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Highlights • The entire brain is susceptible to dose-dependent volume loss after RT. • Future studies should examine the impact of cerebral volume loss on cognition. • Current sparing strategies in RT for brain tumours may need to be reconsidered., Purpose Numerous brain MR imaging studies have been performed to understand radiation-induced cognitive decline. However, many of them focus on a single region of interest, e.g. cerebral cortex or hippocampus. In this study, we use deformation-based morphometry (DBM) and voxel-based morphometry (VBM) to measure the morphological changes in patients receiving fractionated photon RT, and relate these to the dose. Additionally, we study tissue specific volume changes in white matter (WM), grey matter (GM), cerebrospinal fluid and total intracranial volume (TIV). Methods and materials From our database, we selected 28 patients with MRI of high quality available at baseline and 1 year after RT. Scans were rigidly registered to each other, and to the planning CT and dose file. We used DBM to study non-tissue-specific volumetric changes, and VBM to study volume loss in grey matter. Observed changes were then related to the applied radiation dose (in EQD2). Additionally, brain tissue was segmented into WM, GM and cerebrospinal fluid, and changes in these volumes and TIV were tested. Results Performing DBM resulted in clusters of dose-dependent volume loss 1 year after RT seen throughout the brain. Both WM and GM were affected; within the latter both cerebral cortex and subcortical nuclei show volume loss. Volume loss rates ranging from 5.3 to 15.3%/30 Gy were seen in the cerebral cortical regions in which more than 40% of voxels were affected. In VBM, similar loss rates were seen in the cortex and nuclei. The total volume of WM and GM significantly decreased with rates of 5.8% and 2.1%, while TIV remained unchanged as expected. Conclusions Radiotherapy is associated with dose-dependent intracranial morphological changes throughout the entire brain. Therefore, we will consider to revise sparing of organs at risk based on future cognitive and neurofunctional data.

Highlights • Bulbar symptom onset shows more structural impairment than limb-onset in ALS. • Bulbar-onset ALS is characterized by an early and widespread cortical pathology. • Application of the D50 model enables comparability of heterogenous patient cohorts., Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease that is characterized by a high heterogeneity in patients’ disease course. Patients with bulbar onset of symptoms (b-ALS) have a poorer prognosis than patients with limb onset (l-ALS). However, neuroimaging correlates of the assumed biological difference between b-ALS and l-ALS may have been obfuscated by patients’ diversity in the disease course. We conducted Voxel-Based-Morphometry (VBM) and Tract-Based-Spatial-Statistics (TBSS) in a group of 76 ALS patients without clinically relevant cognitive deficits. The subgroups of 26 b-ALS and 52 l-ALS patients did not differ in terms of disease Phase or disease aggressiveness according to the D50 progression model. VBM analyses showed widespread ALS-related changes in grey and white matter, that were more pronounced for b-ALS. TBSS analyses revealed that b-ALS was predominantly characterized by frontal fractional anisotropy decreases. This demonstrates a higher degree of neurodegenerative burden for the group of b-ALS patients in comparison to l-ALS. Correspondingly, higher bulbar symptom burden was associated with right-temporal and inferior-frontal grey matter density decreases as well as fractional anisotropy decreases in inter-hemispheric and long association tracts. Contrasts between patients in Phase I and Phase II further revealed that b-ALS was characterized by an early cortical pathology and showed a spread only outside primary motor regions to frontal and temporal areas. In contrast, l-ALS showed ongoing structural integrity loss within primary motor-regions until Phase II. We therefore provide a strong rationale to treat both onset types of disease separately in ALS studies.

Highlights • In aMCI, apathy severity was associated with lower FA in widespread WM pathways. • WM aberrations are related to apathy severity after controlling for depression. • Disruptions related to apathy severity are not limited to frontal-subcortical area., Apathy is recognized as a prevalent behavioral symptom of amnestic Mild Cognitive Impairment (aMCI). In aMCI, apathy is associated with an increased risk and increases the risk of progression to Alzheimer’s Disease (AD). Previous DTI study in aMCI showed that apathy has been associated with white matter alterations in the cingulum, middle and inferior longitudinal fasciculus, fornix, and uncinate fasciculus. However, the underlying white matter correlates associated with apathy in aMCI are still unclear. We investigated this relationship using whole-brain diffusion tensor imaging (DTI). Twenty-nine aMCI patients and 20 matched cognitively healthy controls were included. Apathy severity was assessed using the Apathy Evaluation Scale Clinician version. We applied the tract-based spatial statistics analyses to DTI parameters: fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity to investigate changes in white matter pathways associated with the severity of apathy. No significant difference was found in any of the DTI parameters between aMCI and the control group. In aMCI, higher severity of apathy was associated with lower FA in various white matter pathways including the left anterior part of inferior fronto-occipital fasciculus/uncinate fasciculus, genu and body of the corpus callosum, superior and anterior corona radiata, anterior thalamic radiation of both hemispheres and in the right superior longitudinal fasciculus/anterior segment of arcuate fasciculus (p

