Testing the expensive-tissue hypothesis' prediction of inter-tissue competition using causal modelling with latent variables.

The expensive-tissue hypothesis (ETH) posited a brain-gut trade-off to explain how humans evolved large, costly brains. Versions of the ETH interrogating gut or other body tissues have been tested in non-human animals, but not humans. We collected brain and body composition data in 70 South Asian women and used structural equation modelling with instrumental variables, an approach that handles threats to causal inference including measurement error, unmeasured confounding and reverse causality. We tested a negative, causal effect of the latent construct 'nutritional investment in brain tissues' (MRI-derived brain volumes) on the construct 'nutritional investment in lean body tissues' (organ volume and skeletal muscle). We also predicted a negative causal effect of the brain latent on fat mass. We found negative causal estimates for both brain and lean tissue (-0.41, 95% CI, -1.13, 0.23) and brain and fat (-0.56, 95% CI, -2.46, 2.28). These results, although inconclusive, are consistent with theory and prior evidence of the brain trading off with lean and fat tissues, and they are an important step in assessing empirical evidence for the ETH in humans. Analyses using larger datasets, genetic data and causal modelling are required to build on these findings and expand the evidence base.

Fibre orientation atlas guided rapid segmentation of white matter tracts.

Fibre tract delineation from diffusion magnetic resonance imaging (MRI) is a valuable clinical tool for neurosurgical planning and navigation, as well as in research neuroimaging pipelines. Several popular methods are used for this task, each with different strengths and weaknesses making them more or less suited to different contexts. For neurosurgical imaging, priorities include ease of use, computational efficiency, robustness to pathology and ability to generalise to new tracts of interest. Many existing methods use streamline tractography, which may require expert neuroimaging operators for setting parameters and delineating anatomical regions of interest, or suffer from as a lack of generalisability to clinical scans involving deforming tumours and other pathologies. More recently, data-driven approaches including deep-learning segmentation models and streamline clustering methods have improved reproducibility and automation, although they can require large amounts of training data and/or computationally intensive image processing at the point of application. We describe an atlas-based direct tract mapping technique called 'tractfinder', utilising tract-specific location and orientation priors. Our aim was to develop a clinically practical method avoiding streamline tractography at the point of application while utilising prior anatomical knowledge derived from only 10-20 training samples. Requiring few training samples allows emphasis to be placed on producing high quality, neuro-anatomically accurate training data, and enables rapid adaptation to new tracts of interest. Avoiding streamline tractography at the point of application reduces computational time, false positives and vulnerabilities to pathology such as tumour deformations or oedema. Carefully filtered training streamlines and track orientation distribution mapping are used to construct tract specific orientation and spatial probability atlases in standard space. Atlases are then transformed to target subject space using affine registration and compared with the subject's voxel-wise fibre orientation distribution data using a mathematical measure of distribution overlap, resulting in a map of the tract's likely spatial distribution. This work includes extensive performance evaluation and comparison with benchmark techniques, including streamline tractography and the deep-learning method TractSeg, in two publicly available healthy diffusion MRI datasets (from TractoInferno and the Human Connectome Project) in addition to a clinical dataset comprising paediatric and adult brain tumour scans. Tract segmentation results display high agreement with established techniques while requiring less than 3 min on average when applied to a new subject. Results also display higher robustness than compared methods when faced with clinical scans featuring brain tumours and resections. As well as describing and evaluating a novel proposed tract delineation technique, this work continues the discussion on the challenges surrounding the white matter segmentation task, including issues of anatomical definitions and the use of quantitative segmentation comparison metrics.

The incidence of movement disorder increases with age and contrasts with subtle and limited neuroimaging abnormalities in argininosuccinic aciduria.

