Susie M.D. Henley

Head size, age and gender adjustment in MRI studies: a necessary nuisance?

Imaging studies of cerebral volumes often adjust for factors such as age that may confound between-subject comparisons. However the use of nuisance covariates in imaging studies is inconsistent, which can make interpreting results across studies difficult. Using magnetic resonance images of 78 healthy controls we assessed the effects of age, gender, head size and scanner upgrade on region of interest (ROI) volumetry, cortical thickness and voxel-based morphometric (VBM) measures. We found numerous significant associations between these variables and volumetric measures: cerebral volumes and cortical thicknesses decreased with increasing age, men had larger volumes and smaller thicknesses than women, and increasing head size was associated with larger volumes. The relationships between most ROIs and head size volumes were non-linear. With age, gender, head size and upgrade in one model we found that volumes and thicknesses decreased with increasing age, women had larger volumes than men (VBM, whole-brain and white matter volumes), increasing head size was associated with larger volumes but not cortical thickness, and scanner upgrade had an effect on thickness and some volume measures. The effects of gender on cortical thickness when adjusting for head size, age and upgrade showed some non-significant effect (women>men), whereas the independent effect of head size showed little pattern. We conclude that age and head size should be considered in ROI volume studies, age, gender and upgrade should be considered for cortical thickness studies and all variables require consideration for VBM analyses. Division of all volumes by head size is unlikely to be adequate owing to their non-proportional relationship.

Ten simple rules for reporting voxel-based morphometry studies.

Voxel-based morphometry [Ashburner, J. and Friston, K.J., 2000. Voxel-based morphometry-the methods. NeuroImage 11(6 Pt 1), 805-821] is a commonly used tool for studying patterns of brain change in development or disease and neuroanatomical correlates of subject characteristics. In performing a VBM study, many methodological options are available; if the study is to be easily interpretable and repeatable, the processing steps and decisions must be clearly described. Similarly, unusual methods and parameter choices should be justified in order to aid readers in judging the importance of such options or in comparing the work with other studies. This editorial suggests core principles that should be followed and information that should be included when reporting a VBM study in order to make it transparent, replicable and useful.

The structural neuroanatomy of music emotion recognition: Evidence from frontotemporal lobar degeneration

Despite growing clinical and neurobiological interest in the brain mechanisms that process emotion in music, these mechanisms remain incompletely understood. Patients with frontotemporal lobar degeneration (FTLD) frequently exhibit clinical syndromes that illustrate the effects of breakdown in emotional and social functioning. Here we investigated the neuroanatomical substrate for recognition of musical emotion in a cohort of 26 patients with FTLD (16 with behavioural variant frontotemporal dementia, bvFTD, 10 with semantic dementia, SemD) using voxel-based morphometry. On neuropsychological evaluation, patients with FTLD showed deficient recognition of canonical emotions (happiness, sadness, anger and fear) from music as well as faces and voices compared with healthy control subjects. Impaired recognition of emotions from music was specifically associated with grey matter loss in a distributed cerebral network including insula, orbitofrontal cortex, anterior cingulate and medial prefrontal cortex, anterior temporal and more posterior temporal and parietal cortices, amygdala and the subcortical mesolimbic system. This network constitutes an essential brain substrate for recognition of musical emotion that overlaps with brain regions previously implicated in coding emotional value, behavioural context, conceptual knowledge and theory of mind. Musical emotion recognition may probe the interface of these processes, delineating a profile of brain damage that is essential for the abstraction of complex social emotions.

The progression of regional atrophy in premanifest and early Huntington's disease: a longitudinal voxel-based morphometry study

Background Unbiased longitudinal studies are needed to understand the distributed neurodegenerative changes of Huntingtons disease (HD). They may also provide tools for assessing disease-modifying interventions. The authors investigated the progression of regional atrophy in premanifest and early HD compared with controls. Methods Nine controls, 17 premanifest and 21 early HD subjects underwent volumetric MRI at baseline and 2 years. Premanifest subjects were on average 18.1 years before predicted motor onset. Non-linear registration was used to model within-subject change over the scanning interval, and statistical parametric mapping was used to examine group differences and associations with clinical variables. Results In early HD, increased grey-matter (GM) atrophy rates were evident throughout the subcortical GM and over selective cortical regions compared with controls. This group also demonstrated strikingly widespread increases in white-matter (WM) atrophy rates. The authors observed no significant differences between premanifest HD and controls. Longer CAG was associated with higher atrophy rates over large WM areas including brainstem and internal capsule and over small GM regions including thalamus and occipital cortex. Worse baseline motor score was associated with regionally increased rates in the thalamus, internal capsule and occipital lobe. Sample-size calculations indicate that 19 and 24 early HD subjects per treatment arm would need to complete a 2-year trial in order to detect a 50% reduction in WM and GM atrophy rates respectively. Conclusions Degeneration of structural connectivity may play an important role in early HD symptoms. Assessment of WM and GM changes will be important in understanding the complexity of HD and its treatment.

