Amygdala and Insula Connectivity Changes Following Psychotherapy for Posttraumatic Stress Disorder: A Randomized Clinical Trial.

BACKGROUND: Exposure-based psychotherapy is a first-line treatment for posttraumatic stress disorder (PTSD), but its mechanisms are poorly understood. Functional brain connectivity is a promising metric for identifying treatment mechanisms and biosignatures of therapeutic response. To this end, we assessed amygdala and insula treatment-related connectivity changes and their relationship to PTSD symptom improvements. METHODS: Individuals with a primary PTSD diagnosis (N = 66) participated in a randomized clinical trial of prolonged exposure therapy (n = 36) versus treatment waiting list (n = 30). Task-free functional magnetic resonance imaging was completed prior to randomization and 1 month following cessation of treatment/waiting list. Whole-brain blood oxygenation level-dependent responses were acquired. Intrinsic connectivity was assessed by subregion in the amygdala and insula, limbic structures key to the disorder pathophysiology. Dynamic causal modeling assessed evidence for effective connectivity changes in select nodes informed by intrinsic connectivity findings. RESULTS: The amygdala and insula displayed widespread patterns of primarily subregion-uniform intrinsic connectivity change, including increased connectivity between the amygdala and insula; increased connectivity of both regions with the ventral prefrontal cortex and frontopolar and sensory cortices; and decreased connectivity of both regions with the left frontoparietal nodes of the executive control network. Larger decreases in amygdala-frontal connectivity and insula-parietal connectivity were associated with larger PTSD symptom reductions. Dynamic causal modeling evidence suggested that treatment decreased left frontal inhibition of the left amygdala, and larger decreases were associated with larger symptom reductions. CONCLUSIONS: PTSD psychotherapy adaptively attenuates functional interactions between frontoparietal and limbic brain circuitry at rest, which may reflect a potential mechanism or biosignature of recovery.

Internet-delivered computerized cognitive & affective remediation training for the treatment of acute and chronic posttraumatic stress disorder: Two randomized clinical trials.

Treatment of posttraumatic stress disorder (PTSD) is time and cost-intensive. New, readily implementable interventions are needed. Two parallel randomized clinical trials tested if cognitive/affective computerized training improves cognitive/affective functions and PTSD symptoms in acute (N = 80) and chronic PTSD (N = 84). Adults age 18-65 were recruited from an Israeli hospital emergency room (acute) or from across the United States (chronic). Individuals were randomized to an active intervention (acute N = 50, chronic N = 48) that adaptively trains cognition and an affective positivity bias, or a control intervention (acute N = 30, chronic N = 36) of engaging computer games. Participants, blind to assignment, completed exercises at home for 30 min/day over 30 days (acute) or 45 min/day over 45 days (chronic). Primary outcomes were computerized cognitive/affective function metrics. Secondary outcomes were Clinician-Administered PTSD Scale (CAPS) total scores. In chronic PTSD, the active arm demonstrated facilitated speed of fearful face identification (F = 20.96, q < 0.001; d = 1.21) and a trend towards improvement in total PTSD symptoms (F = 2.91, p = 0.09, d = 0.47), which was due to improvement in re-experiencing symptoms (F = 6.14, p = 0.015; d = 0.73). Better cognitive performance at baseline moderated the training effect and was associated with more favorable improvements on both metrics. Cognitive and affective training does not have widespread benefit on symptoms and cognitive/affective functions in PTSD. Future studies targeting re-experiencing a priori, stratifying on cognitive capacity, and with modified methods to infer on mechanisms and optimized training parameters may be warranted. ClinicalTrials.gov Identifiers: NCT01694316 &NCT02085512.

Using fMRI connectivity to define a treatment-resistant form of post-traumatic stress disorder.

A mechanistic understanding of the pathology of psychiatric disorders has been hampered by extensive heterogeneity in biology, symptoms, and behavior within diagnostic categories that are defined subjectively. We investigated whether leveraging individual differences in information-processing impairments in patients with post-traumatic stress disorder (PTSD) could reveal phenotypes within the disorder. We found that a subgroup of patients with PTSD from two independent cohorts displayed both aberrant functional connectivity within the ventral attention network (VAN) as revealed by functional magnetic resonance imaging (fMRI) neuroimaging and impaired verbal memory on a word list learning task. This combined phenotype was not associated with differences in symptoms or comorbidities, but nonetheless could be used to predict a poor response to psychotherapy, the best-validated treatment for PTSD. Using concurrent focal noninvasive transcranial magnetic stimulation and electroencephalography, we then identified alterations in neural signal flow in the VAN that were evoked by direct stimulation of that network. These alterations were associated with individual differences in functional fMRI connectivity within the VAN. Our findings define specific neurobiological mechanisms in a subgroup of patients with PTSD that could contribute to the poor response to psychotherapy.

