Showing papers by "Michael E. Sughrue published in 2021"

Reducing the Cognitive Footprint of Brain Tumor Surgery.

Abstract: The surgical management of brain tumors is based on the principle that the extent of resection improves patient outcomes. Traditionally, neurosurgeons have considered that lesions in "non-eloquent" cerebrum can be more aggressively surgically managed compared to lesions in "eloquent" regions with more known functional relevance. Furthermore, advancements in multimodal imaging technologies have improved our ability to extend the rate of resection while minimizing the risk of inducing new neurologic deficits, together referred to as the "onco-functional balance." However, despite the common utilization of invasive techniques such as cortical mapping to identify eloquent tissue responsible for language and motor functions, glioma patients continue to present post-operatively with poor cognitive morbidity in higher-order functions. Such observations are likely related to the difficulty in interpreting the highly-dimensional information these technologies present to us regarding cognition in addition to our classically poor understanding of the functional and structural neuroanatomy underlying complex higher-order cognitive functions. Furthermore, reduction of the brain into isolated cortical regions without consideration of the complex, interacting brain networks which these regions function within to subserve higher-order cognition inherently prevents our successful navigation of true eloquent and non-eloquent cerebrum. Fortunately, recent large-scale movements in the neuroscience community, such as the Human Connectome Project (HCP), have provided updated neural data detailing the many intricate macroscopic connections between cortical regions which integrate and process the information underlying complex human behavior within a brain "connectome." Connectomic data can provide us better maps on how to understand convoluted cortical and subcortical relationships between tumor and human cerebrum such that neurosurgeons can begin to make more informed decisions during surgery to maximize the onco-functional balance. However, connectome-based neurosurgery and related applications for neurorehabilitation are relatively nascent and require further work moving forward to optimize our ability to add highly valuable connectomic data to our surgical armamentarium. In this manuscript, we review four concepts with detailed examples which will help us better understand post-operative cognitive outcomes and provide a guide for how to utilize connectomics to reduce cognitive morbidity following cerebral surgery.

The Frontal Aslant Tract and Supplementary Motor Area Syndrome: Moving towards a Connectomic Initiation Axis

Abstract: Connectomics is the use of big data to map the brain's neural infrastructure; employing such technology to improve surgical planning may improve neuro-oncological outcomes. Supplementary motor area (SMA) syndrome is a well-known complication of medial frontal lobe surgery. The 'localizationist' view posits that damage to the posteromedial bank of the superior frontal gyrus (SFG) is the basis of SMA syndrome. However, surgical experience within the frontal lobe suggests that this is not entirely true. In a study on n = 45 patients undergoing frontal lobe glioma surgery, we sought to determine if a 'connectomic' or network-based approach can decrease the likelihood of SMA syndrome. The control group (n = 23) underwent surgery avoiding the posterior bank of the SFG while the treatment group (n = 22) underwent mapping of the SMA network and Frontal Aslant Tract (FAT) using network analysis and DTI tractography. Patient outcomes were assessed post operatively and in subsequent follow-ups. Fewer patients (8.3%) in the treatment group experienced transient SMA syndrome compared to the control group (47%) (p = 0.003). There was no statistically significant difference found between the occurrence of permanent SMA syndrome between control and treatment groups. We demonstrate how utilizing tractography and a network-based approach decreases the likelihood of transient SMA syndrome during medial frontal glioma surgery. We found that not transecting the FAT and the SMA system improved outcomes which may be important for functional outcomes and patient quality of life.

A Phase 2 Randomised Clinical Trial Assessing the Tolerability of Two Different Ratios of Medicinal Cannabis in Patients With High Grade Gliomas

