Polygenic scores for autism are associated with neurite density in adults and children from the general population.

Genetic variants linked to autism are thought to change cognition and behaviour by altering the structure and function of the brain. Although a substantial body of literature has identified structural brain differences in autism, it is unknown whether autism-associated common genetic variants are linked to changes in cortical macro- and micro-structure. We investigated this using neuroimaging and genetic data from adults (UK Biobank, N = 31,748) and children (ABCD, N = 4,928). Using polygenic scores and genetic correlations we observe a robust negative association between common variants for autism and a magnetic resonance imaging derived phenotype for neurite density (intracellular volume fraction) in the general population. This result is consistent across both children and adults, in both the cortex and in white matter tracts, and confirmed using polygenic scores and genetic correlations. There were no sex differences in this association. Mendelian randomisation analyses provide no evidence for a causal relationship between autism and intracellular volume fraction, although this should be revisited using better powered instruments. Overall, this study provides evidence for shared common variant genetics between autism and cortical neurite density.

Brain tumour microstructure is associated with post-surgical cognition.

Brain tumour microstructure is potentially predictive of changes following treatment to cognitive functions subserved by the functional networks in which they are embedded. To test this hypothesis, intra-tumoural microstructure was quantified from diffusion-weighted MRI to identify which tumour subregions (if any) had a greater impact on participants' cognitive recovery after surgical resection. Additionally, we studied the role of tumour microstructure in the functional interaction between the tumour and the rest of the brain. Sixteen patients (22-56 years, 7 females) with brain tumours located in or near speech-eloquent areas of the brain were included in the analyses. Two different approaches were adopted for tumour segmentation from a multishell diffusion MRI acquisition: the first used a two-dimensional four group partition of feature space, whilst the second used data-driven clustering with Gaussian mixture modelling. For each approach, we assessed the capability of tumour microstructure to predict participants' cognitive outcomes after surgery and the strength of association between the BOLD signal of individual tumour subregions and the global BOLD signal. With both methodologies, the volumes of partially overlapped subregions within the tumour significantly predicted cognitive decline in verbal skills after surgery. We also found that these particular subregions were among those that showed greater functional interaction with the unaffected cortex. Our results indicate that tumour microstructure measured by MRI multishell diffusion is associated with cognitive recovery after surgery.

Accelerated Cortical Thinning in Schizophrenia is Associated With Rare and Common Predisposing Variation to Schizophrenia and Neurodevelopmental Disorders.

BACKGROUND: Schizophrenia is a highly heritable disorder characterized by increased cortical thinning throughout the lifespan. Studies have reported a shared genetic basis between schizophrenia and cortical thickness. However, no genes whose expression is related to abnormal cortical thinning in schizophrenia have been identified. METHODS: We conducted linear mixed models to estimate the rates of accelerated cortical thinning across 68 regions from the Desikan-Killiany atlas in individuals with schizophrenia compared to healthy controls from a large longitudinal sample (NCases = 169 and NControls = 298, aged 16-70 years). We studied the correlation between gene expression data from the Allen Human Brain Atlas and accelerated thinning estimates across cortical regions. We finally explored the functional and genetic underpinnings of the genes most contributing to accelerated thinning. RESULTS: We described a global pattern of accelerated cortical thinning in individuals with schizophrenia compared to healthy controls. Genes underexpressed in cortical regions exhibiting this accelerated thinning were downregulated in several psychiatric disorders and were enriched for both common and rare disrupting variation for schizophrenia and neurodevelopmental disorders. In contrast, none of these enrichments were observed for baseline cross-sectional cortical thickness differences. CONCLUSIONS: Our findings suggest that accelerated cortical thinning, rather than cortical thickness alone, serves as an informative phenotype for neurodevelopmental disruptions in schizophrenia. We highlight the genetic and transcriptomic correlates of this accelerated cortical thinning, emphasizing the need for future longitudinal studies to elucidate the role of genetic variation and the temporal-spatial dynamics of gene expression in brain development and aging in schizophrenia.

Cost-effectiveness Analysis of Single-Use Duodenoscope Applied to Endoscopic Retrograde Cholangiopancreatography.

