Wisconsin Card Sorting Test performance in bipolar disorder: effects of mood state and early course

Objectives:  Patients experiencing an acute mood episode of bipolar disorder are impaired on cognitive tests of executive functioning when compared with healthy subjects. However, it is unclear to what extent executive dysfunction exists (i) during syndromal remission, when mood symptoms are attenuated, and (ii) during the early course of bipolar disorder.
Methods:  To clarify these issues, we examined retrospective data on a standard clinical version of the Wisconsin Card Sorting Test (WCST) administered to 25 euthymic, 21 first-episode manic or mixed, and 34 multiple-episode manic or mixed patients with bipolar I disorder, and 48 healthy comparison subjects. These groups were compared on five WCST measures of executive ability.
Results:  On all but one measure the healthy group's performance was superior to that of both first- and multiple-episode groups. The euthymic group outperformed the multiple-episode group, but performed similarly to the first-episode group on all but one measure. The healthy and euthymic groups did not differ significantly on any measure. Effect sizes ranged from small to moderate.
Conclusions:  Executive dysfunction may be a mediating vulnerability indicator of bipolar disorder that is strongly related to mood state, but only modestly related to chronicity of illness during the early disease course.     

Impaired recognition of facial emotion in mania

OBJECTIVE: Recognition of facial emotion was examined in manic subjects to explore whether aberrant interpersonal interactions are related to impaired perception of social cues. METHOD: Manic subjects with bipolar I disorder (N=8), euthymic subjects with bipolar I (N=8) or bipolar II (N=8) disorder, and healthy comparison subjects (N=10) matched pictures of faces to the words "fear," "disgust," "anger," "sadness," "surprise," and "happiness." RESULTS: The manic subjects showed worse overall recognition of facial emotion than all other groups. They showed worse recognition of fear and disgust than the healthy subjects. The euthymic bipolar II disorder subjects showed greater fear recognition than the manic and euthymic bipolar I disorder subjects. CONCLUSIONS: Impaired perception of facial emotion may contribute to behaviors in mania. Impaired recognition of fear and disgust, with relatively preserved recognition of other basic emotions, contrasts with findings for depression and is consistent with a mood-congruent positive bias.     

The neurocognitive performance of drug‐free and medicated euthymic bipolar patients do not differ

Objective: Although it is established that euthymic bipolar patients have neurocognitive deficits, the influence of medication on their cognitive performance is uncertain and requires investigation. Method: Neuropsychological tests of executive function, memory and attention were performed on 44 prospectively verified, euthymic bipolar I patients, 22 of whom were drug‐free. Residual mood symptom effects were controlled statistically using ancova . Results: Drug‐free and medicated patients differed only in delayed verbal recall (Rey AVLT list A7, drug‐free > medicated), and perseverations during the five‐point test (drug‐free > medicated). When residual mood symptoms were controlled statistically, differences between drug‐free and medicated subjects became insignificant. Medication effect sizes were modest. Significant correlations were found between residual depression scores and measures of verbal learning. Conclusion: Medications did not have any significant influence on neurocognitive performance, suggesting that neurocognitive deficits are an integral part of bipolar disorder.     

Impairment of executive function but not memory in first-degree relatives of patients with bipolar I disorder and in euthymic patients with unipolar depression

OBJECTIVE: The authors' goal was to characterize cognitive flexibility and verbal learning in relatives of patients with bipolar disorder and in euthymic patients with recurrent major depression. METHOD: The intradimensional/extradimensional shift task and California Verbal Learning Test were administered to 27 first-degree relatives of probands with bipolar I disorder, 15 euthymic outpatients with recurrent unipolar depression, and 47 healthy comparison subjects. RESULTS: The relatives of patients with bipolar I disorder and the euthymic patients with unipolar depression were more likely to fail the intradimensional/extradimensional shift task than the healthy comparison subjects. The impairments at the extradimensional shift stage were pronounced. Verbal learning, delayed recall, and recognition were unimpaired in all groups. CONCLUSIONS: Attentional set shifting may represent an endophenotype in mood disorder, related to underlying vulnerability rather than the actual disease phenotype.     

