Personalized, parcel-guided non-invasive transcranial magnetic stimulation for the treatment of post-concussive syndrome: safety and proof of concept.

OBJECTIVE: To determine the safety and proof of concept of a parcel-guided, repetitive Transcranial Magnetic Stimulation (rTMS) in patients who develop a heterogeneous array of symptoms, known collectively as post-concussive syndrome (PCS), following traumatic brain injury (TBI). METHODS: We performed a retrospective review of off-label, individualized, parcel-guided rTMS in 19 patients from December 2020 to May 2023. Patients had at least one instance of mild, moderate, or severe TBI and developed symptoms not present prior to injury. rTMS targets were identified based on machine learning connectomic software using functional connectivity anomaly matrices compared to healthy controls. EuroQol (EQ-5D), as a measurement of quality of life, and additional questionnaires dependent on individual's symptoms were submitted prior to, after, and during follow-up from rTMS. RESULTS: Nineteen patients showed improvement in EQ-5D and Rivermead Post Concussion Symptoms Questionnaires - 3 after treatment and follow-up. For nine patients who developed depression, five (55%) attained response and remission based on the Beck Depression Inventory after treatment. Eight of ten patients with anxiety had a clinically significant reduction in Generalized Anxiety Disorder-7 scores during follow-up. CONCLUSION: Parcel-guided rTMS is safe and may be effective in reducing PCS symptoms following TBI and should incite further controlled studies.

Improving quality of life post-tumor craniotomy using personalized, parcel-guided TMS: safety and proof of concept.

PURPOSE: Deficits in neuro-cognitive function are not uncommon for patients who have undergone surgical removal of brain tumors. Our goal is to evaluate the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) as a non-invasive tool for the treatment of neuro-cognitive dysfunctions following craniotomy. METHODS: We present a retrospective review of individualized rTMS in twelve patients from Cingulum Health from December 2019 to July 2021 who presented with neuro-cognitive deficits following craniotomy. Multiple cortical targets were selected based on the patient's neurological disorder, associated networks, and anomalies in the functional connectivity of the brain as determined by machine-learning. TMS treatment was performed for five consecutive days. EuroQol quality of life (EQ-5D), functional extremity scales, and neuropsychiatric questionnaires related to the patient's deficit were assessed prior to, after, and during two-month follow-up of rTMS treatment. RESULTS: Nine patients had unilateral functional deficits in either upper, lower, or both limbs. One patient reported post-operative depression, another experienced short term memory difficulties, and a third reported hypobulia. All twelve patients reported significantly improved EQ5D after rTMS treatment and during follow-up. More than half of the patients with lower and upper functional deficits had a 9-point improvement during follow-up. In the patient who developed depression, an 88% reduction in depressive symptoms based on the Beck's Depression Inventory (BDI) was observed during follow-up. No adverse events, such as seizures, occurred. CONCLUSION: The personalized functional connectivity approach to rTMS treatment may be effective and safe for patients with post-craniotomy neuro-cognitive dysfunction.

Endoscopic-assisted surgical approach for butterfly glioma surgery.

PURPOSE: Gliomas that spread along the white matter tracts of the corpus callosum to both hemispheres have traditionally been considered surgically challenging largely due to the relative complexity of safely achieving complete resections. We present a series of endoscopic-assisted resections of butterfly gliomas with post-operative radiological assessment of EOR and clinical outcome data. METHODS: Retrospective review of patients who underwent surgical resection of a butterfly glioma from 2007 to 2020. Butterfly gliomas were defined as gliomas, which appeared to arise from the corpus callosum with significant bilateral extension. All records were retrospectively reviewed with operative/clinical outcomes and complications recorded. RESULTS: 70 patients who underwent an endoscopic-assisted transcortical or interhemispheric approach for butterfly glioma resection met inclusion criteria. A unilateral transcortical approach was used in 86% of cases and an interhemispheric approach in 14%. The endoscope enhanced the visualization of the contralateral hemisphere and allowed for resection of tumor, not reached by standard microscopic visualization, in 100% of cases. 90% of resections resulted in greater than a 95% resection rate. Neurological deficits mostly consisted of motor (10%) and memory (6%) deficits and were most common with posterior tumors of the splenium. CONCLUSION: The endoscopic-assisted transcortical or interhemispheric approach for butterfly glioma resection is effective in achieving a greater than 95% resection with minimal complications. An angled approach allows careful maneuvering around complex anatomic structures and difficult corners, and should be examined further for its clinical benefits in a prospective manner.

