The effect of impulsivity and inhibitory control deficits in the saccadic behavior of premanifest Huntington’s disease individuals

Abstract

Background: This study aims to test response inhibition in premanifest Huntington's disease individuals (Pre-HD), in the context of a saccadic paradigm with working memory demands and fronto-executive load as a way to measure inhibitory control deficits and impulsive behavior in Huntington's disease (HD). Methods: The oculomotor function of 15 Pre-HD and 22 Control individuals was assessed using an experimental paradigm comprising four horizontal saccadic tasks: prosaccade (PS), antisaccade (AS), 1-or 2-back memory prosaccade (MPS), and 1-or 2-back memory antisaccade (MAS). Success rate, latency, directional and timing errors were calculated for each task. A comprehensive battery of neuropsychological tests was also used to assess the overall cognitive functioning of study participants. Statistical correlations between oculomotor, clinical and cognitive measures were computed for the Pre-HD group. Results: Pre-HD participants showed reduced success rate in the AS task, increased direction errors in the AS and MAS tasks and decreased latency in the MAS task when compared to Controls, despite presenting similar executive and memory scores in the conventional neuropsychological tests applied. Significant associations were identified between specific AS and MAS parameters and disease-related measures, cognitive skills and other oculomotor results of Pre-HD participants. Conclusions: Our results show that oculomotor performance in premanifest Huntington's disease deteriorates once inhibitory control, working memory and/or fronto-executive load are added to the task. A more automatic pattern of performance, including a faster response time and directionally erroneous eye movements were detected in the oculomotor behavior of the Pre-HD group-these alterations were significantly correlated with disease stage and cognitive status. Our saccadic paradigm was able to capture impulsivity and inhibitory control deficits in a group of Pre-HD individuals on average far from symptom onset, thus holding the potential to identify the earliest diseaserelated changes.

Eye movement alterations in presymptomatic C9orf72 expansion gene carriers

“…Biomarkers will play an important role in future therapeutic decisions now that C9orf72 mutation carriers can be identified by genetic testing many decades before symptoms begin [ 34 ], given that, with the emergence of antisense oligonucleotide therapies, the characterization of presymptomatic disease burden has now gained practical relevance [ 35 ]. Like in presymptomatic Huntington’s disease [ 36 ] and pre-ataxic Machado–Joseph disease [ 37 ] individuals, the recording of eye movements in presymptomatic C9orf72 gene carriers may have the potential as a biological marker. Thus, video-oculographic recording as an unbiased assessment of the neuropsychological condition might further prove its potential as a technical biomarker in the longitudinal work-up of the clinical condition from the presymptomatic to the symptomatic stage.…”

Time will tell: Decision making in premanifest and manifest Huntington’s disease

“…Several studies have shown that HD is associated with deficits in decision making, which could explain the increased presence of dysfunctional behavior such as increased risk taking (Eddy & Rickards, 2012; Kalkhoven et al, 2014). Furthermore, impaired decision making, cognitive decline, obsessive behavior, and deficits in inhibitory control have been reported in HD mutation carriers without distinct motor symptoms (Beglinger et al, 2008; D'Aurizio et al, 2019; De Lucia, Peluso, Roca, De Michele, et al, 2019; Julio et al, 2019; Migliore et al, 2019; Paulsen & Long, 2014; Stout et al, 2011). Neuropsychological tasks assessing frontal executive functions such as the Symbol Digit Modalities Test, the Stroop Test, the Trail Making Test, and tasks requiring mental flexibility have been described to detected early impairment in HD mutation carriers (McGarry & Biglan, 2017; O'Rourke et al, 2011).…”

The striatum in time production: The model of Huntington's disease in longitudinal study

“…Indeed, previous research has shown that temporal durations are judged as shorter when fewer attentional resources are engaged towards temporal information (Zakay, 1989). One could also speculate that this underestimation of time might be related to the impulsivity of HD patients, which has been documented with questionnaires (Johnson et al, 2017) or with inhibitory control tasks (Júlio et al, 2019), but we acknowledge that further research is needed to examine this issue more specifically.…”