Argininosuccinate lyase (ASL) is integral to the urea cycle detoxifying neurotoxic ammonia and the nitric oxide (NO) biosynthesis cycle. Inherited ASL deficiency causes argininosuccinic aciduria (ASA), a rare disease with hyperammonemia and NO deficiency. Patients present with developmental delay, epilepsy and movement disorder, associated with NO-mediated downregulation of central catecholamine biosynthesis. A neurodegenerative phenotype has been proposed in ASA. To better characterise this neurodegenerative phenotype in ASA, we conducted a retrospective study in six paediatric and adult metabolic centres in the UK in 2022. We identified 60 patients and specifically looked for neurodegeneration-related symptoms: movement disorder such as ataxia, tremor and dystonia, hypotonia/fatigue and abnormal behaviour. We analysed neuroimaging with diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) in an individual with ASA with movement disorders. We assessed conventional and DTI MRI alongside single photon emission computer tomography (SPECT) with dopamine analogue radionuclide 123 I-ioflupane, in Asl-deficient mice treated by hASL mRNA with normalised ureagenesis. Movement disorders in ASA appear in the second and third decades of life, becoming more prevalent with ageing and independent from the age of onset of hyperammonemia. Neuroimaging can show abnormal DTI features affecting both grey and white matter, preferentially basal ganglia. ASA mouse model with normalised ureagenesis did not recapitulate these DTI findings and showed normal 123 I-ioflupane SPECT and cerebral dopamine metabolomics. Altogether these findings support the pathophysiology of a late-onset movement disorder with cell-autonomous functional central catecholamine dysregulation but without or limited neurodegeneration of dopaminergic neurons, making these symptoms amenable to targeted therapy.

Extent of piriform cortex resection in children with temporal lobe epilepsy.

OBJECTIVE: A greater extent of resection of the temporal portion of the piriform cortex (PC) has been shown to be associated with higher likelihood of seizure freedom in adults undergoing anterior temporal lobe resection (ATLR) for drug-resistant temporal lobe epilepsy (TLE). There have been no such studies in children, therefore this study aimed to investigate this association in a pediatric cohort. METHODS: A retrospective, neuroimaging cohort study of children with TLE who underwent ATLR between 2012 and 2021 was undertaken. The PC, hippocampal and amygdala volumes were measured on the preoperative and postoperative T1-weighted MRI. Using these volumes, the extent of resection per region was compared between the seizure-free and not seizure-free groups. RESULTS: In 50 children (median age 9.5 years) there was no significant difference between the extent of resection of the temporal PC in the seizure-free (median = 50%, n = 33/50) versus not seizure-free (median = 40%, n = 17/50) groups (p = 0.26). In a sub-group of 19 with ipsilateral hippocampal atrophy (quantitatively defined by ipsilateral-to-contralateral asymmetry), the median extent of temporal PC resection was greater in children who were seizure-free (53%) versus those not seizure-free (19%) (p = 0.009). INTERPRETATION: This is the first study demonstrating that, in children with TLE and hippocampal atrophy, more extensive temporal PC resection is associated with a greater chance of seizure freedom-compatible with an adult series in which 85% of patients had hippocampal sclerosis. In a combined group of children with and without hippocampal atrophy, the extent of PC resection was not associated with seizure outcome, suggesting different epileptogenic networks within this cohort.

Accuracy of robot-assisted stereotactic MRI-guided laser ablation in children with epilepsy.