OBJECTIVES: Secondary infections due to transmission via the duodenoscope have been reported in up to 3% of endoscopic retrograde cholangiopancreatographies. The use of single-use duodenoscopes has been suggested. We investigate the cost-effectiveness of these duodenoscopes use in cholangiopancreatography. MATERIALS AND METHODS: A cost-effectiveness analysis was implemented to compare the performance of cholangiopancreatographies with reusable duodenoscopes versus single-use duodenoscopes. Effectiveness was analyzed by calculating quality-adjusted life years (QALY) from the perspective of the National Health System. Possibility of crossover from single-use to reusable duodenoscopes was considered. A willingness-to-pay of €25,000/QALY was set, the incremental cost-effectiveness ratio (ICER) was calculated, and deterministic and probabilistic sensitivity analyses were performed. RESULTS: Considering cholangiopancreatographies with single-use and reusable duodenoscopes at a cost of €2900 and €1333, respectively, and a 10% rate of single-use duodenoscopes, ICER was greater than €3,000,000/QALY. A lower single-use duodenoscope cost of €1211 resulted in an ICER of €23,583/QALY. When the unit cost of the single-use duodenoscope was €1211, a crossover rate of more than 9.5% made the use of the single-use duodenoscope inefficient. CONCLUSIONS: Single-use duodenoscopes are cost-effective in a proportion of cholangiopancreatographies if its cost is reduced. Increased crossover rate makes single-use duodenoscope use not cost-effective.

Tumour-infiltrated cortex participates in large-scale cognitive circuits.

The extent to which tumour-infiltrated brain tissue contributes to cognitive function remains unclear. We tested the hypothesis that cortical tissue infiltrated by diffuse gliomas participates in large-scale cognitive circuits using a unique combination of intracranial electrocorticography (ECoG) and resting-state functional magnetic resonance (fMRI) imaging in four patients. We also assessed the relationship between functional connectivity with tumour-infiltrated tissue and long-term cognitive outcomes in a larger, overlapping cohort of 17 patients. We observed significant task-related high gamma (70-250 Hz) power modulations in tumour-infiltrated cortex in response to increased cognitive effort (i.e., switch counting compared to simple counting), implying preserved functionality of neoplastic tissue for complex tasks probing executive function. We found that tumour locations corresponding to task-responsive electrodes exhibited functional connectivity patterns that significantly co-localised with canonical brain networks implicated in executive function. Specifically, we discovered that tumour-infiltrated cortex with larger task-related high gamma power modulations tended to be more functionally connected to the dorsal attention network (DAN). Finally, we demonstrated that tumour-DAN connectivity is evident across a larger cohort of patients with gliomas and that it relates to long-term postsurgical outcomes in goal-directed attention. Overall, this study contributes convergent fMRI-ECoG evidence that tumour-infiltrated cortex participates in large-scale neurocognitive circuits that support executive function in health. These findings underscore the potential clinical utility of mapping large-scale connectivity of tumour-infiltrated tissue in the care of patients with diffuse gliomas.

Two human brain systems micro-structurally associated with obesity.

The relationship between obesity and human brain structure is incompletely understood. Using diffusion-weighted MRI from ∼30,000 UK Biobank participants, we test the hypothesis that obesity (waist-to-hip ratio, WHR) is associated with regional differences in two micro-structural MRI metrics: isotropic volume fraction (ISOVF), an index of free water, and intra-cellular volume fraction (ICVF), an index of neurite density. We observed significant associations with obesity in two coupled but distinct brain systems: a prefrontal/temporal/striatal system associated with ISOVF and a medial temporal/occipital/striatal system associated with ICVF. The ISOVF~WHR system colocated with expression of genes enriched for innate immune functions, decreased glial density, and high mu opioid (MOR) and other neurotransmitter receptor density. Conversely, the ICVF~WHR system co-located with expression of genes enriched for G-protein coupled receptors and decreased density of MOR and other receptors. To test whether these distinct brain phenotypes might differ in terms of their underlying shared genetics or relationship to maps of the inflammatory marker C-reactive Protein (CRP), we estimated the genetic correlations between WHR and ISOVF (rg = 0.026, P = 0.36) and ICVF (rg = 0.112, P < 9×10-4) as well as comparing correlations between WHR maps and equivalent CRP maps for ISOVF and ICVF (P<0.05). These correlational results are consistent with a two-way mechanistic model whereby genetically determined differences in neurite density in the medial temporal system may contribute to obesity, whereas water content in the prefrontal system could reflect a consequence of obesity mediated by innate immune system activation.

