Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

Limited evidence for a moderating effect of HIV status on brain age in heavy episodic drinkers.

We set out to test the hypothesis that greater brain ageing will be observed in people with HIV (PWH) and those who engage in heavy episodic drinking (HED), with their combined effects being especially detrimental in cognitive control brain networks. We correlated measures of "brain age gap" (BAG) and neurocognitive impairment in participants with and without HIV and HED. Sixty-nine participants were recruited from a community health centre in Cape Town: HIV - /HED - (N = 17), HIV + /HED - (N = 14), HIV - /HED + (N = 21), and HIV + /HED + (N = 17). Brain age was modelled using structural MRI features from the whole brain or one of six brain regions. Linear regression models were employed to identify differences in BAG between patient groups and controls. Associations between BAG and clinical data were tested using bivariate statistical methods. Compared to controls, greater global BAG was observed in heavy drinkers, both with (Cohen's d = 1.52) and without (d = 1.61) HIV. Differences in BAG between HED participants and controls were observed for the cingulate and parietal cortex, as well as subcortically. A larger BAG was associated with higher total drinking scores but not nadir CD4 count or current HIV viral load. The association between heavy episodic drinking and BAG, independent of HIV status, points to the importance of screening for alcohol use disorders in primary care. The relatively large contribution of cognitive control brain regions to BAG highlights the utility of assessing the contribution of different brain regions to brain age.

The impact of prenatal alcohol and/or tobacco exposure on brain structure in a large sample of children from a South African birth cohort.

BACKGROUND: Neuroimaging studies have emphasized the impact of prenatal alcohol exposure (PAE) on brain development, traditionally in heavily exposed participants. However, less is known about how naturally occurring community patterns of PAE (including light to moderate exposure) affect brain development, particularly in consideration of commonly occurring concurrent impacts of prenatal tobacco exposure (PTE). METHODS: Three hundred thirty-two children (ages 8 to 12) living in South Africa's Cape Flats townships underwent structural magnetic resonance imaging. During pregnancy, their mothers reported alcohol and tobacco use, which was used to evaluate PAE and PTE effects on their children's brain structure. Analyses involved the main effects of PAE and PTE (and their interaction) and the effects of PAE and PTE quantity on cortical thickness, surface area, and volume. RESULTS: After false-discovery rate (FDR) correction, PAE was associated with thinner left parahippocampal cortices, while PTE was associated with smaller cortical surface area in the bilateral pericalcarine, left lateral orbitofrontal, right posterior cingulate, right rostral anterior cingulate, left caudal middle frontal, and right caudal anterior cingulate gyri. There were no PAE × PTE interactions nor any associations of PAE and PTE exposure on volumetrics that survived FDR correction. CONCLUSION: PAE was associated with reduction in the structure of the medial temporal lobe, a brain region critical for learning and memory. PTE had stronger and broader associations, including with regions associated with executive function, reward processing, and emotional regulation, potentially reflecting continued postnatal exposure to tobacco (i.e., second-hand smoke exposure). These differential effects are discussed with respect to reduced PAE quantity in our exposed group versus prior studies within this geographical location, the deep poverty in which participants live, and the consequences of apartheid and racially and economically driven payment practices that contributed to heavy drinking in the region. Longer-term follow-up is needed to determine potential environmental and other moderators of the brain findings here and assess the extent to which they endure over time.

Pharmacotherapy for post traumatic stress disorder (PTSD).

BACKGROUND: Posttraumatic stress disorder (PTSD) is a prevalent and disabling disorder. Evidence that PTSD is characterised by specific psychobiological dysfunctions has contributed to a growing interest in the use of medication in its treatment. OBJECTIVES: To assess the effects of medication for reducing PTSD symptoms in adults with PTSD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 11, November 2020); MEDLINE (1946-), Embase (1974-), PsycINFO (1967-) and PTSDPubs (all available years) either directly or via the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR). We also searched international trial registers. The date of the latest search was 13 November 2020. SELECTION CRITERIA: All randomised controlled trials (RCTs) of pharmacotherapy for adults with PTSD. DATA COLLECTION AND ANALYSIS: Three review authors (TW, JI, and NP) independently assessed RCTs for inclusion in the review, collated trial data, and assessed trial quality. We contacted investigators to obtain missing data. We stratified summary statistics by medication class, and by medication agent for all medications. We calculated dichotomous and continuous measures using a random-effects model, and assessed heterogeneity. MAIN RESULTS: We include 66 RCTs in the review (range: 13 days to 28 weeks; 7442 participants; age range 18 to 85 years) and 54 in the meta-analysis.  For the primary outcome of treatment response, we found evidence of beneficial effect for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.59 to 0.74; 8 studies, 1078 participants), which improved PTSD symptoms in 58% of SSRI participants compared with 35% of placebo participants, based on moderate-certainty evidence.  For this outcome we also found evidence of beneficial effect for the noradrenergic and specific serotonergic antidepressant (NaSSA) mirtazapine: (RR 0.45, 95% CI 0.22 to 0.94; 1 study, 26 participants) in 65% of people on mirtazapine compared with 22% of placebo participants, and for the tricyclic antidepressant (TCA) amitriptyline (RR 0.60, 95% CI 0.38 to 0.96; 1 study, 40 participants) in 50% of amitriptyline participants compared with 17% of placebo participants, which improved PTSD symptoms. These outcomes are based on low-certainty evidence. There was however no evidence of beneficial effect for the number of participants who improved with the antipsychotics (RR 0.51, 95% CI 0.16 to 1.67; 2 studies, 43 participants) compared to placebo, based on very low-certainty evidence. For the outcome of treatment withdrawal, we found evidence of a harm for the individual SSRI agents compared with placebo (RR 1.41, 95% CI 1.07 to 1.87; 14 studies, 2399 participants). Withdrawals were also higher for the separate SSRI paroxetine group compared to the placebo group (RR 1.55, 95% CI 1.05 to 2.29; 5 studies, 1101 participants). Nonetheless, the absolute proportion of individuals dropping out from treatment due to adverse events in the SSRI groups was low (9%), based on moderate-certainty evidence. For the rest of the medications compared to placebo, we did not find evidence of harm for individuals dropping out from treatment due to adverse events. AUTHORS' CONCLUSIONS: The findings of this review support the conclusion that SSRIs improve PTSD symptoms; they are first-line agents for the pharmacotherapy of PTSD, based on moderate-certainty evidence. The NaSSA mirtazapine and the TCA amitriptyline may also improve PTSD symptoms, but this is based on low-certainty evidence. In addition, we found no evidence of benefit for the number of participants who improved following treatment with the antipsychotic group compared to placebo, based on very low-certainty evidence. There remain important gaps in the evidence base, and a continued need for more effective agents in the management of PTSD.

