Layla Banihashemi

Reduced gray matter volume in ventral prefrontal cortex but not amygdala in bipolar disorder: significant effects of gender and trait anxiety

Neuroimaging studies in bipolar disorder report gray matter volume (GMV) abnormalities in neural regions implicated in emotion regulation. This includes a reduction in ventral/orbital medial prefrontal cortex (OMPFC) GMV and, inconsistently, increases in amygdala GMV. We aimed to examine OMPFC and amygdala GMV in bipolar disorder type 1 patients (BPI) versus healthy control participants (HC), and the potential confounding effects of gender, clinical and illness history variables and psychotropic medication upon any group differences that were demonstrated in OMPFC and amygdala GMV. Images were acquired from 27 BPI (17 euthymic, 10 depressed) and 28 age- and gender-matched HC in a 3T Siemens scanner. Data were analyzed with SPM5 using voxel-based morphometry (VBM) to assess main effects of diagnostic group and gender upon whole brain (WB) GMV. Post-hoc analyses were subsequently performed using SPSS to examine the extent to which clinical and illness history variables and psychotropic medication contributed to GMV abnormalities in BPI in a priori and non-a priori regions has demonstrated by the above VBM analyses. BPI showed reduced GMV in bilateral posteromedial rectal gyrus (PMRG), but no abnormalities in amygdala GMV. BPI also showed reduced GMV in two non-a priori regions: left parahippocampal gyrus and left putamen. For left PMRG GMV, there was a significant group by gender by trait anxiety interaction. GMV was significantly reduced in male low-trait anxiety BPI versus male low-trait anxiety HC, and in high- versus low-trait anxiety male BPI. Our results show that in BPI there were significant effects of gender and trait-anxiety, with male BPI and those high in trait-anxiety showing reduced left PMRG GMV. PMRG is part of medial prefrontal network implicated in visceromotor and emotion regulation.

Noradrenergic inputs to the bed nucleus of the stria terminalis and paraventricular nucleus of the hypothalamus underlie hypothalamic-pituitary-adrenal axis but not hypophagic or conditioned avoidance responses to systemic yohimbine.

The α2 adrenoceptor antagonist yohimbine (YO) increases transmitter release from adrenergic/noradrenergic (NA) neurons. Systemic YO activates the hypothalamic–pituitary–adrenal (HPA) axis, inhibits feeding, and supports conditioned flavor avoidance (CFA) in rats. To determine whether these effects require NA inputs to the bed nucleus of the stria terminalis (BNST), vehicle or saporin toxin conjugated to an antibody against dopamine β hydroxylase (DSAP) was microinjected bilaterally into the BNST to remove its NA inputs. Subsequent tests failed to reveal any lesion effect on the ability of YO (5.0 mg/kg, i.p.) to inhibit food intake or to support CFA. Conversely, HPA axis responses to YO were significantly blunted in DSAP rats. In a terminal experiment, DSAP and control rats were perfused 90–120 min after intraperitoneal injection of YO or vehicle. Brains were processed to reveal Fos immunolabeling and lesion extent. NA fibers were markedly depleted in the BNST and medial parvocellular paraventricular hypothalamus (PVNmp) in DSAP rats, evidence for collateralized NA inputs to these regions. DSAP rats displayed significant loss of caudal medullary NA neurons, and markedly blunted Fos activation in the BNST and in corticotropin-releasing hormone-positive PVNmp neurons after YO. We conclude that a population of medullary NA neurons provides collateral inputs to the BNST and PVNmp, and that these inputs contribute importantly to Fos expression and HPA axis activation after YO treatment. Conversely, NA-mediated activation of BNST and PVNmp neurons is unnecessary for YO to inhibit food intake or support CFA, evidence for the sufficiency of other intact neural pathways in mediating those effects.

The anxiogenic drug yohimbine activates central viscerosensory circuits in rats.

