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Beyond the amygdala: Linguistic threat modulates peri-sylvian semantic access cortices

Weisholtz, Daniel S; Root, James C; Butler, Tracy; Tuscher, Oliver; Epstein, Jane; Pan, Hong; Protopopescu, Xenia; Goldstein, Martin; Isenberg, Nancy; Brendel, Gary; LeDoux, Joseph; Silbersweig, David A; Stern, Emily
In this study, healthy volunteers were scanned using functional magnetic resonance imaging (fMRI) to investigate the neural systems involved in processing the threatening content conveyed via visually presented "threat words." The neural responses elicited by these words were compared to those elicited by matched neutral control words. The results demonstrate that linguistic threat, when presented in written form, can selectively engage areas of lateral temporal and inferior frontal cortex, distinct from the core language areas implicated in aphasia. Additionally, linguistic threat modulates neural activity in visceral/emotional systems (amygdala, parahippocampal gyrus and periaqueductal gray), and at earlier stages of the visual-linguistic processing stream involved in visual word form representations (ventral occipitotemporal cortex). We propose a model whereby limbic activation modulates activity at multiple nodes along the visual-linguistic-semantic processing stream, including a perisylvian "semantic access network" involved in decoding word meaning, suggesting a dynamic interplay between feedforward and feedback processes.
PMID: 26575986
ISSN: 1090-2155
CID: 1848492

Bridging the gap between neuroscientific and psychodynamic models in child and adolescent psychiatry

Protopopescu, Xenia; Gerber, Andrew J
This article provides a selective review of the neuroscience and child-psychoanalytic literature, focusing on areas of significant overlap and emphasizing comprehensive theories in developmental neuroscience and child psychoanalysis with testable mechanisms of action. Topics include molecular biology and genetics findings relevant to psychotherapy research, neuroimaging findings relevant to psychotherapy, brain regions of interest for psychotherapy, neurobiologic changes caused by psychotherapy, use of neuroimaging to predict treatment outcome, and schemas as a bridging concept between psychodynamic and cognitive neuroscience models. The combined efforts of neuroscientists and psychodynamic clinicians and theorists are needed to unravel the mechanisms of human mental functioning.
PMID: 23164125
ISSN: 1056-4993
CID: 955282

Differential activity of subgenual cingulate and brainstem in panic disorder and PTSD

Tuescher, Oliver; Protopopescu, Xenia; Pan, Hong; Cloitre, Marylene; Butler, Tracy; Goldstein, Martin; Root, James C; Engelien, Almut; Furman, Daniella; Silverman, Michael; Yang, Yihong; Gorman, Jack; LeDoux, Joseph; Silbersweig, David; Stern, Emily
Most functional neuroimaging studies of panic disorder (PD) have focused on the resting state, and have explored PD in relation to healthy controls rather than in relation to other anxiety disorders. Here, PD patients, posttraumatic stress disorder (PTSD) patients, and healthy control subjects were studied with functional magnetic resonance imaging utilizing an instructed fear conditioning paradigm incorporating both Threat and Safe conditions. Relative to PTSD and control subjects, PD patients demonstrated significantly less activation to the Threat condition and increased activity to the Safe condition in the subgenual cingulate, ventral striatum and extended amygdala, as well as in midbrain periaquaeductal grey, suggesting abnormal reactivity in this key region for fear expression. PTSD subjects failed to show the temporal pattern of activity decrease found in control subjects
PMID: 21075593
ISSN: 1873-7897
CID: 134298