OBJECTIVE: Robot-assisted (RA) stereotactic MRI-guided laser ablation has been reported to be a safe and effective technique for the treatment of epileptogenic foci in children and adults. In this study the authors aimed to assess the accuracy of RA stereotactic MRI-guided laser fiber placement in children and to identify factors that might increase the risk of misplacement. METHODS: A retrospective single-institution review of all children from 2019 to 2022 who underwent RA stereotactic MRI-guided laser ablation for epilepsy was undertaken. Placement error was calculated at the target by measuring the Euclidean distance between the implanted laser fiber position and the preoperatively planned position. Collected data included age at surgery, sex, pathology, date of robot calibration, number of catheters, entry position, entry angle, extracranial soft-tissue thickness, bone thickness, and intracranial catheter length. A systematic review of the literature was also performed using Ovid Medline, Ovid Embase, and the Cochrane Central Register of Controlled Trials. RESULTS: In 28 children with epilepsy, the authors assessed 35 RA stereotactic MRI-guided laser ablation fiber placements. Twenty (71.4%) children had undergone ablation for hypothalamic hamartoma, 7 children (25.0%) for presumed insular focal cortical dysplasia, and 1 patient (3.6%) for periventricular nodular heterotopia. Nineteen children were male (67.9.%) and 9 were female (32.1%). The median age at the time of the procedure was 7.67 years (IQR 4.58-12.26 years). The median target point localization error (TPLE) was 1.27 mm (IQR 0.76-1.71 mm). The median offset error between the planned and actual trajectories was 1.04° (IQR 0.73°-1.46°). Patient age, sex, pathology and the time interval between date of surgery and robot calibration, entry position, entry angle, soft-tissue thickness, bone thickness, and intracranial length were not associated with the placement accuracy of the implanted laser fibers. However, the number of catheters placed did correlate with the offset angle error on univariate analysis (ρ = 0.387, p = 0.022). There were no immediate surgical complications. Meta-analysis indicated that the overall pooled mean TPLE was 1.46 mm (95% CI -0.58 to 3.49 mm). CONCLUSIONS: RA stereotactic MRI-guided laser ablation for epilepsy in children is highly accurate. These data will aid surgical planning.

Implications of leg length for metabolic health and fitness.

Background and objectives: Several studies have linked longer legs with favorable adult metabolic health outcomes and greater offspring birth weight. A recent Mendelian randomization study suggested a causal link between height and cardiometabolic risk; however, the underlying reasons remain poorly understood. Methodology: Using a cross-sectional design, we tested in a convenience sample of 70 healthy young women whether birth weight and tibia length as markers of early-life conditions associated more strongly with metabolically beneficial traits like organ size and skeletal muscle mass (SMM) than a statistically derived height-residual variable indexing later, more canalized growth. Results: Consistent with the 'developmental origins of health and disease' hypothesis, we found relatively strong associations of tibia length-but not birth weight-with adult organ size, brain size, SMM and resting energy expenditure measured by magnetic resonance imaging (MRI), dual-energy X-ray absorptiometry and indirect calorimetry, respectively. Conclusions and implications: Building on prior work, these results suggest that leg length is a sensitive marker of traits directly impacting metabolic and reproductive health. Alongside findings in the same sample relating tibia length and height-residual to MRI-measured pelvic dimensions, we suggest there may exist a degree of coordination in the development of long bone, lean mass and pelvic traits, possibly centered on early, pre-pubertal growth periods. Such phenotypic coordination has important implications for fitness, serving to benefit both adult health and the health of offspring in subsequent generations.

Amygdalar Functional Connectivity Differences Associated With Reduced Pain Intensity in Pediatric Peripheral Neuropathic Pain.

Background: There is evidence of altered corticolimbic circuitry in adults with chronic pain, but relatively little is known of functional brain mechanisms in adolescents with neuropathic pain (NeuP). Pediatric NeuP is etiologically and phenotypically different from NeuP in adults, highlighting the need for pediatric-focused research. The amygdala is a key limbic region with important roles in the emotional-affective dimension of pain and in pain modulation. Objective: To investigate amygdalar resting state functional connectivity (rsFC) in adolescents with NeuP. Methods: This cross-sectional observational cohort study compared resting state functional MRI scans in adolescents aged 11-18 years with clinical features of chronic peripheral NeuP (n = 17), recruited from a tertiary clinic, relative to healthy adolescents (n = 17). We performed seed-to-voxel whole-brain rsFC analysis of the bilateral amygdalae. Next, we performed post hoc exploratory correlations with clinical variables to further explain rsFC differences. Results: Adolescents with NeuP had stronger negative rsFC between right amygdala and right dorsolateral prefrontal cortex (dlPFC) and stronger positive rsFC between right amygdala and left angular gyrus (AG), compared to controls (P FDR <0.025). Furthermore, lower pain intensity correlated with stronger negative amygdala-dlPFC rsFC in males (r = 0.67, P = 0.034, n = 10), and with stronger positive amygdala-AG rsFC in females (r = -0.90, P = 0.006, n = 7). These amygdalar rsFC differences may thus be pain inhibitory. Conclusions: Consistent with the considerable affective and cognitive factors reported in a larger cohort, there are rsFC differences in limbic pain modulatory circuits in adolescents with NeuP. Findings also highlight the need for assessing sex-dependent brain mechanisms in future studies, where possible.