Systemic administration of the α2‐adrenoceptor antagonist yohimbine (YO) activates the HPA stress axis and promotes anxiety in humans and experimental animals. We propose that visceral malaise contributes to the stressful and anxiogenic effects of systemic YO and that YO recruits brainstem noradrenergic (NA) and peptidergic neurons that relay viscerosensory signals to the hypothalamus and limbic forebrain. To begin testing these hypotheses, the present study explored dose‐related effects of YO on food intake, conditioned flavor avoidance (CFA), and Fos immunolabeling in rats. Systemic YO (5.0 mg/kg BW, i.p.) inhibited food intake, supported CFA, and increased Fos immunolabeling in identified NA neurons in the ventrolateral medulla, nucleus of the solitary tract, and locus coeruleus. YO also increased Fos in the majority of corticotropin releasing hormone‐positive neurons in the paraventricular nucleus of the hypothalamus. YO administered at 1.0 mg/kg BW did not inhibit food intake, did not support CFA, and did not increase Fos immunolabeling. Retrograde neural tracing demonstrated that neurons activated by YO at 5.0 mg/kg BW included medullary and pontine neurons that project to the central nucleus of the amygdala and to the lateral bed nucleus of the stria terminalis, the latter region receiving comparatively greater input by Fos‐positive neurons. We conclude that YO produces anorexigenic and aversive effects that correlate with activation of brainstem viscerosensory inputs to the limbic forebrain. These findings invite continued investigation of how central viscerosensory signaling pathways interact with hypothalamic and limbic regions to influence interrelated physiological and behavioral components of anxiety, stress, and visceral malaise. J. Comp. Neurol. 492:426–441, 2005.

Emotion Reactivity and Regulation in Late-Life Generalized Anxiety Disorder: Functional Connectivity at Baseline and Post-Treatment

OBJECTIVES Generalized anxiety disorder (GAD) is one of the most prevalent mental disorders in the elderly, but its functional neuroanatomy is not well understood. Given the role of emotion dysregulation in GAD, we sought to describe the neural bases of emotion regulation in late-life GAD by analyzing the functional connectivity (FC) in the Salience Network and the Executive Control Network during worry induction and worry reappraisal. METHODS The study included 28 elderly GAD and 31 non-anxious comparison participants. Twelve elderly GAD completed a 12-week pharmacotherapy trial. We used an in-scanner worry script that alternates blocks of worry induction and reappraisal. We assessed network FC, using the following seeds: anterior insula (AI), dorsolateral prefrontal cortex (dlPFC), the bed nucleus of stria terminalis (BNST), and the paraventricular nucleus (PVN). RESULTS GAD participants exhibited greater FC during worry induction between the left AI and the right orbitofrontal cortex, and between the BNST and the subgenual cingulate. During worry reappraisal, the non-anxious participants had greater FC between the left dlPFC and the medial PFC, as well as between the left AI and the medial PFC, and elderly GAD patients had greater FC between the PVN and the amygdala. Following 12 weeks of pharmacotherapy, GAD participants had greater connectivity between the dlPFC and several prefrontal regions during worry reappraisal. CONCLUSION FC during worry induction and reappraisal points toward abnormalities in both worry generation and worry reappraisal. Following successful pharmacologic treatment, we observed greater connectivity in the prefrontal nodes of the Executive Control Network during reappraisal of worry.

