India Bohanna

Magnetic resonance imaging as an approach towards identifying neuropathological biomarkers for Huntington's disease

Magnetic Resonance Imaging (MRI), functional MRI (fMRI) and Diffusion Tensor Imaging (DTI) have been central to characterisation of abnormalities in brain structure and function in both clinical and preclinical Huntingtons disease (HD). One current challenge in clinical HD research is the identification of sensitive and reliable biomarkers to detect progressive neurodegeneration and neural dysfunction, which could be used to assess the effect of therapeutic intervention on brain structure and function in a HD clinical trial. To this end, both established and novel neuroimaging approaches could potentially provide sensitive, reliable and non-invasive tools to assess long-term and dynamic effects of treatment on specific brain regions, including their microstructure and connectivity. This review examines contributions from structural MRI, fMRI and DTI studies to our current understanding of preclinical and clinical HD, and critically appraises MRI methods potentially suitable for both scientific characterisation and for use as biomarkers in HD clinical trials. A combined neuroimaging approach incorporating structural MRI, fMRI and DTI is yet to be realised in HD clinical trials, however if proven to be sensitive and reliable, these methods could potentially serve as biomarkers for use in future clinical drug trials in HD.

Connectivity-based segmentation of the striatum in Huntington's disease: vulnerability of motor pathways.

The striatum, the primary site of degeneration in Huntingtons disease (HD), connects to the cerebral cortex via topographically organized circuits subserving unique motor, associative and limbic functions. Currently, it is not known whether all cortico-striatal circuits are equally affected in HD. We aimed to study the selective vulnerability of individual cortico-striatal circuits within the striatum in HD, and hypothesized that motor cortico-striatal pathways would be most affected, consistent with HD being a primarily motor disorder. Diffusion Tensor Imaging (DTI) tractography was used to identify connections between the striatum and seven major cortical regions in 12 HD patients and 14 matched controls. The striatum of both groups was parcellated into subregions based on connectivity with the cerebral cortex. Volumetric and DTI microstructural measures of Fractional Anisotropy (FA) and Mean Diffusivity (MD) were obtained within each subregion and compared statistically between groups. Tractography demonstrated the topographic organization of cortical connections in the striatum of both controls and HD patients. In HD patients, the greatest difference from controls in volume, FA and MD was observed in M1 and S1 subregions of the caudate and putamen. Motor symptoms correlated with volume and MD in sensorimotor striatal subregions, suggesting that sensorimotor striatal degeneration is closely related to motor dysfunction. DTI tractography provides a novel approach to sensitively examine circuit-specific abnormalities in HD and has identified that the motor cortico-striatal circuit is selectively vulnerable in HD.

Diffusion Tensor Imaging in Huntington’s disease reveals distinct patterns of white matter degeneration associated with motor and cognitive deficits

White matter (WM) degeneration is an important feature of Huntington’s disease (HD) neuropathology. To investigate WM degeneration we used Diffusion Tensor Imaging and Tract-Based Spatial Statistics to compare Fractional Anisotropy, Mean Diffusivity (MD), parallel diffusivity and perpendicular diffusivity (λ⊥) in WM throughout the whole brain in 17 clinically diagnosed HD patients and 16 matched controls. Significant WM diffusivity abnormalities were identified primarily in the corpus callosum (CC) and external/extreme capsules in HD patients compared to controls. Significant correlations were observed between motor symptoms and MD in the CC body, and between global cognitive impairment and λ⊥ in the CC genu. Probabilistic tractography from these regions revealed degeneration of functionally relevant interhemispheric WM tracts. Our findings suggest that WM degeneration within interhemispheric pathways plays an important role in the deterioration of cognitive and motor function in HD patients, and that improved understanding of WM pathology early in the disease is required.

A longitudinal diffusion tensor imaging study in symptomatic Huntington's disease

Objective The striatum and its projections are thought to be the earliest sites of Huntingtons disease (HD) pathology. This study aimed to investigate progression of striatal pathology in symptomatic HD using diffusion tensor imaging. Method Diffusion weighted images were acquired in 18 HD patients and in 17 healthy controls twice, 1 year apart. Mean diffusivity (MD) was calculated in the caudate, putamen, thalamus and corpus callosum, and compared between groups. In addition, caudate width was measured using T1 high resolution images and correlated with caudate MD. Correlation analyses were also performed in HD between caudate/putamen MD and clinical measures. Results MD was significantly higher in the caudate and putamen bilaterally for patients compared with controls at both time points although there were no significant MD differences in the thalamus or corpus callosum. For both groups, MD did not change significantly in any region from baseline to year 1. There was a significant negative correlation between caudate width and MD in patients at baseline but no correlation between these parameters in controls. There was also a significant negative correlation between Mini-Mental State Examination scores and caudate MD and putamen MD at both time points in HD. Conclusions It appears that microstructural changes influence cognitive status in HD. Although MD was significantly higher in HD compared with controls at both time points, there were no longitudinal changes in either group. This finding does not rule out the possibility that MD could be a sensitive biomarker for detecting early change in preclinical HD.

