Faculty Bibliography

Temporal lobe epilepsy represents a major cause of drug-resistant epilepsy. Cognitive impairment is a frequent comorbidity, but the mechanisms are not fully elucidated. We hypothesized that the cognitive impairment in drug-resistant temporal lobe epilepsy could be due to perturbations of amyloid and tau signalling pathways related to activation of stress kinases, similar to those observed in Alzheimer's disease. We examined these pathways, as well as amyloid-β and tau pathologies in the hippocampus and temporal lobe cortex of drug-resistant temporal lobe epilepsy patients who underwent temporal lobe resection (n = 19), in comparison with age- and region-matched samples from neurologically normal autopsy cases (n = 22). Post-mortem temporal cortex samples from Alzheimer's disease patients (n = 9) were used as positive controls to validate many of the neurodegeneration-related antibodies. Western blot and immunohistochemical analysis of tissue from temporal lobe epilepsy cases revealed increased phosphorylation of full-length amyloid precursor protein and its associated neurotoxic cleavage product amyloid-β*56. Pathological phosphorylation of two distinct tau species was also increased in both regions, but increases in amyloid-β1-42 peptide, the main component of amyloid plaques, were restricted to the hippocampus. Furthermore, several major stress kinases involved in the development of Alzheimer's disease pathology were significantly activated in temporal lobe epilepsy brain samples, including the c-Jun N-terminal kinase and the protein kinase R-like endoplasmic reticulum kinase. In temporal lobe epilepsy cases, hippocampal levels of phosphorylated amyloid precursor protein, its pro-amyloidogenic processing enzyme beta-site amyloid precursor protein cleaving enzyme 1, and both total and hyperphosphorylated tau expression, correlated with impaired preoperative executive function. Our study suggests that neurodegenerative and stress-related processes common to those observed in Alzheimer's disease may contribute to cognitive impairment in drug-resistant temporal lobe epilepsy. In particular, we identified several stress pathways that may represent potential novel therapeutic targets.

The spinal cord is frequently affected by atrophy and/or lesions in multiple sclerosis (MS) patients. Segmentation of the spinal cord and lesions from MRI data provides measures of damage, which are key criteria for the diagnosis, prognosis, and longitudinal monitoring in MS. Automating this operation eliminates inter-rater variability and increases the efficiency of large-throughput analysis pipelines. Robust and reliable segmentation across multi-site spinal cord data is challenging because of the large variability related to acquisition parameters and image artifacts. In particular, a precise delineation of lesions is hindered by a broad heterogeneity of lesion contrast, size, location, and shape. The goal of this study was to develop a fully-automatic framework - robust to variability in both image parameters and clinical condition - for segmentation of the spinal cord and intramedullary MS lesions from conventional MRI data of MS and non-MS cases. Scans of 1042 subjects (459 healthy controls, 471 MS patients, and 112 with other spinal pathologies) were included in this multi-site study (n = 30). Data spanned three contrasts (T₁-, T₂-, and T₂^∗-weighted) for a total of 1943 vol and featured large heterogeneity in terms of resolution, orientation, coverage, and clinical conditions. The proposed cord and lesion automatic segmentation approach is based on a sequence of two Convolutional Neural Networks (CNNs). To deal with the very small proportion of spinal cord and/or lesion voxels compared to the rest of the volume, a first CNN with 2D dilated convolutions detects the spinal cord centerline, followed by a second CNN with 3D convolutions that segments the spinal cord and/or lesions. CNNs were trained independently with the Dice loss. When compared against manual segmentation, our CNN-based approach showed a median Dice of 95% vs. 88% for PropSeg (p ≤ 0.05), a state-of-the-art spinal cord segmentation method. Regarding lesion segmentation on MS data, our framework provided a Dice of 60%, a relative volume difference of -15%, and a lesion-wise detection sensitivity and precision of 83% and 77%, respectively. In this study, we introduce a robust method to segment the spinal cord and intramedullary MS lesions on a variety of MRI contrasts. The proposed framework is open-source and readily available in the Spinal Cord Toolbox.

PURPOSE/OBJECTIVE:Iniparib is a purported prodrug causing cell death through intracellular conversion to nitro radical ions. We assessed the efficacy and safety of iniparib with standard radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM). EXPERIMENTAL DESIGN/METHODS:Adults meeting eligibility criteria were enrolled in this prospective, single arm, open-label multi-institution phase II trial with median overall survival (mOS) compared to a historical control as the primary objective. A safety run-in component of RT+TMZ+iniparib (n=5) was followed by an efficacy study (n=76) with the recommended phase II doses of iniparib (8.0 mg/kg IV twice/week with RT + daily TMZ followed by 8.6 mg/kg IV twice/week with 5/28 day TMZ). RESULTS:The median age of the 81 evaluable participants was 58 years (63% male). Baseline KPS was ≥80% in 87% of participants. The mOS was 22 months (95%CI: 17-24) and the hazard rate was 0.44 (95%CI: 0.35-0.55) per-person year of follow-up. The 2 and 3 year survival rates were 38% and 25%, respectively. Treatment-related grade 3 adverse events (AE) occurred in 27% of patients; nine patients had AEs requiring drug discontinuation including: infusion-related reaction, rash, gastritis, increased liver enzymes, and thrombocytopenia. CONCLUSIONS:Iniparib is well tolerated with RT and TMZ in patients with newly diagnosed GBM at up to 17.2mg/kg weekly. The primary objective of improved mOS compared with historical a control was met, indicating potential antitumor activity of iniparib in this setting. Dosing optimization (frequency and sequence) is needed prior to additional efficacy studies.

