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

Abstract

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].

Keywords: BOLD functional MRI; Efavirenz; HIV; HIV-associated neurocognitive disorders (HAND); Neurocognition; Response inhibition.

Fig. 1

Schematic representation of the Stop-Signal Anticipation task. Three horizontal lines were displayed during the task. A bar moved from the bottom line to the top in 1000 ms. At 800 ms the bar reached the middle colored line and had to be stopped (GO trials, A). In a small proportion of trials, the bar stopped moving on its own before reaching the middle colored line, requiring the stop response to be withheld (STOP trials, B). The color of the middle line indicated the stop signal probability (C) [27]

Fig. 2

Regions used to assess activation levels related to reactive and proactive inhibition after discontinuing EFV. Regions were (1) right striatum; (2) right inferior frontal cortex ventral; (3) left middle frontal gyrus; (4) left temporoparietal junction; (5) left superior parietal gyrus; (6) right superior parietal gyrus; (7) right temporoparietal junction; (8) left precuneus; (9) anterior cingulate gyrus; (10) right superior frontal gyrus; (11) left superior frontal gyrus; (12) left inferior frontal gyrus; (13) right anterior insula; (14) right inferior frontal cortex dorsal; (15) right caudate; (16) left subthalamic nucleus; (17) right subthalamic nucleus

Fig. 3

Trial flowchart of participants enrolled and included in our analysis. EFV efavirenz, fMRI functional magnetic resonance imaging, FTC emtricitabine, RPV rilpivirine, TDF tenofovirdisoproxil fumarate