Underlying Neural Mechanisms of Cognitive Improvement in Fronto-striatal Response Inhibition in People Living with HIV Switching Off Efavirenz: A Randomized Controlled BOLD fMRI Trial.

INTRODUCTION: It is unclear whether neurotoxicity due to the antiretroviral drug efavirenz (EFV) results in neurocognitive impairment in people living with HIV (PLWH). Previously, we found that discontinuing EFV was associated with improved processing speed and attention on neuropsychological assessment. In this imaging study, we investigate potential neural mechanisms underlying this cognitive improvement using a BOLD fMRI task assessing cortical and subcortical functioning. METHODS: Asymptomatic adult PLWH stable on emtricitabine/tenofovirdisoproxil/efavirenz were randomly (1:2) assigned to continue their regimen (n = 12) or to switch to emtricitabine/tenofovirdisoproxil/rilpivirine (n = 28). At baseline and after 12 weeks, both groups performed the Stop-Signal Anticipation Task, which tests reactive and proactive inhibition (indicative of subcortical and cortical functioning, respectively), involving executive functioning, working memory, and attention. Behavior and BOLD fMRI activation levels related to processing speed and attention Z-scores were assessed in 17 pre-defined brain regions. RESULTS: Both groups had comparable patient and clinical characteristics. Reactive inhibition behavioral responses improved for both groups on week 12, with other responses unchanged. Between-group activation did not differ significantly. For reactive inhibition, positive Pearson coefficients were observed for the change in BOLD fMRI activation levels and change in processing speed and attention Z-scores in all 17 regions in participants switched to emtricitabine/tenofovir disoproxil/rilpivirine, whereas in the control group, negative correlation coefficients were observed in 10/17 and 13/17 regions, respectively. No differential pattern was observed for proactive inhibition. CONCLUSION: Potential neural mechanisms underlying cognitive improvement after discontinuing EFV in PLWH were found in subcortical functioning, with our findings suggesting that EFV's effect on attention and processing speed is, at least partially, mediated by reactive inhibition. TRIAL REGISTRATION: Clinicaltrials.gov identifier [NCT02308332].

Effects of menstrual cycle on hemodynamic and autonomic responses to central hypovolemia.

Background: Estrogen and progesterone levels undergo changes throughout the menstrual cycle. Existing literature regarding the effect of menstrual phases on cardiovascular and autonomic regulation during central hypovolemia is contradictory. Aims and study: This study aims to explore the influence of menstrual phases on cardiovascular and autonomic responses in both resting and during the central hypovolemia induced by lower body negative pressure (LBNP). This is a companion paper, in which data across the menstrual phases from healthy young females, whose results are reported in Shankwar et al. (2023), were further analysed. Methods: The study protocol consisted of three phases: (1) 30 min of supine rest; (2) 16 min of four LBNP levels; and (3) 5 min of supine recovery. Hemodynamic and autonomic responses (assessed via heart rate variability, HRV) were measured before-, during-, and after-LBNP application using Task Force Monitor® (CNSystems, Graz, Austria). Blood was also collected to measure estrogen and progesterone levels. Results: In this companion paper, we have exclusively assessed 14 females from the previous study (Shankwar et al., 2023): 8 in the follicular phase of the menstrual cycle (mean age 23.38 ± 3.58 years, height 166.00 ± 5.78 cm, weight 57.63 ± 5.39 kg and BMI of 20.92 ± 1.96 25 kg/m2) and 6 in the luteal phase (mean age 22.17 ± 1.33 years, height 169.83 ± 5.53 cm, weight 62.00 ± 7.54 kg and BMI of 21.45 ± 2.63 kg/m2). Baseline estrogen levels were significantly different from the follicular phase as compared to the luteal phase: (33.59 pg/ml, 108.02 pg/ml, respectively, p < 0.01). Resting hemodynamic variables showed no difference across the menstrual phases. However, females in the follicular phase showed significantly lower resting values of low-frequency (LF) band power (41.38 ± 11.75 n.u. and 58.47 ± 14.37 n.u., p = 0.01), but higher resting values of high frequency (HF) band power (58.62 ± 11.75 n.u. and 41.53 ± 14.37 n.u., p = 0.01), as compared to females in the luteal phase. During hypovolemia, the LF and HF band powers changed only in the follicular phase F(1, 7) = 77.34, p < 0.0001 and F(1, 7) = 520.06, p < 0.0001, respectively. Conclusions: The menstrual phase had an influence on resting autonomic variables, with higher sympathetic activity being observed during the luteal phase. Central hypovolemia leads to increased cardiovascular and autonomic responses, particularly during the luteal phase of the menstrual cycle, likely due to higher estrogen levels and increased sympathetic activity.

Fronto-limbic white matter microstructural changes in psychiatrically healthy adults with childhood trauma.

Childhood trauma (CT) may influence brain white matter microstructure; however, few studies have examined the differential impact of distinct CT types on white matter microstructure in psychiatrically healthy adults living in a developing country. In adults without significant medical or psychiatric disorders, we investigated the association(s) between CT, including abuse and neglect, and fractional anisotropy (FA) of limbic tracts previously shown to be associated with CT. Participants underwent diffusion tensor imaging and completed the Childhood Trauma Questionnaire. Multivariate analysis of variance models were used to test the effects of total overall CT, as well as CT subtypes, on FA in six fronto-limbic tracts, adjusting for age, sex, and educational level. The final sample included 69 adults (age 47 ± 17 years; 70% female). Overall, CT had a significant main effect on FA for tracts of interest (p < .001). Greater CT severity was associated with lower FA for the bilateral and left stria terminalis (uncorrected) as well as the bilateral, left, and right anterior limb of the internal capsule (ALIC; corrected). Exposure to total non-violent/deprivational trauma specifically was associated with lower FA of the bilateral, left, and right ALIC, suggesting that distinct types of CT are associated with differential white matter changes in apparently healthy adults. The ALIC predominantly carries fibers connecting the thalamus with prefrontal cortical regions. Microstructural alterations in the ALIC may be associated with functional brain changes, which may be adaptive or increase the risk of accelerated age-related cognitive decline, maladaptive behaviors, and subsyndromal psychiatric symptoms.

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

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

Implications of Exposure to Air Pollution on Male Reproduction: The Role of Oxidative Stress.

Air pollution, either from indoor (household) or outdoor (ambient) sources, occurs when there is presence of respirable particles in the form of chemical, physical, or biological agents that modify the natural features of the atmosphere or environment. Today, almost 2.4 billion people are exposed to hazardous levels of indoor pollution, while 99% of the global population breathes air pollutants that exceed the World Health Organization guideline limits. It is not surprising that air pollution is the world's leading environmental cause of diseases and contributes greatly to the global burden of diseases. Upon entry, air pollutants can cause an increase in reactive oxygen species (ROS) production by undergoing oxidation to generate quinones, which further act as oxidizing agents to yield more ROS. Excessive production of ROS can cause oxidative stress, induce lipid peroxidation, enhance the binding of polycyclic aromatic hydrocarbons (PAHs) to their receptors, or bind to PAH to cause DNA strand breaks. The continuous and prolonged exposure to air pollutants is associated with the development or exacerbation of pathologies such as acute or chronic respiratory and cardiovascular diseases, neurodegenerative and skin diseases, and even reduced fertility potential. Males and females contribute to infertility equally, and exposure to air pollutants can negatively affect reproduction. In this review, emphasis will be placed on the implications of exposure to air pollutants on male fertility potential, bringing to light its effects on semen parameters (basic and advanced) and male sexual health. This study will also touch on the clinical implications of air pollution on male reproduction while highlighting the role of oxidative stress.