Faculty Bibliography

We studied the relationship between uninstructed, unstructured movements and neural activity in three epilepsy patients with intracranial electroencephalographic (iEEG) recordings. We used a custom system to continuously record high definition video precisely time-aligned to clinical iEEG data. From these video recordings, movement periods were annotated via semi-automatic tracking based on dense optical flow. We found that neural signal features (8--32 Hz and 76--100 Hz power) previously identified from task-based experiments are also modulated before and during a variety of movement behaviors. These movement behaviors are coarsely labeled by time period and movement side (e.g. `Idle' and `Move', `Right' and `Left'); movements within a label can include a wide variety of uninstructed behaviors. A rigorous nested cross-validation framework was used to classify both movement onset and lateralization with statistical significance for all subjects. We demonstrate an evaluation framework to study neural activity related to natural movements not evoked by a task, annotated over hours of video. This work further establishes the feasibility to study neural correlates of unstructured behavior through continuous recording in the epilepsy monitoring unit. The insights gained from such studies may advance our understanding of how the brain naturally controls movement, which may inform the development of more robust and generalizable brain-computer interfaces.

OBJECTIVE:Information encoding in neurons can be described through their response fields. The spatial response field of a neuron is the region of space in which a sensory stimulus or a behavioral event causes that neuron to fire. Neurons can also exhibit temporal response fields (TRFs), which characterize a transient response to stimulus or behavioral event onsets. These neurons can thus be described by a spatio-temporal response field (STRF). The activity of neurons with STRFs can be well-described with point process models that characterize binary spike trains with an instantaneous firing rate that is a function of both time and space. However, developing decoders for point process models of neurons that exhibit TRFs is challenging because it requires prior knowledge of event onset times, which are unknown. Indeed, point process filters (PPF) to date have largely focused on decoding neuronal activity without considering TRFs. Also, neural classifiers have required data to be behavior- or stimulus-aligned, i.e. event times to be known, which is often not possible in real-world applications. Our objective in this work is to develop a viable decoder for neurons with STRFs when event times are unknown. APPROACH:To enable decoding of neurons with STRFs, we develop a novel point-process matched filter (PPMF) that can detect events and estimate their onset times from population spike trains. We also devise a PPF for neurons with transient responses as characterized by STRFs. When neurons exhibit STRFs and event times are unknown, the PPMF can be combined with the PPF or with discrete classifiers for continuous and discrete brain state decoding, respectively. MAIN RESULTS:We validate our algorithm on two datasets: simulated spikes from neurons that encode visual saliency in response to stimuli, and prefrontal spikes recorded in a monkey performing a delayed-saccade task. We show that the PPMF can estimate the stimulus times and saccade times accurately. Further, the PPMF combined with the PPF can decode visual saliency maps without knowing the stimulus times. Similarly, the PPMF combined with a point process classifier can decode the saccade direction without knowing the saccade times. SIGNIFICANCE:These event detection and decoding algorithms can help develop neurotechnologies to decode cognitive states from neural responses that exhibit STRFs.

Cardiorespiratory dysfunction during or after seizures may contribute to sudden unexpected death in epilepsy. Disruption of lower brainstem cardiorespiratory systems by seizures is postulated to impair respiratory and cardiac function. Here, we explore the effects of brainstem seizures and stimulation on cardiorespiratory function using a rat model of intrahippocampal 4-aminopyridine (4-AP)-induced acute recurrent seizures. Cardiac and respiratory monitoring together with local field potential recordings from hippocampus, contralateral parietal cortex and caudal dorsomedial brainstem, were conducted in freely moving adult male Wistar rats. Seizures were induced by intrahippocampal injection of 4-AP. Increased respiratory rate but unchanged heart rate occurred during hippocampal and secondarily generalized cortical seizures. Status epilepticus without brainstem seizures increased respiratory and heart rates, whereas status epilepticus with intermittent brainstem seizures induced repeated episodes of cardiorespiratory depression leading to death. Respiratory arrest occurred prior to asystole which was the terminal event. Phenytoin (100 mg/kg, intraperitoneal injection), administered after 4-AP intrahippocampal injection, terminated brainstem seizures and the associated cardiorespiratory depression, preventing death in five of six rats. Focal electrical stimulation of the caudal dorsomedial brainstem also suppressed cardiorespiratory rates. We conclude that in our model, brainstem seizures were associated with respiratory depression followed by cardiac arrest, and then death. We hypothesize this model shares mechanisms in common with the classic sudden unexpected death in epilepsy (SUDEP) syndrome associated with spontaneous seizures.

