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INTRODUCTION: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. METHODS: 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. DISCUSSION: Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease tr

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., E. Vaportzis, School of Psychological Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC, Australia, CONFERENCE ABSTRACT

To identify gait and balance measures that are responsive to change during the timeline of a clinical trial in Friedreich ataxia (FRDA), we administered a battery of potential measures three times over a 12-month period. Sixty-one ambulant individuals with FRDA underwent assessment of gait and balance at baseline, 6 months and 12 months. Outcomes included GAITRite spatiotemporal gait parameters; Biodex Balance System Postural Stability Test (PST) and Limits of Stability; Berg Balance Scale (BBS); Timed 25-Foot Walk Test; Dynamic Gait Index (DGI); SenseWear MF Armband step and energy activity; and the Friedreich Ataxia Rating Scale Upright Stability Subscale (FARS USS). The standardised response mean (SRM) or correlation coefficients were reported as effect size indices for comparison of internal responsiveness. Internal responsiveness was also analysed in subgroups. SenseWear Armband daily step count had the largest effect size of all the variables over 6 months (SRM = -0.615), while the PST medial-lateral index had the largest effect size (SRM = 0.829) over 12 months. The FARS USS (SRM = 0.824) and BBS (SRM = -0.720) were the only outcomes able to detect change over 12 months in all subgroups. The DGI was the most responsive outcome in children, detecting a mean change of -2.59 (95% CI -3.52 to -1.66, p < 0.001, SRM = -1.429). In conclusion, the FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.Copyright © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Huntington disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin (HTT) gene. The typical motor symptoms have been associated with basal ganglia pathology. However, psychiatric and cognitive symptoms often precede the motor component and may be due to changes in the limbic system. Recent work has indicated pathology in the hypothalamus in HD but other parts of the limbic system have not been extensively studied. Emerging evidence suggests that changes in HD also include white matter pathology. Here we investigated if the main white matter tract of the limbic system, the fornix, is affected in HD. We demonstrate that the fornix is 34% smaller already in prodromal HD and 41% smaller in manifest HD compared to controls using volumetric analyses of MRI of the IMAGE-HD study. In post-mortem fornix tissue from HD cases, we confirm the smaller fornix volume in HD which is accompanied by signs of myelin breakdown and reduced levels of the transcription factor myelin regulating factor but detect no loss of oligodendrocytes. Further analyses using RNA-sequencing demonstrate downregulation of oligodendrocyte identity markers in the fornix of HD cases. Analysis of differentially expressed genes based on transcription-factor/target-gene interactions also revealed enrichment for binding sites of SUZ12 and EZH2, components of the Polycomb Repressive Complex 2, as well as RE1 Regulation Transcription Factor. Taken together, our data show that there is early white matter pathology of the fornix in the limbic system in HD likely due to a combination of reduction in oligodendrocyte genes and myelin break down.

OBJECTIVE: Friedreich ataxia (FRDA) is an inherited neurological disease defined by progressive movement incoordination. We undertook a comprehensive characterization of the spatial profile and progressive evolution of structural brain abnormalities in people with FRDA. METHODS: A coordinated international analysis of regional brain volume using magnetic resonance imaging data charted the whole-brain profile, interindividual variability, and temporal staging of structural brain differences in 248 individuals with FRDA and 262 healthy controls. RESULTS: The brainstem, dentate nucleus region, and superior and inferior cerebellar peduncles showed the greatest reductions in volume relative to controls (Cohen d = 1.5-2.6). Cerebellar gray matter alterations were most pronounced in lobules I-VI (d = 0.8), whereas cerebral differences occurred most prominently in precentral gyri (d = 0.6) and corticospinal tracts (d = 1.4). Earlier onset age predicted less volume in the motor cerebellum (rmax = 0.35) and peduncles (rmax = 0.36). Disease duration and severity correlated with volume deficits in the dentate nucleus region, brainstem, and superior/inferior cerebellar peduncles (rmax = -0.49); subgrouping showed these to be robust and early features of FRDA, and strong candidates for further biomarker validation. Cerebral white matter abnormalities, particularly in corticospinal pathways, emerge as intermediate disease features. Cerebellar and cerebral gray matter loss, principally targeting motor and sensory systems, preferentially manifests later in the disease course. INTERPRETATION: FRDA is defined by an evolving spatial profile of neuroanatomical changes beyond primary pathology in the cerebellum and spinal cord, in line with its progressive clinical course. The design, interpretation, and generalization of research studies and clinical trials must consider neuroanatomical staging and associated interindividual variability in brain measures. ANN NEUROL 2021;90:570-583.