Pharmacotherapy for trichotillomania.

BACKGROUND: Trichotillomania (TTM; hair-pulling disorder) is a prevalent and disabling disorder characterised by recurrent hair-pulling. Here we update a previous Cochrane Review on the effects of medication for TTM. OBJECTIVES: To assess the effects of medication for trichotillomania (TTM) in adults, children and adolescents compared with placebo or other medication. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PsycINFO, eleven other bibliographic databases, trial registries and grey literature sources (to 26 November 2020). We checked reference lists and contacted subject experts. SELECTION CRITERIA: We selected randomised controlled trials of medication versus placebo or other medication for TTM in adults, children and adolescents. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: Twelve studies were included. We identified 10 studies in adults (286 participants) with a mean sample size of 29 participants per trial; one study in children and adolescents (39 participants); and, one study in adults and adolescents (22 participants: 18 adults and 4 adolescents). All studies were single-centre, outpatient trials. Eleven studies compared medication and placebo (334 participants); one study compared two medications (13 participants). Studies were 5 to 13 weeks duration. We undertook meta-analysis only for opioid antagonists as other comparisons contained a single study, or reported insufficient data. Antioxidants versus placebo in adults There was little to no difference in treatment response between antioxidant (35.7%) and placebo groups (28.6%) after six weeks, based on a single trial of silymarin (risk ratio (RR) 2.25, 95% confidence interval (CI) 0.84 to 5.99; 36 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (18 participants; low-certainty evidence). Antioxidants versus placebo in adolescents There was little to no difference in treatment response between antioxidant (50%) and placebo groups (25%) after six weeks, based on a single trial of silymarin (RR 2.00, 95% CI 0.28 to 14.20; 8 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (8 participants; low-certainty evidence). Antipsychotics versus placebo in adults There may be greater treatment response in the antipsychotic group (85%) compared to the placebo group (17%) after 12 weeks, based on a single trial of olanzapine (RR 5.08, 95% CI 1.4 to 18.37; 25 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (25 participants; low-certainty evidence). Cell signal transducers versus placebo in adults There was little to no difference in treatment response between cell signal transducer (42.1%) and placebo groups (31.6%) after 10 weeks, based on a single trial of inositol (RR 1.33, 95% CI 0.57 to 3.11; 38 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (38 participants; low-certainty evidence). Glutamate modulators versus placebo in adults There is probably greater treatment response in the glutamate modulator group (56%) compared to the placebo group (16%) after 12 weeks, based on a single trial of N-acetylcysteine (RR 3.5, 95% CI 1.34 to 9.17; 50 participants; moderate-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (50 participants; low-certainty evidence). Glutamate modulators versus placebo in children and adolescents There was little to no difference in treatment response between the glutamate modulator (25%) and placebo groups (21.1%) in children and adolescents, based on a single trial of N-acetylcysteine (RR 1.19, 95% CI 0.37 to 3.77; 39 participants; low-certainty evidence). There was little to no difference in dropouts due to adverse events between glutamate modulator (5%) and placebo (0%) groups, based on a single trial (RR 2.86, 95% CI 0.12 to 66.11; 39 participants; low-certainty evidence). Opioid antagonists versus placebo in adults There may be little to no difference in treatment response between opioid antagonist (37.5%) and placebo groups (25%) after six to eight weeks, based on two studies of naltrexone, but the evidence is very uncertain (RR 2.14, 95% CI 0.25 to 18.17; 2 studies, 68 participants; very low-certainty evidence). No data were available regarding dropouts due to adverse events. Selective serotonin reuptake inhibitors (SSRIs) versus placebo in adults There were no data available for treatment response to SSRIs. There was little to no difference in dropouts due to adverse events in the SSRI group (5.1%) compared to the placebo group (0%) after 6 to 12 weeks, based on two trials of fluoxetine (RR 3.00, 95% CI 0.33 to 27.62; 2 studies, 78 participants; low-certainty evidence). Tricyclic antidepressants (TCAs) with predominantly serotonin reuptake inhibitor (SRI) actions versus placebo in adults There may be greater treatment response in the TCAs with predominantly SRI actions group (40%) compared to the placebo group (0%) after nine weeks, but the evidence is very uncertain, based on a single trial of clomipramine (RR 5.73, 95% CI 0.36 to 90.83; 16 participants; very low-certainty evidence). There may be increased dropouts due to adverse events in the TCAs with predominantly SRI actions group (30%) compared to the placebo group (0%), but the evidence is very uncertain (RR 4.45, 95% CI 0.27 to 73.81; 16 participants; very low-certainty evidence). TCAs with predominantly SRI actions versus other TCAs in adults There may be greater treatment response in the TCAs with predominantly SRI actions group compared to the other TCAs group after five weeks, based on a single trial comparing clomipramine to desipramine (mean difference (MD) -4.00, 95% CI -6.13 to -1.87; 26 participants; low-certainty evidence). We could not calculate differences in number of dropouts as there were no events in either group (26 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There was insufficient evidence from meta-analysis to confirm or refute the efficacy of any agent or class of medication for the treatment of TTM in adults, children or adolescents. Preliminary evidence suggests there may be beneficial treatment effects for N-acetylcysteine, clomipramine and olanzapine in adults based on four trials, albeit with relatively small sample sizes.