Highlights • The D50 disease progression model well characterized a cross-sectional ALS cohort. • VBM reveled ALS-related widespread gray and white matter density decreases. • A spread of structural alterations occurs along with D50 model derived disease phases. • White-matter alterations were associated with higher disease aggressiveness., Therapeutic management and research in Amyotrophic Laterals Sclerosis (ALS) have been limited by the substantial heterogeneity in progression and anatomical spread that are endemic of the disease. Neuroimaging biomarkers represent powerful additions to the current monitoring repertoire but have yielded inconsistent associations with clinical scores like the ALS functional rating scale. The D50 disease progression model was developed to address limitations with clinical indices and the difficulty obtaining longitudinal data in ALS. It yields overall disease aggressiveness as time taken to reach halved functionality (D50); individual disease covered in distinct phases; and calculated functional state and calculated functional loss as acute descriptors of local disease activity. It greatly reduces the noise of the ALS functional rating scale and allows the comparison of highly heterogeneous disease and progression subtypes. In this study, we performed Voxel-Based Morphometry for 85 patients with ALS (60.1 ± 11.5 years, 36 female) and 62 healthy controls. Group-wise comparisons were performed separately for gray matter and white matter using ANCOVA testing with threshold-free cluster enhancement. ALS-related widespread gray and white matter density decreases were observed in the bilateral frontal and temporal lobes (p

Highlights • Aerobic fitness level, but not physical activity, is related to white matter properties in the brain. • The relation between physical activity and working memory is moderated by fractional anisotropy (FA) of the corpus callosum. • The FA of the corpus callosum and superior corona radiata moderates the relation between aerobic fitness and working memory., Physical activity and exercise beneficially link to brain properties and cognitive functions in older adults, but the findings concerning adolescents remain tentative. During adolescence, the brain undergoes significant changes, which are especially pronounced in white matter. Studies provide contradictory evidence regarding the influence of physical activity or aerobic-exercise on executive functions in youth. Little is also known about the link between both fitness and physical activity with the brain’s white matter during puberty. We investigated the connection between aerobic fitness and physical activity with the white matter in 59 adolescents. We further determined whether white matter interacts with the connection of fitness or physical activity with core executive functions. Our results show that only the level of aerobic fitness, but not of physical activity relates to white matter. Furthermore, the white matter of the corpus callosum and the right superior corona radiata moderates the links of aerobic fitness and physical activity with working memory. Our results suggest that aerobic fitness and physical activity have an unequal contribution to the white matter properties in adolescents. We propose that the differences in white matter properties could underlie the variations in the relationship between either physical activity or aerobic fitness with working memory.

Highlights • Patients with congenital heart disease (CHD) are at risk for lower working memory. • CHD patients showed widespread alterations in white matter microstructure using DTI. • Alterations in frontal white matter were associated with working memory problems. • This association was independent of CHD type, IQ and group., Children and adolescents with congenital heart disease (CHD) are at risk for mild to moderate cognitive impairments. In particular, impaired working memory performance has been found in CHD patients of all ages. Working memory is an important domain of higher order cognitive function and is crucial for everyday activities, with emerging importance in adolescence. However, the underlying neural correlate of working memory impairments in CHD is not yet fully understood. Diffusion tensor imaging and tract based spatial statistics analyses were conducted in 47 adolescent survivors of childhood cardiopulmonary bypass surgery (24 females) and in 44 healthy controls (24 females) between 11 and 16 years of age (mean age = 13.9, SD = 1.6). Fractional anisotropy (FA) of white matter diffusion was compared between groups and was correlated with working memory performance, derived from the Wechsler Intelligence Scale for Children-IV. CHD patients had significantly poorer working memory compared to controls (p = 0.001). Widespread bilateral reduction in FA was observed in CHD patients compared to healthy controls (threshold-free cluster enhancement (TFCE) corrected p < 0.05). This reduction in FA was present both in cyanotic and acyanotic CHD patients compared to healthy controls (both p < 0.001). The FA reduction in the frontal lobe, mainly in the forceps minor, was associated with poorer working memory performance in both patients with CHD and healthy controls (TFCE corrected p < 0.05). The current findings underline that in CHD patients, irrespective of disease severity, disrupted or delayed maturation of white matter may persist into adolescence and is associated with working memory impairments, particularly if present in the frontal lobe. Adolescence, which is a crucial period for prefrontal brain maturation, may offer a window of opportunity for intervention in order to support the maturation of frontal brain regions and therefore improve higher order cognitive function in patients with CHD.

Highlights • Fractionating insight into objects aids its neuroanatomical exploration in dementia. • Distinctive neural correlates seem to underpin different insight objects in FTD. • Altered insight into disease/health condition mostly involves right frontal areas. • Altered insight into social cognition implicates frontal, temporal and limbic areas. • Frontal, medial temporal and parietal areas underpin insight into memory problems., Altered insight into disease or specific symptoms is a prominent clinical feature of frontotemporal dementia (FTD). Understanding the neural bases of insight is crucial to help improve FTD diagnosis, classification and management. A systematic review to explore the neural correlates of altered insight in FTD and associated syndromes was conducted. Insight was fractionated to examine whether altered insight into different neuropsychological/behavioural objects is underpinned by different or compatible neural correlates. 6 databases (Medline, Embase, PsycINFO, Web of Science, BIOSIS and ProQuest Dissertations & Theses Global) were interrogated between 1980 and August 2019. 15 relevant papers were found out of 660 titles screened. The studies included suggest that different objects of altered insight are associated with distinctive brain areas in FTD. For example, disease unawareness appears to predominantly correlate with right frontal involvement. In contrast, altered insight into social cognition potentially involves, in addition to frontal areas, the temporal gyrus, insula, parahippocampus and amygdala. Impaired insight into memory problems appears to be related to the frontal lobes, postcentral gyrus, parietal cortex and posterior cingulate. These results reflect to a certain extent those observed in other neurodegenerative conditions like Alzheimer's disease (AD) and also other brain disorders. Nevertheless, they should be cautiously interpreted due to variability in the methodological aspects used to reach those conclusions. Future work should triangulate different insight assessment approaches and brain imaging techniques to increase the understanding of this highly relevant clinical phenomenon in dementia.