An accurate measure of the complexity of patterns of cortical folding or gyrification is necessary for understanding normal brain development and neurodevelopmental disorders. Conventional gyrification indices (GIs) are calculated based on surface curvature (curvature-based GI) or an outer hull surface of the cortex (outer surface-based GI). The latter is dependent on the definition of the outer hull surface and a corresponding function between surfaces. In the present study, we propose the Laplace Beltrami-based gyrification index (LB-GI). This is a new curvature-based local GI computed using the first three Laplace Beltrami eigenfunction level sets. As with outer surface-based GI methods, this method is based on the hypothesis that gyrification stems from a flat surface during development. However, instead of quantifying gyrification with reference to corresponding points on an outer hull surface, LB-GI quantifies the gyrification at each point on the cortical surface with reference to their surrounding gyral points, overcoming several shortcomings of existing methods. The LB-GI was applied to investigate the cortical maturation profile of the human brain from preschool to early adulthood using the PING database. The results revealed more detail in patterns of cortical folding than conventional curvature-based methods, especially on frontal and posterior tips of the brain, such as the frontal pole, lateral occipital, lateral cuneus, and lingual. Negative associations of cortical folding with age were observed at cortical regions, including bilateral lingual, lateral occipital, precentral gyrus, postcentral gyrus, and superior frontal gyrus. The results also indicated positive significant associations between age and the LB-GI of bilateral insula, the medial orbitofrontal, frontal pole and rostral anterior cingulate regions. It is anticipated that the LB-GI will be advantageous in providing further insights in the understanding of brain development and degeneration

Friedreich ataxia is a progressive neurodegenerative disorder with reported abnormalities in cerebellar, brainstem, and cerebral white matter. White matter structure can be measured using in vivo neuroimaging indices sensitive to different white matter features. For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities. Diffusion-tensor, magnetization transfer, and T1-weighted structural images were acquired from 31 individuals with Friedreich ataxia and 36 controls. Six white matter indices were extracted: fractional anisotropy, diffusivity (mean, axial, radial), magnetization transfer ratio (microstructure), and volume (macrostructure). For each index, whole-brain voxel-wise between-group comparisons and correlations with disease severity, onset age, and gene triplet-repeat length were undertaken. Correlations between pairs of indices were assessed in the Friedreich ataxia cohort. Spatial similarities in the voxel-level pattern of between-group differences across the indices were also assessed. Microstructural abnormalities were maximal in cerebellar and brainstem regions, but evident throughout the brain, while macroscopic abnormalities were restricted to the brainstem. Poorer microstructure and reduced macrostructural volume correlated with greater disease severity and earlier onset, particularly in peri-dentate nuclei and brainstem regions. Microstructural and macrostructural abnormalities were largely independent. Reduced fractional anisotropy was most strongly associated with axial diffusivity in cerebral tracts, and magnetization transfer in cerebellar tracts. Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.

Fragile X-associated tremor ataxia syndrome is an inherited neurodegenerative disorder caused by premutation expansions (55–200 CGG repeats) of the FMR1 gene. There is accumulating evidence to suggest that early cognitive and brain imaging signs may be observed in some premutation carriers without motor signs of FXTAS, but few studies have examined the relationships between subcortical brain volumes and cognitive performance in this group. This study examined the relationships between caudate volume and select cognitive measures (executive function and information processing speed) in men at risk of developing FXTAS and controls with normal FMR1 alleles (<45 CGG repeats). The results showed that men with premutation alleles performed worse on measures of executive function and information processing speed, and had significantly reduced caudate volume, compared to controls. Smaller caudate volume in the premutation group was associated with slower processing speed. These findings provide preliminary evidence that early reductions in caudate volume may be associated with cognitive slowing in men with the premutation who do not present with cardinal motor signs of FXTAS. If confirmed in future studies with larger PM cohorts, these findings will have important implications for the identification of sensitive measures with potential utility for tracking cognitive decline.

