Targeting the glutamatergic system is posited as a potentially novel therapeutic strategy for psychotic disorders. While studies in subjects indicate that antipsychotic medication reduces brain glutamatergic measures, they were unable to disambiguate clinical changes from drug effects.

To address this, we investigated the effects of a dopamine D2 receptor partial agonist (aripiprazole) and a dopamine D2 receptor antagonist (amisulpride) on glutamatergic metabolites in the anterior cingulate cortex (ACC), striatum and thalamus in healthy controls.

A double-blind, within-subject, cross-over, placebo-controlled study design with two arms (n = 25 per arm) was conducted. Healthy volunteers received either aripiprazole (up to 10 mg/day) for 7 days or amisulpride (up to 400 mg/day) and a corresponding period of placebo treatment in a pseudo-randomised order. Magnetic resonance spectroscopy (1H-MRS) was used to measure glutamatergic metabolite levels and was carried out at three different time points: baseline, after 1 week of drug and after 1 week of placebo. Values were analysed as a combined measure across the ACC, striatum and thalamus.

Aripiprazole significantly increased glutamate + glutamine (Glx) levels compared with placebo (β = 0.55, 95% CI [0.15, 0.95], P = 0.007). At baseline, the mean Glx level was 8.14 institutional units (s.d. = 2.15); following aripiprazole treatment, the mean Glx level was 8.16 institutional units (s.d. = 2.40) compared with 7.61 institutional units (s.d. = 2.36) for placebo. This effect remained significant after adjusting for plasma parent and active metabolite drug levels. There was an observed increase with amisulpride that did not reach statistical significance.

One week of aripiprazole administration in healthy participants altered brain Glx levels as compared with placebo administration. These findings provide novel insights into the relationship between antipsychotic treatment and brain metabolites in a healthy participant cohort.

Despite advances in antiretroviral treatment (ART), human immunodeficiency virus (HIV) can detrimentally affect everyday functioning. Neurocognitive impairment (NCI) and current depression are common in people with HIV (PWH) and can contribute to poor functional outcomes, but potential synergies between the two conditions are less understood. Thus, the present study aimed to compare the independent and combined effects of NCI and depression on everyday functioning in PWH. We predicted worse functional outcomes with comorbid NCI and depression than either condition alone.

PWH enrolled at the UCSD HIV Neurobehavioral Research Program were assessed for neuropsychological performance, depression severity (≤minimal, mild, moderate, or severe; Beck Depression Inventory-II), and self-reported everyday functioning.

Participants were 1,973 PWH (79% male; 66% racial/ethnic minority; Age: M = 48.6; Education: M = 13.0, 66% AIDS; 82% on ART; 42% with NCI; 35% BDI>13). ANCOVA models found effects of NCI and depression symptom severity on all functional outcomes (ps < .0001). With NCI and depression severity included in the same model, both remained significant (ps < .0001), although the effects of each were attenuated, and yielded better model fit parameters (i.e., lower AIC values) than models with only NCI or only depression.

Consistent with prior literature, NCI and depression had independent effects on everyday functioning in PWH. There was also evidence for combined effects of NCI and depression, such that their comorbidity had a greater impact on functioning than either alone. Our results have implications for informing future interventions to target common, comorbid NCI and depressed mood in PWH and thus reduce HIV-related health disparities.

Economic variables such as socioeconomic status and debt are linked with an increased risk of a range of mental health problems and appear to increase the risk of developing of post-traumatic stress disorder (PTSD). Previous research has shown that people living in more deprived areas have more severe symptoms of depression and anxiety after treatment in England’s NHS Talking Therapies services. However, no research has examined if there is a relationship between neighbourhood deprivation and outcomes for PTSD specifically. This study was an audit of existing data from a single NHS Talking Therapies service. The postcodes of 138 service users who had received psychological therapy for PTSD were used to link data from the English Indices of Deprivation. This was analysed with the PCL-5 measure of PTSD symptoms pre- and post-treatment. There was no significant association between neighbourhood deprivation measures on risk of drop-out from therapy for PTSD, number of sessions received or PTSD symptom severity at the start of treatment. However, post-treatment PCL-5 scores were significantly more severe for those living in highly deprived neighbourhoods, with lower estimated income and greater health and disability. There was also a non-significant trend for the same pattern based on employment and crime rates. There was no impact of access to housing and services or living environment. Those living in more deprived neighbourhoods experienced less of a reduction in PTSD symptoms after treatment from NHS Talking Therapies services. Given the small sample size in a single city, this finding needs to be replicated with a larger sample.