Neuropsychological task performance in bipolar spectrum illness: genetics, alcohol abuse, medication and childhood trauma

Introduction:  Impaired executive and memory function is a putative genetic trait marker of bipolar I disorder (BPD I). Although executive/memory function has been posited to be an endophenotype of BPD I, it is unclear whether this extends to bipolar spectrum illness. It is also unclear to what extent non-genetic factors such as childhood abuse, alcoholism and medication influence neurocognitive function. We assessed the neuropsychological performance of a large cohort of bipolar disorder probands and their affectively ill and healthy family members, while controlling for self-reported childhood sexual and emotional abuse, emotional neglect, alcohol abuse and medication.
Methods:  A total of 230 largely euthymic participants from 47 families, comprising 49 subjects with BPD I, 19 with bipolar II disorder (BPD II), 44 with recurrent major depression (MDE-R), 33 with a single lifetime episode of depression (MDE-S), 20 with other DSM-IV diagnoses and 65 unaffected relatives, were assessed with a battery of neuropsychological tasks.
Results:  Sexual abuse, emotional abuse and emotional neglect scores were associated with poorer cognitive performance. After controlling for childhood trauma, the BPD I group performed worse than unaffected relatives on tests of visual recall memory as well as verbal recall and recognition memory. In contrast, individuals with BPD II and bipolar spectrum illness did not differ significantly from unaffected relatives. Treatment with lithium and antipsychotic medication was associated with reduced executive and verbal recognition memory function. After controlling for medication and other covariates, only verbal recall memory was significantly impaired in the BPD I cohort.
Conclusions:  Verbal recall deficits may be one manifestation of a genetically driven dysfunction of frontal-striatal cortical networks in BPD I.     

Spontaneous and directed application of verbal learning strategies in bipolar disorder and obsessive-compulsive disorder

OBJECTIVES: Individuals with bipolar disorder exhibit neuropsychological impairments when they are euthymic (neither depressed nor manic). One of the most consistently reported cognitive problems in euthymic individuals with bipolar disorder is impairment in verbal episodic memory. Recent findings suggest that episodic memory difficulties in these individuals are attributable to difficulties using organizational strategies during encoding. The purpose of the present study was (i) to investigate whether difficulties using organizational strategies in bipolar disorder are due to a failure in spontaneously initiating verbal organization strategies or are due to difficulties implementing such strategies, and (ii) to compare the characteristics of verbal organizational impairment in bipolar disorder with those observed in individuals with obsessive-compulsive disorder (OCD). METHODS: Study participants were 20 individuals with bipolar I disorder (BP-I), 20 individuals with OCD, and 20 healthy control participants matched for age, gender, and education. Participants completed a verbal encoding paradigm that involved spontaneous and directed use of verbal organization strategies during encoding of word lists. RESULTS: Compared with control subjects, both BP-I and OCD participants showed impaired verbal organization in the spontaneous encoding condition. In the directed encoding condition, OCD patients organized the word lists as well as control participants whereas BP-I participants exhibited lower verbal organization than both control and OCD participants. OCD and BP-I participants' free recall performance did not differ from that of control participants in the spontaneous encoding condition. In the directed encoding condition, BP-I participants recalled fewer words than OCD or control participants. CONCLUSIONS: Episodic memory difficulties in OCD are associated with difficulties spontaneously initiating verbal organization strategies during encoding whereas the ability to implement verbal organization when instructed to do so is preserved. BP-I participants, on the other hand, exhibit difficulties in both spontaneously initiating verbal organization strategies and in the ability to implement such strategies when instructed to do so.     

Impaired verbal memory and otherwise spared cognition in remitted bipolar patients on monotherapy with lithium or valproate

Objectives:  Patients with bipolar disorder have been reported to have neurocognitive deficits; however, it is not known whether the cognitive dysfunctions are state-dependent or a stable trait. Lithium and valproate, 2 of the most widely used mood stabilizers in the treatment of bipolar disorder, have also been associated with cognitive impairment. However, the degree and pattern of neurocognitive impairment in euthymic bipolar patients on either monotherapy with lithium or valproate have not been compared before in depth.
Methods:  We compared 17 euthymic outpatients with bipolar disorder (BD) on lithium monotherapy to 11 euthymic outpatients with BD on valproate monotherapy and 29 comparison subjects using tests measuring immediate verbal memory and executive functions in addition to 3 subtests of the Wechsler Adult Intelligence Scale Revised. The groups were similar in terms of level of education, duration and severity of illness, and gender distribution. Patients on lithium monotherapy were older than patients on valproate and healthy controls. Mood symptoms as assessed by standardized scales were mild to non-existent in both patient groups.
Results:  Immediate verbal memory was impaired in both patient groups compared to controls, where the main effect of age was not significant. No significant differences could be found on the other cognitive measures.
Conclusions:  Both lithium and valproate may be associated with immediate verbal memory impairment, sparing other cognitive functions. Presence of a similar verbal memory deficit in the lithium and valproate groups suggests that this deficit might be intrinsic to BD or that the 2 medications influence immediate verbal memory similarly. Larger samples of remitted bipolar patients on monotherapy should be studied for more precise conclusions.     

