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

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

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

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

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

Funder: Alan Turing Institute; doi: http://dx.doi.org/10.13039/100012338Funder: Guarantors of Brain; doi: http://dx.doi.org/10.13039/501100000627The 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

The neurosurgical treatment of spasmodic dysphonia : thinking outside the voice box

Spasmodic Dysphonia (SD) is a neurological speech disorder characterized by sudden and involuntary contractions in the laryngeal musculature during speech production. In adductor SD (80-90% of cases), the vocal cords slam together and stiffen making it difficult to produce speech. As a result, an individual’s quality of life is impacted due to significant social embarrassment and the inability to work. Since the 1980s, the standard of care for SD has been to inject botulinum toxin A (BTX) into the affected laryngeal muscles thereby diminishing the spasms. Unfortunately, this therapy is limited by the delayed-onset of benefits, wearing-off effects, and repeated injections required every 3 months. To make a quantum leap in treating SD and providing patients with long-term therapy, the central neurological problem needs to be addressed and not the resultant peripheral spasms. Deep Brain Stimulation (DBS) is a neurosurgical therapy that repairs malfunctioning neural circuits giving rise to pathological behavior; DBS is the standard of care for movement disorders such as Parkinson’s disease and essential tremor (ET). In this thesis, we set out to investigate 1) which motor thalamic neural circuit required neuromodulation for SD, 2) if thalamic laryngeal control was lateralized, and for the first time, 3) if chronic subcortical electrical stimulation can provide long-term relief in SD. First, we systematically interrogated the pallidal and cerebellar inputs into the thalamus of an ET patient with coincident SD. Next, we studied n=6 with ET and coincident voice tremor to assessed if left, right, or both thalamic electrodes were crucial for vocal fold control. Finally, we launched a Phase 1 trial (DEBUSSY) on unilateral thalamic DBS for SD. Overall, we determined that unilateral left thalamic Vim DBS can safely and instantaneously abort laryngeal spasms in n=4 SD. There were no serious complications or adverse events to report. If voltage increased above the therapeutic range, dysarthria and contralateral dysmetria was induced but resolved with stimulation adjustment. Finally, the dentato-rubro-thalamic tract appears to be preferentially affected during DBS treatment for SD. Future work will characterize the long-term benefit of DBS in SD and further elucidate the mechanism by which DBS mediates improvement.Medicine, Faculty ofExperimental Medicine, Division ofMedicine, Department ofGraduat

Elucidating the Principles of Brain Network Organisation through Neurosurgery

Recently, leaders in human brain mapping and the clinical neurosciences outlined the need for prospective trials in neurosurgery to establish the clinical relevance of connectomics. This doctoral dissertation addresses this challenge by using diffuse gliomas as a model to study the principles of brain network organisation through neurosurgery. Specifically, I combined insight from a normative cohort of healthy individuals across the lifespan with a highly rare neurosurgical cohort of diffuse glioma patients who underwent longitudinal connectomic and cognitive testing throughout their clinical care. By understanding how gliomas infiltrate eloquent cortex with little to no cognitive deficits, we may be able to better understand the brain and cancer and ultimately devise new treatment approaches. Overall, the twin scientific and clinical aims were to i) understand how gliomas embed themselves within circuits governing higher-order cognition and ii) determine the utility of connectomics in mapping higher-order cognitive functions for presurgical planning and postsurgical rehabilitation. In the first set of investigations, I deployed structural connectomics to demonstrate that the structural integrity of the Multiple Demand (MD) system for domain-general cognition uniquely predicts interindividual differences in executive functioning across the lifespan. I then demonstrated that diffuse gliomas primarily co-localise to the MD system’s core frontoparietal network, with connectomic, transcriptomic, and neurochemical analyses revealing that connector hubs, oligodendrocyte precursor cells (OPCs), and proto-oncogenes are uniquely enriched in the MD system making it vulnerable to oncogenesis. When investigating the cognitive impact of gliomas infiltrating the MD system, the data reveals long-term cognitive improvements, indicating the brain underwent structural changes to accommodate the tumour and consequently minimize its impact. Presurgical structural analyses of glioma patients’ brains revealed decreases in cortical thickness in the MD system and homotopic areas compared to age- and sex-matched controls. Remarking, normative modelling revealed that the presence of gliomas induced cortical thinning and accelerated ‘brain ageing’, which was partially normalised following surgery and more consistent with healthy adults. In the second set of investigations, I complemented the structural investigation with functional connectomics to demonstrate that gliomas strategically embed themselves within hierarchical gradients and that long-term cognitive deficits result from increased cortical gradient dispersion. Given that meningiomas exert their deleterious effects by compressing brain tissue whereas gliomas infiltrate the tissue, contrasting both patient groups with healthy controls, gliomas decreased global gradient dispersion whereas meningiomas did not. More regionally, to assess mesoscale cortical dynamics, resecting more presurgical connector hubs leads to long-term cognitive deficits whereas resecting provincial hubs did not cause long-term deficits. In addition, changes in perioperative modularity differentiated patients with long-term cognitive deficits from those with long-term improvements. Finally, in the last section of this dissertation, I deployed interventional connectomics to demonstrate how non-invasive brain stimulation is safe and can be utilised in the perioperative setting to promote functional recovery and potentially accelerate long-term cognitive outcomes. Specifically, transcranial magnetic stimulation can be safely applied without causing seizures to improve deficits in motor or language function. In summary, this dissertation presents new evidence on how gliomas embed themselves within the connectome and the clinical utility of connectomics for neurosurgery. Based on connectomic data, the stage is set for future studies to carry this work forward with prospective randomized clinical trials (RCTs) on modulating the presurgical connectome and/or accelerating postsurgical cognitive rehabilitation. Finally, I conclude with providing future directions on how systems neuroscience and functional neurosurgery can be strategically combined to advance the emerging field of cancer neuroscience.The Alan Turing Institute (the Turing). Natural Sciences and Engineering Research Council of Canada (NSERC)

