Mitotic tethering enables inheritance of shattered micronuclear chromosomes.

Chromothripsis, the shattering and imperfect reassembly of one (or a few) chromosome(s)1, is an ubiquitous2 mutational process generating localized and complex chromosomal rearrangements that drive genome evolution in cancer. Chromothripsis can be initiated by mis-segregation errors in mitosis3,4 or DNA metabolism5-7 that lead to entrapment of chromosomes within micronuclei and their subsequent fragmentation in the next interphase or following mitotic entry6,8-10. Here we use inducible degrons to demonstrate that chromothriptically produced pieces of a micronucleated chromosome are tethered together in mitosis by a protein complex consisting of mediator of DNA damage checkpoint 1 (MDC1), DNA topoisomerase II-binding protein 1 (TOPBP1) and cellular inhibitor of PP2A (CIP2A), thereby enabling en masse segregation to the same daughter cell. Such tethering is shown to be crucial for the viability of cells undergoing chromosome mis-segregation and shattering after transient inactivation of the spindle assembly checkpoint. Transient, degron-induced reduction in CIP2A following chromosome micronucleation-dependent chromosome shattering is shown to drive acquisition of segmental deletions and inversions. Analyses of pancancer tumour genomes showed that expression of CIP2A and TOPBP1 was increased overall in cancers with genomic rearrangements, including copy number-neutral chromothripsis with minimal deletions, but comparatively reduced in cancers with canonical chromothripsis in which deletions were frequent. Thus, chromatin-bound tethers maintain the proximity of fragments of a shattered chromosome enabling their re-encapsulation into, and religation within, a daughter cell nucleus to form heritable, chromothriptically rearranged chromosomes found in the majority of human cancers.

Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA.

Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1-5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7-9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.

Signatures of copy number alterations in human cancer.

Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy1,2. These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5. Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations.

Decreased long-range temporal correlations in the resting-state functional magnetic resonance imaging blood-oxygen-level-dependent signal reflect motor sequence learning up to 2 weeks following training.

Decreased long-range temporal correlations (LRTC) in brain signals can be used to measure cognitive effort during task execution. Here, we examined how learning a motor sequence affects long-range temporal memory within resting-state functional magnetic resonance imaging signal. Using the Hurst exponent (HE), we estimated voxel-wise LRTC and assessed changes over 5 consecutive days of training, followed by a retention scan 12 days later. The experimental group learned a complex visuomotor sequence while a complementary control group performed tightly matched movements. An interaction analysis revealed that HE decreases were specific to the complex sequence and occurred in well-known motor sequence learning associated regions including left supplementary motor area, left premotor cortex, left M1, left pars opercularis, bilateral thalamus, and right striatum. Five regions exhibited moderate to strong negative correlations with overall behavioral performance improvements. Following learning, HE values returned to pretraining levels in some regions, whereas in others, they remained decreased even 2 weeks after training. Our study presents new evidence of HE's possible relevance for functional plasticity during the resting-state and suggests that a cortical subset of sequence-specific regions may continue to represent a functional signature of learning reflected in decreased long-range temporal dependence after a period of inactivity.

Sleep health among US Navy afloat versus ashore personnel in the Millennium Cohort Study.

Despite emerging public concern regarding the sleep health of military personnel over the past two decades, there remains a dearth of research examining sleep health among naval personnel assigned to sea duty. This study examined sleep metrics (e.g. fatigue, short sleep duration) and mental (e.g. posttraumatic stress disorder, depression) and physical health (e.g. type 2 diabetes, bodily pain) outcomes among naval personnel with recent sea duty (i.e. afloat) compared with naval personnel with recent shore duty (i.e. ashore). Prevalence ratios and mean differences for all outcomes were estimated and adjusted for demographic and military variables, and subsequently stratified by obesity. Sleep metrics were similar between afloat and ashore sailors except for short sleep duration, while sailors with recent shore duty had poorer physical health compared with those with recent sea duty. Stratified analyses suggested naval personnel with obesity had a higher proportion of nearly all adverse sleep-related health outcomes than those without obesity. Among participants without obesity, afloat personnel were more likely to report very short sleep (≤ 5 hours) and fewer hours of average nightly sleep, but were less likely to report physical health outcomes compared with ashore personnel. These findings suggest potential differences in sleep metrics and sleep-related health outcomes between afloat and ashore naval personnel. Additional research examining sleep outcomes using more objective measures is required to further investigate these findings, which may inform strategies to foster consolidated sleep despite environmental and occupational challenges in order to maintain high-performing naval personnel.

