No change in network connectivity measurements between separate rsfMRI acquisition times.

The role of resting state functional MRI (rsfMRI) is increasing in the field of epilepsy surgery because it is possible to interpolate network connectivity patterns across the brain with a high degree of spatial resolution. Prior studies have shown that by rsfMRI with scalp electroencephalography (EEG), an epileptogenic network can be modeled and visualized with characteristic patterns of connectivity that are relevant to both seizure-related and neuropsychological outcomes after surgery. The aim of this study is to show that a 5-min acquisition time provides reproducible results related to the relevant connectivity metrics when compared to a separately acquired 5-min scan. Fourteen separate rsfMRI sessions from ten different patients were used for comparison, comprised of patients with temporal lobe epilepsy both pre- and post-operation. Results showed that there was no significant difference in any of the connectivity metrics when comparing both 5-min scans to each other. These data support the continued use of a 5-min scan for epileptogenic network modeling in future studies because the inter-scan variability is sufficiently low as not to alter the output metrics characterizing the network connectivity.

Long-term outcomes of mesial temporal laser interstitial thermal therapy for drug-resistant epilepsy and subsequent surgery for seizure recurrence: a multi-centre cohort study.

BACKGROUND: Magnetic resonance-guided laser interstitial thermal therapy (MRgLITT) is a minimally invasive alternative to surgical resection for drug-resistant mesial temporal lobe epilepsy (mTLE). Reported rates of seizure freedom are variable and long-term durability is largely unproven. Anterior temporal lobectomy (ATL) remains an option for patients with MRgLITT treatment failure. However, the safety and efficacy of this staged strategy is unknown. METHODS: This multicentre, retrospective cohort study included 268 patients consecutively treated with mesial temporal MRgLITT at 11 centres between 2012 and 2018. Seizure outcomes and complications of MRgLITT and any subsequent surgery are reported. Predictive value of preoperative variables for seizure outcome was assessed. RESULTS: Engel I seizure freedom was achieved in 55.8% (149/267) at 1 year, 52.5% (126/240) at 2 years and 49.3% (132/268) at the last follow-up ≥1 year (median 47 months). Engel I or II outcomes were achieved in 74.2% (198/267) at 1 year, 75.0% (180/240) at 2 years and 66.0% (177/268) at the last follow-up. Preoperative focal to bilateral tonic-clonic seizures were independently associated with seizure recurrence. Among patients with seizure recurrence, 14/21 (66.7%) became seizure-free after subsequent ATL and 5/10 (50%) after repeat MRgLITT at last follow-up≥1 year. CONCLUSIONS: MRgLITT is a viable treatment with durable outcomes for patients with drug-resistant mTLE evaluated at a comprehensive epilepsy centre. Although seizure freedom rates were lower than reported with ATL, this series represents the early experience of each centre and a heterogeneous cohort. ATL remains a safe and effective treatment for well-selected patients who fail MRgLITT.

Surgical disconnection of epilepsy network correlates with improved outcomes.

PURPOSE: A novel software algorithm combining non-invasive EEG and resting state functional MRI data to map networks of cortex correlated to epileptogenic tissue was used to map an epilepsy network non-invasively. The relationship between epilepsy network connectivity and outcomes after surgery was investigated using this non-invasive and non-concurrent modeling algorithm. METHOD: Scalp EEG and resting state functional MRI were acquired for nineteen patients with temporal lobe epilepsy. The hypothetical irritative zone was mapped, and resting state functional MRI data was used to model regions functionally correlated with the irritative zone. Epilepsy network connectivity was measured in patient with temporal lobe epilepsy (n = 19) both pre- and post-operatively. Temporal networks were also mapped in healthy control participants (n = 6). RESULTS: Thirteen of nineteen patients (68 %) were seizure free after 20.3 ± 4.8 months. Epilepsy network connectivity within the temporal lobe was significantly higher among patients with temporal lobe epilepsy compared to the healthy control patients (p < 0.05). Disconnection of the epilepsy network was significantly higher in patients who were seizure free. Using spearman rho analyses, neuropsychological function after surgery was found to be relatively better in patients with higher degree of epilepsy network disconnection. CONCLUSIONS: The magnitude of network disconnection after surgery was strongly associated with increased rates of seizure freedom and relatively better neuropsychological measures of memory and naming function. It was shown that seizure-free outcomes and relatively improved neuropsychological function correlated with surgical disconnection of a highly synchronous epilepsy network.

