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Prefrontal cortex in mood disorder following stroke
Prefrontal cortex and affective disorders
BIOL. PSYCHIATRY
2168
1997;42:15-297S
Symposia
78. Prefrontal cortex and affective disorders
178-1 I
Prefrontal cortex In mood disorder following stroke
R.G. Robinson. University of Iowa College of Medicine. USA Major depressive disorder occurs in approximately 20% of patients with acute stroke and a small number of patients develop mania. Clinical-pathological studies in both depression and mania have demonstrated an Increased frequency of mood disorders associated with lesions involving the prefrontal cortex or basal ganglia. Major depressive disorder occurs in approximately 60% of patients with lesions involving the left prefrontal cortex or the left basal ganglia. Lesions of the orbitofrontal cortex or right basal ganglia are associated with the development of mania. These clinical-pathological c0rre• lations, however, change over time and the association of major depression with left prefrontal lesions occurs only during the acute post-stroke period. A follow-up study of 60 patients with single stroke lesions of the right or left hemisphere and short-term (3 to 6 months) or long-term (1 to 2 years) follow-up demonstrated that, during the acute post-stroke period, severity of depression as measured by total score on the Present State Examination was significantly correlated with both the proximity of the lesion to the frontal pole and the lesion volume but only among patients with left hemisphere stroke (N 34). At short-term follow-up. there were significant correlations with severity of depression and proximity of the lesion to the frontal pole in both patients with right or left hemisphere lesions. At long-term follow-up, however, severity of depression correlated only with proximity of the lesion to the occipital pole in right hemisphere but not left hemisphere stroke. These time-related changes in the clinical-pathological correlations asso• ciated with stroke suggest that the neuronal and physiological mechanism mediating depression Is different in the acute and chronic post-stroke period. Studies using positron emission tomography in 3 patients with depression follOWing subcortical lesions and 3 patients with mania following subcortical lesions have demonstrated the importance of distant effects of the lesion on the development of mood disorders. The patients with depression fol• lowing basal ganglia lesions of the left hemisphere showed evidence of hypometabolic effect Involving the prefrontal cortex and basotemporal cor• tex In the left hemisphere while patients with mania following basal ganglia lesions showed evidence of hypometabolic activity in the right basotemporal cortex. These findings suggest that lesions may induce mood disorders through their effect on distant but related brain areas. In conclusion, these findings in patients with stroke suggest that either direct injury or metabolic abnormalities in left prefrontal cortex may play an Important role In the development of major depression. The lateral limbic circuits Involving prefrontal cortex, basal ganglia, basotemporal cortex. and thalamus may mediate the mood disorders with hemispheric asymmetries In the mediation or production of mood.
=
178-21
PET studies of prefrontal cortical activation by serotonin In major depression
J.J. Mann, S. Anjilvel, C.E. Campbell. R.L Van Heertum, K.M. Malone.
Department of Neuroscience, New York State Psychiatry, and Department of Psychiatry, Columbia University, New York. NY, USA
It has been difficult to directly study neurotransmitter function in human brain and evidence for the serotonin deficiency hypothesis of major depression has rested on indirect approaches Involving CSF 5-hydroxyindoacetic acid, neuroendocrine responses to serotonin agents and platelet studies. Although these studies have cumulatively suggested abnormalities in the serotonergic system, which areas In the brain are affected and whether the brain circuitry in areas relevant to mood regulation are Involved, has not been known. We recently developed a method for looking at brain serotonin responsivlty by positron emission tomographic (PET) visualization of 18F-2-deoxyglucose (FOG) uptake In normal subjects after placebo and following fenfluramine, a serotonin-releasing agent and reuptake inhibitor. This method showed signif.
leant responses in prefrontal cortical and other brain regions and we, there• fore, applied this approach to the study of patients with major depression. Method: We studied a group of patients with major depression who were admitted to the hospital for evaluation and treatment. All patients were drug-free for a minimum of two weeks. Patients received either placebo or fenlluramine In a single blind design and on two different days. Three hours after administration of drug 18F-deoxyglucose was Injected Intravenously and the patients were scanned 45 minutes later for one hour. Data were analyzed using the Statistical Parametric Mapping software (SPM, 1995 version). Results: Significant blunting of both areas of relative increase and relative decrease in metabolism were found In the depressed patients compared to healthy control SUbjects. Moreover, we found that the degree of blunting of regional brain metabolic responses in the prefrontal cortex was more pronounced in patients with particular features of psychopathology such as suicidal behavior. This appeared to be Independent of the overall severity of depression. These differences between patients and healthy controls and, also, the differences between suicide attempters and non-attempters were independent of differences in blood levels of fenlluramlne and its major metabolite, norfenlluramine. In contrast to the Imaging results, which were striking, prolactin levels showed only modest differences between the groups. Conclusions: This study provides further evidence supporting the sero• tonin deficiency hypothesis of major depression. It confirms results of a pilot report in six patients and six controls by our group (Mann et aI•• 1996, Demonstration In vivo of reduced serotonin responslvlty In the brain of un• treated depressed patients. American J Psychiatry. 153:174-182). Not only does this study confine our previous finding, but It also shows that certain patients with depression, such as those predisposed to suicidal acts. have further blunting of serotonin responsivity In areas of medial and ventral prefrontal cortex, where serotonin receptor changes are most striking in suicide victims. Finally, these results demonstrate that regional brain Imag• ing of serotonin responses may be a far more sensitive way of detecting biological abnormalities In major depression than techniques involving the measurement of neuroendocrine responses alone.