Importance/UNASSIGNED:Despite secondary prevention strategies with proven efficacy, recurrent stroke rates remain high, particularly in racial/ethnic minority populations who are disproportionately affected by stroke. Objective/UNASSIGNED:To determine the efficacy of a culturally tailored skills-based educational intervention with telephone follow-up compared with standard discharge care on systolic blood pressure reduction in a multiethnic cohort of patients with mild/moderate stroke/transient ischemic attack. Design, Setting, and Participants/UNASSIGNED:Randomized clinical trial with 1-year follow-up. Participants were white, black, and Hispanic patients with mild/moderate stroke/transient ischemic attack prospectively enrolled from 4 New York City, New York, medical centers during hospitalization or emergency department visit between August 2012 and May 2016. Through screening of stroke admissions and emergency department notifications, 1083 eligible patients were identified, of whom 256 declined to participate and 275 were excluded for other reasons. Analyses were intention to treat. Interventions/UNASSIGNED:The Discharge Educational Strategies for Reduction of Vascular Events (DESERVE) intervention is a skills-based, culturally tailored discharge program with follow-up calls delivered by a community health coordinator. This intervention was developed using a community engagement approach. Main Outcomes and Measures/UNASSIGNED:The primary outcome was systolic blood pressure reduction at 12 months postdischarge. Results/UNASSIGNED:A total of 552 participants were randomized to receive intervention or usual care (281 women [51%]; mean [SD] age, 64.61 [2.9] years; 180 Hispanic [33%], 151 non-Hispanic white [27%], and 183 non-Hispanic black [33%]). At 1-year follow-up, no significant difference in systolic blood pressure reduction was observed between intervention and usual care groups (β = 2.5 mm Hg; 95% CI, -1.9 to 6.9). Although not powered for subgroup analysis, we found that among Hispanic individuals, the intervention arm had a clinically and statically significant 9.9 mm Hg-greater mean systolic blood pressure reduction compared with usual care (95% CI, 1.8-18.0). There were no significant differences between arms among non-Hispanic white (β = 3.3; 95% CI, -4.1 to 10.7) and non-Hispanic black participants (β = -1.6; 95% CI, -10.1 to 6.8). Conclusions and Relevance/UNASSIGNED:Few behavioral intervention studies in individuals who have had stroke have reported clinically meaningful reductions in blood pressure at 12 months, and fewer have focused on a skills-based approach. Results of secondary analyses suggest that culturally tailored, skills-based strategies may be an important alternative to knowledge-focused approaches in achieving sustained vascular risk reduction and addressing racial/ethnic stroke disparities; however, these findings should be tested in future studies. Trial Registration/UNASSIGNED:ClinicalTrials.gov identifier: NCT01836354.

BACKGROUND:Electrical stimulation of the cortex using subdurally implanted electrodes can causally reveal structural connectivity by eliciting cortico-cortical evoked potentials (CCEPs). While many studies have demonstrated the potential value of CCEPs, the methods to evaluate them were often relatively subjective, did not consider potential artifacts, and did not lend themselves to systematic scientific investigations. NEW METHOD/UNASSIGNED:We developed an automated and quantitative method called SIGNI (Stimulation-Induced Gamma-based Network Identification) to evaluate cortical population-level responses to electrical stimulation that minimizes the impact of electrical artifacts. We applied SIGNI to electrocorticographic (ECoG) data from eight human subjects who were implanted with a total of 978 subdural electrodes. Across the eight subjects, we delivered 92 trains of approximately 200 discrete electrical stimuli each (amplitude 4-15 mA) to a total of 64 electrode pairs. RESULTS:We verified SIGNI's efficacy by demonstrating a relationship between the magnitude of evoked cortical activity and stimulation amplitude, as well as between the latency of evoked cortical activity and the distance from the stimulated locations. CONCLUSIONS:SIGNI reveals the timing and amplitude of cortical responses to electrical stimulation as well as the structural connectivity supporting these responses. With these properties, it enables exploration of new and important questions about the neurophysiology of cortical communication and may also be useful for pre-surgical planning.