Surgical treatment of symptomatic pineal cysts without hydrocephalus-meta-analysis of the published literature.

BACKGROUND: To examine published data and assess evidence relating to safety and efficacy of surgical management of symptomatic pineal cysts without hydrocephalus (nhSPC), we performed a systematic review of the literature and meta-analysis. METHODS: Following the PRISMA guidelines, we searched Pubmed and SCOPUS for all reports with the query 'Pineal Cyst' AND 'Surgery' as of March 2021, without constraints on study design, publication year or status (PROSPERO_CRD:42,021,242,517). Assessment of 1537 hits identified 26 reports that met inclusion and exclusion criteria. RESULTS: All 26 input studies were either case reports or single-centre retrospective cohorts. The majority of outcome data were derived from routine physician-recorded notes. A total of 294 patients with surgically managed nhSPC were identified. Demographics: Mean age was 29 (range: 4-63) with 77% females. Mean cyst size was 15 mm (5-35). Supracerebellar-infratentorial approach was adopted in 90% of cases, occipital-transtentorial in 9%, and was not reported in 1%. Most patients were managed by cyst resection (96%), and the remainder by fenestration. Mean post-operative follow-up was 35 months (0-228). PRESENTATION: Headache was the commonest symptom (87%), followed by visual (54%), nausea/vomit (34%) and vertigo/dizziness (31%). Other symptoms included focal neurology (25%), sleep disturbance (17%), cognitive impairment (16%), loss of consciousness (11%), gait disturbance (11%), fatigue (10%), 'psychiatric' (2%) and seizures (1%). Mean number of symptoms reported at presentation was 3 (0-9). OUTCOMES: Improvement rate was 93% (to minimise reporting bias only consecutive cases from cohort studies were considered, N = 280) and was independent of presentation. Predictors of better outcomes were large cyst size (OR = 5.76; 95% CI: 1.74-19.02) and resection over fenestration (OR = 12.64; 3.07-52.01). Age predicted worse outcomes (OR = 0.95; 0.91-0.99). Overall complication rate was 17% and this was independent of any patient characteristics. Complications with long-term consequences occurred in 10 cases (3.6%): visual disturbance (3), chronic incisional pain (2), sensory disturbance (1), fatigue (1), cervicalgia (1), cerebellar stroke (1) and mortality due to myocardial infarction (1). CONCLUSIONS: Although the results support the role of surgery in the management of nhSPCs, they have to be interpreted with a great deal of caution as the current evidence is limited, consisting only of case reports and retrospective surgical series. Inherent to such studies are inhomogeneity and incompleteness of data, selection bias and bias related to assessment of outcome carried out by the treating surgeon in the majority of cases. Prospective studies with patient-reported and objective outcome assessment are needed to provide higher level of evidence.

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

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.

Beyond eloquence and onto centrality: a new paradigm in planning supratentorial neurosurgery.

PURPOSE: Minimizing post-operational neurological deficits as a result of brain surgery has been one of the most pertinent endeavours of neurosurgical research. Studies have utilised fMRIs, EEGs and MEGs in order to delineate and establish eloquent areas, however, these methods have not been utilized by the wider neurosurgical community due to a lack of clinical endpoints. We sought to ascertain if there is a correlation between graph theory metrics and the neurosurgical notion of eloquent brain regions. We also wanted to establish which graph theory based nodal centrality measure performs the best in predicting eloquent areas. METHODS: We obtained diffusion neuroimaging data from the Human Connectome Project (HCP) and applied a parcellation scheme to it. This enabled us to construct a weighted adjacency matrix which we then analysed. Our analysis looked at the correlation between PageRank centrality and eloquent areas. We then compared PageRank centrality to eigenvector centrality and degree centrality to see what the best measure of empirical neurosurgical eloquence was. RESULTS: Areas that are considered neurosurgically eloquent tended to be predicted by high PageRank centrality. By using summary scores for the three nodal centrality measures we found that PageRank centrality best correlated to empirical neurosurgical eloquence. CONCLUSION: The notion of eloquent areas is important to neurosurgery and graph theory provides a mathematical framework to predict these areas. PageRank centrality is able to consistently find areas that we consider eloquent. It is able to do so better than eigenvector and degree central measures.

