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Background Huntington's disease (HD) is associated with difficulty performing concurrent tasks, an ability which is a requirement of everyday activities and of potential functional significance in HD. Aims We compared dual task performance in HD and healthy controls using choice reaction time (CRT) with digit span tasks. We manipulated task difficulty and tested for interactions between difficulty level and group which would indicate differential effects of difficulty on dual tasking in HD. Methods/techniques 14 participants in the early stages of HD and 14 controls performed two series of dual tasks. Series one paired simple CRT with digit span forward; series two paired complex CRT with digit span backward. Each of the tasks within each series had easy and hard conditions. In the simple CRT easy condition participants viewed single letters and had to press a key labelled Yes if the letter was X or Z or No for other letters. For the hard condition, there were four target letters (X, Z, O, Y); participants had to repeat four (easy) or five (hard) digits forward. The complex CRT task comprised 333 matrices of Xs and Os. Participants had to respond whether three Xs (easy) or three Xs or three Os (hard) appeared in a row. Complex CRT was paired with three (easy) or four (hard) digit span backward. Task order was counterbalanced for series, but within series it was proceeded from easier to harder pairs. Measures were speed and accuracy. Results/outcome Participants with HD were slower and less accurate, a finding that, surprisingly, was more profound in the simple CRT with digit span forward than in the more difficult conditions. Error rates were higher in HD when the simple CRT tasks were performed with the hard digit span forward, suggesting that task difficulty may affect cognitive load in HD. Conclusion Simple CRT with digit span forward appeared to be more affected in HD than complex CRT with digit span backwards, suggesting that impaired automaticity may underlie

Background Functional changes in the brain have been shown in both premanifest Huntington's disease (pre-HD) and symptomatic HD (symp-HD) individuals during both cognitive and motor task performance. Aims One aim of the IMAGE-HD study is to improve understanding of functional brain reorganisation during pre-HD via functional MRI (fMRI). Here, we report on the longitudinal investigation of working memory using a modified version of the N-BACK paradigm consisting of 0-BACK, 1-BACK, and 2-BACK conditions. We report only on 0-BACK and 1-BACK for this investigation. Methods Participants were recruited as part of IMAGE-HD and were assessed at baseline and 18 months. Data for a total of 70 participants was included in the analyses (19 symp-HD, 28 pre-HD and 23 controls). Results Behavioural results revealed a significant difference in the rate of change in per cent correct between controls and symp-HD participants (0-BACK only) and shorter response times for controls (0-BACK and 1-BACK). FMRI showed decreased BOLD activations at 18 months for controls in frontal and parietal regions and only within the parietal region for symp-HD. There was significantly increased BOLD activation across a number of cortical and subcortical regions at 18 months in the pre-HD group. Pair-wise correlation based functional connectivity analysis was used to evaluate synchronicity in neuronal activity between various cortical and sub-cortical regions that showed robust activation during 1- BACK performance (ie, prefrontal, posterior, parietal, caudate, and cingulate areas). We found a significant longitudinal reduction in connectivity only for the pre-HD group, specifically between prefrontal and parietal regions with anterior cingulate. Conclusions These findings demonstrate that functional and connectivity changes occur well before disease onset. The increased functional activation, taken together with decreased functional connectivity, may offer new and important insights on brain compensatio

Huntington's disease (HD) affects GABA-mediated inhibitory circuitry in the cortex. As there is evidence that sex hormones affect GABAergic function, we investigated whether gender modulates GABA-related pathophysiological changes in HD. Fifteen premanifest HD, 11 symptomatic HD and 16 healthy control participants were assessed with paired-pulse transcranial magnetic stimulation applied to the primary motor cortex. Cortical inhibition was significantly reduced in symptomatic HD, compared with premanifest HD and controls. There was reduced inhibition in females overall, but no Group-by-Sex interaction. These findings suggest that sex hormones do not exert a direct influence on the mechanisms underpinning cortical inhibitory deficits in HD.Copyright © 2016 Elsevier Ireland Ltd

Striatal degeneration in Huntington's disease (HD) causes changes in cortico-subcortical pathways. Transcranial magnetic stimulation (TMS) is a valuable tool for assessing pathophysiology within these pathways, yet has had limited application in HD. As cortico-subcortical pathways are largely mediated by GABA and dopamine receptor genes, understanding how these genes modulate neurophysiology in HD may provide new insights into how underlying pathology maps onto clinical phenotype. Twenty-nine participants with HD underwent motor cortex stimulation, while corticospinal excitability, cortical inhibition and intracortical facilitation were indexed via peripheral electromyography. Single-nucleotide polymorphism mapping was performed across six genes that are known to modulate cortico-subcortical pathways (GABRA2, GABBR1, GABBR2, DRD1, DRD2, DRD4). Genetic associations with six TMS measures and age at onset were investigated. Our hierarchical multiple regression analysis, controlling for CAG and age, revealed that a GABBR2 variant, predicted to be disease-causative, was significantly associated with corticospinal excitability at corrected levels. A subsequent uncorrected exploratory analysis revealed associations between GABBR2, GABRA2 and DRD2 variants with TMS measures of corticospinal excitability and cortical inhibition in HD, as well as with age at onset. Our findings support the notion that uncovering genetic associations with pathophysiological measures and age at onset is an important way forward in terms of generating meaningful biomarkers with diagnostic and prognostic sensitivity, and identifying novel human-validated targets for future clinical trials.Copyright © 2016 Elsevier Ireland Ltd.

Subjective reports of sleep disturbance are a common feature of Huntington's disease (HD); however, there is limited research investigating the relationship between sleep problems with changes in brain and behaviour. This study aimed to investigate whether subjective reports of sleep problems in HD are associated with brain volume, neurocognitive decline, and neuropsychiatric symptoms. This retrospective pilot study used brain volume, neurocognitive and neuropsychiatric data from premanifest (pre-HD) and symptomatic HD (symp-HD). Subjective sleep problem was measured using the sleep item of the Beck's Depression Inventory-II (BDI-II). Pre-HD individuals reporting sleep problems had significantly poorer neuropsychiatric outcomes compared to those not reporting sleep problems. In the symp-HD group, those with sleep problems had significantly accelerated thalamic degeneration and poorer neuropsychiatric outcomes compared to those without sleep problems. There was no relationship between subjective sleep problems and neurocognitive measures. These findings suggest an association between subjective sleep disturbance, neuropathology, and development of neuropsychiatric symptoms in HD. Further studies using quantitative EEG-based monitoring of sleep in HD and changes in the brain and behaviour will be necessary to establish the causal nature of this relationship.Copyright © 2016 Elsevier B.V. All rights reserved.

