Salvatore Torrisi

Frontal-Amygdala Connectivity Alterations During Emotion Downregulation in Bipolar I Disorder

BACKGROUND The symptoms of bipolar disorder suggest dysfunction of emotion regulatory networks. In healthy control populations, downregulation of emotional responses activates the ventral lateral prefrontal cortex (vlPFC) and dampens amygdala activation. This study investigated frontal and limbic function and connectivity during emotion downregulation in euthymic subjects with bipolar I disorder (BPI) and healthy control subjects. METHODS Thirty BPI and 26 control subjects underwent functional magnetic resonance imaging scanning while performing an emotion processing task with passive viewing and emotion downregulation conditions. Contrasts were made for each group comparing the downregulation and passive viewing conditions, and these were entered into a between-group random effects analysis to assess group differences in activation. Psychophysiological interaction analyses were conducted to test for significant group differences in functional connectivity between the amygdala and inhibitory frontal regions (i.e., vlPFC). RESULTS Control subjects showed the expected robust bilateral activation of frontal and limbic regions during passive viewing and emotion downregulation tasks. Between-group analyses revealed similar activation of BPI and control subjects during passive viewing but significantly decreased activation in bilateral vlPFC, bilateral anterior and posterior cingulate, medial frontal gyrus, and bilateral dorsal lateral prefrontal cortex during emotion downregulation in subjects with BPI. Connectivity analysis demonstrated that control subjects had significantly greater negative functional connectivity between the left amygdala and bilateral vlPFC compared with subjects with BPI. CONCLUSIONS This study provides evidence that dysfunction in the neural networks responsible for emotion regulation, including the prefrontal cortex, cingulate, and subcortical structures, are present in BPI subjects, even while euthymic.

Striatal FoxP2 Is Actively Regulated during Songbird Sensorimotor Learning

Background Mutations in the FOXP2 transcription factor lead to language disorders with developmental onset. Accompanying structural abnormalities in cortico-striatal circuitry indicate that at least a portion of the behavioral phenotype is due to organizational deficits. We previously found parallel FoxP2 expression patterns in human and songbird cortico/pallio-striatal circuits important for learned vocalizations, suggesting that FoxP2s function in birdsong may generalize to speech. Methodology/Principal Findings We used zebra finches to address the question of whether FoxP2 is additionally important in the post-organizational function of these circuits. In both humans and songbirds, vocal learning depends on auditory guidance to achieve and maintain optimal vocal output. We tested whether deafening prior to or during the sensorimotor phase of song learning disrupted FoxP2 expression in song circuitry. As expected, the songs of deafened juveniles were abnormal, however basal FoxP2 levels were unaffected. In contrast, when hearing or deaf juveniles sang for two hours in the morning, FoxP2 was acutely down-regulated in the striatal song nucleus, area X. The extent of down-regulation was similar between hearing and deaf birds. Interestingly, levels of FoxP2 and singing were correlated only in hearing birds. Conclusions/Significance Hearing appears to link FoxP2 levels to the amount of vocal practice. As juvenile birds spent more time practicing than did adults, their FoxP2 levels are likely to be low more often. Behaviorally-driven reductions in the mRNA encoding this transcription factor could ultimately affect downstream molecules that function in vocal exploration, especially during sensorimotor learning.

Regional fMRI Hypoactivation and Altered Functional Connectivity During Emotion Processing in Nonmedicated Depressed Patients With Bipolar II Disorder

OBJECTIVE Although the amygdala and ventrolateral prefrontal cortex have been implicated in the pathophysiology of bipolar I disorder, the neural mechanisms underlying bipolar II disorder remain unknown. The authors examined neural activity in response to negative emotional faces during an emotion perception task that reliably activates emotion regulatory regions. METHOD Twenty-one nonmedicated depressed bipolar II patients and 21 healthy comparison subjects underwent functional MRI (fMRI) while performing an emotional face-matching task. Within- and between-group whole-brain fMRI activation and seed-based connectivity analyses were conducted. RESULTS In depressed bipolar II patients, random-effects between-group fMRI analyses revealed a significant reduction in activation in several regions, including the left and right ventrolateral prefrontal cortices (Brodmanns area [BA] 47) and the right amygdala, a priori regions of interest. Additionally, bipolar patients exhibited significantly reduced negative functional connectivity between the right amygdala and the right orbitofrontal cortex (BA 10) as well as the right dorsolateral prefrontal cortex (BA 46) relative to healthy comparison subjects. CONCLUSIONS These findings suggest that bipolar II depression is characterized by reduced regional orbitofrontal and limbic activation and altered connectivity in a fronto-temporal circuit implicated in working memory and emotional learning. While the amygdala hypoactivation observed in bipolar II depression is opposite to the direction seen in bipolar I mania and may therefore be state dependent, the observed orbitofrontal cortex hypoactivation is consistent with findings in bipolar I depression, mania, and euthymia, suggesting a physiologic trait marker of the disorder.

