Circulating PACAP levels are associated with altered imaging measures of entorhinal cortex neurite density in posttraumatic stress disorder.

Introduction: Pituitary adenylate cyclase-activating polypeptide (PACAP) regulates plasticity in brain systems underlying arousal and memory and is associated with posttraumatic stress disorder (PTSD). Research in animal models suggests that PACAP modulates entorhinal cortex (EC) input to the hippocampus, contributing to impaired contextual fear conditioning. In PTSD, PACAP is associated with higher activity of the amygdala to threat stimuli and lower functional connectivity of the amygdala and hippocampus. However, PACAP-affiliated structural alterations of these regions have not been investigated in PTSD. Here, we examined whether peripheral PACAP levels were associated with neuronal morphology of the amygdala and hippocampus (primary analyses), and EC (secondary) using Neurite Orientation Dispersion and Density Imaging.Methods: Sixty-four (44 female) adults (19 to 54 years old) with DSM-5 Criterion A trauma exposure completed the Clinician-Administered PTSD Scale (CAPS-5), a blood draw, and magnetic resonance imaging. PACAP38 radioimmunoassay was performed and T1-weighted and multi-shell diffusion-weighted images were acquired. Neurite Density Index (NDI) and Orientation Dispersion Index (ODI) were quantified in the amygdala, hippocampus, and EC. CAPS-5 total score and anxious arousal score were used to test for clinical associations with brain structure.Results: Higher PACAP levels were associated with greater EC NDI (ß = 0.0099, q = 0.032) and lower EC ODI (ß = -0.0073, q = 0.047), and not hippocampal or amygdala measures. Neither EC NDI nor ODI was associated with clinical measures.Conclusions: Circulating PACAP levels were associated with altered neuronal density of the EC but not the hippocampus or amygdala. These findings strengthen evidence that PACAP may impact arousal-associated memory circuits in PTSD.

PACAP was associated with altered entorhinal cortex neurite density in PTSD.PACAP was not associated with altered neurite density in amygdala or hippocampus.PACAP may impact arousal-associated memory circuits.

Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.

Anhedonia and Delay Discounting: Differing Patterns of Brain-Behavior Relationships in Healthy Control Participants Versus Individuals With Posttraumatic Stress Disorder.

BACKGROUND: Anhedonia may contribute to individual differences in delay discounting (DD). In prior work, we found that higher anhedonia was associated with shallower DD in healthy control (HC) participants but steeper DD in individuals with posttraumatic stress disorder (PTSD). In this study, we aimed to directly compare the relationship between anhedonia and DD across groups and to identify functional brain correlates of this interaction. METHODS: Participants (HC group: n = 23, DSM-5 PTSD group: n = 23) completed a questionnaire assessing anhedonia (Snaith-Hamilton Pleasure Scale [SHAPS]), task-based functional magnetic resonance imaging of decision making including DD, and resting-state functional magnetic resonance imaging. Task-based activity and resting-state functional connectivity were evaluated in reward-related regions that have also been implicated in PTSD (nucleus accumbens [NAcc], right anterior insula). RESULTS: Higher SHAPS scores were associated with steeper DD in PTSD, but there was no relationship between DD and SHAPS in the HC group. There was a significant group-by-SHAPS interaction for NAcc activity, t31 = 2.92, p = .007: Greater NAcc activity when immediate rewards were chosen was associated with higher SHAPS in the PTSD group but lower SHAPS in the HC group. In resting-state functional connectivity, there was a group-by-SHAPS interaction between the NAcc seed and right parietal and frontal pole clusters. CONCLUSIONS: These results extend prior findings that anhedonia is associated with steeper DD in PTSD and demonstrate that this behavioral finding occurs in the context of NAcc hyperactivity to immediate rewards and hyperconnectivity in anhedonic individuals with PTSD.

Circulating PACAP levels are associated with altered imaging measures of entorhinal cortex neurite density in posttraumatic stress disorder.

