Attentional compensation in neurodegenerative diseases: the model of premanifest Huntington's disease mutation carriers

The ability of the brain to actively cope with neuropathological insults is known as neural compensation. It explains the delayed appearance of cognitive symptoms in neurodegenerative diseases. In contrast to the neural signature of compensation, its cognitive counterpart is largely unknown due to the difficulty of identifying cognitive dysfunctions concealed by compensation mechanisms. We combined computational modelling and neuroanatomical analysis to explore cognitive compensation. We used Huntingtons disease (HD) as a genetic model of neurodegenerative disease allowing to study compensation in premanifest mutation carriers (preHDs) free from overt cognitive deficits despite incipient brain atrophy. Twenty preHDs, 28 HD patients and 45 controls performed a discrimination task. We investigated the processes underlying cognitive compensation using drift diffusion models. They assume that the discrimination process relies on the accumulation of evidence at a certain rate and terminates when a response threshold is reached. HD patients performances were lower than controls and explained by a higher response threshold and a lower accumulation rate compared to controls. PreHDs performed similarly to controls but had a response threshold between those of controls and HD patients. This nascent increase in response threshold predicted the accumulation rate, which was faster than controls. This suggests that the higher accumulation rate conceals the nascent deficit in response threshold corroborating the capacity of the brain to resist neuropathological insults in preHDs. The higher accumulation rate was associated with parietal hypertrophy in mutation carriers, and with higher hippocampal volumes in preHDs suggesting that cognitive compensation may rely on attentional capacities. Significance statementEnhancing mechanisms compensating brain degeneration in neurodegenerative diseases might allow to delay their onset and progression. Yet, the cognitive mechanisms of compensation remain to be identified. In order to explore this issue, we used Huntingtons disease as a genetic model of neurodegenerative diseases and combined computational modelling (drift diffusion models) and neuroanatomical data analysis. In the early stage of the disease, before the appearance of overt cognitive symptoms, we showed the involvement of the left superior parietal cortex and hippocampus in maintaining normal behavioural performances. This suggests that attention is used to compensate for brain atrophy early in the disease. This work describes promising means of measuring and understanding compensation mechanisms in neurodegenerative diseases and might help developing new therapies.