Drug-resistant focal epilepsy in children is associated with increased modal controllability of the whole brain and epileptogenic regions.

Network control theory provides a framework by which neurophysiological dynamics of the brain can be modelled as a function of the structural connectome constructed from diffusion MRI. Average controllability describes the ability of a region to drive the brain to easy-to-reach neurophysiological states whilst modal controllability describes the ability of a region to drive the brain to difficult-to-reach states. In this study, we identify increases in mean average and modal controllability in children with drug-resistant epilepsy compared to healthy controls. Using simulations, we purport that these changes may be a result of increased thalamocortical connectivity. At the node level, we demonstrate decreased modal controllability in the thalamus and posterior cingulate regions. In those undergoing resective surgery, we also demonstrate increased modal controllability of the resected parcels, a finding specific to patients who were rendered seizure free following surgery. Changes in controllability are a manifestation of brain network dysfunction in epilepsy and may be a useful construct to understand the pathophysiology of this archetypical network disease. Understanding the mechanisms underlying these controllability changes may also facilitate the design of network-focussed interventions that seek to normalise network structure and function.

High-resolution microscopic diffusion anisotropy imaging in the human hippocampus at 3T.

PURPOSE: Several neurological conditions are associated with microstructural changes in the hippocampus that can be observed using DWI. Imaging studies often use protocols with whole-brain coverage, imposing limits on image resolution and worsening partial-volume effects. Also, conventional single-diffusion-encoding methods confound microscopic diffusion anisotropy with size variance of microscopic diffusion environments. This study addresses these issues by implementing a multidimensional diffusion-encoding protocol for microstructural imaging of the hippocampus at high resolution. METHODS: The hippocampus of 8 healthy volunteers was imaged at 1.5-mm isotropic resolution with a multidimensional diffusion-encoding sequence developed in house. Microscopic fractional anisotropy (µFA) and normalized size variance (CMD ) were estimated using q-space trajectory imaging, and their values were compared with DTI metrics. The overall scan time was 1 hour. The reproducibility of the protocol was confirmed with scan-rescan experiments, and a shorter protocol (14 minutes) was defined for situations with time constraints. RESULTS: Mean µFA (0.47) was greater than mean FA (0.20), indicating orientation dispersion in hippocampal tissue microstructure. Mean CMD was 0.17. The reproducibility of q-space trajectory imaging metrics was comparable to DTI, and microstructural metrics in the healthy hippocampus are reported. CONCLUSION: This work shows the feasibility of high-resolution microscopic anisotropy imaging in the human hippocampus at 3 T and provides reference values for microstructural metrics in a healthy hippocampus.

Estimating brain volume loss after radiation therapy in children treated for posterior fossa tumors (Corpus callosum and whole brain volume changes following radiotherapy in children).