Objectives: To measure iron accumulation in the basal ganglia in Huntington's disease (HD) using quantitative susceptibility mapping (QSM), and to ascertain its relevance in terms of clinical and disease severity. Method(s): In this cross-sectional investigation, T2* weighted imaging was undertaken on 31 premanifest HD, 32 symptomatic HD and 30 control participants as part of the observational IMAGE-HD study. Group differences in iron accumulation were ascertained with QSM. Associations between susceptibility values and disease severity were also investigated. Result(s): Compared with controls, both premanifest and symptomatic HD groups showed significantly greater iron content in pallidum, putamen and caudate. Additionally, iron accumulation in both putamen and caudate was significantly associated with disease severity. Conclusion(s): These findings provide the first evidence that QSM is sensitive to iron deposition in subcortical target areas across premanifest and symptomatic stages of HD. Such findings could open up new avenues for biomarker development and therapeutic intervention.Copyright © 2016, BMJ Publishing Group. All rights reserved.

Neuropsychiatric disturbances are common in Huntingtons Disease (HD) and have been observed in genepositive individuals several years prior to the onset of motor symptoms. The neural mechanism underpinning the development of neuropsychiatric problems in HD remain unclear. Objective(s): To investigate whether neural activity during working memory is associated with neuropsychiatric symptoms in premanifest Huntingtons Disease. Method(s): functional magnetic resonance imaging (fMRI) data from Pre-HD far from onset (pre-HDfar , n = 18), pre-HD close to onset (pre-HDclose , n = 17), and controls (n = 32) were analysed. Correlations were performed between fMRI activity in three regions of interest [bilateral dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC)] and neuropsychiatric scores. Result(s): In the pre-HDclose group, increased symptoms of obsessive compulsion and depression were associated with decreased blood-oxygen-level-dependent (BOLD) fMRI activity in the right DLPFC and ACC during 1-BACK and 2-BACK working memory conditions. In the pre-HDfar group increased symptoms of depression was associated with decreased right DLPFC BOLD fMRI activity during 2-BACK working memory only. Conclusion(s): The findings suggest that association between neuropsychiatric function and fMRI activity is more readily detectable at higher working memory loads, and becomes more pronounced in those closer to onset.Copyright © 2015 IOS Press and the authors. All rights reserved.

BACKGROUND: Huntington's disease (HD) causes progressive atrophy to the striatum, a critical node in frontostriatal circuitry. Maintenance of motor function is dependent on functional connectivity of these premotor, motor, and dorsolateral frontostriatal circuits, and structural integrity of the striatum itself. We aimed to investigate whether size and shape of the striatum as a measure of frontostriatal circuit structural integrity was correlated with functional frontostriatal electrophysiological neural premotor processing (contingent negative variation, CNV), to better understand motoric structure-function relationships in early HD. METHODS: Magnetic resonance imaging (MRI) scans and electrophysiological (EEG) measures of premotor processing were obtained from a combined HD group (12 presymptomatic, 7 symptomatic). Manual segmentation of caudate and putamen was conducted with subsequent shape analysis. Separate correlational analyses (volume and shape) included covariates of age, gender, intracranial volume, and time between EEG and MRI. RESULTS: Right caudate volume correlated with early CNV latency over frontocentral regions and late CNV frontally, whereas right caudate shape correlated with early CNV latency centrally. Left caudate volume correlated with early CNV latency over centroparietal regions and late CNV frontally. Right and left putamen volumes correlated with early CNV latency frontally, and right and left putamen shape/volume correlated with parietal CNV slope. CONCLUSIONS: Timing (latency) and pattern (slope) of frontostriatal circuit-mediated premotor functional activation across scalp regions were correlated with abnormalities in structural integrity of the key frontostriatal circuit component, the striatum (size and shape). This was accompanied by normal reaction times, suggesting it may be undetected in regular tasks due to preserved motor "performance." Such differences in functional activation may reflect atrophy-based frontostriatal circuitr

BACKGROUND: There is evidence that sensitivity to noxious stimuli differs between the sexes and across the body, but few studies have investigated differences in the perception and experience of acute pain stimuli across the body in healthy individuals. METHODS: We recruited 52 healthy participants, aged 18-36 (50% men) and administered 39, 42 and 45 °C stimuli at four body sites bilaterally to examine differences in the experience of pain intensity and unpleasantness between body sites via an 11-point numerical rating scale. RESULTS: Noxious and innocuous thermal heat stimuli were perceived as significantly more intense when delivered to the wrist (M = 3.98, SD = 1.93) and back (M = 4.07, SD = 1.98) compared to the shoulder (M = 3.45, SD = 1.91) and leg (M = 3.46, SD = 1.87). Pain unpleasantness ratings yielded similar findings; stimuli were perceived as more unpleasant when administered to the wrist (M = 2.83, SD = 1.93) and lower back (M = 3.04, SD = 2.11) compared to the shoulder (M = 2.63, SD = 1.85) and leg (M = 2.26, SD = 1.82). CONCLUSIONS: These findings suggest that painful thermal stimuli delivered to the wrist and back are perceived as more intense and unpleasant compared with other body sites in healthy persons. These differences may be due to variations in receptor density, or the relative importance of these sites for daily living and survival. SIGNIFICANCE: Moreover, these insights are helpful for the design of studies investigating pain experience in healthy persons in experimental or clinical settings. WHAT DOES THIS STUDY ADD?: We tested sensitivity to acute suprathreshold thermal stimulations across a range of body sites to investigate for potential variability. We found significant differences in the perceived intensity and unpleasantness of noxious and innocuous thermal stimuli at the wrist and lower back, compared with the shoulder and leg. These results suggest that pain experience is driven by receptor density or the relative functional impo

Background: Past research has found cancellation tasks to be reliable markers of cognitive decline in Huntington's disease (HD). Objective(s): The aim of this study was to extend previous findings by adopting the use of a dual task paradigm that paired cancellation and auditory tasks. Method(s): We compared performance in 14 early stage HD participants and 14 healthy controls. HD participants were further divided into groups with and without cognitive impairment. Result(s): Results suggested that HD participants were not slower or less accurate compared with controls; however, HD participants showed greater dual task interference in terms of speed. In addition, HD participants with cognitive impairment were slower and less accurate than HD participants with no cognitive impairment, and showed greater dual task interference in terms of speed and accuracy. Conclusion(s): Our findings suggest that dual task measures may be a better measure of cognitive processing in HD compared with more traditional measures.Copyright © 2015 - IOS Press and the authors. All rights reserved.