Keyhole retrosigmoid approach for large vestibular schwannomas: strategies to improve outcomes.

OBJECTIVE There are numerous treatment strategies in the management for large vestibular schwannomas, including resection only, staged resections, resections followed by radiosurgery, and radiosurgery only. Recent evidence has pointed toward maximal resection as being the optimum strategy to prevent tumor recurrence; however, durable tumor control through aggressive resection has been shown to occur at the expense of facial nerve function and to risk other approach-related complications. Through a retrospective analysis of their single-institution series of keyhole neurosurgical approaches for large vestibular schwannomas, the authors aim to report and justify key techniques to maximize tumor resection and reduce surgical morbidity. METHODS A retrospective chart review was performed at the Centre for Minimally Invasive Neurosurgery. All patients who had undergone a keyhole retrosigmoid approach for the resection of large vestibular schwannomas, defined as having a tumor diameter of ≥ 3.0 cm, were included in this review. Patient demographics, preoperative cranial nerve status, perioperative data, and postoperative follow-up were obtained. A review of the literature for resections of large vestibular schwannomas was also performed. The authors' institutional data were compared with the historical data from the literature. RESULTS Between 2004 and 2017, 45 patients met the inclusion criteria for this retrospective chart review. When compared with findings in a historical cohort in the literature, the authors' minimally invasive, keyhole retrosigmoid technique for the resection of large vestibular schwannomas achieved higher rates of gross-total or near-total resection (100% vs 83%). Moreover, these results compare favorably with the literature in facial nerve preservation (House-Brackmann I-II) at follow-up after gross-total resections (81% vs 47%, p < 0.001) and near-total resections (88% vs 75%, p = 0.028). There were no approach-related complications in this series. CONCLUSIONS It is the experience of the senior author that complete or near-complete resection of large vestibular schwannomas can be successfully achieved via a keyhole approach. In this series of 45 large vestibular schwannomas, a greater extent of resection was achieved while demonstrating high rates of facial nerve preservation and low approach-related and postoperative complications compared with the literature.

Aggressive repeat surgery for focally recurrent primary glioblastoma: outcomes and theoretical framework.

OBJECT The relative benefit of repeat surgery for recurrent glioblastoma is unclear, in part due to the very heterogeneous nature of the patient population and the effect of clinician philosophy on the duration and aggressiveness of treatment. The authors sought to investigate the role of time to last recurrence on patient outcomes following aggressive repeat surgery for recurrent glioblastoma. METHODS The authors present outcomes in 104 patients undergoing repeat surgery for focally recurrent glioblastoma with at least 95% resection and adjuvant treatment at most recent prior surgery. In addition to common variables, they provide data regarding the period of progression-free survival (PFS) following an aggressive lesionectomy for focally recurrent primary glioblastoma (T2) and the time the tumor took to recur since the previous surgery (T1). They term the ratio T1/T2 the relative aggressivity index (RAI). RESULTS The median PFS was 7.8 months, 6.0 months, and 4.8 months following the second, third, and fourth-sixth craniotomies, respectively. Importantly, there was a wide range of outcomes, with time to postoperative recurrence ranging from 1 to 24 months in this group. Analysis showed no meaningful relationship between T1 and T2, meaning that previous PFS is entirely unable to predict the PFS that another surgery will provide the patient. CONCLUSIONS Repeat surgery for glioblastoma is beneficial in many cases, however this is hard to predict preoperatively. Often, surgery can provide the patient with a good period of disease freedom, but this is variable and in general it is not possible to reliably predict who these patients are.

Sinonasal morbidity following tumour resection with and without nasoseptal flap reconstruction.