Abstract: Background Cannabis for cancer is very topical and, given the use of illicit cannabis preparations used in this vulnerable population, research investigating standardised, quality-assured medicinal cannabis is critical to inform clinicians and assist patient safety. Methods A randomized trial involving adult patients diagnosed with a high-grade glioma, no history of substance abuse, liver or kidney damage or myocardial infarction were eligible for inclusion in a tolerability study on two different ratios of medicinal cannabis. Baseline screening of brain morphology, blood pathology, functional status, and cognition was conducted. A retrospective control group was used for comparison for secondary outcomes. Results Participants (n=88) were on average 53.3 years old. A paired t-test assessed the Functional Assessment of Cancer Therapy for Brain Cancer (FACT-Br) between groups from baseline to week 12 found that the 1:1 ratio favoured both physical (p=0.025) and functional (p=0.014) capacity and improved sleep (p=0.009). Analysis of changes from baseline to week 12 also found 11% of 61 participants had a reduction in disease, 34% were stable, 16% had slight enhancement, and 10% had progressive disease. No serious adverse events occurred. Side effects included dry mouth, tiredness at night, dizziness, drowsiness. Conclusion This study demonstrated that a single nightly dose of THC-containing medicinal cannabis was safe, had no serious adverse effects and was well tolerated in patients. Medicinal cannabis significantly improved sleep, functional wellbeing and quality of life. Trial registration The trial is registered on the Australian New Zealand Clinical Trials Registry (ANZCTR), registration number ACTRN12617001287325. http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=373556&isReview=true

Anatomy and white-matter connections of the precuneus

Abstract: Purpose Advances in neuroimaging have provided an understanding of the precuneus’(PCu) involvement in functions such as visuospatial processing and cognition. While the PCu has been previously determined to be apart of a higher-order default mode network (DMN), recent studies suggest the presence of possible dissociations from this model in order to explain the diverse functions the PCu facilitates, such as in episodic memory. An improved structural model of the white-matter anatomy of the PCu can demonstrate its unique cerebral connections with adjacent regions which can provide additional clarity on its role in integrating information across higher-order cerebral networks like the DMN. Furthermore, this information can provide clinically actionable anatomic information that can support clinical decision making to improve neurologic outcomes such as during cerebral surgery. Here, we sought to derive the relationship between the precuneus and underlying major white-mater bundles by characterizing its macroscopic connectivity. Methods Structural tractography was performed on twenty healthy adult controls from the Human Connectome Project (HCP) utilizing previously demonstrated methodology. All precuneus connections were mapped in both cerebral hemispheres and inter-hemispheric differences in resultant tract volumes were compared with an unpaired, corrected Mann–Whitney U test and a laterality index (LI) was completed. Ten postmortem dissections were then performed to serve as ground truth by using a modified Klingler technique with careful preservation of relevant white matter bundles. Results The precuneus is a heterogenous cortical region with five major types of connections that were present bilaterally. (1) Short association fibers connect the gyri of the precuneus and connect the precuneus to the superior parietal lobule and the occipital cortex. (2) Four distinct parts of the cingulum bundle connect the precuneus to the frontal lobe and the temporal lobe. (3) The middle longitudinal fasciculus from the precuneus connects to the superior temporal gyrus and the dorsolateral temporal pole. (4) Parietopontine fibers travel as part of the corticopontine fibers to connect the precuneus to pontine regions. (5) An extensive commissural bundle connects the precuneus bilaterally. Conclusion We present a summary of the anatomic connections of the precuneus as part of an effort to understand the function of the precuneus and highlight key white-matter pathways to inform surgical decision-making. Our findings support recent models suggesting unique fiber connections integrating at the precuneus which may suggest finer subsystems of the DMN or unique networks, but further study is necessary to refine our model in greater quantitative detail.

Connectivity-based parcellation of normal and anatomically distorted human cerebral cortex.

Abstract: For over a century, neuroscientists have been working toward parcellating the human cortex into distinct neurobiological regions. Modern technologies offer many parcellation methods for healthy cortices acquired through magnetic resonance imaging. However, these methods are suboptimal for personalized neurosurgical application given that pathology and resection distort the cerebrum. We sought to overcome this problem by developing a novel connectivity-based parcellation approach that can be applied at the single-subject level. Utilizing normative diffusion data, we first developed a machine-learning (ML) classifier to learn the typical structural connectivity patterns of healthy subjects. Specifically, the Glasser HCP atlas was utilized as a prior to calculate the streamline connectivity between each voxel and each parcel of the atlas. Using the resultant feature vector, we determined the parcel identity of each voxel in neurosurgical patients (n = 40) and thereby iteratively adjusted the prior. This approach enabled us to create patient-specific maps independent of brain shape and pathological distortion. The supervised ML classifier re-parcellated an average of 2.65% of cortical voxels across a healthy dataset (n = 178) and an average of 5.5% in neurosurgical patients. Our patient dataset consisted of subjects with supratentorial infiltrating gliomas operated on by the senior author who then assessed the validity and practical utility of the re-parcellated diffusion data. We demonstrate a rapid and effective ML parcellation approach to parcellation of the human cortex during anatomical distortion. Our approach overcomes limitations of indiscriminately applying atlas-based registration from healthy subjects by employing a voxel-wise connectivity approach based on individual data.