This study investigated whether dual tasks make disproportionately high demands in Huntington's disease (HD) compared with controls, and also tested the Multiple Resources Theory. Method(s): Thirteen HD participants and 13 controls completed 2 dual task sets that varied in difficulty and complexity: Set 1 paired simple choice reaction time (RT) with digit forward, and Set 2 paired complex choice RT with digit backward. Result(s): We found that HD participants were overall slower; however, although they maintained similar levels of accuracy in the simple choice RT tasks with controls, their accuracy decreased in the complex choice RT tasks. In addition, we found that HD participants were more susceptible to speed-accuracy trade-offs. Despite that, they did not show greater dual task costs than controls. Conclusion(s): Overall, our findings do not support the Multiple Resources Theory, but they do provide some support for the Unitary Resource Theory and the attentional impairment hypothesis.Copyright © 2014 American Psychological Association.

Although progress has been made towards understanding the gross cortical and subcortical pathology of Huntington's disease (HD), there remains little understanding of the progressive pathophysiological changes that occur in the brain circuits underlying the disease. Transcranial magnetic stimulation (TMS) enables investigation of the functional integrity of cortico-subcortical pathways, yet it has not been widely applied in HD research to date. This study sought to characterise profiles of cortical excitability, including inhibition and facilitation, in groups of premanifest and symptomatic HD participants via the use of TMS. We also investigated the clinical, neurocognitive and psychiatric correlates of cortical excitability to better understand the development of phenotypic heterogeneity. The sample comprised 16 premanifest HD, 12 early symptomatic HD and 17 healthy control participants. Single- and paired-pulse TMS protocols were administered to the left primary motor cortex, with surface electromyography recorded from the abductor pollicis brevis muscle. Short-interval cortical inhibition was significantly reduced in symptomatic HD, compared with premanifest HD and controls, and was significantly correlated with pathological burden and neurocognitive performance. There was also reduced long-interval cortical inhibition in both premanifest and symptomatic HD, compared with controls, which was associated with pathological burden and psychiatric disturbances. Motor thresholds, cortical silent periods and intracortical facilitation did not differ across groups. Our results provide important new insights into pathophysiological changes in cortico-subcortical circuits across disease stages in HD. We propose that neurophysiological measures obtained via TMS have potential utility as endophenotypic biomarkers in HD, given their association with both pathological burden and clinical phenotype.Copyright © 2015 Published by Elsevier B.V.

Background A better understanding of pathophysiological abnormalities in key cortico-subcortical pathways in Huntington's disease (HD) will enhance our understanding of the causal relationships between the gene mutation and symptomatology during disease progression. Aims Transcranial magnetic stimulation (TMS), with a pairedpulse paradigm, was used to assess cortical excitability and inhibition in eight individuals with early symptomatic HD (symp-HD; mean age=56.0 years), twelve individuals with premanifest HD (pre-HD; mean age=41.5 years), and eight healthy controls (mean age=43.1 years). Methods Following TMS to left motor cortex, electromyographic (EMG) responses were recorded from the right abductor pollicis brevis muscle at rest. Amplitudes of motor-evoked potentials (MEPs), after paired-pulse stimulation, were compared to MEPs elicited by single pulses, and the degree of inhibition was calculated. Results Resting motor threshold was significantly lower in pre- HD compared with symp-HD and controls, whereas symp-HD did not differ from controls. Symp-HD individuals had significantly reduced short-interval cortical inhibition (SICI) compared with pre-HD and controls, whereas pre-HD did not differ from controls. Further, investigation of the relationship between these electrophysiological indices and neurocognitive measures revealed that for pre-HD and symp-HD individuals, the degree of SICI was significantly correlated with finger tapping performance. Conclusions These findings suggest very early pathophysiological changes during the premanifest stages of HD. In pre-HD, increased cortical excitability may be an early compensatory response to the neurodegenerative changes in cortico-striatal circuits. Our preliminary data suggest that TMS-EMG may be a sensitive tool for teasing apart the compensatory response observed during the premanifest stages of HD.

Huntington's disease (HD) is associated with impairments in dual-task performance. Despite that, only a few studies have investigated dual-tasking in HD. We examined dual-task performance in 15 participants in the early stages of HD and 15 healthy controls. Participants performed direct circle tracing (able to view arm) and indirect circle tracing (arm obscured) either on their own (single tasks) or paired with serial subtraction by twos or threes (dual tasks). Overall, our results suggested that HD participants were significantly slower and less accurate than controls. Both groups were slower and less accurate when performing indirect circle tracing compared with direct circle tracing. HD participants experienced greater dual-task interference in terms of accuracy when performing direct circle tracing compared with indirect circle tracing. Despite that, controls were more inclined to speed-accuracy trade-offs compared with HD participants. Importantly, unlike controls, HD participants were not disproportionately faster when performing direct circle tracing as a single task compared with the dual-task conditions. Our results suggest that simple tasks place greater attentional demands on HD participants compared with controls. These findings support that impaired automaticity may be responsible for some of the attentional deficits manifested in HD.Copyright © 2014, Springer-Verlag Berlin Heidelberg.

Background Huntington's disease (HD) is associated with difficulty in dual-tasking, which is performing two tasks at the same time. Aims We investigated whether different dual-tasks and levels of difficulty are affected in people with early HD. Methods/techniques Twelve HD participants and 12 controls performed four pairs of dual-tasks. Each task within each dual-task had easy and hard levels. Pair 1 was circle tracing with counting backward: participants traced a circle while viewing (easy) or not viewing their arm (hard), and counted backward in twos (easy) or threes (hard). Pair 2 was simple choice reaction time (CRT) with digit forward: participants viewed single letters and responded to two (easy) or four target letters (hard) while repeating 4 (easy) or 5 (hard) digits forward. Pair 3 was complex CRT with digit backward: participants viewed 3X3 matrices of Xs and Os. They responded whether 3 Xs (easy) or 3 Xs or 3 Os (hard) appeared in a row, while repeating 3 (easy) or 4 (hard) digits backward. Pair 4 was cancellation with auditory tasks. Participants circled the target letter O on a sheet with distractor letters: other letters (easy) or the letter Q (hard). Concurrently, they reported the number of high-pitched sounds from a series of high-pitched sounds (easy) or a combination of high- and low-pitched sounds (hard). We measured speed and accuracy. Results/outcome Participants with HD were slower and less accurate across all task conditions, compared to controls. Dualtasks were performed slower and less accurately than single tasks; and harder levels slower and less accurately than easier levels. Differences reached statistical significance either in terms of speed or in terms of accuracy within each task pair. Conclusion Our findings suggest differential effects of dual-task performance on HD versus controls, and highlight the importance of considering different performance measures, as the relationship between HD and these measures may be different.

