CLINICAL AND RESEARCH importance of considering contributing factor. REPORTS depressive symptoms as one This study was supported in part by grants from the Province of Alberta Mental Health Advisory Council (PMI-IAC) and the National Institute of Mental Health (MH-42209). The authors thank Ms. T. Bazylewich for technical assistance and Dr. W.G. Dewhurst for helpful discussions. References 1. Clark DM, and accessibility ID: Diurnal Teasdale of memories J Abnorm ences. 2. Coyne 3. Glass Psycho! RM, deficit 1978; 14:10-13 4. Riskind Bull Uhlenhuth nitive effects 6. Weingartner 1983; EM, and Weinreb negative experi- in depression: H: Imipramine a critical and Velten in depression. DL, et al: Cognitive cesses in depression. Arch Gen Psychiatry 7. Gass CS, Russell EW: Differential impact pression on memory test performance. pro- Psychol Arch pro- 1981; 38:42-47 of brain damage and I Consult Clin Psychol do- 1986;54:261-263 8. Hamilton M: Development ml Neurosurg Psychiatry 9. Russell plex EW: A multiple scoring memory functions. I Consult 10. Stukenberg validation Psychological J Neu- method Clin for the assessment of com- Psychol 1975; 43:800-809 Dura JR. Kiecolt-Glaser JK: Depression screening in an elderly community dwelling population. Assessment: A Journal of Consulting and Clinical Psychology 1990; 2:134-138 11. Beck AT, Beck RW: Screening tice: a rapid kins depression. KW, scale 12. Derogatis istration, for of a rating scale 1967; 23:56-62 technique. Postgrad LR, Spencer Scoring and PM: The Procedures University, depressed patients Med 1972:81-85 of and Temporal Changes in Cortical S2-S erotonin Receptors Helen Rajesh Philip Robert S. Mayberg, M.D. M. Parikh, M.D. L.P. Morris, M.D. G. Robinson, M.D. cog- induction Clin functions 1976; 33:219-224 H, Cohen RM, Murphy Remission Depression Bull mood I Consult memory. Memory reversible Psychopharmacol J: The WS, Eggers ME: depression 94:472-505 depressives. on mood 1982; 50:146-147 5. Sternber DE, Jarvik Gen Psychiatry of positive in outpatient JH, Rholes cedure: in clinical Psychol 1982; 91 :87-95 IH: The role of cognition JC, Gotlib appraisal. variation Spontaneous Post-Stroke in family Brief Symptom Inventory Manual-I. Baltimore, prac- AdminJohns Hop- A patient with post-stroke depression following infarction of the left basal ganglia is described. The patient’s depression remitted during a 6-week double-blind treatment trial while receiving placebo medication. Cortical S2-receptor binding that was measured using 11C-N methyl spiperone and positron emission tomography (PET), increased in the left temporal cortex by more than 25% during the treatment trial. The change in serotonin receptor binding and its relationship to the improvement in mood observed in this patient are consistent with previously published data demonstrating a correlation between serotonin receptor binding in the left temporal cortex and severity of symptoms of depression. (The Journal of Neuropsychiatry Neurosciences 1991; and Clinical 3:80-83) 1982 In recent studies, we have reported that post-stroke major depression is more frequent following lesions of either the left frontal cortex or left basal ganglia (particularly the caudate nucleus) than any other lesion location.’2 In addition, cortical measured in noninjured etal using cortex areas positron S2-serotonin receptors, of the temporal and emission pari- tomography (PET) and “C-N methyl spiperone (NMSP), were differentially affected, depending on whether the stroke was present in the right or left hemisphere.3 Right, but not left, hemisphere strokes were associated with an increase in the Received April From the Departments 25, 1990; Johns Hopkins University print requests to Dr. Mayberg, Medicine, Department 1-130, Baltimore, MD Copyright 80 © 1991 revised July 10, 1990; of Radiology, Psychiatry, School of Medicine, The of Radiology, 21205. The Johns 600 Hopkins North American Psychiatric VOLUME 3 #{149} NUMBER accepted and July 16, 1990. Neuroscience, The Baltimore. Address University Wolfe Street, Press, Inc. 1 #{149} WINTER re- School of Tower B 1991 CLINICAL ratio of ipsilateral-to-contralateral (stroke to nonstroke) cortical S2-serotonin receptor binding, compared to agecomparable normal controls. Furthermore, the ratio of ipsilateral-to-contralateral NMSP receptor binding in the temporal cortex of patients with left hemisphere stroke was significantly correlated lower with severity ratio, of depressive (the depression non could score). Neither of these lateralized be explained by interhemispheric in lesion size clinical characteristics or posure. Based on these location, left demographic or or medication ex- we postulated that to up-regulate may in NMSP ations in mood FIGURE 1. the phenomedifferences patients, lead to the patients with left-sided lesions. we present the following case changes higher up-regula- S2-serotonin