BACKGROUND: Sinonasal function can be affected by multiple treatment modalities but surgical techniques, such as the nasoseptal flap or Draf 3 procedure, have been implicated in poor post-treatment function. Prior studies have rarely used comparable populations and this study aims to assess the impact of surgical technique, mainly the nasoseptal flap, on sinonasal function in a group of comparable patients. METHODS: A prospective cohort of patients undergoing endoscopic surgery for sinonasal and skull base tumours was studied. Patients were analysed according to whether a nasoseptal flap was used. Other treatment factors included; use of the Draf 3, radiotherapy, removal of olfactory apparatus and dural resection. The Sinonasal Outcome Test 22 (SNOT22), a nasal symptom score (NSS), global function score and nasal obstruction scores were recorded pre and post treatment. RESULTS: One hundred and eighteen patients were assessed. Forty-two patients had a nasoseptal flap. Perioperative radiotherapy was higher in the nasoseptal group, as was dural resection and the need to remove the olfactory apparatus. Despite this, there was no significant difference in SNOT22 scores and NSS. Radiotherapy was detrimental to sinonasal function with SNOT22 and NSS. CONCLUSION: The use of a nasospetal flap in surgery does not affect patient quality of life and sinonasal function after endoscopic tumour resection. Pathology is a better predictor of morbidity, with loss of function from radiotherapy or resection of functional areas such as the olfactory apparatus having a greater impact.

Endoscopic supraorbital eyebrow approach for the surgical treatment of extraaxialand intraaxial tumors.

OBJECT: The supraorbital eyebrow approach is a minimally invasive technique that offers wide access to the anterior skull base region and parasellar area through asubfrontal corridor. The use of neuroendoscopy allows one to extend the approach further to the pituitary fossa, the anterior third ventricle, the interpeduncular cistern, the anterior and medial temporal lobe, and the middle fossa. The supraorbital approach involves a limited skin incision, with minimal soft-tissue dissection and a small craniotomy, thus carrying relatively low approach-related morbidity. METHODS: All consecutive patients who underwent the endoscopic supraorbital eyebrow approach were retrospectively analyzed for lesion location, pathology, length of stay, complications, and cosmetic results. RESULTS: During a 56-month period, 97 patients (mean age 58.5 years) underwent an endoscopic eyebrow approach to resect extra- and intraaxial brain lesions. The most common pathologies treated were meningiomas (n = 41); craniopharyngiomas (n = 22); dermoid tumors (n = 7); metastases (n = 4); gliomas (n = 3); and other miscellaneous frontal, parasellar, and midbrain (n = 23) lesions. The median length of postoperative hospital stay was 2.7 days (range 1-8 days). In 82 patients a total removal of the lesion was performed, while in 15 patients a near-total or subtotal removal was achieved. There were no postoperative hematomas, cerebrospinal fluid leaks, or severe neurological deficits, with the exception of 2 cases of visual deterioration and 1 case each of meningitis, stroke, and third cranial nerve paresis. Other complications directly related to the approach included 2 cases of skin burn as a direct result of heat transmission from the microscope light, 1 case of right frontal palsy, 2 cases of frontal numbness, and 1 case of bone remodeling 1 year after surgery. CONCLUSIONS: The endoscopic supraorbital eyebrow approach is a safe and effective minimally invasive approach to remove extra- and intraaxial anterior skull base, parasellar, and frontal lesions, promoting a rapid recovery and short hospital stay. The location of the eyebrow incision demands a meticulous cosmetic closure, but, with proper technique, cosmetic results are excellent.

Telovelar vs. Transvermian approach for the fourth ventricle tumors: A systematic review and meta-analysis.