Repeated brief postnatal maternal separation enhances hypothalamic gastric autonomic circuits in juvenile rats

Maternal separation of rat pups for 15 min each day over the first one to two postnatal weeks (MS15) has been shown to increase the active maternal care received by pups and to decrease their later neuroendocrine and behavioral stress reactivity compared to non-separated (NS) controls. Stress responses prominently feature altered gastric secretion and motility, and we previously reported that the developmental assembly of forebrain circuits underlying gastric autonomic control, including gastric responses to stress, is delayed by MS15 in neonatal rats [Card JP, Levitt P, Gluhovsky M, Rinaman L (2005) J Neurosci 25(40):9102-9111]. To determine how this early delay affects the later organization of central gastric autonomic circuits, the present study examined the effects of neonatal MS15 on central pre-gastric circuits assessed in post-weaning, juvenile rats. For this purpose, the retrograde transynaptic viral tracer, pseudorabies virus (PRV), was microinjected into the stomach wall of 28-30 day old male rats with an earlier developmental history of either MS15 or NS. Rats were perfused 72 h later and tissue was processed to reveal PRV-positive cells. Transynaptic PRV immunolabeling was quantified in selected preautonomic brainstem and forebrain regions, including the area postrema, bed nucleus of the stria terminalis, central nucleus of the amygdala, paraventricular nucleus of the hypothalamus (PVN), and visceral cortices. Compared to NS controls, MS15 rats displayed a significantly greater amount of PRV labeling within the PVN, including both the dorsal cap and ventral subnuclei. There were no postnatal group differences in the amount of PRV labeling within any other brain region examined in this study. This effect of MS15 to enhance hypothalamic preautonomic circuit structure indicates a strengthening of this pathway and may provide insight into how early life experience produces differential effects on later stress reactivity, including gastric secretory and motor responses to stress.

Early life experience shapes the functional organization of stress-responsive visceral circuits.

Emotions are closely tied to changes in autonomic (i.e., visceral motor) function, and interoceptive sensory feedback from body to brain exerts powerful modulatory control over motivation, affect, and stress responsiveness. This manuscript reviews evidence that early life experience can shape the structure and function of central visceral circuits that underlie behavioral and physiological responses to emotive and stressful events. The review begins with a general discussion of descending autonomic and ascending visceral sensory pathways within the brain, and then summarizes what is known about the postnatal development of these central visceral circuits in rats. Evidence is then presented to support the view that early life experience, particularly maternal care, can modify the developmental assembly and structure of these circuits in a way that impacts later stress responsiveness and emotional behavior. The review concludes by presenting a working hypothesis that endogenous cholecystokinin signaling and subsequent recruitment of gastric vagal sensory inputs to the caudal brainstem may be an important mechanism by which maternal care influences visceral circuit development in rat pups. Early life experience may contribute to meaningful individual differences in emotionality and stress responsiveness by shaping the postnatal developmental trajectory of central visceral circuits.

Childhood physical abuse predicts stressor-evoked activity within central visceral control regions

Early life experience differentially shapes later stress reactivity, as evidenced by both animal and human studies. However, early experience-related changes in the function of central visceral neural circuits that control stress responses have not been well characterized, particularly in humans. The paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis (BNST), amygdala (Amyg) and subgenual anterior cingulate cortex (sgACC) form a core visceral stress-responsive circuit. The goal of this study is to examine how childhood emotional and physical abuse relates to adulthood stressor-evoked activity within these visceral brain regions. To evoke acute states of mental stress, participants (n = 155) performed functional magnetic resonance imaging (fMRI)-adapted versions of the multi-source interference task (MSIT) and the Stroop task with simultaneous monitoring of mean arterial pressure (MAP) and heart rate. Regression analyses revealed that childhood physical abuse correlated positively with stressor-evoked changes in MAP, and negatively with unbiased, a priori extractions of fMRI blood-oxygen level-dependent signal change values within the sgACC, BNST, PVN and Amyg (n = 138). Abuse-related changes in the function of visceral neural circuits may reflect neurobiological vulnerability to adverse health outcomes conferred by early adversity.