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) regulates plasticity in brain systems underlying arousal and memory and is associated with posttraumatic stress disorder (PTSD). Research in animal models suggests that PACAP modulates entorhinal cortex (EC) input to the hippocampus, contributing to impaired contextual fear conditioning. In PTSD, PACAP is associated with higher activity of the amygdala to threat stimuli and lower functional connectivity of the amygdala and hippocampus. However, PACAP-affiliated structural alterations of these regions have not been reported. Here, we examined whether peripheral PACAP levels were associated with neuronal morphology of the amygdala and hippocampus (primary analysis), and EC (secondary analysis) using Neurite Orientation Dispersion and Density Imaging. Methods: Sixty-four (44 female) adults (19 to 54 years old) with DSM-5 Criterion A trauma exposure completed the Clinician-Administered PTSD Scale (CAPS-5), a blood draw, and magnetic resonance imaging. PACAP38 radioimmunoassay was performed and T1-weighted and multi-shell diffusion- weighted images were acquired. Neurite Density Index (NDI) and Orientation Dispersion Index (ODI) were quantified in the amygdala, hippocampus, and EC. CAPS-5 total score and anxious arousal score were used to test for clinical associations with brain structure. Results: Higher PACAP levels in blood were associated with greater EC NDI (ß=0.31, q=0.034) and lower EC ODI (ß=-0.30, q=0.042) and not hippocampal or amygdala measures. Neither EC NDI nor ODI was associated with clinical measures. Conclusions: Circulating PACAP levels were associated with altered neuronal density of the EC but not hippocampus or amygdala. These findings strengthen evidence that PACAP may impact arousal- associated memory circuits.

Reduced anhedonia following internet-based cognitive-behavioral therapy for depression is mediated by enhanced reward circuit activation.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent psychiatric condition, yet many patients do not receive adequate treatment. Novel and highly scalable interventions such as internet-based cognitive-behavioral-therapy (iCBT) may help to address this treatment gap. Anhedonia, a hallmark symptom of MDD that refers to diminished interest and ability to experience pleasure, has been associated with reduced reactivity in a neural reward circuit that includes medial prefrontal and striatal brain regions. Whether iCBT can reduce anhedonia severity in MDD patients, and whether these therapeutic effects are accompanied by enhanced reward circuit reactivity has yet to be examined. METHODS: Fifty-two MDD patients were randomly assigned to either 10-week iCBT (n = 26) or monitored attention control (MAC, n = 26) programs. All patients completed pre- and post-treatment assessments of anhedonia (Snaith-Hamilton Pleasure Scale; SHAPS) and reward circuit reactivity [monetary incentive delay (MID) task during functional magnetic resonance imaging (fMRI)]. Healthy control participants (n = 42) also underwent two fMRI scans while completing the MID task 10 weeks apart. RESULTS: Both iCBT and MAC groups exhibited a reduction in anhedonia severity post-treatment. Nevertheless, only the iCBT group exhibited enhanced nucleus accumbens (Nacc) and subgenual anterior cingulate cortex (sgACC) activation and functional connectivity from pre- to post-treatment in response to reward feedback. Enhanced Nacc and sgACC activations were associated with reduced anhedonia severity following iCBT treatment, with enhanced Nacc activation also mediating the reduction in anhedonia severity post-treatment. CONCLUSIONS: These findings suggest that increased reward circuit reactivity may contribute to a reduction in anhedonia severity following iCBT treatment for depression.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Reexperiencing and anxious arousal symptoms in relation to volumes of thalamus nuclei in posttraumatic stress spectrum adults.

