Emotion perception and electrophysiological correlates in Huntington\u27s disease

Objective This study aimed to characterise, emotion perception deficits in symptomatic Huntington\u27s disease (HD) via the use of event-related potentials (ERPs). Methods 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. Results 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 (\u27neutral minus scrambled\u27 and \u27each emotion minus neutral\u27, respectively) did not differ between groups. Conclusions Our data suggest that the facial emotion recognition performance deficits in HD are primarily related to neural degeneration underlying \u27generalised\u27 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

"Schöne Welt, du gingst in Fransen!" : Auf der Suche nach dem authentischen deutschen Tango

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.To characterize the upper limb motor profile in HD with various levels of difficulty, with and without visual targets.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.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.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

Impact of External Cue Validity on Driving Performance in Parkinson's Disease

This study sought to investigate the impact of external cue validity on simulated driving performance in 19 Parkinson's disease (PD) patients and 19 healthy age-matched controls. Braking points and distance between deceleration point and braking point were analysed for red traffic signals preceded either by Valid Cues (correctly predicting signal), Invalid Cues (incorrectly predicting signal), and No Cues. Results showed that PD drivers braked significantly later and travelled significantly further between deceleration and braking points compared with controls for Invalid and No-Cue conditions. No significant group differences were observed for driving performance in response to Valid Cues. The benefit of Valid Cues relative to Invalid Cues and No Cues was significantly greater for PD drivers compared with controls. Trail Making Test (B-A) scores correlated with driving performance for PDs only. These results highlight the importance of external cues and higher cognitive functioning for driving performance in mild to moderate PD

The effect of multidisciplinary rehabilitation on brain structure and cognition in Huntington\u27s disease: An exploratory study

Background: There is a wealth of evidence detailing gray matter degeneration and loss of cognitive function over time in individuals with Huntington\u27s disease (HD). Efforts to attenuate disease-related brain and cognitive changes have been unsuccessful to date. Multidisciplinary rehabilitation, comprising motor and cognitive intervention, has been shown to positively impact on functional capacity, depression, quality of life and some aspects of cognition in individuals with HD. This exploratory study aimed to evaluate, for the first time, whether multidisciplinary rehabilitation can slow further deterioration of disease-related brain changes and related cognitive deficits in individuals with manifest HD. Methods: Fifteen participants who manifest HD undertook a multidisciplinary rehabilitation intervention spanning 9 months. The intervention consisted of once-weekly supervised clinical exercise, thrice-weekly self-directed home based exercise and fortnightly occupational therapy. Participants were assessed using MR imaging and validated cognitive measures at baseline and after 9 months. Results: Participants displayed significantly increased gray matter volume in the right caudate and bilaterally in the dorsolateral prefrontal cortex after 9 months of multidisciplinary rehabilitation. Volumetric increases in gray matter were accompanied by significant improvements in verbal learning and memory (Hopkins Verbal Learning-Test). A significant association was found between gray matter volume increases in the dorsolateral prefrontal cortex and performance on verbal learning and memory. Conclusions: This study provides preliminary evidence that multidisciplinary rehabilitation positively impacts on gray matter changes and cognitive functions relating to verbal learning and memory in individuals with manifest HD. Larger controlled trials are required to confirm these preliminary findings

Dual tasking impairments are associated with striatal pathology in Huntington’s disease

