Fay Y. Womer

Relation Between Amygdala Structure and Function in Adolescents With Bipolar Disorder

OBJECTIVE Previous study supports the presence of reduced volume and elevated response to emotional stimuli in amygdala in adolescents with bipolar disorder (BD). In the present study, structural and functional magnetic resonance imaging scans were obtained during the same neuroimaging session to examine amygdala structure-function relations in adolescents with BD. We hypothesized that amygdala volume would be inversely associated with amygdala response to emotional stimuli, such that BD participants with the smallest amygdala volumes would exhibit the highest amygdala response. METHOD Fifty-one adolescents (21 with BD I and 30 control adolescents, ages 10-18 years) underwent structural and functional magnetic resonance imaging scans. Amygdala volume (n = 49) and signal change (n = 44) during emotional face processing were compared between groups, and structure-function correlations were examined within the BD group (n = 16). RESULTS Adolescents with BD showed decreased amygdala volume (p =.009) and increased amygdala response to emotional faces (p =.043). There was no significant interaction between diagnosis and emotion type. A significant inverse association between amygdala volume and activation during emotional face processing was observed (r = -0.54, p =.029). CONCLUSIONS Decreased volume and increased response to emotional stimuli in the amygdala in adolescents with BD are consistent with previous reports. This study represents the first report, to our knowledge, of the two findings in the same adolescent BD sample and supports an amygdala structure-function relation characterized by an inverse association between volume and response to emotional stimuli. This preliminary finding requires replication and suggests a possible pathophysiological link between abnormalities in amygdala structure and response to emotional stimuli in BD.

Childhood abuse and neglect and cognitive flexibility in adolescents

Childhood maltreatment (CM) has been associated with diminished executive functioning in children and adults; however, there is a relative paucity of study of executive function in adolescents exposed to CM. Yet, executive dysfunction in adolescence may have important adverse consequences including increased vulnerability to risky behaviors and impaired school functioning. This study investigates the relationship between self-reported CM and an executive function, cognitive flexibility, in adolescents without identified psychiatric disorders. Effects of physical and emotional, abuse and neglect, maltreatment subtypes were explored. Thirty adolescents ages 12–17 years, 50% females, completed the retrospective self-report Childhood Trauma Questionnaire (CTQ) and were administered the Wisconsin Card Sorting Test (WCST). Correlational analyses assessed the relationship between WCST perseverative error scores norm-referenced for age and education with CTQ total scores. The relationship with nonperseverative errors, as well as with physical and emotional abuse and neglect CM subscores, were explored. Total CTQ scores showed significant associations with perseverative errors on the WCST, but not with nonperseverative errors. Significant associations with perseverative errors were seen for physical abuse and physical neglect among the CTQ subscales. The results suggest both physical abuse and physical neglect are associated with diminished cognitive flexibility in adolescents. These effects were detected in adolescents without identified psychiatric diagnoses suggesting the importance of considering executive dysfunction in adolescents exposed to CM who may not meet diagnostic criteria for an Axis I disorder and that tests of perseverative errors, such as those of the WCST, may be sensitive indicators of this dysfunction.

Alterations in amplitude of low frequency fluctuation in treatment-naïve major depressive disorder measured with resting-state fMRI

There are limited resting‐state functional magnetic resonance imaging (fMRI) studies in major depressive disorder (MDD). Of these studies, functional connectivity analyses are mostly used. However, a new method based on the magnitude of low frequency fluctuation (LFF) during resting‐state fMRI may provide important insight into MDD. In this study, we examined the amplitude of LFF (ALFF) within the whole brain during resting‐state fMRI in 30 treatment‐naïve MDD subjects and 30 healthy control (HC) subjects. When compared with HC, MDD subjects showed increased ALFF in the frontal cortex (including the bilateral ventral/dorsal anterior cingulate cortex, orbitofrontal cortex, premotor cortex, ventral prefrontal cortex, left dorsal lateral frontal cortex, left superior frontal cortex), basal ganglia (including the right putamen and left caudate nucleus), left insular cortex, right anterior entorhinal cortex and left inferior parietal cortex, together with decreased ALFF in the bilateral occipital cortex, cerebellum hemisphere, and right superior temporal cortex. These findings may relate to characteristics of MDD, such as excessive self‐referential processing and deficits in cognitive control of emotional processing, which may contribute to the persistent and recurrent nature of the disorder. Hum Brain Mapp 35:4979–4988, 2014.