INTRODUCTION: Trauma reexperiencing is dominated by recollection of sensory-perceptual elements of the trauma, pointing to involvement of the sensory thalamus. This study examined posttraumatic stress symptoms in relation to volumes of thalamic nuclei that were grouped based on their predominant functions. We hypothesized that reexperiencing, controlling for other symptom dimensions, would correlate with volumes of thalamic nuclei involved in primary and higher-order sensory processing. METHODS: Seventy-two trauma-exposed adults were interviewed with the Clinician Administered PTSD Scale for DSM-IV and underwent 3T magnetic resonance imaging. Scores were derived for reexperiencing, anxious arousal, dysphoric arousal, emotional numbing, and avoidance symptoms. These were entered as simultaneous predictors in five separate regression analyses, with age, sex, and total thalamus volume as covariates, predicting volumesf of five thalamus nuclear groupings corrected for intracranial volume: Specific sensory, associative-sensory, associative-cognitive, intralaminar, and motor groupings. RESULTS: Reexperiencing symptoms were significantly positively correlated with volumes of the motor thalamic grouping, which included the ventral anterior, ventral lateral, and ventromedial nuclei. Anxious arousal was significantly negatively correlated with volumes of all five thalamic groupings. CONCLUSIONS: Reexperiencing symptoms were correlated with volumes of the motor thalamus, while anxious arousal symptoms were related to all thalamic subregion volumes. Thalamic nuclei involved in motor functions, including oculomotor control and motor planning, may be implicated in posttraumatic reexperiencing symptoms.

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium.

BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.

Assessment of brain age in posttraumatic stress disorder: Findings from the ENIGMA PTSD and brain age working groups.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. METHOD: Adult subjects (N = 2229; 56.2% male) aged 18-69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age - chronological age) controlling for chronological age, sex, and scan site. RESULTS: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. DISCUSSION: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.

Regional specificity and clinical correlates of cortical GABA alterations in posttraumatic stress disorder.

Gamma-aminobutyric acid (GABA) metabolism is implicated in posttraumatic stress disorder (PTSD) and may be altered in prefrontal-limbic brain regions involved in arousal regulation. This study used proton magnetic resonance spectroscopy (MRS) to test the hypothesis that PTSD and trauma-exposed non-PTSD comparison (TENC) adults have significantly different GABA than healthy comparison (HC) subjects in two brain areas implicated in arousal (medial prefrontal cortex, insula) but not in a control brain area (posterior temporal cortex). We also examined whether GABA alterations correlated with hyperarousal and dissociation symptoms. One hundred and fourteen participants (39 PTSD, 34 TENC, 41 HC) underwent 3T MRS of the medial prefrontal, right insular, and right posterior temporal cortices, and the GABA plus macromolecule signal (GABA+) was normalized to creatine (Cr). The Clinician Administered PTSD Scale measured hyperarousal symptoms, including sleep disruption. The Dissociative Experiences Scale assessed dissociation symptoms. PTSD and TENC participants had significantly lower mPFC GABA+/Cr than HC participants, and this deficit was significantly correlated with greater dissociation. Compared with HC, PTSD patients but not TENC had significantly lower insula GABA+/Cr. Total hyperarousal symptoms and sleep disruption were not significantly associated with GABA+/Cr alterations in either region. Our findings point to lower GABA in cortical areas implicated in arousal regulation in PTSD and suggest that GABA alterations are associated with symptoms of trauma-related psychopathology but not always a biomarker of diagnosis. These findings also add to evidence that dissociation has distinct neural correlates within PTSD, including high excitability of medial prefrontal cortex.

Social Anhedonia is Associated with Low Social Network Diversity in Trauma-Exposed Adults.

Social anhedonia has been proposed to contribute to social isolation in several psychiatric disorders, but it has not been examined in relation to deficits in social connection that also characterize posttraumatic stress disorder (PTSD). A growing body of evidence emphasizes the health importance of structural features of social networks, including their size and complexity. The current study examined the association between social anhedonia and social network features in a sample of trauma-exposed participants with and without PTSD as well as in non-trauma-exposed controls. Participants (N = 101; n = 37 healthy controls, n = 23 trauma-exposed without PTSD; n = 41 lifetime PTSD) completed self-report measures of social anhedonia (Revised Social Anhedonia Scale) and structural social network features, including social network size, diversity, and the number of embedded networks (Social Network Index). Relative to healthy controls, participants with PTSD reported significantly lower social network sizes and fewer embedded networks. In the combined trauma-exposed sample, higher ratings of social anhedonia were associated with lower social network diversity, r(62) = -.43, p < .001, an effect that remained statistically significant after controlling for PTSD and depression symptom severity. These results suggest that elevated social anhedonia in trauma-exposed individuals may contribute to disruptions in social network structure consistent with social isolation.

