Metabolic evidence of corticolimbic dysregulation in bipolar mania

Findings from previous research on the neural substrates of mania have been variable, in part because of heterogeneity of techniques and patients. Though some findings have been replicated, the constellation of neurophysiological changes has not been demonstrated simultaneously. We sought to determine resting state cerebral metabolic changes associated with relatively severe acute mania. Resting positron emission tomography with ¹⁸fluorodeoxyglucose was performed in bipolar disorder patients with severe mania and in healthy controls. Statistical parametric mapping was used to determine regions of differential metabolism. Relative to controls, bipolar disorder patients with mania exhibited significantly decreased cerebral metabolism in both the dorsolateral prefrontal regions and the precuneus. Conversely, manic patients exhibited significant hypermetabolism in the parahippocampal complex, temporal lobe, anterior cingulate, and subgenual prefrontal cortex compared with controls. These results demonstrate simultaneous resting limbic/paralimbic hypermetabolism and prefrontal hypometabolism during mania. The findings support the hypothesis of corticolimbic dysregulation as a crucial contributor to the pathophysiology of bipolar disorder.     

Altered neural function in pediatric bipolar disorder during reversal learning

Dickstein DP, Finger EC, Skup M, Pine DS, Blair JR, Leibenluft E. Altered neural function in pediatric bipolar disorder during reversal learning.
Bipolar Disord 2010: 12: 707–719. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objective: Data documenting the functional impairment associated with the diagnosis of bipolar disorder (BD) in children and adolescents highlight the need for greater understanding of its pathophysiology. Toward that end, we demonstrated previously that BD youth have behavioral deficits on reversal learning tasks. On such tasks, participants must first acquire a stimulus/response relationship through trial‐and‐error learning, and then discern when the stimulus/reward relationship reverses. Here, we use event‐related functional magnetic resonance imaging (fMRI) to elucidate neural correlates of reversal learning deficits in euthymic BD youth compared to typically developing controls. Method: We compared euthymic pediatric BD participants (n = 16) versus age‐, sex‐, and IQ‐matched controls (n = 16). Our main outcome measure was blood oxygen level‐dependent (BOLD) signal measured with fMRI during an event‐related probabilistic reversal task. Results: Pediatric BD participants had significantly greater neural activity than controls in fronto‐parietal regions during the reversal phase, particularly in response to punished reversal errors (p < 0.05 corrected for multiple comparisons). Conclusions: Our current study suggests that during reversal learning, BD youths inefficiently recruit regions associated with processing response conflict and implementing alternative responses, including subdivisions of the frontal cortex and the parietal cortex. Such deficits are present in euthymic BD youth. Further work is necessary to evaluate the specificity of such alterations.     

Sustained attention deficit in bipolar disorder is not a working memory impairment in disguise

Euthymic patients with bipolar disorder have been reported to show persistent deficits in sustained attention. However, the sustained attention task which was used also placed demands on working memory. Bipolar disorder patients in the euthymic state were therefore compared with healthy controls on two measures of sustained attention with and without a working memory component. Signal detection methodology was applied to the results. Euthymic patients with bipolar disorder were particularly impaired at detecting targets in the sustained attention task without a working memory component. This deficit was still apparent in a sub-group of patients who were not currently receiving lithium medication. By contrast, performance in the sustained attention task involving working memory task was not significantly different in the two groups. Sustained attention deficits apparent during the euthymic period of bipolar disorder cannot be explained in terms of working memory impairment and represents a reduced inherent capacity rather than a change in response bias. Deficits in sustaining attention may help explain the difficulties in psychological and occupational functioning in bipolar disorder patients during remission.     

Effects of mood and subtype on cerebral glucose metabolism in treatment-resistant bipolar disorder.