The association of peripheral immune markers with brain cortical thickness and surface area in South African people living with HIV.

A spectrum of cognitive impairments known as HIV-associated neurocognitive disorders (HAND) are consequences of the effects of HIV-1 within the central nervous system. Regardless of treatment status, an aberrant chronic neuro-immune regulation is a crucial contributor to the development of HAND. However, the extent to which inflammation affects brain structures critical for cognitive status remains unclear. The present study aimed to determine associations of peripheral immune markers with cortical thickness and surface area. Participants included 65 treatment-naïve HIV-positive individuals and 26 HIV-negative controls. Thickness and surface area of all cortical regions were derived using automated parcellation of T1-weighted images acquired at 3 T. Peripheral immune markers included C-C motif ligand 2 (CCL2), matrix metalloproteinase 9 (MMP9), neutrophil gelatinase-associated lipocalin (NGAL), thymidine phosphorylase (TYMP), transforming growth factor (TGF)-ß1, and vascular endothelial growth factor (VEGF), which were measured using enzyme-linked immunosorbent assays. Associations of these markers with thickness and surface area of cortical regions were evaluated. A mediation analysis examined whether associations of inflammatory markers with cognitive functioning were mediated by brain cortical thickness and surface area. After controlling for multiple comparisons, higher NGAL was associated with reduced thickness of the bilateral orbitofrontal cortex in HIV-positive participants. The association of NGAL with worse motor function was mediated by cortical thickness of the bilateral orbitofrontal region. Taken together, this study suggests that NGAL plays a potential role in the neuropathophysiology of neurocognitive impairments of HIV.

Distinct intrinsic functional brain network abnormalities in methamphetamine-dependent patients with and without a history of psychosis.

Chronic methamphetamine use is associated with executive functioning deficits that suggest dysfunctional cognitive control networks (CCNs) in the brain. Likewise, abnormal connectivity between intrinsic CCNs and default mode networks (DMNs) has also been associated with poor cognitive function in clinical populations. Accordingly, we tested the extent to which methamphetamine use predicts abnormal connectivity between these networks, and whether, as predicted, these abnormalities are compounded in patients with a history of methamphetamine-associated psychosis (MAP). Resting-state fMRI data were acquired from 46 methamphetamine-dependent patients [19 with MAP, 27 without (MD)], as well as 26 healthy controls (CTRL). Multivariate network modelling and whole-brain voxel-wise connectivity analyses were conducted to identify group differences in intrinsic connectivity across four cognitive control and three DMN networks identified using an independent components analysis approach (meta-ICA). The relationship of network connectivity and psychotic symptom severity, as well as antipsychotic treatment and methamphetamine use variables, was also investigated. Robust evidence of hyper-connectivity was observed between the right frontoparietal and anterior DMN networks in MAP patients, and 'normalized' with increased duration of treatment with antipsychotics. Attenuation of anticorrelated anterior DMN-dorsal attention network activity was also restricted to this group. Elevated coupling detected in MD participants between anterior and posterior DMN networks became less apparent with increasing duration of abstinence from methamphetamine. In summary, we observed both alterations of RSN connectivity between DMN networks with chronic methamphetamine exposure, as well as DMN-CCN coupling abnormalities consistent with possible MAP-specific frontoparietal deficits in the biasing of task-appropriate network activity.

Social cognition and aggression in methamphetamine dependence with and without a history of psychosis.

In substance use and psychotic disorders, socially problematic behaviours, such as high aggression may, in part, be explained by deficits in social cognition skills, like the detection of emotions or intentions in others. The aim of this study was to assess the magnitude of social cognition impairment and its association with aggression in individuals with methamphetamine (MA) dependence, methamphetamine-associated psychosis (MAP), and healthy controls (CTRL). A total of 20 MAP participants, 21 MA-dependent participants without psychosis, and 21 CTRL participants performed a facial morphing emotion recognition task (ERT) across four basic emotions (anger, fear, happiness and sadness) and the reading the mind in the eyes task (RMET), and completed the aggression questionnaire. Both MA-dependent groups showed impairment in social cognition in terms of lower RMET scores relative to CTRL participants (MA; p = .047; MAP: p < .001). Additionally, performance decrements were significantly greater in MAP (p = .040), compared to MA-dependent participants. While deficits in recognising emotional expressions were restricted to anger in the MA group (p = .020), a generalized impairment across all four emotions was observed in MAP (all p ≤ .001). Additionally, both patient groups demonstrated higher levels of aggression than CTRLs, yet no association was found with social cognition. This study supported the notion of deficits in recognising facial emotional expressions and inferring mental states of others in MA dependence, with additional impairments in MAP. Failure to detect an association between social cognitive impairment and aggressive behaviour may implicate independent disturbances of the two phenomena in MA dependence.

Pharmacotherapy for social anxiety disorder (SAnD).