BACKGROUND: Tumors in the fourth ventricle can be critical due to the small size of the fourth ventricle, which causes symptoms to be detected even in the presence of lesser mass effects. A proper surgical approach to the fourth ventricle poses challenges due to its deep location and proximity to vital compartments within the brainstem. The two commonly used approaches to these tumors are the transvermian and telovelar approaches. METHODS: A comprehensive systematic study was conducted based on a literature search of the databases. All case controls, cohorts, and case series including patients with fourth ventricle tumors, who were operated on with either telovelar or transvermian approaches were considered eligible. The evaluated outcomes were comparative postoperative complications of the telovelar vs. transvermian approach. After screening and data extraction, a meta-analysis was performed whenever adequate quantitative data were available. RESULTS: Seven studies with a total number of 848 patients, discussed both telovelar and transvermian approaches, with comparative reporting of outcomes in each group. Postoperative outcomes including cranial nerve deficit, mutism, diplopia, CSF leak, need for CSF diversion, and postoperative gait disturbance were not significantly different between telovelar and transvermian approaches. CONCLUSION: Postoperative complications were not significantly different between telovelar and transvermian approaches. Moreover, it could be proposed that such complications would be more likely to be a multifactorial matter concerning the patient's clinical condition, tumor characteristics, and surgeon's experience, rather than the surgical approach alone.

Personalized, parcel-guided rTMS for the treatment of major depressive disorder: Safety and proof of concept.

BACKGROUND: Not all patients with major depressive disorder (MDD) benefit from the US Food and Drug Administration-approved use of repetitive transcranial magnetic stimulation (rTMS) at the dorsolateral prefrontal cortex. We may be undertreating depression with this one-size-fits-all rTMS strategy. METHODS: We present a retrospective review of targeted and connectome-guided rTMS in 26 patients from Cingulum Health from 2020 to 2023 with MDD or MDD with associated symptoms. rTMS was conducted by identifying multiple cortical targets based on anomalies in individual functional connectivity networks as determined by machine learning connectomic software. Quality of life assessed by the EuroQol (EQ-5D) score and depression symptoms assessed by the Beck Depression Inventory (BDI) were administered prior to treatment, directly after, and at a follow-up consultation. RESULTS: Of the 26 patients treated with rTMS, 16 (62%) attained remission after treatment. Of the 19 patients who completed follow-up assessments after an average interval of 2.6 months, 11 (58%) responded to treatment and 13 (68%) showed significant remission. Between patients classified with or without treatment-resistant depression, there was no difference in BDI improvement. Additionally, there was significant improvement in quality of life after treatment and during follow-up compared to baseline. LIMITATIONS: This review is retrospective in nature, so there is no control group to assess the placebo effect on patient outcomes. CONCLUSION: The personalized, connectome-guided approach of rTMS is safe and may be effective for depression. This personalized rTMS treatment allows for co-treatment of multiple disorders, such as the comorbidity of depression and anxiety.

Topology of the lateral visual system: The fundus of the superior temporal sulcus and parietal area H connect nonvisual cerebrum to the lateral occipital lobe.

BACKGROUND AND PURPOSE: Mapping the topology of the visual system is critical for understanding how complex cognitive processes like reading can occur. We aim to describe the connectivity of the visual system to understand how the cerebrum accesses visual information in the lateral occipital lobe. METHODS: Using meta-analytic software focused on task-based functional MRI studies, an activation likelihood estimation (ALE) of the visual network was created. Regions of interest corresponding to the cortical parcellation scheme previously published under the Human Connectome Project were co-registered onto the ALE to identify the hub-like regions of the visual network. Diffusion Spectrum Imaging-based fiber tractography was performed to determine the structural connectivity of these regions with extraoccipital cortices. RESULTS: The fundus of the superior temporal sulcus (FST) and parietal area H (PH) were identified as hub-like regions for the visual network. FST and PH demonstrated several areas of coactivation beyond the occipital lobe and visual network. Furthermore, these parcellations were highly interconnected with other cortical regions throughout extraoccipital cortices related to their nonvisual functional roles. A cortical model demonstrating connections to these hub-like areas was created. CONCLUSIONS: FST and PH are two hub-like areas that demonstrate extensive functional coactivation and structural connections to nonvisual cerebrum. Their structural interconnectedness with language cortices along with the abnormal activation of areas commonly located in the temporo-occipital region in dyslexic individuals suggests possible important roles of FST and PH in the integration of information related to language and reading. Future studies should refine our model by examining the functional roles of these hub areas and their clinical significance.

An agile, data-driven approach for target selection in rTMS therapy for anxiety symptoms: Proof of concept and preliminary data for two novel targets.