Cognitive function and serum levels of brain-derived neurotrophic factor in patients with bipolar disorder

Objectives:  Brain-derived neurotrophic factor (BDNF) is an important contributor to the pathophysiology of bipolar disorder (BD), and abnormalities in the BDNF-signaling system may be implicated in the cognitive decline observed in BD patients. We aimed to investigate serum BDNF levels in BD patients and its relation to neurocognitive function.
Methods:  We measured serum BDNF levels using an enzyme-linked immunosorbent assay method in 65 euthymic type I BD patients and 50 healthy controls, and administered a neuropsychological test battery to assess attention and mental control, perceptual-motor skills, executive functions, verbal fluency and abstraction, visuospatial attention, and memory.
Results:  We found no significant differences regarding serum BDNF levels in BD patients and healthy controls. We found significant positive associations between serum BDNF levels and illness duration, and manic and depressive episodes in female BD patients only. Serum BDNF levels were lower in patients medicated with antipsychotics and/or lithium, whereas patients on valproate and/or antidepressants showed higher serum BDNF levels. Patients performed significantly worse on 11 out of 16 neurocognitive tests as compared to controls. We found a significant positive association between serum BDNF levels and a test of verbal fluency in both BD patients and controls.
Conclusions:  Present results support the hypothesis that BDNF normalizes with mood stabilization and pharmacological treatment. Our findings in young and physically healthy patients with short illness duration and few mood episodes may explain the lack of association between serum BDNF levels and neurocognitive performance, even though cognitive performance in patients was overall significantly worse as compared to healthy controls.     

A neuropsychological investigation of prefrontal cortex involvement in acute mania

OBJECTIVE: Mania has received little attention from a contemporary neuropsychological perspective despite its clear resemblance to the disinhibition syndrome sometimes seen after frontal brain injury, particularly injury to the inferior aspect of the prefrontal cortex. The purpose of this investigation was to describe the neuropsychological profile of severe acute mania by using a range of tasks selected primarily for the detection of localized neural disruption within the prefrontal cortex. METHOD: Fifteen acutely manic inpatients were compared with 30 nonpsychiatric subjects on tasks from the Cambridge Automated Neuropsychological Test Battery (Tower of London, spatial working memory, intradimensional-extradimensional attentional shift, and rapid visual information processing tasks) and on the Iowa Gambling Task, Stroop Color and Word Test, a verbal fluency task, and the California Verbal Learning Test. RESULTS: Discriminant function analysis identified deficits in sustained attention (on the rapid visual information processing task) and verbal learning (on the California Verbal Learning Test) as the best indicators of manic performance, rather than deficits on any of the tests of executive functioning. The model correctly classified 91% of subjects overall and 87% of manic subjects. Manic patients did not resemble patients with ventromedial prefrontal cortex damage in their performance on the Iowa Gambling Task. CONCLUSIONS: Acute mania is characterized by core deficits in verbal memory and sustained attention against a background of milder impairments in functions that are traditional measures of prefrontal cortex integrity (attentional set shifting, planning, working memory). The data do not implicate ventral prefrontal cortex disruption as a locus of pathology in acute mania. Verbal memory and sustained attention deficits may relate differentially to the state and trait characteristics of bipolar disorder.     

