Adaptive working memory training improved brain function in human immunodeficiency virus-seropositive patients

Abstract

Objective: We aimed to evaluate the effectiveness of an adaptive working memory (WM) training (WMT) program, the corresponding neural correlates, and LMX1A-rs4657412 polymorphism on the adaptive WMT, in human immunodeficiency virus (HIV) participants compared to seronegative (SN) controls.

Methods: A total of 201 of 206 qualified participants completed baseline assessments before randomization to 25 sessions of adaptive WMT or nonadaptive WMT. A total of 74 of 76 (34 HIV, 42 SN) completed adaptive WMT and all 40 completed nonadaptive WMT (20 HIV, 20 SN) and were assessed after 1 month, and 55 adaptive WMT participants were also assessed after 6 months. Nontrained near-transfer WM tests (Digit-Span, Spatial-Span), self-reported executive functioning, and functional magnetic resonance images during 1-back and 2-back tasks were performed at baseline and each follow-up visit, and LMX1A-rs4657412 was genotyped in all participants.

Results: Although HIV participants had slightly lower cognitive performance and start index than SN at baseline, both groups improved on improvement index (>30%; false discovery rate [FDR] corrected p < 0.0008) and nontrained WM tests after adaptive WMT (FDR corrected, p ≤ 0.001), but not after nonadaptive WMT (training by training type corrected, p = 0.01 to p = 0.05) 1 month later. HIV participants (especially LMX1A-G carriers) also had poorer self-reported executive functioning than SN, but both groups reported improvements after adaptive WMT (Global: training FDR corrected, p = 0.004), and only HIV participants improved after nonadaptive WMT. HIV participants also had greater frontal activation than SN at baseline, but brain activation decreased in both groups at 1 and 6 months after adaptive WMT (FDR corrected, p < 0.0001), with normalization of brain activation in HIV participants, especially the LMX1A-AA carriers (LMX1A genotype by HIV status, cluster-corrected-p < 0.0001).

Interpretation: Adaptive WMT, but not nonadaptive WMT, improved WM performance in both SN and HIV participants, and the accompanied decreased or normalized brain activation suggest improved neural efficiency, especially in HIV-LMX1A-AA carriers who might have greater dopaminergic reserve. These findings suggest that adaptive WMT may be an effective adjunctive therapy for WM deficits in HIV participants. ANN NEUROL 2017;81:17-34.

© 2016 The Authors Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.

Figures

Figure 1

CONSORT diagram showing the number of participants at each stage of the study. CONSORT = CONsolidated Standards Of Reporting Trials; HIV = human immunodeficiency virus; SN, seronegative controls; WM – working memory.

Figure 2

Improvements After Adaptive WMT and Comparisons of Adaptive WMT and Nonadaptive WMT 1 Month Later on Nontrained WM Tasks. p values are from the inverse proportional weighting, using the generalized estimating equations (GEE) method, including baseline longitudinal data from the dropout subjects; categorical factors included HIV serostatus (A), HIV serostatus and LMX1A (B), and HIV serostatus and training type (C). Covariates included age, sex, index of social position, and crossover effects from the 12 subjects that had nonadaptive WMT before baseline adaptive WMT; furthermore, given that the dropout subjects also had higher depression scores, lower FSIQ and higher proportion with HAND compared to the completers, the GEE model additionally adjusted for CES‐D, FSIQ, and HAND status. All p values were also FDR corrected. (A) The HIV group (red line, n = 34) had a lower start index than SN controls (black line: n = 42) at baseline, but both groups showed similar gains after the WMT; hence, the max index remains higher in SN than HIV. (B) When subjects were stratified by LMX1A genotypes, both groups with the GG/GA genotypes (dotted lines: 16 SN and 21 HIV) showed a lower start index than those with AA genotype (solid lines, 24 SN and 12 HIV). However, all four groups showed similarly strong indices of improvement. (C) Top Row: Digit‐Span Tests: Both HIV and SN groups showed improved performance after adaptive WMT (black and red lines), but not after nonadaptive WMT (green lines), on Digit‐Span Backward (Training by training type, FDR corrected, p = 0.02), Digit‐Span Forward (Training by training type, FDR corrected, p = 0.05), and Digit‐Span Total (Training by training type, FDR corrected p = 0.02). HIV subjects also had lower performance on Digit‐Span Backward and Total and Spatial‐Span Forward and Total. CES‐D = Center for Epidemiological Studies–Depression Scale; FDR = false discovery rate; FSIQ = full‐scale IQ; HAND = HIV‐associated neurological disorder; HIV = human immunodeficiency virus; SN, seronegative controls; WMT = working memory training.