OBJECTIVE: To determine the effectiveness of a six-week rehabilitation programme followed by a home exercise programme for Friedreich's ataxia. DESIGN: Randomized, delayed-start control single-blind trial. SETTING: Outpatient rehabilitation centre. SUBJECTS: Ambulant or non-ambulant individuals with Friedreich's ataxia. INTERVENTION: Participants were randomized to a six-week outpatient rehabilitation programme, immediately (intervention group) or after a six-week delayed-start (control group). The rehabilitation was followed by a six-week home exercise programme. MAIN MEASURES: The primary outcome was the Functional Independence Measure. Other measures included the Friedreich Ataxia Impact Scale and the Friedreich Ataxia Rating Scale. Outcomes were administered at baseline, 6, 12 and 18 weeks. RESULT(S): Of 159 individuals screened, 92 were excluded and 48 declined to participate. A total of 19 participants were enrolled in the study. There was no significant difference in Functional Independence Measure change from baseline to six weeks in the intervention group (mean +/- standard deviation, 2.00 +/- 3.16) as compared to the control group (0.56 +/- 4.06). Change in the Friedreich Ataxia Impact Scale body movement subscale indicated a significant improvement in health and well-being in the intervention group compared to the control group ( P = 0.003). Significant within-group improvements in the Friedreich Ataxia Impact Scale and the motor domain of the Functional Independence Measure post-rehabilitation were not sustained post-home exercise programme. CONCLUSION(S): Our study indicates that rehabilitation can improve health and well-being in individuals with Friedreich's ataxia; however, a larger study is required to have sufficient power to detect a significant change in the most sensitive measure of function, the motor domain of the Functional Independence Measure.

We aimed to investigate the relationship between striatal morphology in Huntington disease (HD) and measures of motor and cognitive dysfunction. MRI scans, from the IMAGE-HD study, were obtained from 36 individuals with pre-symptomatic HD (pre-HD), 37 with early symptomatic HD (symp-HD), and 36 healthy matched controls. The neostriatum was manually segmented and a surface-based parametric mapping protocol derived two pointwise shape measures: thickness and surface dilation ratio. Significant shape differences were detected between all groups. Negative associations were detected between lower thickness and surface area shape measure and CAG repeats, disease burden score, and UHDRS total motor score. In symp-HD, UPSIT scores were correlated with higher thickness in left caudate tail and surface dilation ratio in left posterior putamen; Stroop scores were positively correlated with the thickness of left putamen head and body. Self-paced tapping (slow) was correlated with higher thickness and surface dilation ratio in the right caudate in symp-HD and with bilateral putamen in pre-HD. Self-paced tapping (fast) was correlated with higher surface dilation ratio in the right anterior putamen in symp-HD. Shape changes correlated with functional measures subserved by corticostriatal circuits, suggesting that the neostriatum is a potentially useful structural basis for characterisation of endophenotypes of HD.Copyright © 2019

Objective: This study aims to determine valid and responsive gait and balance outcome measures to detect progressive change over 12 months for individuals with FRDA. Background(s): Gait ataxia and instability are common presenting features of Friedreich ataxia (FRDA). Mobility declines with disease progression until ambulation is no longer possible, approximately 10-15 years following initial symptoms. Design/Methods: Fifty-one individuals with FRDA underwent assessment at baseline and six months (12-month data is being collected). Measures included (i) gait parameters at preferred and fast speeds using the GAITRite instrumented walkway, (ii) Biodex Balance SystemTM postural stability test (PST) and limits of stability (LOS), (iii) Berg Balance Scale (BBS), (iv) Timed 25 Foot Walk Test, (v) Dynamic Gait Index and (iv) Friedreich Ataxia Rating Scale (FARS) upright stability subscale. Correlations between objective measures, the FARS neurological exam, Scale for the Assessment and Rating of Ataxia (SARA) and disease characteristics were examined. The standardised response mean was reported as the effect size index (ES) for comparison of internal responsiveness. Result(s): Significant correlations were found between the BBS and SARA (p<0.001). Increased stride time variability was associated with a higher FARS score (p<0.001). The SARA and FARS did not detect a significant change over six months. However, the FARS upright stability subscale significantly increased with an ES of 0.571 (p<0.001) over this time. The BBS (ES: -0.519, p=0.001) and PST anteriorposterior index with eyes-closed (ES=0.667, p=0.010) also detected balance decline. A significant decrease in stride length during fast walking was also evident (ES=-0.323, p=0.030). Conclusion(s): Clinical balance measures, PST eyes-closed anterior-posterior index and stride length are more sensitive to the decline in individuals with FRDA as compared to previously validated measures of disease severity, the SARA and