BACKGROUND: Functional brain imaging studies in unipolar and secondary depression have generally found decreased prefrontal cortical activity, but in bipolar disorders findings have been more variable. METHODS: Forty-three medication-free, treatment-resistant, predominantly rapid-cycling bipolar disorder patients and 43 age- and gender-matched healthy control subjects had cerebral glucose metabolism assessed using positron emission tomography and fluorine-18-deoxyglucose. RESULTS: Depressed bipolar disorder patients compared to control subjects had decreased global, absolute prefrontal and anterior paralimbic cortical, and increased normalized subcortical (ventral striatum, thalamus, right amygdala) metabolism. Degree of depression correlated negatively with absolute prefrontal and paralimbic cortical, and positively with normalized anterior paralimbic subcortical metabolism. Increased normalized cerebello-posterior cortical metabolism was seen in all patient subgroups compared to control subjects, independent of mood state, disorder subtype, or cycle frequency. CONCLUSIONS: In bipolar depression, we observed a pattern of prefrontal hypometabolism, consistent with observations in primary unipolar and secondary depression, suggesting this is part of a common neural substrate for depression independent of etiology. In contrast, the cerebello-posterior cortical normalized hypermetabolism seen in all bipolar subgroups (including euthymic) suggests a possible congenital or acquired trait abnormality. The degree to which these findings in treatment-resistant, predominantly rapid-cycling patients pertain to community samples remains to be established.     

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.     

Cognitive functioning in elderly patients with early onset bipolar disorder

BACKGROUND: Very little is known about the long term cognitive sequelae of bipolar disorder. AIM: To investigate neuropsychological functioning in older euthymic persons with early onset bipolar disorder. METHOD: Fifteen older patients (age >60) with an early onset (<50 years) bipolar-I disorder in a euthymic mood were tested using a comprehensive neuropsychological test battery. Neuropsychological functioning was compared with that of a sex, age and education-matched group of 15 comparison subjects without mood disorders or memory complaints. RESULTS: Bipolar subjects scored lower than comparison subjects on selective attention, verbal memory, verbal fluency and mental effort tests. CONCLUSIONS: The findings suggest that euthymic bipolar patients are impaired across a range of cognitive domains. This could represent a trait-like cognitive disability related to the disease, as the impairments are comparable with those found in younger bipolar patients.     

Corticolimbic metabolic dysregulation in euthymic older adults with bipolar disorder

The corticolimbic dysregulation hypothesis of bipolar disorder suggests that depressive symptoms are related to dysregulation of components of an anterior paralimbic network (anterior cingulate, anterior temporal cortex, dorsolateral prefrontal cortex, parahippocampal gyrus, and amygdala) with excessive anterior limbic activity accompanied by diminished prefrontal activity. In younger patients, such abnormalities tend to resolve with remission of depression, but it remains to be established whether the same is true for older patients. This was a cross-sectional, between-subjects design conducted with 16 euthymic, medicated patients with bipolar disorder (10 type I, six type II) and 11 age-matched healthy controls. All participants were over age 50. Our main outcome measures were relative rates of cerebral metabolism derived from a resting ¹⁸flourodeoxyglucose positron emission tomography scan in specified regions of interest in the corticolimbic network. Resting metabolic rates in bipolar patients were significantly greater than in controls in bilateral amygdalae, bilateral parahippocampal gyri, and right anterior temporal cortex (BA 20, 38); they were significantly lower in bipolar patients than in controls in the bilateral dorsolateral prefrontal cortices (BA 9, 10, 46). The evidence of corticolimbic dysregulation observed is consistent with the hypothesis that bipolar disorder entails progressive, pernicious neurobiological disruptions that may eventually persist during euthymia. Persistent corticolimbic dysregulation may be related to residual affective, behavioral, and cognitive symptoms in older patients with bipolar disorder, even when not experiencing syndromal mood disturbance.     