Stress is inevitably linked to life. It has many and complex facets. Notably, perception of stressful stimuli is an important factor when mounting stress responses and measuring its impact. Indeed, moved by the increasing number of stress-triggered pathologies, several groups drew on advanced neuroimaging techniques to explore stress effects on the brain. From that, several regions and circuits have been linked to stress, and a comprehensive integration of the distinct findings applied to common individuals is being pursued, but with conflicting results. Herein, we performed a volumetric regression analysis using participants’ perceived stress as a variable of interest. Data shows that increased levels of perceived stress positively associate with the right amygdala and anterior hippocampal volumes., Highlights • Discrepant stress effects on morphology are reported in the literature. • Stress definition and analysis software are the main causes of conflicting findings. • Psychological measures and multi-technique analysis are highly recommended. • We found that perceived stress positively associates with right amygdala volumes.

The cardinal movement abnormalities of Parkinson's disease (PD), including tremor, muscle rigidity, and reduced speed and frequency of movements, are caused by degeneration of dopaminergic neurons in the substantia nigra that project to the putamen, compromising information flow through frontal-subcortical circuits. Typically, the nigrostriatal pathway is more severely affected on the side of the brain opposite (contralateral) to the side of the body that manifests initial symptoms. Several studies have suggested that PD is also associated with changes in white matter microstructural integrity. The goal of the present study was to further develop methods for measuring striatonigral connectivity differences between PD patients and age-matched controls using diffusion weighted magnetic resonance imaging (MRI). In this cross-sectional study, 40 PD patients and 44 controls underwent diffusion weighted imaging (DWI) using a 40-direction MRI sequence as well as an optimized 60-direction sequence with overlapping slices. Regions of interest (ROIs) encompassing the putamen and substantia nigra were hand drawn in the space of the 40-direction data using high-contrast structural images and then coregistered to the 60-direction data. Probabilistic tractography was performed in the native space of each dataset by seeding the putamen ROI with an ipsilateral substantia nigra classification target. The effect of disease group (PD versus control) on mean putamen-SN connection probability and streamline density were then analyzed using generalized linear models controlling for age, gender, education, as well as seed and target region characteristics. Mean putamen-SN streamline density was lower in PD on both sides of the brain and in both 40- and 60-direction data. The optimized sequence provided a greater separation between PD and control means; however, individual values overlapped between groups. The 60-direction data also yielded mean connection probability values either trending (ipsilateral) or significantly (contralateral) lower in the PD group. There were minor between-group differences in average diffusion measures within the substantia nigra ROIs that did not affect the results of the GLM analyses when included as covariates. Based on these results, we conclude that mean striatonigral structural connectivity differs between PD and control groups and that use of an optimized 60-direction DWI sequence with overlapping slices increases the sensitivity of the technique to putative disease-related differences. However, overlap in individual values between disease groups limits its use as a classifier., Highlights • The nigrostriatal pathway degenerates in Parkinson's disease. • Two diffusion tensor imaging (DTI) sequences were acquired in 84 participants. • Structural connectivity between putamen and substantia nigra was quantified. • Parkinson's patients had lower connection probability and streamline density. • A 60-direction DTI sequence with overlapping slices was most sensitive.

Highlights: • Large study of encoding and subsequent memory for words, faces, and scenes. • Less ipsilateral mesial temporal activity in mesial temporal lobe epilepsy (mTLE). • Extra-mTL activity in mTLE only partly relevant for memory formation. • Across materials contralateral mTL decisive to maintain intact memory in mTLE. • Left frontal activation correlates with better verbal memory only in left mTLE., The mesial temporal lobe is a key region for episodic memory. Accordingly, memory impairment is frequent in patients with mesial temporal lobe epilepsy. However, the functional relevance of potentially epilepsy-induced reorganisation for memory formation is still not entirely clear. Therefore, we investigated whole-brain functional correlates of verbal and non-verbal memory encoding and subsequent memory formation in 56 (25 right sided) mesial temporal lobe epilepsy patients and 21 controls. We applied an fMRI task of learning scenes, faces, and words followed by an out-of-scanner recognition test. During encoding of faces and scenes left and right mesial temporal lobe epilepsy patients had consistently reduced activation in the epileptogenic mesial temporal lobe compared with controls. Activation increases in patients were apparent in extra-temporal regions, partly associated with subsequent memory formation (left frontal regions and basal ganglia), and patients had less deactivation in regions often linked to the default mode and auditory networks. The more specific subsequent memory contrast indicated only marginal group differences. Correlating patients’ encoding activation with memory performance both within the paradigm and with independent clinical measures demonstrated predominantly increased contralateral mesio-temporal activation supporting intact memory performance. In left temporal lobe epilepsy patients, left frontal activation was also correlated with better verbal memory performance. Taken together, our findings hint towards minor extra-temporal plasticity in mesial temporal lobe epilepsy patients, which is in line with pre-surgical impairment and post-surgical memory decline in many patients. Further, data underscore the importance of particularly the contralateral mesial temporal lobe itself, to maintain intact memory performance.