Toward a functional neuroanatomy of premenstrual dysphoric disorder

Protopopescu, Xenia; Tuescher, Oliver; Pan, Hong; Epstein, Jane; Root, James; Chang, Luke; Altemus, Margaret; Polanecsky, Margaret; McEwen, Bruce; Stern, Emily; Silbersweig, David
BACKGROUND: Premenstrual dysphoric disorder (PMDD) is a prevalent disorder in the spectrum of affective illness, and is associated with significant morbidity. The neurobiology of this underdiagnosed and undertreated illness is poorly understood. A functional magnetic resonance imaging (fMRI) probe of fronto-limbic function was used to advance understanding of PMDD pathophysiology. METHODS: We applied BOLD fMRI and Statistical Parametric Mapping to study neural response to emotional words in the context of an emotional Go/NoGo inhibitory control task. We examined alterations in this response across the menstrual cycle, in the premenstrual (late luteal) phase and the postmenstrual (late follicular) phase. RESULTS: In the premenstrual (vs. postmenstrual) phase, PMDD subjects, compared with asymptomatic subjects, showed an increased amygdala response to negative vs. neutral stimuli, and a decreased ventral striatum response to positive vs. neutral stimuli. PMDD subjects failed to show the asymptomatic subjects' patterns of increased medial and decreased lateral orbitofrontal cortex (OFC) response to negative vs. neutral stimuli in the premenstrual vs. postmenstrual phase. This decreased premenstrual medial OFC response to negative stimuli in PMDD subjects was further enhanced in the context of behavioral inhibition. LIMITATIONS: Further studies with larger numbers of subjects are needed. CONCLUSIONS: The results support a neurobiological model of enhanced negative emotional processing, diminished positive emotional processing, and diminished top-down control of limbic activity in PMDD during the premenstrual phase. These findings provide a basis for a neurocircuitry model of PMDD, and have implications for studies of mood/emotional regulation across the human menstrual cycle in health and disease.
PMID: 18031826
ISSN: 0165-0327
CID: 170024

Hippocampal structural changes across the menstrual cycle

Protopopescu, Xenia; Butler, Tracy; Pan, Hong; Root, James; Altemus, Margaret; Polanecsky, Margaret; McEwen, Bruce; Silbersweig, David; Stern, Emily
Magnetic resonance imaging (MRI) in association with Jacobian-modulated voxel-based morphometry (VBM) was used to test for regional variation in gray matter over the menstrual cycle. T1-weighted anatomical images were acquired using a spoiled gradient recalled acquisition sequence in 21 women. Each subject was scanned twice: once during the postmenstrual late-follicular phase (Days 10-12 after onset of menses), and once during the premenstrual late-luteal phase (1-5 days before the onset of menses). Gray matter was relatively increased in the right anterior hippocampus and relatively decreased in the right dorsal basal ganglia (globus pallidus/putamen) in the postmenstrual phase. Verbal declarative memory was increased in the postmenstrual vs. premenstrual phase. This first report of human brain structural plasticity associated with the endogenous menstrual cycle extends well-established animal findings of hormone-mediated hippocampal plasticity to humans, and has implications for understanding alterations in cognition and behavior across the menstrual cycle
PMID: 18767068
ISSN: 1098-1063
CID: 106035

Human fear-related motor neurocircuitry

Butler, T; Pan, H; Tuescher, O; Engelien, A; Goldstein, M; Epstein, J; Weisholtz, D; Root, J C; Protopopescu, X; Cunningham-Bussel, A C; Chang, L; Xie, X-H; Chen, Q; Phelps, E A; Ledoux, J E; Stern, E; Silbersweig, D A
Using functional magnetic resonance imaging and an experimental paradigm of instructed fear, we observed a striking pattern of decreased activity in primary motor cortex with increased activity in dorsal basal ganglia during anticipation of aversive electrodermal stimulation in 42 healthy participants. We interpret this pattern of activity in motor neurocircuitry in response to cognitively-induced fear in relation to evolutionarily-conserved responses to threat that may be relevant to understanding normal and pathological fear in humans
PMID: 17980493
ISSN: 0306-4522
CID: 90568