A prospective, longitudinal study of percentage of time spent ill in patients with bipolar I or bipolar II disorders

Background:  There is a recent appreciation that patients with bipolar disorder spend a substantial period of time with minor or subsyndromal mood symptoms both manic and depressive. This study examined time spent in minor and subsyndromal mood states as well as with mania and depression in a cohort of well characterized bipolar I and II patients who were followed prospectively for an average of three years.
Method:  Detailed life-charting data were obtained from 138 patients with bipolar disorder. Mood states were characterized as euthymic, subsyndromal, minor or major affective episodes based on rigorously defined criteria. The amount of time spent in these mood states during follow-up was examined.
Results:  Patients in the total sample and within each bipolar subtype spent approximately half of their time euthymic. The remainder of the time was spent in varying severity of mood states. However, the majority of time was spent with minor and subsyndromal symptoms, both manic and depressive. Bipolar I patients differ from bipolar II in that significantly more time was spent with subsyndromal, minor and manic symptoms. There was no difference in time spent with depressive symptoms between the two groups.
Conclusions:  Patients with bipolar disorder spend a substantial proportion of time with depressive or manic symptoms with the preponderance being minor or subsyndromal. Awareness of subthreshold symptoms in bipolar disorders and treatment of such symptoms may be improved by establishing guidelines that specifically outline appropriate strategies for reducing the duration of subsyndromal symptoms in bipolar disorder.     

Executive functioning and theory of mind in euthymic bipolar disorder

Objectives:  To examine the nature of executive deficits in euthymic patients with bipolar disorder (BD).
Methods:  Fifteen euthymic BD patients and 13 controls were administered a battery of executive tasks including verbal fluency, Stroop, Theory of Mind (ToM) tests and selected subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). Self-report and clinician ratings of mood and social and occupational functioning were also obtained.
Results:  There were no significant differences between BD patients and controls on the primary measures of the following executive tasks: verbal fluency, attentional set-shifting, problem solving or planning. On secondary measures of speed, BD patients were slower to complete the first trial of the Stroop task (p = 0.001). Patients with BD committed more errors across all secondary measures. Patients performed poorly when compared with controls on tests of verbal ToM (p = 0.02), and although they performed non-verbal ToM tasks at a level comparable to controls (p = 0.60), they were slower to initiate a response (p = 0.006). ToM was not significantly correlated with any measure of social and occupational functioning; however it correlated with the achievement scores of the CANTAB Stockings of Cambridge task (Pearson's r  = 0.68, p < 0.01).
Conclusions:  Deficits found in euthymic bipolar patients suggest fronto-subcortical pathway dysfunction. This is consistent with other neuropsychological and neuroimaging research that points to a trait deficit in BD. Further investigation is necessary perhaps using more real-world tests.     

Episodic memory impairment in bipolar disorder and obsessive-compulsive disorder: the role of memory strategies

BACKGROUND: There is evidence that individuals with bipolar disorder exhibit neuropsychological impairments not only during mood episodes but also when they are euthymic. One of the most consistently reported cognitive problems in euthymic individuals with bipolar disorder is an impairment in verbal episodic memory. Verbal learning and memory depend on individuals' ability to organize verbal information appropriately during learning. The purpose of the present study was (i) to determine whether episodic memory impairment in euthymic individuals with bipolar disorder is mediated by impairments in organization of verbal information during learning and (ii) to compare the characteristics of memory impairment in bipolar disorder with that previously found in obsessive-compulsive disorder (OCD). METHODS: Study participants were 30 individuals with DSM-IV bipolar I disorder (BP-I), 30 individuals with DSM-IV OCD and 30 normal control participants matched for age, gender and education. Participants completed the California Verbal Learning Test (CVLT), a well-established measure of verbal learning and memory that enables assessment of verbal organization strategies during learning. RESULTS: Compared with control subjects, both BP-I and OCD participants showed impaired performance in long-delayed free recall and verbal organization strategies during learning. BP-I participants showed greater long-delay free recall difficulties but not greater verbal organization difficulties during learning than OCD participants. For OCD participants, the long-delay recall impairment was mediated by difficulties using verbal organizational strategies during learning. In contrast, the group difference in long-delayed free recall between BP-I and control participants remained significant even when semantic clustering was introduced as a mediator. This indicated that BP-I participants' long-delayed free recall difficulties were mediated to a lesser extent by difficulties using verbal organizational strategies than for OCD participants. CONCLUSIONS: Verbal episodic memory problems in individuals with bipolar I disorder and OCD are mediated to different degrees by difficulties using semantic clustering encoding strategies compared with control participants.     