Cerebellar ataxia often results in impairment in ambulation secondary to gait pattern dysfunction and compensatory gait adjustments. Pharmaceutical and therapy-based interventions with potential benefit for gait in ataxia are starting to emerge, however evaluation of such interventions is hampered by the lack of outcome measures that are responsive, valid and reliable for measurement of gait decline in cerebellar ataxia. This systematic review aimed for the first time to evaluate the psychometric properties of gait and walking outcomes applicable to individuals with cerebellar ataxia. Only studies evaluating straight walking were included. A comprehensive search of three databases (MEDLINE, CINAHL and EMBASE) identified 53 studies meeting inclusion criteria. Forty-nine were rated as 'poor' as assessed by the COnsensus-based Standards for the selection of health Measurement INstruments checklist. The primary objective of most studies was to explore changes in gait related to ataxia, rather than to examine psychometric properties of outcomes. This resulted in methodologies not specific for psychometric assessment. Thirty-nine studies examined validity, 11 examined responsiveness and 12 measured reliability. Review of the data identified double and single support and swing percentage of the gait cycle, velocity, step length and the Scale for Assessment and Rating of Ataxia (SARA) gait item as the most valid and responsive measures of gait in cerebellar ataxia. However, further evaluation to establish their reliability and applicability for use in clinical trials is clearly warranted. We recommend that inter-session reliability of gait outcomes should be evaluated to ensure changes are reflective of intervention effectiveness in cerebellar ataxia.Copyright © 2018 Elsevier B.V.

BACKGROUND: Persons with chronic pain often report problems with cognitive abilities, such as memory or attention. There is limited understanding of whether objective performance is consistent with subjective reports, and how psychological factors contribute. We aimed to investigate these relationships in a group of patients expressing cognitive concerns, and evaluate the utility of self-report tools for pain management settings. METHOD: Participants with chronic pain (n = 41) completed standardized neuropsychological tests, and self-report measures of cognitive functioning, pain, mood and sleep, as part of a broader study investigating cognitive performance in pain. RESULTS: Average neuropsychological test performance was subtly below normative means (within one standard deviation). Twenty-five percent of the sample scored substantially below age-adjusted norms on one or more objective tests. There were moderate-to-large associations between objective performance (e.g. Trail-Making B) and subjective cognitive complaints (e.g. Everyday Memory Questionnaire - Revised), controlling for age and education level. This was moderated by anxiety, such that subjective-objective relationships were particularly strong in those with higher anxiety. Poorer test performance was associated with higher pain intensity and catastrophizing. Subjective-objective cognition relationships remained after controlling for catastrophizing. CONCLUSION: Patients' self-reported cognitive concerns concurred with objectively measured performance, independent of age, education and catastrophizing. Moreover, those with severe anxiety were more accurate in predicting their cognitive performance. The findings highlight some interesting cognition-mood relationships, and suggest that easy-to-administer questionnaires, such as the Everyday Memory Questionnaire - Revised and the Behavior Rating Inventory of Executive Function - Adult Version, may be useful to capture cognitive concerns in clinical setting