Media Guidelines for the Responsible Reporting of Suicide

BACKGROUND The media have a powerful influence on those at risk of suicide. Evidence linking sensational media reporting with imitative suicidal behavior continues to grow, prompting the widespread development of guidelines for media professionals on the reporting of suicide. While such guidelines have been widely implemented, only a small amount of research has addressed their use and effectiveness. AIMS To conduct a systematic literature review aimed at critically evaluating the evidence concerning the use and effectiveness of media guidelines for reporting on suicide. METHODS All research publications that addressed the effectiveness of media guidelines against a variety of outcome measures were examined. RESULTS The findings highlight cases in which guideline implementation has successfully mitigated imitative suicides. Significant variability in the effect of guidelines on the quality of suicide reporting was observed between studies, and research suggests journalist awareness, use, and opinion of guidelines is generally low. The critical positive effects of media collaboration and training on reporting are noted. CONCLUSIONS Overall, the findings of this review suggest that the guidelines can change reporting style and prevent imitative suicide, but that approaches centered on consultation, collaboration, media ownership, and training are likely to achieve the greatest success.

Functional magnetic resonance imaging of working memory in Huntington's disease: cross-sectional data from the IMAGE-HD study.

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 Huntingtons disease (pre‐HD, n = 35), early symptomatic Huntingtons 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. Hum Brain Mapp 35:1847–1864, 2014.

Automated differentiation of pre-diagnosis Huntington's disease from healthy control individuals based on quadratic discriminant analysis of the basal ganglia: the IMAGE-HD study

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 Huntingtons 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-modal imaging measures can accurately classify individuals up to 15 years prior to onset when therapeutic intervention is likely to have maximal effects in slowing the trajectory of disease development.

Description and psychometric properties of the CP QOL-Teen: A quality of life questionnaire for adolescents with cerebral palsy

To assess the measurement properties of a new QOL instrument, the Cerebral Palsy Quality of Life Questionnaire-Teen (CP QOL-Teen), in adolescents with cerebral palsy (CP) aged 13-18 years, examining domain structure, reliability, validity and adolescent-caregiver concordance. Based on age, 695 eligible families were invited to participate by mail. Questionnaires were returned by 112 primary caregivers (71.8% of questionnaires sent). 87 adolescents aged 12-18 years also completed the questionnaires. CP QOL-Teen, generic QOL instruments (KIDSCREEN, Pediatric Quality of Life Inventory), functioning (Gross Motor Function Classification System) and a condition-specific instrument (PedsQL-CP) were used. Principal components analysis produced seven scales: wellbeing and participation; communication and physical health; school wellbeing; social wellbeing; access to services; family health; feelings about functioning. Cronbachs alphas for the derived scales ranged from 0.81 to 0.96 (primary caregiver report) and 0.78 to 0.95 (adolescent report). Test-retest reliability (4 weeks) ranged from 0.57 to 0.88 for adolescent self-report and 0.29 to 0.83 for primary caregiver report. Moderate correlations were observed with other generic and condition specific measures of QOL, indicating adequate construct validity. Moderate correlations were observed between adolescent self-report and primary caregiver proxy report. This study demonstrates acceptable psychometric properties of both the adolescent self-report and the primary caregiver proxy report versions of the CP QOL-Teen.

Cannabis use in Cape York Indigenous communities: High prevalence, mental health impacts and the desire to quit

INTRODUCTION AND AIMS Anecdotal reports suggest that high rates of cannabis use and dependence are significant issues in Indigenous communities in north Queensland; however, there is little scientific evidence to support or refute this. The Cape York Cannabis Project seeks to investigate cannabis use rates, cannabis dependence and mental health impacts for the first time in three Cape York Indigenous communities. DESIGN AND METHODS The current study reports preliminary findings, resulting from interviews with 133 Indigenous participants aged 14-47 years from one Cape York community. Quantitative data were gathered on rates of cannabis use, cannabis dependence as measured by a score of ≥ 3 the Severity of Dependence Scale. Qualitative self-report data were gathered concerning mental health impacts of cannabis and reasons for quitting. RESULTS AND CONCLUSIONS Very high rates of cannabis use were identified, with 66.2% of males and 30.5% of females interviewed being current users. An additional 12.2% of males and 30.5% of females were former users, and 21.6% of males and 39% of females had never used cannabis. High rates of cannabis dependence were also observed. Of those current users who used cannabis at least weekly, 67.7% reported cannabis dependence. A range of mental health impacts due to cannabis were reported. In total, 76.1% of current users were considering quitting or cutting down. Rates of use and dependence were much higher than national rates, and indicate significant mental health harms due to cannabis. Further investigation of mental health impacts of cannabis is required, as is intervention to reduce these impacts.

Stages of change, smoking behaviour and readiness to quit in a large sample of indigenous Australians living in eight remote north Queensland communities.

Tobacco smoking is a major health issue for Indigenous Australians, however there are few interventions with demonstrated efficacy in this population. The Transtheoretical Model may provide a useful framework for describing smoking behaviour and assessing readiness to quit, with the aim of developing better interventions. Interviews were conducted with 593 Indigenous Australians in eight rural and remote communities in north Queensland, to examine stages of change and smoking behaviour. Among current smokers, 39.6% and 43.4% were in Precontemplation and Contemplation stages respectively. A further 13.9% were making preparations to quit (Preparation) whilst only 3.2% said they were actively trying to quit (Action). When analysed by stage of change, the pattern of smoking-related behaviours conformed to the results of past research using the model. Importantly however, distribution of individuals across the stages opposes those observed in investigations of smoking behaviour in non-Indigenous Australian populations. The Transtheoretical Model can be used to meaningfully classify Indigenous smokers in remote north Queensland according to stages along the behaviour change continuum. Importantly, in this large sample across eight communities, most Indigenous smokers were not making preparations to change their smoking behaviour. This suggests that interventions should focus on promoting movement toward the Preparation and Action stages of change.