Fronto-limbic function in unaffected offspring at familial risk for bipolar disorder during an emotional working memory paradigm

Evidence from neuroimaging studies indicate that individuals with bipolar disorder (BD) exhibit altered functioning of fronto-limbic systems implicated in voluntary emotion regulation. Few studies, however, have examined the extent to which unaffected youth at familial risk for BD exhibit such alterations. Using an fMRI emotional working memory paradigm, we investigated the functioning of fronto-limbic systems in fifteen healthy bipolar offspring (8–17 years old) with at least one parent diagnosed with BD (HBO), and 16 age-matched healthy control (HC) participants. Neural activity and functional connectivity analyses focused on a priori neural regions supporting emotion processing (amygdala and ventral striatum) and voluntary emotion regulation (ventrolateral prefrontal cortex (VLPFC), dorsolateral prefrontal cortex (DLPFC), and anterior cingulate cortex (ACC)). Relative to HC, HBO exhibited greater right VLPFC (BA47) activation in response to positive emotional distracters and reduced VLPFC modulation of the amygdala to both the positive and negative emotional distracters; there were no group differences in connectivity for the neutral distracters. These findings suggest that alterations in the functioning of fronto-limbic systems implicated in voluntary emotion regulation are present in unaffected bipolar offspring. Future longitudinal studies are needed to determine the extent to which such alterations represent neurodevelopmental markers of risk for future onset of BD.     

Cognitive control network anatomy correlates with neurocognitive behavior: A longitudinal study

Cognitive control is the process of employing executive functions, such as attention, planning or working memory, to guide appropriate behaviors in order to achieve a specific goal. Functional magnetic resonance imaging studies suggest a superordinate cognitive control network, comprising the dorsal regions of the lateral prefrontal cortex (DLPFC), anterior cingulate cortex (dACC) and parietal cortex (DPC). How gray matter structure changes across this network throughout neurodevelopment and how these changes impact cognitive control are not yet fully understood. Here we investigate changes in gray matter volume of the key nodes of the cognitive control network using structural MRI scans from 176 participants aged 8–38 years. One hundred and eleven of these also completed a longitudinal follow‐up at two years. We compare these with performance on a cognitive battery also measured at these two time points. We found that volume decreases in the cognitive control network were associated with improved performance in executive function (in left DLPFC and bilateral DPC), information processing (in bilateral dACC and right DPC) and emotion identification tasks (left DLPFC). These results were significant after controlling for age. Furthermore, gray matter changes were coordinated across the network. These findings imply age‐independent synaptic pruning in the cognitive control network may have a role in improving performance in cognitive domains. This study provides insight into the direct impact of structural changes on behavior within this network during neurodevelopment and provides a normative evidence base to better understand development of cognitive dysfunction in brain disorders. Hum Brain Mapp 38:631–643, 2017. © 2016 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.     

Elevated striatal and decreased dorsolateral prefrontal cortical activity in response to emotional stimuli in euthymic bipolar disorder: no associations with psychotropic medication load

Objective: To examine abnormal patterns of frontal cortical‐subcortical activity in response to emotional stimuli in euthymic individuals with bipolar disorder type I in order to identify trait‐like, pathophysiologic mechanisms of the disorder. We examined potential confounding effects of total psychotropic medication load and illness variables upon neural abnormalities. Method: We analyzed neural activity in 19 euthymic bipolar and 24 healthy individuals to mild and intense happy, fearful and neutral faces. Results: Relative to healthy individuals, bipolar subjects had significantly increased left striatal activity in response to mild happy faces (p < 0.05, corrected), decreased right dorsolateral prefrontal cortical (DLPFC) activity in response to neutral, mild and intense happy faces, and decreased left DLPFC activity in response to neutral, mild and intense fearful faces (p < 0.05, corrected). Bipolar and healthy individuals did not differ in amygdala activity in response to either emotion. In bipolar individuals, there was no significant association between medication load and abnormal activity in these regions, but a negative relationship between age of illness onset and amygdala activity in response to mild fearful faces (p = 0.007). Relative to those without comorbidities, bipolar individuals with comorbidities showed a trend increase in left striatal activity in response to mild happy faces. Conclusions: Abnormally increased striatal activity in response to potentially rewarding stimuli and decreased DLPFC activity in response to other emotionally salient stimuli may underlie mood instabilities in euthymic bipolar individuals, and are more apparent in those with comorbid diagnoses. No relationship between medication load and abnormal neural activity in bipolar individuals suggests that our findings may reflect pathophysiologic mechanisms of the illness rather than medication confounds. Future studies should examine whether this pattern of abnormal neural activity could distinguish bipolar from unipolar depression.     