1. (1) Previous literature has shown that socioeconomic deprivation increases the risk of a range of mental health problems.

2. (2) Existing research suggests that economic variables such as income and employment are associated with greater incidence of PTSD.

3. (3) In the current study, those living in more deprived areas experienced less of a reduction in PTSD symptoms following psychological therapy through NHS Talking Therapies.

4. (4) The relatively poorer treatment outcomes in the current study are not explained by differences in baseline PTSD severity or drop-out rates, which were not significantly different comparing patients from different socioeconomic strata.

Identifying persons with HIV (PWH) at increased risk for Alzheimer’s disease (AD) is complicated because memory deficits are common in HIV-associated neurocognitive disorders (HAND) and a defining feature of amnestic mild cognitive impairment (aMCI; a precursor to AD). Recognition memory deficits may be useful in differentiating these etiologies. Therefore, neuroimaging correlates of different memory deficits (i.e., recall, recognition) and their longitudinal trajectories in PWH were examined.

We examined 92 PWH from the CHARTER Program, ages 45–68, without severe comorbid conditions, who received baseline structural MRI and baseline and longitudinal neuropsychological testing. Linear and logistic regression examined neuroanatomical correlates (i.e., cortical thickness and volumes of regions associated with HAND and/or AD) of memory performance at baseline and multilevel modeling examined neuroanatomical correlates of memory decline (average follow-up = 6.5 years).

At baseline, thinner pars opercularis cortex was associated with impaired recognition (p = 0.012; p = 0.060 after correcting for multiple comparisons). Worse delayed recall was associated with thinner pars opercularis (p = 0.001) and thinner rostral middle frontal cortex (p = 0.006) cross sectionally even after correcting for multiple comparisons. Delayed recall and recognition were not associated with medial temporal lobe (MTL), basal ganglia, or other prefrontal structures. Recognition impairment was variable over time, and there was little decline in delayed recall. Baseline MTL and prefrontal structures were not associated with delayed recall.

Episodic memory was associated with prefrontal structures, and MTL and prefrontal structures did not predict memory decline. There was relative stability in memory over time. Findings suggest that episodic memory is more related to frontal structures, rather than encroaching AD pathology, in middle-aged PWH. Additional research should clarify if recognition is useful clinically to differentiate aMCI and HAND.

Family involvement in the lives of people who have dementia and live in long-term care is important, but family members may face challenges communicating and connecting with their loved one as dementia progresses. A type of therapeutic humor (Laughter Care) delivered by trained specialists aims to engage people with dementia who reside in long-term care through creative play and laughter. This study aimed to explore the perceptions of Laughter Care Specialists (LCSs) regarding families’ engagement with the program.

Semi-structured interviews were conducted with LCSs (n = 8) and analyzed inductively using thematic analysis.

Family members were reported to initially have varied degrees of openness toward Laughter Care, but often become more accepting after observing positive engagement with the person with dementia. Family members were perceived to benefit from the program through witnessing the person with dementia enjoy joyous and light interactions, learn new ways of communicating and connecting with the person with dementia, and engage in positive interactions at end of life.

Laughter Care may provide family members with novel ways of communicating and connecting with people who have dementia at end of life as well as comfort into bereavement.

Methamphetamine and cannabis are two widely used substances with possibly opposing effects on aspects of central nervous system functioning. Use of these substances is prevalent among people with HIV (PWH), though their combined effects on HIV-associated neurocognitive impairment (NCI) are unknown. Adverse effects of methamphetamine use on cognition are well documented. Cannabis may disturb cognition acutely, though its longer-term effects in PWH are not well understood. Our prior analysis of people without HIV (PWoH) found that cotemporaneous cannabis use was associated with better neurocognitive outcomes among methamphetamine users. The aim of this study was to assess how lifetime cannabis and methamphetamine use disorder relate to neurocognitive outcomes in PWH.