receptors following right may play a role in preventing depresits resolution, while loss of cortical or failure hemisphere the background of the findings, tion of ipsilateral hemisphere stroke sion or facilitating receptors the binding symptoms binding these receptors onset of depression in the In light of this hypothesis, to illustrate longitudinal temporally related to alter- state. Noncontrast CT density involving anterior limb and utamen scan showing irregular area of low the head of the left caudate nucleus, of the left internal capsule (upper arrow), (lower arrow) in CASE AND The patient was a 60-year-old right-handed black female admitted to the stroke unit of the University of Maryland Hospital (Baltimore, MD) in September 1987 with sudden weakness of the right hand and leg. On admission, she was alert, mildly anxious, cooperative, and orientated to time, place, and person. There was no evidence of dysarthria or aphasia. Cranial nerve examination was normal. She had a right hemiparesis with grade II (mild) weakness of the tongue and face and grade V (severe) weakness of both the upper and lower extremities. Sensory examination was normal bilaterally. She had right-sided hyperreflexia and a positive right plantar response. The remainder of the physical examination was normal. Family history was negative for neurological or psychiatric disorders, and her past medical history revealed only remote past alcohol abuse. Routine laboratory studies (including urinalysis, blood count, serum electrolytes, blood glucose, serum B,2 and folate, coagulation profile, serum lipids and triglycerides, and rheumatoid and syphilis serology) were all within normal ranges. An EEG performed I day after admission showed frequent 25 H2 waves in the left anterior quadrant consistent with a lesion in that region. X-ray computed tomography (CT) performed the same day revealed an area of low density in the region of the head of the left caudate nucleus (Figure 1), which was later confirmed by magnetic resonance imaging (MRI) as a comma-shaped involving the of the left caudate and extending internal capsule and putamen. into the anterior limb TABLE scor 1. Psychiatric lacunar examination infarct Pre-Treatment Depressed one with post- patient Post 6 Weeks State Treatment Euthymic State Exam 21 0 Depression 16 0 3 3 Functioning 36 36 Social Ties Checklist 5 5 18 24 Present State Hamilton Rating Johns Scale Hopkins Functional Social Inventory Mini-Mental TABLE State 2. Exam PET measurements of “C-N methyl spiperone binding to S2-serotonin receptors in noninjured before and after treatment of one patient Stroke Hemisphere/Non-Str NMSP Pre-Rx Frontal Temporal Parietal NEUROPSYCHIATRY es for head of the depression Measure OF REPORTS REPORT stroke JOURNAL RESEARCH Cortex Cortex Cortex Study (Depressed) oke Hemisphere 1: NMSP (NMSP) cortex Binding Ratio 2: (Euthymic) Study Post-Treatment 0.92 1.20 0.92 1.17 0.91 1.12 81 CLINICAL AND RESEARCH REPORTS Eight days following the stroke, the patient was observed to be sad, expressing self-deprecatory thoughts, feelings of hopelessness, and a wish to be dead. Informed consent was obtained, and the patient was enrolled in the Stroke Data Bank of the University of Maryland Hospital, a 6-week double-blind post-stroke depression treatment study,4 and the PET imaging study. A baseline detailed neuropsychiatric examination, including the Present State Examination (PSE)5 (modified to elicit primarily depressive and anxiety symptoms), the Hamilton Depression Rating Scale (HDRS),6 the Mini-Mental State Examination (MMSE),7 the Johns Hopkins Functional Inventory (JHFI)8 (a measure of activities of daily living), and a neuropsychological battery,9 were performed. The psychiatric interview revealed that the patient had symptoms meeting the 2-week cluding after the DSM-III symptom comprehensive criteria for major deression duration criteria).’ Fifteen psychiatric and (exdays neuropsychological assessment, and 2 days prior to the initiation of treatment (hospital day 23), a NMSP PET scan measurement of cortical S.2-serotonin receptor binding was performed,3 followed a day later by a PET scan of regional cerebral glucose metabolism using ‘8F-fluoro-2-deoxy-o glucose (FDG).” Following completion of the baseline PET studies, 25 days after the onset of the acute stroke symptoms and 17 days after the onset of the major depression, the double-blind treatment study’2 was started. Over the 6 weeks of the study, the patient was evaluated every 2 weeks of the treatment ropsychological NMSP code PET was with the period, battery scan was HDRS, MMSE, and JHFI. the entire neuropsychiatric was readministered, and performed. subsequently be taking placebo. also first with anticoagulants: and low-dose aspirin treated week, Scores tient The broken During and double-blind the was intravenous thereafter. heparin