THE BASAL GANGLIA
That the basal ganglia are related to the control of
movement has been known for a long time; diseases affecting primarily the basal
ganglia lead to characteristic disturbances of movement and of resting muscle
tone. Improved methods for tracing fiber connections have shown, however, that
the main efferent connections of the basal ganglia do not descend to motor
nuclei in the brain stem and spinal cord but are rather directed 'upstream' to
the motor and other areas of the cerebral cortex. Even though the most obvious
symptoms of the basal ganglia are related to the motor system, both clinical
and experimental evidence indicates that the basal ganglia also play a role in
higher mental functions.
Components: caudate nucleus + putamen = striatum or
neostriatum; putamen + pallidum = nucleus lentiformis. pallidum =
paleostriatum; Neostriatum + paleostriatum = corpus striatum. Other components:
subthalamic nucleus; substantia nigra =
pars compacta (SNc) + pars reticulata (SNr).
Afferent connections: The
striatum, which is the primary receiving part of the basal ganglia, is
characterized by three sets of afferents 1) from the cerebral cortex, 2) from
the intralaminar thalamic nuclei and 3) the dopamine containing cell groups in
the substantia nigra. The largest contingent of afferents comes from the
cerebral cortex. Almost all areas of the cortex send fibers to the striatum,
but the caudate nucleus and the putamen receive from different parts of the
cortex. The putamen is dominated by somatotopically organized inputs from the
SI and MI. The caudate nucleus, on the other hand, receives fibers
predominantly from association areas.
Cell
Types and Compartmental Organization of the Striatum.
More than 90% of the neurons have relatively small
perikarya and dendrites with numerous spines (medium-sized spiny neurons}. This
cell type contain GABA. There appear to exist two subtypes of this medium spiny
neuron: one kind contains Substance P in addition to GABA and project primarily
to the internal segment of the GP (or entopeduncular nucleus in rat) and SNr;
the other contains enkephalin in addition to GABA and projects mainly to the
external segment of the pallidum. Other cell types are interneurons containing
acetylcholine, NPY, somatostatin. The various cell types, and in particular the
neurotransmitters, are not evenly distributed throughout the striatum. Rather,
different smaller compartments can be defined with regard to connections and
cytochemistry. In microscopic sections, a mosaic pattern appears after staining
to demonstrate acetylcholine esterase. Poorly stained patches called striosomes
are embedded in a heavily stained matrix.
Several neuropeptides such
as substance P, somatostatin, and enkephalin, are most abundant within the
striosomes. GABAergic projection neurons are found within both compartments.
The connections of the striosomes and the matrix compartments also differ, for
example, neurons in the deep parts of
Paralell
Circuits, Linking Cortex, Basal Ganglia and Thalamus
The effects exerted by the basal ganglia on other parts
of the nervous system are mediated primarily by efferent fibers from the
pallidum and substantia nigra. These nuclei receive their main efferents from
the striatum. The efferents from the internal pallidal segment goes to the
thalamus (VA,VL, and CM), while the external pallidal segment project to the
subthalamic nucleus, which in turn project to the substantia nigra pars
reticulata. In addition, the external pallidum also projects directly to SNr.
The SNr send fibers to the superior colliculus, thalamus and the mesopontine
tegmentum. The parts of the thalamus that receive fibers from the pallidum and
the nigra project back to different portions of the frontal lobe.
Earlier schemes suggested that projections from diverse
cortical areas including motor, sensory, and "association" fields,
converged within the basal ganglia and were then funneled back upon precentral
motor areas. Currently, however, the weight of evidence suggests a different
type of organization: the basal ganglia, along with their connected cortical
and thalamic areas, are viewed as components of parallel circuits whose
functional and morphological segregation is rather strictly maintained. Each
circuit is thought to engage separate regions of the basal ganglia and
thalamus, and the output of each appears to be centered on a different type of
the frontal lobe: the "motor" circuit is focuses on the precentral
motor fields the "oculomotor" circuit on the frontal eye fields; the
"prefrontal" circuits on dorsolateral prefrontal and lateral
orbitofrontal cortex; and the "limbic" circuit on anterior cingulate
and medial orbitofrontal cortex.