Seizure Freedom After Epilepsy Surgery and Higher Baseline Cognition May Be Associated With a Negatively Correlated Epilepsy Network in Temporal Lobe Epilepsy.

Background: Brain regions positively correlated with the epileptogenic zone in patients with temporal lobe epilepsy vary in spread across the brain and in the degree of correlation to the temporal lobes, thalamus, and limbic structures, and these parameters have been associated with pre-operative cognitive impairment and seizure freedom after epilepsy surgery, but negatively correlated regions have not been as well studied. We hypothesize that connectivity within a negatively correlated epilepsy network may predict which patients with temporal lobe epilepsy will respond best to surgery. Methods: Scalp EEG and resting state functional MRI (rsfMRI) were collected from 19 patients with temporal lobe epilepsy and used to estimate the irritative zone. Using patients' rsfMRI, the negatively correlated epilepsy network was mapped by determining all the brain voxels that were negatively correlated with the voxels in the epileptogenic zone and the spread and average connectivity within the network was determined. Results: Pre-operatively, connectivity within the negatively correlated network was inversely related to the spread (diffuseness) of that network and positively associated with higher baseline verbal and logical memory. Pre-operative connectivity within the negatively correlated network was also significantly higher in patients who would go on to be seizure free. Conclusion: Patients with higher connectivity within brain regions negatively correlated with the epilepsy network had higher baseline memory function, narrower network spread, and were more likely to be seizure free after surgery.

Network connectivity separate from the hypothesized irritative zone correlates with impaired cognition and higher rates of seizure recurrence.

INTRODUCTION: Surgery remains an essential option for the treatment of medically intractable temporal lobe epilepsy (TLE). However, only 66% of patients achieve postoperative seizure freedom, perhaps attributable to an incomplete understanding of brain network alterations in surgical candidates. Here, we applied a novel network modeling algorithm and measured key characteristics of epileptic networks correlated with surgical outcomes and objective measures of cognition. METHODS: Twenty-two patients were prospectively included, and relevant demographic information was attained. Resting state functional magnetic resonance imaging (rsfMRI) and electroencephalography (EEG) data were recorded and preprocessed. Using our novel algorithm, patient-specific epileptic networks were mapped preoperatively, and geographic spread was quantified. Global functional connectivity was also determined using a volumetric functional atlas. Neuropsychological pre- and postsurgical raw and standardized scores obtained blinded to epileptic network status. Key demographic data and features of epileptic networks were then correlated with surgical outcome using Pearson's product-moment correlation. RESULTS: At an average follow-up of 18.4 months, 15/22 (68%) patients were seizure-free. Connectivity was measured globally using a functional 3D atlas. Higher mean global connectivity correlated with worse scores in preoperative neuropsychological testing of executive functioning (Ruff Figural Fluency Test [RFFT]-ER; R = 0.943, p = 0.005). A higher ratio of highly correlated connections between regions of interest (ROIs) in the hemisphere contralateral to the seizure onset correlated with impairment in executive functioning (RFFT-ER; R = 0.943, p = 0.005). Higher numbers of highly correlated connections between ROIs in the contralateral hemisphere correlated with impairment in both short- and long-term measures of verbal memory (Rey Auditory Verbal Learning Test Trials 6, 7 [RAVLT6, RAVLT7]; R = -0.650, p = 0.020, R = -0.676, p = 0.030). Epilepsy networks were modeled in each patient, and localization of the epilepsy network in the bitemporal lobes correlated with lower scores in neuropsychological tests measuring verbal learning and short-term memory (RAVLT6; R = -0.671, p = 0.024). Higher rates of seizure recurrence correlated with localization of the epilepsy network bitemporally (R = -0.542, p = 0.014), with the stronger correlation found with localization to the contralateral temporal lobe from side of surgery (R = - 0.530, p = 0.016). CONCLUSION: Increased connectivity contralateral to seizure onset and epilepsy network spread in the bitemporal lobes correlated with lower measures of executive functioning and verbal memory. Epilepsy network localization to the bitemporal lobes, in particular, the contralateral temporal lobe, is associated with higher rates of seizure recurrence. These findings may reflect network-level disruption that has infiltrated the contralateral hemisphere and the bitemporal lobes contributing to impaired cognition and relatively worse surgical outcomes. Further identification of network parameters that predict patient outcomes may aid in patient selection, resection planning, and ultimately the efficacy of epilepsy surgery.