Visualizing and exploring patterns of large mutational events with SigProfilerMatrixGenerator.

BACKGROUND: All cancers harbor somatic mutations in their genomes. In principle, mutations affecting between one and fifty base pairs are generally classified as small mutational events. Conversely, large mutational events affect more than fifty base pairs, and, in most cases, they encompass copy-number and structural variants affecting many thousands of base pairs. Prior studies have demonstrated that examining patterns of somatic mutations can be leveraged to provide both biological and clinical insights, thus, resulting in an extensive repertoire of tools for evaluating small mutational events. Recently, classification schemas for examining large-scale mutational events have emerged and shown their utility across the spectrum of human cancers. However, there has been no computationally efficient bioinformatics tool that allows visualizing and exploring these large-scale mutational events. RESULTS: Here, we present a new version of SigProfilerMatrixGenerator that now delivers integrated capabilities for examining large mutational events. The tool provides support for examining copy-number variants and structural variants under two previously developed classification schemas and it supports data from numerous algorithms and data modalities. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment. CONCLUSIONS: The new version of SigProfilerMatrixGenerator provides the first standardized bioinformatics tool for optimized exploration and visualization of two previously developed classification schemas for copy number and structural variants. The tool is freely available at https://github.com/AlexandrovLab/SigProfilerMatrixGenerator with an extensive documentation at https://osf.io/s93d5/wiki/home/ .

Visuo-motor transformations in the intraparietal sulcus mediate the acquisition of endovascular medical skill.

Performing endovascular medical interventions safely and efficiently requires a diverse set of skills that need to be practised in dedicated training sessions. Here, we used multimodal magnetic resonance (MR) imaging to determine the structural and functional plasticity and core skills associated with skill acquisition. A training group learned to perform a simulator-based endovascular procedure, while a control group performed a simplified version of the task; multimodal MR images were acquired before and after training. Using a well-controlled interaction design, we found strong multimodal evidence for the role of the intraparietal sulcus (IPS) in endovascular skill acquisition that is in line with previous work implicating the structure in visuospatial transformations including simple visuo-motor and mental rotation tasks. Our results provide a unique window into the multimodal nature of rapid structural and functional plasticity of the human brain while learning a multifaceted and complex clinical skill. Further, our results provide a detailed description of the plasticity process associated with endovascular skill acquisition and highlight specific facets of skills that could enhance current medical pedagogy and be useful to explicitly target during clinical resident training.

Using cortico-cerebellar structural patterns to classify early- and late-trained musicians.

A body of current evidence suggests that there is a sensitive period for musical training: people who begin training before the age of seven show better performance on tests of musical skill, and also show differences in brain structure-especially in motor cortical and cerebellar regions-compared with those who start later. We used support vector machine models-a subtype of supervised machine learning-to investigate distributed patterns of structural differences between early-trained (ET) and late-trained (LT) musicians and to better understand the age boundaries of the sensitive period for early musicianship. After selecting regions of interest from the cerebellum and cortical sensorimotor regions, we applied recursive feature elimination with cross-validation to produce a model which optimally and accurately classified ET and LT musicians. This model identified a combination of 17 regions, including 9 cerebellar and 8 sensorimotor regions, and maintained a high accuracy and sensitivity (true positives, i.e., ET musicians) without sacrificing specificity (true negatives, i.e., LT musicians). Critically, this model-which defined ET musicians as those who began their training before the age of 7-outperformed all other models in which age of start was earlier or later (between ages 5-10). Our model's ability to accurately classify ET and LT musicians provides additional evidence that musical training before age 7 affects cortico-cerebellar structure in adulthood, and is consistent with the hypothesis that connected brain regions interact during development to reciprocally influence brain and behavioral maturation.

Modeling venous bias in resting state functional MRI metrics.

