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3. Vuilleumier P, Ghika-Schmid F, Bogousslavsky J, Assal G, Regli F: Received Jan. 23, 2001; revisions received May 1, May 25, and June Persistent recurrence of hypomania and prosopoaffective ag- 29, 2001; accepted Aug. 11, 2001. From the Department of Psychiatry nosia in a patient with right thalamic infarct. Neuropsychiatry and Behavioral Sciences, Stanford University School of Medicine. Ad- Neuropsychol Behav Neurol 1998; 11:40–44 dress reprint requests to Dr. Lembke, Department of Psychiatry and 4. Ekman P, Friesen WV, O’Sullivan M, Diacoyanni-Tarlatzis I, Behavioral Sciences, 401 Quarry Rd., Stanford University School of Krause R, Pitcairn T, Scherer K, Chan A, Heider K, LeCompte Medicine, Stanford, CA 94305-5723; alembke@stanford.edu (e-mail).
WA, Ricci-Bitti PE, Tomita M, Tzavaras A: Universal and cultural Supported by NIMH grant MH-19938 and the APA/Lilly Psychiatric differences in the judgments of facial expressions of emotion.
5. Young RC, Biggs JT, Ziegler VE, Meyer DA: A rating scale for mania: reliability, validity, and sensitivity. Br J Psychiatry 1978;133:429–435 References
6. Ekman P, Friesen WV: Pictures of Facial Affect. Palo Alto, Calif, 1. David AS: Spatial and selective attention in the cerebral hemi- 7. Rubinow DR, Post RM: Impaired recognition of affect in facial spheres in depression, mania, and schizophrenia. Brain Cogn expression in depressed patients. Biol Psychiatry 1992; 31: 2. George MS, Huggins T, McDermut W, Parekh PI, Rubinow D, 8. Murphy FC, Sahakian BJ, Rubinsztein JS, Michael A, Rogers RD, Post RM: Abnormal facial emotion recognition in depression: Robbins TW, Paykel ES: Emotional bias and inhibitory control serial testing in an ultra-rapid-cycling patient. Behav Modif processes in mania and depression. Psychol Med 1999; 29: Brief Report
Limbic Hyperreactivity in Bipolar II Disorder
Gregory S. Berns, M.D., Ph.D.
presses was determined by a complex sequence that was Megan Martin, B.A.
changed in the latter half of the study.
Shawnette M. Proper, B.S.
Results: In the comparison subjects a spatial attention circuit
in the superior parietal lobe and supplementary motor area
Objective: The authors’ goal was to determine whether pa-
was activated in response to the introduction of the new se- tients with bipolar II disorder had altered regional brain re- quence. Patients did not display this activation pattern; instead, a widespread limbic network was activated in response to thenew sequence.
Method: Regional cerebral blood flow was measured with
positron emission tomography in 13 patients with bipolar II dis-
Conclusions: The attentional resources of patients with bipo-
order and 14 healthy comparison subjects. Participants per- lar II disorder are not reallocated when they are confronted formed a serial reaction time task in which they were visually with a nonemotional motor task; rather, their performance is cued to press one of four buttons at a time. The order of button altered through activation of limbic circuitry.
(Am J Psychiatry 2002; 159:304–306)
Bipolar II disorder, recognized as a distinct type of af- task that confronted subjects with novel finger movement fective illness (1), has not been well characterized in terms sequences and compared the dynamic brain response in of underlying brain dysfunction. Although the demonstra- patients with bipolar II disorder with that of healthy com- tion of resting state changes in bipolar I disorder suggests parison subjects. The task had the advantage of being af- profound alterations in brain function (2), it does not ad- fectively neutral because the stimuli themselves had no dress the dynamic changes associated with cognitive intrinsic emotional valence, isolating the effect of novelty.