Childhood maltreatment experiences are associated with altered diffusion in occipito-temporal white matter pathways.

BACKGROUND: Childhood maltreatment may contribute to brain alterations in posttraumatic stress disorder (PTSD). We previously found that PTSD was associated with white matter compromise, or lower fractional anisotropy (FA), in the left inferior longitudinal fasciculus (ILF). In this study, including non-PTSD controls, we examined whether ILF FA was associated with maltreatment exposures, including those that meet DSM-IV criterion A (physical abuse, sexual abuse) and those that typically do not (emotional abuse, emotional neglect, physical neglect). We hypothesized that lower FA would be associated with PTSD diagnosis and with both categories of maltreatment. METHODS: Ninety-three participants (51 female), ages 20-50, were enrolled, including 32 with lifetime DSM-IV PTSD, 27 trauma-exposed non-PTSD controls, and 34 healthy controls. Participants completed structured interviews, the Childhood Trauma Questionnaire (CTQ), and diffusion-weighted imaging (36 directions). Probabilistic tractography (using FreeSurfer's TRACULA) was used to assess diffusion metrics in the ILF. RESULTS: Contrary to our hypothesis, there was no significant effect of diagnostic group on FA. In contrast, higher CTQ scores were significantly associated with lower FA in the ILF bilaterally. This association of maltreatment with lower FA remained statistically significant after controlling for diagnostic group, and it was significant for both criterion-A-type and noncriterion-A-type maltreatment categories. CONCLUSIONS: This work contributes to a growing body of literature indicating that different forms of childhood maltreatment are associated with altered white matter microstructure in the ILF, an association pathway involved in integrating visual information from occipital regions with emotion processing functions of the anterior temporal lobe.

Regional Prefrontal Resting-State Functional Connectivity in Posttraumatic Stress Disorder.

BACKGROUND: Prefrontal subregions, including the ventromedial prefrontal cortex (PFC), dorsomedial PFC, and dorsolateral PFC (DLPFC), are differentially implicated in the pathophysiology of posttraumatic stress disorder (PTSD), though few existing studies have examined subregional differences in resting-state functional connectivity (rsFC). We hypothesized that PTSD would involve weaker positive rsFC between ventromedial PFC, dorsomedial PFC, and other default mode network regions and increased negative rsFC between DLPFC and posterior default mode network regions. Additionally, we hypothesized that prefrontal regions exhibiting group differences in rsFC would be characterized by alterations in cortical thickness. METHODS: Participants included 36 healthy control subjects, 30 trauma-exposed control subjects, and 21 individuals with current DSM-IV PTSD resulting from community-acquired trauma. Participants completed the Clinician Administered PTSD Scale, questionnaires (Childhood Trauma Questionnaire, Adverse Childhood Events, Life Events Checklist, Beck Depression Inventory), structural neuroimaging, and resting-state functional magnetic resonance imaging. rsFC of DLPFC, ventromedial PFC, and dorsomedial PFC seeds was evaluated in SPM12 and CONN. Cortical thickness for regions with significant rsFC findings was assessed using FreeSurfer. RESULTS: Relative to both healthy control and trauma-exposed control subjects, individuals with PTSD showed increased negative rsFC between the DLPFC and a region of precuneus. This finding was associated with increased overall symptom severity but not with trauma load or childhood trauma exposure. Greater negative DLPFC-precuneus connectivity was associated with greater bilateral precuneus thickness. CONCLUSIONS: Given participation of precuneus subregions in the central executive network, increased anticorrelation between right DLPFC and precuneus in this sample may reflect increased opposition between anterior and posterior central executive network hubs in PTSD.

Anhedonia in Trauma-Exposed Individuals: Functional Connectivity and Decision-Making Correlates.