HIV-positive participants (n=472) were on average 45.6±11.5 years of age, male (86.4%), White (60.6%), and educated 13.9±2.5 years. Most participants were on ART (81.9%) and virally suppressed (70%). Participants were stratified by lifetime methamphetamine (M-/M+) and cannabis (C-/C+) DSM-IV abuse/dependence disorder into four groups: M-C- (n=187), M-C+ (n=68), M+C-, (n=82) and M+C+ (n=135) and completed a comprehensive neurobehavioral assessment. Demographically corrected T-scores and deficit scores were used for analyses. Group differences in global and domain NC performances (i.e., T-scores) were examined using multiple linear regression, holding constant covariates that were associated with study groups and/or cognition. Specifically, M+ participants displayed higher rates of Hepatitis C infection (p=.004), higher current depressive symptom scores (p<.001), and higher rates of detectable plasma HIV RNA (p=.014). Multiple logistic regression was used to test for group differences in probability of neurocognitive impairment (i.e., deficit scores>0.5), including the same covariates. Pooling data with a sample of HIV-negative participants (n=423), we used generalized linear mixed effect models to examine how neurocognitive performance and impairment profiles varied by methamphetamine and/or cannabis use group, HIV disease characteristics, and their interactions.

Compared to M+C+, M+C- performed worse on measures of executive functions (ß=-3.17), learning (ß=-3.95), memory (ß=-5.58), and working memory (ß=-4.05) and were more likely to be classified as impaired in the learning (OR=2.93), memory (OR=5.24), and working memory (OR=2.48) domains. M-C- performed better than M+C+ on measures of learning (ß=3.46) and memory (ß=5.19), but worse than M-C+ on measures of executive functions (ß=-3.90), learning (ß=-3.32), memory (ß=-3.38), and working memory (ß=-3.38). Generalized linear mixed effect models indicate that detectable plasma HIV RNA (ß=-1.85) and low nadir CD4 T-cell counts (nadir CD4<200; ß=-1.07) were associated with worse neurocognitive performance, and these effects did not differ in size or direction by substance use group.

In PWH, lifetime methamphetamine use disorder and both current and legacy markers of HIV disease severity are associated with worse neurocognitive outcomes. Cannabis use disorder does not appear to exacerbate methamphetamine-related deficits in PWH. Instead, results are consistent with findings from preclinical studies that cannabis use may protect against methamphetamine’s deleterious effects. Profile analysis models showed that participants with a history of cannabis use disorder display better overall neurocognitive performance than comparison (M-C-) participants. Mechanisms underlying a potential protective effect of cannabis may be elucidated by examining the temporal relationship between cannabis and methamphetamine consumption and neurocognitive performance.

Many people with HIV (PWH) are at risk for age-related neurodegenerative disorders such as Alzheimer’s disease (AD). Studies on the association between cognition, neuroimaging outcomes, and the Apolipoprotein E4 (APOE4) genotype, which is associated with greater risk of AD, have yielded mixed results in PWH; however, many of these studies have examined a wide age range of PWH and have not examined APOE by race interactions that are observed in HIV-negative older adults. Thus, we examined how APOE status relates to cognition and medial temporal lobe (MTL) structures (implicated in AD pathogenesis) in mid- to older-aged PWH. In exploratory analyses, we also examined race (African American (AA)/Black and non-Hispanic (NH) White) by APOE status interactions on cognition and MTL structures.

The analysis included 88 PWH between the ages of 45 and 68 (mean age=51±5.9 years; 86% male; 51% AA/Black, 38% NH-White, 9% Hispanic/Latinx, 2% other) from the CNS HIV Antiretroviral Therapy Effects Research multi-site study. Participants underwent APOE genotyping, neuropsychological testing, and structural MRI; APOE groups were defined as APOE4+ (at least one APOE4 allele) and APOE4- (no APOE4 alleles). Eighty-nine percent of participants were on antiretroviral therapy, 74% had undetectable plasma HIV RNA (<50 copies/ml), and 25% were APOE4+ (32% AA/Black/15% NH-White). Neuropsychological testing assessed seven domains, and demographically-corrected T-scores were calculated. FreeSurfer 7.1.1 was used to measure MTL structures (hippocampal volume, entorhinal cortex thickness, and parahippocampal thickness) and the effect of scanner was regressed out prior to analyses. Multivariable linear regressions tested the association between APOE status and cognitive and imaging outcomes. Models examining cognition covaried for comorbid conditions and HIV disease characteristics related to global cognition (i.e., AIDS status, lifetime methamphetamine use disorder). Models examining the MTL covaried for age, sex, and

relevant imaging covariates (i.e., intracranial volume or mean cortical thickness).