Background Changes in prefrontal brain responses as well as psychiatric deficits are detected in Huntington's disease (HD) prior to diagnosis. Aims This study investigated the relationship between psychiatric symptoms and functional brain activity during working memory performance in individuals with pre-symptomatic hd (prehd) using the image-hd data set. Methods/techniques Pre-HD far from onset (pre-hd far, n = 17), pre-hd close to onset (pre-hd close, n = 18), and control (n = 32) groups completed an n-back task (0, 1 and 2-back) during functional magnetic resonance imaging (fMRI). Brain regions of interest included the bilateral dorsolateral prefrontal cortex (dlpfc) and anterior cingulate cortex (acc). Correlations were performed between blood-oxygen-level-dependent (bold) activity in each brain region and scores on a battery of neuropsychiatric inventories, while controlling for age, gender, and accuracy on the n-back task. Results/outcome For both 1- and 2-back conditions, significant negative correlations were found in the pre-hd close group between neuropsychiatric disturbance and bold activation in both the right dlpfc and acc. During 2-back, a significant negative correlation was found in the pre-hd far group between depression symptoms and right dlpfc bold. For 1-back, no significant correlations were found in the pre-hd far group. Conclusions These findings suggest that as pre-hd individuals approach onset, increased psychiatric disturbance is associated with decreased functional brain activity, which becomes more wide-spread during higher working memory loads.

Background: Voluntary motor deficits are a common feature in Huntington's disease (HD), characterised by movement slowing and performance inaccuracies. This deficit may be exacerbated when visual cues are restricted. Objective(s): To characterize the upper limb motor profile in HD with various levels of difficulty, with and without visual targets. Method(s): Nine premanifest HD (pre-HD), nine early symptomatic HD (symp-HD) and nine matched controls completed a motor task incorporating Fitts' law, a model of human movement enabling the quantification of movement timing, via the manipulation of task difficulty (i.e., target size, and distance between targets). The task required participants to make reciprocal movements under cued and blind conditions. Dwell times (time stationary between movements), speed, accuracy and variability of movements were compared between groups. Result(s): Symp-HD showed significantly prolonged and less consistent movement times, compared with controls and pre-HD. Furthermore, movement planning and online control were significantly impaired in symp-HD, compared with controls and pre-HD, evidenced by prolonged dwell times and deceleration times. Speed and accuracy were comparable across groups, suggesting that group differences observed in movement time, variability, dwell time and deceleration time were evident over and above simple performance measures. The presence of cues resulted in greater movement time variability in symp-HD, compared with pre-HD and controls, suggesting that the deficit in movement consistency manifested only in response to targeted movements. Conclusion(s): Collectively, these findings provide evidence of a deficiency in both motor planning, particularly in relation to movement timing and online control, which became exacerbated as a function of task difficulty during symp-HD stages. These variables may provide a more sensitive measure of motor dysfunction than speed and/or accuracy alone in symp-HD.Copyright © 2015

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Non-motor symptoms and signs such as psychiatric disturbances, sleep problems and metabolic dysfunction are part of the disease manifestation. These aspects may relate to changes in the hypothalamus, an area of the brain involved in the regulation of emotion, sleep and metabolism. Neuropathological and imaging studies using both voxel-based morphometry (VBM) of magnetic resonance imaging (MRI) as well as positron emission tomography (PET) have demonstrated pathological changes in the hypothalamic region during early stages in symptomatic HD. In this investigation, we aimed to establish a robust method for measurements of the hypothalamic volume in MRI in order to determine whether the hypothalamic dysfunction in HD is associated with the volume of this region. Using T1-weighted imaging, we describe a reproducible delineation procedure to estimate the hypothalamic volume which was based on the same landmarks used in histologically processed postmortem hypothalamic tissue. Participants included 36 prodromal HD (pre-HD), 33 symptomatic HD (symp-HD) and 33 control participants who underwent MRI scanning at baseline and 18 months follow-up as part of the IMAGE-HD study. We found no evidence of cross-sectional or longitudinal changes between groups in hypothalamic volume. Our results suggest that hypothalamic pathology in HD is not associated with volume changes.Copyright © 2015 PLOS ONE.

Background Huntington's disease (HD) is a neurodegenerative disorder associated with both micro and macro structural changes in the brain. Better characterization of longitudinal changes in white matter microstructure is necessary to provide potential new biomarkers to track the effectiveness of potential therapeutics. Aims To investigate 18 month longitudinal changes in white matter microstructure in premanifest (pre-HD) and symptomatic (symp-HD) Huntington's disease. Method/techniques Longitudinal analysis of diffusion tensor imaging (DTI) data was conducted for 28 pre-HD, 25 symp- HD, and 27 controls scanned at baseline and after 18 months. We developed an automated unbiased tensor-based registration pipeline to register diffusion tensor data across time and groups. A tract-based spatial statistics (TBSS) method was used to identify longitudinal changes in fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) in pre-HD and symp- HD compared to controls. Between-group-differences in the change over time was identified non-parametric permutation based comparison. Partial correlations were performed between baseline clinical symptoms (UHDRS) and 18-month change in FA values. Results/outcome Symp-HD, compared to controls, showed an 18-month reduction in FA in corpus callosum and cingulum white matter. Symp-HD, compared to pre-HD, also showed 18 month increased RD in widespread white matter pathways, including corpus callosum, internal capsule, and striatal projection pathways. There was no longitudinal between-group difference in AD. There was a significant correlation between 18- month change in FA and baseline UHDRS across both HD groups. Conclusions We provide the first direct evidence of progressive disease related decline in white matter microstructure in HD, which offers a potentially new sensitive biomarker for future therapeutics.