BACKGROUND: Recognition is growing that social anxiety disorder (SAnD) is a chronic and disabling disorder, and data from early trials demonstrate that medication may be effective in its treatment. This systematic review is an update of an earlier review of pharmacotherapy of SAnD. OBJECTIVES: To assess the effects of pharmacotherapy for social anxiety disorder in adults and identify which factors (methodological or clinical) predict response to treatment. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR-Studies and CCMDCTR-References) to 17 August 2015. The CCMDCTR contains reports of relevant RCTs from MEDLINE (1950-), Embase (1974-), PsycINFO (1967-) and CENTRAL (all years). We scanned the reference lists of articles for additional studies. We updated the search in August 2017 and placed additional studies in Awaiting Classification, these will be incorporated in the next version of the review, as appropriate. SELECTION CRITERIA: We restricted studies to randomised controlled trials (RCTs) of pharmacotherapy versus placebo in the treatment of SAnD in adults. DATA COLLECTION AND ANALYSIS: Two authors (TW and JI) assessed trials for eligibility and inclusion for this review update. We extracted descriptive, methodological and outcome information from each trial, contacting investigators for missing information where necessary. We calculated summary statistics for continuous and dichotomous variables (if provided) and undertook subgroup and sensitivity analyses. MAIN RESULTS: We included 66 RCTs in the review (> 24 weeks; 11,597 participants; age range 18 to 70 years) and 63 in the meta-analysis. For the primary outcome of treatment response, we found very low-quality evidence of treatment response for selective serotonin reuptake inhibitors (SSRIs) compared with placebo (number of studies (k) = 24, risk ratio (RR) 1.65; 95% confidence interval (CI) 1.48 to 1.85, N = 4984). On this outcome there was also evidence of benefit for monoamine oxidase inhibitors (MAOIs) (k = 4, RR 2.36; 95% CI 1.48 to 3.75, N = 235), reversible inhibitors of monoamine oxidase A (RIMAs) (k = 8, RR 1.83; 95% CI 1.32 to 2.55, N = 1270), and the benzodiazepines (k = 2, RR 4.03; 95% CI 2.45 to 6.65, N = 132), although the evidence was low quality. We also found clinical response for the anticonvulsants with gamma-amino butyric acid (GABA) analogues (k = 3, RR 1.60; 95% CI 1.16 to 2.20, N = 532; moderate-quality evidence). The SSRIs were the only medication proving effective in reducing relapse based on moderate-quality evidence. We assessed tolerability of SSRIs and the serotonin and norepinephrine reuptake inhibitor (SNRI) venlafaxine on the basis of treatment withdrawal; this was higher for medication than placebo (SSRIs: k = 24, RR 2.59; 95% CI 1.97 to 3.39, N = 5131, low-quality evidence; venlafaxine: k = 4, RR 3.23; 95% CI 2.15 to 4.86, N = 1213, moderate-quality evidence), but there were low absolute rates of withdrawal for both these medications classes compared to placebo. We did not find evidence of a benefit for the rest of the medications compared to placebo.For the secondary outcome of SAnD symptom severity, there was benefit for the SSRIs, the SNRI venlafaxine, MAOIs, RIMAs, benzodiazepines, the antipsychotic olanzapine, and the noradrenergic and specific serotonergic antidepressant (NaSSA) atomoxetine in the reduction of SAnD symptoms, but most of the evidence was of very low quality. Treatment with SSRIs and RIMAs was also associated with a reduction in depression symptoms. The SSRIs were the only medication class that demonstrated evidence of reduction in disability across a number of domains.We observed a response to long-term treatment with medication for the SSRIs (low-quality evidence), for the MAOIs (very low-quality evidence) and for the RIMAs (moderate-quality evidence). AUTHORS' CONCLUSIONS: We found evidence of treatment efficacy for the SSRIs, but it is based on very low- to moderate-quality evidence. Tolerability of SSRIs was lower than placebo, but absolute withdrawal rates were low.While a small number of trials did report treatment efficacy for benzodiazepines, anticonvulsants, MAOIs, and RIMAs, readers should consider this finding in the context of potential for abuse or unfavourable side effects.

Interhemispheric Functional Brain Connectivity in Neonates with Prenatal Alcohol Exposure: Preliminary Findings.

BACKGROUND: Children exposed to alcohol in utero demonstrate reduced white matter microstructural integrity. While early evidence suggests altered functional brain connectivity in the lateralization of motor networks in school-age children with prenatal alcohol exposure (PAE), the specific effects of alcohol exposure on the establishment of intrinsic connectivity in early infancy have not been explored. METHODS: Sixty subjects received functional imaging at 2 to 4 weeks of age for 6 to 8 minutes during quiet natural sleep. Thirteen alcohol-exposed (PAE) and 14 age-matched control (CTRL) participants with usable data were included in a multivariate model of connectivity between sensorimotor intrinsic functional connectivity networks. Seed-based analyses of group differences in interhemispheric connectivity of intrinsic motor networks were also conducted. The Dubowitz neurological assessment was performed at the imaging visit. RESULTS: Alcohol exposure was associated with significant increases in connectivity between somatosensory, motor networks, brainstem/thalamic, and striatal intrinsic networks. Reductions in interhemispheric connectivity of motor and somatosensory networks did not reach significance. CONCLUSIONS: Although results are preliminary, findings suggest PAE may disrupt the temporal coherence in blood oxygenation utilization in intrinsic networks underlying motor performance in newborn infants. Studies that employ longitudinal designs to investigate the effects of in utero alcohol exposure on the evolving resting-state networks will be key in establishing the distribution and timing of connectivity disturbances already described in older children.

HIV infection is associated with attenuated frontostriatal intrinsic connectivity: a preliminary study.

