to do an
vacations and intercalating years. The competition to get
into medical courses is considerable, but so are the rewards
inte rcalate d Bsc course and I chose
of a career in medicine. to study Ne uroscie nce. T he ye ar
gave me an opportunity to study the
“The privilege of a job in a University is the intellectual core rese arch be hind the me dicine and
freedom. No day is the same. Every day you learn
something new, every day you are stretched and I took a gre at de al from it and
challenged” re ally e njoye d it.”
Maria Fitzgerald, Professor in London University.

“The appeal was, and still is, the prospect of finding
out, being pleasantly surprised by discoveries, and the
small leaps of insight that result”

Richard Ribchester, Neurophysiologist in the
University of Edinburgh




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Industry (Pharmaceutical Industry)
New medicines are constantly being discovered and
developed and the brain is a critical target for drug
treatment. Pharmaceutical companies, as well as financially
supporting academic institutions, conduct their own
research. Many co-operate with universities to offer years in
industry to help develop laboratory skills and experience.
Graduates from a variety of biomedical science courses
including neuroscience make desirable employees, particularly
when they have had associated laboratory experience.

Neuroscience Research
There are a huge variety of opportunities in research. The field
has many elements ranging from brain-imaging and behaviour-
al studies through to neurophysiology and molecular-genetic
research. Researchers within universities are always happy
to encourage keen students to find a path of academic study
that suits them.

Computing Industry
Neuroscience may not spring to mind as a subject to do at
university if you are interested in a career in computing or
information technology. Still, as we have seen in the booklet,
there is growing interest in ‘brain-style’ computing and this is
set to grow with the development of the world-wide web.
There is increasing interest in non-medical applications of
brain science.

School Teaching
Neuroscience is not taught as a subject in schools. However,
graduates with a degree in neuroscience will be well placed to
teach biology and will have many other skills, including
numerical skills, that would be invaluable in a teaching career.

Science and the Media
From journalism to radio and television, a career in the media
is competitive and demanding. However, many opportunities
to enter the field of science communication are available.
Science is continually advancing and new findings need to be
reported for the purposes of both education and public
interest. Work on brain research is no exception. There is
huge social interest, well recognised by the media, and the
latest findings have the potential to have considerable social
impact. With a good scientific background and understanding
of research, obtained while doing a university degree, it would
be much easier to communicate complex findings accurately
and effectively both with other scientists and the public.

Science and art
Science and art are not mutually exclusive. Design which
captures the imagination is crucial in the presentation of
science to a wider audience. Museums, galleries and the
media, and other organisations encourage and fund creative,
experimental collaborations between scientists and artists.
g




Related Internet Sites: http://www.abpi-careers.org.uk/
www.gsk.com www.sciart.org
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Acknowledgements
We are indebted to many people who kindly contributed text and diagrams that are included in this booklet. We hope the list
below is inclusive and apologise to anyone who has helped us but whose contribution has slipped through the net.
Cartoons throughout the booklet: Maddelena Miele and Robert Filipkowski. Front cover illustrations: Peter Brophy, Beverley
Clark, Michael Hausser, David Linden, Richard Ribchester. Inside front cover: Peter Somogyi, Elaine Snell, Lisa Cokayne-Naylor.
Ch 1 (The nervous system): Marina Bentivoglio, Nobel Forum. Ch 2 (The action potential): Tobias Bonhoeffer, Peter Brophy,
Eric Kandel, Nobel Forum. Ch 3 (Chemical messengers): Marianne Fillenz, Ch 4 (Drugs and the brain): Leslie Iversen. Ch 5 (Touch
and pain): Susan Fleetwood-Walker, Han Jiesheng, Donald Price. Ch 6 (Vision): Colin Blakemore, Andy Doherty, Bill Newsome,
Andrew Parker. Ch 7 (Movement): Beverley Clark, Tom Gillingwater, Michael Hausser, Chris Miall, Richard Ribchester, Wolfram
Schultz. Ch 8 (The developing nervous system): Andrew Lumsden. Ch 9 (Dyslexia): John Stein. Ch 10 (Neuronal plasticity):
Graham Collingridge, Andrew Doherty; Kathy Sykes. Ch 11 (Learning and Memory): Ted Berger, Livia de Hoz, Graham Hitch, Eleanor
Maguire, Andrew Doherty, Leslie Ungerleider, Fareneh Vargha-Khadem. Ch 12 (Stress): Jonathan Seckl. Ch 13: (Brain and Immune
System): Nancy Rothwell. Ch 14 (Sleep and Rhythms): Anthony Harmar. Ch 15 (Brain Imaging): Mark Bastin, Richard Frackowiak,
Nikos Logothetis, Eleanor Maguire, Lindsay Murray, Elisabeth Rounis, Semir Zeki. Ch 16 (Neural Networks and Artificial Brains):
Rodney Douglas, Gerry Edelman, Jeff Krichmar, Kevan Martin. Ch 17 (When things go wrong): Malcolm Macleod, Eve Johnstone,
Walter Muir, David Porteous, Ian Reid. Ch 18 (Neuroethics): Colin Blakemore, Kenneth Boyd, Stephen Rose, William Saffire. Ch 19
(Careers) Yvonne Allen (BNA), Victoria Gill. Inside back cover illustration: Eric Kandel (for Hippocrates Quotation), Richard Morris.