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.     

Mindfulness-based cognitive therapy for nonremitted patients with bipolar disorder

Introduction: Bipolar disorder is characterized by recurrent episodes of depression and/or mania along with interepisodic mood symptoms that interfere with psychosocial functioning. Despite periods of symptomatic recovery, many individuals with bipolar disorder continue to experience substantial residual mood symptoms that often lead to the recurrence of mood episodes. Aims: This study explored whether a new mindfulness‐based cognitive therapy (MBCT) for bipolar disorder would increase mindfulness, reduce residual mood symptoms, and increase emotion‐regulation abilities, psychological well‐being, positive affect, and psychosocial functioning. Following a baseline clinical assessment, 12 individuals with DSM‐IV bipolar disorder were treated with 12 group sessions of MBCT. Results: At the end of treatment, as well as at the 3 months follow‐up, participants showed increased mindfulness, lower residual depressive mood symptoms, less attentional difficulties, and increased emotion‐regulation abilities, psychological well‐being, positive affect, and psychosocial functioning. Conclusions: These findings suggest that treating residual mood symptoms with MBCT may be another avenue to improving mood, emotion regulation, well‐being, and functioning in individuals with bipolar disorder.     

Interactive effects of estrogen and serotonin on brain activation during working memory and affective processing in menopausal women

While cognitive changes and mood instability are frequent symptoms reported by menopausal women, the degree to which the decline in estrogen production is responsible is not yet clear. Several lines of evidence suggest that estrogen may produce its effects on cognition and mood through modulation of serotonergic function. To test this hypothesis, we used the tryptophan depletion (TD) paradigm to lower central serotonin levels and pharmacologically manipulated estrogen levels in healthy menopausal women. We examined the individual and combined effects of estradiol and serotonin on working memory, emotion processing and task-related brain activation. Eight healthy predominantly early postmenopausal women underwent TD or sham depletion followed by functional magnetic resonance imaging (fMRI) both before and after short-term transdermal estradiol 75-150 μg/d administration. There was an estradiol treatment by TD interaction for brain activation during performance on both the N-back Task (working memory) and Emotion Identification Task (affective processing). During the 2-back condition, TD attenuated activation prior to, but not after, estradiol treatment in the right and left dorsal lateral prefrontal and middle frontal/cingulate gyrus. During emotion identification, TD heightened activation in the orbital frontal cortex and bilateral amygdala, and this effect was attenuated by estradiol treatment. These results provide preliminary evidence that serotonergic effects directly mediate the impact of estrogen on brain activation during working memory and affective processing.     

An fMRI study of attentional control in the context of emotional distracters in euthymic adults with bipolar disorder

Inability to modulate attention away from emotional stimuli may be a key component of dysregulated emotion in bipolar disorder (BD). Previous studies of BD indicate abnormalities in neural circuitry underlying attentional control, yet few studies examined attentional control in the context of emotional distracters. We compared activity and connectivity in neural circuitry supporting attentional control and emotion processing among 22 individuals with BD type 1, currently remitted and euthymic, and 19 healthy controls. Participants performed an emotional n-back paradigm, comprising high and low attentional demand conditions, each with either emotional (happy, fearful), neutral or no face flanker distracters. During the high attentional control demand conditions without emotional distracters, BD individuals showed reduced activity relative to controls in dorsolateral prefrontal cortex, dorsal anterior cingulate cortex (dACC), and inferior parietal cortex. During the high attentional control demand conditions with fearful-face distracters, BD individuals showed greater activity than controls in these regions and amygdala and striatum. Relative to controls, BD individuals also showed abnormal patterns of effective connectivity between dACC and amygdala during high attentional control demand with emotional face distracters. Inter-episode bipolar disorder is characterized by abnormal recruitment of attentional control neural circuitry, especially in the context of emotionally distracting information.     

