Longitudinal Changes in the Motor Learning-Related Brain Activation Response in Presymptomatic Huntington's Disease

Abstract

Neurocognitive decline, including deficits in motor learning, occurs in the presymptomatic phase of Huntington’s disease (HD) and precedes the onset of motor symptoms. Findings from recent neuroimaging studies have linked these deficits to alterations in fronto-striatal and fronto-parietal brain networks. However, little is known about the temporal dynamics of these networks when subjects approach phenoconversion. Here, 10 subjects with presymptomatic HD were scanned with 15O-labeled water at baseline and again 1.5 years later while performing a motor sequence learning task and a kinematically matched control task. Spatial covariance analysis was utilized to characterize patterns of change in learning-related neural activation occurring over time in these individuals. Pattern expression was compared to corresponding values in 10 age-matched healthy control subjects. Spatial covariance analysis revealed significant longitudinal changes in the expression of a specific learning-related activation pattern characterized by increasing activity in the right orbitofrontal cortex, with concurrent reductions in the right medial prefrontal and posterior cingulate regions, the left insula, left precuneus, and left cerebellum. Changes in the expression of this pattern over time correlated with baseline measurements of disease burden and learning performance. The network changes were accompanied by modest improvement in learning performance that took place concurrently in the gene carriers. The presence of increased network activity in the setting of stable task performance is consistent with a discrete compensatory mechanism. The findings suggest that this effect is most pronounced in the late presymptomatic phase of HD, as subjects approach clinical onset.

Loss-of-Huntingtin in Medial and Lateral Ganglionic Lineages Differentially Disrupts Regional Interneuron and Projection Neuron Subtypes and Promotes Huntington's Disease-Associated Behavioral, Cellular, and Pathological Hallmarks

“…4B). However, the Htt flx ;Gsx2-Cre latency to fall at trial 1/day was comparable to that of controls (Tukey's multiple-comparisons test adjusted p-values ϭ 0.924 and 0.506 for 9 and 12 months of age, respectively), suggesting that rotarod performance in these mice likely resulted from compensatory mechanisms associated with motor learning (Feigin et al, 2006;Holtbernd et al, 2016). In addition to motor changes, both Htt flx ;Gsx2-Cre and Htt flx ;Nkx2.1-Cre mice exhibited very robust hyperkinetic phenotypes from the age of 3 months, as indicated by significant increases in the total distance traveled (F (2,50) ϭ 76.9; p ϭ 5.54E-16; n ϭ 16 control, 16 Htt flx ; Nkx2.1-Cre and 7 Htt flx ;Gsx2-Cre) and in associated locomotion speed (F (2,36) ϭ 32.45; p ϭ 8.77E-09; two-way ANOVA) within the open field arena when compared with controls ( Fig.…”

A single bout of moderate-intensity aerobic exercise improves motor learning in premanifest and early Huntington’s disease

“…However, our recent TMS study of M1 synaptic plasticity following exercise in premanifest and early HD, however, revealed attenuated cortico-motor excitability, GABA-ergic short-interval cortical inhibition and glutamatergic facilitation responses following both high-intensity interval and moderate-intensity continuous cycling, indicating that these mechanisms are altered in HD ( Andrews et al, 2022 ). Given that previous studies in presymptomatic HD participants have found different brain activation patterns during motor learning compared to adults without the HD gene expansion ( Feigin et al, 2006 ; Holtbernd et al, 2016 ), one possibility is that exercise might help to promote neuroplasticity in these other regions to compensate for neurodegeneration in motor learning-related brain areas and boost compensatory networks. This is encouraging, as it suggests that even if M1 plasticity mechanisms are attenuated in HD, exercise may still have a beneficial effect on motor learning.…”

“…In HD, neurocognitive deficits such as motor learning commonly precede the onset of motor symptoms ( Stout et al, 2012 ; Holtbernd et al, 2016 ), although there is individual variation in the order of symptom onset and progression ( McAllister et al, 2021 ). The aim of the current study was therefore to investigate whether an acute bout of moderate-intensity exercise would improve motor learning (both skill acquisition and retention) in people with presymptomatic and early manifest HD, measured using a SVIPT task.…”

“…A task well-suited to quantifying the development of motor skill is the sequential visuomotor isometric pinch force task (SVIPT), as it allows participants to vary their emphasis on speed or accuracy (Reis et al, 2009(Reis et al, , 2015Statton et al, 2015;Stavrinos and Coxon, 2017), but this task has not yet been utilized to investigate motor skill learning in HD. It shares similarities with previous motor learning tasks utilized in HD populations in that it involves sequence learning (Willingham and Koroshetz, 1993;Holtbernd et al, 2016). The task is tailored to a participant's maximum voluntary contraction, and has previously been successfully adapted for use in a clinical population (Hardwick et al, 2017), making it a suitable choice for use with an HD population.…”