HIV-associated cognitive impairments are prevalent, and are consistent with injury to both frontal cortical and subcortical regions of the brain. The current study aimed to assess the association of HIV infection with functional connections within the frontostriatal network, circuitry hypothesized to be highly vulnerable to HIV infection. Fifteen HIV-positive and 15 demographically matched control participants underwent 6 min of resting-state functional magnetic resonance imaging (RS-fMRI). Multivariate group comparisons of age-adjusted estimates of connectivity within the frontostriatal network were derived from BOLD data for dorsolateral prefrontal cortex (DLPFC), dorsal caudate and mediodorsal thalamic regions of interest. Whole-brain comparisons of group differences in frontostriatal connectivity were conducted, as were pairwise tests of connectivity associations with measures of global cognitive functioning and clinical and immunological characteristics (nadir and current CD4 count, duration of HIV infection, plasma HIV RNA). HIV - associated reductions in connectivity were observed between the DLPFC and the dorsal caudate, particularly in younger participants (<50 years, N=9). Seropositive participants also demonstrated reductions in dorsal caudate connectivity to frontal and parietal brain regions previously demonstrated to be functionally connected to the DLPFC. Cognitive impairment, but none of the assessed clinical/immunological variables, was also associated with reduced frontostriatal connectivity. In conclusion, our data indicate that HIV is associated with attenuated intrinsic frontostriatal connectivity. Intrinsic connectivity of this network may therefore serve as a marker of the deleterious effects of HIV infection on the brain, possibly via HIV-associated dopaminergic abnormalities. These findings warrant independent replication in larger studies.

Pharmacotherapy for anxiety and comorbid alcohol use disorders.

BACKGROUND: Anxiety disorders are a potentially disabling group of disorders that frequently co-occur with alcohol use disorders. Comorbid anxiety and alcohol use disorders are associated with poorer outcomes, and are difficult to treat with standard psychosocial interventions. In addition, improved understanding of the biological basis of the conditions has contributed to a growing interest in the use of medications for the treatment of people with both diagnoses. OBJECTIVES: To assess the effects of pharmacotherapy for treating anxiety in people with comorbid alcohol use disorders, specifically: to provide an estimate of the overall effects of medication in improving treatment response and reducing symptom severity in the treatment of anxiety disorders in people with comorbid alcohol use disorders; to determine whether specific medications are more effective and tolerable than other medications in the treatment of particular anxiety disorders; and to identify which factors (clinical, methodological) predict response to pharmacotherapy for anxiety disorders. SEARCH METHODS: Review authors searched the specialized registers of The Cochrane Collaboration Depression, Anxiety and Neurosis Review Group (CCDANCTR, to January 2014) and the Cochrane Drugs and Alcohol Group (CDAG, to March 2013) for eligible trials. These registers contain reports of relevant randomized controlled trials (RCT) from: the Cochrane Central Register of Controlled Trials (CENTRAL, all years), MEDLINE (1950 to date), EMBASE (1974 to date) and PsycINFO (1967 to date). Review authors ran complementary searches on EMBASE, PubMed, PsycINFO and the Alcohol and Alcohol Problems Science Database (ETOH) (to August 2013). We located unpublished trials through the National Institutes of Health (NIH) RePORTER service and the World Health Organization (WHO) International Clinical Trials Registry Platform (to August 2013). We screened reference lists of retrieved articles for additional studies. SELECTION CRITERIA: All true RCTs of pharmacotherapy for treating anxiety disorders with comorbid alcohol use disorders. Trials assessing drugs administered for the treatment of drinking behaviour, such as naltrexone, disulfiram and acomprosate were not eligible for inclusion in this systematic review. DATA COLLECTION AND ANALYSIS: A systematic review is a standardised evaluation of all research studies that address a particular clinical issue.Two review authors independently assessed RCTs for inclusion in the review, collated trial data and assessed trial quality. We contacted investigators to obtain missing data. We calculated categorical and continuous treatment effect estimates and their 95% confidence intervals (CI) for treatment using a random-effects model with effect-size variability expressed using Chi(2) and I(2) heterogeneity statistics. MAIN RESULTS: We included five placebo-controlled pharmacotherapy RCTs (with 290 participants) in the review. Most of the trials provided little information on how randomization was performed or on whether both participants and study personnel were blinded to the intervention. Two of the three trials reporting superiority of medication compared with placebo on anxiety symptom outcomes were industry funded. We regarded one trial as being at high risk of bias due to selective reporting.Study participants had Diagnostic and Statistical Manual (DSM) III- and DSM IV-diagnosed alcohol use disorders and post-traumatic stress disorder (two studies), social anxiety disorder (SAD; two studies) or generalized anxiety disorder (GAD; one study). Four trials assessed the efficacy of the selective serotonin re-uptake inhibitors (SSRIs: sertraline, paroxetine); one RCT investigated the efficacy of buspirone, a 5-hydroxytryptamine (5-HT) partial agonist. Treatment duration lasted between eight and 24 weeks. Overall, 70% of participants included in the review were male.There was very low quality evidence for an effect of paroxetine on global clinical response to treatment, as assessed by the Clinical Global Impressions - Improvement scale (CGI-I). Global clinical response was observed in more than twice as many participants with paroxetine than with placebo (57.7% with paroxetine versus 25.8% with placebo; risk ratio (RR) 2.23, 95% CI 1.13 to 4.41; 2 trials, 57 participants). However, there was substantial uncertainty regarding the size of the effect of paroxetine due to the small number of studies providing data on clinically diverse patient samples. The second primary outcome measure was reduction of anxiety symptom severity. Although study investigators reported that buspirone (one trial) was superior to placebo in reducing the severity of anxiety symptoms over 12 weeks, no evidence of efficacy was observed for paroxetine (mean difference (MD) -14.70, 95% CI -33.00 to 3.60, 2 trials, 44 participants) and sertraline (one trial). Paroxetine appeared to be equally effective in reducing the severity of post-traumatic stress disorder (PTSD) symptoms as the tricyclic antidepressant desipramine in one RCT. The maximal reduction in anxiety disorder symptom severity was achieved after six weeks with paroxetine (two RCTs) and 12 weeks with buspirone (one RCT), with maintenance of medication efficacy extending to 16 with paroxetine and 24 weeks with buspirone. There was no evidence of an effect for any of the medications tested on abstinence from alcohol use or depression symptoms. There was very low quality evidence that paroxetine was well tolerated, based on drop-out due to treatment-emergent adverse effects. Nevertheless, levels of treatment discontinuation were high, with 43.1% of the participants in the studies withdrawing from medication treatment. Certain adverse effects, such as sexual problems, were commonly reported after treatment with paroxetine and sertraline. AUTHORS' CONCLUSIONS: The evidence-base for the effectiveness of medication in treating anxiety disorders and comorbid alcohol use disorders is currently inconclusive. There was a small amount of evidence for the efficacy of medication, but this was limited and of very low quality. The majority of the data for the efficacy and tolerability of medication were for SSRIs; there were insufficient data to establish differences in treatment efficacy between medication classes or patient subgroups. There was a small amount of very low quality evidence that medication was well tolerated. There was no evidence that alcohol use was responsive to medication.Large, rigorously conducted RCTs would help supplement the small evidence-base for the efficacy and tolerability of pharmacotherapy for anxiety and comorbid alcohol use disorders. Further research on patient subgroups who may benefit from pharmacological treatment, as well as novel pharmacological interventions, is warranted.