People with obesity are at greater risk of cardiovascular diseases and metabolic conditions such as type 2 diabetes. More recently obesity has also been linked to changes in the brain that are associated with age-related dementia and cognitive decline. This includes a thinner cortex (the brain's outer layer) and lower volume of grey matter which is where cognitive processes, such as learning, take place. However, questions remain about how obesity and grey matter are connected. For instance, it is unclear whether the change in volume is due to there being fewer cells (and thus more water between them) or fewer connections between cells in these brain areas. It is also unknown whether the reduced volume of grey matter is a cause or consequence of obesity. To address these questions, Kitzbichler et al. analysed 30,000 MRI scans of the human brain which are stored in the UK Biobank. This revealed two characteristics in grey matter that were linked to obesity: higher amounts of water between cells in some areas, and a lower density of connections between neurons in others. The areas with higher levels of free water are known to have more glial cells which provide support to neurons. They also have more receptors that bind to fatty acids (which are often raised in people with obesity) and more receptors for molecules and cells involved in the immune response. In contrast, the areas with a lower density of connections between neurons usually were more closely associated with genetic risk factors associated with obesity, and fewer receptors involved in feeding, appetite and energy use. The findings of Kitzblicher et al. suggest that differences in the density of connections between neurons may contribute to obesity. High water content in grey matter, on the other hand, may be a consequence of obesity that occurs as a result of immune receptors becoming activated. This provides new insights in to how obesity and grey matter in the brain are connected.

Intra-operative applications of augmented reality in glioma surgery: a systematic review.

Background: Augmented reality (AR) is increasingly being explored in neurosurgical practice. By visualizing patient-specific, three-dimensional (3D) models in real time, surgeons can improve their spatial understanding of complex anatomy and pathology, thereby optimizing intra-operative navigation, localization, and resection. Here, we aimed to capture applications of AR in glioma surgery, their current status and future potential. Methods: A systematic review of the literature was conducted. This adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. PubMed, Embase, and Scopus electronic databases were queried from inception to October 10, 2022. Leveraging the Population, Intervention, Comparison, Outcomes, and Study design (PICOS) framework, study eligibility was evaluated in the qualitative synthesis. Data regarding AR workflow, surgical application, and associated outcomes were then extracted. The quality of evidence was additionally examined, using hierarchical classes of evidence in neurosurgery. Results: The search returned 77 articles. Forty were subject to title and abstract screening, while 25 proceeded to full text screening. Of these, 22 articles met eligibility criteria and were included in the final review. During abstraction, studies were classified as "development" or "intervention" based on primary aims. Overall, AR was qualitatively advantageous, due to enhanced visualization of gliomas and critical structures, frequently aiding in maximal safe resection. Non-rigid applications were also useful in disclosing and compensating for intra-operative brain shift. Irrespective, there was high variance in registration methods and measurements, which considerably impacted projection accuracy. Most studies were of low-level evidence, yielding heterogeneous results. Conclusions: AR has increasing potential for glioma surgery, with capacity to positively influence the onco-functional balance. However, technical and design limitations are readily apparent. The field must consider the importance of consistency and replicability, as well as the level of evidence, to effectively converge on standard approaches that maximize patient benefit.

Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes.

Our understanding of the genetics of the human cerebral cortex is limited both in terms of the diversity and the anatomical granularity of brain structural phenotypes. Here we conducted a genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging-derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,663 individuals and identified 4,349 experiment-wide significant loci. These phenotypes include cortical thickness, surface area, gray matter volume, measures of folding, neurite density and water diffusion. We identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with cortical expansion are associated with cephalic disorders. Finally, we identified complex interphenotype and inter-regional genetic relationships among the 13 phenotypes, reflecting the developmental differences among them. Together, these analyses identify distinct genetic organizational principles of the cortex and their correlates with neurodevelopment.

Resilient functioning is associated with altered structural brain network topology in adolescents exposed to childhood adversity.