BACKGROUND: Reward processing deficits have been increasingly associated with trauma exposure and are a core feature of posttraumatic stress disorder (PTSD). While altered resting-state functional connectivity (rsFC) of ventral striatal regions, including the nucleus accumbens (NAcc), has been associated with anhedonia in some stress-related disorders, relationships between NAcc rsFC and anhedonia have not previously been investigated in trauma-exposed individuals. Additionally, relationships between anhedonia and reward-related decision making remain unexplored in relation to trauma exposure. We hypothesized that elevated anhedonia would be associated with altered rsFC between NAcc and default mode network regions and with increased delay discounting. METHODS: The sample included 51 participants exposed to a DSM-IV PTSD Criterion A event related to community trauma. Participants completed the Clinician Administered PTSD Scale, the Snaith-Hamilton Pleasure Scale, the Beck Depression Inventory, a computerized delay discounting paradigm, and resting-state functional magnetic resonance imaging. rsFC data were analyzed in SPM12 and CONN. RESULTS: Higher levels of anhedonia were associated with increased rsFC between seed regions of bilateral NAcc and areas of right dorsomedial prefrontal cortex. This relationship remained significant after accounting for Clinician Administered PTSD Scale total scores, Beck Depression Inventory total scores, or diagnostic group in the regression. Additionally, anhedonia was associated with elevated (increased) delay discounting. CONCLUSIONS: Greater anhedonia was related to higher positive connectivity between NAcc and right dorsomedial prefrontal cortex and to increased delay discounting, i.e., greater preference for smaller immediate versus larger delayed rewards. These findings contribute to a growing body of literature emphasizing the importance of anhedonia in trauma-exposed individuals.

Rostral Anterior Cingulate Cortex Morphology Predicts Treatment Response to Internet-Based Cognitive Behavioral Therapy for Depression.

BACKGROUND: Rostral and subgenual anterior cingulate cortex (rACC and sgACC) activity and, to a lesser extent, volume have been shown to predict depressive symptom improvement across different antidepressant treatments. This study extends prior work by examining whether rACC and/or sgACC morphology predicts treatment response to Internet-based cognitive behavioral therapy (iCBT) for major depressive disorder. This is the first study to examine neural predictors of response to iCBT. METHODS: Hierarchical linear modeling tested whether pretreatment rACC and sgACC volumes predicted depressive symptom improvement during a six-session (10-week) randomized clinical trial of iCBT (n = 35) versus a monitored attention control condition (n = 38). Analyses also tested whether pretreatment rACC and sgACC volumes differed between patients who achieved depression remission versus patients who did not remit. RESULTS: Larger pretreatment right rACC volume was a significant predictor of greater depressive symptom improvement in iCBT even when controlling for demographic (age, gender, race) and clinical (baseline depression, anhedonia, and anxiety) variables previously linked to treatment response. In addition, pretreatment right rACC volume was larger among patients receiving iCBT whose depression eventually remitted relative to patients who did not remit. Corresponding analyses in the monitored attention control group and for the sgACC were not significant. CONCLUSIONS: rACC volume before iCBT demonstrated incremental predictive validity beyond clinical and demographic variables previously found to predict symptom improvement. Such findings may help inform our understanding of the mediating anatomy of iCBT and, if replicated, may suggest neural targets to augment treatment response (e.g., via modulation of rACC function).

Emotional intelligence is associated with connectivity within and between resting state networks.

Emotional intelligence (EI) is defined as an individual's capacity to accurately perceive, understand, reason about, and regulate emotions, and to apply that information to facilitate thought and achieve goals. Although EI plays an important role in mental health and success in academic, professional and social realms, the neurocircuitry underlying this capacity remains poorly characterized, and no study to date has yet examined the relationship between EI and intrinsic neural network function. Here, in a sample of 54 healthy individuals (28 women, 26 men), we apply independent components analysis (ICA) with dual regression to functional magnetic resonance imaging (fMRI) data acquired while subjects were resting in the scanner to investigate brain circuits (intrinsic resting state networks) whose activity is associated with greater self-reported (i.e. Trait) and objectively measured (i.e. Ability) EI. We show that higher Ability EI, but not Trait EI, is associated with stronger negatively correlated spontaneous fMRI signals between the basal ganglia/limbic network (BGN) and posterior default mode network (DMN), and regions involved in emotional processing and regulation. Importantly, these findings suggest that the functional connectivity within and between intrinsic networks associated with mentation, affective regulation, emotion processing, and reward are strongly related to ability EI.