Clinical impairment in premanifest and early Huntington's disease is associated with regionally specific atrophy.

TRACK‐HD is a multicentre longitudinal observational study investigating the use of clinical assessments and 3‐Tesla magnetic resonance imaging as potential biomarkers for future therapeutic trials in Huntingtons disease (HD). The cross‐sectional data from this large well‐characterized dataset provide the opportunity to improve our knowledge of how the underlying neuropathology of HD may contribute to the clinical manifestations of the disease across the spectrum of premanifest (PreHD) and early HD. Two hundred and thirty nine gene‐positive subjects (120 PreHD and 119 early HD) from the TRACK‐HD study were included. Using voxel‐based morphometry (VBM), grey and white matter volumes were correlated with performance in four domains: quantitative motor (tongue force, metronome tapping, and gait); oculomotor [anti‐saccade error rate (ASE)]; cognition (negative emotion recognition, spot the change and the University of Pennsylvania smell identification test) and neuropsychiatric measures (apathy, affect and irritability). After adjusting for estimated disease severity, regionally specific associations between structural loss and task performance were found (familywise error corrected, P < 0.05); impairment in tongue force, metronome tapping and ASE were all associated with striatal loss. Additionally, tongue force deficits and ASE were associated with volume reduction in the occipital lobe. Impaired recognition of negative emotions was associated with volumetric reductions in the precuneus and cuneus. Our study reveals specific associations between atrophy and decline in a range of clinical modalities, demonstrating the utility of VBM correlation analysis for investigating these relationships in HD. Hum Brain Mapp, 2013.

Pitfalls in the Use of Voxel-Based Morphometry as a Biomarker: Examples from Huntington Disease

BACKGROUND AND PURPOSE: VBM is increasingly used in the study of neurodegeneration, and recently there has been interest in its potential as a biomarker. However, although it is largely “automated,” VBM is rarely implemented consistently across studies, and changing user-specified options can alter the results in a way similar to the very biologic differences under investigation. MATERIALS AND METHODS: This work uses data from patients with HD to demonstrate the effects of several user-specified VBM parameters and analyses: type and level of statistical correction, modulation, smoothing kernel size, adjustment for brain size, subgroup analysis, and software version. RESULTS: The results demonstrate that changing these options can alter results in a way similar to the biologic differences under investigation. CONCLUSIONS: If VBM is to be useful clinically or considered for use as a biomarker, there is a need for greater recognition of these issues and more uniformity in its application for the method to be both reproducible and valid.

Biomarkers for neurodegenerative diseases.

Purpose of reviewA major goal of current clinical research in neurodegenerative diseases is to improve early detection of disease and presymptomatic detection of neuronal dysfunction. We also need better tools to assess disease progression in this group of disorders. Currently, many potential disease-modifying therapies are being developed and evaluated at the preclinical stage, and will lead to clinical trials in the near future for which biomarkers are urgently needed. This review summarizes the field of biomarker research in the major neurodegenerative diseases. Recent findingsMany different approaches are being undertaken to identify biomarkers and include imaging, neurophysiological and cognitive testing in addition to newer technologies such as biochemical, proteomic, metabanomic and gene array profiling of tissue and biofluids from patients. Key recent findings in each of these areas are discussed. SummaryThe ideal biomarker needs to be easy to quantify and measure, reproducible, not subject to wide variation in the general population and unaffected by co-morbid factors. For evaluation of therapies the biomarker needs to change linearly with disease progression and closely correlate with established clinico-pathological parameters of the disease. It is unlikely that any one biomarker will fulfil all these characteristics, and it is likely that more than one biomarker will be needed for early diagnosis and similarly for evaluation of disease progression for therapeutic trials. For example, the combination of more detailed clinical assessments encompassing specific cognitive and neurophysiological testing, in addition to imaging, biochemical and genomic profiling, is likely to be needed.

