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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. ------------------------------------------------------------ janet paterson 52 now 41 dx 37 onset [log in to unmask] 613-256-8340 PO Box 171 Almonte Ontario K0A 1A0 Canada a new voice <http://www.geocities.com/SoHo/Village/6263/> ------------------------------------------------------------