Altered frontostriatal coupling in pre‐manifest Huntington’s disease: effects of increasing cognitive load

Background and purpose: Functional neuroimaging studies have suggested a dysfunction of prefrontal regions in clinically pre‐symptomatic individuals with the Huntington’s disease (HD) gene mutation (pre‐HD) during cognitive processing. The objective of this study was to test the impact of cognitive demand on prefrontal connectivity in pre‐HD individuals. Methods: Sixteen healthy controls and sixteen pre‐HD subjects were studied using functional MRI and a verbal working memory task with increasing cognitive load. Load‐dependent functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) was investigated by means of psychophysiological interactions. Results: In pre‐HD subjects, aberrant functional connectivity of the left DLPFC was found at high working memory load levels only. Compared with healthy controls, pre‐HD individuals exhibited lower connectivity strength in the left putamen, the right anterior cingulate and the left medial prefrontal cortex. Pre‐HD individuals close to the onset of motor symptoms additionally exhibited lower connectivity strength in the right putamen and the left superior frontal cortex. The connectivity strength in the left putamen was associated with several clinical measures including CAG repeat length, Unified Huntington's Disease Rating Scale motor score and predicted years to manifest symptom onset. Conclusion: These findings suggest that early prefrontal connectivity abnormalities in pre‐HD individuals are modulated by cognitive demand.     

Activation in dorsolateral prefrontal cortex in response to maternal criticism and praise in recovered depressed and healthy control participants.

BACKGROUND: High family levels of expressed emotion reliably predict relapse in patients with schizophrenia and mood disorders; however, the neural mechanisms linking expressed emotion and relapse are unexplored. Dysfunctional activity in the dorsolateral prefrontal cortex (DLPFC) has been implicated in the pathophysiology of depression. Functional magnetic resonance imaging (fMRI) was used to assess focal activation changes in DLPFC in response to a novel psychosocial challenge stimulus developed from the expressed emotion construct. METHODS: Healthy control subjects and fully remitted unipolar depressed participants completed blood oxygen level-dependent fMRI while they heard their own mothers making critical and praising comments about them. RESULTS: Relative to control subjects, participants with a history of depression failed to activate DLPFC when they heard critical remarks. There were no differences between the two groups in their DLPFC responses to maternal praise. CONCLUSIONS: Even if fully well at the time of testing, participants with a known vulnerability to depression respond differently to the psychosocial challenge of being criticized. These findings might have implications for our understanding of vulnerability to depression and to depressive relapse.     

A longitudinal functional connectivity analysis of the amygdala in bipolar I disorder across mood states

Cerullo MA, Fleck DE, Eliassen JC, Smith MS, DelBello MP, Adler CM, Strakowski SM. A longitudinal functional connectivity analysis of the amygdala in bipolar I disorder across mood states. Bipolar Disord 2012: 14: 175–184. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Bipolar I disorder is characterized by affective symptoms varying between depression and mania. The specific neurophysiology responsible for depression in bipolar I disorder is unknown but previous neuroimaging studies suggest impairments in corticolimbic regions that are responsible for regulating emotion. The amygdala seems to play a central role in this network and is responsible for appraisal of emotional stimuli. To further understand the role of the amygdala in the generation of mood symptoms, we used functional magnetic resonance imaging (fMRI) to examine a group of patients with bipolar I disorder longitudinally. Methods: fMRI was used to study regional brain activation in 15 bipolar I disorder patients followed for up to one year. Patients received an fMRI scan during an initial manic episode and a subsequent depressive episode. During the scans, patients performed an attentional task that incorporated emotional pictures. Fifteen healthy comparison subjects were also scanned at baseline and then at four months. Whole‐brain functional connectivity analysis was performed using the left and right amygdala as seed regions. Results: Significant changes in amygdala functional connectivity were found between the manic and depressed phases of illness. The right amygdala was significantly more positively correlated with the left inferior frontal gyrus during mania and with the right insula during depression. There were no significant differences in left amygdala correlations across mood states in the bipolar I disorder group. Conclusions: In the transition from a manic/mixed episode to a depressive episode, subjects with bipolar I disorder showed unique changes in cortical–amygdala functional connectivity. Increased connectivity between the insula and right amygdala may generate excessive positive feedback, in that both of these regions are involved in the appraisal of emotional stimuli. Increased correlation between the right amygdala and the inferior frontal gyrus in mania is consistent with previous findings of decreased prefrontal modulation of limbic regions in mania. These differences in connectivity may represent neurofunctional markers of mood state as they occurred in the same individuals across manic and depressive episodes.     

