Contextualizing the impact of prenatal alcohol and tobacco exposure on neurodevelopment in a South African birth cohort: an analysis from the socioecological perspective.

Background: Alcohol and tobacco are known teratogens. Historically, more severe prenatal alcohol exposure (PAE) and prenatal tobacco exposure (PTE) have been examined as the principal predictor of neurodevelopmental alterations, with little incorporation of lower doses or ecological contextual factors that can also impact neurodevelopment, such as socioeconomic resources (SER) or adverse childhood experiences (ACEs). Here, a novel analytical approach informed by a socio-ecological perspective was used to examine the associations between SER, PAE and/or PTE, and ACEs, and their effects on neurodevelopment. Methods: N = 313 mother-child dyads were recruited from a prospective birth cohort with maternal report of PAE and PTE, and cross-sectional structural brain neuroimaging of child acquired via 3T scanner at ages 8-11 years. In utero SER was measured by maternal education, household income, and home utility availability. The child's ACEs were measured by self-report assisted by the researcher. PAE was grouped into early exposure (<12 weeks), continued exposure (>=12 weeks), and no exposure controls. PTE was grouped into exposed and non-exposed controls. Results: Greater access to SER during pregnancy was associated with fewer ACEs (maternal education: ß = -0.293,p = 0.01; phone access: ß = -0.968,p = 0.05). PTE partially mediated the association between SER and ACEs, where greater SER reduced the likelihood of PTE, which was positively associated with ACEs (ß = 1.110,p = 0.01). SER was associated with alterations in superior frontal (ß = -1336.036, q = 0.046), lateral orbitofrontal (ß = -513.865, q = 0.046), caudal anterior cingulate volumes (ß = -222.982, q = 0.046), with access to phone negatively associated with all three brain volumes. Access to water was positively associated with superior frontal volume (ß=1569.527, q = 0.013). PTE was associated with smaller volumes of lateral orbitofrontal (ß = -331.000, q = 0.033) and nucleus accumbens regions (ß = -34.800, q = 0.033). Conclusion: Research on neurodevelopment following community-levels of PAE and PTE should more regularly consider the ecological context to accelerate understanding of teratogenic outcomes. Further research is needed to replicate this novel conceptual approach with varying PAE and PTE patterns, to disentangle the interplay between dose, community-level and individual-level risk factors on neurodevelopment.

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.

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.

Peripheral immune dysregulation in the ART era of HIV-associated neurocognitive impairments: A systematic review.

Human immunodeficiency virus-associated neurocognitive impairment (HANI) remains problematic despite the effective use of antiretroviral therapy (ART) and viral suppression. A dysregulated immune response contributes to the development of HANI but findings on the association between peripheral blood immune markers and HANI have been inconsistent. We therefore conducted a systematic review of studies of the association of peripheral blood immune markers with neurocognitive performance in ART experienced HIV-positive participants. Thirty-seven studies were eligible, including 12 longitudinal studies and 25 cross-sectional studies. Findings consistently show that HIV-positive participants have altered immune marker levels, including elevated markers of monocyte activation (neopterin, sCD14, sCD163) and inflammation (CCL2, IL-8, IL-18, IP-10, IFN-α, sTNFR-II and TNF-α). These elevated levels persist in HIV-positive participants despite ART. The majority of studies found associations of HANI with immune markers, including those linked to monocyte activation (sCD14 and sCD163) and inflammation (IL-18 and IP-10). Despite the heterogeneity of studies reviewed, due to the presence of raised peripheral markers, our narrative review provides evidence of chronic inflammation despite ART. The raised levels of these markers may suggest certain mechanisms are active, potentially those involved in the neuropathophysiology of HANI.

The Association of Immune Markers with Cognitive Performance in South African HIV-Positive Patients.

Dysregulated expression of neuro-immune markers has previously been linked to HIV-associated neurocognitive impairment. We undertook an exploratory approach in a HIV clade-C cohort, investigating the association between eight immune markers and neurocognitive performance in 99 HIV+ and 51 HIV- participants. Markers were selected on preliminary and putative evidence of their link to key neuro-immune functions. Cognitive performance was established using a battery of tests sensitive to HIV-associated neurocognitive impairment, with domain-based scores utilized in analysis. The markers Thymidine phosphorylase (TYMP) and Neutrophil gelatinase-associated lipocalin (NGAL) were significantly higher while Matrix Metalloproteinase (MMP)9 was significantly lower in HIV+ participants. Our results further showed that in the HIV+ group, worse psychomotor processing speed was associated with higher TYMP and NGAL levels and worse motor function was associated with higher NGAL levels. Future studies should explore the underlying mechanisms of these markers in HIV-associated neurocognitive impairment. Graphical Abstract The association of peripheral immune markers with neurocognitive performance in South African HIV-positive patients.

Correlates of emotional and behavioural problems in children with perinatally acquired HIV in Cape Town, South Africa.

In the antiretroviral era, youth perinatally infected with HIV (PHIV+) are surviving into adulthood and are at risk for emotional and behavioural problems. Few studies of these problems have been conducted in low- and middle-income countries and even fewer in sub-Saharan Africa. The aims of this study were to provide a quantitative description of emotional and behavioural problems in a group of PHIV+ youth (n = 78) in South Africa compared with a group of demographically matched HIV-negative controls (n = 30) and to identify correlates of emotional and behavioural problems. A cross-sectional study was conducted employing participants from community and hospital-based clinics. Emotional and behavioural problems were assessed using the Child Behaviour Checklist (CBCL). Several measures were used to assess demographic, biological, cognitive and contextual correlates of problem behaviours. Youth were compared by HIV status on demographic, cognitive and contextual variables as well as the Total Problems and subscale scores of the CBCL. Multivariate comparisons of the influence of contextual and cognitive variables on CBCL Total Problems scores were performed using a stepwise linear regression analytic procedure. In this study, there were no significant differences in between-group comparisons for the prevalence of Internalizing, Externalizing and Total Problems in the PHIV+ youth and control group at the clinical and borderline cut-off ranges of the CBCL. Caregiver depression was the only significant predictor of greater Total Problems scores in the full model, after controlling for age and gender (F = 8.57, df = 5.102, P < .01). An interaction between HIV status and caregiver depression was observed (t = -2.20, P = .03), with follow-up within-group analyses confirming that caregiver depression predicted greater Total Problems scores both in HIV-negative youth (ß = 0.61, P < .001), and to a lesser extent, in HIV-positive youth (ß = 0.25, P < .001). This study highlights the need for adequate screening of depression in the caregivers of HIV-infected youth.

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.

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.

Opioids: from physical pain to the pain of social isolation.

The opioid systems play an important role in mediating both physical pain and negative affects (eg, the pain of social isolation). From an evolutionary perspective, it is not surprising that the neurocircuitry and neurochemistry of physical pain would overlap with that involved in complex social emotions. Exposure to trauma as well as a range of gene variants in the opioid system may be associated with alterations in opioid systems function, with changes in reward processing, and with vulnerability to substance abuse. A role for interventions with opioid agents in depression and anxiety disorders has been suggested.