Parcellation-based anatomic model of the semantic network.

Abstract: Introduction The semantic network is an important mediator of language, enabling both speech production and the comprehension of multimodal stimuli. A major challenge in the field of neurosurgery is preventing semantic deficits. Multiple cortical areas have been linked to semantic processing, though knowledge of network connectivity has lacked anatomic specificity. Using attentional task-based fMRI studies, we built a neuroanatomical model of this network. Methods One hundred and fifty-five task-based fMRI studies related to categorization of visual words and objects, and auditory words and stories were used to generate an activation likelihood estimation (ALE). Cortical parcellations overlapping the ALE were used to construct a preliminary model of the semantic network based on the cortical parcellation scheme previously published under the Human Connectome Project. Deterministic fiber tractography was performed on 25 randomly chosen subjects from the Human Connectome Project, to determine the connectivity of the cortical parcellations comprising the network. Results The ALE analysis demonstrated fourteen left hemisphere cortical regions to be a part of the semantic network: 44, 45, 55b, IFJa, 8C, p32pr, SFL, SCEF, 8BM, STSdp, STSvp, TE1p, PHT, and PBelt. These regions showed consistent interconnections between parcellations. Notably, the anterior temporal pole, a region often implicated in semantic function, was absent from our model. Conclusions We describe a preliminary cortical model for the underlying structural connectivity of the semantic network. Future studies will further characterize the neurotractographic details of the semantic network in the context of medical application.

Parcellation-based anatomic modeling of the default mode network.

Abstract: Background The default mode network (DMN) is an important mediator of passive states of mind. Multiple cortical areas, such as the anterior cingulate cortex, posterior cingulate cortex, and lateral parietal lobe, have been linked in this processing, though knowledge of network connectivity had limited tractographic specificity. Methods Using resting-state fMRI studies related to the DMN, we generated an activation likelihood estimation (ALE). We built a tractographical model of this network based on the cortical parcellation scheme previously published under the Human Connectome Project. DSI-based fiber tractography was performed to determine the structural connections between cortical parcellations comprising the network. Results Seventeen cortical regions were found to be part of the DMN: 10r, 31a, 31pd, 31pv, a24, d23ab, IP1, p32, POS1, POS2, RSC, PFm, PGi, PGs, s32, TPOJ3, and v23ab. These regions showed consistent interconnections between adjacent parcellations, and the cingulum was found to connect the anterior and posterior cingulate clusters within the network. Conclusions We present a preliminary anatomic model of the default mode network. Further studies may refine this model with the ultimate goal of clinical application.

Unexpected hubness: a proof-of-concept study of the human connectome using pagerank centrality and implications for intracerebral neurosurgery

Abstract: Understanding the human connectome by parcellations allows neurosurgeons to foretell the potential effects of lesioning parts of the brain during intracerebral surgery. However, it is unclear whether there exist variations among individuals such that brain regions that are thought to be dispensable may serve as important networking hubs. We obtained diffusion neuroimaging data from two healthy cohorts (OpenNeuro and SchizConnect) and applied a parcellation scheme to them. We ranked the parcellations on average using PageRank centrality in each cohort. Using the OpenNeuro cohort, we focused on parcellations in the lower 50% ranking that displayed top quartile ranking at the individual level. We then queried whether these select parcellations with over 3% prevalence would be reproducible in the same manner in the SchizConnect cohort. In the OpenNeuro (n = 68) and SchizConnect cohort (n = 195), there were 27.9% and 43.1% of parcellations, respectively, in the lower half of all ranks that displayed top quartile ranks. We noted three outstanding parcellations (L_V6, L_a10p, and L_7PL) in the OpenNeuro cohort that also appeared in the SchizConnect cohort. In the larger Schizconnect cohort, L_V6, L_a10p, and L_7PL had unexpected hubness in 3.08%, 5.13%, and 8.21% of subjects, respectively. We demonstrated that lowly-ranked parcellations may serve as important hubs in a subset of individuals, highlighting the importance of studying parcellation ranks at the personalized level in planning supratentorial neurosurgery.