Childhood adversity is one of the strongest predictors of adolescent mental illness. Therefore, it is critical that the mechanisms that aid resilient functioning in individuals exposed to childhood adversity are better understood. Here, we examined whether resilient functioning was related to structural brain network topology. We quantified resilient functioning at the individual level as psychosocial functioning adjusted for the severity of childhood adversity in a large sample of adolescents (N = 2406, aged 14-24). Next, we examined nodal degree (the number of connections that brain regions have in a network) using brain-wide cortical thickness measures in a representative subset (N = 275) using a sliding window approach. We found that higher resilient functioning was associated with lower nodal degree of multiple regions including the dorsolateral prefrontal cortex, the medial prefrontal cortex, and the posterior superior temporal sulcus (z > 1.645). During adolescence, decreases in nodal degree are thought to reflect a normative developmental process that is part of the extensive remodeling of structural brain network topology. Prior findings in this sample showed that decreased nodal degree was associated with age, as such our findings of negative associations between nodal degree and resilient functioning may therefore potentially resemble a more mature structural network configuration in individuals with higher resilient functioning.

Longitudinal trajectories in negative symptoms and changes in brain cortical thickness: 10-year follow-up study.

BACKGROUND: Understanding the evolution of negative symptoms in first-episode psychosis (FEP) requires long-term longitudinal study designs that capture the progression of this condition and the associated brain changes. AIMS: To explore the factors underlying negative symptoms and their association with long-term abnormal brain trajectories. METHOD: We followed up 357 people with FEP over a 10-year period. Factor analyses were conducted to explore negative symptom dimensionality. Latent growth mixture modelling (LGMM) was used to identify the latent classes. Analysis of variance (ANOVA) was conducted to investigate developmental trajectories of cortical thickness. Finally, the resulting ANOVA maps were correlated with a wide set of regional molecular profiles derived from public databases. RESULTS: Three trajectories (stable, decreasing and increasing) were found in each of the three factors (expressivity, experiential and attention) identified by the factor analyses. Patients with an increasing trajectory in the expressivity factor showed cortical thinning in caudal middle frontal, pars triangularis, rostral middle frontal and superior frontal regions from the third to the tenth year after the onset of the psychotic disorder. The F-statistic map of cortical thickness expressivity differences was associated with a receptor density map derived from positron emission tomography data. CONCLUSIONS: Stable and decreasing were the most common trajectories. Additionally, cortical thickness abnormalities found at relatively late stages of FEP onset could be exploited as a biomarker of poor symptom outcome in the expressivity dimension. Finally, the brain areas with less density of receptors spatially overlap areas that discriminate the trajectories of the expressivity dimension.

High gamma activity distinguishes frontal cognitive control regions from adjacent cortical networks.

Though the lateral frontal cortex is broadly implicated in cognitive control, functional MRI (fMRI) studies suggest fine-grained distinctions within this region. To examine this question electrophysiologically, we placed electrodes on the lateral frontal cortex in patients undergoing awake craniotomy for tumor resection. Patients performed verbal tasks with a manipulation of attentional switching, a canonical control demand. Power in the high gamma range (70-250 Hz) distinguished electrodes based on their location within a high-resolution fMRI network parcellation of the frontal lobe. Electrodes within the canonical fronto-parietal control network showed increased power in the switching condition, a result absent in electrodes within default mode, language and somato-motor networks. High gamma results contrasted with spatially distributed power decreases in the beta range (12-30 Hz). These results confirm the importance of fine-scale functional distinctions within the human frontal lobe, and pave the way for increased precision of functional mapping in tumor surgeries.

Transcriptomic and connectomic correlates of differential spatial patterning among gliomas.

Unravelling the complex events driving grade-specific spatial distribution of brain tumour occurrence requires rich datasets from both healthy individuals and patients. Here, we combined open-access data from The Cancer Genome Atlas, the UK Biobank and the Allen Brain Human Atlas to disentangle how the different spatial occurrences of glioblastoma multiforme and low-grade gliomas are linked to brain network features and the normative transcriptional profiles of brain regions. From MRI of brain tumour patients, we first constructed a grade-related frequency map of the regional occurrence of low-grade gliomas and the more aggressive glioblastoma multiforme. Using associated mRNA transcription data, we derived a set of differential gene expressions from glioblastoma multiforme and low-grade gliomas tissues of the same patients. By combining the resulting values with normative gene expressions from post-mortem brain tissue, we constructed a grade-related expression map indicating which brain regions express genes dysregulated in aggressive gliomas. Additionally, we derived an expression map of genes previously associated with tumour subtypes in a genome-wide association study (tumour-related genes). There were significant associations between grade-related frequency, grade-related expression and tumour-related expression maps, as well as functional brain network features (specifically, nodal strength and participation coefficient) that are implicated in neurological and psychiatric disorders. These findings identify brain network dynamics and transcriptomic signatures as key factors in regional vulnerability for glioblastoma multiforme and low-grade glioma occurrence, placing primary brain tumours within a well established framework of neurological and psychiatric cortical alterations.