Highlights • Examining associations between physical activity, physical capability and brain health. • Higher global FA were observed in older adults with higher walking speed. • Lower subcortical brain age gap (BAG) were observed in more physically active women., Maintaining high levels of daily activity and physical capability have been proposed as important constituents to promote healthy brain and cognitive aging. Studies investigating the associations between brain health and physical activity in late life have, however, mainly been based on self-reported data or measures designed for clinical populations. In the current study, we examined cross-sectional associations between physical activity, recorded by an ankle-positioned accelerometer for seven days, physical capability (grip strength, postural control, and walking speed), and neuroimaging based surrogate markers of brain health in 122 healthy older adults aged 65–88 years. We used a multimodal brain imaging approach offering complementary structural MRI based indicators of brain health: global white matter fractional anisotropy (FA) and mean diffusivity (MD) based on diffusion tensor imaging, and subcortical and global brain age based on brain morphology inferred from T1-weighted MRI data. In addition, based on the results from the main analysis, follow-up regression analysis was performed to test for association between the volume of key subcortical regions of interest (hippocampus, caudate, thalamus and cerebellum) and daily steps, and a follow-up voxelwise analysis to test for associations between walking speed and FA across the white matter Tract-Based Spatial Statistics (TBSS) skeleton. The analyses revealed a significant association between global FA and walking speed, indicating higher white matter integrity in people with higher pace. Voxelwise analysis supported widespread significant associations. We also found a significant interaction between sex and subcortical brain age on number of daily steps, indicating younger-appearing brains in more physically active women, with no significant associations among men. These results provide insight into the intricate associations between different measures of brain and physical health in old age, and corroborate established public health advice promoting physical activity.

Children born very preterm (VPT, Highlights • Very preterm children have widespread decreased MTR in white matter. • T1-w/T2-w ratio measures showed consistent white matter alterations. • T1-w/T2-w ratio was also reduced in subcortical, occipital and temporal regions. • MTR and T1-w/T2-w were correlated throughout the brain. • MTR and T1-w/T2-w correlated with developmental assessments.

Objective Focused ultrasound thalamotomy is an emerging treatment for essential tremor, and it is ideal for studying reorganization in the human brain after acute injury because it creates a controlled thalamic ablation without breaching the cortex. However, there is not yet a metric capable of detecting microstructural changes in the presence of acute phase edema with good sensitivity in the chronic phase, when the lesion boundaries become inconspicuous. Methods We prospectively studied microstructural changes at the lesion site using generalized q-sampling imaging with restricted diffusion imaging. We obtained diffusion-weighted MRI scans preoperatively, 1 day after (n = 18), and 1 year after (n = 9) focused ultrasound thalamotomy. The restricted diffusion imaging maps were compared at the group level, controlling for improvement in contralateral hand tremor. Results The restricted diffusion imaging metric significantly increased in the 1 day post images, and the area with restricted diffusivity extended beyond the lesion boundaries identified on T2-weighted imaging. Two distinct zones of microstructural changes were identified, and the lesion area was identifiable at 1 year. The anterior and medial aspects of the lesion had a significant changes in RDI at 1 year, potentially signifying reorganization. The voxels with significant changes in restricted diffusion imaging values extend beyond the VIM into the surrounding white matter. Interpretation Correcting for free water contamination with restricted diffusion imaging allowed us to study microstructural changes after focused ultrasound thalamotomy. We observed statistically significant changes in RDI in the anterior and medial aspect of the lesion at 1 year. Whether these changes represent tissue reorganization remains to be confirmed in future studies. These findings may support performing additional ablations antero-medially for durable efficacy., Highlights • Focused ultrasound thalamotomy is an emerging treatment for essential tremor, but challenges remain in determining microstructural changes in the ablated tissue. • We prospectively studied microstructural changes at the lesion site using generalized q-sampling imaging with restrictyed diffusion imaging (RDI) in 18 patients with ET. • The RDI metric significantly increased after focused ultrasound, and the area with restricted diffusivity extended beyond the lesion boundaries identified on T2-weighted imaging. • Two distinct zones of microstructural changes were identified, and the lesion area was also identifiable at 1 year. The anterior and medial aspects of the lesion had a significant RDI change at 1 year, potentially signifying reorganization.

