Describe the anatomy of the basal ganglia and the key

elements affected by one disease of the basal

ganglia.
The basal ganglia are an interconnected collection of cell bodies in the lower parts of
the CNS, specifically the forebrain, midbrain and diencephalon. As such they should
properly be called nuclei: ganglia tend to be found peripherally. Neuroanatomy by
Martin states that they have “captured the imagination of clinicians for over a century
because of the remarkable range of behavioural dysfunction associated with basal
ganglia disease”. The nuclei include the caudate and the putamen (which are
collectively termed the striatum), the internal and external parts of the globus pallidus,
the subthalamic nucleus and the substantia nigra. The putamen and globus pallidum
are together called the lentiform body, since they are shaped like a lentil (or lens).
This however is an anatomical name rather than a functional one, since they seem to
serve different function. Properly speaking the term “basal ganglia” also embraces the
amygdala, but since this serves a different function, this is better thought of as part of
the limbic system.

What is the function of the basal ganglia? They participate in the control of
movement. There are three broad lines of experimental evidence for this. Most of the
inputs and outputs of the basal ganglia are to and from motor areas of the cortex and
thalamus: they seem to form feedback loops. Lesions of the basal ganglia seem to
result in movement disorders. Finally, output of the cells in the basal ganglia seems to
correlate with movement. There are also suggestions that the basal ganglia are
important for some cognitive and emotional aspects of behaviour: once again, this is
demonstrated in aspects of the disease pathology.

The anatomy of the basal ganglia is quite confusing: there are many different names,
some based on structure without regard to function, and analogous structures in other
mammals sometimes have different names. The great degree of interconnection also
adds to the complexity. In general, however, there are some distinctions that can be
made. It is useful to divide the nuclei into three categories: input, output and intrinsic
nuclei. The input nuclei are the caudate nucleus, the putamen and the nucleus
accumbens. These receive afferent connections from brain regions other than the basal
ganglia, and project to intrinsic and output nuclei. The output nuclei receive input
from other basal ganglia nuclei and project to non-basal areas, in particular the medial
dorsal, ventral lateral and ventral anterior thalamus. They also project to the
pedunculopontine nucleus, which is important in locomotion, and the superior
colliculus for the control of saccades. The output nuclei include the internal segment
of the globus pallidus, the ventral pallidum and the substantia nigra pars reticulata.
The intrinsic nuclei do not in general directly communicate with non-basal ganglia
nuclei, and thus their connections are limited to other basal nuclei. They include the
external segment of the globus pallidus, the subthalamic nucleus, the pars compacta of
the substantia nigra and the ventral tegmental area. The external segment of the
globus pallidus and the pars compacta of the substantia nigra are part of the indirect
pathway, which inhibits movement (see below!), while the substantia nigra and the
ventral tegmental area provide dopaminergic input to, among other areas, the input
nuclei of the basal ganglia.
One thing that is immediately obvious from this is that if we think of a circuit as a
pathway through the basal ganglia, that is to say involving an input nucleus, possibly
an intrinsic nucleus, and an output nucleus, then from the list above there seems to be
scope for many such circuits! In general, four circuits, anatomically known as
“loops”, have been identified. They share important common features1. Each of the
loops originates from multiple cortical regions that have similar general functions.
The output of each loop is to a different area of the frontal lobe (i.e. premotor cortex,
frontal eye field, cingulate gyrus and prefrontal cortex). Each passes through different
basal ganglia and thalamic nuclei, or if they pass through the same ones than through
different parts of it. That is to say that there is both a functional and anatomical
separation of the pathways2.

The loop we think of first in connection with the basal ganglia, which we know the
most about, and which seems most vulnerable to disease, is the skeletomotor circuit.
This aids in the control of movement. Input is to the putamen from the motor and
somatosensory cortical areas. Output is to the primary motor cortex and premotor
areas, via ventral anterior3 and ventral lateral thalamus. The oculomotor loop controls
saccades. The caudate nucleus receives input from the posterior parietal cortex,. This
time, output is to the frontal eye fields via VA and medial dorsal thalamus. The
prefrontal cortex loop serves cognitive and behavioural functions. Input from the
posterior parietal cortex, and the middle and inferior temporal lobe, to the caudate
nucleus. Output is via VA and MD thalamus to prefrontal and premotor cortex. Thus
it is possible to form a distinction between the two main input areas of the basal
ganglia, which collectively form the striatum4. The putamen is more concerned with
motor function, while the caudate controls eye movements and more behavioural
functions. Finally, the limbic loop5 receives input from the medial and lateral
temporal lobes, and the hippocampal formation. This loop is anatomically somewhat
different. The ventral striatum, which includes the nucleus accumbens and
ventromedial portions of the caudate and putamen, receives the input. The intrinsic
nuclei involved are the ventral pallidum, as well as the internal part of the globus
pallidus and the pars reticulata of the substantia nigra that are involved in the other
three loops. Output is via MD and VA thalamus to the anterior cingulate gyrus.

