Longitudinal changes in functional connectivity of cortico-basal ganglia networks in manifests and premanifest huntington's disease

Huntington's disease (HD) is a genetic neurological disorder resulting in cognitive and motor impairments. We evaluated the longitudinal changes of functional connectivity in sensorimotor, associative and limbic cortico-basal ganglia networks. We acquired structural MRI and resting-state fMRI in three visits one year apart, in 18 adult HD patients, 24 asymptomatic mutation carriers (preHD) and 18 gender- and age-matched healthy volunteers from the TRACK-HD study. We inferred topological changes in functional connectivity between 182 regions within cortico-basal ganglia networks using graph theory measures. We found significant differences for global graph theory measures in HD but not in preHD. The average shortest path length (L) decreased, which indicated a change toward the random network topology. HD patients also demonstrated increases in degree k, reduced betweeness centrality bc and reduced clustering C. Changes predominated in the sensorimotor network for bc and C and were observed in all circuits for k. Hubs were reduced in preHD and no longer detectable in HD in the sensorimotor and associative networks. Changes in graph theory metrics (L, k, C and bc) correlated with four clinical and cognitive measures (symbol digit modalities test, Stroop, Burden and UHDRS). There were no changes in graph theory metrics across sessions, which suggests that these measures are not reliable biomarkers of longitudinal changes in HD. preHD is characterized by progressive decreasing hub organization, and these changes aggravate in HD patients with changes in local metrics. HD is characterized by progressive changes in global network interconnectivity, whose network topology becomes more random over time. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc

Altered cerebrovascular response to acute exercise in patients with Huntington’s Disease

Objective. To determine whether a single session of exercise is sufficient to induce cerebral adaptations in individuals with Huntington’s disease, and explore the time dynamics of any acute cerebrovascular response. Methods. In this case-control study we employed arterial-spin labelling magnetic resonance imaging in 19 HD gene-positive participants (32-65 years old, 13 males) and 19 controls (29-63 years old, 10 males) matched for age, gender, body mass index and self-reported activity levels, to measure global and regional perfusion in response to 20-minutes of moderate intensity cycling. Cerebral perfusion was measured at baseline and 15-, 40- and 60-minutes after exercise cessation. Results. Relative to baseline, cerebral perfusion increased in HD patients yet was unchanged in control participants in the precentral gyrus, middle frontal gyrus and hippocampus 40 minutes after exercise cessation (+15 to +32.5% change in HD participants, -7.7 to 0.8% change in controls). CAG repeat length predicted the change in the precentral gyrus, and the intensity of the exercise intervention predicted hippocampal perfusion change in HD participants. In both groups, exercise increased hippocampal blood flow 60-minutes after exercise cessation. Conclusions. Here we demonstrate the utility of acute exercise as a clinically sensitive experimental paradigm to modulate the cerebrovasculature. Twenty minutes of aerobic exercise induced transient cerebrovascular adaptations in the hippocampus and cortex selectively in HD participants and likely represents latent neuropathology not evident at rest

Aberrant brain network connectivity in pre-symptomatic and manifest Huntington's disease: a systematic review

Resting-state functional magnetic resonance imaging (rs-fMRI) has the potential to shed light on the pathophysiological mechanisms of Huntington's disease (HD), paving the way to new therapeutic interventions. A systematic review of the literature was conducted in three online databases according to PRISMA guidelines, using keywords for HD, functional connectivity, and rs-fMRI. We included studies investigating connectivity in pre-symptomatic (pre-HD) and manifest HD gene carriers compared to healthy controls, implementing seed-based connectivity, independent component analysis, regional property and graph analysis approaches. Visual network showed reduced connectivity in manifest HD, while network/areas underpinning motor functions were consistently altered in both manifest HD and pre-HD, showing disease stage-dependent changes. Cognitive networks underlying executive and attentional functions showed divergent anterior-posterior alterations, reflecting possible compensatory mechanisms. The involvement of these networks in pre-HD is still unclear. In conclusion, aberrant connectivity of the sensory-motor network is observed in the early stage of HD while, as pathology spreads, other networks might be affected, such as the visual and executive/attentional networks. Moreover, sensory-motor and executive networks exhibit hyper- and hypo-connectivity patterns following different spatiotemporal trajectories. These findings could help to implement future huntingtin-lowering interventions