The cortical organization of language: distilling human connectome insights for supratentorial neurosurgery.

Abstract: Connectomics is the production and study of detailed "connection" maps within the nervous system. With unprecedented advances in imaging and high-performance computing, the construction of individualized connectomes for routine neurosurgical use is on the horizon. Multiple projects, including the Human Connectome Project (HCP), have unraveled new and exciting data describing the functional and structural connectivity of the brain. However, the abstraction from much of these data to clinical relevance remains elusive. In the context of preserving neurological function after supratentorial surgery, abstracting surgically salient points from the vast computational data in connectomics is of paramount importance. Herein, the authors discuss four interesting observations from the HCP data that have surgical relevance, with an emphasis on the cortical organization of language: 1) the existence of a motor speech area outside of Broca's area, 2) the eloquence of the frontal aslant tract, 3) the explanation of the medial frontal cognitive control networks, and 4) the establishment of the second ventral stream of language processing. From these connectome observations, the authors discuss the anatomical basis of their insights as well as relevant clinical applications. Together, these observations provide a firm platform for neurosurgeons to advance their knowledge of the cortical networks involved in language and to ultimately improve surgical outcomes. It is hoped that this report encourages neurosurgeons to explore new vistas in connectome-based neurosurgery.

The Unique Fiber Anatomy of Middle Temporal Gyrus Default Mode Connectivity

Abstract: Background The middle temporal gyrus (MTG) is understood to play a role in language-related tasks such as lexical comprehension and semantic cognition. However, a more specific understanding of its key white matter connections could promote the preservation of these functions during neurosurgery. Objective To provide a detailed description of the underlying white matter tracts associated with the MTG to improve semantic preservation during neurosurgery. Methods Tractography was performed using diffusion imaging obtained from 10 healthy adults from the Human Connectome Project. All tracts were mapped between cerebral hemispheres with a subsequent laterality index calculated based on resultant tract volumes. Ten postmortem dissections were performed for ex vivo validation of the tractography based on qualitative visual agreement. Results We identified 2 major white matter bundles leaving the MTG: the inferior longitudinal fasciculus and superior longitudinal fasciculus. In addition to long association fibers, a unique linear sequence of U-shaped fibers was identified, possibly representing a form of visual semantic transfer down the temporal lobe. Conclusion We elucidate the underlying fiber-bundle anatomy of the MTG, an area highly involved in the brain's language network. Improved understanding of the unique, underlying white matter connections in and around this area may augment our overall understanding of language processing as well as the involvement of higher order cerebral networks like the default mode network in these functions.

International expert consensus statement about methods and indications for keyhole microneurosurgery from International Society on Minimally Invasive Neurosurgery