This is the gross circuitry of the basal ganglia. I shall now briefly try to describe
where all these things are6. The striatum is in the forebrain, and divides into caudate

1
The common features are from Neuroanatomy, Martin
2
Although that said there would seem little point in having them all passing so close to each other if
there were not to be some crosstalk. From personal experience we all know how what we are looking
at, our emotions and our cognition can affect our movements (just as an example, there are many
possible ways in which these factors could influence each other), and it transpires that dendrites from
the medium spiny neurons in the basal ganglia project across the loops. So the basal nuclei do allow
crosstalk between the loops.
3
VA thalamus is particularly associated with the basal ganglia, as the cerebellum forms the main
projection to ventral lateral thalamus.
4
stria: Latin. Furrow or stripe. This appearance is due to the myelinated axons that pass through it.
5
The ventral pallidum and nucleus accumbens are traditionally not thought of as being part of the basal
ganglia. But the functions mediated here are analogous. Since I am not discussing the amygdala,
traditionally considered part of the basal ganglia, due to its function being different, it is only fair to at
least mention these structures, which although not part of the basal ganglia, have similar function.
6
With the help of Neuroanatomy by Crossman and Neary.
and putamen, which are separated by the anterior limb of the internal capsule7. The
caudate is medial to the internal capsule, and the head of the caudate sits on the banks
of the lateral ventricle. It is a useful imaging landmark, since the head forms a
prominent bulge in the wall of the lateral ventricle. The putamen is lateral. The large
head of the caudate communicates with the more medial putamen at its rostral end,
but otherwise is separated from it by the internal capsule. The nucleus accumbens is
the most rostral part of the striatum. The caudate nucleus then has a more slender
body which arches backwards following the lateral ventricle. Then it arches forward,
again with the lateral ventricle to form the tail of the caudate nucleus, which is
incidentally the roof of the inferior horn of the lateral ventricle. The tail of the caudate
nucleus terminates in the amygdala. The overall effect of caudate and putamen, when
viewed laterally, is thus rather like a tadpole. The globus pallidus is medial to the
putamen, and is separated from it by the lateral medullary lamina. Medially it touches
(“nestles”- Crossman and Neary) the internal capsule. In the middle, it is divided into
internal and external portions by the medial medullary lamina. Thus, working inwards
from the insula, we have insula, extreme capsule, claustrum, external capsule,
putamen, lateral medullary lamina, external globus pallidus, medial medullary lamina,
internal medullary lamina. Then we come upon the posterior limb of the internal
capsule, which separates the medial globus pallidus from the functionally similar pars
reticulata of the substantia nigra. The substantia nigra, divided into pars compacta and
pars reticulata anatomically8, is the prominent black area (due to neuromelanin, a
polymer of DOPA, a precursor to dopamine that is found in the pars compacta) that is
in the midbrain, ventral and slightly lateral to the red nucleus. Finally, the subthalamic
nucleus is beneath the thalamus.

There are two main output paths for the basal ganglia, which run from pars reticulata
and the internal segment of the globus pallidus to the thalamus. These are the ansa
lenticularis and the lenticular fasciculus. They run around the internal capsule,
converge beneath the thalamus, join fibres of the cerebellothalamic tract, form the
thalamic fasciculus and supply the thalamus.

Having discussed the gross anatomy and the loops, it is worth considering the cell
types briefly. There is a whole cocktail of neurotransmitters and neuromodulators.
The excitatory neurotransmitter glutamate is used by the cortical and thalamic inputs
to the striatum, as well as by the subthalamic nucleus, which projects to the internal
part of the globus pallidus, the pars reticulata of the substantia nigra and the external
part of the globus pallidus (where it provides feedback). Most of the other neurons of
the basal ganglia are GABAergic. For example, 95% of the neurons in the striatum are
medium spiny neurons, having extensive dendrites and axon collaterals. They are
projection neurons, running to the globus pallidus and substantia nigra. Despite this
broad brush similarity, they show important heterogeneity, with two distinct classes.
The neurons projecting to the external part of the globus pallidus have enkephalin as a
co-transmitter, while those projecting to the internal part and the pars reticulata of the
substantia nigra have substance P and dynorphin. The only other exception to this

