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Influences the processing of motor control and modulates the output of

the descending pathways without directly causing motor output.

Dysfunction causes a set of symptoms that are quite different from

damage to descending motor pathways, and thus the basal ganglia were
at one time considered to form an extrapyramidal motor system that
was distinct from the pyramidal tract pathways. It is now known that the
basal ganglia do not originate a separate motor pathway. Instead, they
influence and modulate the activity of motor cortex and the descending
motor pathways in ways that cause distinct symptoms when different
basal ganglia structures are damaged.

Gross Anatomy of the Basal Ganglia

The basal ganglia comprise a distributed set of brain structures in the

telencephalon, diencephalon, and mesencephalon. The forebrain
structures include the caudate nucleus, the putamen, the nucleus
accumbens (or ventral striatum) and the globus pallidus. Together,
these structures are named the corpus striatum. The caudate nucleus is
a C-shaped structure that is closely associated with the lateral wall of the
lateral ventricle. It is largest at its anterior pole (the head), and its size
diminishes posteriorly as it follows the course of the lateral ventricle (the
body) all the way to the temporal lobe (the tail), where it terminates at the
amygdaloid nuclei. The putamen is also a large structure that is separated
from the caudate nucleus by the anterior limb of the internal capsule. The
putamen is connected to the caudate head by bridges of cells that cut
across the internal capsule. Because of the striated appearance of these
cell bridges, the caudate and putamen are collectively referred to as the
striatum or neostriatum, and the nucleus accumbens is often called the
ventral striatum. Functionally, the caudate nucleus and the putamen are
considered equivalent to each other; indeed, most mammals have only a
single nucleus called the striatum. It is unclear whether there is any
functional significance of the separation of the striatum into the caudate

and putamen in primates. The putamen and the globus pallidus are
collectively called the lenticular nucleus, or lentiform nucleus. The
globus pallidus is divided into two segments: the internal (or medial)
segment and the external (or lateral) segment.

The subthalamic nucleus is part of the diencephalon; as its name

implies, it is located just below the thalamus. The substantia nigra is a
midbrain structure, composed of two distinct parts: the pars compacta
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and the pars reticulata. The substantia nigra is located between the red
nucleus and the crus cerebri (cerebral peduncle) on the ventral part of the
midbrain. The pars compacta is the source of a clinically important
dopaminergic pathway to the striatum; loss of neurons in this area is the
cause of Parkinsons disease (see below). An area that is functionally
analogous to the substantia nigra pars compacta is the ventral tegmental
area, which is located nearby and makes a dopaminergic projection to the
nucleus accumbens.

Basal Ganglia Afferents

The striatum is the main recipient of afferents to the basal ganglia. These
excitatory afferents arise from the entire cerebral cortex and from the
intralaminar nuclei of the thalamus (primarily the centromedian nucleus
and parafascicularis nucleus). The projections from different cortical areas
are segregated, such that the frontal lobe projects predominantly to the
caudate head and the putamen; the parietal and occipital lobes project to
the caudate body; and the temporal lobe projects to the caudate tail. The
primary motor cortex and the primary somatosensory cortex project
mainly to the putamen, whereas the premotor cortex and supplementary
motor areas project to the caudate head. Other cortical areas project
primarily to the caudate. Thus, along
the C-shaped extent of the caudate
nucleus, the caudate cells receive
their input from the cortical regions
that are close by. The enlarged head
of the caudate reflects the large
projection from the frontal cortex to
the caudate. In addition, the nucleus
accumbens (ventral striatum)
receives a large input from limbic
cortex.

In the motor regions of the basal

ganglia, there is a motor homunculus
similar to that seen in the primary
motor cortex. Thus, the projections from the medial wall of the anterior
paracentral lobule (the part of M1 that contains a representation of the
legs and torso) innervate regions of the striatum that are next to the
recipient zones from the dorsal surface of the precentral gyrus (the part of
M1 that contains a representation of the arms and hands). Similarly, the
projections from the lateral surface of the precentral gyrus (the part of M1
that contains a representation of the face) innervate regions that are next
to the arm and hand representation. This topography of projections is
maintained in the intrinsic circuitry of the basal ganglia.

Basal Ganglia Efferents

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The major output structures of the basal

ganglia are the globus pallidus internal
segment (GPint) and the substantia
nigra pars reticulata (SNr). Both of these
structures make GABAergic, inhibitory
connections on their targets. The GPint
projects to a number of thalamic
structures by way of two fibre tracts: the
ansa lenticularis and the lenticular
fasciculus. The loop that processes
sensorimotor information from the
motor cortex and the somatosensory
cortex projects to the ventral anterior
(VA) and ventral lateral (VL) nuclei. The
loop that processes other neocortical information projects to the
dorsomedial nucleus (DM), intralaminar nuclei, and parts of the VA
nucleus. The SNr projects to the superior colliculus, which is involved in
eye movements, as well as to the VA/VL thalamic nuclei.

