Insensitivity to loss predicts apathy in huntington's disease

Abstract

Background Apathy is a deficit in goal‐directed behavior that significantly affects quality of life and function. It is common in Huntington's disease and other disorders affecting corticostriatal pathways. Deficits in processing of reward, altered effort, and executive dysfunction are associated with apathy in other disorders, but the cognitive processes leading to apathy in Huntington's disease remain largely unknown. A previously reported deficit in learning from losses in Huntington's disease raises the possibility of a hitherto unrecognized mechanism leading to apathy. This study's objective was to delineate the cognitive processes associated with apathy in HD. Methods We tested 51 Huntington's disease participants and 26 controls on a battery of novel and established measures to assess the contribution to apathy in Huntington's disease of executive function, reward value, reward‐effort calculations, instrumental learning, and response to reward and loss. Results Huntington's disase participants had deficits in instrumental learning with impaired response to loss, but no evidence to suggest altered reward‐related behavior or effort. We also saw an executive dysfunction contribution to apathy in Huntington's disease. Discussion We report the novel finding that apathy in Huntington's disease is associated with blunted responses to losses and impaired instrumental learning. This association is consistent with the known early degeneration of the indirect pathway and amygdala involvement in apathy in Huntington's disease, but is previously unreported in any disorder. In keeping with the comparative preservation of the ventral striatum and orbitofrontal cortex in Huntington's disease, reward valuation and reward‐effort calculations did not contribute to apathy. © 2019 International Parkinson and Movement Disorder Society

Different depression: motivational anhedonia governs antidepressant efficacy in Huntington’s disease

“…As we have previously reported, 64 mean reaction time (Fig. 2A, B and C, and Supplementary Tables 7-10) was faster for higher reward value trials in the whole group (estimate = −0.0027, P = 3.63 × 10 − 5), whilst Huntington's disease cases had slower reaction times than controls (best model included case status: weight = 0.62, estimate = 0.22, P = 0.032), even when corrected for TMS, which was also strongly associated with slower reaction times (P = 4.98 × 10 −5 ) (Fig.…”

“…We recruited 51 Huntington's disease participants from the South Wales Huntington's disease service as part of a wider study of neuropsychiatric symptoms in Huntington's disease 64,89 (disease stage: pre-symptomatic to Stage IV), and 26 controls were recruited both from family members not at risk of Huntington's disease, and university staff and students through local advertising. We excluded participants under the age of 18, Huntington's disease participants without a confirmatory gene test, pregnant women, and any participant with brain injury or brain disorder other than Huntington's disease.…”

“…54 It is also increasingly recognized that certain antidepressants are more effective at reversing selected cognitive processes underlying MDD compared with others: SSRIs are ineffective at treating (and may even worsen) consummatory anhedonia, 55,56 whilst drugs that increase noradrenergic tone are associated with increased arousal but may reduce effort for reward. [57][58][59][60] Current treatment options for depression in Huntington's disease rely on evidence gleaned from MDD; however, the mechanisms of depression in Huntington's disease may differ: it is known that Huntington's disease patients are comparatively insensitive to negative stimuli, [61][62][63][64] and the cognitive impairment may limit rumination in Huntington's disease. 65 Furthermore depression in other neurodegenerative diseases may not respond to antidepressants in the same way as MDD.…”

Excessive response to provocation rather than disinhibition mediates irritable behaviour in Huntington’s disease

“…First, although the verbal fluency task that we used as a measure of cognitive decline does have extensive evidence of dysfunction in HD ( Ho et al, 2002 ; Stout et al, 2011 ; Landwehrmeyer et al, 2016 ), showing differences from controls and longitudinal progression in premanifest and motor manifest participants, the symbol digit modality task and Stroop task show impairments earlier in the disease course and may be more sensitive to change in HD ( Stout et al, 2011 , 2014 ). Secondly, this study is part of a wider research project into the cognitive basis of neuropsychiatric dysfunction in HD ( McLauchlan, 2018 ; McLauchlan et al, 2019 ) and a total of 14 tasks were completed. Although we randomised task order for each participant, completing these tasks as part of the entire battery may have artificially accentuated irritability.…”

“…Participants completed a phonemic verbal fluency task as a measure of cognitive impairment–a standard assessment of cognition in HD ( Landwehrmeyer et al, 2016 ). This study was part of a wider research project into the cognitive basis of psychopathology in HD ( McLauchlan, 2018 ), the total battery of 14 tasks also included tasks measuring motivation, learning, estimation and other cognitive processes hypothesised to contribute to apathy ( McLauchlan et al, 2019 ) and depression ( McLauchlan et al, 2022 ), although there is no overlap with the tasks and questionnaires presented in this work. The battery was administered in random order.…”