178-31
Prefrontal cortex, emotion and mood disorders
H.A. Sackeim. Department of Biological Psychiatry, New York State Psychiatric Institute and Departments of Psychiatry and Radiology, College of Physicians and Surgeons of Columbia University, NY, NY, USA This presentation will review evidence from studies of neurological samples. normal subjects, and psychiatric patients regarding the role of prefrontal cortex In the regulation of mood and in mood disorders. There Is convinc• ing evidence that different facets of affective functioning. the experience of emotion (mood), the expression of emotion, and the processing of emotion• ally-laden Information have distinct neural representation (Sackeim. 1991). Involvement of prefrontal regions In the experience of emotion and dysregu• lation of such regions during episodes of major depression and acute mania have been repeatedly demonstrated. What Is far less certain Is the nature of the neurophysiological changes that accompany altered mood states and the specific prefrontal systems Involved. This presentation will highlight key paradoxes In attempts to broadly inte• grate Information regarding the role of the prefrontal cortex In the regUlation of mood. For example, one line of research has Indicated that acute stroke In anterior left frontal regions is particularty likely to result In depressive symptoms, with right-sided lesions more commonly resulting in mania This work is compatible with some neuroimaglng studies suggesting that reduced cerebral blood flow and metabolism In major depression is, particularly evident In left frontal regions. However, with surprising consistency neu• ropsychological and Information processing studies have Implicated right posterior deficits In major depression. The tension between these sets of findings has gone unappreciated. Another paradox concems the effects of treatment Interventions. Initial ev• Idence with the new technology, transcranlal magnetic stimulation suggests that repetitive stimulation over the left dorsolateral prefrontal ~rtex has a depressive effect In normal subjects, while right dorsolateral stimulation may elevate mood. In contrast, initial findings with this same technology
BIOL. PSYCHIATRY
2168
1997;42:15-297S
Symposia
78. Prefrontal cortex and affective disorders
178-1 I
Prefrontal cortex In mood disorder following stroke
R.G. Robinson. University of Iowa College of Medicine. USA Major depressive disorder occurs in approximately 20% of patients with acute stroke and a small number of patients develop mania. Clinical-pathological studies in both depression and mania have demonstrated an Increased frequency of mood disorders associated with lesions involving the prefrontal cortex or basal ganglia. Major depressive disorder occurs in approximately 60% of patients with lesions involving the left prefrontal cortex or the left basal ganglia. Lesions of the orbitofrontal cortex or right basal ganglia are associated with the development of mania. These clinical-pathological c0rre• lations, however, change over time and the association of major depression with left prefrontal lesions occurs only during the acute post-stroke period. A follow-up study of 60 patients with single stroke lesions of the right or left hemisphere and short-term (3 to 6 months) or long-term (1 to 2 years) follow-up demonstrated that, during the acute post-stroke period, severity of depression as measured by total score on the Present State Examination was significantly correlated with both the proximity of the lesion to the frontal pole and the lesion volume but only among patients with left hemisphere stroke (N 34). At short-term follow-up. there were significant correlations with severity of depression and proximity of the lesion to the frontal pole in both patients with right or left hemisphere lesions. At long-term follow-up, however, severity of depression correlated only with proximity of the lesion to the occipital pole in right hemisphere but not left hemisphere stroke. These time-related changes in the clinical-pathological correlations asso• ciated with stroke suggest that the neuronal and physiological mechanism mediating depression Is different in the acute and chronic post-stroke period. Studies using positron emission tomography in 3 patients with depression follOWing subcortical lesions and 3 patients with mania following subcortical lesions have demonstrated the importance of distant effects of the lesion on the development of mood disorders. The patients with depression fol• lowing basal ganglia lesions of the left hemisphere showed evidence of hypometabolic effect Involving the prefrontal cortex and basotemporal cor• tex In the left hemisphere while patients with mania following basal ganglia lesions showed evidence of hypometabolic activity in the right basotemporal cortex. These findings suggest that lesions may induce mood disorders through their effect on distant but related brain areas. In conclusion, these findings in patients with stroke suggest that either direct injury or metabolic abnormalities in left prefrontal cortex may play an Important role In the development of major depression. The lateral limbic circuits Involving prefrontal cortex, basal ganglia, basotemporal cortex. and thalamus may mediate the mood disorders with hemispheric asymmetries In the mediation or production of mood.