7
The internal capsule is like a fan, dividing into anterior limb, genu and posterior limb, along with the
retrolenticular and sublenticular portions, named for their positions behind and beneath the lentiform
nucleus, respectively. The posterior limb separates the lentiform nucleus laterally from the body and
tail of the caudate, and the thalamus, medially.
8
The pars reticulata is adjacent to the basis pedunculi. It is GABAergic. The pars compacta is
dopaminergic.
GABAergic rule is the pars compacta of the substantia nigra, from where
dopaminergic neurons project to the striatum as well as to other areas.

There are many disorders of the basal ganglia, at least fifty, making it one of the most
vulnerable points of the CNS. This in a way is unsurprising: the above discussion of
its anatomy has hopefully made clear its complexity, and thus propensity to go wrong!
These diseases have been useful in that they have allowed us to ascertain much of the
mechanisms of the basal ganglia, by looking at what has gone wrong and what effects
this has had. In this essay, I will however take a slightly contrary line. I will first of all
describe briefly what we do know of the circuitry involved in the motor functions of
the basal ganglia. I will then explain how disease can affect them.

There are two pathways for motor function in the basal ganglia: the direct and
indirect. In the direct pathway, the putamen projects with GABAergic fibres (with
substance P and dynorphin as co-transmitters) to the internal part of the globus
pallidus and the pars reticulata of the substantia nigra. This burst of firing will cause a
momentary reduction in their GABAergic to VA and VL thalamus, disinhibiting it9,
and thus facilitating movement via the thalamocortical circuits. The direct pathway
allows movement to occur.

In the indirect pathway, the putamen projects to the external part of the globus
pallidus, with GABAergic neurons using enkephalin as a co-transmitter. This then
projects GABAergic fibres to the subthalamic nucleus. The excitatory glutamate
output of the subthalamic nucleus both projects back to the external part of the globus
pallidus, and on to the internal part of the globus pallidus and the pars reticulata of the
substantia nigra. This will tend to excite their GABAergic output to VA and VL
thalamus. Thus, when this pathway is excited, the burst of GABA from the striate
tends to momentarily inhibit the neurons of the external part of the globus pallidus.
This is turn leaves the subthalamic nucleus free to fire, which they do10. These act on
the output nuclei to stimulate them, and thus their GABAergic output to the thalamus
is increased. The thalamus is inhibited. This produces inhibition of movement via the
thalamocortical circuits. The role of the indirect pathway is to inhibit unwanted
movements. At the same time, the subthalamic nucleus will act on the external part of
the globus pallidus, to increase its output. This is therefore negative feedback, so the
indirect pathway is never allowed to dominate, which would lead to paucity of
movement.

The pars compacta of the substantia nigra projects dopaminergic input to the striatum.
There seem to be two receptors. Via the D1 receptor the dopamine facilitates the
direct pathway, whereas it seems to inhibit the indirect pathway, via D2 receptors.
Thus the overall effect of dopamine on movement is a facilitation of movement, by
inhibiting the GABAergic output of the basal ganglia, and thus disinhibiting the
thalamus, allowing movement.

This model is attractive because by attributing two major roles to the basal ganglia –
inhibiting unwanted movement and facilitating desired movement, it can potentially
explain both the hypokinetic and hyperkinetic signs typically seen in basal ganglia
9
Which is functionally equivalent to excitation.
10
The subthalamic nucleus also receives inputs from motor areas of cerebral cortex, thus allowing more
direct control of its output.
disease11. In Parkinson’s disease there seems to be a dopamine deficiency in the pars
compacta of the substantia nigra. As already mentioned, this diminishes the
disinhibitory effects of the direct pathway and enhances the inhibitory effects of the
indirect pathway. This greatly reduces the thalamic signals to the cortex, and thus
reduce cortical outflow along the corticobulbar and corticospinal tracts. Symptoms of
Parkinson’s, which can be conveniently recalled using the mnemonic TRAP, include
resting “pill rolling” tremor, “cogwheel” rigidity, bradykinesia and even akinesia, and
postural ataxia. The latter three symptoms are all to an extent explainable from what
we have already considered as the functions of the dopamine and the basal ganglia.
For example, there is increased activity in neurons of the internal part of the globus
pallidus in monkey models12, which leads to inhibition, and there is reduced muscle
activity leading to the typical slowness of the Parkinsonian movement. Rigidity has
been attributed to abnormally active transcortical stretch reflexes, which tend to
oppose any change in muscle length. The abnormally active stretch reflexes might
also account for the postural instability: sometimes what would normally be called for
is a judicious inhibition of a stretch reflex, but this ability seems to be lost in
Parkinson’s.

