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A Randomized, Sham-Controlled Trial of Cranial Electrical Stimulation for Fibromyalgia Pain and Physical Function, Using Brain Imaging Biomarkers

Fibromyalgia is a chronic pain syndrome that presents with a constellation of broad symptoms, including decreased physical function, fatigue, cognitive ...

Atlanta Veterans Affairs Healthcare System

Emory University School of Medicine

Studies suggest that exaggerated amygdala reactivity is a vulnerability factor for posttraumatic stress disorder (PTSD); however, our understanding is limited by a paucity of prospective, longitudinal studies. Recent studies in healthy samples indicate that, relative to reactivity, habituation is a more reliable biomarker of individual differences in amygdala function. We investigated reactivity of the amygdala and cortical areas to repeated threat presentations in a prospective study of PTSD.

Amygdala Reactivity and Anterior Cingulate Habituation Predict Posttraumatic Stress Disorder Symptom Maintenance After Acute Civilian Trauma.

Hippocampal structure is particularly sensitive to trauma and other stressors. However, previous findings linking hippocampal function with trauma-related psychopathology have been mixed. Heterogeneity in psychological responses to trauma has not been considered with respect to hippocampal function and may contribute to mixed findings. To address these issues, we examined associations between data-driven symptom dimensions and episodic memory formation, a key function of the hippocampus, in a trauma-exposed sample. Symptom dimensions were defined using principal components analysis (PCA) in 3881 trauma-exposed African-American women recruited from primary care waiting rooms of a large urban hospital. Hippocampal and amygdala function were subsequently investigated in an fMRI study of episodic memory formation in a subset of 54 women. Participants viewed scenes with neutral, negative, and positive content during fMRI, and completed a delayed cued recall task. PCA analysis produced five symptom dimensions interpreted as reflecting negative affect, somatic symptoms, re-experiencing, hyper-arousal, and numbing. -experiencing was the only symptom type associated with hippocampal function, predicting increased memory encoding-related activation in the hippocampus as well as the amygdala. In contrast, the negative affect component predicted lower amygdala activation for subsequently recalled scenes, and lower functional coupling with other important memory-related regions including the precuneus, inferior frontal gyrus, and occipital cortex. Symptom dimensions were not related to hippocampal volume. The fMRI findings for re-experiencing versus negative affect parallel differences in behavioral memory phenomena in PTSD versus MDD, and highlight a need for more complex models of trauma-related pathology.

Episodic memory after trauma exposure: Medial temporal lobe function is positively related to re-experiencing and inversely related to negative affect symptoms.

Longitudinal Risk for Posttraumatic Stress Disorder and Chronic Pain: Shared Circuitry in the Midbrain?

Neurobiological markers of future susceptibility to posttraumatic stress disorder (PTSD) may facilitate identification of vulnerable individuals in the early aftermath of trauma. Variability in resting-state networks (RSNs), patterns of intrinsic functional connectivity across the brain, has previously been linked to PTSD, and may thus be informative of PTSD susceptibility. The present data are part of an initial analysis from the AURORA study, a longitudinal, multisite study of adverse neuropsychiatric sequalae. Magnetic resonance imaging (MRI) data from 109 recently (i.e., ~2 weeks) traumatized individuals were collected and PTSD and depression symptoms were assessed at 3 months post trauma. We assessed commonly reported RSNs including the default mode network (DMN), central executive network (CEN), and salience network (SN). We also identified a proposed arousal network (AN) composed of a priori brain regions important for PTSD: the amygdala, hippocampus, mamillary bodies, midbrain, and pons. Primary analyses assessed whether variability in functional connectivity at the 2-week imaging timepoint predicted 3-month PTSD symptom severity. Left dorsolateral prefrontal cortex (DLPFC) to AN connectivity at 2 weeks post trauma was negatively related to 3-month PTSD symptoms. Further, right inferior temporal gyrus (ITG) to DMN connectivity was positively related to 3-month PTSD symptoms. Both DLPFC-AN and ITG-DMN connectivity also predicted depression symptoms at 3 months. Our results suggest that, following trauma exposure, acutely assessed variability in RSN connectivity was associated with PTSD symptom severity approximately two and a half months later. However, these patterns may reflect general susceptibility to posttraumatic dysfunction as the imaging patterns were not linked to specific disorder symptoms, at least in the subacute/early chronic phase. The present data suggest that assessment of RSNs in the early aftermath of trauma may be informative of susceptibility to posttraumatic dysfunction, with future work needed to understand neural markers of long-term (e.g., 12 months post trauma) dysfunction. Furthermore, these findings are consistent with neural models suggesting that decreased top-down cortico-limbic regulation and increased network-mediated fear generalization may contribute to ongoing dysfunction in the aftermath of trauma.

Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study.

Posttraumatic stress disorder (PTSD) is associated with lower gray matter volume (GMV) in brain regions critical for extinction of learned threat. However, relationships among volume, extinction learning, and PTSD symptom development remain unclear. We investigated subcortical brain volumes in regions supporting extinction learning and fear-potentiated startle (FPS) to understand brain-behavior interactions that may impact PTSD symptom development in recently traumatized individuals. Participants (N = 99) completed magnetic resonance imaging and threat conditioning two weeks following trauma exposure as part of a multisite observational study to understand the neuropsychiatric effects of trauma (AURORA Study). Participants completed self-assessments of PTSD (PTSD Checklist for DSM-5; PCL-5), dissociation, and depression symptoms two- and eight-weeks post-trauma. We completed multiple regressions to investigate relationships between FPS during late extinction, GMV, and PTSD symptom development. The interaction between thalamic GMV and FPS during late extinction at two weeks post-trauma predicted PCL-5 scores eight weeks (t (75) = 2.49, β = 0.28, p = 0.015) post-trauma. Higher FPS predicted higher PCL-5 scores in the setting of increased thalamic GMV. Meanwhile, lower FPS also predicted higher PCL-5 scores in the setting of decreased thalamic GMV. Thalamic GMV and FPS interactions also predicted posttraumatic dissociative and depressive symptoms. Amygdala and hippocampus GMV by FPS interactions were not associated with posttraumatic symptom development. Taken together, thalamic GMV and FPS during late extinction interact to contribute to adverse posttraumatic neuropsychiatric outcomes. Multimodal assessments soon after trauma have the potential to distinguish key phenotypes vulnerable to posttraumatic neuropsychiatric outcomes.

Thalamic volume and fear extinction interact to predict acute posttraumatic stress severity.

Resilience in the face of major life stressors is changeable over time and with experience. Accordingly, differing sets of neurobiological factors may contribute to an adaptive stress response before, during, and after the stressor. Longitudinal studies are therefore particularly effective in answering questions about the determinants of resilience. Here we provide an overview of the rapidly-growing body of longitudinal neuroimaging research on stress resilience. Despite lingering gaps and limitations, these studies are beginning to reveal individual differences in neural circuit structure and function that appear protective against the emergence of future psychopathology following a major life stressor. Here we outline a neural circuit model of resilience to trauma. Specifically, pre-trauma biomarkers of resilience show that an ability to modulate activity within threat and salience networks predicts fewer stress-related symptoms. In contrast, early post-trauma biomarkers of subsequent resilience or recovery show a more complex pattern, spanning a number of major circuits including attention and cognitive control networks as well as primary sensory cortices. This novel synthesis suggests stress resilience may be scaffolded by stable individual differences in the processing of threat cues, and further buttressed by post-trauma adaptations to the stressor that encompass multiple mechanisms and circuits. More attention and resources supporting this work will inform the targets and timing of mechanistic resilience-boosting interventions.

Neural contributors to trauma resilience: a review of longitudinal neuroimaging studies.

Unexpected circuit-level tradeoffs in human stress resilience.

Prior findings suggest that psychopathology following interpersonal trauma or assaultive violence may present differently from prototypical posttraumatic stress disorder (PTSD). However, whether this is true for sexual trauma (ST) in the context of other salient lifetime traumatic experiences is yet unknown. We predicted that ST exposure may result in higher avoidance and numbing symptoms and blunted fear responses, relative to non-sexual trauma (NST), particularly if ST occurred during childhood.

Distinctive impacts of sexual trauma versus non-sexual trauma on PTSD profiles in highly trauma-exposed, Black women.

Female individuals are more likely to be diagnosed with PTSD following trauma exposure than males, potentially due, in part, to underlying neurobiological factors. Several brain regions underlying fear learning and expression have previously been associated with PTSD, with the hippocampus, amygdala, dorsal anterior cingulate cortex (dACC), and rostral ACC (rACC) showing altered volume and function in those with PTSD. However, few studies have examined how sex impacts the predictive value of subcortical volumes and cortical thickness in longitudinal PTSD studies. As part of an emergency department study completed at the Grady Trauma Project in Atlanta, GA, N = 93 (40 Female) participants were enrolled within 24 h following a traumatic event. Multi-echo T1-weighted MRI images were collected one-month post-trauma exposure. Bilateral amygdala and hippocampal volumes and rACC and dACC cortical thickness were segmented. To assess the longitudinal course of PTSD, the PTSD Symptom Scale (PSS) was collected 6 months post-trauma. We investigated whether regional volume/thickness interacted with sex to predict later PTSD symptom severity, controlling for PSS score at time of scan, age, race, and trauma type, as well as intracranial volume (ICV) for subcortical volumes. There was a significant interaction between sex and rACC for 6-month PSS, such that right rACC thickness was positively correlated with 6-month PSS scores in females, but not in males. In examining PTSD symptom subtypes and depression symptoms, greater rACC thickness in females predicted greater avoidance symptoms, while smaller rACC thickness in males predicted greater depression symptoms. Amygdala and hippocampus volume and dACC thickness showed no main effect or interaction with sex. The current findings provide evidence for sex-based differences in how brain volume predicts future PTSD severity and symptoms and supports the rACC as being a vital region regarding PTSD. Gender differences should be assessed in future longitudinal PTSD MRI studies for more accurate identification of future PTSD risk following trauma.