Recent evidence indicates that adults with a premutation (PM: 55–199 CGG repeats) expansion in the fragile X mental retardation 1 (FMR1) gene show postural control deficits that may reflect disruption to cerebellar motor regions. Less is known about the influence of reduced cerebellar volume and structural changes, and increase in CGG repeat and FMR1 mRNA levels on the attentional demands of step initiation in PM males. We investigated the effects of a concurrent cognitive task on choice stepping reaction time (CSRT) and explored the associations between CSRT performance, cerebellar volume, CGG size, and FMR1 mRNA levels in blood in PM males. We examined 19 PM males (ages 28–75) and 23 matched controls (CGG <44; ages 26–77), who performed a verbal fluency task during CSRT performance and single-task stepping without a secondary cognitive task. Our results provide preliminary evidence that smaller cerebellar volume (β = −2.73, p = 0.002) and increasing CGG repeat length (β = 1.69, p = 0.003) were associated with greater dual-task step initiation times in PM males, but not in controls. There was evidence of a mediating effect of cerebellar volume on the relationship between FMR1 mRNA levels and single-task CSRT performance in PM males (estimate coefficient = 8.69, standard error = 4.42, p = 0.049). These findings suggest increasing CGG repeat and FMR1 mRNA levels have neurotoxic effects on cerebellar regions underlying anticipatory postural responses during stepping. Cerebellar postural changes may be predictive of the increased risk of falls in older PM males.

Background. Treatment of genetic degenerative ataxia is currently based on symptom management and maintenance of function. However, utilization of rehabilitation is limited due to a lack of evidence supporting its efficacy. Objective. This systematic review evaluated rehabilitation interventions for individuals with genetic degenerative ataxia. In addition, long-term outcomes from rehabilitation and optimal duration and intensity of rehabilitation were examined. Methods. A comprehensive search of 4 databases (MEDLINE, CINAHL, PEDro, and Cochrane) identified randomized, nonrandomized controlled, and cohort studies published from inception through to January 2016. The studies included at least one measure examining function, ataxia, balance, or gait. Methodological quality was assessed with the Australian National Health and Medical Research Council (NHMRC) Hierarchy of Evidence and the randomized controlled trials were rated according to the PEDro scale. Results. Seventeen studies met eligibility criteria. Five randomized controlled trials were included; however, the majority were classified as level III-3 and IV studies. Of 292 participants included, 148 had autosomal dominant ataxia, and 85 had autosomal recessive ataxia. Rehabilitation interventions included coordination and balance training, multifaceted inpatient rehabilitation, a cycling regime, balance exercises with technology assisted biofeedback, respiratory muscle training, and treadmill training. Two studies examined adjuncts to rehabilitation. Fifteen of the 17 studies demonstrated a statistically significant improvement in at least 1 outcome measuring ataxia, function, gait, or balance. Less than half of the studies included assessment of long-term outcomes and follow-up time frames varied considerably. Conclusion. There is consistent evidence that rehabilitation improves function, mobility, ataxia, and balance in genetic degenerative ataxia.Copyright © American Society of Neurorehabilitation.

Aims To investigate 18 month longitudinal changes in structural connectome in pre-HD and symp-HD, compared with controls. Method Longitudinal analysis of diffusion tensor imaging data was conducted for 28 pre-HD, 25 symp-HD, and 27 controls at baseline and 18 months. Unbiased tensor-based registration pipeline was used to register diffusion tensor data across time and groups. Whole brain probabilistic tractography was performed by seeding 50 million white-matter tracts (streamlines). The SIFT algorithm (spherical-deconvolution informed filtering of tractograms) removed bias in reconstructed tracts. 90x90 structural connectome was generated for each group. Longitudinal change in connectome was analysed using a Network Based Statistics analysis method and a group by time ANOVA model. Results There was a significant within group change in structural connectivity in pre-HD and symp-HD (P < 0.05, FDR Corrected) but not controls. In pre-HD, longitudinal change was observed in two distinct networks: the first connected striatum with motor cortex and the second connected prefrontal cortex with parieto-occipital cortices. In symp-HD, longitudinal change was observed in widespread connexions between frontal and parietal cortices, and striatum and cortex. No distinct networklevel changes were observed in symp-HD. Conclusions Structural connectome analysis can capture network- specific structural disconnectivity. While connectivity change in symp-HD was diffuse overall, the pre-HD group showed distinct networks that changed over time. These connectional pathways offer new avenues to further investigate disease spread pathways in HD.