Background: Recent findings suggest that individuals with Huntington’s disease (HD) have an impaired capacity to execute cognitive and motor tasks simultaneously, or dual task, which gradually worsens as the disease advances. The onset and neuropathological changes mediating impairments in dual tasking in individuals with HD are unclear. The reliability of dual tasking assessments for individuals with HD is also unclear. Objectives: To evaluate differences in dual tasking performance between individuals with HD (presymptomatic and prodromal) and matched controls, to investigate associations between striatal volume and dual tasking performance, and to determine the reliability of dual tasking assessments. Methods: Twenty individuals with HD (10 presymptomatic and 10 prodromal) and 20 healthy controls were recruited for the study. Individuals undertook four single and dual task assessments, comprising motor (postural stability or force steadiness) and cognitive (simple or complex mental arithmetic) components, with single and dual tasks performed three times each. Participants also undertook a magnetic resonance imaging assessment. Results: Compared to healthy controls, individuals with presymptomatic and prodromal HD displayed significant deficits in dual tasking, particularly cognitive task performance when concurrently undertaking motor tasks (P \u3c 0.05). The observed deficits in dual tasking were associated with reduced volume in caudate and putamen structures (P \u3c 0.05),however, not with clinical measures of disease burden. An analysis of the reliability of dual tasking assessments revealed moderate to high test–retest reliability [ICC: 0.61-0.99] for individuals with presymptomatic and prodromal HD and healthy controls. Conclusions: Individuals with presymptomatic and prodromal HD have significant deficits in dual tasking that are associated with striatal degeneration. Findings also indicate that dual tasking assessments are reliable in individuals presymptomatic and prodromal HD and healthy controls

Recommendations to Optimize the Use of Volumetric MRI in Huntington's Disease Clinical Trials

Volumetric magnetic resonance imaging (vMRI) has been widely studied in Huntington's disease (HD) and is commonly used to assess treatment effects on brain atrophy in interventional trials. Global and regional trajectories of brain atrophy in HD, with early involvement of striatal regions, are becoming increasingly understood. However, there remains heterogeneity in the methods used and a lack of widely-accessible multisite, longitudinal, normative datasets in HD. Consensus for standardized practices for data acquisition, analysis, sharing, and reporting will strengthen the interpretation of vMRI results and facilitate their adoption as part of a pathobiological disease staging system. The Huntington's Disease Regulatory Science Consortium (HD-RSC) currently comprises 37 member organizations and is dedicated to building a regulatory science strategy to expedite the approval of HD therapeutics. Here, we propose four recommendations to address vMRI standardization in HD research: (1) a checklist of standardized practices for the use of vMRI in clinical research and for reporting results; (2) targeted research projects to evaluate advanced vMRI methodologies in HD; (3) the definition of standard MRI-based anatomical boundaries for key brain structures in HD, plus the creation of a standard reference dataset to benchmark vMRI data analysis methods; and (4) broad access to raw images and derived data from both observational studies and interventional trials, coded to protect participant identity. In concert, these recommendations will enable a better understanding of disease progression and increase confidence in the use of vMRI for drug development

Utility of Huntington's disease assessments by disease stage: floor/ceiling effects

Introduction: An understanding of the clinimetric properties of clinical assessments, including their constraints, is critical to sound clinical study and trial design. Utilizing data from Enroll-HD—a global, prospective HD observational study and clinical research platform—we examined several well-established HD clinical assessments across all stages of disease for evidence of instrument constraints, specifically floor/ceiling effects, to inform selection of appropriate instruments for use in future studies/trials and identify gaps in instrument utility over the life-course of the disease. Material and Methods: Analyzing publicly available data from 6,614 HD gene-expansion carriers (HDGECs), we grouped participants into deciles based on baseline CAP score, which ranged from 26 to 229. We used descriptive statistics to characterize data distribution for 25 outcome measures (encompassing motor, function, cognition, and psychiatric/behavioral domains) in each CAP decile. A skewness statistic threshold of ±2 was defined a priori to indicate floor/ceiling effects. Results: We found evidence of floor/ceiling effects in the early premanifest stages of disease for most motor and function assessments (e.g., TMS, TFC) and select cognitive tasks (MMSE, Trail Making tests). Other cognitive assessments, and the HADS-SIS scales, performed well ubiquitously, with no evidence of floor/ceiling effects at any disease stage. Floor/ceiling effects were evident at every disease stage for certain assessments, including PBA-s measures. Ceiling effects were apparent for DCL from onset stages onwards, as expected. Discussion: Developing instruments sensitive to subtle differences in performance at the earlier stages of the disease spectrum, particularly in motor and function domains, is warranted

AUSSIE – the Australian United States Scandinavian Imaging Exchange: an innovative virtual integrated health research network embedded in health care