Rethinking the Use of Neutral Faces as a Baseline in fMRI Neuroimaging Studies of Axis‐I Psychiatric Disorders

Major Axis‐I disorders including major depressive disorder (MDD), bipolar disorder (BD), anxiety disorder, and schizophrenia are associated with a host of aberrations in the way social stimuli are processed. Face perception tasks are often used in neuroimaging research of emotion processing in both healthy and patient populations, and to date, there exists a mounting body of evidence, both behavioral and within the brain, indicating that emotional faces compared to neutral faces are processed abnormally by those with Axis‐I disorders relative to healthy control (HC) groups. The use of neutral faces as a “baseline control condition” is predicated on the assumption that neutral faces are processed in the same way HCs and individuals with major Axis‐I disorders. In this paper, existing fMRI studies examining the way neutral faces are processed in groups with Axis‐I disorders involving socioaffective perception are reviewed. In reviewing available studies, a consistent pattern of results demonstrated that these disorders are associated with abnormal frontolimbic activity in response to neutral faces and in particular within the amygdala and prefrontal regions such as the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) compared to HC groups. Specifically, increased amygdala activation was consistently reported in response to neutral faces in anxiety disorders and schizophrenia. Abnormal medial PFC activity was reported in patients with MDD, and patients with BD exhibit decreased activity in the DLPFC and ACC relative to HCs. In addition, specific suggestions to overcome these obstacles with new research and additional analyses are discussed.     

Prefrontal hyperactivation during working memory task in untreated individuals with major depressive disorder

The prefrontal cortex, a part of the limbic-thalamic-cortical network, participates in regulation of mood, cognition and behavior and has been implicated in the pathophysiology of major depressive disorder (MDD). Many neuropsychological studies demonstrate impairment of working memory in patients with MDD. However, there are few functional neuroimaging studies of MDD patients during working memory processing, and most of the available ones included medicated patients or patients with both MDD and bipolar disorder. We used functional magnetic resonance imaging (fMRI) to measure prefrontal cortex function during working memory processing in untreated depressed patients with MDD. Fifteen untreated individuals with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition recurrent MDD (mean age+/-s.d.=34.3+/-11.5 years) and 15 healthy comparison subjects (37.7+/-12.1 years) matched for age, sex and race were studied using a GE/Elscint 2T MR system. An echo-planar MRI sequence was used to acquire 24 axial slices. The n-back task (0-back, 1-back and 2-back) was used to elicit frontal cortex activation. Data were analyzed with a multiple regression analysis using the FSL-FEAT software. MDD patients showed significantly greater left dorsolateral cortex activation during the n-back task compared to the healthy controls (P<0.01), although task performance was similar in the two groups. Furthermore, the patients showed significant anterior cingulate cortex activation during the task, but the comparison subjects did not (P<0.01). This study provides in vivo imaging evidence of abnormal frontolimbic circuit function during working memory processing in individuals with MDD.     