tasks. Both higher measures of novelty-seeking in patients The serial reaction time task taps visuospatial attention with bipolar disorder (3) and the association of novelty- and motor learning and has been extensively studied with seeking with poor treatment outcome (4) suggest a linkage neuroimaging (5). Subjects are repeatedly cued to one of to novelty in bipolar spectrum disorders, raising the possi- several possible button presses, but the order of button bility that patients with bipolar disorder have a hypersen- presses follows a sequence. Subjects get faster as aspects of sitivity to novelty. Therefore, we designed a neuroimaging the sequence are encoded. When the sequence is changed, Am J Psychiatry 159:2, February 2002 BRIEF REPORTS
both attentional and subcortical regions become tran- TABLE 1. Regions in Which the rCBF Change Associated
With a Novel Sequence in a Motor Task Was Significantly
Different in 14 Healthy Comparison Subjects and 13 Pa-
tients With Bipolar II Disordera
Thirteen right-handed outpatients who met DSM-IV criteria for bipolar II disorder and 14 healthy comparison subjects were recruited from two institutions: the University of Pittsburgh and Emory University. The mean age of the patients was 31.2 years (SD=8.3, range=21–47); the mean age of the comparison subjects was 30.8 (SD=8.3, range=20–43). The male-female ratio among the patients was 5:8; among the comparison subjects it was 6:8.
Patients were euthymic at the time of study and had no history of substance abuse within the last year. Antidepressants and mood stabilizers were allowed, but no patients were taking antipsychot- ics. Four of the patients were medication free, two were taking lithium plus sertraline, two were taking divalproex, and one each a Significance was p<0.001; cluster size was greater than 20 voxels.
was taking lithium, divalproex plus sertraline, divalproex plus cit- b Value of the maximum t statistic in each region.
alopram, paroxetine, and lamotrigine plus bupropion. After com-plete description of the study, all subjects gave written informedconsent. This study was approved by the institutional review group. We then examined the interaction of group-by-sequence boards and radiation committees of both the University of Pitts- change, with a threshold for statistical significance of p<0.001 (uncorrected for multiple comparisons).
Fourteen measurements of regional cerebral blood flow (rCBF) were obtained by using positron emission tomography (PET) fol- lowing intravenous bolus injection of [15O]H2O. Imaging was per-formed on a Siemens HR+ (New York) at Pittsburgh (one patient, Complete reaction time data were collected for 23 sub- six comparison subjects) and a Siemens ECAT 921 at Emory (12 jects (10 patients and 13 comparison subjects). Both pa- patients, eight comparison subjects). The dose of [15O]H2O was tients and comparison subjects displayed an increase in 12 mCi on the HR+ and 25 mCi on the 921. Imaging was per- mean reaction time when the sequence was changed formed in three-dimensional mode on both scanners with mea- (mean increase=29.2 msec, SD=4.9) (F=35.0, df=1, 21, sured attenuation correction on the HR+ and calculated correc-tion on the 921. Following injection of [15O]H p<0.001, repeated measures analysis of variance), but this 90 seconds; the interscan duration was 8–10 minutes.
increase was not significantly different between groups Subjects were instructed to perform a reaction time task while (F=1.98, df=1, 21, p=0.17). The mean reaction time was not in the scanner. A computer displayed four boxes arrayed horizon- significantly different between the groups (F=1.33, df=1, tally from left to right. Every 1400 msec one box was illuminated, and the subject had to press a corresponding key on the keyboardas quickly and accurately as possible. The order of the illuminated In the rCBF data, the group-by-sequence change inter- boxes followed a 12-item sequence that repeated seven times action revealed several areas that differed between the during the course of a 2-minute trial block. A 2-minute rest period groups (Table 1). Comparison subjects displayed a signifi- between blocks was provided, during which subjects received cantly greater increase than the patients in the right supe- feedback about their performance. Twenty-seven blocks were rior parietal cortex when the sequence was changed. In performed, and scans were obtained on the odd-numberedblocks. One sequence (sequence A) was used throughout a given contrast, the patients displayed a greater increase than the subject’s task except during blocks 13, 19, 21, and 27, in which a comparison group in a widespread network that included different 12-item sequence was presented (sequence B). This al- the right premotor cortex, right insular cortex, and medial located the first half of the task for the acquisition of sequence A, and the introduction of sequence B in the latter half allowed the Because imaging data were collected on two different measurement of rCBF changes in response to a novel spatial-mo-tor mapping.