Recent evidence suggests that early changes in postural control may be discernible among females with premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene at risk of developing fragile X-associated tremor ataxia syndrome (FXTAS). Cerebellar dysfunction is well described in males and females with FXTAS, yet the interrelationships between cerebellar volume, CGG repeat length, FMR1 messenger RNA (mRNA) levels and changes in postural control remain unknown. This study examined postural sway during standing in a cohort of 22 males with the FMR1 premutation (ages 26-80) and 24 matched controls (ages 26-77). The influence of cerebellar volume, CGG repeat length and FMR1 mRNA levels on postural sway was explored using multiple linear regression. The results provide preliminary evidence that increasing CGG repeat length and decreasing cerebellar volume were associated with greater postural sway among premutation males. The relationship between CGG repeat length and postural sway was mediated by a negative association between CGG repeat size and cerebellar volume. While FMR1 mRNA levels were significantly elevated in the premutation group and correlated with CGG repeat length, FMR1 mRNA levels were not significantly associated with postural sway scores. These findings show for the first time that greater postural sway among males with the FMR1 premutation may reflect CGG repeat-mediated disruption in vulnerable cerebellar circuits implicated in postural control. However, longitudinal studies in larger samples are required to confirm whether the relationships between cerebellar volume, CGG repeat length and postural sway indicate greater risk for neurological decline. Cerebellar volume as a mediator of the effect of CGG repeat length on postural sway in FMR1 premutation males.

Objective: To determine the extent and nature of driving self-regulation in drivers with Parkinson disease (PD) and factors associated with self-regulatory practices. Background(s): Although people with PD have consistently been shown to have driving impairments, few studies have examined self-regulatory driving practices and their relationship to driving performance. Method(s): We used a self-report driving questionnaire to examine driving self-regulation in 37 drivers with PD and 37 healthy agematched controls. We also analyzed factors associated with self-regulatory practices, primarily demographic, disease-related, psychological, and simulated driving performance variables. Result(s): The drivers with PD reported significantly higher rates of self-perceived decline in their driving ability (P = 0.008) and driving significantly shorter distances per week (P = 0.004) than controls. Unfamiliar situations (P = 0.009), in-car distractions (P < 0.001), low visibility conditions (P = 0.004), and long journeys (P = 0.003) were particularly challenging for the drivers with PD, and their pattern of driving avoidance mirrored these difficulties. The use of self-regulatory strategies among drivers with PD was associated with female sex (rho = 0.42, P = 0.009) and perceived decline in driving ability (rho = - 0.55, P < 0.001), but not with age or objective measures of disease severity, cognition, or simulated driving performance. Conclusion(s): Drivers with PD reported driving less overall and restricting their driving to avoid particularly difficult circumstances. Further research is warranted on effective use of self-regulation strategies to improve driving performance in people with PD.Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene. Non-motor symptoms and signs such as psychiatric disturbances, sleep problems and metabolic dysfunction are part of the disease manifestation. These aspects may relate to changes in the hypothalamus, an area of the brain involved in the regulation of emotion, sleep and metabolism. Neuropathological and imaging studies using both voxel-based morphometry (VBM) of magnetic resonance imaging (MRI) as well as positron emission tomography (PET) have demonstrated pathological changes in the hypothalamic region during early stages in symptomatic HD. In this investigation, we aimed to establish a robust method for measurements of the hypothalamic volume in MRI in order to determine whether the hypothalamic dysfunction in HD is associated with the volume of this region. Using T1-weighted imaging, we describe a reproducible delineation procedure to estimate the hypothalamic volume which was based on the same landmarks used in histologically processed postmortem hypothalamic tissue. Participants included 36 prodromal HD (pre-HD), 33 symptomatic HD (symp-HD) and 33 control participants who underwent MRI scanning at baseline and 18 months follow-up as part of the IMAGE-HD study. We found no evidence of cross-sectional or longitudinal changes between groups in hypothalamic volume. Our results suggest that hypothalamic pathology in HD is not associated with volume changes.

BACKGROUND: Huntington's disease (HD) causes progressive motor dysfunction through characteristic atrophy. Changes to neural structure begin in premanifest stages yet individuals are able to maintain a high degree of function, suggesting involvement of supportive processing during motor performance. Electroencephalography (EEG) enables the investigation of subtle impairments at the neuronal level, and possible compensatory strategies, by examining differential activation patterns. We aimed to use EEG to investigate neural motor processing (via the Readiness Potential; RP), premotor processing and sensorimotor integration (Contingent Negative Variation; CNV) during simple motor performance in HD. METHODS: We assessed neural activity associated with motor preparation and processing in 20 premanifest (pre-HD), 14 symptomatic HD (symp-HD), and 17 healthy controls. Participants performed sequential tapping within two experimental paradigms (simple tapping; Go/No-Go). RP and CNV potentials were calculated separately for each group. RESULTS: Motor components and behavioural measures did not distinguish pre-HD from controls. Compared to controls and pre-HD, symp-HD demonstrated significantly reduced relative amplitude and latency of the RP, whereas controls and pre-HD did not differ. However, early CNV was found to significantly differ between control and pre-HD groups, due to enhanced early CNV in pre-HD. CONCLUSIONS: For the first time, we provide evidence of atypical activation during preparatory processing in pre-HD. The increased activation during this early stage of the disease may reflect ancillary processing in the form of recruitment of additional neural resources for adequate motor preparation, despite atrophic disruption to structure and circuitry. We propose an early adaptive compensation mechanism in pre-HD during motor preparation.

Background: Huntington's disease (HD), is accompanied by marked neostriatal atrophy that occurs more than 10 years before clinical onset. Multiple imaging modalities have been used in the search for a biomarker in HD, including the use of MRI for volumetric analysis of the neostriatum, most recently with automated measures. The gold standard for volumetric analysis of the neostriatum however remains manual segmentation. Using this method and scans from the Australian-based IMAGE-HD study we sought to extend the current understanding of neostriatal atrophy as a potential biomarker in HD. We used manual segmentation to quantify longitudinal changes in neostriatal volume in people with premanifest and manifest HD, compared with controls. Method(s): T1-weighted MRI scans were taken of 36 individuals with premanifest HD (pre-HD), 37 with early symptomatic HD (symp-HD), and 36 healthy matched control subjects. Individuals were scanned at baseline, 18 and 30 months. Neostriatal (putaminal and caudate) volumes for each scan were determined by manual tracing according to a validated protocol (intra-rater intraclass correlation (0.88-0.98)). Volumetric differences between groups were tested with multivariate analysis of covariance (with age and intracranial volume as covariates), while longitudinal changes were tested with one-way repeated measures ANOVA. Result(s): Cross-sectional caudate and putaminal volumes were found to be significantly different across all groups, with control volumes larger than pre-HD, and pre-HD larger than symp-HD (p >= 0.001). Furthermore, there was a significant decrease in putaminal volume from the initial scan to 18 months follow-up in both pre-HD and symp-HD (p < 0.001), but not in control subjects. Over 30 months there was a significant decrease in bilateral putamen volumes in control subjects (6.1% reduction, p = 0.002), pre- HD (9.9% reduction, p < 0.001) and symp-HD groups (19.3%, p < 0.001). Despite the differences between groups, no signi