Sleep and Huntington Disease: Polysomnographic Findings and Clinical Correlates

Huntington’s disease (HD) is a progressive, fatal, neurodegenerative disorder caused by an abnormal expansion of a CAG repeat sequence in the gene encoding the protein huntingtin (HTT) on chromosome 4. Clinical features of HD include progressive motor dysfunction, cognitive decline, and psychiatric disturbance. Sleep disturbances are frequent in HD patients. However, sleep alterations as well as their association with other symptoms and signs of the disease have not been systematically studied in large groups of HD patients.The aim of the study was to objectively evaluate sleep features in a large, single-center, population of HD patients by means of nocturnal, laboratory based video-polysomnography (V-PSG), and to correlate PSG findings with clinical parameters;evaluate subjective sleep-related symptoms by subjective sleep evaluation and compare the results with those obtained with the gold standard diagnostic tool, namely V-PSG;finally, evaluate the EEG modifications in HD patients during the sleep-wake cycle, by means of the exact LOw REsolution Tomography (eLORETA) software.The results suggest that sleep is severely disrupted in HD patients.Taken together,our data may suggest that the caudate degenerative process observed in HD account for the increased arousability, increased motor activity during wake and sleep (originating periodic limb movements), reduction of REM sleep and, overall, a general sleep disruption.As concerns the subjective sleep evaluation, our data suggest, overall, that the subjective evaluation of sleep in HD patients shows a poor correlation with PSG results. Our EEG data suggest a defined pattern of motor cortex dysfunction during wake and sleep, which correlates with the clinical and polysomnographic evidence of increased motor activity during wake and NREM, and nearly absent motor abnormalities in REM. It could be hypothesized that EEG modifications reflect motor cortex impairment or, conversely, an effort to counterbalance abnormal motor output

Functional connectivity of primary motor cortex is dependent on genetic burden in prodromal Huntington disease.

Subtle changes in motor function have been observed in individuals with prodromal Huntington disease (prHD), but the underlying neural mechanisms are not well understood nor is the cumulative effect of the disease (disease burden) on functional connectivity. The present study examined the resting-state functional magnetic resonance imaging (rs-fMRI) connectivity of the primary motor cortex (M1) in 16 gene-negative (NEG) controls and 48 gene-positive prHD participants with various levels of disease burden. The results showed that the strength of the left M1 connectivity with the ipsilateral M1 and somatosensory areas decreased as disease burden increased and correlated with motor symptoms. Weakened M1 connectivity within the motor areas was also associated with abnormalities in long-range connections that evolved with disease burden. In this study, M1 connectivity was decreased with visual centers (bilateral cuneus), but increased with a hub of the default mode network (DMN; posterior cingulate cortex). Changes in connectivity measures were associated with worse performance on measures of cognitive-motor functioning. Short- and long-range functional connectivity disturbances were also associated with volume loss in the basal ganglia, suggesting that weakened M1 connectivity is partly a manifestation of striatal atrophy. Altogether, the results indicate that the prodromal phase of HD is associated with abnormal interhemispheric interactions among motor areas and disturbances in the connectivity of M1 with visual centers and the DMN. These changes may, respectively, contribute to increased motor symptoms, visuomotor integration problems, and deficits in the executive control of movement as individuals approach a manifest diagnosis

Functional Connectivity of Primary Motor Cortex Is Dependent on Genetic Burden in Prodromal Huntington Disease

Subtle changes in motor function have been observed in individuals with prodromal Huntington disease (prHD), but the underlying neural mechanisms are not well understood nor is the cumulative effect of the disease (disease burden) on functional connectivity. The present study examined the resting-state functional magnetic resonance imaging (rs-fMRI) connectivity of the primary motor cortex (M1) in 16 gene-negative (NEG) controls and 48 gene-positive prHD participants with various levels of disease burden. The results showed that the strength of the left M1 connectivity with the ipsilateral M1 and somatosensory areas decreased as disease burden increased and correlated with motor symptoms. Weakened M1 connectivity within the motor areas was also associated with abnormalities in long-range connections that evolved with disease burden. In this study, M1 connectivity was decreased with visual centers (bilateral cuneus), but increased with a hub of the default mode network (DMN; posterior cingulate cortex). Changes in connectivity measures were associated with worse performance on measures of cognitive–motor functioning. Short- and long-range functional connectivity disturbances were also associated with volume loss in the basal ganglia, suggesting that weakened M1 connectivity is partly a manifestation of striatal atrophy. Altogether, the results indicate that the prodromal phase of HD is associated with abnormal interhemispheric interactions among motor areas and disturbances in the connectivity of M1 with visual centers and the DMN. These changes may, respectively, contribute to increased motor symptoms, visuomotor integration problems, and deficits in the executive control of movement as individuals approach a manifest diagnosis