Controlling automatic imitative tendencies: Interactions between mirror neuron and cognitive control systems

Humans have an automatic tendency to imitate others. Although several regions commonly observed in social tasks have been shown to be involved in imitation control, there is little work exploring how these regions interact with one another. We used fMRI and dynamic causal modeling to identify imitation-specific control mechanisms and examine functional interactions between regions. Participants performed a pre-specified action (lifting their index or middle finger) in response to videos depicting the same two actions (biological cues) or dots moving with similar trajectories (non-biological cues). On congruent trials, the stimulus and response were similar (e.g. index finger response to index finger or left side dot stimulus), while on incongruent trials the stimulus and response were dissimilar (e.g. index finger response to middle finger or right side dot stimulus). Reaction times were slower on incongruent compared to congruent trials for both biological and non-biological stimuli, replicating previous findings that suggest the automatic imitative or spatially compatible (congruent) response must be controlled on incongruent trials. Neural correlates of the congruency effects were different depending on the cue type. The medial prefrontal cortex, anterior cingulate, inferior frontal gyrus pars opercularis (IFGpo) and the left anterior insula were involved specifically in controlling imitation. In addition, the IFGpo was also more active for biological compared to non-biological stimuli, suggesting that the region represents the frontal node of the human mirror neuron system (MNS). Effective connectivity analysis exploring the interactions between these regions, suggests a role for the mPFC and ACC in imitative conflict detection and the anterior insula in conflict resolution processes, which may occur through interactions with the frontal node of the MNS. We suggest an extension of the previous models of imitation control involving interactions between imitation-specific and general cognitive control mechanisms.

Normal amygdala activation but deficient ventrolateral prefrontal activation in adults with bipolar disorder during euthymia

Functional neuroimaging studies have implicated the involvement of the amygdala and ventrolateral prefrontal cortex (vlPFC) in the pathophysiology of bipolar disorder. Hyperactivity in the amygdala and hypoactivity in the vlPFC have been reported in manic bipolar patients scanned during the performance of an affective faces task. Whether this pattern of dysfunction persists during euthymia is unclear. Using functional magnetic resonance imaging (fMRI), 24 euthymic bipolar and 26 demographically matched healthy control subjects were scanned while performing an affective task paradigm involving the matching and labeling of emotional facial expressions. Neuroimaging results showed that, while amygdala activation did not differ significantly between groups, euthymic patients showed a significant decrease in activation of the right vlPFC (BA47) compared to healthy controls during emotion labeling. Additionally, significant decreases in activation of the right insula, putamen, thalamus and lingual gyrus were observed in euthymic bipolar relative to healthy control subjects during the emotion labeling condition. These data, taken in context with prior studies of bipolar mania using the same emotion recognition task, could suggest that amygdala dysfunction may be a state-related abnormality in bipolar disorder, whereas vlPFC dysfunction may represent a trait-related abnormality of the illness. Characterizing these patterns of activation is likely to help in understanding the neural changes related to the different mood states in bipolar disorder, as well as changes that represent more sustained abnormalities. Future studies that assess mood-state related changes in brain activation in longitudinal bipolar samples would be of interest.

Differences in resting corticolimbic functional connectivity in bipolar I euthymia

Objective:  We examined resting state functional connectivity in the brain between key emotion regulation regions in bipolar I disorder to delineate differences in coupling from healthy subjects.