BACKGROUND: More than half of pediatric tumors of central nervous system (CNS) primarily originate in the posterior fossa and are conventionally treated with radiation therapy (RT). OBJECTIVES: The objective of this study was to establish whether corpus callosum volumes (CCV) and whole brain volumes (WBV) are correlated and to determine the impact of whole-brain lowvs high-dose RT on brain parenchymal volume loss as assessed using each technique. MATERIAL AND METHODS: Of the 30 identified children (6-12 years) with newly diagnosed posterior fossa tumors treated with cranial RT, including focal and whole-brain RT, suitable imaging was obtained for 23. Radiotherapy regimens were the following: no whole-brain RT (Group 1, n = 7), low-dose whole-brain RT (<30 Gy, Group 2, n = 9) and high-dose whole-brain RT (>30 Gy, Group 3, n = 7) in addition to focal boost. Magnetic resonance images (MRIs) were analyzed at baseline and follow-up (median 14 months). The CCVs were manually segmented on midline sagittal slice (n = 23), while WBVs were segmented semi-automatically using Freesurfer (n = 15). This was done twice (6-month interval) for all baseline CCV measurements and 5 randomly selected WBV measurements to establish measurement reproducibility. Correlations between CCV and WBV were investigated and percentage of children demonstrating reduction in CCV or WBV noted. RESULTS: Correlation between baseline CCV and WBV was not significant (p = 0.37). Measurement reproducibility was from 6% to -9% for CCV and from 4.8% to -1.2% for WBV. Among the children studied, 30.4% (7/23) had >9% reduction in CCV at follow-up, while 33.3% (5/15) had >1.2% reduction in WBV. Five of 7 patients with CCV loss were not picked up by WBV measurements. Similarly, 3 of 5 patients with WBV loss were not picked up by CCV measurements. CONCLUSIONS: The CCV and the WBV are unrelated and may indicate different brain parenchymal losses following RT. Up to a third of posterior fossa tumors treated with RT have measurable CCV or WBV loss; incidence was equivalent in lowvs high-dose whole-brain RT.

Accuracy of robot-assisted versus optical frameless navigated stereoelectroencephalography electrode placement in children.

OBJECTIVE The aim of this study was to compare the accuracy of optical frameless neuronavigation (ON) and robot-assisted (RA) stereoelectroencephalography (SEEG) electrode placement in children, and to identify factors that might increase the risk of misplacement. METHODS The authors undertook a retrospective review of all children who underwent SEEG at their institution. Twenty children were identified who underwent stereotactic placement of a total of 218 electrodes. Six procedures were performed using ON and 14 were placed using a robotic assistant. Placement error was calculated at cortical entry and at the target by calculating the Euclidean distance between the electrode and the planned cortical entry and target points. The Mann-Whitney U-test was used to compare the results for ON and RA placement accuracy. For each electrode placed using robotic assistance, extracranial soft-tissue thickness, bone thickness, and intracranial length were measured. Entry angle of electrode to bone was calculated using stereotactic coordinates. A stepwise linear regression model was used to test for variables that significantly influenced placement error. RESULTS Between 8 and 17 electrodes (median 10 electrodes) were placed per patient. Median target point localization error was 4.5 mm (interquartile range [IQR] 2.8­6.1 mm) for ON and 1.07 mm (IQR 0.71­1.59) for RA placement. Median entry point localization error was 5.5 mm (IQR 4.0­6.4) for ON and 0.71 mm (IQR 0.47­1.03) for RA placement. The difference in accuracy between Stealth-guided (ON) and RA placement was highly significant for both cortical entry point and target (p < 0.0001 for both). Increased soft-tissue thickness and intracranial length reduced accuracy at the target. Increased soft-tissue thickness, bone thickness, and younger age reduced accuracy at entry. There were no complications. CONCLUSIONS RA stereotactic electrode placement is highly accurate and is significantly more accurate than ON. Larger safety margins away from vascular structures should be used when placing deep electrodes in young children and for trajectories that pass through thicker soft tissues such as the temporal region. ABBREVIATIONS CTA = CT angiography; IQR = interquartile range; MEG = magnetoencephalography; ON = optical frameless neuronavigation; RA = robot-assisted; SEEG = stereoelectroencephalography.

Metabolic rate of major organs and tissues in young adult South Asian women.

