Early Life Stress-Related Elevations in Reaction Time Variability Are Associated with Brain Volume Reductions in HIV+ Adults

Abstract

There is burgeoning evidence that, among HIV+ adults, exposure to high levels of early life stress (ELS) is associated with increased cognitive impairment as well as brain volume abnormalities and elevated neuropsychiatric symptoms. Currently, we have a limited understanding of the degree to which cognitive difficulties observed in HIV+ High-ELS samples reflect underlying neural abnormalities rather than increases in neuropsychiatric symptoms. Here, we utilized a behavioral marker of cognitive function, reaction time intra-individual variability (RT-IIV), which is sensitive to both brain volume reductions and neuropsychiatric symptoms, to elucidate the unique contributions of brain volume abnormalities and neuropsychiatric symptoms to cognitive difficulties in HIV+ High-ELS adults. We assessed the relation of RT-IIV to neuropsychiatric symptom levels and total gray and white matter volumes in 44 HIV+ adults (26 with high ELS). RT-IIV was examined during a working memory task. Self-report measures assessed current neuropsychiatric symptoms (depression, stress, post-traumatic stress disorder). Magnetic resonance imaging was used to quantify total gray and white matter volumes. Compared to Low-ELS participants, High-ELS participants exhibited elevated RT-IIV, elevated neuropsychiatric symptoms, and reduced gray and white matter volumes. Across the entire sample, RT-IIV was significantly associated with gray and white matter volumes, whereas significant associations with neuropsychiatric symptoms were not observed. In the High-ELS group, despite the presence of elevated neuropsychiatric symptom levels, brain volume reductions explained more than 13% of the variance in RT-IIV, whereas neuropsychiatric symptoms explained less than 1%. Collectively, these data provide evidence that, in HIV+ High-ELS adults, ELS-related cognitive difficulties (as indexed by RT-IIV) exhibit strong associations with global brain volumes, whereas ELS-related elevations in neuropsychiatric symptoms appear to contribute minimally to these cognitive difficulties. Such findings support a growing body of evidence indicating that high ELS exposure is a significant risk factor for neurocognitive dysfunction in HIV+ adults. Further, these data highlight the need to better understand how ELS-related pathophysiological mechanisms contribute to volumetric and other neural abnormalities in HIV+ individuals.

The relationship between potentially traumatic or stressful events, HIV infection and neurocognitive impairment (NCI): a systematic review of observational epidemiological studies

“…The average age for fourteen of fifteen studies, (one study reported the age range only) was 40 years. Eight were all-female studies (Malan-Muller et al, 2013 ; Rubin et al, 2017 , 2015 , 2016 ; Spies et al, 2016 , 2012 ; Spies, Fennema-Notestine, Cherner, & Seedat, 2017 ; Womersley, Spies, Seedat, & Hemmings, 2019 ) and two were all-male studies (Deiss et al, 2019 ; Pukay-Martin, Cristiani, Saveanu, & Bornstein, 2003 ), with the remainder (five studies) including both men and women (Clark, Arce Renteria, Hegde, & Morgello, 2018 ; Clark et al, 2012 ; Kapetanovic et al, 2020 ; Lin et al, 2011 ; Watson et al, 2019 ).…”

“…There were ten case-control studies (Clark et al, 2012 ; Kapetanovic et al, 2020 ; Malan-Muller et al, 2013 ; Pukay-Martin et al, 2003 ; Rubin et al, 2017 , 2015 ; Spies et al, 2016 , 2012 , 2017 ; Watson et al, 2019 ) and five cross-sectional studies (Clark et al, 2018 ; Deiss et al, 2019 ; Lin et al, 2011 ; Rubin et al, 2016 ; Womersley et al, 2019 ). Eight studies were longitudinal in design (Malan-Muller et al, 2013 ; Rubin et al, 2017 , 2015 , 2016 ; Spies et al, 2016 , 2012 , 2017 ; Womersley et al, 2019 ) but only one of these presented longitudinal data examining the relationship between childhood trauma and HIV and change in cognition over time (Spies et al, 2017 ) and one examined the relationship between perceived stress and PTSD and NCI over time (Rubin et al, 2017 ).…”

“…In one of these studies by Rubin et al, which compared HIV-infected women with low stress PSS-10 scores in the lower two tertiles) and HIV-infected women with high stress (PSS-10 scores in the top tertile), high stress and HIV seemed to be associated with worse performance on measures of verbal learning and memory and smaller brain volumes . Similarly in the other study by Clark et al, participants with high early life stress (ELS) (defined as an endorsement of three or more adverse childhood events [ACEs]) exhibited poorer working memory compared to those with low-ELS (defined by endorsement of fewer than three ACEs) (Clark et al, 2018). In studies that included comparison groups with and without trauma (viz.…”

“…In summary, reporting of data is adequate. Moderate Clark et al, 2018 Sample recruited 44 HIV+ participants to explore changes in brain volume affected by ELS. Source, method and entry criteria clearly stated.…”

Childhood trauma interacts with ApoE to influence neurocognitive function in women living with HIV

“…We hypothesised that carriers of the ApoE ε4 isoform would perform worse on cognitive tests, and that these deficits would be further accentuated by a history of CT. Studies have associated ApoE ε4 genotype with a range of cognitive effects in HIV including executive function, perceptual speed, verbal fluency, learning, memory and global cognitive function (Andres et al 2011;Chang et al 2011;Hoare et al 2013;Panos et al 2013;Mukerji et al 2016;Wendelken et al 2016). The interaction of CT and HIV has also been associated with a variety of cognitive impairments including diminished attention/working memory, executive function, language, motor skill and processing speed (Spies et al 2016(Spies et al , 2017Clark et al 2018). Based on the broad spectrum of possible impairment, we thus decided to examine both global cognitive function as well as cognitive domains in our study.…”