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CASE 47
A 63-year-old man is brought to his primary care physician because of concern
on the part of his family that he is acting differently. He has been having a worsening tremor at rest and difficulty walking. His family states that when he
walks, he often has difficulty stopping. He has no personal or family medical
history. On examination, he has a mask-like facial expression with little blinking. He is noted to have a fine tremor at rest in a “pill-rolling” manner. He has
muscular rigidity and a stooped posture. On walking, the patient is noted to
have rapid propulsion forward with an inability to stop. He shows no signs of
dementia or depression. He subsequently is diagnosed with Parkinson disease.
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Which nuclei compose the basal ganglia?
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Where is the lesion for Parkinson disease located?
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What would be the location of the lesion in a patient with
hemiballismus?
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CASE FILES: PHYSIOLOGY
ANSWERS TO CASE 47: BASAL GANGLIA
Summary: A 63-year-old man presents with muscle rigidity, resting tremor,
and difficulty walking, consistent with Parkinson disease.
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Nuclei composing basal ganglia: Caudate, putamen, globus pallidus,
subthalamic, substantia nigra.
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Location of lesion in Parkinson disease: Substantia nigra.
Location of lesion in patient with hemiballismus: Subthalamic
nucleus.
CLINICAL CORRELATION
Properly functioning basal ganglia are necessary to control a person’s movement. A lesion in any part of the basal ganglia will result in a characteristic
movement disorder. Lesions of the striatum result in continuous, quick, and
uncontrolled movements, as seen with Huntington disease. Hemiballismus can
be seen with lesions of the subthalamic nuclei, and postural support may be
lost with lesions of the globus pallidus. A lesion of the substantia nigra will
result in Parkinson disease, the symptoms of which are produced by a loss of
dopamine-containing nerve cells in the substantia nigra. Patients with
Parkinson disease may have a combination of symptoms, including resting
tremor, rigidity, bradykinesia, disturbance of gait, and postural problems. The
cause of Parkinson disease is unknown.
APPROACH TO BASAL GANGLIA PHYSIOLOGY
Objectives
1.
2.
Be able to describe the organization and functions of the basal ganglia.
Know the direct and indirect pathways in the basal ganglia motor loop.
Definitions
Disinhibition: Removal of an inhibitory input, resulting in increased excitation of a target.
Hemiballismus: Movement disorder characterized by large, spontaneous,
uncontrolled throwing motions of the arm and leg (usually unilateral).
Choreiform: Movements that are dance-like, involving large groups of
muscles.
CLINICAL CASES
381
DISCUSSION
The basal ganglia, located near the thalamus in the diencephalon, are composed of five pairs of nuclei: the caudate nucleus, putamen, globus pallidus,
subthalamic nucleus, and substantia nigra. The basal ganglia receive synaptic input from motor cortex (as well as from sensory association and prefrontal
cortex) and send their output to the thalamus, which then feeds back to the cortex. Although the functions of the basal ganglia are not well understood, strong
evidence indicates that through these connections from and back to motor cortical areas, the basal ganglia provide a motor loop that contributes to the
planning and programming of voluntary movements. In addition, the basal
ganglia appear to be important for some cognitive processes, such as those
involving the organization of behavioral responses and verbal problem solving.
The motor loop comprises two parallel pathways that travel from the cortex
through the basal ganglia and then to the thalamus and back to the cortex
(Figure 47-1). Each branch has an opposite effect on thalamic targets. The
direct pathway goes through the caudate and putamen (which together
form the neostriatum) to the internal segment of the globus pallidus and the pars
reticulata segment of the substantia nigra and then to the ventral anterior and
centromedian nuclei of the thalamus. The indirect pathway goes through the
external segment of the globus pallidus, then to the subthalamus, and then
(like the direct pathway) to the internal segment of the globus pallidus and substantia nigra. Each pathway is activated by excitatory synapses (releasing
glutamate) from cortical regions. Both pathways inhibit neurons in the
thalamus via fibers from the globus pallidus and substantia nigra, which release
γ-aminobutyric acid (GABA). In the direct pathway, neurons in the neostriatum
directly inhibit (via GABA release) the neurons in the globus pallidus and substantia nigra. In the indirect pathway, neurons in the neostriatum inhibit neurons
in the external segment of the globus pallidus, which inhibit neurons in the subthalamic nucleus, which then excite neurons in the globus pallidus and substantia nigra. Because the indirect pathway has two inhibitory synapses in
series and the direct pathway has only one inhibitory synapse (onto the globus
pallidus and substantia nigra), activation of the indirect pathway will increase
the activity of the globus pallidus and substantia nigra, whereas activation of the
direct pathway will decrease activity in the same nuclei. See Figure 47-1.