Each circuit contains a number of highly specialized
channels and sub-channels that permit parallel, multilevel processing of a vast
number of variables to process concurrently. Within the "motor"
circuit for example, a well defined somatotopy is maintained throughout all
stages of the circuit, thereby giving rise to clearly differentiated
"leg", "arm" and 'orofacial" channels. There is also
evidence suggesting further subdivisions of the "motor" circuit in
terms of a) the types of behaviors observed (movement preparation vs.
execution) and b) the maintained seggregation of influences from different
cortical areas (e.g. separate subchannels for each of the precentral motor
fields). Moreover, included within each of the basal ganglia thalamocortical
circuit is a direct pathway that passes from the striatum directly to one of
the basal ganglia output nuclei, and an "indirect" pathway which
includes a relay through the external pallidum and subthalamic nucleus. In
addition, within each of the somatotopic channels of the motor circuit (leg,
arm, orofacial) there may be another level of organization comprising
functionally specific sub-channels that encode selectively, but in parallel,
information about such disparate motor behavioral variables as target location,
limb kinematics (direction of limb movement) and muscle pattern. Activity
within these circuits initiated in the cortex, although there is an essentially
complex temporal overlap, suggesting that much of the motor processing proceeds
concurently and functional integration is based upon temporally coincidence of
processing within pathways whose functional separation is rather strict.
The oculomotor circuit The frontal eye fields and several other cortical areas
project to the body of the caudate. The caudate then projects to both the
superior colliculus and the frontal eye field via the thalamus. The circuit is
involved in the saccadic eye movement. The dorsolateral orbitofrontal
circuit The dorsolateral prefontal cortex and several other areas of
association cortex project to dorsolateral head of caudate which in turn
project back to the dorsolateral prefrontal cortex via the thalamus. This
circuit is probable involved in aspects of memory concerned with orientation in
space. The lateral crbitofrontal circuit through the ventromedial
caudate and thalamic MD nucleus is thought to be involved in the ability to
switch behavioral set. The limbic circuit involves the anterior
cingulate area (ACA)-medial orbitofrontal cortex (MOFC)-ventral
striatum-ventral- pallidum-MD projections. This circuit is closed by
thalamocortical projections from MD thalamus to ACA and MOFC. The limbic
circuit may play some role in emotional and/or motivational processes.
ROLE OF THE STRIATUM IN SELECTING THE MOTOR
PROGRAMS
Along
the neuraxis from the spinal cord to the upper brainstem, there are several
neuronal networks or motor programs that when activated will produce different
types of motor behaviour. They are composed of different networks that, for
rhythmic motor patterns such as respiration, chewing and locomotion, are often
referred to as central pattern generators (CPGs). Likewise, the networks
underlying stereotyped single action patterns such as swallowing, coughing or
sneezing, and possibly also the expression of emotions, can be referred to as
CPGs. Even more complex are the motor maps in tectum (superior colliculus)
designed to control saccadic eye movements. Having these different motor
programs available, a mechanism is clearly required to determine when a given
motor program or network should be called into action (i.e. selecting the
appropriate motor program) and to determine how different motor sequences are
timed.
Operational
Features of Basal Ganalia-Thalamocortical Circuits
Physiological activity in the two striatal output
pathways differentially modulate the GABAergic neurons in the SNr. At rest,
striatal output neurons are physiologically quiescent, whereas nigral GABAergic
and pallidal neurons (the output elements of the basal ganglia) are tonically
active (90Hz). These pallidal neurons target a large
number of brainstem nuclei, in addition to their well-known thalamocortical
targets. Subgroups of pallidal neurons project to the command neurons of
several different motor programs (those for saccadic eye movements, locomotion
and postural tone), and prevent them from being active under resting
conditions. Corticostriatal
inputs stimulate activity in striatonigral neurons (direct pathway) which
phasically inhibit the tonic activity of nigral GABAergic neurons, thus
disinhibiting the VL thalamus and thereby gating or facilitating cortically
initiated movements via excitatory thalamocortical connections. The striatal neurons can thus induce activity and
release or select a motor program. Striatal neurons have a high threshold for
activation, and their excitatory input is provided directly from the thalamus
and extensively from different cortical regions. Their membrane properties
stabilize a hyperpolarized level owing to their specific membrane properties
(referred to as down state). The transition to an up state due to excitation is
facilitated by dopamine (via D1 receptors).