Background: Functional neural impairments have been documented in people with symptomatic Huntington disease (symp-HD) and in premanifest gene carriers (pre-HD). This study aimed to characterize synchrony in resting state cerebral networks in both pre-HD and symp-HD populations and to determine its association with disease burden and neurocognitive functions. Method(s): We acquired functional magnetic resonance imaging (fMRI) data from pre-HD, symp-HD and healthy control participants. The fMRI data were analyzed using multisubject independent component analysis and dual regression. We compared networks of interest among the groups using a nonparametric permutation method and correcting for multiple comparisons. Result(s): Our study included 25 people in the pre-HD, 23 in the symp-HD and 18 in the healthy control groups. Compared with the control group, the pre-HD group showed decreased synchrony in the sensorimotor and dorsal attention networks; decreased level of synchrony in the sensorimotor network was associated with poorer motor performance. Compared with the control group, the symp-HD group showed widespread reduction in synchrony in the dorsal attention network, which was associated with poorer cognitive performance. The posterior putamen and superior parietal cortex were functionally disconnected from the frontal executive network in the symp-HD compared with control and pre-HD groups. Furthermore, the left frontoparietal network showed areas of increased synchrony in the symp-HD compared with the pre-HD group. Limitation(s): We could not directly correct for influence of autonomic changes (e.g., heart rate) and respiration on resting state synchronization. Conclusion(s): Our findings suggest that aberrant synchrony in the sensorimotor and dorsal attention networks may serve as an early signature of neural change in pre-HD individuals. The altered synchrony in dorsal attention, frontoparietal and corticostriatal networks may contribute to the development of

Friedreich ataxia (FRDA) is an autosomal recessive disease with gait ataxia being the main source of morbidity. Mobility progressively declines, from initial symptom onset at approximately 10-15 years of age to being unable to ambulate 10-15 years later. Here, we sought to investigate the relationship between spatiotemporal gait parameters and clinical markers of disease severity. Thirteen people with FRDA walked along an 8.3-m GAITRite mat six times each at their preferred fast and slow speeds. Relationships between spatiotemporal gait parameters and a range of clinical and disease characteristics were examined. Significant correlations were found between spatiotemporal gait characteristics at each of the walking speeds and Friedreich Ataxia Rating Scale (FARS) score and disease duration. During the fast-walking condition, gait speed and cadence decreased with an increase in disease duration and the FARS score. GAA1 repeat expansion negatively correlated with double-support percentage of the gait cycle in all speed conditions demonstrating a relationship between the genetic mutation and compensatory strategies for impaired dynamic balance. In all speed conditions, there were correlations between a range of spatiotemporal gait characteristics and the timed 25-ft walk test, a well-established measure of gait mobility. These findings suggest that spatiotemporal gait parameters are a sensitive measure of gait decline in individuals with FRDA and should be considered for inclusion in intervention studies whilst participants are still ambulant.Copyright © 2014, Springer Science+Business Media New York.

Background: Huntington disease (HD) involves atrophy of the neostriatum, as well as progressive motor, psychiatric and cognitive disturbances. As the neostriatum is involved in frontostriatal re-entrant circuits subserving motor, cognitive and emotional functions, we hypothesised that volume changes in the neostriatum would be related to such functional measures. Objective(s): To determine if neostriatal volumes, as a biomarker, correlate with relevant motor, cognitive and neuropsychiatric functional measures. Method(s): T1-weighted MRI scans from the IMAGE-HD baseline dataset were manually traced to produce neostriatal volumes for 36 individuals with pre-symptomatic HD, 37 with symptomatic HD, and 36 controls (intra-rater intra-class correlation, 0.88 - 0.98). Volumes were correlated with scores of motor function (speeded tapping and self-paced tapping), executive function (Symbol Digit Modalities Test and Stroop speeded word), the University of Pennsylvania Smell Identification Test (UPSIT) and the Beck Depression Inventory-II (BDI-II): Hierarchical regression was used, with age, gender and intracranial volume entered first and volumes entered at the second step. Finding(s): Volumes were significantly different between all three groups, with control > pre-symptomatic > symptomatic HD (p < 0.01). Neostriatal volume made a significant contribution to variance in all of the measures, except for BDI-II (p < 0.01). Putamen volume was significantly correlated with scores on motor and executive function tasks (p < 0.05) and caudate was significantly correlated with UPSIT scores (p < 0.05). Conclusion(s): These correlations with motor and executive function tasks may be explained by the multiple frontostriatal circuits in which the neostriatum is involved; we plan further shape analysis to reveal which areas within the striatum correlate with these functional changes.

The dentate nucleus (DN) is the major relay station for neural connection between the cerebellum and cerebrum via the thalamus, and is a significant component of the neuropathological profile of Friedreich ataxia (FRDA). We have previously shown that the size of the superior cerebellar peduncle (SCP), which links the DN to cortical and subcortical structures via the thalamus, is significantly reduced in individuals with FRDA compared to control participants. This study used magnetization transfer imaging (MTI) to examine and contrast the integrity of white matter (WM) in the SCP and the corpus callosum (CC) (control region) in ten individuals with FRDA and ten controls. Individuals with FRDA demonstrated a significant reduction in the magnetization transfer ratio (MTR) in the SCP compared to control participants. However, there was no significant difference between groups in MTR in the CC. When comparing regions within groups, there was a significant reduction in MTR in the SCP compared to CC in participants with FRDA only. We suggest that the reduction in MTR in the SCP may be indicative of lack of myelin secondary to axonal loss and oligodendroglial dysfunction in WM tracts in individuals with FRDA. © 2014 Elsevier B.V.

