Correspondence
Transient Acute Depression Induced by High-Frequency Deep-Brain Stimulation
N Engl J Med 1999; 341:1003-1004September 23, 1999
- Article
To the Editor:
Bejjani et al. (May 13 issue)1 reported the induction of transient acute depression by stimulation of the left subthalamic nucleus in a woman with Parkinson's disease. We have found that pallidotomy may also cause depression in patients with this disease. Among 41 patients (25 men and 16 women; mean age at operation, 60 years) with severe, chronic Parkinson's disease, 17 underwent left-sided pallidotomy, 13 right-sided pallidotomy, and 11 bilateral pallidotomy. All the patients improved after surgery. Persistent major depression, as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition,2 developed immediately after the surgical procedure in five of these patients, all of whom had undergone left-sided pallidotomy. The 5 patients did not differ from the other 36 patients with regard to sex or age, duration of parkinsonian symptoms, severity of symptoms as assessed by the Unified Parkinson's Disease Rating Scale, or extent of improvement after pallidotomy. They were treated with a selective serotonin-reuptake inhibitor and improved markedly.
These findings point to the pivotal role played by the basal ganglia in mood disorders and to the functional asymmetry of the brain.3
3 ReferencesMárcio L.S. Bezerra, M.D.
J.-Victor L. Martínez, M.D.
José A. Nasser, M.D.
Fluminense Federal University, 24030-210 Niterói, Brazil1
Bejjani B-P ,Damier P ,Arnulf I , et al. Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med 1999;340:1476-1480
Full Text | Web of Science | Medline2
Diagnostic and statistical manual of mental disorders, 4th ed: DSM-IV. Washington, D.C.: American Psychiatric Association, 1994.
3
Robinson RG ,Kubos KL ,Starr LB ,Rao K ,Price TR . Mood disorders in stroke patients: importance of location of lesion. Brain 1984;107:81-93
CrossRef | Web of Science | Medline
To the Editor:
In contrast to depression as reported by Bejjani et al., we induced involuntary laughter by stimulation of one contact of electrodes implanted in the subthalamic nucleus in two men with Parkinson's disease; the stimulation was unilateral in one man but bilateral in the other. As the stimulation amplitude was gradually increased, the men described a feeling of well-being. With a further increase in voltage, comments that ordinarily would not be construed as humorous triggered imaginative associations, smiling, and repeated bursts of highly contagious, natural-sounding laughter, which, although embarrass-ing because of its inappropriate nature, was accompanied by merriment. The symptoms of Parkinson's disease improved simultaneously. The laughter continued intermittently for several minutes until the amplitude of stimulation was lowered or stimulation was discontinued.
On two other occasions, similar laughter was reproduced in both men, with institutional approval and the men's consent, with the use of identical stimulation settings. Magnetic resonance imaging showed that each of the responsible contacts was within the subthalamic nucleus. With long-term stimulation at lower amplitudes and with the use of these same contacts, each man had marked improvement in the symptoms of parkinsonism. Of the first 100 patients we treated with electrode implantation, there were only two in whom stimulation induced laughter.
Stimulation of the subthalamic nucleus often improves motor function in patients with Parkinson's disease.1 Current models of the function of the basal ganglia suggest that cortical basal ganglionic loops that include the subthalamic nucleus and the adjacent substantia nigra might also affect associative and limbic function. Electrical stimulation of the anterior supplementary motor area, anterior cingulate gyrus, or basal temporal lobe may cause laughter with or without merriment.2-4 The activity of the supplementary motor area and cingulate gyrus is modified by stimulation of the subthalamic nucleus, whereas the temporal lobe is an output target of the basal ganglia. These observations suggest that the subthalamic nucleus is part of a neuronal network that may influence the emotional state and cause laughter — or depression, as reported by Bejjani et al.
4 ReferencesRajeev Kumar, M.D.
Colorado Neurological Institute, Englewood, CO 80110-2776Paul Krack, M.D.
University of Kiel, 24105 Kiel, GermanyPierre Pollak, M.D.