APOE4+ carriers had worse learning (ß=-0.27, p=.01) and delayed recall (ß=-0.25, p=.02) compared to the APOE4- group, but APOE status was not significantly associated with any other domain (ps>0.24). APOE4+ status was also associated with thinner entorhinal cortex (ß=-0.24, p=.02). APOE status was not significantly associated with hippocampal volume (ß=-0.08, p=0.32) or parahippocampal thickness (ß=-0.18, p=.08). Lastly, race interacted with APOE status such that the negative association between APOE4+ status and cognition was stronger in NH-White PWH as compared to AA/Black PWH in learning, delayed recall, and verbal fluency (ps<0.05). There were no APOE by race interactions for any MTL structures (ps>0.10).

Findings suggest that APOE4 carrier status is associated with worse episodic memory and thinner entorhinal cortex in mid- to older-aged PWH. While APOE4+ groups were small, we found that APOE4 carrier status had a larger association with cognition in NH-White PWH as compared to AA/Black PWH, consistent with studies demonstrating an attenuated effect of APOE4 in older AA/Black HIV-negative older adults. These findings further highlight the importance of recruiting diverse samples and suggest exploring other genetic markers (e.g., ABCA7) that may be more predictive of AD in some races to better understand AD risk in diverse groups of PWH.

Methamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders.

423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M−/M+) and/or cannabis (C−/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition.

Globally, M+C+ performed worse than M−C− but better than M+C−. M+C+ outperformed M+C− on measures of verbal fluency, information processing speed, learning, memory, and working memory. M−C+ did not display lower performance than M−C− globally or on any domain measures, and M−C+ even performed better than M−C− on measures of learning, memory, and working memory.

Our findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.

Emotional functioning is linked to HIV-associated neurocognitive impairment, yet research on this association among diverse people with HIV (PWH) is scant. We examined emotional health and its association with neurocognition in Hispanic and White PWH.

Participants included 107 Hispanic (41% primarily Spanish-speakers; 80% Mexican heritage/origin) and 216 White PWH (Overall age: M = 53.62, SD = 12.19; 86% male; 63% AIDS; 92% on antiretroviral therapy). Emotional health was assessed via the National Institute of Health Toolbox (NIHTB)-Emotion Battery, which yields T-scores for three factor-based summary scores (negative affect, social satisfaction, and psychological well-being) and 13 individual component scales. Neurocognition was measured via demographically adjusted fluid cognition T-scores from the NIHTB-cognition battery.

27%–39% of the sample had problematic socioemotional summary scores. Hispanic PWH showed less loneliness, better social satisfaction, higher meaning and purpose, and better psychological well-being than Whites (ps <.05). Within Hispanics, Spanish-speakers showed better meaning and purpose, higher psychological well-being summary score, less anger hostility, but greater fear affect than English speakers. Only in Whites, worse negative affect (fear affect, perceived stress, and sadness) was associated with worse neurocognition (p <.05); and in both groups, worse social satisfaction (emotional support, friendship, and perceived rejection) was linked with worse neurocognition (p <.05).

Adverse emotional health is common among PWH, with subgroups of Hispanics showing relative strengths in some domains. Aspects of emotional health differentially relate to neurocogntition among PWH and cross-culturally. Understanding these varying associations is an important step towards the development of culturally relevant interventions that promote neurocognitive health among Hispanic PWH.

Recent cannabis exposure has been associated with lower rates of neurocognitive impairment in people with HIV (PWH). Cannabis’s anti-inflammatory properties may underlie this relationship by reducing chronic neuroinflammation in PWH. This study examined relations between cannabis use and inflammatory biomarkers in cerebrospinal fluid (CSF) and plasma, and cognitive correlates of these biomarkers within a community-based sample of PWH.

