Neuropsychological and neuroimaging changes have been observed in individuals with the Huntington's disease (HD) gene expansion prior to the onset of manifest HD. This cross-sectional fMRI study of preclinical HD (pre-HD) individuals was conducted to determine if functional brain changes precede deficits in behavioral performance and striatal atrophy. Twenty-six pre-HD and 13 demographically matched healthy participants performed a time reproduction task while undergoing fMRI scanning. Pre-HD participants were divided into two groups (n=13 each): FAR (>12 years to estimated onset [YEO] of manifest HD) and CLOSE (<12 YEO). The CLOSE group demonstrated behavioral deficits, striatal atrophy, and reduced neural activation in the left putamen, SMA, left anterior insula and right inferior frontal gyrus. The FAR group showed reduced neural activation in the right anterior cingulate and right anterior insula. The FAR group also demonstrated increased neural activation in the left sensorimotor, left medial frontal gyrus, left precentral gyrus, bilateral superior temporal gyri and right cerebellum. The fMRI changes in the FAR group occurred in the relative absence of striatal atrophy and behavioral performance deficits. These results suggest that fMRI is sensitive to neural dysfunction occurring more than 12 years prior to the estimated onset of manifest HD.

Time perception emerges from an interaction among multiple processes that are normally intertwined. Therefore, a challenge has been to disentangle timekeeping from other processes. Though the striatum has been implicated in interval timing, it also modulates nontemporal processes such as working memory. To distinguish these processes, we separated neural activation associated with encoding, working-memory maintenance, and decision phases of a time-perception task. We also asked whether neuronal processing of duration (i.e., pure tone) was distinct from the processing of identity (i.e., pitch perception) or sensorimotor features (i.e., control task). Striatal activation was greater when encoding the duration than the pitch or basic sensory features, which did not differentially engage the striatum. During the maintenance phase, striatal activation was similar for duration and pitch but at baseline in the control task. In the decision phase, a stepwise reduction in striatal activation was found across the 3 tasks, with activation greatest in the timing task and weakest in the control task. Task-related striatal activations in different cognitive phases were distinguished from those of the supplementary motor area, inferior frontal gyrus, thalamus, frontoparietal cortices, and the cerebellum. Our results were consistent with a model in which timing emerges from context-dependent corticostriatal interactions.

Huntington's disease (HD) is a neurodegenerative disorder diagnosed clinically with the development of choreiform movements. However, neuropsychological studies have demonstrated cognitive and psychiatric changes during the preclinical phase (pre-HD) prior to formal diagnosis. Previous studies have demonstrated the sensitivity of time reproduction tasks to basal ganglia pathology, as seen in clinical HD and Parkinson's disease. In this study, 29 pre-HD participants, ranging from 3 to 39 years from estimated onset (YEO) of HD based on genetic testing and chronological age, were administered the paced finger-tapping task using target intervals of 600 and 1200 ms. Mean inter-response interval, a measure of timing accuracy, did not systematically deviate from the target interval as a function of YEO. In contrast, timing variability increased curvilinearly as a function of YEO, but not with chronological age alone. Motor timing variability, but not accuracy, may serve as a marker to define the earliest behavioral changes in HD. The present study is among the first to examine the relationship between behavioral measures and YEO in pre-HD.

Studies involving brain-lesioned subjects have used the paced finger tapping (PFT) task to investigate the neural systems that govern motor timing. Patients with Parkinson's disease (PD), for example, demonstrate abnormal performance on the PFT, characterized by decreased accuracy and variability changes, suggesting that the basal ganglia may play a critical role in motor timing. Consistent with this hypothesis, an fMRI study of healthy participants demonstrated that the medial frontostriatal circuit (dorsal putamen, ventrolateral thalamus, SMA) correlated with explicit time-dependent components of the PFT task. In the current fMRI study, PD patients and healthy age-matched controls were imaged while performing the PFT. PD patients underwent 2 imaging sessions, 1 on and the other off dopamine supplementation. Relative to controls, PD patients were less accurate and showed greater variability on the PFT task relative to controls. No PFT performance differences were observed between the on and off medication states despite significantly greater motor symptoms on the Unified Parkinson's Disease Rating Scale (UPDRS) in the off medication state. Functional imaging results demonstrated decreased activation within the sensorimotor cortex (SMC), cerebellum, and medial premotor system in the PD patients compared to controls. With dopamine replacement, an increase in the spatial extent of activation was observed within the SMC, SMA, and putamen in the PD patients. These results indicate that impaired timing reproduction in PD patients is associated with reduced brain activation within motor and medial premotor circuits. Despite a lack of improvement in PFT performance, PD patient's brain activation patterns were partially "normalized" with dopamine supplementation. These findings could not be attributed to greater head movement artifacts or basal ganglia atrophy within the PD group.