Fmri Functional Connectivity Applied to Adolescent Neurodevelopment

The exponential rise in the number of functional brain connectivity studies, particularly those examining intrinsic functional connectivity (iFC) at rest, and the promises of this work for unraveling the ontogeny of functional neural systems motivate this review. Shortly before this explosion in functional connectivity research, developmental neuroscientists had proposed theories based on neural systems models to explain behavioral changes, particularly in adolescence. The current review presents recent advances in imaging in brain connectivity research, which provides a unique tool for the study of neural systems. Understanding the potential of neuroimaging for refining neurodevelopmental models of brain function requires a description of various functional connectivity approaches. In this review, we describe task-based and resting-state functional magnetic resonance imaging (fMRI) analytic strategies, but we focus on iFC findings from resting-state data to describe general developmental trajectories of brain network organization. Finally, we use the example of drug addiction to frame a discussion of psychopathology that emerges in adolescence.

Advancing understanding of affect labeling with dynamic causal modeling

Mechanistic understandings of forms of incidental emotion regulation have implications for basic and translational research in the affective sciences. In this study we applied Dynamic Causal Modeling (DCM) for fMRI to a common paradigm of labeling facial affect to elucidate prefrontal to subcortical influences. Four brain regions were used to model affect labeling, including right ventrolateral prefrontal cortex (vlPFC), amygdala and Brocas area. 64 models were compared, for each of 45 healthy subjects. Family level inference split the model space to a likely driving input and Bayesian Model Selection within the winning family of 32 models revealed a strong pattern of endogenous network connectivity. Modulatory effects of labeling were most prominently observed following Bayesian Model Averaging, with the dampening influence on amygdala originating from Brocas area but much more strongly from right vlPFC. These results solidify and extend previous correlation and regression-based estimations of negative corticolimbic coupling.

Intrinsic functional connectivity of the central nucleus of the amygdala and bed nucleus of the stria terminalis

ABSTRACT The central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST), two nuclei within the central extended amygdala, function as critical relays within the distributed neural networks that coordinate sensory, emotional, and cognitive responses to threat. These structures have overlapping anatomical projections to downstream targets that initiate defensive responses. Despite these commonalities, researchers have also proposed a functional dissociation between the CeA and BNST, with the CeA promoting responses to discrete stimuli and the BNST promoting responses to diffuse threat. Intrinsic functional connectivity (iFC) provides a means to investigate the functional architecture of the brain, unbiased by task demands. Using ultra‐high field neuroimaging (7‐Tesla fMRI), which provides increased spatial resolution, this study compared the iFC networks of the CeA and BNST in 27 healthy individuals. Both structures were coupled with areas of the medial prefrontal cortex, hippocampus, thalamus, and periaqueductal gray matter. Compared to the BNST, the bilateral CeA was more strongly coupled with the insula and regions that support sensory processing, including thalamus and fusiform gyrus. In contrast, the bilateral BNST was more strongly coupled with regions involved in cognitive and motivational processes, including the dorsal paracingulate gyrus, posterior cingulate cortex, and striatum. Collectively, these findings suggest that responses to sensory stimulation are preferentially coordinated by the CeA and cognitive and motivational responses are preferentially coordinated by the BNST. HIGHLIGHTSThe CeA and BNST have overlapping functional connections.The CeA is more strongly connected to regions involved in sensory processing.The BNST is more strongly connected to regions involved in motivational processing.

Resting state connectivity of the human habenula at ultra-high field

ABSTRACT The habenula, a portion of the epithalamus, is implicated in the pathophysiology of depression, anxiety and addiction disorders. Its small size and connection to other small regions prevent standard human imaging from delineating its structure and connectivity with confidence. Resting state functional connectivity is an established method for mapping connections across the brain from a seed region of interest. The present study takes advantage of 7 T fMRI to map, for the first time, the habenula resting state network with very high spatial resolution in 32 healthy human participants. Results show novel functional connections in humans, including functional connectivity with the septum and bed nucleus of the stria terminalis (BNST). Results also show many habenula connections previously described only in animal research, such as with the nucleus basalis of Meynert, dorsal raphe, ventral tegmental area (VTA), and periaqueductal grey (PAG). Connectivity with caudate, thalamus and cortical regions such as the anterior cingulate, retrosplenial cortex and auditory cortex are also reported. This work, which demonstrates the power of ultra‐high field for mapping human functional connections, is a valuable step toward elucidating subcortical and cortical regions of the habenula network.