T-Regulatory Cells Confer Increased Myelination and Stem Cell Activity after Stroke-Induced White Matter Injury.

Stroke-induced hypoxia causes oligodendrocyte death due to inflammation, lack of oxygen and exacerbation of cell death. Bone marrow-derived stem cells (BMSCs) possess an endogenous population of T-regulatory cells (Tregs) which reduce secretion of pro-inflammatory cytokines that lead to secondary cell death. Here, we hypothesize that oligodendrocyte progenitor cells (OPCs) cultured with BMSCs containing their native Treg population show greater cell viability, less pro-inflammatory cytokine secretion and greater myelin production after exposure to oxygen-glucose deprivation and reoxygenation (OGD/R) than OPCs cultured without Tregs. OPCs were cultured and then exposed to OGD/R. BMSCs with or without Tregs were added to the co-culture immediately after ischemia. The Tregs were depleted by running the BMSCs through a column containing a magnetic substrate. Fibroblast growth factor beta (FGF-ß) and interleukin 6 (IL-6) ELISAs determined BMSC activity levels. Immunohistochemistry assessed OPC differentiation. OPCs cultured with BMSCs containing their endogenous Tregs showed increased myelin production compared to the BMSCs with depleted Tregs. IL-6 and FGF-ß were increased in the group cultured with Tregs. Collectively, these results suggest that BMSCs containing Tregs are more therapeutically active, and that Tregs have beneficial effects on OPCs subjected to ischemia. Tregs play an important role in stem cell therapy and can potentially treat white matter injury post-stroke.

Regulatory T-cells within bone marrow-derived stem cells actively confer immunomodulatory and neuroprotective effects against stroke.

Regulatory T-cells (Tregs) may exert a neuroprotective effect on ischemic stroke by inhibiting both inflammation and effector T-cell activation. Transplantation of human bone marrow-derived stem cells (BMSCs) in ischemic stroke affords neuroprotection that results in part from the cells' anti-inflammatory property. However, the relationship between Tregs and BMSCs in treatment of ischemic stroke has not been fully elucidated. Here, we tested the hypothesis that Tregs within the BMSCs represent active mediators of immunomodulation and neuroprotection in experimental stroke. Primary rat neuronal cells were subjected to an oxygen-glucose deprivation and reperfusion (OGD/R) condition. The cells were re-perfused and co-cultured with Tregs and/or BMSCs. We detected a minority population of Tregs within BMSCs with both immunocytochemistry (ICC) and flow cytometry identifying cells expressing phenotypic markers of CD4, CD25, and FoxP3 protein. BMSCs with the native population of Tregs conferred maximal neuroprotection compared to the treatment conditions containing 0%, 10%, and 100% relative ratio Tregs. Increasing the Treg population resulted in increased IL6 secretion and decreased FGF-ß secretion by BMSCs. This study shows that a minority population of Tregs exists within the therapeutic BMSC population, which serves as robust mediators of the immunomodulatory and neuroprotective effect provided by BMSC transplantation.

Stem cell therapy for neurological disorders: A focus on aging.