Brain and behavioral correlates of insulin resistance in youth with depression and obesity.

Depression, together with insulin resistance, is increasingly prevalent among youth. These conditions have traditionally been compartmentalized, but recent evidence suggests that a shared brain motivational network underlies their co-occurrence. We posit that, in the context of depressive symptoms, insulin resistance is associated with aberrant structure and functional connectivity in the Anterior Cingulate Cortex (ACC) and hippocampus. This motivational neural circuit underlies dysfunctional behavioral responses and increased sensitivity to rewarding aspects of ingesting high calorie food that lead to disinhibition of eating even when satiated. To investigate this shared mechanism, we evaluated a sample of forty-two depressed and overweight (BMI > 85th%) youth aged 9 to 17. Using ACC and hippocampus structural and seed-based regions of interest, we investigated associations between insulin resistance, depression, structure (ACC thickness, and ACC and hippocampal area), and resting-state functional connectivity (RSFC). We predicted that aberrant associations among these neural and behavioral characteristics would be stronger in insulin resistant compared to insulin sensitive youth. We found that youth with greater insulin resistance had higher levels of anhedonia and more food seeking behaviors, reduced hippocampal and ACC volumes, and greater levels of ACC and hippocampal dysconnectivity to fronto-limbic reward networks at rest. For youth with high levels of insulin resistance, thinner ACC and smaller hippocampal volumes were associated with more severe depressive symptoms, whereas the opposite was true for youth with low levels of insulin resistance. The ACC-hippocampal motivational network that subserves depression and insulin resistance separately, may represent a critical neural interaction that link these syndromes together.

Insulin resistance is associated with smaller brain volumes in a preliminary study of depressed and obese children.

OBJECTIVE: During childhood, the brain can consume up to 65% of total calories, and a steady supply of the brain's main fuel glucose needs to be maintained. Although the brain itself is not dependent on insulin for the uptake of glucose, insulin plays an important role in energy homeostasis. Thus, the risk for insulin resistance during brain development may negatively impact the whole brain volume. METHODS: We investigated the link between the insulin resistance and the whole brain volume as measured by structural Magnetic resonance imaging (MRI) in 46 unmedicated depressed and overweight youths between the ages of 9 and 17 years. RESULTS: Smaller whole brain volumes were associated with insulin resistance independent of age, sex, depression severity, body mass index, socioeconomic status, Tanner Stage, and Intelligence quotient (IQ) (r = 0.395, P = .014) CONCLUSIONS: There may be a significant cost for developing insulin resistance on the developing brain. Disentangling the precise relationship between the insulin resistance and the developing brain is critical.

Selective Effects of Psychotherapy on Frontopolar Cortical Function in PTSD.

OBJECTIVE: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but a comprehensive, emotion-focused perspective on how psychotherapy affects brain function is lacking. The authors assessed changes in brain function after prolonged exposure therapy across three emotional reactivity and regulation paradigms. METHOD: Individuals with PTSD underwent functional MRI (fMRI) at rest and while completing three tasks assessing emotional reactivity and regulation. Individuals were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30) and underwent a second scan approximately 4 weeks after the last treatment session or a comparable waiting period, respectively. RESULTS: Treatment-specific changes were observed only during cognitive reappraisal of negative images. Psychotherapy increased lateral frontopolar cortex activity and connectivity with the ventromedial prefrontal cortex/ventral striatum. Greater increases in frontopolar activation were associated with improvement in hyperarousal symptoms and psychological well-being. The frontopolar cortex also displayed a greater variety of temporal resting-state signal pattern changes after treatment. Concurrent transcranial magnetic stimulation and fMRI in healthy participants demonstrated that the lateral frontopolar cortex exerts downstream influence on the ventromedial prefrontal cortex/ventral striatum. CONCLUSIONS: Changes in frontopolar function during deliberate regulation of negative affect is one key mechanism of adaptive psychotherapeutic change in PTSD. Given that frontopolar connectivity with ventromedial regions during emotion regulation is enhanced by psychotherapy and that the frontopolar cortex exerts downstream influence on ventromedial regions in healthy individuals, these findings inform a novel conceptualization of how psychotherapy works, and they identify a promising target for stimulation-based therapeutics.