Neural dysfunction in postpartum depression: an fMRI pilot study

Silverman, Michael E; Loudon, Holly; Safier, Michal; Protopopescu, Xenia; Leiter, Gila; Liu, Xun; Goldstein, Martin
INTRODUCTION: With approximately 4 million births each year in the United States, an estimated 760,000 women annually suffer from a clinically significant postpartum depressive illness. Yet even though the relationship between psychiatric disorders and the postpartum period has been documented since the time of Hippocrates, fewer than half of all these cases are recognized. OBJECTIVE: Because postpartum depression (PPD), the most common complication of childbearing, remains poorly characterized, and its etiology remains unclear, we attempted to address a critical gap in the mechanistic understanding of PPD by probing its systems-level neuropathophysiology, in the context of a specific neurobiological model of fronto-limbic-striatal function. METHODS: Using emotionally valenced word probes, with linguistic semantic specificity within an integrated functional magnetic resonance imaging (fMRI) protocol, we investigated emotional processing, behavioral regulation, and their interaction (functions of clinical relevance to PPD), in the context of fronto-limbic-striatal function. RESULTS: We observed attenuated activity in posterior orbitofrontal cortex for negative versus neutral stimuli with greater PPD symptomatology, increased amygdala activity in response to negative words in those without PPD symptomotology, and attenuated striatum activation to positive word conditions with greater PPD symptomotology. CONCLUSION: Identifying the functional neuroanatomical profile of brain systems involved in the regulation of emotion and behavior in the postpartum period will not only assist in determining whether the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition psychiatric diagnostic specifier of PPD has an associated, unique, functional neuroanatomical profile, but a neurobiological characterization in relation to asymptomatic (postpartum non-depressed) control subjects, will also increase our understanding of the affective disorder spectrum, shed additional light on the possible mechanism(s) responsible for PPD and provide a necessary foundation for the development of more targeted, biologically based diagnostic and therapeutic strategies for PPD.
PMID: 17984858
ISSN: 1092-8529
CID: 170025

Increased brainstem volume in panic disorder: a voxel-based morphometric study

Protopopescu, Xenia; Pan, Hong; Tuescher, Oliver; Cloitre, Marylene; Goldstein, Martin; Engelien, Almut; Yang, Yihong; Gorman, Jack; LeDoux, Joseph; Stern, Emily; Silbersweig, David
Neurocircuitry models of panic disorder have hypothesized that the panic attack itself stems from loci in the brainstem including the ascending reticular system and respiratory and cardiovascular control centers. Voxel-based morphometry with acobian modulation was used to examine gray matter volume changes in 10 panic disorder patients and 23 healthy controls. The panic disorder patients had a relatively increased gray matter volume in the midbrain and rostral pons of the brainstem. Increased ventral hippocampal and decreased regional prefrontal cortex volumes were also noted at a lower significance threshold. This finding has implications for pathophysiologic models of panic disorder, and provides structural evidence for the role of the brainstem in neurocircuitry models of panic disorder
PMID: 16514359
ISSN: 0959-4965
CID: 90514

Orbitofrontal cortex activity related to emotional processing changes across the menstrual cycle

Protopopescu, Xenia; Pan, Hong; Altemus, Margaret; Tuescher, Oliver; Polanecsky, Margaret; McEwen, Bruce; Silbersweig, David; Stern, Emily
The orbitofrontal cortex (OFC) has been implicated in the representation of emotional stimuli, assignment of emotional valence/salience to stimuli, stimulus-reinforcement association learning, motivation, and socio-emotional control. Using functional magnetic resonance imaging in female subjects without premenstrual mood symptoms, we found that OFC activity to emotional linguistic stimuli varies depending on the menstrual cycle phase. Specifically, anterior-medial OFC activity for negative vs. neutral stimuli was increased premenstrually and decreased postmenstrually. The inverse pattern was seen in the lateral OFC. These findings suggest that specific subregional OFC activity to emotional stimuli is modulated across the menstrual cycle. The data also demonstrate that menstrual cycle phase is an important consideration in further studies attempting to elucidate the neural substrates of affective representation.
PMID: 16247013
ISSN: 0027-8424
CID: 170026

Fear-related activity in subgenual anterior cingulate differs between men and women

Butler, Tracy; Pan, Hong; Epstein, Jane; Protopopescu, Xenia; Tuescher, Oliver; Goldstein, Martin; Cloitre, Marylene; Yang, Yihong; Phelps, Elizabeth; Gorman, Jack; Ledoux, Joseph; Stern, Emily; Silbersweig, David
Functional magnetic resonance imaging in association with an instructed fear/anticipatory anxiety paradigm was used to explore sex differences in the human fear response. During anticipation of mild electrodermal stimulation, women, as compared with men, demonstrated increased activity in the subgenual anterior cingulate cortex and functionally related regions of the insula and brainstem. The subgenual anterior cingulate cortex is a region critical for emotional control implicated in the pathogenesis of psychiatric disease. Present findings suggest a contributory neural substrate for the greater susceptibility of women to anxiety and affective disorders, and emphasize the importance of considering participant sex when designing and interpreting functional neuroimaging studies
PMID: 16012355
ISSN: 0959-4965
CID: 90520