Age-related neurological disorders continue to pose a significant societal and economic burden. Aging is a complex phenomenon that affects many aspects of the human body. Specifically, aging can have detrimental effects on the progression of brain diseases and endogenous stem cells. Stem cell therapies possess promising potential to mitigate the neurological symptoms of such diseases. However, aging presents a major obstacle for maximum efficacy of these treatments. In this review, we discuss current preclinical and clinical literature to highlight the interactions between aging, stem cell therapy, and the progression of major neurological disease states such as Parkinson's disease, Huntington's disease, stroke, traumatic brain injury, amyotrophic lateral sclerosis, multiple sclerosis, and multiple system atrophy. We raise important questions to guide future research and advance novel treatment options.

An update on intracerebral stem cell grafts.

INTRODUCTION: Primary neurological disorders are notoriously debilitating and deadly, and over the past four decades stem cell therapy has emerged as a promising treatment. Translation of stem cell therapies from the bench to the clinic requires a better understanding of delivery protocols, safety profile, and efficacy in each disease. Areas covered: In this review, benefits and risks of intracerebral stem cell transplantation are presented for consideration. Milestone discoveries in stem cell applications are reviewed to examine the efficacy and safety of intracerebral stem cell transplant therapy for disorders of the central nervous system and inform design of translatable protocols for clinically feasible stem cell-based treatments. Expert commentary: Intracerebral administration, compared to peripheral delivery, is more invasive and carries the risk of open brain surgery. However, direct cell implantation bypasses the blood-brain barrier and reduces the first-pass effect, effectively increasing the therapeutic cell deposition at its intended site of action. These benefits must be weighed with the risk of graft-versus-host immune response. Rigorous clinical trials are underway to assess the safety and efficacy of intracerebral transplants, and if successful will lead to widely available stem cell therapies for neurologic diseases in the coming years.

Multimodal, noninvasive seizure network mapping software: A novel tool for preoperative epilepsy evaluation.

BACKGROUND: Despite rigorous preoperative evaluation, epilepsy surgery achieves seizure freedom in only two-thirds of cases. Current preoperative evaluation does not include a detailed network analysis despite the association of network-level changes with epilepsy. OBJECTIVE: We sought to create a software algorithm to map individualized epilepsy networks by combining noninvasive electroencephalography (EEG) source localization and nonconcurrent resting state functional magnetic resonance imaging (rsfMRI). METHODS: Scalp EEG and rsfMRI data were acquired for three sample cases: one healthy control case, one case of right temporal lobe epilepsy, and one case of bitemporal seizure onset. Data from rsfMRI were preprocessed, and a time-series function was extracted. Connection coefficients were used to threshold out spurious connections and model global functional networks in a 3D map. Epileptic discharges were localized using a forward model of cortical mesh dipoles followed by an empirical Bayesian approach of inverse source reconstruction and co-registered with rsfMRI. Co-activating brain regions were mapped. RESULTS: Three illustrative sample cases are presented. In the healthy control case, the software showed symmetrical global connectivity. In the right temporal lobe epilepsy case, asymmetry was found in the global connectivity metrics with a paucity of connectivity ipsilateral to the epileptogenic cortex. The superior longitudinal fasciculus, uncinate fasciculus, and commissural fibers connecting disparate and discontinuous cortical regions involved in the epilepsy network were visualized. In the case with bitemporal lobe epilepsy, global connectivity was symmetric. It showed a network of correlating cortical activity local to epileptogenic tissue in both temporal lobes. The network involved white matter tracks in a similar pattern to those seen in the right temporal case. CONCLUSIONS: This modeling algorithm allows better definition of the global brain network and potentially demonstrates differences in connectivity between an epileptic and a non-epileptic brain. This finding may be useful for mapping cortico-cortical connections representing the putative epilepsy networks. With this methodology, we localized the epileptogenic brain and showed network asymmetry and long-distance cortical co-activation. This software tool is the first to use a multimodal, nonconcurrent, and noninvasive approach to model and visualize the epilepsy network.