Cognitive styles in hypomanic episodes of bipolar I disorder

Lex C, Hautzinger M, Meyer TD. Cognitive styles in hypomanic episodes of bipolar I disorder.
Bipolar Disord 2011: 13: 355–364. © 2011 The Authors.
Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Cognitive vulnerability‐stress theories have recently been extended to bipolar disorder by suggesting that an activation of negative cognition might lead to depressive mood episodes and an activation of positive cognition might lead to manic mood episodes. Alternatively, the manic defense hypothesis claims that hypomanic and manic states are not the opposite of depression but rather contain similar underlying negative cognitions. The objective of this study was to further evaluate these theories by examining the cognitive patterns in bipolar I hypomania. Methods: We compared 15 hypomanic bipolar I disorder patients, 26 remitted bipolar I disorder patients, and 21 healthy individuals in a cross‐sectional study. All participants completed the Dysfunctional Attitude Scale, the Attributional Style Questionnaire, the Emotional Stroop Task, and the Emotional Auditory Verbal Learning Test. Results: Hypomanic bipolar disorder individuals showed cognitions associated with depressive states as well as cognitions associated with manic states. The results for the remitted bipolar disorder patients paralleled those for the control group. Conclusion: Dysfunctional cognition in bipolar disorder seems to relate to state rather than to trait. Hypomania includes depression‐related as well as mania‐related cognitions and can therefore not be considered as the mere opposite of depression.     

Brain Activation Patterns Associated with the Effects of Emotional Distracters during Working Memory Maintenance in Patients with Generalized Anxiety Disorder

Few studies have assessed the neural mechanisms of the effects of emotion on cognition in generalized anxiety disorder (GAD) patients. In this functional MRI (fMRI), we investigated the effects of emotional interference on working memory (WM) maintenance in GAD patients. Fifteen patients with GAD participated in this study. Event-related fMRI data were obtained while the participants performed a WM task (face recognition) with neutral and anxiety-provoking distracters. The GAD patients showed impaired performance in WM task during emotional distracters and showed greater activation on brain regions such as DLPFC, VLPFC, amygdala, hippocampus which are responsible for the active maintenance of goal relevant information in WM and emotional processing. Although our results are not conclusive, our finding cautiously suggests the cognitive-affective interaction in GAD patients which shown interfering effect of emotional distracters on WM maintenance.     

Emotion processing and regulation in bipolar disorder: a review

Townsend J, Altshuler LL. Emotion processing and regulation in bipolar disorder: a review.
Bipolar Disord 2012: 14: 326–339. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Bipolar disorder (BP) is characterized by a dysfunction of mood, alternating between states of mania/hypomania and depression. Thus, the primary abnormality appears to be an inability to regulate emotion, the result of which is emotional extremes. The purpose of this paper is to review the current functional magnetic resonance imaging (fMRI) literature on adult patients with BP using emotion processing or regulation paradigms. Methods: A search was conducted on PubMed using the keywords: bipolar disorder, fMRI, mania, bipolar depression, bipolar euthymia, emotion, and amygdala. Only those studies that were conducted in adult patients using an emotion activation task were included in the final review. Results: Using tasks that assess neural functioning during emotion processing and emotion regulation, many fMRI studies have examined BP subjects during mania and euthymia. Fewer fMRI studies have been conducted during depression, and fewer still have included the same subjects in multiple mood states. Despite these limitations, these studies have demonstrated specific abnormalities in frontal–limbic regions. Using a variety of paradigms, investigators have specifically evaluated the amygdala (a structure within the limbic system known to be critical for emotion) and the prefrontal cortex (PFC) (a region known to have a regulatory function over the limbic system). Conclusions: These investigations reveal that amygdala activation varies as a function of mood state, while the PFC remains persistently hypoactivated across mood states. Emotional dysregulation and lability in mania and depression may reflect disruption of a frontal–limbic functional neuroanatomical network.     