scanners, we tested for the possibility of the scanner as a PET images were analyzed to determine changes in rCBF asso- confound. There was no significant difference in the group ciated with the change in sequence and whether this was differ- distribution between the two scanners (Yates-corrected ent for patients and comparison subjects. Using statistical para- χ2=2.71, df=1, p=0.10), nor were there any areas in the metric mapping (SPM 99 [Wellcome Department of Cognitive rCBF analysis that had significant scanner-by-sequence Neurology, University College London]), we corrected images forinterscan head movement, spatially transformed to the Montreal Neurological Institute coordinate system and spatially smoothedwith a 12-mm Gaussian filter. A single contrast image for each Discussion
subject was formed by the difference between the mean adjustedscans of sequence B (blocks 13 and 19) and sequence A (blocks 9, Both patients and comparison subjects were able to en- 11, 15, 17, 23, and 25). This difference represented the change in code aspects of the motor sequence, but when the se- rCBF associated with the novel sequence after the subject had ac- quence was changed they showed different brain re- quired the first sequence. To capture the maximal effect of nov- sponses. This difference in brain activation occurred elty, only the first two blocks of sequence B were used to calculatethe change in rCBF. The single contrast image for each subject despite the fact that both groups had comparable behav- was entered into a random effects analysis with a main effect of ioral responses. Because of the confound of medications Am J Psychiatry 159:2, February 2002 BRIEF REPORTS
in the patient group, it is possible that all of the observed patients with bipolar II disorder react biologically in a way differences were attributable to medication, but the com- that is congruent with the symptom of affective lability.
parable behavioral data show that the medications werenot enough to impair performance.
Received Feb. 6, 2001; revision received Aug. 3, 2001; accepted The activation of the right superior parietal cortex in re- Aug. 11, 2001. From the University of Pittsburgh; and the Depart-ment of Psychiatry and Behavioral Sciences, Emory University School sponse to a novel spatial-motor sequence is consistent of Medicine. Address reprint requests to Dr. Berns, Department of with a large body of literature supporting the role of this Psychiatry and Behavioral Sciences, Emory University School of region in spatial attention (6). The superior parietal activa- Medicine, 1639 Pierce Dr., Suite 4000, Atlanta, GA 30322; gberns@emory.edu (e-mail).
tion was likely related to a shift in spatial attention, but Supported by a grant from the Stanley Foundation and grant DA- this was significantly more active in the comparison sub- 00367 from the National Institute on Drug Abuse.
jects. Most subjects became aware of parts of the sequenceand were aware of when it changed, but this was not de- References
monstrably different between the groups. We used a rela-tively simple repeating sequence, and so the development 1. Akiskal HS: Subaffective disorders: dysthymic, cyclothymic, and of explicit knowledge was not surprising. This may explain bipolar II disorders in the “borderline” realm. Psychiatr ClinNorth Am 1981; 4:25–46 the lack of activation in the basal ganglia, which often oc- 2. Stoll AL, Renshaw PF, Yurgelun-Todd DA, Cohen BM: Neuroim- curs with more complex, implicitly learned sequences. It is aging in bipolar disorder: what have we learned? Biol Psychia- possible that the degree of explicit knowledge differed be- tween the groups, accounting for some activation differ- 3. Janowsky DS, Morter S, Hong L, Howe L: Myers Briggs Type In- ences, but differentiating knowledge from recall is notori- dicator and Tridimensional Personality Questionnaire differ- ences between bipolar patients and unipolar depressed pa-tients. Bipolar Disord 1999; 1:98–108 The lack of parietal activation in the patients, coupled 4. Strakowski SM, Stoll AL, Tohen M, Faedda GL, Goodwin DC: The with widespread medial prefrontal and limbic activation, Tridimensional Personality Questionnaire as a predictor of six- suggests that the adaptation to the novel sequence oc- month outcome in first episode mania. Psychiatry Res 1993; curred by a different mechanism in the patients. The task was designed to be affectively neutral, yet activation of lim- 5. Rauch SL, Savage CR, Brown HD, Curran T, Alpert NM, Kendrick A, Fischman AJ, Kosslyn SM: A PET investigation of implicit and bic regions may be associated with an arousal function explicit sequence learning. Hum Brain Mapp 1995; 3:271–286 rather than an attention function. Although this does not 6. Ungerleider LG, Haxby JV: “What” and “where” in the human demonstrate a hypersensitivity to novelty, it does show that brain. Curr Opin Neurobiol 1994; 4:157–165 Am J Psychiatry 159:2, February 2002

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