Figure 3

(A) Effects of adaptive WMT, HIV serostatus, and LMX1A genotype on nontrained near‐transfer WM tasks. Top row: On the Digit‐Span Tasks, all subjects showed WMT training effects from baseline to 1 (backward, forward, and total) and 6 months after WMT (backward and total). Furthermore, at 6 months, those with AA genotype (solid lines) showed better performance overall and trends for better training effects (LMX1A × training interactions) than those with the GG/GA genotypes (dotted lines), especially on the backward task. Bottom row: On the Spatial‐Span Tasks, subjects also showed significant training effects at 1 month, but on the Forward task, the training effect differed based on genotype and HIV status. Analyses were performed using the inverse proportional weighting generalized estimating equations method for analyzing longitudinal data that have missing follow‐up observations, with training effect across time as a repeated measure, LMX1A and HIV serostatus as categorical factors, and the same four covariates as in Figure 2 (all p values are FDR corrected). Data are from seronegative (SN; 24 AA, 16 GG/GA) and HIV‐positive (12 AA, 21 GG/GA) subjects. (All data are presented as least‐square means and standard errors.) (B) Effects of adaptive WMT, HIV serostatus, and LMX1A on composite scores of the Behavior Rating Inventory of Executive Function‐Adult Version. Data are from 41 SN subjects (24 AA, 15 GG/GA, and 2 unavailable) and 32 HIV subjects (11 AA, 20 GG/GA, and 1 unavailable). HIV subjects with GG/GA genotypes (red dotted line) had higher T‐scores, indicating more difficulty with executive function compared to the other three subject groups. The statistical model and covariates were the same as those in 3A, and p values are FDR corrected. FDR = false discovery rate; HIV = human immunodeficiency virus; WM = working memory; WMT = working memory training.

Figure 4

Changes in brain activation during a working memory (WM) task (2‐back) before and 1 month after adaptive WM training (WMT). (A) Relative to baseline, both groups showed significant decreases in brain activation 1 month after WMT. Top panels: Brain activation (t‐maps) in HIV and SN groups at baseline and 1 month after WMT. Bottom: On the surface p‐maps, note the significantly decreased activation throughout the dorsal and bilateral cortical brain regions in the HIV subjects, whereas seronegative (SN) controls show significantly decreased activation in bilateral anterior cingulate regions as well as the ventral and medial regions of the brain. (B) Top row: Renderings of t‐scores for the difference (reduction) in activation at 1 month compared to baseline. Bottom line‐graphs: BOLD signal changes in select brain regions for SN (blue) and HIV (red) subjects at baseline and 1 month. Comparisons were tested using repeated‐measures ANCOVA (same four covariates as in Fig 2); with cluster minimum > 100 voxels and threshold minimum T >2.1. ANCOVA = analysis of covariance; BOLD blood‐oxygen‐level dependent; FDR = false discovery rate; HIV = human immunodeficiency virus; L = left; R = right.

Figure 5

Changes in brain activation during working memory (1‐back) at baseline, 1 month, and 6 months after adaptive working memory training (data are from 19 HIV and 24 seronegative or SN with all three time points). (A) Top panels: Activation patterns at each time point for both groups. Bottom panels: Surface t‐maps showing similar results from the full cohort; significant decreases in brain activation were observed within each group at 6 months. HIV subjects primarily showed decreases in the right frontal and left parietal and temporal regions, whereas SN subjects had decreases predominantly in subcortical regions, with cluster maxima at the left pons, left anterior cingulate, and right medial frontal regions. (B) Line graphs showing BOLD signals extracted from regions of interest centered at select cluster maxima, showing significantly decreased brain activation either in HIV subjects (red), SN (blue), or in both groups at 6 months (see also Supplementary Table 2). Comparisons were tested using repeated‐measures ANCOVA (same four covariates as in Fig 2), with cluster minimum >100 voxels and threshold minimum T >2.1. ANCOVA = analysis of covariance; BA = Brodmann's area; BOLD blood‐oxygen‐level dependent; HIV = human immunodeficiency virus; L = left.