Sex-dependent risk factors for PTSD: a prospective structural MRI study.

Childhood trauma is a known risk factor for trauma and stress-related disorders in adulthood. However, limited research has investigated the impact of childhood trauma on brain structure linked to later posttraumatic dysfunction. We investigated the effect of childhood trauma on white matter microstructure after recent trauma and its relationship with future posttraumatic dysfunction among trauma-exposed adult participants (n = 202) recruited from emergency departments as part of the AURORA Study. Participants completed self-report scales assessing prior childhood maltreatment within 2-weeks in addition to assessments of PTSD, depression, anxiety, and dissociation symptoms within 6-months of their traumatic event. Fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI) collected at 2-weeks and 6-months was used to index white matter microstructure. Childhood maltreatment load predicted 6-month PTSD symptoms (b = 1.75, SE = 0.78, 95% CI = [0.20, 3.29]) and inversely varied with FA in the bilateral internal capsule (IC) at 2-weeks (p = 0.0294, FDR corrected) and 6-months (p = 0.0238, FDR corrected). We observed a significant indirect effect of childhood maltreatment load on 6-month PTSD symptoms through 2-week IC microstructure (b = 0.37, Boot SE = 0.18, 95% CI = [0.05, 0.76]) that fully mediated the effect of childhood maltreatment load on PCL-5 scores (b = 1.37, SE = 0.79, 95% CI = [-0.18, 2.93]). IC microstructure did not mediate relationships between childhood maltreatment and depressive, anxiety, or dissociative symptomatology. Our findings suggest a unique role for IC microstructure as a stable neural pathway between childhood trauma and future PTSD symptoms following recent trauma. Notably, our work did not support roles of white matter tracts previously found to vary with PTSD symptoms and childhood trauma exposure, including the cingulum bundle, uncinate fasciculus, and corpus callosum. Given the IC contains sensory fibers linked to perception and motor control, childhood maltreatment might impact the neural circuits that relay and process threat-related inputs and responses to trauma.

Article	Year
Amygdala Reactivity and Anterior Cingulate Habituation Predict Posttraumatic Stress Disorder Symptom Maintenance After Acute Civilian Trauma. Biological psychiatry\| PubMed ID: 28117048	2017
Episodic memory after trauma exposure: Medial temporal lobe function is positively related to re-experiencing and inversely related to negative affect symptoms. NeuroImage. Clinical\| PubMed ID: 29204343	2018
Longitudinal Risk for Posttraumatic Stress Disorder and Chronic Pain: Shared Circuitry in the Midbrain? Biological psychiatry. Cognitive neuroscience and neuroimaging\| PubMed ID: 32896298	2020
Prognostic neuroimaging biomarkers of trauma-related psychopathology: resting-state fMRI shortly after trauma predicts future PTSD and depression symptoms in the AURORA study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 33479509	2021
Thalamic volume and fear extinction interact to predict acute posttraumatic stress severity. Journal of psychiatric research\| PubMed ID: 34304036	2021
Neural contributors to trauma resilience: a review of longitudinal neuroimaging studies. Translational psychiatry\| PubMed ID: 34611129	2021
Unexpected circuit-level tradeoffs in human stress resilience. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 35918467	2023
Distinctive impacts of sexual trauma versus non-sexual trauma on PTSD profiles in highly trauma-exposed, Black women. Journal of affective disorders\| PubMed ID: 36055528	2022
Sex-dependent risk factors for PTSD: a prospective structural MRI study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 36114284	2022
Internal capsule microstructure mediates the relationship between childhood maltreatment and PTSD following adulthood trauma exposure. Molecular psychiatry\| PubMed ID: 36932158	2023
It's Not All in Your Head: Discrimination and Its Association With the Brain-Gut Axis. Biological psychiatry\| PubMed ID: 37437988	2023

Jennifer S Stevens

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