Impaired sustained attention in euthymic bipolar disorder patients and non‐affected relatives: an fMRI study

Sepede G, De Berardis D, Campanella D, Perrucci MG, Ferretti A, Serroni N, Moschetta FS, Del Gratta C, Salerno RM, Ferro FM, Di Giannantonio M, Onofrj M, Romani GL, Gambi F. Impaired sustained attention in euthymic bipolar disorder patients and non‐affected relatives: an fMRI study. Bipolar Disord 2012: 14: 764–779. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Behavioral deficits in sustained attention have been reported during both acute and euthymic phases of type I bipolar disorder (BD‐I) and also in non‐affected relatives of bipolar disorder (BD) patients. In particular, selective failure in target recognition was proposed as a potential trait marker for BD, but there are few studies exploring the neural correlates. The aim of the present study was to analyze the behavioral and functional magnetic resonance imaging (fMRI) response of euthymic BD‐I patients and non‐affected relatives during a sustained attention task. Methods: Twenty‐four euthymic BD‐I patients, 22 non‐affected first‐degree relatives of BD‐I subjects, and 24 matched controls underwent a continuous performance test (CPT) with two levels of difficulty during event‐related fMRI scanning. Results: Both patients and relatives showed a lower accuracy in target detection when compared to controls. The fMRI data analysis revealed between‐group differences in several brain regions involved in sustained attention. During error in target recognition, both patients and relatives showed a larger activation in the bilateral insula and the posterior part of the middle cingulate cortex. By contrast, during correct target response, only patients failed to activate the right insula, whereas relatives showed an increased activation of the left insula and bilateral inferior parietal lobule – limited to the higher attention load – and an augmented deactivation of the posterior cingulate/retrosplenial cortex. Conclusions: A selective impairment in target recognition during a CPT was behaviorally and functionally detectable in both euthymic BD‐I patients and non‐affected first‐degree relatives, suggesting that specific sustained attention deficits may be a potential trait marker for BD‐I.     

Neuropsychological impairment in bipolar disorder: the relationship with glucocorticoid receptor function

OBJECTIVE: Basal levels of glucocorticoids, such as cortisol, are generally unaltered in bipolar disorder. However, neuroendocrine tests of glucocorticoid receptor (GR) function such as the dexamethasone suppression test (DST) are frequently abnormal. Neuropsychological impairment is well documented in healthy volunteers after administration of glucocorticoids and in patients with bipolar affective disorder. This suggests a potential link between neuropsychological and hypothalamic-pituitary-adrenal axis function. We examined the hypothesis that neuropsychological impairment in bipolar disorder is associated with abnormal GR function. METHODS: Seventeen euthymic bipolar patients and 16 controls completed tests of verbal declarative and working memory (WM) tests and the DST. The correlation between neuroendocrine and neuropsychological function was examined. RESULTS: Bipolar patients made significantly more errors of omission and commission on the WM paradigm and demonstrated impaired verbal recognition memory. Patients' post-dexamethasone cortisol correlated with WM commission errors (r(s) = 0.64, p = 0.0006). No such relationship was evident in controls. CONCLUSION: Deficits in declarative memory and WM are evident in patients with bipolar disorder. The deficit in retrieval accuracy from WM appears to be correlated with abnormal GR function.     

Decreased prefrontal, anterior cingulate, insula, and ventral striatal metabolism in medication-free depressed outpatients with bipolar disorder

This study explored whether cerebral metabolic changes seen in treatment resistant and rapid cycling bipolar depression inpatients are also found in an outpatient sample not specifically selected for treatment resistance or rapid cycling. We assessed 15 depressed outpatients with bipolar disorder (six type I and nine type II) who were medication-free for at least 2 weeks and were not predominantly rapid cycling. The average 28-item Hamilton Depression Scale (HAM-D) total score was 33.9. The healthy control group comprised 19 age-matched subjects. All participants received a resting quantitative ¹⁸F-fluoro-deoxyglucose positron emission tomography scan. Data analyses were performed with Statistical Parametric Mapping (SPM5). Analyses revealed that depressed patients exhibited similar global metabolism, but decreased absolute regional metabolism in the left much more than right dorsolateral prefrontal cortex, bilateral (left greater than right) insula, bilateral subgenual prefrontal cortex, anterior cingulate, medial prefrontal cortex, ventral striatum, and right precuneus. No region exhibited absolute hypermetabolism. Moreover, HAM-D scores inversely correlated with absolute global metabolism and regional metabolism in the bilateral medial prefrontal gyrus, postcentral gyrus, and middle temporal gyrus. Analysis of relative cerebral metabolism yielded a similar, but less robust pattern of findings. Our findings confirm prefrontal and anterior paralimbic metabolic decreases in cerebral metabolism outside of inpatients specifically selected for treatment resistant and rapid cycling bipolar disorder. Prefrontal metabolic rates were inversely related to severity of depression. There was no evidence of regional hypermetabolism, perhaps because this phenomenon is less robust or more variable than prefrontal hypometabolism.     