The common adolescent bipolar phenotype shows positive biases in emotional processing

Rock PL, Goodwin GM, Harmer CJ. The common adolescent bipolar phenotype shows positive biases in emotional processing.
Bipolar Disord 2010: 12: 606–615. © 2010 The Authors.
Journal compilation © 2010 John Wiley & Sons A/S. Objectives: Bipolar disorder is associated with abnormalities in emotional processing that persist into periods of remission. However, studies of euthymic bipolar disorder patients may be confounded by the experience of mood episodes and medication. We therefore assessed an adolescent group for vulnerability markers associated with the bipolar phenotype. Methods: The Mood Disorder Questionnaire (MDQ) is a screening tool for bipolar disorder that targets mood‐elevation symptoms. We selected 32 high‐scoring students (≥ 7 symptoms) with the adolescent bipolar phenotype and 30 low‐scoring controls (≤ 3 symptoms) and screened them with the Mini International Neuropsychiatric Interview–Plus for bipolar disorder and other psychiatric disorders. We investigated emotional processing by assessing facial expression recognition, emotional memory, emotion‐potentiated startle, and a dot‐probe task. Results: Of the high‐MDQ participants, 12 were in remission from bipolar disorder defined by DSM‐IV‐TR and interview (bipolar II disorder/bipolar disorder not otherwise specified) and 3 from major depressive disorder. High‐MDQ participants had higher levels of neuroticism, low mood, and lifetime anxiety comorbidity and alcohol dependence compared with low‐MDQ participants. The high‐MDQ group showed facilitated recognition of surprised and neutral facial expressions and enhanced processing of positive versus negative information in emotional recognition memory and emotion‐potentiated startle. There were no effects on emotional categorisation/recall memory or attentional bias in the dot‐probe task. Conclusions: These results suggest that students with the common adolescent bipolar phenotype show positive emotional processing biases despite increased levels of neuroticism, low mood, and anxiety. Such effects may represent a psychological vulnerability marker associated with the bipolar phenotype.     

Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults

Nusslock R, Almeida JRC, Forbes EE, Versace A, Frank E, LaBarbara EJ, Klein CR, Phillips ML. Waiting to win: elevated striatal and orbitofrontal cortical activity during reward anticipation in euthymic bipolar disorder adults. Bipolar Disord 2012: 14: 249–260. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objective: Bipolar disorder may be characterized by a hypersensitivity to reward‐relevant stimuli, potentially underlying the emotional lability and dysregulation that characterizes the illness. In parallel, research highlights the predominant role of striatal and orbitofrontal cortical (OFC) regions in reward‐processing and approach‐related affect. We aimed to examine whether bipolar disorder, relative to healthy, participants displayed elevated activity in these regions during reward processing. Methods: Twenty‐one euthymic bipolar I disorder and 20 healthy control participants with no lifetime history of psychiatric disorder underwent functional magnetic resonance imaging (fMRI) scanning during a card‐guessing paradigm designed to examine reward‐related brain function to anticipation and receipt of monetary reward and loss. Data were collected using a 3T Siemens Trio scanner. Results: Region‐of‐interest analyses revealed that bipolar disorder participants displayed greater ventral striatal and right‐sided orbitofrontal [Brodmann area (BA) 11] activity during anticipation, but not outcome, of monetary reward relative to healthy controls (p < 0.05, corrected). Whole‐brain analyses indicated that bipolar disorder, relative to healthy, participants also displayed elevated left‐lateral OFC (BA 47) activity during reward anticipation (p < 0.05, corrected). Conclusions: Elevated ventral striatal and OFC activity during reward anticipation may represent a neural mechanism for predisposition to expansive mood and hypo/mania in response to reward‐relevant cues that characterizes bipolar disorder. Our findings contrast with research reporting blunted activity in the ventral striatum during reward processing in unipolar depressed individuals, relative to healthy controls. Examination of reward‐related neural activity in bipolar disorder is a promising research focus to facilitate identification of biological markers of the illness.     

A functional magnetic resonance imaging study of bipolar disorder: state- and trait-related dysfunction in ventral prefrontal cortices

