Linda, your excellent (as always) review did not include the following editorial
(or its companion article).  Please send me the article you cited please. It
will be helpful to have. As a result of on-going efforts to follow-up the
implementation of the NIH Parkinson's research agenda, I have been invited to
participate next Spring in a work group sponsored by NIMH on mood disorder
comorbidities. This part of their research planning process.

While DBS certainly helps many patients for which medications are no longer
effective, it is not without risks. The recommendation of the FDA Panel that
reviewed DBS earlier this year indicated only certain kinds of patients were
tested (e.g. under 75, not suffering from dementia, etc.) in clinical trials.
More research is needed.  For example the effect of placement of the stimulator
in the STN vs the GPI is not well understood. The NIH is initiating a
significant research effort on DBS.

Perry Cohen
Washington DC
-----------------

The New England Journal of Medicine -- May 13, 1999 -- Vol. 340, No. 19

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. (1) 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. (2) 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. (3) In a
subsequent report, Penfield and Perot described the responses to electrical
stimulation in 1132 patients undergoing surgery for focal epilepsy. (4) 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." (5)

          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. (6) In addition, the two illnesses often coexist, with a 40 percent
mean frequency of depression among patients with Parkinson's disease. (7)

          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 (8) and Parkinson's disease (9); 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. (10) 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