Meta-analysis of neuropsychological functioning in euthymic bipolar disorder: an update and investigation of moderator variables

Mann‐Wrobel MC, Carreno JT, Dickinson D. Meta‐analysis of neuropsychological functioning in euthymic bipolar disorder: an update and investigation of moderator variables.
Bipolar Disord 2011: 13: 334–342. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Cognitive impairment is frequently observed among individuals with bipolar disorder during acute and euthymic phases of the illness. The purpose of this study was to provide an updated meta‐analysis on the neuropsychological functioning of euthymic bipolar disorder individuals and to explore study design, demographic, and clinical variables that could moderate observed effects. Methods: Searches were conducted on Medline and PsychInfo databases and 28 studies were selected that met inclusion criteria. A total of 28 cognitive variables were examined in the meta‐analysis. The effects of four continuous (age, percent female, education, and illness duration) and two dichotomous (clinical course and diagnostic rigor) moderator variables were explored. Results: Compared to controls, euthymic bipolar disorder individuals demonstrated impaired neuropsychological functioning across almost all domains, with medium‐large effect sizes. Notably, vocabulary and word reading did not differ from controls. Sex did not impact neuropsychological functioning, and neuropsychological impairment decreased as education increased. Contrary to expectations, age and illness duration were negatively correlated with cognitive impairment. Diagnostic rigor of euthymia did not appear to impact effect sizes; however, clinical course received some tentative support as a moderator variable. Conclusions: Current results suggest that generalized, rather than specific, cognitive impairment characterizes euthymic bipolar disorder. Age, illness duration, education, and clinical course may moderate these broad cognitive effects. Against this general impairment backdrop, there may be a relative preservation of crystallized verbal ability.     

Evidence for theory of mind deficits in euthymic patients with bipolar disorder

OBJECTIVE: i) To investigate the subtle ToM (theory of mind) deficits in euthymic patients with bipolar disorder. ii) To investigate the impact of non-ToM cognitive deficits on ToM abilities. METHOD: Forty-three euthymic patients with bipolar disorder and 30 healthy control subjects were involved in this study. ToM was assessed by the Eyes test and the Hinting task. Both groups were also evaluated with a comprehensive neuropsychological battery including tasks for basic emotion and face recognition. RESULTS: The patient group was impaired on both of the ToM tasks. The patient group also showed impairment in many cognitive tasks including tasks related to sustained attention. CONCLUSION: Even euthymic patients with bipolar disorder may be impaired in advanced ToM tasks. Executive dysfunction and some other cognitives deficits such as basic emotion recognition may be at least partly responsible for this result.     

Paced finger-tapping abnormalities in bipolar disorder indicate timing dysfunction