Abstract: Microneurosurgery made its debut in the early 1960s. It became popular quickly in the medical field and soon became a primary method in neurosurgery, as it improved the efficacy of neurosurgery, reducing surgically related injuries. Over the past five decades, the accumulation of microsurgery experience, improvements in microsurgical techniques, refinement of microinstruments, and advanced preoperative diagnostic imaging have enabled the evolution of microneurosurgical techniques and the further reduction of surgery-related trauma. These advancements have made it possible for neurosurgeons to treat more complicated lesions via smaller craniotomies [35, 60]. Keyhole neurosurgery, a combination of modern microsurgical techniques, preoperative imaging, neuroendoscopy, and the modern concept of minimally invasive surgery, is a technique representing the medical advances from microneurosurgery to minimally invasive neurosurgery [19, 63, 88]. Keyhole neurosurgery is a new, minimally invasive concept of microsurgery based on tailored, targeted, and direct microneurosurgical techniques [26, 70]. With specific anatomic and pathological structures and utilizing the “keyhole effect”, this method is designed precisely as an individualized approach to minimize the anatomic window and expose the lesions adequately, thus reduces unnecessary exploration of the surgical site and brain retraction. The “keyhole” concept involves not only smaller exposures, but also fewer surgery-related complications, the main and more important goal [62]. Pre-calculation of the size of the incision, bone window, and location of the craniotomy is based on the need for only a small dura opening with less brain exposure and retraction and is done in accordance with the principle of “maximal surgical efficiency while minimizing approach-related injury [10,19,30,64].” In general, a 4-cm incision and a cranial bone window of about 2.5 cm in diameter are applied wieldy in the keyhole surgery for deep lesions [74, 79, 87]. Keyhole microsurgery optimizes the cosmetic outcomes. This fact, along with the reduction in surgery-related complications, which improves patient’s acceptance of the surgery. In addition, surgeons can spend more time and focus on treating the lesions, thus achieving maximal surgical effects, shortening hospitalization times, and reducing treatment costs [49, 61, 88]. It has become clear to many of us that despite a growing literature supporting the use of selected keyhole approaches for certain intracranial pathologies, the literature lacks on well-established and standardized practices in this field. Given the importance of developing a collection of standard practices and acceptable indications for these relatively new approaches, we felt that an expert description was timely and important for both guidance about best practices, medicolegal protection, and for defining terms so the literature could be more clearly elaborated in the future. To this end, the International Society on Minimally Invasive Neurosurgery (ISMIN) assembled organized experts in keyhole and minimally invasive surgery in Suzhou, China, in November 2018 from all over the world to compile a summary of the literature and expert opinions and guidance into a single statement. That is intended to improve neurosurgeons’ knowledge of keyhole microsurgical technology, to standardize the operative procedures, and to promote the development of minimally invasive neurosurgery all over the world.

A Cortical Parcellation Based Analysis of Ventral Premotor Area Connectivity.

Abstract: Introduction. The ventral premotor area (VPM) plays a crucial role in executing various aspects of motor control. These include hand reaching, joint coordination, and direction of movement in space. While many studies discuss the VPM and its relationship to the rest of the motor network, there is minimal literature examining the connectivity of the VPM outside of the motor network. Using region-based fMRI studies, we built a neuroanatomical model to account for these extra-motor connections.Methods. Thirty region-based fMRI studies were used to generate an activation likelihood estimation (ALE) using BrainMap software. Cortical parcellations overlapping the ALE were used to construct a preliminary model of the VPM connections outside the motor network. Diffusion spectrum imaging (DSI)-based fiber tractography was performed to determine the connectivity between cortical parcellations in both hemispheres, and a laterality index (LI) was calculated with resultant tract volumes. The resulting connections were described using the cortical parcellation scheme developed by the Human Connectome Project (HCP).Results. Four cortical regions were found to comprise the VPM. These four regions included 6v, 4, 3b, and 3a. Across mapped brains, these areas showed consistent interconnections between each other. Additionally, ipsilateral connections to the primary motor cortex, supplementary motor area, and dorsal premotor cortex were demonstrated. Inter-hemispheric asymmetries were identified, especially with areas 1, 55b, and MI connecting to the ipsilateral VPM regions.Conclusion. We describe a preliminary cortical model for the underlying connectivity of the ventral premotor area. Future studies should further characterize the neuroanatomic underpinnings of this network for neurosurgical applications.

Surgical management of anterior clinoidal meningiomas: consensus statement on behalf of the EANS skull base section

Abstract: The optimal management of clinoidal meningiomas (CMs) continues to be debated. We constituted a task force comprising the members of the EANS skull base committee along with international experts to derive recommendations for the management of these tumors. The data from the literature along with contemporary practice patterns were discussed within the task force to generate consensual recommendations. This article represents the consensus opinion of the task force regarding pre-operative evaluations, patient’s counselling, surgical classification, and optimal surgical strategy. Although this analysis yielded only Class B evidence and expert opinions, it should guide practitioners in the management of patients with clinoidal meningiomas and might form the basis for future clinical trials.

Anatomy and White Matter Connections of the Superior Parietal Lobule.