Epi-Cease : A Non-Invasive Closed-Loop Transcranial Direct Current Stimulation (tDCS)-based Device for Antiepileptic Drug Resistant Epilepsy

Epilepsy is a chronic neurological disorder characterized by recurrent and unprovoked seizures due to abnormal electrical activity in the brain. Unfortunately, this disorder affects 50 million people worldwide and of all ages, making it the fourth most common neurological disorder. As a result, epilepsy reduces an individual’s quality of life and provides a challenge for family members and caregivers. Over the last few decades, many advances have been made in effectively treating and controlling epilepsy. Today, a focused history, physical examination, blood work, and video-EEG are all part of the standard protocol in the accurate and timely diagnosis of epilepsy. Once the epileptic etiology is identified, anti-epileptic drugs (AED) represent a first-line pharmacological treatment for these patients. Unfortunately, a portion of patients do not respond to multiple AEDs and may display dose-dependent side effects that warrant AED discontinuation. These patients are considered for neurosurgical intervention after case and extensive review. Many centres, including Vancouver General Hospital, employ temporal lobectomy for focal temporal lobe epilepsies. This procedure is quite effective for a small portion of patients but is highly invasive and can lead to complications in verbal memory in 0.4-4% of patients. More importantly, brain surgery is not for all patients and can only be applied to patients suffering from temporal lobe seizures. The goal of this proposal is to “non-invasively reduce the frequency, duration and/or severity of seizures in drug-resistant focal epilepsy patients”. Particularly, we set out to circumvent the highly invasive nature of brain surgery and its limited widespread use. Moreover, we wished to develop a technology that would non-invasively “abort” seizures in real-time. Our proposed solution, Epi-Cease, is a non-invasive closed-looped system that consists of a wearable head-strap tDCS (transcranial direct-current stimulation) that delivers non-invasive stimulation to abort a seizure. This device will communicate with an Apple Watch that will detect seizures based on motion sensing and physiological data. When detecting the onset of a seizure, the Apple Watch app will signal the tDCS module to deliver stimulation to the brain in real-time in order to suppress/abort seizure initiation.To assess the safety and efficacy of Epi-Cease, we will conduct a two-staged proof-of-concept study. First, we will validate the Apple Watch motion-sensing and physiological data app compared to traditional methods of epilepsy monitoring. Once validated, we will then recruit a small cohort (n=3) of low-risk epilepsy patients to test the technology before expansion. This technology would represent a quantum leap forward in the care of epilepsy patients as it would be the first, real-time non-invasive solution to abort seizures and effectively control focal epilepsies. Course name: Applied PathophysiologyApplied Science, Faculty ofUnreviewedGraduat

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

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

Practical Application of Networks in Neurosurgery: Combined 3-Dimensional Printing, Neuronavigation, and Preoperative Surgical Planning

BACKGROUND: A plethora of cutting-edge neuroimaging analyses have been developed and published, yet they have not hitherto been realized as improvements in neurosurgical outcomes. In this paper we propose a novel interface be- tween neuroimaging and neurosurgery for aiding translational research. Our objective is to create a method for applying advanced neuroimaging and network analysis findings to neurosurgery and illustrate its application through the presentation of 2 detailed case vignettes. METHODS: This interface comprises a combination of network visualization, 3-dimensional printing, and ex-vivo neuronavigation to enable preoperative planning according to functional neuroanatomy. Clinical cases were selected from a prospective cohort study. RESULTS: The first case vignette describes a low-grade glioma with potential language and executive function network involvement that underwent a successful complete resection of the lesion with preservation of network features. The second case describes a low-grade glioma in an apparently noneloquent location that underwent a subtotal resection but demonstrated unexpected and significant impairment in executive function postoperatively that subsequently abated during follow-up. In both examples the neuroimaging and network data highlight the complexity of the surrounding functional neuroanatomy at the individual level, beyond that which can be perceived on standard structural sequences. CONCLUSIONS: The described interface has widespread applications for translational research including preoperative planning, neurosurgical training, and detailed patient counseling. A protocol for assessing its effectiveness and safety is proposed. Finally, recommendations for effective translation of findings from neuroimaging to neurosurgery are discussed, with the aim of making clinically meaningful improvements to neurosurgical practice.Alan Turing Institute Doctoral ScholarshipBrain Post-Doctoral Fellowship awardBrain Tumour Charity RG86218MRC MC_UU_00005/6National Institute for Health Research (NIHR) (UK)Clinician Scientist Award NIHR/CS/009/011Royal Society Dorothy Hodgkin Research Fellowshi