PTSD Psychotherapy Outcome Predicted by Brain Activation During Emotional Reactivity and Regulation.

OBJECTIVE: Exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD), but many patients do not respond. Brain functions governing treatment outcome are not well characterized. The authors examined brain systems relevant to emotional reactivity and regulation, constructs that are thought to be central to PTSD and exposure therapy effects, to identify the functional traits of individuals most likely to benefit from treatment. METHOD: Individuals with PTSD underwent functional MRI (fMRI) while completing three tasks assessing emotional reactivity and regulation. Participants were then randomly assigned to immediate prolonged exposure treatment (N=36) or a waiting list condition (N=30). A random subset of the prolonged exposure group (N=17) underwent single-pulse transcranial magnetic stimulation (TMS) concurrent with fMRI to examine whether predictive activation patterns reflect causal influence within circuits. Linear mixed-effects modeling in line with the intent-to-treat principle was used to examine how baseline brain function moderated the effect of treatment on PTSD symptoms. RESULTS: At baseline, individuals with larger treatment-related symptom reductions (compared with the waiting list condition) demonstrated 1) greater dorsal prefrontal activation and 2) less left amygdala activation, both during emotion reactivity; 3) better inhibition of the left amygdala induced by single TMS pulses to the right dorsolateral prefrontal cortex; and 4) greater ventromedial prefrontal/ventral striatal activation during emotional conflict regulation. Reappraisal-related activation was not a significant moderator of the treatment effect. CONCLUSIONS: Capacity to benefit from prolonged exposure in PTSD is gated by the degree to which prefrontal resources are spontaneously engaged when superficially processing threat and adaptively mitigating emotional interference, but not when deliberately reducing negative emotionality.

Identification of a common neurobiological substrate for mental illness.

IMPORTANCE: Psychiatric diagnoses are currently distinguished based on sets of specific symptoms. However, genetic and clinical analyses find similarities across a wide variety of diagnoses, suggesting that a common neurobiological substrate may exist across mental illness. OBJECTIVE: To conduct a meta-analysis of structural neuroimaging studies across multiple psychiatric diagnoses, followed by parallel analyses of 3 large-scale healthy participant data sets to help interpret structural findings in the meta-analysis. DATA SOURCES: PubMed was searched to identify voxel-based morphometry studies through July 2012 comparing psychiatric patients to healthy control individuals for the meta-analysis. The 3 parallel healthy participant data sets included resting-state functional magnetic resonance imaging, a database of activation foci across thousands of neuroimaging experiments, and a data set with structural imaging and cognitive task performance data. DATA EXTRACTION AND SYNTHESIS: Studies were included in the meta-analysis if they reported voxel-based morphometry differences between patients with an Axis I diagnosis and control individuals in stereotactic coordinates across the whole brain, did not present predominantly in childhood, and had at least 10 studies contributing to that diagnosis (or across closely related diagnoses). The meta-analysis was conducted on peak voxel coordinates using an activation likelihood estimation approach. MAIN OUTCOMES AND MEASURES: We tested for areas of common gray matter volume increase or decrease across Axis I diagnoses, as well as areas differing between diagnoses. Follow-up analyses on other healthy participant data sets tested connectivity related to regions arising from the meta-analysis and the relationship of gray matter volume to cognition. RESULTS: Based on the voxel-based morphometry meta-analysis of 193 studies comprising 15 892 individuals across 6 diverse diagnostic groups (schizophrenia, bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety), we found that gray matter loss converged across diagnoses in 3 regions: the dorsal anterior cingulate, right insula, and left insula. By contrast, there were few diagnosis-specific effects, distinguishing only schizophrenia and depression from other diagnoses. In the parallel follow-up analyses of the 3 independent healthy participant data sets, we found that the common gray matter loss regions formed a tightly interconnected network during tasks and at resting and that lower gray matter in this network was associated with poor executive functioning. CONCLUSIONS AND REVELANCE: We identified a concordance across psychiatric diagnoses in terms of integrity of an anterior insula/dorsal anterior cingulate-based network, which may relate to executive function deficits observed across diagnoses. This concordance provides an organizing model that emphasizes the importance of shared neural substrates across psychopathology, despite likely diverse etiologies, which is currently not an explicit component of psychiatric nosology.