Resting-state (rs) functional magnetic resonance imaging (fMRI) is used to detect low-frequency fluctuations in the blood oxygen-level dependent (BOLD) signal across brain regions. Correlations between temporal BOLD signal fluctuations are commonly used to infer functional connectivity. However, because BOLD is based on the dilution of deoxyhemoglobin, it is sensitive to veins of all sizes, and its amplitude is biased by draining veins. These biases affect local BOLD signal location and amplitude, and may also influence BOLD-derived connectivity measures, but the magnitude of this venous bias and its relation to vein size and proximity is unknown. Here, veins were identified using high-resolution quantitative susceptibility maps and utilized in a biophysical model to investigate systematic venous biases on common local rsfMRI-derived measures. Specifically, we studied the impact of vein diameter and distance to veins on the amplitude of low-frequency fluctuations (ALFF), fractional ALFF (fALFF), Hurst exponent (HE), regional homogeneity (ReHo), and eigenvector centrality values in the grey matter. Values were higher across all distances in smaller veins, and decreased with increasing vein diameter. Additionally, rsfMRI values associated with larger veins decrease with increasing distance from the veins. ALFF and ReHo were the most biased by veins, while HE and fALFF exhibited the smallest bias. Across all metrics, the amplitude of the bias was limited in voxel-wise data, confirming that venous structure is not the dominant source of contrast in these rsfMRI metrics. Finally, the models presented can be used to correct this venous bias in rsfMRI metrics.

An overview of mutational and copy number signatures in human cancer.

The genome of each cell in the human body is constantly under assault from a plethora of exogenous and endogenous processes that can damage DNA. If not successfully repaired, DNA damage generally becomes permanently imprinted in cells, and all their progenies, as somatic mutations. In most cases, the patterns of these somatic mutations contain the tell-tale signs of the mutagenic processes that have imprinted and are termed mutational signatures. Recent pan-cancer genomic analyses have elucidated the compendium of mutational signatures for all types of small mutational events, including (1) single base substitutions, (2) doublet base substitutions, and (3) small insertions/deletions. In contrast to small mutational events, where, in most cases, DNA damage is a prerequisite, aneuploidy, which refers to the abnormal number of chromosomes in a cell, usually develops from mistakes during DNA replication. Such mistakes include DNA replication stress, mitotic errors caused by faulty microtubule dynamics, or cohesion defects that contribute to chromosomal breakage and can lead to copy number (CN) alterations (CNAs) or even to structural rearrangements. These aberrations also leave behind genomic scars which can be inferred from sequencing as CN signatures and rearrangement signatures. The analyses of mutational signatures of small mutational events have been extensively reviewed, so we will not comprehensively re-examine them here. Rather, our focus will be on summarising the existing knowledge for mutational signatures of CNAs. As studying CN signatures is an emerging field, we briefly summarise the utility that mutational signatures of small mutational events have provided in basic science, cancer treatment, and cancer prevention, and we emphasise the future role that CN signatures may play in each of these fields. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The impact of lesion side on bilateral upper limb coordination after stroke.

BACKGROUND: A stroke frequently results in impaired performance of activities of daily life. Many of these are highly dependent on effective coordination between the two arms. In the context of bimanual movements, cyclic rhythmical bilateral arm coordination patterns can be classified into two fundamental modes: in-phase (bilateral homologous muscles contract simultaneously) and anti-phase (bilateral muscles contract alternately) movements. We aimed to investigate how patients with left (LHS) and right (RHS) hemispheric stroke are differentially affected in both individual-limb control and inter-limb coordination during bilateral movements. METHODS: We used kinematic measurements to assess bilateral coordination abilities of 18 chronic hemiparetic stroke patients (9 LHS; 9 RHS) and 18 age- and sex-matched controls. Using KINARM upper-limb exoskeleton system, we examined individual-limb control by quantifying trajectory variability in each hand and inter-limb coordination by computing the phase synchronization between hands during anti- and in-phase movements. RESULTS: RHS patients exhibited greater impairment in individual- and inter-limb control during anti-phase movements, whilst LHS patients showed greater impairment in individual-limb control during in-phase movements alone. However, LHS patients further showed a swap in hand dominance during in-phase movements. CONCLUSIONS: The current study used individual-limb and inter-limb kinematic profiles and showed that bilateral movements are differently impaired in patients with left vs. right hemispheric strokes. Our results demonstrate that both fundamental bilateral coordination modes are differently controlled in both hemispheres using a lesion model approach. From a clinical perspective, we suggest that lesion side should be taken into account for more individually targeted bilateral coordination training strategies. TRIAL REGISTRATION: the current experiment is not a health care intervention study.