Differentiating Patterns of Amygdala-Frontal Functional Connectivity in Schizophrenia and Bipolar Disorder

BACKGROUND Insight into the neural mechanisms underlying the shared and disparate features of schizophrenia (SZ) and bipolar disorder (BD) is limited. The amygdala and prefrontal cortex (PFC) appear to have crucial roles in SZ and BD, yet abnormalities appear to manifest differently in the 2 disorders. METHODS Eighteen participants with SZ, 18 participants with BD, and 18 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Resting-state functional connectivity (rsFC) between the PFC and the amygdala divided into 3 subregions (the laterobasal, centromedial, and superficial amygdala) was examined using probabilistic anatomic maps. For each participant, rsFC maps of the 3 amygdala subregions were computed and compared across the 3 groups. RESULTS Compared with the HC group, we found significant differences in rsFC between the amygdala and PFC in the SZ and BD groups. In direct comparison between the SZ and BD groups, distinct patterns of rsFC between the amygdala and PFC were observed, particularly in the superficial amygdala. RsFC between the amygdala and the dorsal lateral PFC was significantly decreased in the SZ group, whereas rsFC between the amygdyala and the ventral PFC was significantly decreased in the BD group. CONCLUSIONS These results strongly suggest dorsal vs ventral PFC differentiation in amygdala-PFC neural system abnormalities between SZ and BD. These regional differences in SZ and BD may give rise to the differences in clinical characteristics observed in SZ and BD, and may implicate potential avenues for differentiating the 2 disorders during early stages of illness.

Functional connectivity between the amygdala and prefrontal cortex in medication-naive individuals with major depressive disorder

BACKGROUND Convergent evidence suggests dysfunction within the prefrontal cortex (PFC) and amygdala, important components of a neural system that subserves emotional processing, in individuals with major depressive disorder (MDD). Abnormalities in this system in the left hemisphere and during processing of negative emotional stimuli are especially implicated. In this study, we used functional magnetic resonance imaging (fMRI) to investigate amygdala-PFC functional connectivity during emotional face processing in medication-naive individuals with MDD. METHODS Individuals with MDD and healthy controls underwent fMRI scanning while processing 3 types of emotional face stimuli. We compared the strength of functional connectivity from the amygdala between the MDD and control groups. RESULTS Our study included 28 individuals with MDD and 30 controls. Decreased amygdala-left rostral PFC (rPFC) functional connectivity was observed in the MDD group compared with controls for the fear condition (p < 0.05, corrected). No significant differences were found in amygdala connectivity to any cerebral regions between the MDD and control groups for the happy or neutral conditions. LIMITATIONS All participants with MDD were experiencing acute episodes, therefore the findings could not be generalized to the entire MDD population. CONCLUSION Medication-naive individuals with MDD showed decreased amygdala-left rPFC functional connectivity in response to negative emotional stimuli, suggesting that abnormalities in amygdala-left rPFC neural circuitry responses to negative emotional stimuli might play an important role in the pathophysiology of MDD.

Impaired interhemispheric connectivity in medication- naive patients with major depressive disorder

BACKGROUND Abnormalities in the anterior interhemispheric connections provided by the corpus callosum (CC) have long been implicated in major depressive disorder (MDD). The purpose of this study was to investigate interhemispheric connectivity in medication-naive patients with MDD by measuring fractional anisotropy in the CC with diffusion tensor imaging (DTI) techniques. METHODS We obtained DTI scans from medication-naive patients with MDD and from matched healthy controls. Fractional anisotropy values were compared using semiautomatic region of interest methods to localize the regional CC differences between these 2 groups. RESULTS We enrolled 27 patients and 27 controls in our study. Fractional anisotropy values were significantly lower in the anterior genu of the CC in the MDD group than in the control group (p = 0.009, corrected); results were not significantly different in any other CC subregions. LIMITATIONS As patients with MDD were already experiencing acute episodes, future studies of individuals at risk for MDD are warranted to elucidate the interhemispheric connectivity abnormalities associated with the predisposition to MDD. CONCLUSION The findings demonstrate abnormalities in the structural integrity of the anterior genu of the CC in medication-naive individuals with MDD, which may contribute to impairment of interhemispheric connectivity in patients with this disorder.

A ventral prefrontal‐amygdala neural system in bipolar disorder: a view from neuroimaging research

In the past decade, neuroimaging research has identified key components in the neural system that underlies bipolar disorder (BD). The ventral prefrontal cortex (VPFC) and amygdala are highly interconnected structures that jointly play a central role in emotional regulation. Numerous research groups have reported prominent structural and functional abnormalities within the VPFC and amygdala supporting their essential role in a neural system underlying the emotional dysregulation that is a core feature of BD. Findings in BD also include those in brain regions interconnected with the VPFC and amygdala, including the ventral striatum, hippocampus and the cerebellum. Abnormalities in these regions may contribute to symptoms that reflect disruption in functions sub-served by these structures, including motivational, mnemonic and psychomotor functions. This article will first review leads from behavioural neurology that implicated these neural system abnormalities in BD. It will then review findings from structural and functional imaging studies to support the presence of abnormalities within these neural system components in BD. It will also review new findings from studies using diffusion tensor imaging (DTI) that provide increasing evidence of abnormalities in the connections between these neural system components in BD. Emerging data supporting differences in this neural system during adolescence, as well as potential beneficial effects of treatment on structure and function will also be presented. Finally, the article will discuss the implications for future investigations, including those for early identification and treatment of BD.