University of Grenoble, 38043 Grenoble CEDEX 9, France1
Limousin P ,Greene J ,Pollak P ,Rothwell J ,Benabid AL ,Frackowiak R . Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson's disease. Ann Neurol 1997;42:283-291
CrossRef | Web of Science | Medline2
Arroyo S ,Lesser RP ,Gordon B , et al. Mirth, laughter, and gelastic seizures. Brain 1993;116:757-780
CrossRef | Web of Science | Medline3
Fried I ,Wilson CL ,MacDonald KA ,Behnke EJ . Electric current stimulates laughter. Nature 1998;391:650-650
CrossRef | Web of Science | Medline4
Talairach J ,Bancaud J ,Geier S , et al. The cingulate gyrus and human behaviour. Electroencephalogr Clin Neurophysiol 1973;34:45-52
CrossRef | Medline
To the Editor:
The case reported by Bejjani et al.1 presents a complex physiologic conundrum. John Hughlings Jackson insisted that “the symptomatology of all nervous diseases is duplex; that in every case there is a negative, and there is also a positive element.”2 Destructive lesions of the motor cortex result in negative symptoms of clumsiness and paresis; the characteristic positive “release” symptom is increased muscle-stretch reflexes, and a positive “irritative” symptom is a focal motor seizure.
Bejjani et al. point out that “the effects of high-frequency thalamic or subthalamic stimulation are similar to those of thalamotomy in humans or subthalamotomy in nonhuman primates.”1 The physiologic explanation of this paradox is that excitable nervous tissue is incapable of transmitting action potentials when stimulated at a rate of 130 shocks per second after the first few shocks; the excitable membranes are maintained then in a state of depolarization block. Prolonged improvement of tremor in patients with Parkinson's disease indicates that this block is sustainable. The validity of this idea is supported by the fact that when an appropriate “tremorogenic” site in the thalamus is first stimulated, there may be several seconds of contralateral paresthesia.
The simplistic Jacksonian inference to explain the findings of Bejjani et al. would be that the stimulation somehow turned off a “happiness system” rather than turned on a “depression center.” The hypothesis that stimulation functionally ablates some subthalamic neurons requires that depression be the product of other active structures. The measurements by positron-emission tomography of increased circulation in several regions could relate to any combination of increased excitation, disinhibition, and direct inhibition, and no regions of decreased perfusion were discovered. The challenge now is to ascertain the nature of the changes in neuronal activity in the regions of increased circulation.
2 ReferencesWilliam M. Landau, M.D.
Joel S. Perlmutter, M.D.
Washington University School of Medicine, St. Louis, MO 631101
Bejjani B-P ,Damier P ,Arnulf I , et al. Transient acute depression induced by high-frequency deep-brain stimulation. N Engl J Med 1999;340:1476-1480
Full Text | Web of Science | Medline2
Taylor J, Holmes G, Walshe FMR, eds. Jackson JH: selected writings. Vol. 2. New York: Basic Books, 1958:54.
Author/Editor Response
The authors reply:
To the Editor: Bezerra and colleagues have observed persistent depression in patients with Parkinson's disease who were treated by pallidotomy — suggesting, as in the case we report, that the basal ganglia have a role in mood disorders. In contrast to their observation, however, in our patient the depression induced by stimulation was transient, related solely to the stimulation, and reversible, and the site of the stimulation that induced depression was confined to the left substantia nigra, apart from the subthalamic therapeutic target, where stimulation improved parkinsonian disability.
The role of other factors, such as drug withdrawal, surgical stress, and the dramatic changes in daily life that resulted from surgical treatment, cannot be ruled out in the depressed patients described by Bezerra and colleagues. In 4 of 30 patients treated by bilateral subthalamic stimulation in our center, we likewise observed a persistent depressive state that was not modified by changes in the conditions or site of stimulation but that could be relieved by antidepressant drugs.
Like Kumar and colleagues, we observed a transient euphoric state with laughter in two patients whom we treated with bilateral subthalamic stimulation. Obtained with a high voltage applied at sites where stimulation improves parkinsonian disability, the feeling of well-being that accompanied the improvement in motor state might have contributed to the euphoria, but the involvement of subthalamic and nigral neural circuits that participate in the control of emotion can in no way be excluded.
We totally agree with Landau and Perlmutter that our observation does not allow us to reach a firm conclusion about the nature of neural systems turning on or off a putative “depression center.”
Boulos-Paul Bejjani, M.D.
Philippe Damier, M.D., Ph.D.
Yves Agid, M.D., Ph.D.
Hôpital Pitié-Salpêtrière, 75651 Paris CEDEX 13, France- Citing Articles (26)
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