Background: Traumatic injury can lead to loss, suffering and feelings of injustice. Previous research has shown that perceived injustice is associated with poorer physical and mental wellbeing in persons with chronic pain. This study aimed to identify the relative association between injury, compensation and pain-related characteristics and perceived injustice 12-months after traumatic injury. Methods: 433 participants were recruited from the Victorian Orthopedic Trauma Outcomes Registry and Victorian State Trauma Registry, and completed questionnaires at 12-14 months after injury as part of an observational cohort study. Using hierarchical linear regression we examined the relationships between baseline demographics (sex, age, education, comorbidities), injury (injury severity, hospital length of stay), compensation (compensation status, fault, lawyer involvement), and health outcomes (SF-12) and perceived injustice. We then examined how much additional variance in perceived injustice was related to worse pain severity, interference, self-efficacy, catastrophizing, kinesiophobia or disability.Results: Only a small portion of variance in perceived injustice was related to baseline demographics (especially education level), and injury severity. Attribution of fault to another, consulting a lawyer, health-related quality of life, disability and the severity of pain-related cognitions explained the majority of variance in perceived injustice. While univariate analyses showed that compensable injury led to higher perceptions of injustice, this did not remain significant when adjusting for all other factors, including fault attribution and consulting a lawyer. Conclusions: In addition to the "justice" aspects of traumatic injury, the health impacts of injury, emotional distress related to pain (catastrophizing), and the perceived impact of pain on activity (pain self-efficacy), had stronger associations with perceptions of injustice than either injury or pain s

BACKGROUND: Traumatic injury can lead to loss, suffering and feelings of injustice. Previous research has shown that perceived injustice is associated with poorer physical and mental wellbeing in persons with chronic pain. This study aimed to identify the relative association between injury, compensation and pain-related characteristics and perceived injustice 12-months after traumatic injury. METHODS: 433 participants were recruited from the Victorian Orthopedic Trauma Outcomes Registry and Victorian State Trauma Registry, and completed questionnaires at 12-14 months after injury as part of an observational cohort study. Using hierarchical linear regression we examined the relationships between baseline demographics (sex, age, education, comorbidities), injury (injury severity, hospital length of stay), compensation (compensation status, fault, lawyer involvement), and health outcomes (SF-12) and perceived injustice. We then examined how much additional variance in perceived injustice was related to worse pain severity, interference, self-efficacy, catastrophizing, kinesiophobia or disability. RESULTS: Only a small portion of variance in perceived injustice was related to baseline demographics (especially education level), and injury severity. Attribution of fault to another, consulting a lawyer, health-related quality of life, disability and the severity of pain-related cognitions explained the majority of variance in perceived injustice. While univariate analyses showed that compensable injury led to higher perceptions of injustice, this did not remain significant when adjusting for all other factors, including fault attribution and consulting a lawyer. CONCLUSIONS: In addition to the "justice" aspects of traumatic injury, the health impacts of injury, emotional distress related to pain (catastrophizing), and the perceived impact of pain on activity (pain self-efficacy), had stronger associations with perceptions of injustice than either injury or pain severity.

INTRODUCTION: Chronic pain is common after traumatic injury and frequently co-occurs with posttraumatic stress disorder (PTSD) and PTSD symptoms (PTSS). OBJECTIVES: This study sought to understand the association between probable PTSD, PTSS, and pain. METHODS: Four hundred thirty-three participants were recruited from the Victorian Orthopaedic Trauma Outcomes Registry and Victorian State Trauma Registry and completed outcome measures. Participants were predominantly male (n = 324, 74.8%) and aged 17-75 years at the time of their injury (M = 44.83 years, SD = 14.16). Participants completed the Posttraumatic Stress Disorder Checklist, Brief Pain Inventory, Pain Catastrophizing Scale, Pain Self-Efficacy Questionnaire, Tampa Scale of Kinesiophobia, EQ-5D-3L and Roland-Morris Disability Questionnaire 12 months after hospitalization for traumatic injury. Data were linked with injury and hospital admission data from the trauma registries. RESULTS: Those who reported having current problems with pain were 3 times more likely to have probable PTSD than those without pain. Canonical correlation showed that pain outcomes (pain severity, interference, catastrophizing, kinesiophobia, self-efficacy, and disability) were associated with all PTSSs, but especially symptoms of cognition and affect, hyperarousal, and avoidance. Posttraumatic stress disorder symptoms, on the contrary, were predominantly associated with high catastrophizing and low self-efficacy. When controlling for demographics, pain and injury severity, depression, and self-efficacy explained the greatest proportion of the total relationship between PTSS and pain-related disability. CONCLUSION: Persons with both PTSS and chronic pain after injury may need tailored interventions to overcome fear-related beliefs and to increase their perception that they can engage in everyday activities, despite their pain.