263 individuals were categorized into four groups: HIV− non-cannabis users (n = 65), HIV+ non-cannabis users (n = 105), HIV+ moderate cannabis users (n = 62), and HIV+ daily cannabis users (n = 31). Differences in pro-inflammatory biomarkers (IL-6, MCP-1/CCL2, IP-10/CXCL10, sCD14, sTNFR-II, TNF-α) by study group were determined by Kruskal–Wallis tests. Multivariable linear regressions examined relationships between biomarkers and seven cognitive domains, adjusting for age, sex/gender, race, education, and current CD4 count.

HIV+ daily cannabis users showed lower MCP-1 and IP-10 levels in CSF compared to HIV+ non-cannabis users (p = .015; p = .039) and were similar to HIV− non-cannabis users. Plasma biomarkers showed no differences by cannabis use. Among PWH, lower CSF MCP-1 and lower CSF IP-10 were associated with better learning performance (all ps < .05).

Current daily cannabis use was associated with lower levels of pro-inflammatory chemokines implicated in HIV pathogenesis and these chemokines were linked to the cognitive domain of learning which is commonly impaired in PWH. Cannabinoid-related reductions of MCP-1 and IP-10, if confirmed, suggest a role for medicinal cannabis in the mitigation of persistent inflammation and cognitive impacts of HIV.

Frascati international research criteria for HIV-associated neurocognitive disorders (HAND) are controversial; some investigators have argued that Frascati criteria are too liberal, resulting in a high false positive rate. Meyer et al. recommended more conservative revisions to HAND criteria, including exploring other commonly used methodologies for neurocognitive impairment (NCI) in HIV including the global deficit score (GDS). This study compares NCI classifications by Frascati, Meyer, and GDS methods, in relation to neuroimaging markers of brain integrity in HIV.

Two hundred forty-one people living with HIV (PLWH) without current substance use disorder or severe (confounding) comorbid conditions underwent comprehensive neurocognitive testing and brain structural magnetic resonance imaging and magnetic resonance spectroscopy. Participants were classified using Frascati criteria versus Meyer criteria: concordant unimpaired [Frascati(Un)/Meyer(Un)], concordant impaired [Frascati(Imp)/Meyer(Imp)], or discordant [Frascati(Imp)/Meyer(Un)] which were impaired via Frascati criteria but unimpaired via Meyer criteria. To investigate the GDS versus Meyer criteria, the same groupings were utilized using GDS criteria instead of Frascati criteria.

When examining Frascati versus Meyer criteria, discordant Frascati(Imp)/Meyer(Un) individuals had less cortical gray matter, greater sulcal cerebrospinal fluid volume, and greater evidence of neuroinflammation (i.e., choline) than concordant Frascati(Un)/Meyer(Un) individuals. GDS versus Meyer comparisons indicated that discordant GDS(Imp)/Meyer(Un) individuals had less cortical gray matter and lower levels of energy metabolism (i.e., creatine) than concordant GDS(Un)/Meyer(Un) individuals. In both sets of analyses, the discordant group did not differ from the concordant impaired group on any neuroimaging measure.

The Meyer criteria failed to capture a substantial portion of PLWH with brain abnormalities. These findings support continued use of Frascati or GDS criteria to detect HIV-associated CNS dysfunction.

This literature review aimed to identify the range of methods used in after action reviews (AARs) of public health emergencies and to develop appraisal tools to compare methodological reporting and validity standards.

A review of biomedical and gray literature identified key approaches from AAR methodological research, real-world AARs, and AAR reporting templates. We developed a 50-item tool to systematically document AAR methodological reporting and a linked 11-item summary tool to document validity. Both tools were used sequentially to appraise the literature included in this study.

This review included 24 highly diverse papers, reflecting the lack of a standardized approach. We observed significant divergence between the standards described in AAR and qualitative research literature, and real-world AAR practice. The lack of reporting of basic methods to ensure validity increases doubt about the methodological basis of an individual AAR and the validity of its conclusions.

The main limitations in current AAR methodology and reporting standards may be addressed through our 11 validity-enhancing recommendations. A minimum reporting standard for AARs could help ensure that findings are valid and clear for others to learn from. A registry of AARs, based on a common reporting structure, may further facilitate shared learning. (Disaster Med Public Health Preparedness. 2019;13:618-625)