Augmentation of cognitive and behavioural therapies (CBT) with d-cycloserine for anxiety and related disorders.

BACKGROUND: A significant number of patients who suffer with anxiety and related disorders (that is post-traumatic stress disorder (PTSD), social anxiety disorder (SAnD), panic disorder with or without agoraphobia (PD), specific phobia (SPh) and obsessive compulsive disorder (OCD)) fail to respond optimally to first-line treatment with medication or cognitive and behavioural therapies. The addition of d-cycloserine (DCS) to cognitive and behavioural therapies may improve treatment response by impacting the glutamatergic system. This systematic review aimed to investigate the effects of adding DCS to cognitive and behavioural therapies by synthesising data from relevant randomised controlled trials and following the guidelines recommended by Cochrane. OBJECTIVES: To assess the effect of DCS augmentation of cognitive and behavioural therapies compared to placebo augmentation of cognitive and behavioural therapies in the treatment of anxiety and related disorders. Additionally, to assess the efficacy and tolerability of DCS across different anxiety and related disorders. SEARCH METHODS: This review fully incorporates studies identified from a search of the Cochrane Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) to 12 March 2015. This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date), PsycINFO (1967 to date), the World Health Organization's trials portal (ICTRP) and ClinicalTrials.gov . Reference lists from previous meta-analyses and reports of RCTs were also checked. No restrictions were placed on language, setting, date or publication status. SELECTION CRITERIA: All RCTs of DCS augmentation of cognitive and behavioural therapies versus placebo augmentation of cognitive and behavioural therapies for anxiety and related disorders were included. DATA COLLECTION AND ANALYSIS: Two authors (RO and TA) independently assessed RCTs for eligibility and inclusion, extracted outcomes and risk of bias data and entered these into a customised extraction form. Investigators were contacted to obtain missing data. In addition, data entry and analysis were performed by two review authors (KSW and HB). MAIN RESULTS: Twenty-one published RCTs, with 788 participants in outpatient settings, were included in the review. Sixteen studies had an age range of 18 to 75 years, while four investigated paediatric populations aged 8 to 17 years and one included children, adolescents and adults. The 21 RCTs investigated OCD (number of RCTs (N) = 6), PTSD (N = 5), SAnD (N = 5), SPh (N = 3) and PD (N = 2). Most information from the studies was rated as having either low risk or unclear risk of bias.There was no evidence of a difference between DCS augmentation of cognitive and behavioural therapies and placebo augmentation of cognitive and behavioural therapies for the treatment of anxiety and related disorders in adults at the endpoint (treatment responders, N = 9, risk ratio (RR) 1.10; 95% confidence interval (CI) 0.89 to 1.34; number of participants (n) = 449; low quality evidence) and between 1 and 12 months follow-up (N = 7, RR 1.08; 95% CI 0.90 to 1.31; n = 383). DCS augmentation of cognitive and behavioural therapies was not superior to placebo augmentation of cognitive and behavioural therapies for children and adolescents, both at the endpoint (N = 4, RR 1.01; 95% CI 0.78 to 1.31; n = 121; low quality evidence) and between 3 and 12 months follow-up (N = 3, RR 0.86; 95% CI 0.67 to 1.09; n = 91).There was no evidence of a difference in treatment acceptability for DCS augmentation of cognitive and behavioural therapies compared with placebo augmentation of cognitive and behavioural therapies in adults (N = 16, RR 0.88; 95% CI 0.61 to 1.25; n = 740), nor in children and adolescents (N = 4, RR 0.90; 95% CI 0.17 to 4.69; n = 131). These conclusions were based on moderate quality evidence for adults, and very low quality evidence for children and adolescents. Although the observed difference was small, it is noteworthy that there was a high efficacy of exposure-based therapies alone in the included trials. Due to the limited number of studies, subgroup analysis of moderating factors for clinical and methodological effect could not take place. AUTHORS' CONCLUSIONS: This review found no evidence of a difference between DCS augmentation of cognitive and behavioural therapies and placebo augmentation of cognitive and behavioural therapies for treating anxiety and related disorders in children, adolescents and adults. These findings are based on low quality evidence from heterogenous studies with small sample sizes and incomplete data for clinical response, which precludes us from drawing conclusions on the use of DCS augmentation of cognitive and behavioural therapies at this stage. Given there is some promising preliminary data from individual studies, further research is necessary to assess DCS compared with placebo augmentation of cognitive and behavioural therapies, and determine mechanisms of action as well as magnitude of effect in anxiety and related disorders.