Objective: This study aimed to characterise, emotion perception deficits in symptomatic Huntington's disease (HD) via the use of event-related potentials (ERPs). Method(s): ERP data were recorded during a computerised facial expression task in 11 HD participants and 11 matched controls. Expression (scrambled, neutral, happy, angry, disgust) classification accuracy and intensity were assessed. Relationships between ERP indices and clinical disease characteristics were also examined. Result(s): Accuracy was significantly lower for HD relative to controls, due to reduced performance for neutral, angry and disgust (but not happy) faces. Intensity ratings did not differ between groups. HD participants displayed significantly reduced visual processing amplitudes extending across pre-face (P100) and face-specific (N170) processing periods, whereas subsequent emotion processing amplitudes (N250) were similar across groups. Face-specific and emotion-specific derivations of the N170 and N250 ('neutral minus scrambled' and 'each emotion minus neutral', respectively) did not differ between groups. Conclusion(s): Our data suggest that the facial emotion recognition performance deficits in HD are primarily related to neural degeneration underlying 'generalised' visual processing, rather than face or emotional specific processing. Significance: ERPs are a useful tool to separate functionally discreet impairments in HD, and provide an important avenue for biomarker application that could more-selectively track disease progression. © 2014 International Federation of Clinical Neurophysiology.

Objective: To investigate structural connectivity and the relationship between axonal microstructure and clinical, cognitive, and motor functions in premanifest (pre-HD) and symptomatic (symp-HD) Huntington's disease. Method(s): Diffusion tensor imaging (DTI) data were acquired from 35 pre-HD, 36 symp-HD, and 35 controls. Structural connectivity was mapped between 40 brain regions of interest using tractography. Between-group differences in structural connectivity were identified using network based statistics. Radial diffusivity (RD) and fractional anisotropy (FA) were compared in the white matter tracts from aberrant networks. RD values in aberrant tracts were correlated with clinical severity, and cognitive and motor performance. Result(s): A network connecting putamen with prefrontal and motor cortex demonstrated significantly reduced tractography streamlines in pre-HD. Symp-HD individuals showed reduced streamlines in a network connecting prefrontal, motor, and parietal cortices with both caudate and putamen. The symp-HD group, compared to controls and pre-HD, showed both increased RD and decreased FA in the fronto-parietal and caudate-paracentral tracts and increased RD in the putamen-prefrontal and putamen-motor tracts. The pre-HDclose, compared to controls, showed increased RD in the putamen-prefrontal and fronto-parietal tracts. In the pre-HD group, significant negative correlations were observed between SDMT and Stroop performance and RD in the bilateral putamen-prefrontal tract. In the symp-HD group, RD in the fronto-parietal tract was significantly positively correlated with UHDRS motor scores and significantly negatively correlated with performance on SDMT and Stroop tasks. Conclusion(s): We have provided evidence of aberrant connectivity and microstructural integrity in white matter networks in HD. Microstructural changes in the cortico-striatal fibers were associated with cognitive and motor performance in pre-HD, suggesting that changes in axonal int

We used functional magnetic resonance imaging (fMRI) to investigate spatial working memory (WM) in an N-BACK task (0, 1, and 2-BACK) in premanifest Huntington's disease (pre-HD, n = 35), early symptomatic Huntington's disease (symp-HD, n = 23), and control (n = 32) individuals. Overall, both WM conditions (1-BACK and 2-BACK) activated a large network of regions throughout the brain, common to all groups. However, voxel-wise and time-course analyses revealed significant functional group differences, despite no significant behavioral performance differences. During 1-BACK, voxel-wise blood-oxygen-level-dependent (BOLD) signal activity was significantly reduced in a number of regions from the WM network (inferior frontal gyrus, anterior insula, caudate, putamen, and cerebellum) in pre-HD and symp-HD groups, compared with controls; however, time-course analysis of the BOLD response in the dorsolateral prefrontal cortex (DLPFC) showed increased activation in symp-HD, compared with pre-HD and controls. The pattern of reduced voxel-wise BOLD activity in pre-HD and symp-HD, relative to controls, became more pervasive during 2-BACK affecting the same structures as in 1-BACK, but also incorporated further WM regions (anterior cingulate gyrus, parietal lobe and thalamus). The DLPFC BOLD time-course for 2-BACK showed a reversed pattern to that observed in 1-BACK, with a significantly diminished signal in symp-HD, relative to pre-HD and controls. Our findings provide support for functional brain reorganisation in cortical and subcortical regions in both pre-HD and symp-HD, which are modulated by task difficulty. Moreover, the lack of a robust striatal BOLD signal in pre-HD may represent a very early signature of change observed up to 15 years prior to clinical diagnosis. © 2013 Wiley Periodicals, Inc.

Brain pathology in Friedreich ataxia is characterized by progressive degeneration of nervous tissue in the brainstem, cerebellum and cerebellar peduncles. Evidence of cerebral involvement is however equivocal. This brain imaging study investigates cerebello-cerebral white matter connectivity in Friedreich ataxia with diffusion MRI and tractography performed in 13 individuals homozygous for a GAA expansion in intron one of the frataxin gene and 14 age- and gender-matched control participants. New evidence is presented for disrupted cerebello-cerebral connectivity in the disease, leading to secondary effects in distant cortical and subcortical regions. Remote regions affected by primary cerebellar and brainstem pathology include the supplementary motor area, cingulate cortex, frontal cortices, putamen and other subcortical nuclei. The connectivity disruptions identified provide an explanation for some of the non-ataxic symptoms observed in the disease and support the notion of reverse cerebellar diaschisis. This is the first study to comprehensively map white matter connectivity disruptions in Friedreich ataxia using tractography, connectomic techniques and super-resolution track density imaging.

Recent studies report a higher risk of dementia and motor symptoms in females with the fragile X mental retardation 1 premutation (PM-carriers) than has hitherto been appreciated. Here, we use dual-task gait paradigms to identify potential markers of cognitive and motor decline in female PM-carriers. Spatiotemporal gait characteristics and variability of gait were assessed during single- and dual-task conditions in 28 female PM-carriers (mean age 41.32 ± 8.03 years) and 31 female controls with normal fragile X mental retardation 1 alleles (mean age 41.61 ± 8.30 years). Despite comparable gait characteristics at baseline, gait performance was significantly poorer for PM-carriers when performing concurrent working memory tasks (counting backwards by 3's or 7's) when compared with controls. Correlational analyses showed that low working memory capacity was significantly associated with dual-task interference for the gait domains of pace (speed, step length) and variability (step time, swing time) in PM-carriers. Multiple regression analyses further showed that the interaction between age and CGG repeat length was strongly predictive of gait variability during dual-task performance. These findings indicate for the first time that vulnerability in specific domains of gait control may act as sensitive surrogate markers of future decline in female PM-carriers.