administered depression were treatment found the patient to was in the to the pa- are shown in Table 1. By the second week, the patient a clear reduction in depressive symptoms. Over the of treatment, her MMSE score and scores on six of nine subtests of the neuropsychological battery improved, and diagnostic criteria for major the 6-week treatment patient the hospitalization, on each of the instruments during At the end and neua second period showed course no longer met. The FDG PET study demonstrated pronounced hypometabolism in the ipsilateral (left) frontal and temporal cortices, caudate and thalamic nuclei, and contralateral (right) cerebellum. The mean decrease in metabolic rate, expressed as a ratio of matched regions in the left and was approximately 20%. The relative ceptor binding in the frontal, temporal, was estimated by calculating the ratio right hemispheres, concentration of S2-re-- and parietal cortex of binding in symmetri- cal regions of the left compared to right hemisphere. In a group of age-comparable normal controls, the mean±SD asymmetry injection ratio for these regions, calculated 70-90 mm 82 in cortical in temporal, and 21 % in parietal evaluated clinically lowing her stroke at 3 months, binding and ratio was 28% in frontal, cortex. The patient 6 months, continued and 25% was re- 2 years fol- no previous to be euthymic. DISCUSSION This case of a 60-year history of depression following changes infarction in cortical old who woman with developed a major depression of the basal ganglia, demonstrated S2-serotonin binding that were associ- ated with the resolution of her depressive disorder. The increase in the ratio of left to right hemisphere NMSP binding in frontal, temporal, and parietal regions coincided with both the remission of the patient’s major depressive episode and improvement in cognitive function. The increase in receptor binding could not be attributed to because There a direct the interpretation the observed the effect of antidepressant the patient received are methodological effects of the may have of the basal neurotransmitter covery from depression. ganglia that We cannot binding direct interactions of other S2-serotonin neurological ceptor phase changes may occur in all patients of recovery from stroke. Although data currently, it will be critical ing It is, however, ratio Repeat was unlikely due NMSP in the subacute we do not have that studies whether or increases in patients depressions do not to a test-retest PET sites, or redeficits. Re- to examine not S2-serotonin receptor binding with left hemisphere lesions whose resolve. stroke-related to it, including lesion, with complicate conclude that relate solely to Other contributed systems non-mood-related medication placebo. limitations of this study. changes in NMSP resolution variables the change in bind- measurement performed error. in two non- depressed stroke patients (scans I and 2 separated by 1 year) demonstrated cortical NMSP binding ratio changes of less than 5% in both patients (Mayberg, unpublished data). The change in binding in the case reported here was 25% over a 6-week period-greater than two standard deviations above the single study ipsilateral-to-contralateral ratio obtained in normal control subjects (1.0±0.11). Lastly, although the patient met symptom and duration criteria for major depression, the abbreviated course of her illness (approximately 3-4 weeks) was somewhat after of NMSP, was i.#{248}±o.ii. Over this time interval, the of NMSP previously had been shown to be sensitive to changes in receptor binding and not blood flow.’3”4 The changes in the binding ratios between the first and second PET study are shown in Table 2. Over the course of 6 weeks, binding the increase which short atypical of post-stroke major last 1 year.4 characteristically duration of depression about may suggest depressions, Although a an adjustment disorder (DSM-III), we have previously noted that taneous remission of major depression within 6 months is more likely to occur with VOLUME spon- subcortical or brain stem 3 #{149} NUMBER 1 #{149} WINTER 1991 CLINICAL infarcts than location in this cortical lesions.’5 The and clinical patient her basal ganglia course lesion are consis- tent with these previous observations. Furthermore, minor depression using DSM-III criteria for dysthymic disorder’#{176}is unlikely to be associated with cognitive impairment, which is more often a concomitant of poststroke major depression.9 We have previously hypothesized iology of depression following might be mediated, tion resulting in part, from that left the ischemic injury to the or serotonergic systems pass through pathways. the ventral striatum as they frontal have ascend to the at risk for injuring been negative ratio and correlation the severity observed3 creased, would suggest mood improved. NMSP receptor mood