Spinal muscular atrophy (SMA) type III and IV are autosomal recessive, slowly progressive lower motor neuron syndromes. Nevertheless, wider cerebral involvement has been consistently reported in mouse models. The objective of this study is the characterisation of spinal and cerebral pathology in adult forms of SMA using multimodal quantitative imaging. Methods Twenty-five type III and IV adult SMA patients and 25 age-matched healthy controls were enrolled in a spinal cord and brain imaging study. Structural measures of grey and white matter involvement and diffusion parameters of white matter integrity were evaluated at each cervical spinal level. Whole-brain and region-of-interest analyses were also conducted in the brain to explore cortical thickness, grey matter density and tract-based white matter alterations. Results In the spinal cord, considerable grey matter atrophy was detected between C2-C6 vertebral levels. In the brain, increased grey matter density was detected in motor and extra-motor regions of SMA patients. No white matter pathology was identified neither at brain and spinal level. Conclusions Adult forms of SMA are associated with selective grey matter degeneration in the spinal cord with preserved white matter integrity. The observed increased grey matter density in the motor cortex may represent adaptive reorganisation., Highlights • (SMA) type 3 and 4 is a lower motor neuron syndrome. Nevertheless, wider involvement of the nervous system might be possible. • 25 adults type 3 and 4 SMA patients were studied using brain and cervical spinal cord neuroimaging techniques. • Grey matter atrophy was observed in the spinal cord. No white matter degeneration was present at brain and spinal level. • Increased grey matter density was detected in cerebral motor regions and explained as compensatory mechanism.

Background Cerebral microbleeds (CMBs) are considered to be risk factors for cognitive dysfunction. The specific pathology and clinical manifestations of CMBs are different based on their locations. We investigated the association between CMBs at different locations and cognitive dysfunction and explored the potential underlying pathways in a rural Han Chinese population. Methods We used baseline data from 562 community-dwelling adults (55–65 years old) in the Taizhou Imaging Study between 2013 and 2015. All individuals underwent multimodal brain magnetic resonance imaging (MRI) and 444 subjects completed neuropsychological tests: the Mini-Mental Status Examination and the Montreal Cognitive Assessment. Multinomial logistic regression was used to estimate the association between CMBs and cognitive dysfunction. The volume of brain regions and white matter microstructure were analyzed using Freesurfer and tract-based spatial statistics, respectively. Results CMBs were detected in 104 individuals (18.5%) in our study. Multinomial logistic regression found deep/mixed CMBs were associated with global cognitive dysfunction (OR 3.52; 95% CI 1.21 to 10.26), whereas lobar CMBs (OR 1.76; 95% CI 0.56 to 5.53) were not. Quantification of multimodal brain MRI showed that deep/mixed CMBs were accompanied by decreased thalamic volume and loss of fractional anisotropy of bilateral anterior thalamic radiations. Conclusion Deep/mixed CMBs were associated with cognitive dysfunction in this Chinese cross-sectional study. Disruption of thalamocortical connectivity might be a potential pathway underlying this relationship., Highlights • Cerebral microbleeds (CMBs) are found in 18.5% of middle-aged Chinese population. • Deep/mixed CMBs, not lobar CMBs, are associated with cognitive dysfunction. • Atrophy and fiber connectivity disruption might be the underlying neural pathways.

Highlights • Women lost more total brain volume than men during 8.5 years follow-up in midlife. • Women showed greater brain reduction in bilateral brain regions with and without co-varying for total brain volume loss. • Men exhibited greater brain reduction in mid-line brain regions after correcting for the total brain volume loss., Brain development during childhood and adolescence differs between boys and girls. Structural changes continue during adulthood and old age, particularly in terms of brain volume reductions that accelerate beyond age 35 years. We investigated whether brain structural change in mid-life differs between men and women. 43 men and 28 women from the Northern Finland 1966 Birth Cohort underwent MRI brain scans at age 33–35 (SD = 0.67) and then again at age 42–44 (SD = 0.41). We examined sex differences in total percentage brain volume change (PBVC) and regional brain change with FSL SIENA software. Women showed significant PBVC reduction compared with men between the ages of 33–35 and 42–44 years (Mean = −3.21% in men, Mean = −4.03% in women, F (1, 68) = 6.37, p

The ventral intermediate nucleus (VIM) of the thalamus is an established surgical target for stereotactic ablation and deep brain stimulation (DBS) in the treatment of tremor in Parkinson's disease (PD) and essential tremor (ET). It is centrally placed on a cerebello-thalamo-cortical network connecting the primary motor cortex, to the dentate nucleus of the contralateral cerebellum through the dentato-rubro-thalamic tract (DRT). The VIM is not readily visible on conventional MR imaging, so identifying the surgical target traditionally involved indirect targeting that relies on atlas-defined coordinates. Unfortunately, this approach does not fully account for individual variability and requires surgery to be performed with the patient awake to allow for intraoperative targeting confirmation. The aim of this study is to identify the VIM and the DRT using probabilistic tractography in patients that will undergo thalamic DBS for tremor. Four male patients with tremor dominant PD and five patients (three female) with ET underwent high angular resolution diffusion imaging (HARDI) (128 diffusion directions, 1.5 mm isotropic voxels and b value = 1500) preoperatively. Patients received VIM-DBS using an MR image guided and MR image verified approach with indirect targeting. Postoperatively, using parallel Graphical Processing Unit (GPU) processing, thalamic areas with the highest diffusion connectivity to the primary motor area (M1), supplementary motor area (SMA), primary sensory area (S1) and contralateral dentate nucleus were identified. Additionally, volume of tissue activation (VTA) corresponding to active DBS contacts were modelled. Response to treatment was defined as 40% reduction in the total Fahn-Tolosa-Martin Tremor Rating Score (FTMTRS) with DBS-ON, one year from surgery. Three out of nine patients had a suboptimal, long-term response to treatment. The segmented thalamic areas corresponded well to anatomically known counterparts in the ventrolateral (VL) and ventroposterior (VP) thalamus. The dentate-thalamic area, lay within the M1-thalamic area in a ventral and lateral location. Streamlines corresponding to the DRT connected M1 to the contralateral dentate nucleus via the dentate-thalamic area, clearly crossing the midline in the mesencephalon. Good response was seen when the active contact VTA was in the thalamic area with highest connectivity to the contralateral dentate nucleus. Non-responders had active contact VTAs outside the dentate-thalamic area. We conclude that probabilistic tractography techniques can be used to segment the VL and VP thalamus based on cortical and cerebellar connectivity. The thalamic area, best representing the VIM, is connected to the contralateral dentate cerebellar nucleus. Connectivity based segmentation of the VIM can be achieved in individual patients in a clinically feasible timescale, using HARDI and high performance computing with parallel GPU processing. This same technique can map out the DRT tract with clear mesencephalic crossing., Highlights • The thalamic target for surgery for tremor is not readily visible on conventional MRI. • Probabilistic tractography is used to segment the thalamus based on connectivity. • The best target area is connected to the contralateral dentate cerebellar nucleus. • GPU processing is used to segment the thalamus in a clinically feasible timescale. • This technique can map out the DRT tract with clear mesencephalic crossing.