INTRODUCTION: Data-driven approaches to transcranial magnetic stimulation (TMS) might yield more consistent and symptom-specific results based on individualized functional connectivity analyses compared to previous traditional approaches due to more precise targeting. We provide a proof of concept for an agile target selection paradigm based on using connectomic methods that can be used to detect patient-specific abnormal functional connectivity, guide treatment aimed at the most abnormal regions, and optimize the rapid development of new hypotheses for future study. METHODS: We used the resting-state functional MRI data of 28 patients with medically refractory generalized anxiety disorder to perform agile target selection based on abnormal functional connectivity patterns between the Default Mode Network (DMN) and Central Executive Network (CEN). The most abnormal areas of connectivity within these regions were selected for subsequent targeted TMS treatment by a machine learning based on an anomalous functional connectivity detection matrix. Areas with mostly hyperconnectivity were stimulated with continuous theta burst stimulation and the converse with intermittent theta burst stimulation. An image-guided accelerated theta burst stimulation paradigm was used for treatment. RESULTS: Areas 8Av and PGs demonstrated consistent abnormalities, particularly in the left hemisphere. Significant improvements were demonstrated in anxiety symptoms, and few, minor complications were reported (fatigue (n = 2) and headache (n = 1)). CONCLUSIONS: Our study suggests that a left-lateralized DMN is likely the primary functional network disturbed in anxiety-related disorders, which can be improved by identifying and targeting abnormal regions with a rapid, data-driven, agile aTBS treatment on an individualized basis.

p38 MAPK inhibitors attenuate pro-inflammatory cytokine production and the invasiveness of human U251 glioblastoma cells.

Increasing evidence suggests that an inflammatory microenvironment promotes invasion by glioblastoma (GBM) cells. Together with p38 mitogen-activated protein kinase (MAPK) activation being regarded as promoting inflammation, we hypothesized that elevated inflammatory cytokine secretion and p38 MAPK activity contribute to expansion of GBMs. Here we report that IL-1ß, IL-6, and IL-8 levels and p38 MAPK activity are elevated in human glioblastoma specimens and that p38 MAPK inhibitors attenuate the secretion of pro-inflammatory cytokines by microglia and glioblastoma cells. RNAi knockdown and immunoprecipitation experiments suggest that the p38α MAPK isoform drives inflammation in GBM cells. Importantly, p38 MAPK inhibition strongly reduced invasion of U251 glioblastoma cells in an inflammatory microenvironment, providing evidence for a p38 MAPK-regulated link between inflammation and invasiveness in GBM pathophysiology.

Insular gliomas and tractographic visualization of the connectome.

In this video, the authors present a connectome-guided surgical resection of an insular glioma in a 39-year-old woman. Preoperative study with constrained spherical deconvolution (CSD)-based tractography revealed the surrounding brain connectome architecture around the tumor relevant for safe surgical resection. Connectomic information provided detailed maps of the surrounding language and salience networks, including eloquent white matter fibers and cortical regions, which were visualized intraoperatively with image guidance and artificial intelligence (AI)-based brain mapping software. Microsurgical dissection is presented with detailed discussion of the safe boundaries and angles of resection when entering the insular operculum defined by connectomic information. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21194.

Delayed, Progressive Multivessel Occlusion After Resection of a Recurrent Glioma.

Glioblastoma multiforme (GBM) is one of the most common primary brain tumors with an aggressive natural history consistent with a median survival of less than two years. Most clinical research has primarily focused on improving overall survival through aggressive cytoreductive surgery and adjuvant radiochemotherapy. However, far less clinical guidance has been given for unexpected instances of neurologic decline following safe glioma resection in the setting of vascular etiology. Here, we report a 50-year-old man who presented to our clinic with a seizure. His preoperative magnetic resonance imaging (MRI) demonstrated a left hippocampal glioblastoma. Ten months following total resection, the patient presented again with rapid loss of vision and hemorrhagic papilledema. An MRI demonstrated a recurrence of his glioma, which was partially resected with no complications. Eight days after surgery, the patient suddenly became unresponsive and imaging revealed moderate blood in the resection cavity, which was evacuated in the operating room. Follow-up scans showed a posterior cerebral artery infarction, and two days later, a middle cerebral artery infarction, upon which care was withdrawn. We do not propose a mechanism by which this delayed ischemia occurred, especially as the middle cerebral artery was not damaged during surgery, however, we note that delayed ischemia may be one mechanism of damage following glioma resection, which should be studied further to improve patient outcomes.