Basal Ganglia Intrinsic Connections

A number of intrinsic pathways interconnect various basal ganglia

structures.

Striatopallidal pathway: inhibitory (GABA) connection between the

striatum and both segments of the globus pallidus.

Striatonigral pathway: inhibitory (GABA) connection between the

striatum and the SNr.

Globus pallidus (external): inhibitory (GABA) connection to the

subthalamic nucleus.

Subthalamic nucleus: excitatory (glutamate) connection onto both

segments of the globus pallidus and the SNr. This pathway is the only
purely excitatory pathway among the intrinsic pathways of the basal
ganglia.

Nigrostriatal pathway: mixed (dopamine) connection onto striatal

neurons. Has excitatory effects on some striatal neurons and inhibitory
effects on others.

Two Pathways Process Signals in the Basal Ganglia

The direct pathway has a net excitatory effect on thalamic neurons

(which in turn make excitatory connections onto cortical neurons).

The indirect pathway has a net inhibitory effect of inhibiting thalamic

neurons (rendering them unable to excite motor cortex neurons).
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The normal functioning of the basal ganglia apparently involves a proper

balance between the activity of these two pathways. One hypothesis is
that the direct pathway selectively facilitates certain motor (or cognitive)
programs in the cerebral cortex that are adaptive for the present task,
whereas the indirect pathway simultaneously inhibits the execution of
competing motor programs. An upset of the balance between the direct
and indirect pathways results in the motor dysfunctions that characterize
the extrapyramidal syndrome (see below).

Direct pathway. Although the connectivity patterns of the direct and

indirect pathways are relatively straightforward, the predominance of
inhibitory connections in the system can make an understanding of the
functional circuitry complicated and non-intuitive (Figure 4.5).

The direct pathway starts with cells in the striatum that make inhibitory
connections with cells in the GPint. The GPint cells in turn make inhibitory
connections on cells in the thalamus. Thus, the firing of GPint neurons
inhibits the thalamus, making the thalamus less likely to excite the
neocortex. When the direct pathway striatal neurons fire, however, they
inhibit the activity of the GPint neurons. This inhibition releases the
thalamic neurons from inhibition (i.e., it disinhibits the thalamic neurons),
allowing them to fire to excite the cortex. Thus, because of the double
negative in the pathway between the striatum and GPint and the GPint
and thalamus, the net result of exciting the direct pathway striatal
neurons is to excite motor cortex.

Because the two negative numbers cancel each other out.

Indirect pathway. The indirect pathway starts with a different set of cells in
the striatum. These neurons make inhibitory connections to the external
segment of the globus pallidus (GPext). The GPext neurons make
inhibitory connections to cells in the subthalamic nucleus, which in turn
make excitatory connections to cells in the GPint. (Remember that the
subthalamic-GPint pathway is the only purely excitatory pathway within
the intrinsic basal ganglia circuitry.) As we saw before, the GPint neurons
make inhibitory connections on the thalamic neurons. To see the net
effects of activation of the indirect pathway, let us work backwards from
the GPint. When the GPint cells are active, they inhibit thalamic neurons,
thus making cortex less active. When the subthalamic neurons are firing,
they increase the firing rate of GPint neurons, thus increasing the net
inhibition on cortex. Firing of the GPext neurons inhibits the subthalamic
neurons, thus making the GPint neurons less active and disinhibiting the
thalamus. However, when the indirect pathway striatal neurons are active,
they inhibit the GPext neurons, thus disinhibiting the subthalamic neurons.
With the subthalamic neurons free to fire, the GPint neurons inhibit the
thalamus, thereby producing a net inhibition on the motor cortex.

Again, think of a multiplication analogy:

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Because there are 3 negative numbers in the equation, the net effect is
negative.

Thus, as a result of the complex sequences of excitation, inhibition, and

disinhibition, the net effect of the cortex exciting the direct pathway is to
further excite the cortex (positive feedback loop), whereas the net effect
of cortex exciting the indirect pathway is to inhibit the cortex (negative
feedback loop). Presumably, the function of the basal ganglia is related to
a proper balance between these two pathways. Motor cortex neurons
have to excite the proper direct pathway neurons to further increase their
own firing, and they have to excite the proper indirect pathways neurons
that will inhibit other motor cortex neurons that are not adaptive for the
task at hand (see below).