BACKGROUND/OBJECTIVES: Major organ-specific and tissue-specific metabolic rate (Ki) values were initially estimated using in vivo methods, and values reported by Elia (Energy metabolism: tissue determinants and cellular corollaries, Raven Press, New York, 1992) were subsequently supported by statistical analysis. However, the majority of work to date on this topic has addressed individuals of European descent, whereas population variability in resting energy metabolism has been reported. We aimed to estimate Ki values in South Asian females. SUBJECTS/METHODS: This cross-sectional study recruited 70 healthy young women of South Asian ancestry. Brain and organs were measured using magnetic resonance imaging, skeletal muscle mass by dual-energy X-ray absorptiometry, fat mass by the 4-component model, and whole-body resting energy expenditure by indirect calorimetry. Organ and tissue Ki values were estimated indirectly using regression analysis through the origin. Preliminary analysis suggested overestimation of heart mass, hence the modeling was repeated with a literature-based 22.5% heart mass reduction. RESULTS: The pattern of derived Ki values across organs and tissues matched that previously estimated in vivo, but the values were systematically lower. However, adjusting for the overestimation of heart mass markedly improved the agreement. CONCLUSIONS: Our results support variability in Ki values among organs and tissues, where some are more metabolically "expensive" than others. Initial findings suggesting lower organ/tissue Ki values in South Asian women were likely influenced by heart mass estimation bias. The question of potential ethnic variability in organ-specific and tissue-specific energy metabolism requires further investigation.

Brain Regions Showing White Matter Loss in Huntington's Disease Are Enriched for Synaptic and Metabolic Genes.

BACKGROUND: The earliest white matter changes in Huntington's disease are seen before disease onset in the premanifest stage around the striatum, within the corpus callosum, and in posterior white matter tracts. While experimental evidence suggests that these changes may be related to abnormal gene transcription, we lack an understanding of the biological processes driving this regional vulnerability. METHODS: Here, we investigate the relationship between regional transcription in the healthy brain, using the Allen Institute for Brain Science transcriptome atlas, and regional white matter connectivity loss at three time points over 24 months in subjects with premanifest Huntington's disease relative to control participants. The baseline cohort included 72 premanifest Huntington's disease participants and 85 healthy control participants. RESULTS: We show that loss of corticostriatal, interhemispheric, and intrahemispheric white matter connections at baseline and over 24 months in premanifest Huntington's disease is associated with gene expression profiles enriched for synaptic genes and metabolic genes. Corticostriatal gene expression profiles are predominately associated with motor, parietal, and occipital regions, while interhemispheric expression profiles are associated with frontotemporal regions. We also show that genes with known abnormal transcription in human Huntington's disease and animal models are overrepresented in synaptic gene expression profiles, but not in metabolic gene expression profiles. CONCLUSIONS: These findings suggest a dual mechanism of white matter vulnerability in Huntington's disease, in which abnormal transcription of synaptic genes and metabolic disturbance not related to transcription may drive white matter loss.

Topological length of white matter connections predicts their rate of atrophy in premanifest Huntington's disease.

We lack a mechanistic explanation for the stereotyped pattern of white matter loss seen in Huntington's disease (HD). While the earliest white matter changes are seen around the striatum, within the corpus callosum, and in the posterior white matter tracts, the order in which these changes occur and why these white matter connections are specifically vulnerable is unclear. Here, we use diffusion tractography in a longitudinal cohort of individuals yet to develop clinical symptoms of HD to identify a hierarchy of vulnerability, where the topological length of white matter connections between a brain area and its neighbors predicts the rate of atrophy over 24 months. This demonstrates a new principle underlying neurodegeneration in HD, whereby brain connections with the greatest topological length are the first to suffer damage that can account for the stereotyped pattern of white matter loss observed in premanifest HD.

Long-term white matter tract reorganization following prolonged febrile seizures.