Central neural responses to restraint stress are altered in rats with an early life history of repeated brief maternal separation

Repeated brief maternal separation (i.e. 15 min daily, MS15) of rat pups during the first one to two postnatal weeks enhances active maternal care received by the pups and attenuates their later behavioral and neuroendocrine responses to stress. In previous work, we found that MS15 also alters the developmental assembly and later structure of central neural circuits that control autonomic outflow to the viscera, suggesting that MS15 may alter central visceral circuit responses to stress. To examine this, juvenile rats with a developmental history of either MS15 or no separation (NS) received microinjection of retrograde neural tracer, FluoroGold (FG), into the hindbrain dorsal vagal complex (DVC). After 1 week, FG-injected rats and surgically intact littermates were exposed to either a 15-min restraint stress or an unrestrained control condition, and then perfused 1 h later. Brain tissue sections from surgically intact littermates were processed for Fos alone or in combination with phenotypic markers to examine stress-induced activation of neurons within the paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis (BNST), and hindbrain DVC. Compared to NS controls, MS15 rats displayed less restraint-induced Fos activation within the dorsolateral BNST (dBNST), the caudal PVN, and noradrenergic neurons within the caudal DVC. To examine whether these differences corresponded with altered neural inputs to the DVC, sections from tracer-injected rats were double-labeled for FG and Fos to quantify retrogradely labeled neurons within hypothalamic and limbic forebrain regions of interest, and the proportion of these neurons activated after restraint. Only the dBNST displayed a significant effect of postnatal experience on restraint-induced Fos activation of DVC-projecting neurons. The distinct regional effects of MS15 on stress-induced recruitment of neurons within hypothalamic, limbic forebrain, and hindbrain regions has interesting implications for understanding how early life experience shapes the functional organization of stress-responsive circuits.

Childhood maltreatment is associated with altered frontolimbic neurobiological activity during wakefulness in adulthood

Childhood maltreatment can disturb brain development and subsequently lead to adverse socioemotional and mental health problems across the life span. The long-term association between childhood maltreatment and resting-wake brain activity during adulthood is unknown and was examined in the current study. Forty-one medically stable and medication-free military veterans (M = 29.31 ± 6.01 years, 78% male) completed a battery of clinical assessments and had [18F]-fluorodeoxyglucose positron emission tomography neuroimaging scans during quiet wakefulness. After statistically adjusting for later-life trauma and mental health problems, childhood maltreatment was negatively associated with brain activity within a priori defined regions that included the left orbital frontal cortex and left hippocampus. Childhood maltreatment was significantly associated with increased and decreased brain activity within six additional whole-brain clusters that included the frontal, parietal-temporal, cerebellar, limbic, and midbrain regions. Childhood maltreatment is associated with altered neural activity in adulthood within regions that are involved in executive functioning and cognitive control, socioemotional processes, autonomic functions, and sleep/wake regulation. This study provides support for taking a life span developmental approach to understanding the effects of early-life maltreatment on later-life neurobiology, socioemotional functioning, and mental health.

Childhood maltreatment moderates the effect of combat exposure on cingulum structural integrity

Limbic white matter pathways link emotion, cognition, and behavior and are potentially malleable to the influences of traumatic events throughout development. However, the impact of interactions between childhood and later life trauma on limbic white matter pathways has yet to be examined. Here, we examined whether childhood maltreatment moderated the effect of combat exposure on diffusion tensor imaging measures within a sample of military veterans (N = 28). We examined five limbic tracts of interest: two components of the cingulum (cingulum, cingulate gyrus, and cingulum hippocampus [CGH]), the uncinate fasciculus, the fornix/stria terminalis, and the anterior limb of the internal capsule. Using effect sizes, clinically meaningful moderator effects were found only within the CGH. Greater combat exposure was associated with decreased CGH fractional anisotropy (overall structural integrity) and increased CGH radial diffusivity (perpendicular water diffusivity) among individuals with more severe childhood maltreatment. Our findings provide preliminary evidence of the moderating effect of childhood maltreatment on the relationship between combat exposure and CGH structural integrity. These differences in CGH structural integrity could have maladaptive implications for emotion and memory, as well as provide a potential mechanism by which childhood maltreatment induces vulnerability to later life trauma exposure.