Computerized Cognitive Training Increases Gray Matter Volumes in Huntington's Disease: A Pilot Study

Computerized cognitive training (CCT) aims to improve cognition through practice on tasks that invoke targeted cognitive domains. CCT improvements to cognition and gray matter structure have been found in healthy older adults and clinical populations.^{1, 2} However, its effects in Huntington's disease (HD) have not been thoroughly examined.³

We conducted a pilot randomized controlled trial to examine the effects of CCT in pre-manifest and early-stage HD. Participants were randomized to either multidomain CCT (two 1-hour sessions weekly) or lifestyle education (monthly newsletters) over 3 months. A sub-sample of participants (n = 6 CCT, n = 10 lifestyle education) completed structural magnetic resonance imaging and cognitive assessments at baseline and follow up. We predicted increased or preserved gray matter volumes in the CCT group, compared to the lifestyle education group. Methods are provided in Supplementary Data S1.

There were no significant differences between groups on demographic or clinical variables at baseline (Supplementary Table S1). Adherence to CCT ranged from 96% to 100% (5/6 participants had 100% adherence). Voxel-based morphometry analyses showed that change in gray matter volumes between baseline and follow up significantly differed between groups in the left putamen, right Heschl's gyrus, right superior temporal gyrus, right middle cingulate, and right middle frontal gyrus (Fig. 1A). Analyses of simple effects (Fig. 1B; Supplementary Table S2) revealed that in all regions, except left putamen, volumes significantly decreased in the lifestyle education group and significantly increased in the CCT group. In left putamen, volume significantly decreased in the lifestyle education group and was preserved in the CCT group. Examination of individual effects showed consistency in directions of effects across participants in each group.

Exploratory correlations between changes in gray matter volumes and cognitive outcomes revealed positive correlations between increased volumes and improvement on various cognitive outcomes (Supplementary Data S2). Increased volumes in all regions correlated with improved performance on a task switching paradigm.

The brain regions showing significant change in volume (putamen, Heschl's gyrus, superior temporal gyrus, middle cingulate, and middle frontal gyrus) may be more responsive to CCT given their atrophy in the pre-manifest stage.⁴ Similarly, deficits in task switching can occur decades prior to diagnosis as it engages a widespread brain network.⁵

Although our results are susceptible to small sample bias and overestimated effect sizes, results are consistent with studies in older adults with similar training doses.¹ Although significant decline in gray matter volumes in the lifestyle education group over 3 months was unexpected, this may be due to use of a segmentation model optimized for detecting short-term plasticity changes.⁶ Our results complement studies that demonstrate significant change in gray matter volumes in early-stage HD across intervals as short as 6 months.⁷

We urge caution when interpreting our results considering the small sample size, imbalanced numbers across groups, and potential self-selection bias. However, our data suggest that multidomain CCT alone may help preserve gray matter volumes in pre-manifest and early-stage HD. These results encourage further research in this area, with larger multi-site trials or synthesis of data across smaller studies.

Financial Disclosures for the Preceding 12 Months: N.G-K. received research funding from Friedreich Ataxia Research Alliance (USA) and CHDI Foundation New York, USA. J.C.S. is the Director (Managing) of ZindaMetrix, Director of Stout Neuropsych, and received research funding from PPD Australia, Australia National Health and Medical Research Council, and CHDI Foundation. K.H., M.N.S., A.L., and S.D.J., declare that there are no additional disclosures to report.

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing the First Draft, B. Review and Critique.

K.H.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B

N.G-K.: 1A, 1B, 2C, 3B

A.L.: 1A, 2C

M.N.S.: 1C

J.C.S.: 1A, 2C, 3B

S.D.J.: 1A, 2A, 2C, 3B