The output neurons for both pathways in the globus pallidus and substantia nigra are usually active at high frequency and tonically inhibit target nuclei in the thalamus. When the direct pathway is activated transiently,
the tonically active output neurons are inhibited transiently, and this disinhibition increases activity in the thalamus and thereby in the cortex (the motor
loop shows positive feedback). When the indirect pathway is activated transiently, the output neurons are excited, and activity in the thalamus and cortex
is inhibited (negative feedback). In the basal ganglia, most of the synapses are
inhibitory (releasing GABA), and excitation is produced by inhibiting an
inhibitory pathway (disinhibition).
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CASE FILES: PHYSIOLOGY
Dopamine
Supplemental
motor area
D2
D1
Direct
pathway facilitates
movement
Thalamus
Indirect
pathway inhibits
movement
From
SNc
Direct
GPi
GPe
Indirect
Caudate
nucleus
STN
Putamen
Figure 47-1. Direct and indirect pathways in the motor loop connecting the
basal ganglia to the thalamus and cortex. SNc—pars compacta segment of
substantia nigra, GPe—external segment of globus pallidus, GPi—internal
segment of globus pallidus, STN—subthalamic nucleus, solid lines—excitatory pathways, dashed lines—inhibitory pathways, D1 and D2—classes of
dopamine receptors.
CLINICAL CASES
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Both the direct and indirect pathways are modulated by the nigrostriatal pathway by neurons in the pars compacta segment of the substantia
nigra that release dopamine onto neurons in the neostriatum. Neurons in
the neostriatum that mediate the direct pathway have D1 dopamine receptors that produce excitation. In contrast, neurons in the neostriatum that
mediate the indirect pathway have D2 dopamine receptors that produce
inhibition.
Thus, dopamine release from pars compacta neurons excites the direct pathway, which inhibits the output neurons, thereby increasing thalamic activity and
ultimately facilitating movements initiated in the cortex. Synergistically,
dopamine inhibits the indirect pathway, further increasing the inhibition of the
output neurons. Many of the effects of Parkinson disease can be explained by
a marked reduction in dopamine release (caused by degeneration and death
of neurons in the substantia nigra) that results in less disinhibition of thalamic activity and thus decreased facilitation of movements initiated in the
cortex. The substantia nigra is also the source of dopaminergic input to the rest
of the brain with the exception of the pituitary gland, which receives dopaminergic fibers from the arcuate nucleus of the hypothalamus. The mesolimbic and
mesocortical tracts arising from the substantia nigra contribute to affect, emotion, and motivation and also are involved in schizophrenia.
Basal ganglia disorders also occur after lesions to these nuclei, most commonly caused by small strokes. Lesions of the subthalamic nucleus often
result in involuntary, sometimes violent movements of the contralateral limbs;
this is termed hemiballism because of the resemblance to throwing movements. Hemiballism appears to result from disinhibition of the thalamus
caused by reduction of activity in the output nuclei of the basal ganglia
(especially the internal pallidal segment) that sometimes is caused by a
decrease in excitation from the subthalamic nucleus. Huntington disease, a
heritable hyperkinetic disorder, is caused by widespread loss of neurons that
begins in the striatum with loss of the neurons that give rise to the indirect
pathway. This results in inhibition of subthalamic nucleus neurons and choreiform movements and hemiballism-like movements in early stages of the disease. After the disease progresses, rigidity and akinesia develop (as in
Parkinson disease) because the neurons that project directly to the internal pallidal segment are lost.
COMPREHENSION QUESTIONS
[47.1]
Which of the following is the major neurotransmitter released by
most neurons within the basal ganglia?
A.
B.
C.
D.
E.
Acetylcholine
Dopamine
GABA
Glycine
Glutamate
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[47.2]
CASE FILES: PHYSIOLOGY
Which of the following provide, respectively, the predominant input
to, the output from, and the direct synaptic target of the basal ganglia?
A.
B.
C.
D.
E.