Sexually divergent development of depression-related brain networks during healthy human adolescence.

Sexual differences in human brain development could be relevant to sex differences in the incidence of depression during adolescence. We tested for sex differences in parameters of normative brain network development using fMRI data on N = 298 healthy adolescents, aged 14 to 26 years, each scanned one to three times. Sexually divergent development of functional connectivity was located in the default mode network, limbic cortex, and subcortical nuclei. Females had a more "disruptive" pattern of development, where weak functional connectivity at age 14 became stronger during adolescence. This fMRI-derived map of sexually divergent brain network development was robustly colocated with i prior loci of reward-related brain activation ii a map of functional dysconnectivity in major depressive disorder (MDD), and iii an adult brain gene transcriptional pattern enriched for genes on the X chromosome, neurodevelopmental genes, and risk genes for MDD. We found normative sexual divergence in adolescent development of a cortico-subcortical brain functional network that is relevant to depression.

A deep graph neural network architecture for modelling spatio-temporal dynamics in resting-state functional MRI data.

Resting-state functional magnetic resonance imaging (rs-fMRI) has been successfully employed to understand the organisation of the human brain. Typically, the brain is parcellated into regions of interest (ROIs) and modelled as a graph where each ROI represents a node and association measures between ROI-specific blood-oxygen-level-dependent (BOLD) time series are edges. Recently, graph neural networks (GNNs) have seen a surge in popularity due to their success in modelling unstructured relational data. The latest developments with GNNs, however, have not yet been fully exploited for the analysis of rs-fMRI data, particularly with regards to its spatio-temporal dynamics. In this paper, we present a novel deep neural network architecture which combines both GNNs and temporal convolutional networks (TCNs) in order to learn from both the spatial and temporal components of rs-fMRI data in an end-to-end fashion. In particular, this corresponds to intra-feature learning (i.e., learning temporal dynamics with TCNs) as well as inter-feature learning (i.e., leveraging interactions between ROI-wise dynamics with GNNs). We evaluate our model with an ablation study using 35,159 samples from the UK Biobank rs-fMRI database, as well as in the smaller Human Connectome Project (HCP) dataset, both in a unimodal and in a multimodal fashion. We also demonstrate that out architecture contains explainability-related features which easily map to realistic neurobiological insights. We suggest that this model could lay the groundwork for future deep learning architectures focused on leveraging the inherently and inextricably spatio-temporal nature of rs-fMRI data.

Assessment of neuropsychological function in brain tumor treatment: a comparison of traditional neuropsychological assessment with app-based cognitive screening.

BACKGROUND: Gliomas are typically considered to cause relatively few neurological impairments. However, cognitive difficulties can arise, for example during treatment, with potential detrimental effects on quality of life. Accurate, reproducible, and accessible cognitive assessment is therefore vital in understanding the effects of both tumor and treatments. Our aim is to compare traditional neuropsychological assessment with an app-based cognitive screening tool in patients with glioma before and after surgical resection. Our hypotheses were that cognitive impairments would be apparent, even in a young and high functioning cohort, and that app-based cognitive screening would complement traditional neuropsychological assessment. METHODS: Seventeen patients with diffuse gliomas completed a traditional neuropsychological assessment and an app-based touchscreen tablet assessment pre- and post-operatively. The app assessment was also conducted at 3- and 12-month follow-up. Impairment rates, mean performance, and pre- and post-operative changes were compared using standardized Z-scores. RESULTS: Approximately 2-3 h of traditional assessment indicated an average of 2.88 cognitive impairments per patient, while the 30-min screen indicated 1.18. As might be expected, traditional assessment using multiple items across the difficulty range proved more sensitive than brief screening measures in areas such as memory and attention. However, the capacity of the screening app to capture reaction times enhanced its sensitivity, relative to traditional assessment, in the area of non-verbal function. Where there was overlap between the two assessments, for example digit span tasks, the results were broadly equivalent. CONCLUSIONS: Cognitive impairments were common in this sample and app-based screening complemented traditional neuropsychological assessment. Implications for clinical assessment and follow-up are discussed.

Interventional neurorehabilitation for promoting functional recovery post-craniotomy: a proof-of-concept.