The
activity of a subgroup of striatal neurons is depressed by dopamine (they have
D2 DA receptors) and they are instead connected to the globus pallidus pars
externa, which in turn disinhibits the excitatory subthalamic neurons. These
also receive input directly from the cortex, and they add excitation to the
pallidal neurons – thus, they can brake or terminate a motor program (or part
of a motor program). Cortically driven activity of striatopallidal neurons
inhibits external pallidal GABAergic neurons, resulting in the disinhibition of
the subthalamic nucleus, which increases the tonic firing of nigral GABAergic
neurons. Phasic increases in GPi/SNr discharge increases the inhibition in the
superior colliculus or thalamic target nuclei, thus there is a reduced feedback
to the cortex. The function of the
arousing striatal disinhibition is to set a pattern of readiness in premotor
network that will be further activated for the execution of movement.
Important factors for the down and up states in medium spiny neurons. The down state is stabilized by K+ currents of the inward-rectifier type (Kir). An excitatory input from the cortex or thalamus can depolarize the MSN so that it is transferred to an up state and Kir will then be turned off. MSNs are unusual in that their Cl− equilibrium potential is comparatively depolarized and close to the membrane potential of the up state. This could mean that the lateral GABAergic interaction between MSNs can to some degree facilitate the occurrence of an up state. During the up state, an MSN can respond to additional excitation with action potentials; only then can it act on pallidal neurons and possibly disinhibit a motor target. The transition from a down state to an up state is facilitated by dopamine. MSN neurons thus have three states: a down state, an up state and, with further depolarization, a state in which they fire action potentials.
The
Action of Dopamine in the Striatum is Complex
The relative responsiveness of striatonigral and
striatopallidal neurons to cortical input determines the pattern of activity of
the output neurons of the basal ganglia. As determined by in situ hybridization histochemistry, striatopallidal GABAergic
neurons express enkephalin and D2 dopamine receptor, whereas the majority of
striatonigral GABAergic neurons express substance P, dynorphin (Dyn) and D1
dopamine receptor. Dopamine depletion in the striatum results in increased ENK
mRNA expression in striatopallidal neurons and decreased expression of Dyn and
substance P mRNA in striatonigral neurons. Subsequent to dopamine depleting
lesions, D1 or D2 selective agonist treatments reverses the lesion induces
changes (see Gerfen's Fig.). The increases and decreases in gene expression in
striatonigral and striatopallidal neurons parallel changes in the physiological
activity of these neurons in similar experimental paradigms assayed by
2-deoxyglucose and in electrophysiological studies. These studies suggest that
dopamine deafferentation produces an imbalance in the activity of
striatopallidal (indirect) and striatonigral (direct) output pathways, which
results in increased tonic activity of nigral output neurons through the
polysynaptic circuits.
The
most frequent disease affecting the basal ganglia is Parkinson’s disease
(PD). Typically, voluntary movements are hard mo initiate (akinesia) and they are slower and smaller than normal (bradykinesia). The akinesia also leads
to a conspicuous lack of facial movements (mask like face). In addition, there
is an increased muscular rigidity (rigidity results when agonist and antagonist
muscles are activated simultaneously) and resting
tremor (the tremor becomes quieter, if not entirely quiescent, once the
patient initiates a volitional movement). When the limb is displaced passively, the neurologist can feel alternations between resistance and relaxation, a
phenomenon known as cogwheeling. Patients with Parkinson's disease have a
pronounced cell loss in the SNc and a corresponding decrease of dopamine in the
striatum. Akinesia, the dominant symptom in PD has been related to increased
striatopallidal activity (through activating D2 receptors in ENK/GABA
striatopallidal neurons) and the resultant increase in excitatory subthalamic
inputs to nigral GABAergic neurons, which then predominate over the
disinhibitory mechanisms required for the generation of movements, This model
is supported by the report that lesions of the subthalamic nucleus reverse
akinesia in monkeys made Parkinsonian with lesions induced by MPTP. To
alleviate the symptoms, L-dopa, the precursor of dopamine is used. The L-dopa
treatment, has, however, side effects. Especially, long term treatment may
provoke motor symptoms than are different from those caused by the disease,
such as chorea-like and athetoid dyskinesias. The mechanisms of these
dyskinesias may be the same as proposed for the one in
In Huntington’s disease, in which there is a
marked loss of GABAergic neurons of the striatum, the most pronounced symptom
is involuntary, jerky often, dance-like movement (chorea). Apparently, the cell
loss in the striatum mainly concerns the neurons projecting to the external
pallidal segment (GABA/ENK/D2), whereas
the loss of neurons projecting to the internal pallidal segment (containing
GABA/SP/D1) occurs at a later stage. Accordingly, the loss of striatopallidal
GABAergic neurons leads to increased activity of inhibitory pallido-subthalamic
neurons. The reduced activity of the subtalamo-nigral projection then leads to
reduced inhibition of the nigro-thalamic neurons which finally results in
increased thalamocortical activity. Another hypothesis focuses on the possible
hyperactivity of dopaminergic nigrostriatal neurons which are normally
inhibited by GABAergic striatonigral neurons. This is consistent with the
experience that antidopaminergic therapies tend to reduce the choreiform
movements.