Basal ganglia and thalamic morphology in schizophrenia and bipolar disorder

In this study, we examined the morphology of the basal ganglia and thalamus in bipolar disorder (BP), schizophrenia-spectrum disorders (SCZ-S), and healthy controls (HC) with particular interest in differences related to the absence or presence of psychosis. Volumetric and shape analyses of the basal ganglia and thalamus were performed in 33 BP individuals [12 without history of psychotic features (NPBP) and 21 with history of psychotic features (PBP)], 32 SCZ-S individuals [28 with SCZ and 4 with schizoaffective disorder], and 27 HC using FreeSurfer-initiated large deformation diffeomorphic metric mapping. Significant volume differences were found in the caudate and globus pallidus, with volumes smallest in the NPBP group. Shape abnormalities showing inward deformation of superior regions of the caudate were observed in BP (and especially in NPBP) compared with HC. Shape differences were also found in the globus pallidus and putamen when comparing BP and SCZ-S groups. No significant differences were seen in the nucleus accumbens and thalamus. In summary, structural abnormalities in the caudate and globus pallidus are present in BP and SCZ-S. Differences were more apparent in the NPBP subgroup. The findings herein highlight the potential importance of separately examining BP subgroups in neuroimaging studies.

Amplitude of low-frequency fluctuations in bipolar disorder: a resting state fMRI study.

OBJECTIVES The spontaneous low frequency fluctuations (LFF) of blood oxygenation level-dependent (BOLD) signal in resting state have been identified as a biological measure of baseline spontaneous activity in the brain. Increasingly, studies of spontaneous resting state functional connectivity have demonstrated neural network abnormalities in bipolar disorder (BD). This study used the amplitude of low frequency fluctuations (ALFF) to explore the regional functional changes in BD during resting state. METHODS Twenty-nine BD participants and 29 matched healthy controls (HC) were recruited to undergo resting-state functional magnetic resonance imaging scan on a 3.0T magnetic resonance imaging system. The ALFF of BOLD signal in gray matter for each participant was calculated, and then was compared between BD and HC using ALFF maps. RESULTS Compared to the HC group, the BD group showed increased ALFF in ventral prefrontal cortex, dorsal lateral prefrontal cortex, frontal eye field, insula, and putamen with extension into the ventral striatum, as well as decreased ALFF in the lingual gyrus (p<0.05, corrected). LIMITATIONS Although we observed differences in ALFF between BD and HC, we cannot conclusively state that these differences are caused by the pathophysiology of BD since most of BD participants were being treated with medications at the time of scanning. CONCLUSIONS Our results revealed altered regional brain activity in BD during resting state. The affected regions have been associated with BD pathophysiology. This suggests that methods using ALFF method may potentially be useful in further studies of this disorder.

Sexually dimorphic features of vermis morphology in bipolar disorder.

OBJECTIVES The cerebellar vermis is increasingly implicated in bipolar disorder (BD). In this study, we investigated vermis morphology in BD using a quantitative volumetric analysis. METHODS Volumes for total vermis and vermis subregions V1 (lobules I-V), V2 (lobules VI-VII), and V3 (lobules VIII-X) were calculated using high-resolution structural magnetic resonance imaging obtained from 44 individuals with BD (25 females and 19 males) and 43 healthy comparison (HC) subjects (26 females and 17 males). Total vermis volumes were compared between the BD and HC groups. Potential effects of vermis subregions and clinical features were explored. RESULTS Total vermis volumes were significantly larger in the BD group than in the HC group (p = 0.02). There was a significant group-by-sex interaction (p = 0.02). Total vermis volumes were significantly larger in males with BD than HC males (p = 0.004); vermis volumes did not differ significantly between females with and without BD (p = 0.95). Subregion analyses showed a trend-level interaction between diagnosis and subregion (p = 0.07) in which subregion V1 volumes were significantly larger in BD participants (p = 0.001), with differences primarily driven by males (p = 0.001). CONCLUSIONS Our findings demonstrate increases in cerebellar vermis volumes in males with BD. These findings support the presence of structural alterations in the cerebellar vermis in BD and furthermore the influence of sex on such changes.