Mapping pontocerebellar connectivity with diffusion MRI.

The cerebellum's involvement in cognitive, affective and motor functions is mediated by connections to different regions of the cerebral cortex. A distinctive feature of cortico-cerebellar loops that has been demonstrated in the animal work is a topographic organization that is preserved across its corticopontine, pontocerebellar, and cerebello-thalmo-cortical segments. Here we used tractography derived from diffusion imaging data to characterize the connections between the pons and the individual lobules of the cerebellum and generate a parcellation of the pons and middle cerebellar peduncle based on the pattern of connectivity. We identified a rostral to caudal gradient in the pons, similar to that observed in the animal work, such that rostral regions were preferentially connected to cerebellar lobules involved in non-motor, and caudal regions with motor regions. These findings advance our fundamental understanding of the cerebellum, and the parcellations we generated provide context for future research into the pontocerebellar tract's involvement in health and disease.

The genomics of undifferentiated sarcoma of soft tissue: Progress, challenges and opportunities.

Undifferentiated sarcoma of soft tissue (USTS) are aggressive sarcomas that remain a diagnosis of exclusion and show extreme genomic complexity. Many advances in diagnostic criteria have resulted in several revisions in the definition of this rare cancer type. Recent sequencing efforts have illuminated the nature of the genome complexity and have revealed extensive copy number heterogeneity and multiple evolutionary patterns of development. This review places these recent advances into their historical and translational context and covers the changes in nomenclature, molecular classification, and the promise of personalised medicine.

H3K27me3 expression and methylation status in histological variants of malignant peripheral nerve sheath tumours.

Diagnosing MPNST can be challenging, but genetic alterations recently identified in polycomb repressive complex 2 (PRC2) core component genes, EED and SUZ12, resulting in global loss of the histone 3 lysine 27 trimethylation (H3K27me3) epigenetic mark, represent drivers of malignancy and a valuable diagnostic tool. However, the reported loss of H3K27me3 expression ranges from 35% to 84%. We show that advances in molecular pathology now allow many MPNST mimics to be classified confidently. We confirm that MPNSTs harbouring mutations in PRC2 core components are associated with loss of H3K27me3 expression; whole-genome doubling was detected in 68%, and SSTR2 was amplified in 32% of MPNSTs. We demonstrate that loss of H3K27me3 expression occurs overall in 38% of MPNSTs, but is lost in 76% of histologically classical cases, whereas loss was detected in only 23% cases with heterologous elements and 14% where the diagnosis could not be provided on morphology alone. H3K27me3 loss is rarely seen in other high-grade sarcomas and was not found to be associated with an inferior outcome in MPNST. We show that DNA methylation profiling distinguishes MPNST from its histological mimics, was unrelated to anatomical site, and formed two main clusters, MeGroups 4 and 5. MeGroup 4 represents classical MPNSTs lacking H3K27me3 expression in the majority of cases, whereas MeGroup 5 comprises MPNSTs exhibiting non-classical histology and expressing H3K27me3 and cluster with undifferentiated sarcomas. The two MeGroups are distinguished by differentially methylated PRC2-associated genes, the majority of which are hypermethylated in the promoter regions in MeGroup 4, indicating that the PRC2 target genes are not expressed in these tumours. The methylation profiles of MPNSTs with retention of H3K27me3 in MeGroups 4 and 5 are independent of mutations in PRC2 core components and the driver(s) in these groups remain to be identified. Our results open new avenues of investigation. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Investigating microstructural variation in the human hippocampus using non-negative matrix factorization.