Bolbecker AR, Hong SL, Kent JS, Forsyth JK, Klaunig MJ, Lazar EK, O’Donnell BF, Hetrick WP. Paced finger‐tapping abnormalities in bipolar disorder indicate timing dysfunction.
Bipolar Disord 2011: 13: 99–110. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Theoretical and empirical evidence suggests that impaired time perception and the neural circuitry contributing to internal timing mechanisms may contribute to severe psychiatric disorders, including mood disorders. The structures that are involved in subsecond timing, i.e., cerebellum and basal ganglia, have also been implicated in the pathophysiology of bipolar disorder. However, the timing of subsecond intervals has infrequently been studied in this population. Methods: Paced finger‐tapping tasks have been used to characterize internal timing processes in neuropsychiatric disorders. A total of 42 bipolar disorder patients (25 euthymic, 17 manic) and 42 age‐matched healthy controls completed a finger‐tapping task in which they tapped in time with a paced (500‐ms intertap interval) auditory stimulus (synchronization), then continued tapping without auditory input while attempting to maintain the same pace (continuation). This procedure was followed using the dominant index finger, then with alternating thumbs. Results: Bipolar disorder participants showed greater timing variability relative to controls regardless of pacing stimulus (synchronization versus continuation) or condition (dominant index finger versus alternating thumbs). Decomposition of timing variance into internal clock versus motor implementation components using the Wing–Kristofferson model showed higher clock variability in the bipolar disorder groups compared to controls, with no differences between groups on motor implementation variability. Conclusions: These findings suggest that internal timing mechanisms are disrupted in bipolar disorder patients, independent of symptom status. Increased clock variability in bipolar disorder may be related to abnormalities in cerebellar function.     

Sustained attention as a potential endophenotype for bipolar disorder

Ancín I, Santos JL, Teijeira C, Sánchez‐Morla EM, Bescós MJ, Argudo I, Torrijos S, Vázquez‐Álvarez B, De La Vega I, López‐Ibor JJ, Barabash A, Cabranes‐Díaz JA. Sustained attention as a potential endophenotype for bipolar disorder. Objective: Nowadays, it is accepted that to identify the biological basis of psychiatric illnesses it would be useful to deconstruct them into the most basic manifestations, such as cognitive deficits. The aim of this study was to set attention deficit as a stable vulnerability marker of bipolar disorder. Method: Sustained attention was evaluated by the Continuous Performance Test (DS‐CPT) in 143 euthymic bipolar patients and 105 controls. To estimate the influence of clinical profile in attention, patients completed a semi‐structured interview. Results: Bipolar patients showed a deficit in attention during euthymic periods. This disturbance correlated with years of evolution, age of onset and age of first hospitalisation; and was not influenced by other clinical data. Conclusion: Sustained attention may be considered as an endophenotype of the illness.     

Neuropsychological deficits and functional impairment in bipolar depression, hypomania and euthymia

OBJECTIVE: To examine whether patients with bipolar disorder (BD) have subtle neuropsychological deficits that manifest clinically as cognitive and functional compromise, and this study attempted to determine the pattern of such cognitive deficits and their functional impact across all three phases of BD. We hypothesised that euthymia does not equate with normal neuropsychological function and that each phase has a characteristic pattern of deficits, with disturbance in attention and memory being common across all phases of the illness: (i) bipolar depression - psychomotor slowing and impairment of memory; (ii) hypomania by frontal-executive deficits and (iii) euthymia - a mild disturbance of attention, memory and executive function. METHODS: Twenty-five patients with a diagnosis of bipolar I disorder underwent neuropsychological testing over a period of 30 months in the natural course of their illness while hypomanic and/or depressed and/or euthymic. The results from these assessments were compared with findings from neuropsychological tests conducted on 25 healthy controls matched for age, sex, education and handedness. RESULTS: Initial analyses revealed modest impairment in executive functioning, memory and attention in both hypomanic and depressed bipolar patients, with additional fine motor skills impairment in the latter. Memory deficits, also noted in euthymic patients, were non-significant after controlling for confounding variables, although bipolar depressed patients remained significantly impaired on tests of verbal recall. Bipolar depressed and hypomanic patients differed with respect to the nature of their memory impairment. Depressed patients were more impaired as compared with euthymic patients on tests of verbal recall and fine motor skills. Psychosocial functioning was impaired across all three patient groups, but only in depressed and hypomanic patients did this correlate significantly with neuropsychological performance. CONCLUSIONS: The mood-state-related cognitive deficits in both bipolar depression and hypomania compromise psychosocial function when patients are unwell. In euthymic patients, subtle impairments in attention and memory suggest that an absence of symptoms does not necessarily equate to 'recovery'. The possibility of persistent cognitive deficits in BD is an issue of profound clinical and research interest that warrants further investigation; however, future research needs to adopt more sophisticated neuropsychological probes that are able to better define state and trait deficits and determine their functional impact.     

Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study

Chou Y‐H, Wang S‐J, Lin C‐L, Mao W‐C, Lee S‐M, Liao M‐H. Decreased brain serotonin transporter binding in the euthymic state of bipolar I but not bipolar II disorder: a SPECT study.
Bipolar Disord 2010: 12: 312–318. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Previous positron emission tomography studies have demonstrated that serotonin transporter (SERT) binding in the midbrain is decreased in the depressive state of bipolar disorder (BD). The aim of this study was to assess SERT binding in the midbrain of patients in a euthymic state of BD. Methods: Twenty‐eight healthy controls and 24 patients in a euthymic state of medicated BD were recruited. Euthymic state was defined as Montgomery‐Åsberg Depression Rating Scale scores < 10 and Young Mania Rating Scale scores < 7 within a consecutive eight‐week period. Single photon emission computed tomography with the radiotracer ¹²³I‐ADAM was used to measure SERT binding in the midbrain. An equilibrium ratio model was used for data analysis. Specific uptake ratio (SUR), which represents availability of SERT binding in the midbrain, was the primary measurement outcome. Results: The averaged SURs were not different between healthy controls and BD patients in euthymic state (p = 0.27). However, a three‐way ANCOVA analysis comparing SURs in healthy controls, bipolar I disorder (BD I) patients, and bipolar II disorder (BD II) patients, covarying education duration and sex, showed that the averaged SURs were significantly lower in BD I than BD II patients and healthy controls (p = 0.042). The decreased SURs in BD I patients were well correlated with duration of illness (R = ?0.742, p = 0.014) only. Conclusions: Our findings demonstrate that there is differential biological regulation in BD I and BD II patients after stable treatment, which may support the existence of a dichotomy in BD.     

Deficits in inferior frontal cortex activation in euthymic bipolar disorder patients during a response inhibition task

Townsend JD, Bookheimer SY, Foland‐Ross LC, Moody TD, Eisenberger NI, Fischer JS, Cohen MS, Sugar CA, Altshuler LL. Deficits in inferior frontal cortex activation in euthymic bipolar disorder patients during a response inhibition task.
Bipolar Disord 2012: 14: 442–450. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: The inferior frontal cortical–striatal network plays an integral role in response inhibition in normal populations. While inferior frontal cortex (IFC) impairment has been reported in mania, this study explored whether this dysfunction persists in euthymia. Methods: Functional magnetic resonance imaging (fMRI) activation was evaluated in 32 euthymic patients with bipolar I disorder and 30 healthy subjects while performing the Go/NoGo response inhibition task. Behavioral data were collected to evaluate accuracy and response time. Within‐group and between‐group comparisons of activation were conducted using whole‐brain analyses to probe significant group differences in neural function. Results: Both groups activated bilateral IFC. However, between‐group comparisons showed a significantly reduced activation in this brain region in euthymic patients with bipolar disorder compared to healthy subjects. Other frontal and basal ganglia regions involved in response inhibition were additionally significantly reduced in bipolar disorder patients, in both the medicated and the unmedicated subgroups. No areas of greater activation were observed in bipolar disorder patients versus healthy subjects. Conclusions: Bipolar disorder patients, even during euthymia, have a persistent reduction in activation of brain regions involved in response inhibition, suggesting that reduced activation in the orbitofrontal cortex and striatum is not solely related to the state of mania. These findings may represent underlying trait abnormalities in bipolar disorder.     