=
178-21
PET studies of prefrontal cortical activation by serotonin In major depression
J.J. Mann, S. Anjilvel, C.E. Campbell. R.L Van Heertum, K.M. Malone.
Department of Neuroscience, New York State Psychiatry, and Department of Psychiatry, Columbia University, New York. NY, USA
It has been difficult to directly study neurotransmitter function in human brain and evidence for the serotonin deficiency hypothesis of major depression has rested on indirect approaches Involving CSF 5-hydroxyindoacetic acid, neuroendocrine responses to serotonin agents and platelet studies. Although these studies have cumulatively suggested abnormalities in the serotonergic system, which areas In the brain are affected and whether the brain circuitry in areas relevant to mood regulation are Involved, has not been known. We recently developed a method for looking at brain serotonin responsivlty by positron emission tomographic (PET) visualization of 18F-2-deoxyglucose (FOG) uptake In normal subjects after placebo and following fenfluramine, a serotonin-releasing agent and reuptake inhibitor. This method showed signif.
leant responses in prefrontal cortical and other brain regions and we, there• fore, applied this approach to the study of patients with major depression. Method: We studied a group of patients with major depression who were admitted to the hospital for evaluation and treatment. All patients were drug-free for a minimum of two weeks. Patients received either placebo or fenlluramine In a single blind design and on two different days. Three hours after administration of drug 18F-deoxyglucose was Injected Intravenously and the patients were scanned 45 minutes later for one hour. Data were analyzed using the Statistical Parametric Mapping software (SPM, 1995 version). Results: Significant blunting of both areas of relative increase and relative decrease in metabolism were found In the depressed patients compared to healthy control SUbjects. Moreover, we found that the degree of blunting of regional brain metabolic responses in the prefrontal cortex was more pronounced in patients with particular features of psychopathology such as suicidal behavior. This appeared to be Independent of the overall severity of depression. These differences between patients and healthy controls and, also, the differences between suicide attempters and non-attempters were independent of differences in blood levels of fenlluramlne and its major metabolite, norfenlluramine. In contrast to the Imaging results, which were striking, prolactin levels showed only modest differences between the groups. Conclusions: This study provides further evidence supporting the sero• tonin deficiency hypothesis of major depression. It confirms results of a pilot report in six patients and six controls by our group (Mann et aI•• 1996, Demonstration In vivo of reduced serotonin responslvlty In the brain of un• treated depressed patients. American J Psychiatry. 153:174-182). Not only does this study confine our previous finding, but It also shows that certain patients with depression, such as those predisposed to suicidal acts. have further blunting of serotonin responsivity In areas of medial and ventral prefrontal cortex, where serotonin receptor changes are most striking in suicide victims. Finally, these results demonstrate that regional brain Imag• ing of serotonin responses may be a far more sensitive way of detecting biological abnormalities In major depression than techniques involving the measurement of neuroendocrine responses alone.
178-31
Prefrontal cortex, emotion and mood disorders
H.A. Sackeim. Department of Biological Psychiatry, New York State Psychiatric Institute and Departments of Psychiatry and Radiology, College of Physicians and Surgeons of Columbia University, NY, NY, USA This presentation will review evidence from studies of neurological samples. normal subjects, and psychiatric patients regarding the role of prefrontal cortex In the regulation of mood and in mood disorders. There Is convinc• ing evidence that different facets of affective functioning. the experience of emotion (mood), the expression of emotion, and the processing of emotion• ally-laden Information have distinct neural representation (Sackeim. 1991). Involvement of prefrontal regions In the experience of emotion and dysregu• lation of such regions during episodes of major depression and acute mania have been repeatedly demonstrated. What Is far less certain Is the nature of the neurophysiological changes that accompany altered mood states and the specific prefrontal systems Involved. This presentation will highlight key paradoxes In attempts to broadly inte• grate Information regarding the role of the prefrontal cortex In the regUlation of mood. For example, one line of research has Indicated that acute stroke In anterior left frontal regions is particularty likely to result In depressive symptoms, with right-sided lesions more commonly resulting in mania This work is compatible with some neuroimaglng studies suggesting that reduced cerebral blood flow and metabolism In major depression is, particularly evident In left frontal regions. However, with surprising consistency neu• ropsychological and Information processing studies have Implicated right posterior deficits In major depression. The tension between these sets of findings has gone unappreciated. Another paradox concems the effects of treatment Interventions. Initial ev• Idence with the new technology, transcranlal magnetic stimulation suggests that repetitive stimulation over the left dorsolateral prefrontal ~rtex has a depressive effect In normal subjects, while right dorsolateral stimulation may elevate mood. In contrast, initial findings with this same technology