ÐÓ°ÉÔ­´´

PARKINSON’S and Huntington’s diseases are crippling disorders in which
the smooth coordination of movements is lost. In both of them, something
goes wrong in the basal ganglia, a group of nerve centres buried deep in
the forebrain that is crucial for regulating movements . Last November,
neuroscientists at the annual meeting of the Society of Neurosciences in
Phoenix pinpointed an almond-sized group of nerve cells, known as the subthalamic
nucleus, as a key to understanding how the basal ganglia work.

The symptoms of Parkinson’s and Huntington’s differ in many ways, but
both diseases involve disturbances of the ‘motor drive’ – the nerve circuits
that are responsible for the smooth initiation and execution of movement.
The painfully slow, often seemingly ‘frozen’ movements of people with Parkinson’s
represent too little drive (hypokinetic), whereas the jerky, uncontrolled,
‘flapping’ movements, that characterise the chorea of Huntington’s disease,
come from too much drive (hyperkinetic). In each disease, the problem is
caused by the death of nerve cells in the basal ganglia, with the result
that the instructions reaching the subthalamic nucleus are altered. The
result is that the signals from this nucleus to the rest of the system become
either too strong or too weak.

Complex movements are planned and generated by the motor areas of the
cerebral cortex, in response to information from the environment and from
the whole body. The cortex sends instructions to the spinal cord, which
contains the neural machinery for controlling movements. But information
passing through another circuit regulates these signals, in a way that is
still not well understood: this circuit runs from the cortex to the basal
ganglia and back to the cortex. This loop seems to provide the volume control
or fine tuning for the signals going from the cortex to the spinal cord
and to ensure that movements are performed smoothly and coherently.

How does the basal ganglia accomplish these feats? The wiring that connects
the various parts of the basal ganglia and links them to the cortex is so
complicated that electronic circuit designers would throw up their hands
in horror. There is not just one loop involving the cortex and the basal
ganglia but several loops in parallel, all with the same basic organisation
(see Boxes 2 and 3). Each is made up of a series of centres with connections
between them. Some connections are excitatory – that is, the signals they
send turn on activity in the receiving centre – while others are inhibitory,
slowing down or stopping activity. To make matters more difficult, different
groups of nerve cells use different chemicals to transmit their messages,
for reasons that are not yet clear.

At least five parallel circuits have been found so far. They are physically
separated, each starting with inputs from particular parts of the cortex
to specific parts of the striatum, the first of the centres in the basal
ganglia. From here, the pathways run through the globus pallidus and substantia
nigra. (Early anatomists named many structures in the brain according to
how they look to the naked eye – here, literally, the ‘pale globe’ and the
‘black substance’.)

The pathways proceed to a part of the brain called the thalamus, which
is the main receiving station for inputs to the cortex. From the thalamus,
connections run back to at least one of the centres of the cortex from which
the loop started. A pathway from the cortex then carries the final instructions
to the neural machinery in the spinal cord that controls the details of
movements.

Each loop has a different function: the two best-known ones control
movements of the body (motor loop) and of the eyes; the others are involved
in cognitive processes, such as spatial perception, learning and memory,
and in integrating emotional states such as hunger, fear or sex with the
experience of the outside world. Quite how all the checks and balances in
the circuits of the basal ganglia operate to modulate cortical operations
is only now beginning to be sorted out.

In the motor loop, the subthalamic nucleus forms part of a special sub-loop
linking two parts of the globus pallidus. The nerve cells in the subthalamic
nucleus are very active, firing up to 500 times per second. Their activity
is regulated by a balance between two inputs, direct excitation from part
of the motor cortex and an inhibitory input from the external part of the
globus pallidus that comes indirectly from the cortex through the striatum.
The nerve cells of the subthalamic nuclei in their turn excite the cells
in the internal part of the globus pallidus and part of the substantia nigra.
These centres reduce the activity in the return pathway from the thalamus
to the cortex, so the more activity there is in the subthalamic nucleus,
the less the flow back to the cortex.