OBJECTIVE: Diffusion magnetic resonance imaging (MRI) studies have demonstrated acute white matter changes following prolonged febrile seizures (PFS), but their longer-term evolution is unknown. We investigated a population-based cohort to determine white matter diffusion properties 8 years after PFS. METHODS: We used diffusion tensor imaging (DTI) and applied Tract-Based Spatial Statistics for voxel-wise comparison of white matter microstructure between 26 children with PFS and 27 age-matched healthy controls. Age, gender, handedness, and hippocampal volumes were entered as covariates for voxel-wise analysis. RESULTS: Mean duration between the episode of PFS and follow-up was 8.2 years (range 6.7-9.6). All children were neurologically normal, and had normal conventional neuroimaging. On voxel-wise analysis, compared to controls, the PFS group had (1) increased fractional anisotropy in early maturing central white matter tracts, (2) increased mean and axial diffusivity in several peripheral white matter tracts and late-maturing central white matter tracts, and (3) increased radial diffusivity in peripheral white matter tracts. None of the tracts had reduced fractional anisotropy or diffusivity indices in the PFS group. SIGNIFICANCE: In this homogeneous, population-based sample, we found increased fractional anisotropy in early maturing central white matter tracts and increased mean and axial diffusivity with/without increased radial diffusivity in several late-maturing peripheral white matter tracts 8 years post-PFS. We propose disruption in white matter maturation secondary to seizure-induced axonal injury, with subsequent neuroplasticity and microstructural reorganization as a plausible explanation.

Structural and functional brain network correlates of depressive symptoms in premanifest Huntington's disease.

Depression is common in premanifest Huntington's disease (preHD) and results in significant morbidity. We sought to examine how variations in structural and functional brain networks relate to depressive symptoms in premanifest HD and healthy controls. Brain networks were constructed using diffusion tractography (70 preHD and 81 controls) and resting state fMRI (92 preHD and 94 controls) data. A sub-network associated with depression was identified in a data-driven fashion and network-based statistics was used to investigate which specific connections correlated with depression scores. A replication analysis was then performed using data from a separate study. Correlations between depressive symptoms with increased functional connectivity and decreased structural connectivity were seen for connections in the default mode network (DMN) and basal ganglia in preHD. This study reveals specific connections in the DMN and basal ganglia that are associated with depressive symptoms in preHD. Hum Brain Mapp 38:2819-2829, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

White matter predicts functional connectivity in premanifest Huntington's disease.

OBJECTIVES: The distribution of pathology in neurodegenerative disease can be predicted by the organizational characteristics of white matter in healthy brains. However, we have very little evidence for the impact these pathological changes have on brain function. Understanding any such link between structure and function is critical for understanding how underlying brain pathology influences the progressive behavioral changes associated with neurodegeneration. Here, we demonstrate such a link between structure and function in individuals with premanifest Huntington's. METHODS: Using diffusion tractography and resting state functional magnetic resonance imaging to characterize white matter organization and functional connectivity, we investigate whether characteristic patterns of white matter organization in the healthy human brain shape the changes in functional coupling between brain regions in premanifest Huntington's disease. RESULTS: We find changes in functional connectivity in premanifest Huntington's disease that link directly to underlying patterns of white matter organization in healthy brains. Specifically, brain areas with strong structural connectivity show decreases in functional connectivity in premanifest Huntington's disease relative to controls, while regions with weak structural connectivity show increases in functional connectivity. Furthermore, we identify a pattern of dissociation in the strongest functional connections between anterior and posterior brain regions such that anterior functional connectivity increases in strength in premanifest Huntington's disease, while posterior functional connectivity decreases. INTERPRETATION: Our findings demonstrate that organizational principles of white matter underlie changes in functional connectivity in premanifest Huntington's disease. Furthermore, we demonstrate functional antero-posterior dissociation that is in keeping with the caudo-rostral gradient of striatal pathology in HD.

NODDI reproducibility and variability with magnetic field strength: A comparison between 1.5 T and 3 T.