Cognitive disturbances and bipolar depression

The existence of cognitive deficits during the acute phases of bipolar disorder (manic, depressive, hypomanic or mixed episodes) has long been demonstrated and by numerous studies. The existence of cognitive deficits during euthymic periods has been much less studied. In addition, these studies are hampered by several methodological difficulties (small sample sizes, confounding factors influencing cognitive performance such as residual symptoms, comorbidities, age.. not considered). More recently, several studies have clearly documented the existence of memory deficits (especially, verbal), attention and executive function during euthymic periods in bipolar patients. In addition, several prospective studies and meta-analyses suggest that these deficits independent predictors of the functional. Thus the development of specific cognitive remediation programs is a major stake. These deficits may be markers of vulnerability to bipolar disorder, but may also reflect the cognitive ? toxicity ? of major mood episodes.     

Trait and state dependent functional impairments in bipolar disorder

Bipolar disorder (BD) is characterized by abnormalities in emotion processing. Specifically, the processing of affective faces appears to be impaired. This study explored functional abnormalities in the neural network underlying the processing of facial affect in three different mood states (euthymic, depressed, and manic) associated with BD. Functional magnetic resonance imaging (fMRI) data were acquired from 18 healthy controls and 18 euthymic, 12 depressed, and 12 manic BD patients while viewing affective or neutral faces. Compared with controls, BD patients in all mood states showed reduced activation in the bilateral orbitofrontal cortex (OFC), indicating that activation in this region is independent of mood state. Activation in the amygdala, dorsolateral prefrontal cortex (DLPFC), and right temporal pole depended on mood state. Whereas activation levels of depressed patients were not significantly different from those of controls, activation levels in both euthymic and manic patients were significantly reduced compared with activation levels of both controls and depressed patients. However in the right DLPFC euthymic patients showed an increased level of activation compared with manic patients. These results add to the evidence for functional deficits in the affective network in BD patients, of which reduced bilateral OFC activation was found to be the most pronounced deficit across all mood states.     

Processing efficiency and directed forgetting in bipolar disorder.

We hypothesized that patients with bipolar disorder would demonstrate verbal recognition performance deficits consistent with processing efficiency theory, a theory about how emotional states modulate performance by interfering with working memory resources or increasing cognitive arousal/effort. We predicted that (1) a manic group (n=26) would demonstrate slow reaction time (RT) and low accuracy, (2) a euthymic group (n=23) would demonstrate slow RT to maintain high accuracy; and (3) a healthy comparison group (n=25) would demonstrate fast RT and high accuracy. The groups were administered symptom-rating scales and compared on a computerized, trial-by-trial, directed forgetting in recognition task. This task requires participants to comply with an overt instruction to forget irrelevant studied words, and it places a relatively high demand on working memory. The manic group was impaired on directed-forgetting sensitivity; however, when RT was statistically controlled, the groups demonstrated similar directed-forgetting effects. These findings are consistent with processing efficiency theory. They suggest that bipolar patients perform directed forgetting in recognition by increasing effortful control at encoding at the expense of processing efficiency, although acute mania reduces the capacity for control, thereby impairing recognition performance. Problems with processing efficiency are viewed as trait characteristics of bipolar disorder that may be overlooked by traditional error-based assessments.     

Effect of schizophrenia on frontotemporal activity during word encoding and recognition: a PET cerebral blood flow study.

OBJECTIVE: Neuropsychological studies have shown that deficits in verbal episodic memory in schizophrenia occur primarily during encoding and retrieval stages of information processing. The current study used positron emission tomography to examine the effect of schizophrenia on change in cerebral blood flow (CBF) during these memory stages. METHOD: CBF was measured in 23 healthy comparison subjects and 23 patients with schizophrenia during four conditions: resting baseline, motor baseline, word encoding, and word recognition. The motor baseline was used as a reference that was subtracted from encoding and recognition conditions by using statistical parametric mapping. RESULTS: Patients' performance was similar to that of healthy comparison subjects. During word encoding, patients showed reduced activation of left prefrontal and superior temporal regions. Reduced left prefrontal activation in patients was also seen during word recognition, and additional differences were found in the left anterior cingulate, left mesial temporal lobe, and right thalamus. Although patients' performance was similar to that of healthy comparison subjects, left inferior prefrontal activation was associated with better performance only in the comparison subjects. CONCLUSIONS: Left frontotemporal activation during episodic encoding and retrieval, which is associated with better recognition in healthy people, is disrupted in schizophrenia despite relatively intact recognition performance and right prefrontal function. This may reflect impaired strategic use of semantic information to organize encoding and facilitate retrieval.     