The nigrostriatal projection

An important pathway in the modulation of the direct and indirect

pathways is the dopaminergic, nigrostriatal projection from the substantia
nigra pars compacta to the striatum (Figure 4.5). Direct pathway striatal
neurons have D1 dopamine receptors, which depolarize the cell in
response to dopamine. In contrast, indirect pathway striatal neurons have
D2 dopamine receptors, which hyperpolarize the cell in response to
dopamine. The nigrostriatal pathway thus has the dual effect of exciting
the direct pathway while simultaneously inhibiting the indirect pathway.
Because of this dual effect, excitation of the nigrostriatal pathway has the
net effect of exciting cortex by two routes, by exciting the direct pathway
(which itself has a net excitatory effect on cortex) and inhibiting the
indirect pathway (thereby disinhibiting the net inhibitory effect of the
indirect pathway on cortex). The loss of these dopamine neurons in
Parkinsons disease causes the poverty of movement that characterizes
this disease, as the balance between direct pathway excitation of cortex
and indirect pathway inhibition of cortex is tipped in favor of the indirect
pathway, with a subsequent pathological global inhibition of motor cortex
areas.

4.6 Functions of the Basal Ganglia

Motor functions

The function of the basal ganglia in motor control is not understood in

detail. It appears that the basal ganglia is involved in the enabling of
practiced motor acts and in gating the initiation of voluntary movements
by modulating motor programs stored in the motor cortex and elsewhere
in the motor hierarchy (Figure 4.6). Thus, voluntary movements are not
initiated in the basal ganglia (they are initiated in the cortex); however,
proper functioning of the basal ganglia appears to be necessary in order
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for the motor cortex to relay the appropriate motor commands to the
lower levels of the hierarchy.

Figure 4.6
The basal ganglia and motor cortex form a processing loop whereby the
basal ganglia enables the proper motor program stored in motor cortex
circuits via the direct pathway and inhibits competing motor programs via
the indirect pathway. The proper motor programs are selected based on
the desired motor output relayed from cortex. Note that the complex
circuits of the direct and indirect pathways are schematically diagramed
as single neurons for clarity of illustration.

Recall that the major output from the basal ganglia is an inhibitory
connection from the GPint (or SNr) to the thalamus (or superior colliculus).
Studies of eye movements in monkeys have shed light on the function of
the basal ganglia loop. Normally, the SNr neurons are tonically active,
suppressing the output of the collicular neurons that control saccadic eye
movements. When the direct pathway striatal neurons are excited by the
cortical frontal eye fields, the SNr neurons are momentarily inhibited,
releasing the collicular neurons from inhibition. This allows the appropriate
collicular neurons to signal the target of the eye movement, allowing the
monkey to change its gaze to a new location. The movement was initiated
in the frontal eye fields; however, the proper activation of the eye
movement required that collicular neurons be released from the inhibition
of the basal ganglia.

What is the function of the tonic inhibitory output of the basal ganglia?
Recall from the Motor Cortex chapter that stimulating the motor cortex of
monkeys at various locations results in stereotyped sequences of
movements, such as bringing the hand to the mouth or adopting a
defensive posture. It appears that a number of primitive motor
programs are stored in the cortex, and motor control may require the
activation of these elemental motor programs in the precise temporal
order to accomplish a sophisticated motor plan. It is important that only
one motor program be active at a given time, however, such that one
motor act (e.g., use hand to bring food to the mouth) is not competing
with a conflicting motor act (e.g., use hand to shield face from dangerous
object). It is thought that the basal ganglia is normally active in
suppressing inappropriate motor programs, and that activation of the
direct pathway temporarily releases one motor program from inhibition,
enabling it to be executed by the organism. Thus, the basal ganglia act as
a gate that enables the execution of automatic programs in the hierarchy.

Figure 4.7
Dopaminergic neurons signal unexpected reward or unexpected absence
of reward (Hollerman and Schultz, 1998). (A) If a reward occurs
unexpectedly, the dopaminergic neuron fires briskly. This may strengthen
 BASAL GANGLIA

the cortical motor programs that led up to the reward. (B) If a reward
occurs that the monkey previously learned was predicted by a stimulus,
the neuronal firing is not altered, thus signaling that all is proceeding
normally. (C) If the reward-predicting stimulus does not produce a reward,
the neuronal firing is inhibited. This inhibition may weaken the cortical
motor programs that did not produce the expected reward.

Which motor programs should be released from inhibition at a given

moment? The basal ganglia may have a major role in learning what motor
acts result in rewards for the organism. This information is provided by the
dopaminergic neurons of the SNc and ventral tegmental nucleus.
Recordings from these neurons in monkeys have shown that they tend to
respond when the monkey receives an unexpected reward, and they tend
to be inhibited when the monkey fails to receive an expected reward
(Figure 4.7). Because the net effect of activation of the nigrostriatal
pathway is to excite the direct pathway and inhibit the indirect pathway,
this pattern of dopaminergic firing may be involved in tuning the relative
balance of direct/indirect pathway activity to enhance the firing of cortical
motor programs that produce rewarding outcomes and to suppress the
activity of motor programs that do not result in reward. In this way, motor
habits can be constructed that tend to reward the animal.