Diffusion models are advantageous for examining brain microstructure non-invasively and their validation is important for transference into the clinical domain. Neurite Orientation Dispersion and Density Imaging (NODDI) is a promising model for estimating multiple diffusion compartments from MRI data acquired in a clinically feasible time. As a relatively new model, it is necessary to examine NODDI under certain experimental conditions, such as change in magnetic field-strength, and assess it in relation to diffusion tensor imaging (DTI), an established model that is largely understood by the neuroimaging community. NODDI measures (intracellular volume fraction, νic , and orientation distribution, OD) were compared with DTI at 1.5 and 3 T data in healthy adults in whole-brain tissue masks and regions of white- and deep grey-matter. Within-session reproducibility and between-subject differences of NODDI with field-strength were also investigated. Field-strength had a significant effect on NODDI measures, suggesting careful interpretation of results from data acquired at 1.5 and 3 T. It was demonstrated that NODDI is feasible at 1.5 T, but with lower νic in white-matter regions compared with 3 T. Furthermore, the advantages of NODDI over DTI in a region of complex microstructure were shown. Specifically, in the centrum-semiovale where FA is typically as low as in grey-matter, νic was comparable to other white-matter regions yet accompanied by an OD similar to deep grey-matter. In terms of reproducibility, NODDI measures varied more than DTI. It may be that NODDI is more susceptible to noisier parameter estimates when compared with DTI, conversely it may have greater sensitivity to true within- and between-subject heterogeneity. Hum Brain Mapp 37:4550-4565, 2016. © 2016 Wiley Periodicals, Inc.

Natural variation in sensory-motor white matter organization influences manifestations of Huntington's disease.

While the HTT CAG-repeat expansion mutation causing Huntington's disease (HD) is highly correlated with the rate of pathogenesis leading to disease onset, considerable variance in age-at-onset remains unexplained. Therefore, other factors must influence the pathogenic process. We asked whether these factors were related to natural biological variation in the sensory-motor system. In 243 participants (96 premanifest and 35 manifest HD; 112 controls), sensory-motor structural MRI, tractography, resting-state fMRI, electrophysiology (including SEP amplitudes), motor score ratings, and grip force as sensory-motor performance were measured. Following individual modality analyses, we used principal component analysis (PCA) to identify patterns associated with sensory-motor performance, and manifest versus premanifest HD discrimination. We did not detect longitudinal differences over 12 months. PCA showed a pattern of loss of caudate, grey and white matter volume, cortical thickness in premotor and sensory cortex, and disturbed diffusivity in sensory-motor white matter tracts that was connected to CAG repeat length. Two further major principal components appeared in controls and HD individuals indicating that they represent natural biological variation unconnected to the HD mutation. One of these components did not influence HD while the other non-CAG-driven component of axial versus radial diffusivity contrast in white matter tracts were associated with sensory-motor performance and manifest HD. The first component reflects the expected CAG expansion effects on HD pathogenesis. One non-CAG-driven component reveals an independent influence on pathogenesis of biological variation in white matter tracts and merits further investigation to delineate the underlying mechanism and the potential it offers for disease modification. Hum Brain Mapp 37:4615-4628, 2016. © 2016 Wiley Periodicals, Inc.

Sexual Dimorphism in White Matter Developmental Trajectories Using Tract-Based Spatial Statistics.

Increasing evidence is emerging for sexual dimorphism in the trajectory of white matter development in children assessed using volumetric magnetic resonance imaging (MRI) and more recently diffusion MRI. Recent studies using diffusion MRI have examined cohorts with a wide age range (typically between 5 and 30 years) showing focal regions of differential diffusivity and fractional anisotropy (FA) and have implicated puberty as a possible contributory factor. To further investigate possible dimorphic trajectories in a young cohort, presumably closer to the expected onset of puberty, we used tract-based spatial statistics to investigate diffusion metrics. The cohort consisted of 23 males and 30 females between the ages of 8 and 16 years. Differences in diffusion metrics were corrected for age, total brain volume, and full scale IQ. In contrast to previous studies showing focal differences between males and females, widespread sexually dimorphic trajectories in structural white matter development were observed. These differences were characterized by more advanced development in females compared to males indicated by lower mean diffusivity, radial and axial diffusivity, and higher FA in females. This difference appeared to be larger at lower ages (8-9 years) with diffusion measures from males and females tending to converge between 10 and 14 years of age. Males showed a steeper slope for age-diffusion metric correlations compared to females, who either did not correlate with age or correlated in fewer regions. Further studies are now warranted to determine the role of hormones on the observed differences, particularly in 8-9-year-old children.