Background In Parkinson's disease (PD), the relation between cortical brain atrophy on MRI and clinical progression is not straightforward. Determination of changes in structural covariance networks - patterns of covariance in grey matter density - has shown to be a valuable technique to detect subtle grey matter variations. We evaluated how structural network integrity in PD is related to clinical data. Methods 3 Tesla MRI was performed in 159 PD patients. We used nine standardized structural covariance networks identified in 370 healthy subjects as a template in the analysis of the PD data. Clinical assessment comprised motor features (Movement Disorder Society-Unified Parkinson's Disease Rating Scale; MDS-UPDRS motor scale) and predominantly non-dopaminergic features (SEverity of Non-dopaminergic Symptoms in Parkinson's Disease; SENS-PD scale: postural instability and gait difficulty, psychotic symptoms, excessive daytime sleepiness, autonomic dysfunction, cognitive impairment and depressive symptoms). Voxel-based analyses were performed within networks significantly associated with PD. Results The anterior and posterior cingulate network showed decreased integrity, associated with the SENS-PD score, p = 0.001 (β = − 0.265, ηp2 = 0.070) and p = 0.001 (β = − 0.264, ηp2 = 0.074), respectively. Of the components of the SENS-PD score, cognitive impairment and excessive daytime sleepiness were associated with atrophy within both networks. Conclusions We identified loss of integrity and atrophy in the anterior and posterior cingulate networks in PD patients. Abnormalities of both networks were associated with predominantly non-dopaminergic features, specifically cognition and excessive daytime sleepiness. Our findings suggest that (components of) the cingulate networks display a specific vulnerability to the pathobiology of PD and may operate as interfaces between networks involved in cognition and alertness., Highlights • A novel approach, structural covariance networks, was used in Parkinson's disease. • Loss of integrity and atrophy in two cingulate networks was found in patients. • Structural changes were associated with cognition and alertness.

Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE: rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: − 5.3 ppb, right: − 6.7 ppb, p, Highlights • Magnetic susceptibility and common gene variants linked to iron were investigated. • The C282Y and H63D alleles were associated with putamen and thalamus susceptibility changes. • Dependent on allele status, men and women differed in deep GM susceptibility in MS.

This prospective study explored whether an approach combining structural [cortical thickness and white matter (WM) microstructure] and resting state functional MRI can aid differentiation between 62 early onset Alzheimer's disease (EOAD) and 27 behavioural variant of frontotemporal dementia (bvFTD) patients. Random forest and receiver operator characteristic curve analyses assessed the ability of MRI in classifying the two clinical syndromes. All patients showed a distributed pattern of brain alterations relative to controls. Compared to bvFTD, EOAD patients showed bilateral inferior parietal cortical thinning and decreased default mode network functional connectivity. Compared to EOAD, bvFTD patients showed bilateral orbitofrontal and temporal cortical thinning, and WM damage of the corpus callosum, bilateral uncinate fasciculus, and left superior longitudinal fasciculus. Random forest analysis revealed that left inferior parietal cortical thickness (accuracy 0.78, specificity 0.76, sensitivity 0.83) and WM integrity of the right uncinate fasciculus (accuracy 0.81, specificity 0.96, sensitivity 0.43) were the best predictors of clinical diagnosis. The combination of cortical thickness and DT MRI measures was able to distinguish patients with EOAD and bvFTD with accuracy 0.82, specificity 0.76, and sensitivity 0.96. The diagnostic ability of MRI models was confirmed in a subsample of patients with biomarker-based clinical diagnosis. Multiparametric MRI is useful to identify brain alterations which are specific to EOAD and bvFTD. A severe cortical involvement is suggestive of EOAD, while a prominent WM damage is indicative of bvFTD., Highlights • Multimodal MRI distinguishes in vivo EOAD and bvFTD patients • EOAD and bvFTD show a distributed pattern of structural brain alterations • A severe cortical involvement is suggestive of EOAD relative to bvFTD • A prominent WM damage is indicative of bvFTD relative to EOAD