Changes in neuronal activation in patients with bipolar disorder during performance of a working memory task

OBJECTIVES: Several lines of evidence suggest that deficits in cognition persist in bipolar patients during periods of euthymia. Working memory impairment has been observed in euthymic bipolar patients and noted to be a significant source of functional deficits in psychiatric disorders. Functional changes associated with these cognitive deficits however, remain poorly understood. We hypothesized that patients with bipolar disorder would demonstrate changes in neuronal activation in specific regions forming part of the working memory network. METHODS: Fifteen euthymic bipolar patients and fifteen age- and gender-matched healthy controls were recruited. Subjects participated in fMRI scans during which a two-back working memory task alternated with a zero-back control/attention task using a block-design paradigm. Groups were analyzed separately, and intergroup comparisons were made using an exploratory, voxel-by-voxel analysis. RESULTS: Bipolar patients performed more poorly on the cognitive tasks than did healthy controls (F = 3.77, p = 0.04). After covarying for task performance and reaction time, bipolar patients demonstrated significantly greater activation than healthy subjects in several regions including the fronto-polar prefrontal cortex, temporal cortex, basal ganglia, thalamus, and posterior parietal cortex. No areas showed a significant decrease in activation, compared with healthy controls. CONCLUSIONS: Our findings suggest that decreased working memory performance in bipolar patients reflects specific neurofunctional deficits. These deficits may represent primary areas of neuropathology or be secondary to neuropathology elsewhere in the working memory network. Continued research utilizing other imaging modalities may further clarify the underlying neuropathology involved in these cognitive deficits.     

Performance monitoring and executive control of attention in euthymic bipolar disorder: Employing the CPT-AX paradigm

Reduced cognitive test performance has been demonstrated in patients with bipolar disorder (BD), even when euthymic. Several studies have explored aspects of attention, including sustained attention, and reported patients show lower accuracy compared to controls. It is necessary to modify existing attentional paradigms to fully characterise such deficits. The present study sought to examine if there are changes in the profile of performance and error-types during a sustained attention task in BD. Twenty-two euthymic patients with DSM-IV diagnosed BD and 21 healthy controls were recruited. Participants completed a modified CPT-AX paradigm with a high proportion of target trials (70%) with cues and probes presented at continuous intervals. This modification increases the demands on response inhibition and permits the deconstruction of attentional/executive deficits previously described. Overall, BD patients showed significantly poorer target discriminability compared to controls. In block one (first quarter) of the task, patients showed no significant differences to controls, but by the final fourth block (last quarter) they made significantly fewer hits and more errors (both ‘AX’ misses and ‘BX’ false alarms). BD patients completed initial stages of the task similarly to controls, but as demands on the attentional system continued difficulties emerged, consistent with problems in context-maintenance.     

Impairment of verbal learning and memory and executive function in unaffected siblings of probands with bipolar disorder

Kulkarni S, Jain S, Janardhan Reddy YC, Kumar KJ, Kandavel T. Impairment of verbal learning and memory and executive function in unaffected siblings of probands with bipolar disorder.
Bipolar Disord 2010: 12: 647–656. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Impairments in executive function and memory have been reported in relatives of patients with bipolar disorder, suggesting that they could be potential endophenotypes for genetic studies, but the findings are inconsistent. In this study, neuropsychological performance in unaffected siblings of probands with family loading for bipolar disorder is compared to that of individually matched healthy controls. We hypothesized that performance on tests of executive functions and memory would be impaired in unaffected siblings of probands with bipolar disorder compared to matched healthy controls. Methods: We evaluated 30 unaffected siblings of probands with bipolar I disorder and 30 individually matched healthy controls using tests of attention, executive function, and memory. Unaffected siblings and healthy control subjects did not differ with respect to gender, age, and years of education. Results: Unaffected siblings performed poorly on the Tower of London test (TOL), the Rey’s auditory verbal learning test (RAVLT), and the Rey’s complex figure test. In the multivariate analysis, significance was noted for the TOL, total number of moves (p = 0.007) and the RAVLT total learning score (p = 0.001). Conclusions: Our study suggests that the deficits in verbal learning and memory and executive functions (planning) could be potential endophenotypes in bipolar disorder. These deficits are consistent with the proposed neurobiological model of bipolar disorder involving the frontotemporal and subcortical circuits. Future studies could couple cognitive and imaging strategies and genomics to identify neurocognitive endophenotypes in bipolar disorder.