The human brain is a highly plastic 'complex' network-it is highly resilient to damage and capable of self-reorganisation after a large perturbation. Clinically, neurological deficits secondary to iatrogenic injury have very few active treatments. New imaging and stimulation technologies, though, offer promising therapeutic avenues to accelerate post-operative recovery trajectories. In this study, we sought to establish the safety profile for 'interventional neurorehabilitation': connectome-based therapeutic brain stimulation to drive cortical reorganisation and promote functional recovery post-craniotomy. In n = 34 glioma patients who experienced post-operative motor or language deficits, we used connectomics to construct single-subject cortical networks. Based on their clinical and connectivity deficit, patients underwent network-specific transcranial magnetic stimulation (TMS) sessions daily over five consecutive days. Patients were then assessed for TMS-related side effects and improvements. 31/34 (91%) patients were successfully recruited and enrolled for TMS treatment within two weeks of glioma surgery. No seizures or serious complications occurred during TMS rehabilitation and 1-week post-stimulation. Transient headaches were reported in 4/31 patients but improved after a single session. No neurological worsening was observed while a clinically and statistically significant benefit was noted in 28/31 patients post-TMS. We present two clinical vignettes and a video demonstration of interventional neurorehabilitation. For the first time, we demonstrate the safety profile and ability to recruit, enroll, and complete TMS acutely post-craniotomy in a high seizure risk population. Given the lack of randomisation and controls in this study, prospective randomised sham-controlled stimulation trials are now warranted to establish the efficacy of interventional neurorehabilitation following craniotomy.

Examining the immune signatures of SARS-CoV-2 infection in pregnancy and the impact on neurodevelopment: Protocol of the SIGNATURE longitudinal study.

The COVID-19 pandemic represents a valuable opportunity to carry out cohort studies that allow us to advance our knowledge on pathophysiological mechanisms of neuropsychiatric diseases. One of these opportunities is the study of the relationships between inflammation, brain development and an increased risk of suffering neuropsychiatric disorders. Based on the hypothesis that neuroinflammation during early stages of life is associated with neurodevelopmental disorders and confers a greater risk of developing neuropsychiatric disorders, we propose a cohort study of SARS-CoV-2-infected pregnant women and their newborns. The main objective of SIGNATURE project is to explore how the presence of prenatal SARS-CoV-2 infection and other non-infectious stressors generates an abnormal inflammatory activity in the newborn. The cohort of women during the COVID-19 pandemic will be psychological and biological monitored during their pregnancy, delivery, childbirth and postpartum. The biological information of the umbilical cord (foetus blood) and peripheral blood from the mother will be obtained after childbirth. These samples and the clinical characterisation of the cohort of mothers and newborns, are tremendously valuable at this time. This is a protocol report and no analyses have been conducted yet, being currently at, our study is in the recruitment process step. At the time of this publication, we have identified 1,060 SARS-CoV-2 infected mothers and all have already given birth. From the total of identified mothers, we have recruited 537 SARS-COV-2 infected women and all of them have completed the mental health assessment during pregnancy. We have collected biological samples from 119 mothers and babies. Additionally, we have recruited 390 non-infected pregnant women.

Memory recovery in relation to default mode network impairment and neurite density during brain tumor treatment.

OBJECTIVE: The aim of this study was to test brain tumor interactions with brain networks, thereby identifying protective features and risk factors for memory recovery after resection. METHODS: Seventeen patients with diffuse nonenhancing glioma (ages 22-56 years) underwent longitudinal MRI before and after surgery, and during a 12-month recovery period (47 MRI scans in total after exclusion). After each scanning session, a battery of memory tests was performed using a tablet-based screening tool, including free verbal memory, overall verbal memory, episodic memory, orientation, forward digit span, and backward digit span. Using structural MRI and neurite orientation dispersion and density imaging (NODDI) derived from diffusion-weighted images, the authors estimated lesion overlap and neurite density, respectively, with brain networks derived from normative data in healthy participants (somatomotor, dorsal attention, ventral attention, frontoparietal, and default mode network [DMN]). Linear mixed-effect models (LMMs) that regressed out the effect of age, gender, tumor grade, type of treatment, total lesion volume, and total neurite density were used to test the potential longitudinal associations between imaging markers and memory recovery. RESULTS: Memory recovery was not significantly associated with either the tumor location based on traditional lobe classification or the type of treatment received by patients (i.e., surgery alone or surgery with adjuvant chemoradiotherapy). Nonlocal effects of tumors were evident on neurite density, which was reduced not only within the tumor but also beyond the tumor boundary. In contrast, high preoperative neurite density outside the tumor but within the DMN was associated with better memory recovery (LMM, p value after false discovery rate correction [Pfdr] < 10-3). Furthermore, postoperative and follow-up neurite density within the DMN and frontoparietal network were also associated with memory recovery (LMM, Pfdr = 0.014 and Pfdr = 0.001, respectively). Preoperative tumor and postoperative lesion overlap with the DMN showed a significant negative association with memory recovery (LMM, Pfdr = 0.002 and Pfdr < 10-4, respectively). CONCLUSIONS: Imaging biomarkers of cognitive recovery and decline can be identified using NODDI and resting-state networks. Brain tumors and their corresponding treatment affecting brain networks that are fundamental for memory functioning such as the DMN can have a major impact on patients' memory recovery.