Altered brain mechanisms of emotion processing in pre-manifest Huntington's disease

Huntingtons disease is an inherited neurodegenerative disease that causes motor, cognitive and psychiatric impairment, including an early decline in ability to recognize emotional states in others. The pathophysiology underlying the earliest manifestations of the disease is not fully understood; the objective of our study was to clarify this. We used functional magnetic resonance imaging to investigate changes in brain mechanisms of emotion recognition in pre-manifest carriers of the abnormal Huntingtons disease gene (subjects with pre-manifest Huntingtons disease): 16 subjects with pre-manifest Huntingtons disease and 14 control subjects underwent 1.5 tesla magnetic resonance scanning while viewing pictures of facial expressions from the Ekman and Friesen series. Disgust, anger and happiness were chosen as emotions of interest. Disgust is the emotion in which recognition deficits have most commonly been detected in Huntingtons disease; anger is the emotion in which impaired recognition was detected in the largest behavioural study of emotion recognition in pre-manifest Huntingtons disease to date; and happiness is a positive emotion to contrast with disgust and anger. Ekman facial expressions were also used to quantify emotion recognition accuracy outside the scanner and structural magnetic resonance imaging with voxel-based morphometry was used to assess the relationship between emotion recognition accuracy and regional grey matter volume. Emotion processing in pre-manifest Huntingtons disease was associated with reduced neural activity for all three emotions in partially separable functional networks. Furthermore, the Huntingtons disease-associated modulation of disgust and happiness processing was negatively correlated with genetic markers of pre-manifest disease progression in distributed, largely extrastriatal networks. The modulated disgust network included insulae, cingulate cortices, pre- and postcentral gyri, precunei, cunei, bilateral putamena, right pallidum, right thalamus, cerebellum, middle frontal, middle occipital, right superior and left inferior temporal gyri, and left superior parietal lobule. The modulated happiness network included postcentral gyri, left caudate, right cingulate cortex, right superior and inferior parietal lobules, and right superior frontal, middle temporal, middle occipital and precentral gyri. These effects were not driven merely by striatal dysfunction. We did not find equivalent associations between brain structure and emotion recognition, and the pre-manifest Huntingtons disease cohort did not have a behavioural deficit in out-of-scanner emotion recognition relative to controls. In addition, we found increased neural activity in the pre-manifest subjects in response to all three emotions in frontal regions, predominantly in the middle frontal gyri. Overall, these findings suggest that pathophysiological effects of Huntingtons disease may precede the development of overt clinical symptoms and detectable cerebral atrophy.

Emotion recognition in Huntington's disease: A systematic review

There is increasing interest in the nature of the emotion recognition deficit in Huntingtons disease (HD). There are conflicting reports of disproportionate impairments for some emotions in some modalities in HD. A systematic review and narrative synthesis was conducted for studies investigating emotion recognition in HD. Embase, MEDLINE, PsychINFO and Pubmed were searched from 1993 to 2010, and citations and reference lists were searched. 1724 citations were identified. Sixteen studies were included. In manifest HD evidence of impaired recognition of facial expressions of anger was found consistently, although recognition of all negative emotions (facial and vocal) tended to be impaired. In premanifest HD impairments were inconsistent, but are seen in all facial expressions of negative emotion. Inconsistency may represent the variability inherent in HD although may also be due to between-study differences in methodology. Current evidence supports the conclusion that recognition of all negative emotions tends to be impaired in HD, particularly in the facial domain. Future work should focus on using more ecologically-valid tests, and testing inter-modality differences.

Magnetic resonance imaging of Huntington's disease: preparing for clinical trials

The known genetic mutation causing Huntingtons disease (HD) makes this disease an important model to study links between gene and brain function. An autosomal dominant family history and the availability of a sensitive and specific genetic test allow pre-clinical diagnosis many years before the onset of any typical clinical signs. This review summarizes recent magnetic resonance imaging (MRI)–based findings in HD with a focus on the requirements if imaging is to be used in treatment trials. Despite its monogenetic cause, HD presents with a range of clinical manifestations, not explained by variation in the number of CAG repeats in the affected population. Neuroimaging studies have revealed a complex pattern of structural and functional changes affecting widespread cortical and subcortical regions far beyond the confines of the striatal degeneration that characterizes this disorder. Besides striatal dysfunction, functional imaging studies have reported a variable pattern of increased and decreased activation in cortical regions in both pre-clinical and clinically manifest HD-gene mutation carriers. Beyond regional brain activation changes, evidence from functional and diffusion-weighted MRI further suggests disrupted connectivity between corticocortical and corticostriatal areas. However, substantial inconsistencies with respect to structural and functional changes have been reported in a number of studies. Possible explanations include methodological factors and differences in study samples. There may also be biological explanations but these are poorly characterized and understood at present. Additional insights into this phenotypic variability derived from study of mouse models are presented to explore this phenomenon.