Figure 6

Changes in brain activation during WM (2‐back) at baseline, 1 month, and 6 months after adaptive WM training (in the two groups with data at all three time points, 21 SN and 16 HIV, for this task). (A) Similar to results from the full cohort, significant decreases in brain activation at 1 month were observed within each group, primarily in the right frontal, left parietal, and temporal regions in HIV subjects, but in subcortical regions in HIV subjects. However, when the BOLD signal was compared between 6 months after WMT and baseline, the spatial pattern was similar for HIV and SN subjects, with decreases primarily in cortical regions. (B) BOLD signals extracted from ROIs centered at the cluster maxima at left and medial precuneus, and left superior frontal gyrus, showing significantly decreased brain activation in both groups at 6 months (see also Supplementary Table 3). Comparisons were tested using repeated‐measure ANCOVA (same four covariates as in Fig 2), with cluster minimum >100 voxels and threshold minimum T >2.1. ANCOVA = analysis of covariance; BA = Brodmann's area; BOLD blood‐oxygen‐level dependent; FDR = false discovery rate; HIV = human immunodeficiency virus; L Sup = left superior; SN, seronegative; WM = working memory; WMT = working memory training.

Figure 7

Changes in brain activation during working memory (WM) tasks (1‐back and 2‐back) correlated with improvements on WM after adaptive WM training (WMT). (A) At 1 month after WMT, HIV subjects, but not seronegative (SN) controls, showed decreased brain activation on the 2‐back task in the right middle frontal gyrus; the decreased activation correlated with improved score on the Digit‐Span Backward task in HIV subjects (red dots and line; r = –0.51; p = 0.02). (B) At 6 months after WMT, both HIV and SN controls showed a decrease in activation in the left anterior cingulate (BA 24) during the 1‐back task, which correlated with improvements on the Spatial‐Span Total scores across both groups (r = –0.39; p = 0.02; HIV: red, SN: blue). (C) Also at 6‐months after WMT, both groups showed further deactivation in the right medial frontal gyrus (BA 11) during the 1‐back task. Across both groups, those with lesser additional deactivation showed greater improvement on the Digit‐Span Forward task (r = 0.43; p = 0.004). BA = Brodmann's area; BOLD blood‐oxygen‐level dependent; HIV = human immunodeficiency virus; L = left; R = right.

Figure 8

Changes in brain activation during WM (2‐back) before and 1 month after adaptive WM training in relation to LMX1A genotype and HIV serostatus. These results are from two‐way ANCOVA with HIV serostatus and genotype (LMX1A‐AA vs LMX1A‐GG/GA) as factors and age, sex, index of social position, and crossover (after placebo training) as covariates. SPM maps show significant clusters of LMX1A‐genotype effects or LMX1A × HIV interactions on BOLD signal changes; values in the bar graphs are extracted from major cluster maxima shown in the upper panels. Changes in BOLD response are shown as least square means and standard errors. (A) SPM t‐maps showing genotype effects regardless of HIV serostatus. Subjects with LMX1A‐AA genotype showed greater decreases in BOLD signals compared to G‐carriers (cluster corrected, p < 0.0001), especially in right middle frontal gyrus (24, –4, 49, Brodmann area 6) and left superior temporal gyrus (–57, –43, 7, Brodmann area 22). (B) Whereas HIV subjects with the LMX1A‐AA genotype showed significant decreases in BOLD signals, SN subjects showed increases or no change in BOLD signals in the parietal and frontal regions. Bar graphs show region of interest data extracted from the cluster shown in SPM maps above (cluster corrected, p = 0.0001; 4,623 voxels; T‐max, 3.81). ANCOVA = analysis of covariance; BA = Brodmann's area; BOLD blood‐oxygen‐level dependent; HIV = human immunodeficiency virus; L = left; R = right; SN, seronegative; WM = working memory.