A connectivity model of the anatomic substrates underlying Gerstmann syndrome.

The Gerstmann syndrome is a constellation of neurological deficits that include agraphia, acalculia, left-right discrimination and finger agnosia. Despite a growing interest in this clinical phenomenon, there remains controversy regarding the specific neuroanatomic substrates involved. Advancements in data-driven, computational modelling provides an opportunity to create a unified cortical model with greater anatomic precision based on underlying structural and functional connectivity across complex cognitive domains. A literature search was conducted for healthy task-based functional MRI and PET studies for the four cognitive domains underlying Gerstmann's tetrad using the electronic databases PubMed, Medline, and BrainMap Sleuth (2.4). Coordinate-based, meta-analytic software was utilized to gather relevant regions of interest from included studies to create an activation likelihood estimation (ALE) map for each cognitive domain. Machine-learning was used to match activated regions of the ALE to the corresponding parcel from the cortical parcellation scheme previously published under the Human Connectome Project (HCP). Diffusion spectrum imaging-based tractography was performed to determine the structural connectivity between relevant parcels in each domain on 51 healthy subjects from the HCP database. Ultimately 102 functional MRI studies met our inclusion criteria. A frontoparietal network was found to be involved in the four cognitive domains: calculation, writing, finger gnosis, and left-right orientation. There were three parcels in the left hemisphere, where the ALE of at least three cognitive domains were found to be overlapping, specifically the anterior intraparietal area, area 7 postcentral (7PC) and the medial intraparietal sulcus. These parcels surround the anteromedial portion of the intraparietal sulcus. Area 7PC was found to be involved in all four domains. These regions were extensively connected in the intraparietal sulcus, as well as with a number of surrounding large-scale brain networks involved in higher-order functions. We present a tractographic model of the four neural networks involved in the functions which are impaired in Gerstmann syndrome. We identified a 'Gerstmann Core' of extensively connected functional regions where at least three of the four networks overlap. These results provide clinically actionable and precise anatomic information which may help guide clinical translation in this region, such as during resective brain surgery in or near the intraparietal sulcus, and provides an empiric basis for future study.

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.

Parcellation-based tractographic modeling of the salience network through meta-analysis.

BACKGROUND: The salience network (SN) is a transitory mediator between active and passive states of mind. Multiple cortical areas, including the opercular, insular, and cingulate cortices have been linked in this processing, though knowledge of network connectivity has been devoid of structural specificity. OBJECTIVE: The current study sought to create an anatomically specific connectivity model of the neural substrates involved in the salience network. METHODS: A literature search of PubMed and BrainMap Sleuth was conducted for resting-state and task-based fMRI studies relevant to the salience network according to PRISMA guidelines. Publicly available meta-analytic software was utilized to extract relevant fMRI data for the creation of an activation likelihood estimation (ALE) map and relevant parcellations from the human connectome project overlapping with the ALE data were identified for inclusion in our SN model. DSI-based fiber tractography was then performed on publicaly available data from healthy subjects to determine the structural connections between cortical parcellations comprising the network. RESULTS: Nine cortical regions were found to comprise the salience network: areas AVI (anterior ventral insula), MI (middle insula), FOP4 (frontal operculum 4), FOP5 (frontal operculum 5), a24pr (anterior 24 prime), a32pr (anterior 32 prime), p32pr (posterior 32 prime), and SCEF (supplementary and cingulate eye field), and 46. The frontal aslant tract was found to connect the opercular-insular cluster to the middle cingulate clusters of the network, while mostly short U-fibers connected adjacent nodes of the network. CONCLUSION: Here we provide an anatomically specific connectivity model of the neural substrates involved in the salience network. These results may serve as an empiric basis for clinical translation in this region and for future study which seeks to expand our understanding of how specific neural substrates are involved in salience processing and guide subsequent human behavior.