Lesion covariance networks reveal proposed origins and pathways of diffuse gliomas.

Diffuse gliomas have been hypothesized to originate from neural stem cells in the subventricular zone and develop along previously healthy brain networks. Here, we evaluated these hypotheses by mapping independent sources of glioma localization and determining their relationships with neurogenic niches, genetic markers and large-scale connectivity networks. By applying independent component analysis to lesion data from 242 adult patients with high- and low-grade glioma, we identified three lesion covariance networks, which reflect clusters of frequent glioma localization. Replicability of the lesion covariance networks was assessed in an independent sample of 168 glioma patients. We related the lesion covariance networks to important clinical variables, including tumour grade and patient survival, as well as genomic information such as molecular genetic subtype and bulk transcriptomic profiles. Finally, we systematically cross-correlated the lesion covariance networks with structural and functional connectivity networks derived from neuroimaging data of over 4000 healthy UK BioBank participants to uncover intrinsic brain networks that may that underlie tumour development. The three lesion covariance networks overlapped with the anterior, posterior and inferior horns of the lateral ventricles respectively, extending into the frontal, parietal and temporal cortices. These locations were independently replicated. The first lesion covariance network, which overlapped with the anterior horn, was associated with low-grade, isocitrate dehydrogenase -mutated/1p19q-codeleted tumours, as well as a neural transcriptomic signature and improved overall survival. Each lesion covariance network significantly coincided with multiple structural and functional connectivity networks, with the first bearing an especially strong relationship with brain connectivity, consistent with its neural transcriptomic profile. Finally, we identified subcortical, periventricular structures with functional connectivity patterns to the cortex that significantly matched each lesion covariance network. In conclusion, we demonstrated replicable patterns of glioma localization with clinical relevance and spatial correspondence with large-scale functional and structural connectivity networks. These results are consistent with prior reports of glioma growth along white matter pathways, as well as evidence for the coordination of glioma stem cell proliferation by neuronal activity. Our findings describe how the locations of gliomas relate to their proposed subventricular origins, suggesting a model wherein periventricular brain connectivity guides tumour development.

BOLD Coupling between Lesioned and Healthy Brain Is Associated with Glioma Patients' Recovery.

Predicting functional outcomes after surgery and early adjuvant treatment is difficult due to the complex, extended, interlocking brain networks that underpin cognition. The aim of this study was to test glioma functional interactions with the rest of the brain, thereby identifying the risk factors of cognitive recovery or deterioration. Seventeen patients with diffuse non-enhancing glioma (aged 22-56 years) were longitudinally MRI scanned and cognitively assessed before and after surgery and during a 12-month recovery period (55 MRI scans in total after exclusions). We initially found, and then replicated in an independent dataset, that the spatial correlation pattern between regional and global BOLD signals (also known as global signal topography) was associated with tumour occurrence. We then estimated the coupling between the BOLD signal from within the tumour and the signal extracted from different brain tissues. We observed that the normative global signal topography is reorganised in glioma patients during the recovery period. Moreover, we found that the BOLD signal within the tumour and lesioned brain was coupled with the global signal and that this coupling was associated with cognitive recovery. Nevertheless, patients did not show any apparent disruption of functional connectivity within canonical functional networks. Understanding how tumour infiltration and coupling are related to patients' recovery represents a major step forward in prognostic development.