252 SECTION III Central & Peripheral Neurophysiology
the caudate nuclei, also play a role in some cognitive processes.
Possibly because of the interconnections of this nucleus with
the frontal portions of the neocortex, lesions of the caudate
nuclei disrupt performance on tests involving object reversal
and delayed alternation. In addition, lesions of the head of the
left but not the right caudate nucleus and nearby white matter
in humans are associated with a dysarthric form of aphasia
that resembles Wernicke aphasia.
DISEASES OF THE BASAL
GANGLIA IN HUMANS
Three distinct biochemical pathways in the basal ganglia nor-
mally operate in a balanced fashion: (1) the nigrostriatal dopa-
minergic system, (2) the intrastriatal cholinergic system, and
(3) the GABAergic system, which projects from the striatum to
the globus pallidus and substantia nigra. When one or more of
these pathways become dysfunctional, characteristic motor ab-
normalities occur. Diseases of the basal ganglia lead to two gen-
eral types of disorders: hyperkinetic and hypokinetic. The
hyperkinetic conditions are those in which movement is exces-
sive and abnormal, including chorea, athetosis, and ballism.
Hypokinetic abnormalities include akinesia and bradykinesia.
Chorea is characterized by rapid, involuntary “dancing”
movements. Athetosis is characterized by continuous, slow
writhing movements. Choreiform and athetotic movements
have been likened to the start of voluntary movements occurring
in an involuntary, disorganized way. In ballism, involuntaryCLINICAL BOX 16–4
Basal Ganglia Diseases
The initial detectable damage in Huntington disease is to
medium spiny neurons in the striatum. This loss of this
GABAergic pathway to the globus pallidus external segment
releases inhibition, permitting the hyperkinetic features of
the disease to develop. An early sign is a jerky trajectory of the
hand when reaching to touch a spot, especially toward the
end of the reach. Later, hyperkinetic choreiform movements
appear and gradually increase until they incapacitate the pa-
tient. Speech becomes slurred and then incomprehensible,
and a progressive dementia is followed by death, usually
within 10–15 years after the onset of symptoms. Huntington
disease affects 5 out of 100,000 people worldwide. It is inher-
ited as an autosomal dominant disorder, and its onset is usu-
ally between the ages of 30 and 50. The abnormal gene re-
sponsible for the disease is located near the end of the short
arm of chromosome 4. It normally contains 11–34 cytosine-
adenine-guanine (CAG) repeats, each coding for glutamine. In
patients with Huntington disease, this number is increased to
42–86 or more copies, and the greater the number of repeats,
the earlier the age of onset and the more rapid the progres-
sion of the disease. The gene codes for huntingtin, a protein
of unknown function. Poorly soluble protein aggregates,
which are toxic, form in cell nuclei and elsewhere. However,
the correlation between aggregates and symptoms is less
than perfect. It appears that a loss of the function of hunting-
tin occurs that is proportionate to the size of the CAG insert.
At present, no effective treatment is available, and the disease
is uniformly fatal. However, there are a few glimmers of hope.
In animal models of the disease, intrastriatal grafting of fetal
striatal tissue improves cognitive performance. In addition,
tissue caspase-1 activity is increased in the brains of humans
and animals with the disease and in mice in which the gene
for this apoptosis-regulating enzyme has been knocked out,
progression of the disease is slowed.Another basal ganglia disorder is Wilson disease (or
hepatolenticular degeneration), which is a rare disorder of
copper metabolism which has an onset between 6 to 25
years of age, affecting about four times as many females as
males. Wilson disease affects about 30,000 people world-
wide. It is a genetic autosomal recessive disorder due to a
mutation on the long arm of chromosome 13q. It affects the
copper-transporting ATPase gene (ATP7B) in the liver, lead-
ing to an accumulation of copper in the liver and resultant
progressive liver damage. About 1% of the population carries
a single abnormal copy of this gene but do not develop any
symptoms. A child who inherits the gene from both parents
may develop the disease. In affected individuals, copper ac-
cumulates in the periphery of the cornea in the eye account-
ing for the characteristic yellow Kayser–Fleischer rings. The
dominant neuronal pathology is degeneration of the puta-
men, a part of the lenticular nucleus. Motor disturbances in-
clude “wing-beating” tremor or asterixis, dysarthria, un-
steady gait, and rigidity. Treatment is to reduce the copper in
the body.
Another disease commonly referred to as a disease of the
basal ganglia is tardive dyskinesia. This disease indeed in-
volves the basal ganglia, but it is caused by medical treat-
ment of another disorder with neuroleptic drugs such as
phenothiazides or haloperidol. Therefore, tardive dyskinesia
is iatrogenic in origin. Long-term use of these drugs may pro-
duce biochemical abnormalities in the striatum. The motor
disturbances include either temporary or permanent uncon-
trolled involuntary movements of the face and tongue and
cogwheel rigidity. The neuroleptic drugs act via blockade of
dopaminergic transmission. Prolonged drug use leads to hy-
persensitivity of D 3 dopaminergic receptors and an imbal-
ance in nigrostriatal influences on motor control.