In this work we use non-negative matrix factorization to identify patterns of microstructural variance in the human hippocampus. We utilize high-resolution structural and diffusion magnetic resonance imaging data from the Human Connectome Project to query hippocampus microstructure on a multivariate, voxelwise basis. Application of non-negative matrix factorization identifies spatial components (clusters of voxels sharing similar covariance patterns), as well as subject weightings (individual variance across hippocampus microstructure). By assessing the stability of spatial components as well as the accuracy of factorization, we identified 4 distinct microstructural components. Furthermore, we quantified the benefit of using multiple microstructural metrics by demonstrating that using three microstructural metrics (T1-weighted/T2-weighted signal, mean diffusivity and fractional anisotropy) produced more stable spatial components than when assessing metrics individually. Finally, we related individual subject weightings to demographic and behavioural measures using a partial least squares analysis. Through this approach we identified interpretable relationships between hippocampus microstructure and demographic and behavioural measures. Taken together, our work suggests non-negative matrix factorization as a spatially specific analytical approach for neuroimaging studies and advocates for the use of multiple metrics for data-driven component analyses.

Improving Safety of MRI in Patients with Deep Brain Stimulation Devices.

MRI is a valuable clinical and research tool for patients undergoing deep brain stimulation (DBS). However, risks associated with imaging DBS devices have led to stringent regulations, limiting the clinical and research utility of MRI in these patients. The main risks in patients with DBS devices undergoing MRI are heating at the electrode tips, induced currents, implantable pulse generator dysfunction, and mechanical forces. Phantom model studies indicate that electrode tip heating remains the most serious risk for modern DBS devices. The absence of adverse events in patients imaged under DBS vendor guidelines for MRI demonstrates the general safety of MRI for patients with DBS devices. Moreover, recent work indicates that-given adequate safety data-patients may be imaged outside these guidelines. At present, investigators are primarily focused on improving DBS device and MRI safety through the development of tools, including safety simulation models. Existing guidelines provide a standardized framework for performing safe MRI in patients with DBS devices. It also highlights the possibility of expanding MRI as a tool for research and clinical care in these patients going forward.

Undifferentiated pleomorphic sarcomas with PRDM10 fusions have a distinct gene expression profile.

Undifferentiated pleomorphic sarcoma (UPS) is a highly aggressive soft tissue tumor. A subset of UPS is characterized by a CITED2-PRDM10 or a MED12-PRDM10 gene fusion. Preliminary data suggest that these so-called PRDM10-rearranged tumors (PRT) are clinically more indolent than classical high-grade UPS, and hence important to recognize. Here, we assessed the spectrum of accompanying mutations and the gene expression profile in PRT using genomic arrays and sequencing of the genome (WGS) and transcriptome (RNA-seq). The fusion protein's function was further investigated by conditional expression of the CITED2-PRDM10 fusion in a fibroblast cell line, followed by RNA-seq and an assay for transposase-accessible chromatin (ATAC-seq). The CADM3 gene was found to be differentially up-regulated in PRT and cell lines and was also evaluated for expression at the protein level using immunohistochemistry (IHC). The genomic analyses identified few and nonrecurrent mutations in addition to the structural variants giving rise to the gene fusions, strongly indicating that the PRDM10-fusions represent the critical driver mutations. RNA-seq of tumors showed a distinct gene expression profile, separating PRT from high-grade UPS and other soft tissue tumors. CADM3 was among the genes that was consistently and highly expressed in both PRT and fibroblasts expressing CITED2-PRDM10, suggesting that it is a direct target of the PRDM10 transcription factor. This conclusion is in line with sequencing data from ATAC-seq, showing enrichment of PRDM10 binding sites, suggesting that the amino-terminal fusion partner contributes by making the DNA more accessible to PRDM10 binding. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Immune activation by DNA damage predicts response to chemotherapy and survival in oesophageal adenocarcinoma.