To describe the development, design and function of an innovative international clinical research network for neuroimaging research based in Australia within a joint state health service/medical school. This network focuses upon identifying neuroimaging biomarkers for neuropsychiatric and neurodegenerative disease

Longitudinal imaging highlights preferential basal ganglia circuit atrophy in Huntington's disease

Huntington's disease is caused by a CAG repeat expansion in the Huntingtin gene (HTT), coding for polyglutamine in the Huntingtin protein, with longer CAG repeats causing earlier age of onset. The variable 'Age' × ('CAG'-L), where 'Age' is the current age of the individual, 'CAG' is the repeat length and L is a constant (reflecting an approximation of the threshold), termed the 'CAG Age Product' (CAP) enables the consideration of many individuals with different CAG repeat expansions at the same time for analysis of any variable and graphing using the CAG Age Product score as the X axis. Structural MRI studies have showed that progressive striatal atrophy begins many years prior to the onset of diagnosable motor Huntington's disease, confirmed by longitudinal multicentre studies on three continents, including PREDICT-HD, TRACK-HD and IMAGE-HD. However, previous studies have not clarified the relationship between striatal atrophy, atrophy of other basal ganglia structures, and atrophy of other brain regions. The present study has analysed all three longitudinal datasets together using a single image segmentation algorithm and combining data from a large number of subjects across a range of CAG Age Product score. In addition, we have used a strategy of normalizing regional atrophy to atrophy of the whole brain, in order to determine which regions may undergo preferential degeneration. This made possible the detailed characterization of regional brain atrophy in relation to CAG Age Product score. There is dramatic selective atrophy of regions involved in the basal ganglia circuit-caudate, putamen, nucleus accumbens, globus pallidus and substantia nigra. Most other regions of the brain appear to have slower but steady degeneration. These results support (but certainly do not prove) the hypothesis of circuit-based spread of pathology in Huntington's disease, possibly due to spread of mutant Htt protein, though other connection-based mechanisms are possible. Therapeutic targets related to prion-like spread of pathology or other mechanisms may be suggested. In addition, they have implications for current neurosurgical therapeutic approaches, since delivery of therapeutic agents solely to the caudate and putamen may miss other structures affected early, such as nucleus accumbens and output nuclei of the striatum, the substantia nigra and the globus pallidus

A sleeping phantom leg awakened following hemicolectomy, thrombosis, and chemotherapy: a case report

INTRODUCTION: We describe the case of a patient who experienced phantom pain that began 42 years after right above-the-knee amputation. Immediately prior to phantom pain onset, this long-term amputee had experienced, in rapid succession, cancer, hemicolectomy, chemotherapy, and thrombotic occlusion. Very little has been published to date on the association between chemotherapy and exacerbation of neuropathic pain in amputees, let alone the phenomenon of bringing about pain in amputees who have been pain-free for many decades. While this patient presented with a unique profile following a rare sequence of medical events, his case should be recognized considering the frequent co-occurrence of osteomyelitis, chemotherapy, and amputation. CASE PRESENTATION: A 68-year-old Australian Caucasian man presented 42 years after right above-the-knee amputation with phantom pain immediately following hemicolectomy, thrombotic occlusion in the amputated leg, and chemotherapy treatment with leucovorin and 5-fluorouracil. He exhibited probable hyperalgesia with a reduced pinprick threshold and increased stump sensitivity, indicating likely peripheral and central sensitization. CONCLUSION: Our patient, who had long-term nerve injury due to amputation, together with recent ischemic nerve and tissue injury due to thrombosis, exhibited likely chemotherapy-induced neuropathy. While he presented with unique treatment needs, cases such as this one may actually be quite common considering that osteosarcoma can frequently lead to amputation and be followed by chemotherapy. The increased susceptibility of amputees to developing potentially intractable chemotherapy-induced neuropathic pain should be taken into consideration throughout the course of chemotherapy treatment. Patients in whom chronic phantom pain then develops, perhaps together with mobility issues, inevitably place greater demands on healthcare service providers that require treatment by various clinical specialists, including oncologists, neurologists, prosthetists, and, most frequently, general practitioners