Sustained attention deficits in manic and euthymic patients with bipolar disorder

Sustained attention deficits are proposed to be both state and trait indicators of bipolar disorder. The nature of these deficits and their association with medication and symptoms is not clear yet. The aim of this study was to investigate the impairments in various components of sustained attention task in euthymic and manic patients and was to investigate the relationship between the deficits in the manic state and medication effects. The performances of 37 manic patients, 34 euthymic patients with bipolar disorder and 34 control subjects on eight scores from Conners' CPT II, reflecting three different dimensions of sustained attention were compared. Similar to some recent findings, euthymic patients had decreased target sensitivity (omission errors) and response time inconsistency. The increased false responding (commission errors), perseveration and vigilance deficits were prominent in the manic patients. These state dependent impairments could not be explained by the impact of medication. In contrast, the exacerbation of seemingly trait-related impairments in the manic state can be at least partly explained by the impact of pharmacological therapy.     

Social cognition throughout the three phases of bipolar disorder: A state-of-the-art overview

Although it is now well documented that bipolar disorder (BD) often presents with cognitive deficits and suboptimal social adjustment, the social cognitive profile of the illness throughout its three phases remains unclear. An extensive search was conducted through the online databases EBSCO, PsychInfo, PubMed, ScienceDirect, and Wiley–Blackwell, covering the period between 1990 and 2012. Fifty-one studies comparing the social cognitive performance of bipolar patients with that of healthy controls were identified. Deficits in emotion recognition and theory of mind were found in manic, depressed, and euthymic bipolar subjects. Furthermore, altered face emotion recognition and brain-related abnormalities were noted both in euthymic patients and subjects at risk for BD. The influence of clinical and neurocognitive variables on the social cognitive performance of bipolar patients remains to be ascertained. Future directions for research are discussed.     

Eyeblink conditioning anomalies in bipolar disorder suggest cerebellar dysfunction

Objectives:  Accumulating research implicates the cerebellum in non-motor psychological processes and psychiatric diseases, including bipolar disorder (BD). Despite recent evidence that cerebellar lesions have been documented to trigger bipolar-like symptoms, few studies have directly examined the functional integrity of the cerebellum in those afflicted with BD.
Methods:  Using a single-cue delay eyeblink conditioning procedure, the functional integrity of the cerebellum was examined in 28 individuals with BD (9 manic, 8 mixed, and 11 euthymic) and 28 age-matched healthy controls.
Results:  Analysis of the bipolar group as a whole indicated a conditioned response acquisition and timing deficit compared to controls. However, when the bipolar group was categorized according to mood state (mixed, manic, euthymic), individuals tested during mixed episodes were strikingly impaired, performing significantly worse than all other groups on both the acquisition and timing of conditioned responses.
Conclusions:  These findings extend prior research implicating cerebellar functional abnormalities in BD and suggest that cerebellar dysfunction may be associated with mood state and course of illness.     

Fronto‐temporal dysregulation in asymptomatic bipolar I patients: A paired associate functional MRI study

Bipolar disorder is associated with persistent declarative memory disturbances, but the neural basis of these deficits is not well understood. We used fMRI to investigate brain activity during performance on a face‐name paired associate task, which allows for the dissociation of encoding and recall‐related memory processes. Fifteen clinically remitted bipolar I disorder patients and 24 demographically matched healthy comparison subjects were scanned during task performance. At the voxel level, bipolar patients showed reduced cortical activation, relative to controls, in multiple task‐related brain regions during encoding. During recognition, bipolar patients under‐activated left hippocampal and parahippocampal regions, despite adequate task performance. Region of interest analyses indicated that, during encoding, bipolar patients had greater bilateral dorsolateral prefrontal (DLPFC) activity than healthy subjects. In contrast, during recognition patients showed hypo‐activation relative to controls in the right, but not the left, DLPFC. Although hippocampal activity did not differ between groups during encoding, bipolar patients failed to activate hippocampal regions to the same extent as healthy subjects during recognition. Finally, while better task performance was associated with recognition‐related hippocampal activity in healthy subjects, bipolar patients showed an inverse relationship between task performance and hippocampal activity. Remitted bipolar patients over‐engaged dorsolateral prefrontal regions when learning face‐name pairs, but relative hypoactivation in both prefrontal and medial temporal regions during recognition. These findings suggest a neural basis for the long‐term memory deficits consistently observed in patients with bipolar disorder; further, as these patterns appear in symptomatically remitted patients, they are unlikely to be an artifact of mood symptoms. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.