This part of the circuit, according to Mahlon DeLong and Garret Alexander
of Johns Hopkins University Medical School in Baltimore, is the key to the
problems of ‘too little’ in Parkinson’s and ‘too much’ in Huntington’s.
One clue comes from a rare condition called ballism, marked by flailing
limbs, rather like the chorea in Huntington’s. This is the result of strokes
that destroy the subthalamic nucleus. A further clue comes from brain imaging
studies, which show increased activity in the subthalamic nucleus in people
with Parkinson’s disease. Perhaps the control of the nerve cells in the
subthalamic nucleus is altered in Parkinson’s and Huntington’s. To test
this idea, DeLong and his colleague William Miller have examined monkeys
in which a parkinsonian-like disease has been induced by the chemical MPTP.
This drug is a contaminant of some types of designer heroin and causes acute
parkinsonian symptoms in humans unlucky enough to consume it. In these parkinsonian
monkeys, the external division of the globus pallidus is much more inhibited
than normal, so the output from the subthalamic nucleus is stronger. The
result is a strong inhibition of the pathway from thalamus to cortex, which
reduces the drive in the whole motor loop as well as in the instructions
to the spinal cord. It may help to explain why parkinsonian patients find
it difficult to start moving and why their movements are so slow.

Why should the globus pallidus be more inhibited in Parkinson’s disease?
Nerve cells in the substantia nigra release the chemical dopamine in the
striatum, the centre that produces the inhibition of the globus pallidus.
It is well known that the primary problem in Parkinson’s disease is the
death of precisely these cells, and the drug L-DOPA, a standard treatment
for Parkinson’s disease, encourages the cells that remain to produce more
dopamine. But there is still debate about the action of dopamine in the
striatum; most probably it increases the activity of the nerve cells that
inhibit the globus pallidus.

Loss of fine control

There is yet another twist to this complex story: at the meeting in
Phoenix, Steven Kitai of the University of Tennesee at Memphis reported
that subthalamic nerve cells also regulate the activity of the dopamine-containing
cells. In a quiet animal, the dopamine cells fire steadily, continually
releasing dopamine into the striatum, but their responses can change when
the activity of the subthalamic cells is varied experimentally. So the subthalamic
nucleus does not just drive the system but also regulates how it responds.
Because the dopamine cells disappear in Parkinson’s disease, this fine control
is lost. No one knows, however, just what role the dopamine cells play in
controlling behaviour. Their activity varies very little as animals go about
their normal business; the only marked changes seem to be when an animal
is engaging in a complex task that involves investigation and learning.

The evidence for Huntington’s disease is less direct. Here, the primary
problem seems to be the death of nerve cells in the striatum itself. The
end result, suggest DeLong and Alexander, is the opposite to that in Parkinson’s
disease: the output of the subthalamic nucleus is reduced, leading ultimately
to an increase in the activity in the pathway from the thalamus to the motor
cortex.

In both diseases the effects of the missing nerve cells are probably
not restricted to the motor circuit. Similar disturbances in the other four
circuits may well contribute to the spectrum of clinical problems afflicted
people suffer from. Their control of eye movements may be disturbed or they
may have difficulty in learning or remembering things. But in both diseases,
degeneration is progressive and spreads to other parts of the brain, including
the cortex, so it is difficult to pinpoint where some of the problems may
arise.

These new insights offer some prospects for therapy. Removing all or
part of the subthalamic nucleus could relieve the inhibition of the pathway
from thalamus to cortex in people with Parkinson’s, making movements easier
to initiate and carry out. Trials with two monkeys showed improvements of
voluntary movements, but both animals made more involuntary movements. Precisely
targeted injections of compounds that counteract the transmitter chemical
used by inhibitory neurons might also help to bring the circuits back to
a more normal function. The difficulty remains that cause and effect in
these diseases are as complex as the nerve circuits themselves. Although
such interventions may relieve the worst of the motor symptoms, they are
unlikely to cure the more subtle associated problems.

The painstaking detective work of the past 10 years has produced a framework
for understanding the intricate functions of the basal ganglia and what
goes wrong in disease. Progress in filling in the details should now be
rapid. Kitai closed the discussion on an optimistic note with the remark:
‘Next year we should know what dopamine does in the striatum.’ That story
alone will warrant another symposium.

* * *

A centre for movement in the heart of the brain

THE BASAL ganglia lie in the centre of the brain, under the cerebral
cortex, which is the enormous, convoluted sheet of nerve cells in which
sensory and motor information is processed and stored. The side view of
the brain, on the right of the diagram, shows the position of the basal
ganglia relative to its neighbours: the cortex, the thalamus (the main distribution
centre for sensory and motor information) and the posterior parts of the
brain that lead to the spinal cord, which contains the machinery for generating
movements. Instructions from the motor cortex go direct to the spinal cord
(red arrows) but the signals in this path are modified by information from
a loop passing from the cortex through the basal ganglia and back to the
cortex (blue arrows).