Highlights • We tested whether CMT affects neurodevelopment in preterm infants. • CMT improved functional brain networks and functional brain integration. • CMT improved thalamocortical processing. • Improvement in prefrontal, supplementary motor and temporal brain regions. • Association with higher-order cognitive, socio-emotional, and motor functions., Cognitive and neurobehavioral problems are among the most severe adverse outcomes in very preterm infants. Such neurodevelopmental impairments may be mitigated through nonpharmacological interventions such as creative music therapy (CMT), an interactive, resource- and needs-oriented approach that provides individual social contact and musical stimulation. The aim was to test the feasibility of a study investigating the role of CMT and to measure the short- and medium-term effects of CMT on structural and functional brain connectivity with MRI. In this randomized, controlled clinical pilot feasibility trial, 82 infants were randomized to either CMT or standard care. A specially trained music therapist provided CMT via infant-directed humming and singing in lullaby style. To test the short-term effects of CMT on brain structure and function, diffusion tensor imaging data and resting-state functional imaging data were acquired. Clinical feasibility was achieved despite moderate parental refusal mainly in the control group after randomization. 40 infants remained as final cohort for the MRI analysis. Structural brain connectivity appears to be moderately affected by CMT, structural connectomic analysis revealed increased integration in the posterior cingulate cortex only. Lagged resting-state MRI analysis showed lower thalamocortical processing delay, stronger functional networks, and higher functional integration in predominantly left prefrontal, supplementary motor, and inferior temporal brain regions in infants treated with CMT. This trial provides unique evidence that CMT has beneficial effects on functional brain activity and connectivity in networks underlying higher-order cognitive, socio-emotional, and motor functions in preterm infants. Our results indicate the potential of CMT to improve long-term neurodevelopmental outcomes in children born very preterm.

Increased functional connectivity in resting state networks was found in several studies of patients with motor neuron disorders, although diffusion tensor imaging studies consistently show loss of white matter integrity. To understand the relationship between structural connectivity and functional connectivity, we examined the structural connections between regions with altered functional connectivity in patients with primary lateral sclerosis (PLS), a long-lived motor neuron disease. Connectivity matrices were constructed from resting state fMRI in 16 PLS patients to identify areas of differing connectivity between patients and healthy controls. Probabilistic fiber tracking was used to examine structural connections between regions of differing connectivity. PLS patients had 12 regions with increased functional connectivity compared to controls, with a predominance of cerebro-cerebellar connections. Increased functional connectivity was strongest between the cerebellum and cortical motor areas and between the cerebellum and frontal and temporal cortex. Fiber tracking detected no difference in connections between regions with increased functional connectivity. We conclude that functional connectivity changes are not strongly based in structural connectivity. Increased functional connectivity may be caused by common inputs, or by reduced selectivity of cortical activation, which could result from loss of intracortical inhibition when cortical afferents are intact., Highlights • Functional connectivity is increased in primary lateral sclerosis. • Functional connections with the cerebellum were prominent. • Cortico-cerebellar connectivity correlated with clinical measures. • No corresponding changes occurred in structural connectivity.

Diffusion magnetic resonance imaging is increasingly used as a non-invasive method to investigate white matter structure in neurological and neuropsychiatric disease. However, many options are available for the acquisition sequence and analysis method. Here we used Parkinson's disease as a model neurodegenerative disorder to compare imaging protocols and analysis options. We investigated fractional anisotropy and mean diffusivity of white matter in patients and age-matched controls, comparing two datasets acquired with different imaging protocols. One protocol prioritised the number of b value acquisitions, whilst the other prioritised the number of gradient directions. The dataset with more gradient directions was more sensitive to reductions in fractional anisotropy in Parkinson's disease, whilst the dataset with more b values was more sensitive to increases in mean diffusivity. Moreover, the areas of reduced fractional anisotropy were highly similar to areas of increased mean diffusivity in PD patients. Next, we compared two widely used analysis methods: tract-based spatial statistics identified reduced fractional anisotropy and increased mean diffusivity in Parkinson's disease in many of the major white matter tracts in the frontal and parietal lobes. Voxel-based analyses were less sensitive, with similar patterns of white matter pathology observed only at liberal statistical thresholds. We also used tract-based spatial statistics to identify correlations between a test of executive function (phonemic fluency), fractional anisotropy and mean diffusivity in prefrontal white matter in both Parkinson's disease patients and controls. These findings suggest that in Parkinson's disease there is widespread pathology of cerebral white matter, and furthermore, pathological white matter in the frontal lobe may be associated with executive dysfunction. Diffusion imaging protocols that prioritised the number of directions versus the number of b values were differentially sensitive to alternative markers of white matter pathology, such as fractional anisotropy and mean diffusivity., Highlights ► DTI shows abnormal frontal white matter in Parkinson's disease. ► FA and MD in the frontal lobe correlate with executive function in PD. ► The number of directions and b values affects sensitivity to FA/MD changes in PD. ► TBSS is more sensitive than VBM to white matter change in Parkinson's disease.