The basic pathophysiologic mechanism suggested for the
generation of involuntary movements in Huntington's disease may also be
involved in a rare disorder known as hemiballismus which is usually
caused by a vascular lesion in the subthalamic nucleus. In this instance, the
loss of excitatory subthalamic input to basal ganglia output structures results
in disinhibition of their targets, which results in suddenly developing
symptoms of violent flinging movements of the extremities contralateral to the
lesion.
DISEASES AS LESIONS OF THE
CORTICO-STRIATO-PALLIDO-THALAMIC CIRCUITRIES
The
concept of parallel circuits also explains why often the same symptoms can be
observed caused by lesions at different locations in the
fronto-striato-pallido-thalamocortical loop. In other words, behavioral
syndromes observed with frontal lobe lesions are recapitulated with striatal or
thalamic lesions and there are recognizable circuit-specifc behaviors.
Dorsal
caudate lesions produce executive function
deficits (impaired performance on the
Globus
pallidus lesions. Three discrete syndromes
equivalent to the frontal lobe symptom complexes cannot be identified in
patients with GP lesions. Neverheless,
mixture of apathy, irritability and neuropsychological deficits affecting
memory and executive functions resembling those of patients with frontal lobe
lesions are present. Given the progressive spatial restriction of the parallel
circuits at this anatomical level, focal lesions may involve several circuits
simultaneously, resulting in mixed behavioral syndromes.
Thalamic
syndromes. Vascular and degenerative
disorders affecting the thalamus reveal that typical frontal lobe type
behaviors can be observed with lesions of the thalamus. With bilateral
paramedian thalamic infarction, patients were dysphoric, irritable, sometimes
alternated between fretfulness and silly cheerfulness, disinhibition and inappropriate behavior. The
patients had memory deficits. Patients with bilateral medial thalamic
infarction showed disinhibition, apathetic irritability, utilization behavior
and distractibility. Neurobehavioral examination revealed decreased mental
control, poor memory and reduced verbal fluency. Poor performance with WCST.
PARKINSON’S DISEASE,
TOURETTE SYNDROME AND OCD as FAILURE TO SHIFT between MOTOR PROGRAMS
According
to this notion the BG perform an operation critical for shifting mental set. In
the motor domain, a problem in initiating movements can be viewed as a deficit
in set shifting. The Parkinsonian patient gets stuck in one position or posture
and cannot shift to a new one. The BG is in a position to monitor activation
across wide regions of the cortex, allowing a shift between different actions
and mental sets by removing an inhibitory influence in selected neurons. In one experiment (Brotchie et al, 1991),
monkeys were trained to make a pair of movements with a variable delay between
the first and second movements. A burst in pallid neurons observed at the end
of the delay period was interpreted as a releasing signal for the cortex to
switch from one plan to another.
This shifting hypothesis also may
hold the key to the basal ganglia’s role in learning. Dopamine is known to play
a critical role in reward system of the brain, providing the organism with
neurochemical marker of the reinforcement contingencies that exist for
different responses in the context of the current environment. Learning
involves change in behavior –either acquiring the appropriate response in an
unfamiliar context or breaking a habitual response when contingencies change in
a familiar context. For a rat in the wild, this might mean being sensitive to a
change in the availability of food at a foraging site. For a human, it might
mean recognizing that a demanding problem cannot be solved by conventional
means. One can hypothesize that within the BG, dopamine serves to bias the
system to produce certain responses over others. Dopamine release in the
striatum follows successful actions. This transmitter may modify the
input-output channels in the BG, making it more likely that the animal will
shift to the previously rewarded action when the associated input pattern is
reactivated in the future.
Viewed this way, the ability to
shift is required for producing novel behavior or for combining patterns of
behavior into novel sequences. A cardinal feature of Tourette’s syndrome (TS)
and OCD is the repetitive production of stereotyped movement patterns. For the
patient with TS, this might be a simple tic, or a hand brushing across the
face; with OCD, an entire behavioral sequence, such as hand washing can be
performed over and over again. A failure to shift may result in an absence of
movement, the problem of the PD patient, or in the repeated production of a
single pattern.