Many factors can influence the way in which we perceive painful events and noxious stimuli, but less is known about how pain perception is altered by explicit knowledge about the impending sensation. This study aimed to investigate the impact of explicit cueing on anxiety, arousal, and pain experience during the anticipation and delivery of noxious thermal heat stimulations. Fifty-two healthy volunteers were randomised to receive explicit instructions about visual cue-stimulus temperature pairings, or no explicit instructions about the cue-stimulus pairs. A pain anxiety task was used to investigate the effects of explicit cueing on anticipatory anxiety, pain experience and electrophysiological responses. Participants who received explicit instructions about the cue-stimulus pairs (i.e., the relationship between the colour of the cue and the temperature of the associated stimuli) reported significantly higher subjective anxiety prior to the delivery of the thermal heat stimuli (p = .025, partial eta squared = .10). There were no effects of explicit cueing on subsequent pain intensity, unpleasantness, or the electrophysiological response to stimulus delivery. The perceived intensity and unpleasantness of the stimuli decreased across the blocks of the paradigm. In both groups anticipating the ambiguous cue elicited the largest change in electrophysiological arousal, indicating that not knowing the impending stimulus temperature led to increased arousal, compared to being certain of receiving a high temperature thermal stimulus (both p < .001). Perceived stimulus intensity varied between ambiguous and non-ambiguous cues, depending on the temperature of the stimulus. Together these findings highlight the impact and importance of explicit cueing and uncertainty in experimental pain studies, and how these factors influence the way healthy individuals perceive and react to noxious and innocuous thermal stimuli.

Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder defined by pathology within the cerebellum and spinal tracts. Although FRDA is most readily linked to motor and sensory dysfunctions, reported impairments in working memory and executive functions indicate that abnormalities may also extend to associations regions of the cerebral cortex and/or cerebello-cerebral interactions. To test this hypothesis, 29 individuals with genetically confirmed FRDA and 34 healthy controls performed a verbal n-back working memory task while undergoing functional magnetic resonance imaging. No significant group differences were evident in task performance. However, individuals with FRDA had deficits in brain activations both in the lateral cerebellar hemispheres, principally encompassing lobule VI, and the prefrontal cortex, including regions of the anterior insular and rostrolateral prefrontal cortices. Functional connectivity between these brain regions was also impaired, supporting a putative link between primary cerebellar dysfunction and subsequent cerebral abnormalities. Disease severity and genetic markers of disease liability were correlated specifically with cerebellar dysfunction, while correlations between behavioural performance and both cerebral activations and cerebello-cerebral connectivity were observed in controls, but not in the FRDA cohort. Taken together, these findings support a diaschisis model of brain dysfunction, whereby primary disease effects in the cerebellum result in functional changes in downstream fronto-cerebellar networks. These fronto-cerebellar disturbances provide a putative biological basis for the nonmotor symptoms observed in FRDA, and reflect the consequence of localized cerebellar pathology to distributed brain function underlying higher-order cognition. Hum Brain Mapp 37:338-350, 2016. © 2015 Wiley Periodicals, Inc.Copyright © 2016 Wiley Periodicals, Inc.

Lower limb spasticity compromises the independence of people with Friedreich's ataxia (FRDA). This study sought to examine lower limb spasticity in FRDA in order to offer new insight as to the best approach and timing of spasticity management. Gastrocnemius and soleus spasticity and muscle length were measured by the Modified Tardieu Scale (MTS) in 31 participants with typical and late-onset FRDA. Relationships between the MTS and the Friedreich Ataxia Rating Scale (FARS), Functional Independence Measure (FIM), and disease duration were analysed. Differences between ambulant (n = 18) and non-ambulant (n = 13) participants were also examined. All participants had spasticity in at least one muscle, and 38.9% of ambulant and 69.2% of non-ambulant participants had contracture in one or both of their gastrocnemius muscles. Significant negative correlations were found between both gastrocnemius and soleus angle of catch and the FARS score. The FIM score also demonstrated significant correlations with gastrocnemius muscle length and angle of catch. Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function.Copyright © 2016 Elsevier Ltd. All rights reserved.