Parkinson's Disease, Depression, and Electrical Stimulation of the Brain

On November 6, 1780, the Italian anatomist Luigi Galvani made an entry in
his diary that recorded his observation of electrically stimulated muscle
contractions in the legs of a freshly killed frog. Galvani performed
subsequent experiments in which a similar reaction was evoked by the
contact of different regions of a frog's body with two disparate metals,
such as brass and iron.

However, Galvani misunderstood the phenomenon as the result of the
extraction of the frog's "animal electricity" by the dissimilar metals. His
contemporary, Count Alessandro Volta, discovered that the muscle
contraction was evoked by the passage through the frog's body of an
electrical current produced by the two metals. Volta invented the electric
battery by similarly pairing two different metals in electrolyte solutions.

About 150 years later, neurosurgeon Wilder Penfield reported the electrical
activation of auditory, visual, and what he later termed "psychical" states
by stimulation with an electrical probe of the superior and lateral
surfaces of the temporal lobes of the brains of living human beings.

In a subsequent report, Penfield and Perot described the responses to
electrical stimulation in 1132 patients undergoing surgery for focal
epilepsy. They categorized the patients' responses to the electrical
stimulation according to whether they were auditory, visual, both visual
and auditory, or "unclassified." The unclassified reactions included
dreams, flashbacks, and somatic sensations.

Curiously, Penfield and Perot did not document that primary mood states,
such as depression, were evoked by cortical stimulation. A primary mood
state would be unrelated to the ideations or sensory experiences that were
elicited by the electrical stimulation.

Neuroscientist Larry Squire summarized the conclusions that Penfield drew
from his observations as follows: "Penfield interpreted these experiential
hallucinations as veridical reproductions of past experi-ence.... The
stimulating electrode drew the reproduction from its place of storage, much
as if a tape recorder were switched on at some arbitrary position."

Over the course of the second half of the 20th century, evidence from
several sources has advanced explanations for perceptual and cognitive
phenomena arising from cortical stimulation that are different from that
posited by Penfield. One fertile source of such evidence has been the
exploration, from multiple perspectives, of the association of two chronic,
disabling neuropsychiatric disorders: Parkinson's disease and major
depression.
These conditions share common symptoms, including slowing of psychomotor
function, diminished energy, sleep disturbances, reduced appetite, and
decreased motivation. In addition, the two illnesses often coexist, with a
40 percent mean frequency of depression among patients with Parkinson's
disease.

Evidence from a variety of sources integrates the clinical features of
Parkinson's disease and depression with neuroanatomical and
pathophysiologic findings. This evidence comes from the correlation of
clinical symptoms with structural lesions and focal neuropathology; results
of brain-imaging studies of patients with Parkinson's disease or
depression; the use of pharmacologic interventions that improve both
disorders (including the use of levodopa, monoamine oxidase inhibitors, and
catechol O-methyltransferase inhibitors); the use of neurosurgical
procedures that treat Parkinson's disease (including pallidotomy,
thalamotomy, and transplantation of fetal mesencephalic tissue); the use of
electrical-stimulation techniques, including electroconvulsive therapy,
that ameliorate the symptoms of both Parkinson's disease and depression;
the use of transcranial magnetic stimulation, reported to be effective in
both depression and Parkinson's disease; and the use of high-frequency
deep-brain stimulation, a new treatment for Parkinson's disease.

In this issue of the Journal, Bejjani and colleagues report the case of a
patient who received high-frequency deep-brain stimulation to treat her
intractable Parkinson's disease. Although stimulation of the left
subthalamic nucleus of her brain through an electrode improved the symptoms
of Parkinson's disease, electrical stimulation delivered through a second
electrode positioned in the central region of the left substantia nigra
evoked, during the course of the stimulation, unequivocal symptoms and
signs of depression.

This effect is remarkable, not only because the patient had no previous
known episodes of depression (thus diminishing the likelihood that the
memory of a previously experienced mood state was evoked) but also because
only a few cubic millimeters of neural tissue were being stimulated in a
part of the brain not usually associated with mood regulation.

This discovery will spark a plethora of new hypotheses related to the
neuropathological features of both Parkinson's disease and depression, and
these speculations will encompass assessments of the roles of localized
neuronal destruction, disruption of neural pathways coursing through the
substantia nigra, and disturbances of neurotransmitter systems.

However, because of the extraordinary complexity of the human central
nervous system and the limitations of our current knowledge of brain
function and dysfunction, these hypotheses and speculations will be
embraced and inevitably refined or discarded -- as have those from the work
of Galvani and Penfield.

The report by Bejjani et al. raises fundamental and far-reaching questions
about depression, as well as about electrical treatments for
neuropsychiatric illnesses. Among such questions are the following: If the
full constellation of depressive symptoms can be evoked by the electrical
stimulation of a minute region of the brain in a person with no history of
depression, does this indicate that depression may be "hard-wired" in the
brain?

Could there be an evolutionary advantage or purpose for depression -- such
as an intensification of a grief reaction that aids in parental and
conjugal bonding and that protects vulnerable offspring from familial
predation? Can symptoms of mania be similarly induced by deep stimulation
of a different region of the brain, and would this procedure be therapeutic
for a patient with depression?

Would stimulation of the locus in the substantia nigra reported to have
evoked the symptoms of depression treat another patient with manic illness?
Would electrical stimulation or modification of other regions of the brain
treat alcoholism, substance abuse, sociopathy, aggression, violence, and
other conditions of far-reaching importance to individuals and society?

What are the implications of focal electrical stimulation of the brain for
the elicitation of nonpathologic states of feeling, such as humor,
astonishment, curiosity, well-being, and love? What are the ethical
considerations and social implications of our being able to modify our
responses, experiences, and abilities by electrical alteration of our brains?

Finally, will a world that is filled with the pain and suffering caused by
severe neuropsychiatric disorders eventually be replaced by one in which we
control our feelings, perceptions, and behavior -- and those of others --
with electrical devices that stimulate the cells of our brains?


Stuart C. Yudofsky, M.D. Baylor College of Medicine Houston, TX 77030
Subject: Editorials -- NEJM 1999; 340: 1500-1502
http://www.nejm.org/content/1999/0340/0019/1500.asp
The New England Journal of Medicine -- May 13, 1999 -- Vol. 340, No. 19
Copyright 1999 by the Massachusetts Medical Society. All rights reserved.

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