The vertical line indicates the position of the section through the
forebrain, cut parallel to the face, shown on the left of the diagram. The
section displays the various centres of the basal ganglia. From the cortex,
information enters the striatum and then passes to the globus pallidus,
which is divided into external and internal parts, to the reticular part
of the substantia nigra and to the subthalamic nucleus. From the internal
part of the globus pallidus, the pathway leads back through the thalamus
to the cortex. A second, path runs from the globus pallidus to the spinal
cord.

The substantia nigra has a second part, the compact zone, which contains
the nerve cells that die in Parkinson’s disease. People with this disease
typically have rigid muscles, tremor at rest, very slow movements (sometimes
freezing in mid-movement), and difficulty in initiating voluntary movements
or moving in response to a command. Curiously, even quite immobile patients
can make adequate reflex re sponses, such as catching a ball. The organisation
of these reflexes probably does not require the basal ganglia and the ability
to make such movements demonstrates that the basic motor circuitry of the
brain and spinal cord remain relatively unaffected.

* * *

A ground plan for neuronal loops

EACH OF the five loops between the cortex and the basal ganglia has
the general organisation shown in this scheme. In each, several areas of
the cortex (A,B,C) send nerve fibres to one part of the striatum, the first
centre of the basal ganglia, where their terminals overlap to some extent.

The receiving cells in the striatum in turn send their fibres to the
globus pallidus and substantia nigra, where there is considerably more overlap
in the information that comes from A, B and C. Finally, all three converge
in one area of the thalamus, which returns the signals to the cortex but
to only one of the starting areas.

(The diagram below is modified from G. E. Alexander, M. R. DeLong, and
P. L. Strick, Annual Reviews of Neuroscience 1986, pp 357-381.) unaffected.

* * *

The motor loop and what can go wrong

THE MOTOR loop starts in several parts of the sensory and motor cortex.
The return pathway from the thalamus ends in just one of these areas, part
of the motor cortex known as the supplementary motor area or SMA. This seems
to be involved in the programming, initiation and execution of movements.
The cortical motor areas also have outputs to the spinal cord, where details
of movements are organised.

The cortical pathways converge in the motor division of the striatum
in an orderly fashion that reflects the parts of the body they represent
– all nerve cells involved with arm movements end in one area, which is
further subdivided into zones for wrist, elbow and so on. The cortical inputs
excite (green pathways) the nerve cells of striatum, which themselves inhibit
(red pathways) the nerve cells of the globus pallidus. The more active the
inputs from the cortex to the striatum, the stronger the inhibition of the
cells in the globus pallidus.

In the normal brain, shown on the left, the external part of the globus
pallidus inhibits the cells of the subthalamic nucleus, which receives its
own excitatory input direct from the SMA in the cortex. The output of the
subthalamic nucleus thus reflects a balance between these two opposing inputs.
The internal part of the globus pallidus, together with the reticular part
of the substantia nigra, receives inhibition from the striatum and excitation
from the subthalamic nucleus – again the output results from a balance between
the two inputs.

The internal part of globus pallidus and the reticular part of the substantia
nigra inhibit their target area in the thalamus, from which an excitatory
pathway runs back to SMA. If activity in these two areas is low, as shown
in the right-hand diagram, there will be a strong input from the

thalamus to the cortex, and vice versa. ÐÓ°ÉÔ­´´s now think that in
Parkinson’s disease the excitatory input to the cortex from the thalamus
is very weak because the inhibition from striatum to the external globus
pallidus is increased. As a result, the inhibition of the subthalamic nucleus
is decreased, so the excitatory drive from the subthalamic nucleus to the
internal globus pallidus is stronger than normal. This in turn increases
the inhibitory input to the thalamus and so reduces the activity in the
pathway back to the cortex.

For reasons that are not well understood, the direct inhibitory input
from the striatum to the internal globus pallidus seems to be diminished,
making the in creased drive from the subthalamic nucleus even more effective.

In Huntington’s disease, the opposite is likely to happen. Here, loss
of nerve cells in the striatum reduces the inhibitory input to the external
globus pallidus, ultimately resulting in over-activity in the pathway from
thalamus to cortex.

The subthalamic nucleus also has an input to the dopamine nerve cells
(blue) in the second, compact, part of the substantia nigra, which can slow
them down or stop them firing. The dopamine cells end diffusely in the striatum
and may regulate the output of the inhibitory cells there. The death of
these dopamine cells is the primary problem in Parkinson’s disease.

Jennifer Altman is a research consultant and freelance writer, specialising
in the neurosciences.