Prodromal Variability in Huntington\u27s Disease Progression and Resistance

Huntington’s disease (HD) is a neurodegenerative movement disorder caused by abnormal cytosine-adenine-guanine (CAG) expansion on the HTT gene. As both a proteinopathy and the most common PolyQ disease, HD shares key features with several disorders that disproportionately affect the growing elderly population in the United States, including delayed-onset, selective neuronal death, and protein misfolding. Across these conditions, there are few treatments and no known cures; however, their shared features suggest common underlying mechanisms, and delayed-onset hints at possible prevention or reversal. CAG-expansion-number and age are related to diagnosis and can be used to estimate age-of-onset for prodromal (pre-diagnosis) individuals, who possess the causal mutation but have not manifested diagnosis-associated motor symptoms. Over a decade before diagnosis, prodromal individuals differ from controls in brain structure and connectivity, cognition, and motor functioning. Although age and CAG-number account for most observed variability in HD-onset, persons with identical CAG-numbers often develop symptoms at different ages, indicating that additional genetic and environmental factors also mediate decline. Little is known about detrimental and protective genetic factors in HD. Studying prodromal progression can inform interventions by highlighting early prevention targets. This research leverages advanced multivariate techniques applied to legacy PREDICT-HD data to characterize brain structure, cognition, and motor functioning across prodromal HD and investigate genetic factors accounting for variability in these domains. Regarding brain structure, these experiments provide evidence for: regional co-occurrence in prodromal decline, early fronto-striatal degradation, dorso-ventral reduction gradients, and delayed atrophy in certain movement-related and subcortical regions. The genetic findings suggest a protective role of NTRK2 and identify NCOR1 and ADORA2B variants with early, CAG-independent detrimental effects on gray matter. Previously identified onset-delaying variants are also confirmed as CAG-independent modulators of brain structure and clinical functioning. Clinical findings highlight motor functioning as the best indicator of brain-structural integrity until the late prodrome and demonstrate that distinct regions coincide with cognitive compared to motor functioning; furthermore, regions that most align with clinical functioning vary at different prodromal stages

Electrophysiological premotor processing in Huntington's disease: an issue of functional connectivity

Huntington’s disease is a neurodegenerative disease which presents with cognitive, motor and emotional-behavioural changes. Neural degeneration begins up to 20 years prior to symptom onset, arising initially in the striatum. Motor symptoms are a hallmark; disturbances occur due to disruption of crucial motor pathways through atrophy. However, these are not seen until much later in the disease. Such findings raise questions about the role internal processes play in maintenance of function, but little is known about functional motor connectivity during early stages. Electroencephalography is a sensitive measure of the integrity of neural process occurring prior to, and at, motor execution. This thesis explores the relationship between electrophysiological premotor/motor activation and structural integrity of critical neuroanatomy providing intra-hemispheric and inter-hemispheric connectivity – the striatum and corpus callosum. In the principal study, presymptomatic persons showed abnormal premotor activation (Contingent Negative Variation); greater relative activation across the premotor period, accompanied by normal motor potentials (Readiness Potential) and execution (response time). Aberrant premotor activation likely reflects disruption of critical inter-hemispheric circuitry such as fronto-striatal networks and the corpus callosum. Results implicated compensation in a context of early atrophy and/or an inability to regulate responses. Extending this hypothesis, Study Two examines the relationship between premotor electrophysiological activity and morphology of the striatum using magnetic resonance imaging. Structural integrity of the caudate and putamen was theorised to determine the fronto-striatal neuroanatomical circuits subserving electrophysiological responses. Quantification of volume/shape yielded structure and function associations in our combined sample: timing (latency) and consistency (relative activation/slope) of the premotor response was determined by degeneration, with greater atrophy predicting later and less consistent activation. This suggests compromise to motor pathways is progressive, and may first emerge as delayed, inefficient, and inconsistent electrophysiology. In Study Three, investigation was extended to the corpus callosum, which provides inter-hemispheric connectivity between primary and supplementary motor regions distinct from fronto-striatal pathways. It was proposed that atrophy to the corpus callosum (thinning) would disrupt both homotopic (e.g. parietal to frontal lobe) and heterotopic (e.g. left and right frontal lobe) circuits supporting premotor/motor connectivity. Raw correlations suggested compromise to mid- posterior (motor) and mid-anterior (frontal cortex/premotor/supplementary motor) affects premotor performance (extent and consistency of response). While results did not survive stringent FDR error corrections, they followed known anatomical relationships, suggesting functional motor connectivity and premotor processing are also determined by structural integrity of the corpus callosum. These findings are important in showing early, disease-related morphological changes to the striatum and corpus callosum do disrupt critical fronto-striatal and inter-hemispheric networks. Morphological changes accompanied by abnormal electrophysiological premotor activation support hypotheses of dysfunctional connectivity arising from atrophy to anatomical landmarks. Progression of circuit derangement may be mediated by secondary activation (e.g. supplementary motor areas, executive circuits) and typically indirect subcortical structures, which preserve function as connectivity with the primary motor area declines. Future studies using technology such as transcranial magnetic stimulation and diffusion tensor imaging may allow identification and stimulation of vulnerable and robust circuits respectively, potential intervention targets to preserve function and quality of life for longer