Back cover illustration and words: Jennifer Altman, David Concar; Spike Gerrell.


The British Neuroscience Association is a non-profit making body and is registered as a charity No. 264450.



Further Reading
There are many fascinating books available for continued reading about science and neuroscience. Here is a list of a few of them:

V.S. Ramachandran, (Sandra Blakeslee) Phantoms in the Brain: Human Nature and the Architecture of the Mind
Fourth Dimension Publications
(Paperback - 6 May, 1999) ISBN: 1857028953
A fascinating account of phantom-limb pain and related disorders of the nervous system.

Oliver Sacks, The Man Who Mistook His Wife for a Hat (Picador)
Picador
(Paperback - 7 November, 1986) ISBN: 0330294911
An amusing and well-written account of the effects of brain damage on the mind.

Jean-Dominique Bauby, The Diving-bell and the Butterfly
Fourth Estate
(Paperback - 7 May, 2002) ISBN: 0007139845
A very personal and moving account of the consequences of a stroke.

Richard P. Feynman, Surely You’re Joking, Mr Feynman: Adventures of a Curious Character
Paperback
19 November, 1992 ISBN: 009917331X
Physicist, bongo-drum man, and all round polymath. A hero for all young scientists.

Nancy Rothwell, Who Wants to Be a Scientist?: Choosing Science as a Career
Smudge (Illustrator) Cambridge University Press
(Paperback - 19 September, 2002) ISBN: 0521520924
Sound practical advice on choosing science as a career.




To order additional copies: Online ordering: www.bna.org.uk/publications

56 Postal: The British Neuroscience Association, c/o: The Sherrington Buildings, Ashton Street, Liverpool L68 3GE
Telephone: 44 (0) 151 794 4943/5449 Fax: 44 (0) 794 5516/5517
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“Men ought to know that from the brain, and from the brain only,
arise our pleasures, joys, laughters and jests,
as well as our sorrows, pains, griefs and fears.
Through it, in particular, we think, see,
hear and distinguish the ugly from the beautiful,
the bad from the good,
the pleasant from the unpleasant”

Hippocrates- 5th Century B.C.




Financial Support
This project was supported by the British Neuroscience Association, Neurology & GI Centre of Excellence for
Drug Discovery, GlaxoSmithKline and the Centre for Neuroscience of the University of Edinburgh. The
authors are grateful for their generous support.
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Cartoon by Spike Gerrell; words by Jennifer Altman and David Concar


De: Zicutake USA
Enviada em: ‎1/‎28/‎2017 1:02 PM
Para: operation.monte.carlo@gmail.com
Assunto: [Book] Neuroscience: Science of the Brain


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