Highlights • Computational neuroimaging captures focal brainstem pathology in motor neuron diseases in contrast to both healthy- and disease controls. • ALS patients exhibit progressive medulla oblongata, pontine and mesencephalic volume loss over time. • Brainstem atrophy in ALS and PLS is dominated by medulla oblongata volume reductions. • Vertex analyses of ALS patients reveal flattening of the medullary pyramids bilaterally. • Morphometric analyses in ALS detect density reductions in the mesencephalic crura consistent with corticospinal tract degeneration., Background Brainstem pathology is a hallmark feature of ALS, yet most imaging studies focus on cortical grey matter alterations and internal capsule white matter pathology. Brainstem imaging in ALS provides a unique opportunity to appraise descending motor tract degeneration and bulbar lower motor neuron involvement. Methods A prospective longitudinal imaging study has been undertaken with 100 patients with ALS, 33 patients with PLS, 30 patients with FTD and 100 healthy controls. Volumetric, vertex and morphometric analyses were conducted correcting for demographic factors to characterise disease-specific patterns of brainstem pathology. Using a Bayesian segmentation algorithm, the brainstem was segmented into the medulla, pons and mesencephalon to measure regional volume reductions, shape analyses were performed to ascertain the atrophy profile of each study group and region-of-interest morphometry was used to evaluate focal density alterations. Results ALS and PLS patients exhibit considerable brainstem atrophy compared to both disease- and healthy controls. Volume reductions in ALS and PLS are dominated by medulla oblongata pathology, but pontine atrophy can also be detected. In ALS, vertex analyses confirm the flattening of the medullary pyramids bilaterally in comparison to healthy controls and widespread pontine shape deformations in contrast to PLS. The ALS cohort exhibit bilateral density reductions in the mesencephalic crura in contrast to healthy controls, central pontine atrophy compared to disease controls, peri-aqueduct mesencephalic and posterior pontine changes in comparison to PLS patients. Conclus ions: Computational brainstem imaging captures the degeneration of both white and grey matter components in ALS. Our longitudinal data indicate progressive brainstem atrophy over time, underlining the biomarker potential of quantitative brainstem measures in ALS. At a time when a multitude of clinical trials are underway worldwide, there is an unprecedented need for accurate biomarkers to monitor disease progression and detect response to therapy. Brainstem imaging is a promising addition to candidate biomarkers of ALS and PLS.

Background Progressive brain volume loss in schizophrenia has been reported in previous studies but its cause and regional distribution remains unclear. We investigated progressive regional brain reductions in schizophrenia and correlations with potential mediators. Method Participants were drawn from the Northern Finland Birth Cohort 1966. A total of 33 schizophrenia individuals and 71 controls were MRI scanned at baseline (mean age = 34.7, SD = 0.77) and at follow-up (mean age = 43.4, SD = 0.44). Regional brain change differences and associations with clinical mediators were examined using FSL voxelwise SIENA. Results Schizophrenia cases exhibited greater progressive brain reductions than controls, mainly in the frontal and temporal lobes. The degree of periventricular brain volume reductions were predicted by antipsychotic medication exposure at the fourth ventricular edge and by the number of days in hospital between the scans (a proxy measure of relapse duration) at the thalamic ventricular border. Decline in social and occupational functioning was associated with right supramarginal gyrus reduction. Conclusion Our findings are consistent with the possibility that antipsychotic medication exposure and time spent in relapse partially explain progressive brain reductions in schizophrenia. However, residual confounding could also account for the findings and caution must be applied before drawing causal inferences from associations demonstrated in observational studies of modest size. Less progressive brain volume loss in schizophrenia may indicate better preserved social and occupational functions.

In brain regions containing crossing fibre bundles, voxel-average diffusion MRI measures such as fractional anisotropy (FA) are difficult to interpret, and lack within-voxel single fibre population specificity. Recent work has focused on the development of more interpretable quantitative measures that can be associated with a specific fibre population within a voxel containing crossing fibres (herein we use fixel to refer to a specific fibre population within a single voxel). Unfortunately, traditional 3D methods for smoothing and cluster-based statistical inference cannot be used for voxel-based analysis of these measures, since the local neighbourhood for smoothing and cluster formation can be ambiguous when adjacent voxels may have different numbers of fixels, or ill-defined when they belong to different tracts. Here we introduce a novel statistical method to perform whole-brain fixel-based analysis called connectivity-based fixel enhancement (CFE). CFE uses probabilistic tractography to identify structurally connected fixels that are likely to share underlying anatomy and pathology. Probabilistic connectivity information is then used for tract-specific smoothing (prior to the statistical analysis) and enhancement of the statistical map (using a threshold-free cluster enhancement-like approach). To investigate the characteristics of the CFE method, we assessed sensitivity and specificity using a large number of combinations of CFE enhancement parameters and smoothing extents, using simulated pathology generated with a range of test-statistic signal-to-noise ratios in five different white matter regions (chosen to cover a broad range of fibre bundle features). The results suggest that CFE input parameters are relatively insensitive to the characteristics of the simulated pathology. We therefore recommend a single set of CFE parameters that should give near optimal results in future studies where the group effect is unknown. We then demonstrate the proposed method by comparing apparent fibre density between motor neurone disease (MND) patients with control subjects. The MND results illustrate the benefit of fixel-specific statistical inference in white matter regions that contain crossing fibres., Graphical abstract, Highlights • We introduce the fixel—a specific fibre population within a voxel. • A novel method for whole-brain fixel-based analysis of diffusion MRI is presented. • Structural connectivity between fixels is derived from template-based tractography. • Connectivity information is used for tract-specific smoothing and enhancement. • Quantitative assessment and an in vivo demonstration is performed.