Cognitive functions

As mentioned earlier, there are a number of cortical loops through the

basal ganglia that involve prefrontal association cortex and limbic cortex.
Through these loops, the basal ganglia are thought to play a role in
cognitive function that is similar to their role in motor control. That is, the
basal ganglia are involved in selecting and enabling various cognitive,
executive, or emotional programs that are stored in these other cortical
areas. Moreover, the basal ganglia appear to be involved in certain types
of learning. For example, in rodents the striatum is necessary for the
animal to learn certain stimulus-response tasks (e.g., make a right turn if
stimulus A is present and make a left turn if stimulus B is present).
Recordings from rat striatal neurons show that early in training, striatal
neurons fire at many locations while a rat learns such a task on a T-shaped
maze (Figure 4.8). This suggests that initially the striatum is involved
throughout the execution of the task. As the animal learns the task and
becomes exceedingly good at its performance, the striatal neurons
change their activity patterns, firing only at the beginning of the trial and
at the end. It appears that the learned programs to solve this task are now
stored elsewhere; the firing of the striatal neurons at the beginning of the
maze presumably reflects the enabling of the appropriate motor/cognitive
plan in the cortex, and the firing at the end of the maze is presumably
involved in evaluating the reward outcome of the trial.

Figure 4.8
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Habit learning in striatum (Jog et al., 1999). (A) A rat is trained to run
down a T-shaped maze and make a left turn for food reward if it hears a
high-pitch tone or make a right turn for food reward if it hears a low-pitch
tone. (B) Early in training, as the rat is beginning to learn the task, striatal
neurons fire at locations all over the maze, especially at the choice point.
(C) Late in training, when the rat has mastered the task and performs very
quickly and accurately, the striatal neurons now fire only at the start and
ends of the maze.

In humans, the basal ganglia appear to be necessary for certain forms of

implicit memory tasks. Like motor habit learning discussed above, many
types of cognitive learning require repeated trials and are often
unconscious. An example is probabilistic classification (Figure 4.9). In this
type of task, people have to learn to classify objects based on the
probability of belonging to a class, rather than on any explicit rule. In one
experiment, subjects were shown a deck of cards with different symbols.
Each symbol was associated with a certain probability of predicting rain or
sunshine, and the subjects had to say on each trial whether the symbol
was a predictor of rain or sunshine. Because the same symbol sometimes
predicted sunshine and other times predicted rain, the subjects could not
devise a simple rule, and they made many errors at first. Over time,
however, they began to get better at classifying the symbols
appropriately, although they still often claimed to be guessing. Patients
with basal ganglia disorders were impaired at this task, suggesting that
the processing of the cognitive loops of the basal ganglia are somehow
involved in our ability to subconsciously learn the probabilities of
predicted outcomes associated with particular stimuli.

Figure 4.9
Patients with basal ganglia disorders are impaired in learning this implicit
probabilistic classification task in which they have to predict the weather
based on a set of 4 cue cards (Packard and Knowlton, 2002).

Disorders of the Basal Ganglia

A number of neurological disorders result from damage to the basal

ganglia.

Nigrostriatal pathway and Parkinsons disease

Parkinsons disease is characterized by slowness or absence of movement

(bradykinesia or akinesia), rigidity, and a resting tremor (especially in the
hands and fingers). Patients have difficulty initiating movements, and
once initiated the movements are abnormally slow. The cause of
Parkinsons disease is the loss of the dopaminergic neurons in the
substantia nigra pars compacta. From ones knowledge of the effects of
the nigrostriatal pathway on the direct and indirect pathways, it becomes
straightforward to see why the loss of this pathway results in the poverty
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of movement symptomatic of Parkinsons disease. Because the

nigrostriatal pathway excites the direct pathway and inhibits the indirect
pathway, the loss of this input tips the balance in favor of activity in the
indirect pathway. Thus, the GPint neurons are abnormally active, keeping
the thalamic neurons inhibited. Without the thalamic input, the motor
cortex neurons are not as excited, and therefore the motor system is less
able to execute the motor plans in response to the patients volition.

Indirect pathway and Huntingtons disease

The symptoms of Huntingtons disease are in many respects the opposite

of the symptoms of Parkinsons disease. Huntingtons disease is
characterized by choreiform movements: involuntary, continuous
movement of the body, especially of the extremities and face. Often these
movements resemble pieces of adaptive movements, but they occur
involuntarily and without behavioral significance. Huntingtons disease
results from the selective loss of striatal neurons in the indirect pathway
(Figure 4.10). Thus, the balance between the direct and indirect pathways
becomes tipped in favor of the direct pathway. Without the normal
inhibitory influence on the thalamus that is provided by the indirect
pathway, thalamic neurons can fire randomly and inappropriately, causing
the motor cortex to execute motor programs with no control by the
patient.