BACKGROUND: Abnormalities in prefrontal and anterior cingulate cortices are implicated in disturbances of attention, cognition, and impulse regulation in bipolar disorder. Acute episodes have been associated with dysfunction in these brain regions, and more enduring trait-related dysfunction has been implicated by volumetric and cellular abnormalities in these regions. The relative contributions of prefrontal regions to state and trait disturbances in bipolar disorder, however, have not been defined. We sought to characterize state- and trait-related functional impairment in frontal systems in bipolar disorder. METHODS: Thirty-six individuals with bipolar disorder I (11 with elevated, 10 with depressed, and 15 with euthymic mood states) and 20 healthy control subjects matched for handedness and sex participated in an event-related functional magnetic resonance imaging study of the color-word Stroop to determine mean percentage of regional task-related signal change. RESULTS: Signal increased during the Stroop task similarly across diagnostic groups in a distribution that included dorsal anterior cingulate and prefrontal cortices, consistent with previously reported activations in this task. Signal changes associated with specific mood states in bipolar disorder were detected in ventral prefrontal cortex, with a blunted increase in signal on the right side in the elevated mood group (P =.005) and an exaggerated increase in signal on the left side in the depressed group (P =.02) compared with the euthymic group. Patients (vs healthy controls) demonstrated blunted activation in a spatially distinct, rostral region of left ventral prefrontal cortex that was independent of mood state (P<.005). CONCLUSIONS: Bipolar disorder is associated with a trait abnormality in left ventral prefrontal cortex. Additional ventral prefrontal abnormalities may be associated with specific acute mood states. The hemispheric laterality of the abnormality and the directions of signal change may relate to the valence of the mood episode.     

The neural correlates of non-spatial working memory in velocardiofacial syndrome (22q11.2 deletion syndrome)

Velocardiofacial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a neurogenetic disorder that is associated with both learning disabilities and a consistent neuropsychological phenotype, including deficits in executive function, visuospatial perception, and working memory. Anatomic imaging studies have identified significant volumetric reductions in the parietal lobe of individuals with VCFS, but several studies have reported that the frontal lobe is relatively preserved. We used functional magnetic resonance imaging to investigate the neural correlates of non-spatial working memory in 17 youths with VCFS, 10 of their unaffected siblings, and 10 community controls (with the same proportion of learning disabilities as the VCFS youths). Task performance of siblings tended to be more accurate than children with VCFS, who did not differ from community controls. All three-study groups recruited parietal regions that were equivalent in location and magnitude. Whereas the sibling group also recruited the dorsolateral prefrontal cortex (DLPFC), Broca's area, and anterior cingulate, DLPFC activation was absent in the whole brain analyses of children with VCFS and controls. Moreover, the magnitude of frontal activation in VCFS participants was restricted relative to both siblings and controls. These findings suggest that VCFS participants exhibit frontal hypoactivation that is not attributable to performance. In addition, VCFS children and controls (many with idiopathic learning disabilities) appear to rely on phonological rehearsal to hold information on line instead of the DLPFC. Despite previous anatomic MRI reports of preserved frontal lobe volumes in VCFS therefore, these fMRI findings suggest that the frontal component of the distributed network subserving executive function and working memory may be disrupted in youth with this disorder.     

Emotion perception and executive control interact in the salience network during emotionally charged working memory processing

Processing of emotional stimuli can either hinder or facilitate ongoing working memory (WM); however, the neural basis of these effects remains largely unknown. Here we examined the neural mechanisms of these paradoxical effects by implementing a novel emotional WM task in an fMRI study. Twenty‐five young healthy participants performed an N‐back task with fearful and neutral faces as stimuli. Participants made more errors when performing 0‐back task with fearful versus neutral faces, whereas they made fewer errors when performing 2‐back task with fearful versus neutral faces. These emotional impairment and enhancement on behavioral performance paralleled significant interactions in distributed regions in the salience network including anterior insula (AI) and dorsal cingulate cortex (dACC), as well as in emotion perception network including amygdala and temporal‐occipital association cortex (TOC). The dorsal AI (dAI) and dACC were more activated when comparing fearful with neutral faces in 0‐back task. Contrarily, dAI showed reduced activation, while TOC and amygdala showed stronger responses to fearful as compared to neutral faces in the 2‐back task. These findings provide direct neural evidence to the emerging dual competition model suggesting that the salience network plays a critical role in mediating interaction between emotion perception and executive control when facing ever‐changing behavioral demands. Hum Brain Mapp 35:5606–5616, 2014. © 2014 Wiley Periodicals, Inc.