Abstract: Background The superior parietal lobule (SPL) is involved in somatosensory and visuospatial integration with additional roles in attention, written language, and working memory. A detailed understanding of the exact location and nature of associated white matter tracts could improve surgical decisions and subsequent postoperative morbidity related to surgery in and around this gyrus. Objective To characterize the fiber tracts of the SPL based on relationships to other well-known neuroanatomic structures through diffusion spectrum imaging (DSI)-based fiber tracking validated by gross anatomical dissection as ground truth. Methods Neuroimaging data of 10 healthy, adult control subjects was obtained from a publicly accessible database published in Human Connectome Project for subsequent tractographic analyses. White matter tracts were mapped between both cerebral hemispheres, and a lateralization index was calculated based on resultant tract volumes. Post-mortem dissections of 10 cadavers identified the location of major tracts and validated our tractography results based on qualitative visual agreement. Results We identified 9 major connections of the SPL: U-fiber, superior longitudinal fasciculus, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, middle longitudinal fasciculus, extreme capsule, vertical occipital fasciculus, cingulum, and corpus callosum. There was no significant fiber lateralization detected. Conclusion The SPL is an important region implicated in a variety of tasks involving visuomotor and visuospatial integration. Improved understanding of the fiber bundle anatomy elucidated in this study can provide invaluable information for surgical treatment decisions related to this region.

Hollow-tree super: A directional and scalable approach for feature importance in boosted tree models.

Abstract: Purpose Current limitations in methodologies used throughout machine-learning to investigate feature importance in boosted tree modelling prevent the effective scaling to datasets with a large number of features, particularly when one is investigating both the magnitude and directionality of various features on the classification into a positive or negative class. This manuscript presents a novel methodology, "Hollow-tree Super" (HOTS), designed to resolve and visualize feature importance in boosted tree models involving a large number of features. Further, this methodology allows for accurate investigation of the directionality and magnitude various features have on classification and incorporates cross-validation to improve the accuracy and validity of the determined features of importance. Methods Using the Iris dataset, we first highlight the characteristics of HOTS by comparing it to other commonly used techniques for feature importance, including Gini Importance, Partial Dependence Plots, and Permutation Importance, and explain how HOTS resolves the weaknesses present in these three strategies for investigating feature importance. We then demonstrate how HOTS can be utilized in high dimensional spaces such as neuroscientific setting, by taking 60 Schizophrenic subjects from the publicly available SchizConnect database and applying the method to determine which regions of the brain were most important for the positive and negative classification of schizophrenia as determined by the positive and negative syndrome scale (PANSS). Results HOTS effectively replicated and supported the findings of feature importance for classification of the Iris dataset when compared to Gini importance, Partial Dependence Plots and Permutation importance, determining 'petal length' as the most important feature for positive and negative classification. When applied to the Schizconnect dataset, HOTS was able to resolve from 379 independent features, the top 10 most important features for classification, as well as their directionality for classification and magnitude compared to other features. Cross-validation supported that these same 10 features were consistently used in the decision-making process across multiple trees, and these features were localised primarily to the occipital and parietal cortices, commonly disturbed brain regions in those afflicted with Schizophrenia. Conclusion HOTS effectively overcomes previous challenges of identifying feature importance at scale, and can be utilized across a swathe of disciplines. As computational power and data quantity continues to expand, it is imperative that a methodology is developed that is able to handle the demands of working with large datasets that contain a large number of features. This approach represents a unique way to investigate both the directionality and magnitude of feature importance when working at scale within a boosted tree model that can be easily visualized within commonly used software.

Akinetic mutism reversed by inferior parietal lobule repetitive theta burst stimulation: Can we restore default mode network function for therapeutic benefit?

Abstract: Background Transcranial magnetic stimulation is a noninvasive treatment used to modulate cortical excitability. Its use over the last two decades has expanded, ranging from psychiatric disorders to traumatic brain injury and poststroke rehabilitation. Objectives We present the case of a 59-year-old male patient who presented in a decreased state of consciousness due to a right frontal glioblastoma, wherein his state was not improved by a successful surgery and could not be explained by any other condition. Due to his poor prognosis, we examine the benefits of receiving transcranial magnetic stimulation treatment to improve his akinetic mutism. Methods We utilized independent component analysis with resting-state functional magnetic resonance imaging (rsfMRI) to better understand his cortical functionality. The imaging suggested absence of the default mode network (DMN). The patient underwent five sessions of navigated intermittent theta burst stimulation to the ipsilesional inferior parietal lobule and inferior frontal gyrus, with the aim of improving his default mode network functionality. Results No other treatments resulted in an improvement of this patient's condition; however, 3 weeks following transcranial magnetic stimulation treatment, the patient was more alert and interactive, and his follow-up rsfMRI scan demonstrated a partially intact default mode network. Conclusion This case raises important questions regarding the clinical utility of transcranial magnetic stimulation to improve the connectivity of important cerebral networks and subsequent related functional recovery.