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD).

BACKGROUND: Post-traumatic stress disorder (PTSD) is a debilitating disorder which, after a sufficient delay, may be diagnosed amongst individuals who respond with intense fear, helplessness or horror to traumatic events. There is some evidence that the use of pharmacological interventions immediately after exposure to trauma may reduce the risk of developing of PTSD. OBJECTIVES: To assess the effects of pharmacological interventions for the prevention of PTSD in adults following exposure to a traumatic event. SEARCH METHODS: We searched the Cochrane Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR-Studies and CCDANCTR-References) (to 14 February 2014). This register contains relevant reports of randomised controlled trials from the following bibliographic databases: CENTRAL (all years); EMBASE (1974 to date); MEDLINE (1950 to date) and PsycINFO (1967 to date). We identified unpublished trials by searching the National Institute of Health (NIH) Reporter, the metaRegister of Controlled Trials database (mRCT) and the WHO International Clinical Trials Registry Platform (to December 2013). We scanned the reference lists of articles for additional studies. We placed no constraints on language and setting. SELECTION CRITERIA: We restricted studies to randomised controlled trials (RCTs) of pharmacological interventions compared with placebo for the prevention of PTSD in adults. DATA COLLECTION AND ANALYSIS: Two authors (TA and JI) independently assessed trials for eligibility and inclusion based on the review selection criteria. We independently extracted sample, methodological, outcome and 'Risk of bias' data, as well as the number of side effects, from each trial and entered these into a customised data extraction form. We contacted investigators for missing information. We calculated summary statistics for continuous and dichotomous variables (if provided). We did not undertake subgroup analyses due to the small number of included studies. MAIN RESULTS: We included nine short-term RCTs (duration 12 weeks or less) in the analysis (345 participants; age range 18 to 76 years). Participants were exposed to a variety of traumas, ranging from assault, traffic accidents and work accidents to cardiac surgery and septic shock. Seven studies were conducted at single centres. The seven RCTs included four hydrocortisone studies, three propranolol studies (of which one study had a third arm investigating gabapentin), and single trials of escitalopram and temazepam. Outcome assessment measures included the Clinician-Administered PTSD Scale (CAPS), the 36-Item Short-Form Health Survey (SF-36) and the Center for Epidemiological Studies - Depression Scale (CES-D).In four trials with 165 participants there was moderate quality evidence for the efficacy of hydrocortisone in preventing the onset of PTSD (risk ratio (RR) 0.17; 95% confidence interval (CI) 0.05 to 0.56; P value = 0.004), indicating that between seven and 13 patients would need to be treated with this agent in order to prevent the onset of PTSD in one patient. There was low quality evidence for preventing the onset of PTSD in three trials with 118 participants treated with propranolol (RR 0.62; 95% CI 0.24 to 1.59; P value = 0.32). Drop-outs due to treatment-emergent side effects, where reported, were low for all of the agents tested. Three of the four RCTs of hydrocortisone reported that medication was more effective than placebo in reducing PTSD symptoms after a median of 4.5 months after the event. None of the single trials of escitalopram, temazepam and gabapentin demonstrated evidence that medication was superior to placebo in preventing the onset of PTSD.Seven of the included RCTs were at a high risk of bias. Differential drop-outs between groups undermined the results of three studies, while one study failed to describe how the allocation of medication was concealed. Other forms of bias that might have influenced study results included possible confounding through group differences in concurrent medication and termination of the study based on treatment response. AUTHORS' CONCLUSIONS: There is moderate quality evidence for the efficacy of hydrocortisone for the prevention of PTSD development in adults. We found no evidence to support the efficacy of propranolol, escitalopram, temazepam and gabapentin in preventing PTSD onset. The findings, however, are based on a few small studies with multiple limitations. Further research is necessary in order to determine the efficacy of pharmacotherapy in preventing PTSD and to identify potential moderators of treatment effect.

Examining the association between posttraumatic stress disorder and disruptions in cortical networks identified using data-driven methods.

Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.

Pharmacotherapy for trichotillomania.