Atrophy of the dentate nucleus is one of the major neuropathological changes in Friedreich ataxia (FRDA). Neuroimaging studies demonstrated white matter (WM) degeneration in FRDA. In this study, we used advanced tractography techniques to quantitatively measure WM changes in the dentato-thalamic and dentato-rubral tracts, and correlated these changes with cognitive profiles of FRDA. We also analysed diffusivity changes of the thalamo-cortical tract to assess whether neurological degeneration of WM extends beyond the primary site of involvement in FRDA. Twelve genetically proven individuals with FRDA and 14 controls were recruited. Sixty directions diffusion tensor images were acquired. The WM bundles from the dentate nucleus were estimated using a constrained spherical deconvolution method and the diffusivity characteristics measured. The Simon task was used to assess cognitive profile of FRDA. The dentato-rubral, dentato-thalamic and thalamo-cortical tracts manifested significantly lower fractional anisotropy, higher mean diffusivity and increased radial diffusivity in FRDA compared with controls. There was no difference in axial diffusivity between the two groups. The mean and radial diffusivity of the dentato-rubral tract was positively correlated with choice reaction time, congruent reaction time, incongruent reaction time and Simon effect reaction time and negatively with the larger GAA repeat. Significant changes in diffusivity characteristics were observed in the dentato-thalamic and thalamo-cortical tracts, suggesting extensive WM degeneration and affected WM structures in FRDA. Correlation of WM changes in the dentato-rubral tract with the cognitive assessment suggested that this tract is an important contributor to cognitive disturbances in FRDA.

We characterized 30-month longitudinal change in functional activation and connectivity during working memory in premanifest (pre-HD) and symptomatic (symp-HD) Huntington's disease (HD). In a case-control longitudinal study (baseline, 18 months, and 30 months), we compared change in fMRI activity over time during working memory in 22 pre-HD, 11 symp-HD, and 20 control participants. Outcome measures were BOLD (blood-oxygen-level-dependent) activity during 1-BACK and 2-BACK working memory and functional connectivity between dorsolateral prefrontal cortex (DLPFC) and caudate. Compared with controls, the pre-HD group showed significantly increased activation longitudinally during 1-BACK in the left DLPFC and medial frontal cortex, and further increased activation during 2-BACK in the bilateral caudate, putamen, and temporal cortex. Longitudinal change in symp-HD was not significantly different from controls. Longitudinal changes in pre-HD were associated with disease burden and years to onset. The pre-HD group showed longitudinal decreased functional connectivity between left DLPFC and caudate during both 1-BACK and 2-BACK performance. We provide an evidence for longitudinal changes in BOLD activity during working memory prior to clinical manifestations of HD. The ability to increase activation in the prefrontal cortex over time may represent an early compensatory response during the premanifest stage, which may reflect an early marker for clinically relevant functional changes in HD. © 2013 Springer-Verlag Berlin Heidelberg.

We investigated two measures of neural integrity, T1-weighted volumetric measures and diffusion tensor imaging (DTI), and explored their combined potential to differentiate pre-diagnosis Huntington's disease (pre-HD) individuals from healthy controls. We applied quadratic discriminant analysis (QDA) to discriminate pre-HD individuals from controls and we utilised feature selection and dimension reduction to increase the robustness of the discrimination method. Thirty six symptomatic HD (symp-HD), 35 pre-HD, and 36 control individuals participated as part of the IMAGE-HD study and underwent T1-weighted MRI, and DTI using a Siemens 3. Tesla scanner. Volume and DTI measures [mean diffusivity (MD) and fractional anisotropy (FA)] were calculated for each group within five regions of interest (ROI; caudate, putamen, pallidum, accumbens and thalamus). QDA was then performed in a stepwise manner to differentiate pre-HD individuals from controls, based initially on unimodal analysis of motor or neurocognitive measures, or on volume, MD or FA measures from within the caudate, pallidum and putamen. We then tested for potential improvements to this model, by examining multi-modal MRI classifications (volume, FA and MD), and also included motor and neurocognitive measures, and additional brain regions (i.e., accumbens and thalamus). Volume, MD and FA differed across the three groups, with pre-HD characterised by significant volumetric reductions and increased FA within caudate, putamen and pallidum, relative to controls. The QDA results demonstrated that the differentiation of pre-HD from controls was highly accurate when both volumetric and diffusion data sets from basal ganglia (BG) regions were used. The highest discriminative accuracy however was achieved in a multi-modality approach and when including all available measures: motor and neurocognitive scores and multi-modal MRI measures from the BG, accumbens and thalamus. Our QDA findings provide evidence that combined multi

Background: This study aimed to characterize, for the first time, 18. month longitudinal changes in both functional activation and functional connectivity during working memory in premanifest Huntington's disease (pre-HD) and symptomatic HD (symp-HD). Method(s): Functional magnetic resonance imaging (fMRI) was used to investigate longitudinal changes in neuronal activity during working memory performance via an N-BACK task (0-BACK and 1-BACK) in 27 pre-HD, 17 symp-HD, and 23 control participants. Whole-brain analysis of activation and region-of-interest analysis of functional connectivity was applied to longitudinal fMRI data collected at baseline and 18. months follow-up. Result(s): Compared with controls, the pre-HD group showed significantly increased activation longitudinally during 1-BACK versus 0-BACK in the lateral and medial prefrontal, anterior cingulate, primary motor, and temporal areas cortically, and caudate and putamen subcortically. Pre-HD far from onset, compared with controls, showed further longitudinal increases in the right and left dorsolateral prefrontal cortex (DLPFC). Longitudinal increased activation in anterior cingulate and medial primary motor areas were associated with disease burden in the pre-HD group. Moreover, in pre-HD increased activation over time in primary motor and putamen regions were associated with average response time during 1-BACK performance. During 1-BACK, functional connectivity between the right DLPFC and posterior parietal, anterior cingulate, and caudate was significantly reduced over 18. months only in the pre-HD group. Conclusion(s): Longitudinal reductions in connectivity over 18. months may represent an early signature of cortico-cortical and cortico-striatal functional disconnectivity in pre-HD, whereas the concomitant increased cortical and subcortical activation may reflect a compensatory response to the demands for cognitive resources required during task performance. Our findings demonstrate that functional