Changes in the Brain Connectome Following Repetitive Transcranial Magnetic Stimulation for Stroke Rehabilitation.

Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a promising approach for post-stroke rehabilitation but there lacks a rationale strategy to plan, execute, and monitor treatment. We present a case of targeted rTMS using the Omniscient Infinitome software to devise targets for treatment in a post-stroke patient and describe the functional connectomic changes after treatment. A 19-year-old female with no medical history presented 19 months after suffering a left middle cerebral artery (MCA) superior division ischemic stroke, resulting in language impairment and diminished right upper extremity motor function. She underwent a resting-state MRI (rsMRI) with tractography and images were processed using the Omniscient Infinitome software. Analysis using the anomaly detection within the software enabled us to identify three targets for rTMS (left area 1, left area 45, and right area SFL). These areas were treated with 25 sessions of intermittent Theta Burst Stimulation (iTBS) over five days at 80% of motor threshold concomitantly with targeted physical therapy and speech therapy. At five months follow-up, her language and right upper extremity functions significantly improved. Her connectomic analysis revealed substantial neural changes, including normalization of the sensorimotor network, substantially thicker callosal fiber bundle connecting the two hemispheres, and increased cortical recruitment in her language network. We present the first description of robust connectomic alterations in a post-stroke patient following targeted rTMS treatment. Further studies on the use of rTMS with an emphasis on functional connectomics are warranted.

PODNL1 Methylation Serves as a Prognostic Biomarker and Associates with Immune Cell Infiltration and Immune Checkpoint Blockade Response in Lower-Grade Glioma

Abstract: Lower-grade glioma (LGG) is a diffuse infiltrative tumor of the central nervous system, which lacks targeted therapy. We investigated the role of Podocan-like 1 (PODNL1) methylation in LGG clinical outcomes using the TCGA-LGG transcriptomics dataset. We identified four PODNL1 CpG sites, cg07425555, cg26969888, cg18547299, and cg24354933, which were associated with unfavorable overall survival (OS) and disease-free survival (DFS) in univariate and multivariate analysis after adjusting for age, gender, tumor-grade, and IDH1-mutation. In multivariate analysis, the OS and DFS hazard ratios ranged from 0.44 to 0.58 (p < 0.001) and 0.62 to 0.72 (p < 0.001), respectively, for the four PODNL1 CpGs. Enrichment analysis of differential gene and protein expression and analysis of 24 infiltrating immune cell types showed significantly increased infiltration in LGGs and its histological subtypes with low-methylation levels of the PODNL1 CpGs. High PODNL1 expression and low-methylation subgroups of the PODNL1 CpG sites were associated with significantly increased PD-L1, PD-1, and CTLA4 expressions. PODNL1 methylation may thus be a potential indicator of immune checkpoint blockade response, and serve as a biomarker for determining prognosis and immune subtypes in LGG.

Aggressive Progression of a WHO Grade I Meningioma of the Posterior Clinoid Process: An Illustration of the Risks Associated With Observation of Skull Base Meningiomas.

Abstract: Benign, small, and asymptomatic World Health Organization grade I meningiomas are usually managed expectantly with surveillance imaging with the assumption that they are predictably slowing growing. In this paper, we report the case of an incidentally discovered small, right-sided posterior clinoid meningioma in a 53-year-old female. The tumor was managed conservatively but an annual surveillance magnetic resonance imaging demonstrated that the meningioma had an unexpected significant growth impinging on the brainstem, requiring surgical resection and radiosurgery for residual tumor. Despite histopathological confirmation of a grade I meningioma, the tumor recurred significantly and incurred substantial neurological deficits, requiring further surgery and radiotherapy. This report illustrates the potential pitfall for expectant management of small meningiomas in anatomically precarious locations and draws attention to the need for detailed informed discussions with patients regarding the management of these tumors.