[47.3]
Cerebellum, globus pallidus, substantia nigra
Cerebral cortex, globus pallidus, cerebral cortex
Cerebral cortex, globus pallidus, thalamus
Cerebral cortex, putamen, substantia nigra
Thalamus, globus pallidus, cerebral cortex
A 62-year-old nursing home patient is brought into the emergency
department for evaluation of altered mental status. Magnetic resonance
imaging indicates degeneration of dopamine-containing neurons in the
substantia nigra. This loss is most likely to do which of the following?
A.
B.
C.
D.
E.
Decrease activity in basal ganglia output nuclei
Produce dyskinesias such as choreiform movements
Produce hemiballism
Suppress activity in the subthalamic nucleus
Suppress the direct pathway and facilitate the indirect pathway
from the striatum to the basal ganglia output nuclei
Answers
[47.1]
C. The majority of synapses from neurons in the basal ganglia are
inhibitory and release GABA. The other major inhibitory neurotransmitter, glycine, is not important in the basal ganglia and is released
primarily from inhibitory interneurons in the spinal cord. Dopamine
is an important neurotransmitter that is released by neurons in the
substantia nigra, but these neurons account for only a small fraction
of the total number of neurons in the basal ganglia. In addition, other
neurotransmitters (eg, acetylcholine, NO, various neuropeptides) are
released from some neurons in the basal ganglia, but the largest number of synapses are GABAergic.
[47.2]
C. The basal ganglia and thalamus form a motor loop with the cerebral cortex. Input to the basal ganglia comes from prefrontal and sensory association areas of the cerebral cortex and leaves the basal
ganglia via the internal segment of the globus pallidus. The immediate target of these neurons is the thalamus (ventral anterior, ventral
lateral, and centromedian nuclei). These thalamic nuclei then project
to motor areas in the cerebral cortex.
[47.3]
E. Under normal conditions, dopamine released by neurons in the substantia nigra affects both the direct and indirect pathways in the motor
loop to the cerebral cortex, exciting the direct, stimulatory pathway to
the thalamus and inhibiting the indirect, inhibitory pathway to the thalamus. Thus, if the dopamine-containing neurons degenerate (as occurs in
Parkinson disease), the excitatory actions on the thalamus are inhibited
CLINICAL CASES
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and there is less disinhibition of the inhibitory actions, with the consequence that excitation from the thalamus to motor areas in the cortex is
decreased and it becomes more difficult to initiate movements. The
other effects listed (answers A–D) would not be produced by selective
loss of dopaminergic neurons, but instead by lesions of the subthalamic
nucleus or early stages of striatal neuron loss.
PHYSIOLOGY PEARLS
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The four principal nuclei of the basal ganglia are the striatum,
globus pallidus, substantia nigra, and subthalamic nucleus.
The motor loop comprises two parallel pathways that travel from the
cortex through the basal ganglia and then to the thalamus and back
to the cortex. In the direct pathway, excitatory input to the basal
ganglia excites thalamic neurons by inhibiting the inhibitory output neurons in the internal segment of the globus pallidus. In the
indirect pathway, excitatory input to the basal ganglia further
inhibits thalamic neurons by disinhibiting the inhibitory output
neurons in the internal segment of the globus pallidus.
GABA is the most prominent inhibitory neurotransmitter in most of
the brain, although glycine is an important inhibitory neurotransmitter in the spinal cord and brainstem.
Dopamine release from pars compacta neurons in the substantia nigra
excites the direct pathway (by D1 receptors), which inhibits the
inhibitor output neurons, thereby increasing thalamic activity and
ultimately facilitating movements initiated in the cortex, whereas
dopamine simultaneously inhibits the indirect pathway (by D2
receptors), further increasing the inhibition of the inhibitory output neurons.
Loss of dopaminergic neurons in Parkinson disease reduces the activation of the direct pathway as well as the inhibition of the indirect pathway, allowing greater inhibition of thalamic neurons and
greater suppression of movements initiated in the cortex, resulting in the hypokinetic signs of this disease.
REFERENCES
Johnson DA. The basal ganglia. In: Johnson LR, ed. Essential Medical Physiology.
San Diego, CA: Elsevier Academic Press; 2003:881-887.
Mahlong RD. The basal ganglia. In: Kandel ER, Schwartz JH, Jessell TM. Principles
of Neuroscience. New York, NY: McGraw-Hill; 2000: 853-867.
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