Surely, however, the tremor is the opposite of what would be expected? The
mechanisms for the tremor are indeed poorly understood. It has been suggested it is
due to abnormal bursting of neurons in the thalamus. Interestingly, the Parkinsonian
shuffle can be reduced, that is to say the gait can be made more normal in some cases,
if the patient is presented with a chequered floor, or stairs to climb, in other words,
some external stimulus to move. This is no accident, and there are a couple of
hypotheses as to why. The basal ganglia project via ventral anterior thalamus to the
supplementary motor area, which is responsible for internal generation of movement.
Somehow this ability is lost with the loss of basal ganglia function. The other
hypothesis is that the dopamine reward pathways are also affected by Parkinson’s,
and this somehow leads to a reduction in motivation to walk.

Traditionally, the treatment for Parkinson’s involved dopamine replacement with L-

dopa, with non blood brain barrier crossing carbidopa applied to inhibit excessive
dopamine synthesis outside the brain. Dopamine agonists such as ropinerole are also
used. Recently, however, there has been a lot of interest in deep brain stimulation
(John Stein and others). Here, the electrode is placed into the thalamus, subthalamic
nucleus or basal ganglia. Exactly where depends on what symptoms are specifically
being targeted. It takes time to calibrate the machine, up to a year, but once this has
been performed there is often a marked reduction in symptoms.

Both Huntington’s and Parkinson’s lead to cognitive defects eventually, and so it

seems that in late stages of these basal ganglia diseases, other loops in addition to the
motor loop are affected, with corresponding loss of function. In Parkinson’s there can
be memory loss, and 20 to 40% of patients eventually suffer dementia. Instead of
dwelling on these sad outcomes, however, I will end by briefly discussing a different
11
A paradigm example of disease of the basal ganglia leading to hyperkinesia is the autosomal
dominant disease Huntington’s chorea, where the abnormal protein huntingtin forms aggregates which
seem toxic to the medium spiny neurons in some way. There is a loss of the inhibition of movement
normally provided by the basal ganglia, hyperkinesia results, and the disease is invariably fatal.
12
The effects of Parkinson’s can be mimicked by the chemical MPTP, which had been allowed to
contaminate MPPP, a street alternative for heroin for a time in the 1980’s. This has been used to
generate a monkey model for Parkinson’s.
disease, possibly of the basal ganglia, with cognitive connotations: obsessive
compulsive disorder13.

OCD is a chronic disorder characterized by motor and cognitive symptoms. There are
recurrent intrusive thoughts, and simple behaviours can become ritualistic. Typically,
the intrusive thoughts will be about harming oneself or others, or about contamination
and compulsive cleanliness. Since people are aware of these thoughts and are often
made very anxious by it, it is classed as an anxiety disorder. As such, SSRI’s can be
useful, to alleviate the anxiety. The exact pathology of OCD is unknown, but PET
scanning has indicated that there is abnormal resting blood flow in the orbital cortex
and caudate nucleus. On presentation with something “unclean”, for example, there is
further increase of blood flow in the orbital cortex, caudate, putamen, thalamus and
anterior cingulate cortex. On drug treatment, caudate and orbital blood flows reduce.
This suggests a role for the basal ganglia in the obsessive thoughts experienced by
these patients. Evidence from lesioning suggests that the orbital cortex is involved in
trying to alter already set patterns of thought, which leaves the basal ganglia as the
main suspect! In addition, lesions of the basal ganglia can lead to secondary
obsessions. Examples of this include lesions of the lentiform nuclei that include
lesions of the globus pallidus, Sydenham chorea, which is a post streptococcal
autoimmune disease which causes neuronal atrophy in the caudate and putamen, and
Tourette’s syndrome, which is another disease of the basal ganglia, one which it is
thought might have a genetic link with OCD. Indeed, in a disease like Tourette’s, and
for that matter many other basal ganglia diseases, there are complex motor tics:
stereotyped quite complicated patterns of movement that are altogether involuntary.
Since thought is in a way just internalised motion, it is not unreasonable to suggest a
conceptual link between the motor disorders discussed earlier in the essay, and these
cognitive manifestations. This suggests that the basal ganglia are potentially an
important and interesting area for future research.

13
The ensuing discussion is after that in Zigmond and Bloom.