were binding function that The by our hypothesis. whether a low ratio preceded or followed the increase in the ratio associated symptoms suggests the least, improved a correlate cognitive cognitive While that onset with ascending ders. Brain 2. Starkstein our patient The binding previously in Although we NMSP binding of depression, the reduction serotonergic dysfunction depression. also associated an in is, at As ratio, we might speculate may also be involved the with that in the in the ipsilateral hemisphere and con- tralateral cerebellum. These regional changes were consistent with those that were observed in nondepressed stroke patients with comparable lesion locations.’6 Hypometabolic areas overlapped regions showing low receptor binding in the first NMSP study. Unfortunately, a follow-up FDG scan was not obtained due to radiation dosimetry limitations. Thus, it remains undetermined if there were regional changes in metabolism in association with pressive tigation the S2-serotonin binding symptoms, and of these interactions neurotransmitter systems In conclusion, the data suggest that neuroreceptor insult state is not static and cognitive JOURNAL OF changes, reduction in de- cognitive improvement. as well as of the role Invesof other awaits further study. obtained function from this following and may be related performance. to changes NEUROPSYCHIATRY case was supported by the following Award MI-I-00163 changes Neurol 3. Mayberg SE, Robinson RG, Price TR: Comparison lesions production of post-stroke study cerebral in the following basal 1988; 45:725-730 HS, Robinson RG, Kubos patients: importance 5. Wing JK, Cooper RG, NIH (R.G.R.), MH- DF, stroke: J Psychiatry Am scale for clinician. J Psychiatr Res 8. Robinson quency, RG, Benson severity and DF: Depression clinical-pathological for grading the 1975; 1981; 14:282-291 K, Robinson ME, ment of local 3rd Association, 1980 Huang RG, 1:297-300 DF, Wagner HN 14. Wong mine DF, Gjedde and serotonin binding 15. Starkstein 16. Mayberg HM, 1989; and Statistical Washington, DC, Man- et al: Tomographic rate measure- in humans GD, et al: Nortriptyline a double-blind study. RF, et al: Effects with Ann (FNeurol treatLancet of age on do- measured by positron tomograScience 1984; 226:1393-1396 RF, et al: Quantification in living human brain: of dopaequilibrium J Nucl Med 9(suppl Price SE, Sadzot (FDG-PET) matter lesions the American 1987; 28:611 TR: Comparison of spontaneversus nonrecovered patients with post-stroke 1988; 19:1491-1496 Starkstein hypometabolism grey and white Metab A, Dannals receptors kinetics, III (abstract). SE, Robinson RG, ously recovered pression. Stroke Diagnostic of method. Jr, Dannals pamine and serotonin receptors phy in the living human brain. a for SE, et al: Lateralization validation Pearlson 1984; 13. Wong State”: of patients I Psychiatry Edition. 18)2-fluoro-2-deoxy-D-glucose: depressions: Neurosurg Am EH, of post-stroke Uni- patients. metabolic ment Cambridge state Starkstein glucose 1979; 6:371 -388 12. Lipsey JR, Robinson in stroke in aphasic patients: frecorrelations. Brain and SC, Hoffman cerebral disorders rela- 12:189-198 RG, Disorders, and 1984; 107:81-93 and classification “Mini-Mental cognitive of dementia of depression in stroke 1989; 146:627-634 10. American Psychiatric Association: 11. Phelps of corti- J Neurol PR: method of Mental imaging depression. practical ual et al: PET England, 1960; 23:56-62 MF, Folstein SE, McHugh Language 9. Bolla-Wilson Arch LB, et al: Mood M: A rating mood lesions. lateralized changes 1988; 145:937-943 Cambridge, and disor- et al: Differential location. Brain N: Measurement symptoms. of cortical mood thalamic Starr 1975 Psychiatry 7. Folstein Wong after KL, versity 6. Hamilton ML, versus of lesion JE, Sartorius of psychiatric Press, Berthier ganglia cal S2-serotonin receptors tionship to depression. Psychiatric deficits seen in these depressed patients. depressed, the patient showed widespread hypometabolism study 1987; 110:1045-1059 SE, Robinson RG, 4. Robinson S2-serotonin to changes of post-stroke function was binding dysfunction This Research Scientist and NS-15080. 1. Starkstein as serotonin binding inchange in this patient’s ratio suggests that cortical may be directly related acquisition. grants: 40355, subcortical pathways. between the S2-serotonin of depressive symptoms state, as predicted not able to determine increased NMSP monoaminergic cortex, REPORTS The authors thank Robert F. Dannals, Ph.D., Hayden T. Ravert, Ph.D., Alan A. Wilson, Ph.D., and Dean F. Wong, M.D., for radiotracer synthesis and assistance with PET scan dysfuncSince fibers of aspect of the these RESEARCH References stroke by monoaminergic noradrenergic these two would pathophys- hemisphere AND B, et al: Patterns in subcortical (abstract). strokes I Cereb de- of remote differentiates Blood Flow 1):621 in mood 83