Disruption of white matter structural integrity and connectivity in posttraumatic stress disorder: A TBSS and tractography study.

BACKGROUND: Most studies of brain white matter (WM) in posttraumatic stress disorder (PTSD) have focused on combat trauma, and often were confounded by neurological and substance dependence comorbidity. This study used tract-based spatial statistics (TBSS) and probabilistic tractography to characterize WM microstructure in a mixed-sex community sample of PTSD patients exposed to diverse and multiple traumas, and in trauma-exposed normal comparison (TENC) subjects. METHODS: TBSS compared diffusion measures between 20 adults with DSM-IV PTSD and 17 TENC, using a whole-brain voxel-wise approach. Probabilistic tractography using Freesurfer's TRACULA was employed to measure diffusion tensor imaging (DTI) metrics within anatomically defined pathways. DTI metrics were compared between groups and correlated with PTSD symptom severity and trauma load. RESULTS: Controlling for age, sex, and motion, PTSD subjects had significantly reduced fractional anisotropy (FA) in a left frontal lobe cluster compared with TENC, at p < .05, family-wise error corrected. Tractography identified significant group differences in the inferior longitudinal fasciculus (ILF), including lower FA and higher radial diffusivity in PTSD compared with TENC. Within the PTSD group, FA values were not correlated with symptom severity or trauma load. Results remained significant after removing participants using psychotropic medication or those with comorbid major depression. CONCLUSIONS: PTSD patients had reduced WM integrity in left hemisphere frontal WM and temporal-occipital WM tracts, compared to trauma-exposed controls. Reduced frontal FA is consistent with compromised top-down attentional control and emotion regulation in PTSD, while reduced ILF FA may be related to sensory processing and gating abnormalities in this disorder.

Internet-based cognitive behavior therapy for major depressive disorder: A randomized controlled trial.

BACKGROUND: Prior research has shown that the Sadness Program, a technician-assisted Internet-based cognitive behavioral therapy (iCBT) intervention developed in Australia, is effective for treating major depressive disorder (MDD). The current study aimed to expand this work by adapting the protocol for an American population and testing the Sadness Program with an attention control group. METHODS: In this parallel-group, randomized controlled trial, adult MDD participants (18-45 years) were randomized to a 10-week period of iCBT (n = 37) or monitored attention control (MAC; n = 40). Participants in the iCBT group completed six online therapy lessons, which included access to content summaries and homework assignments. During the 10-week trial, iCBT and MAC participants logged into the web-based system six times to complete self-report symptom scales, and a nonclinician technician contacted participants weekly to provide encouragement and support. The primary outcome was the Hamilton Rating Scale for Depression (HRSD), and the secondary outcomes were the Patient Health Questionnaire-9 and Kessler-10. RESULTS: Intent-to-treat analyses revealed significantly greater reductions in depressive symptoms in iCBT compared with MAC participants, using both the self-report measures and the clinician-rated HRSD (d = -0.80). Importantly, iCBT participants also showed significantly higher rates of clinical response and remission. Exploratory analyses did not support illness severity as a moderator of treatment outcome. CONCLUSIONS: The Sadness Program led to significant reductions in depression and distress symptoms. With its potential to be delivered in a scalable, cost-efficient manner, iCBT is a promising strategy to enhance access to effective care.

Daytime Sleepiness Is Associated With Reduced Integration of Temporally Distant Outcomes on the Iowa Gambling Task.

Sleep deprivation is associated with performance decrements on some measures of executive functioning. For instance, sleep deprivation results in altered decision making on the Iowa Gambling Task. However, it is unclear which component processes of the task may be driving the effect. In this study, Iowa Gambling task performance was decomposed using the Expectancy-Valence model. Recent sleep debt and greater daytime sleepiness were associated with higher scores on the updating parameter, which reflects the extent to which recent experiences are emphasized over remote ones. Findings suggest that the effects of insufficient sleep on IGT performance are due to shortening of the time horizon over which decisions are integrated. These findings may have clinical implications in that individuals with sleep problems may not integrate more temporally distant information when making decisions.