OBJECTIVE: Current strategies to guide selection of neoadjuvant therapy in oesophageal adenocarcinoma (OAC) are inadequate. We assessed the ability of a DNA damage immune response (DDIR) assay to predict response following neoadjuvant chemotherapy in OAC. DESIGN: Transcriptional profiling of 273 formalin-fixed paraffin-embedded prechemotherapy endoscopic OAC biopsies was performed. All patients were treated with platinum-based neoadjuvant chemotherapy and resection between 2003 and 2014 at four centres in the Oesophageal Cancer Clinical and Molecular Stratification consortium. CD8 and programmed death ligand 1 (PD-L1) immunohistochemical staining was assessed in matched resection specimens from 126 cases. Kaplan-Meier and Cox proportional hazards regression analysis were applied according to DDIR status for recurrence-free survival (RFS) and overall survival (OS). RESULTS: A total of 66 OAC samples (24%) were DDIR positive with the remaining 207 samples (76%) being DDIR negative. DDIR assay positivity was associated with improved RFS (HR: 0.61; 95% CI 0.38 to 0.98; p=0.042) and OS (HR: 0.52; 95% CI 0.31 to 0.88; p=0.015) following multivariate analysis. DDIR-positive patients had a higher pathological response rate (p=0.033), lower nodal burden (p=0.026) and reduced circumferential margin involvement (p=0.007). No difference in OS was observed according to DDIR status in an independent surgery-alone dataset.DDIR-positive OAC tumours were also associated with the presence of CD8+ lymphocytes (intratumoural: p<0.001; stromal: p=0.026) as well as PD-L1 expression (intratumoural: p=0.047; stromal: p=0.025). CONCLUSION: The DDIR assay is strongly predictive of benefit from DNA-damaging neoadjuvant chemotherapy followed by surgical resection and is associated with a proinflammatory microenvironment in OAC.

Neuroimaging Technological Advancements for Targeting in Functional Neurosurgery.

PURPOSE OF REVIEW: Ablations and particularly deep brain stimulation (DBS) of a variety of CNS targets are established therapeutic tools for movement disorders. Accurate targeting of the intended structure is crucial for optimal clinical outcomes. However, most targets used in functional neurosurgery are sub-optimally visualized on routine MRI. This article reviews recent neuroimaging advancements for targeting in movement disorders. RECENT FINDINGS: Dedicated MRI sequences can often visualize to some degree anatomical structures commonly targeted during DBS surgery, including at 1.5-T field strengths. Due to recent technological advancements, MR images using ultra-high magnetic field strengths and new acquisition parameters allow for markedly improved visualization of common movement disorder targets. In addition, novel neuroimaging techniques have enabled group-level analysis of DBS patients and delineation of areas associated with clinical benefits. These areas might diverge from the conventionally targeted nuclei and may instead correspond to white matter tracts or hubs of functional networks. Neuroimaging advancements have enabled improved direct visualization-based targeting as well as optimization and adjustment of conventionally targeted structures.

Gray-matter structural variability in the human cerebellum: Lobule-specific differences across sex and hemisphere.

Though commonly thought of as a "motor structure", we now know that the cerebellum's reciprocal connections to the cerebral cortex underlie contributions to both motor and non-motor behavior. Further, recent research has shown that cerebellar dysfunction may contribute to a wide range of neuropsychiatric disorders. However, there has been little characterization of normative variability at the level of cerebellar structure that can facilitate and further our understanding of disease biomarkers. In this manuscript we examine normative variation of the cerebellum using data from the Human Connectome Project (HCP). The Multiple Automatically Generated Templates (MAGeT) segmentation tool was used to identify the cerebella and 33 anatomically-defined lobules from 327 individuals from the HCP. To characterize normative variation, we estimated population mean volume and variability, assessed differences in hemisphere and sex, and related lobular volume to motor and non-motor behavior. We found that the effects of hemisphere and sex were not homogeneous across all lobules of the cerebellum. Greater volume in the right hemisphere was primarily driven by lobules Crus I, II, and H VIIB, with H VIIIA exhibiting the greatest left>right asymmetry. Relative to total cerebellar gray-matter volume, females had larger Crus II (known to be connected with non-motor regions of the cerebral cortex) while males had larger motor-connected lobules including H V, and VIIIA/B. When relating lobular volume to memory, motor performance, and emotional behavior, we found some evidence for relationships that have previously been identified in the literature. Our observations of normative cerebellar structure and variability in young adults provide evidence for lobule-specific differences in volume and the relationship with sex and behavior - indicating that the cerebellum cannot be considered a single structure with uniform function, but as a set of regions with functions that are likely as diverse as their connectivity with the cerebral cortex.