BACKGROUND: Trichotillomania (TTM) (hair-pulling disorder) is a prevalent and disabling disorder characterised by recurrent hair-pulling. The effect of medication on trichotillomania has not been systematically evaluated. OBJECTIVES: To assess the effects of medication for trichotillomania in adults compared with placebo or other active agents. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials and the Cochrane Depression, Anxiety and Neurosis Group Register (to 31 July 2013), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years); EMBASE (1974 to date); MEDLINE (1950 to date) and PsycINFO (1967 to date). Two review authors identified relevant trials by assessing the abstracts of all possible studies. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) of a medication versus placebo or active agent for TTM in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the data extraction and 'Risk of bias' assessments, and disagreements were resolved through discussion with a third review author. Primary outcomes included the mean difference (MD) in reduction of trichotillomania symptoms on a continuous measure of trichotillomania symptom severity, and the risk ratio (RR) of the clinical response based on a dichotomous measure, with 95% confidence intervals (CIs). MAIN RESULTS: We identified eight studies with a total of 204 participants and a mean sample size of 25. All trials were single-centre trials, and participants seen on an outpatient basis. Seven studies compared medication and placebo (n = 184); one study compared medication and another active agent (n = 13). Duration of the studies was six to twelve weeks. Meta-analysis was not undertaken because of the methodological heterogeneity of the trials. The studies did not employ intention-to-treat analyses and were at a high risk of attrition bias. Adverse events were not well-documented in the studies.None of the three studies of selective serotonin reuptake inhibitors (SSRIs) demonstrated strong evidence of a treatment effect on any of the outcomes of interest. The unpublished naltrexone study did not provide strong evidence of a treatment effect. Two studies, an olanzapine study and a N-acetylcysteine (NAC) study, reported statistically significant treatment effects. One study of clomipramine demonstrated a treatment effect on two out of three measures of response to treatment. AUTHORS' CONCLUSIONS: No particular medication class definitively demonstrates efficacy in the treatment of trichotillomania. Preliminary evidence suggests treatment effects of clomipramine, NAC and olanzapine based on three individual trials, albeit with very small sample sizes.

Meta-analysis of functional brain imaging in specific phobia.

Although specific phobia is a prevalent anxiety disorder, evidence regarding its underlying functional neuroanatomy is inconsistent. A meta-analysis was undertaken to identify brain regions that were consistently responsive to phobic stimuli, and to characterize changes in brain activation following cognitive behavioral therapy (CBT). We searched the PubMed, SCOPUS and PsycINFO databases to identify positron emission tomography and functional magnetic resonance imaging studies comparing brain activation in specific phobia patients and healthy controls. Two raters independently extracted study data from all the eligible studies, and pooled coordinates from these studies using activation likelihood estimation, a quantitative meta-analytic technique. Resulting statistical parametric maps were compared between patients and healthy controls, in response to phobic versus fear-evoking stimuli, and before and after therapy. Thirteen studies were included, comprising 327 participants. Regions that were consistently activated in response to phobic stimuli included the left insula, amygdala, and globus pallidus. Compared to healthy controls, phobic subjects had increased activation in response to phobic stimuli in the left amygdala/globus pallidus, left insula, right thalamus (pulvinar), and cerebellum. Following exposure-based therapy widespread deactivation was observed in the right frontal cortex, limbic cortex, basal ganglia and cerebellum, with increased activation detected in the thalamus. Exposure to phobia-specific stimuli elicits brain activation that is consistent with current understandings of the neuroanatomy of fear conditioning and extinction. There is evidence that the effects of CBT in specific phobia may be mediated through the same underlying neurocircuitry.

PTSD and comorbid MDD is associated with activation of the right frontoparietal network.

There is growing evidence of abnormalities in intrinsic functional connectivity (FC) in posttraumatic stress disorder (PTSD) and major depressive disorder (MDD). However, there has been less work on the commonly occurring co-presentation of PTSD and MDD. Characterising intrinsic FC abnormalities in this clinical population is important for understanding how they may contribute towards impairments underpinned by different networks. Participants were mothers enroled in the Drakenstein Child Health Study from Western Cape, South Africa. Mothers between 18 and 50 years of age were recruited and divided into 4 groups: PTSD, MDD, PTSD with MDD, and healthy controls. Participants underwent resting-state fMRI at the 18-month postpartum time point. Functional connectivity within and between higher order cognitive control networks, including the salience, dorsal attention, frontoparietal, and default mode networks were compared across the 4 groups. PTSD with comorbid MDD was associated with greater intrinsic FC within the R FPAR, relative to controls and the mono-diagnostic groups. Intrinsic FC differences were observed within the default mode network for the MDD group. No group differences in connectivity between networks were observed. Differential intrinsic connectivity in participants with comorbidity are consistent with evidence that such individuals have more severe illness and require more robust intervention.

Advanced brain ageing in adult psychopathology: A systematic review and meta-analysis of structural MRI studies.

Evidence suggests that psychopathology is associated with an advanced brain ageing process, typically mapped using machine learning models that predict an individual's age based on structural neuroimaging data. The brain predicted age difference (brain-PAD) captures the deviation of brain age from chronological age. Substantial heterogeneity between studies has introduced uncertainty regarding the magnitude of the brain-PAD in adult psychopathology. The present meta-analysis aimed to quantify structural MRI-based brain-PAD in adult psychotic and mood disorders, while addressing possible sources of heterogeneity related to diagnosis subtypes, segmentation method, age and sex. Clinical factors influencing brain ageing in axis 1 psychiatric disorders were systematically reviewed. Thirty-three studies were included for review. A random-effects meta-analysis revealed a brain-PAD of +3.12 (standard error = 0.49) years in psychotic disorders (n = 16 studies), +2.04 (0.10) years in bipolar disorder (n = 5), and +0.90 (0.20) years in major depression (n = 7). An exploratory meta-analysis found a brain-PAD of +1.57 (0.67) in first episode psychosis (n = 4), which was smaller than that observed in psychosis and schizophrenia (n = 10, +3.87 (0.61)). Patient mean age significantly explained heterogeneity in effect size estimates in psychotic disorders, but not mood disorders. The systematic review determined that clinical factors, such as higher symptom severity, may be associated with a larger brain-PAD in psychopathology. In conclusion, larger structural MRI-based brain-PAD was confirmed in adult psychopathology. Preliminary evidence was obtained that brain ageing is greater in those with prolonged duration of psychotic disorders. Accentuated brain ageing may underlie the cognitive difficulties experienced by some patients, and may be progressive in nature.