The use of fixed fibroblasts from familial and sporadic Alzheimer's disease patients has previously indicated an upregulation of mitochondria-ER contacts (MERCs) as a hallmark of Alzheimer's disease. Despite its potential significance, the relevance of these results is limited because they were not extended to live neurons. Here we performed a dynamic in vivo analysis of MERCs in hippocampal neurons from McGill-R-Thy1-APP transgenic rats, a model of Alzheimer's disease-like amyloid pathology. Live FRET imaging of neurons from transgenic rats revealed perturbed 'lipid-MERCs' (gap width <10 nm), while 'Ca²⁺-MERCs' (10-20 nm gap width) were unchanged. In situ TEM showed no significant differences in the lipid-MERCs:total MERCs or lipid-MERCs:mitochondria ratios; however, the average length of lipid-MERCs was significantly decreased in neurons from transgenic rats as compared to controls. In accordance with FRET results, untargeted lipidomics showed significant decreases in levels of 12 lipids and bioenergetic analysis revealed respiratory dysfunction of mitochondria from transgenic rats. Thus, our results reveal changes in MERC structures coupled with impaired mitochondrial functions in Alzheimer's disease-related neurons.This article has an associated First Person interview with the first author of the paper.

OBJECTIVE:Presenting the diagnosis of psychogenic nonepileptic seizures (PNES) can be a difficult task, but disclosing this information effectively is important to optimize patient outcomes. We sought to develop a standardized method to teach neurology residents how to introduce the diagnosis of PNES via an objective structured clinical examination (OSCE) with a standardized patient (SP). METHODS:In conjunction with the New York University School of Medicine Simulation Center (NYSIM), we designed an OSCE in which a resident had to inform a SP of her diagnosis of PNES and discuss a treatment plan. The SP was provided with details to gradually disclose depending on what the resident said about the history of her episodes, triggers for her episodes and her history of sexual abuse. Each encounter was observed by an attending physician who provided real-time feedback to the resident after the session. Additionally, the SP completed an objective written checklist of items the resident should have covered in the session and gave them verbal feedback. RESULTS:Twenty-six adult neurology (n = 22), child neurology (n = 3), and neuropsychiatry (n = 1) residents participated in this OSCE in 2018 and 2019, with full data available for 25 participants. Residents reported the OSCE was very useful (mean Likert score of 4.9/5). They felt moderately prepared (mean Likert score 3.8/5) and rated their performance as a mean of 3.3/5. On the SP's checklist, most residents were rated as Well Done in the domains of information gathering, relationship development, and education and counseling. Only in the domain of psychosocial assessment were most residents rated as Not Done (only 7/25 inquired about past trauma as a risk factor for PNES). SIGNIFICANCE/CONCLUSIONS:The OSCEs are a feasible and useful way to teach neurology residents about discussing PNES, as they allow for provision of real-time practice and feedback in a safe environment without real patients.

In legal physician-hastened death, a physician prescribes medication with the primary intent of causing the death of a willing terminally ill patient. This practice differs radically from palliative sedation, intended to relieve a patient's suffering rather than cause a patient's death. In this position paper, we argue that the practice of physician-hastened death is contrary to the interests of patients, their families, and the sound ethical practice of medicine. Therefore, the American Academy of Neurology should advise its members against this practice, as it had done until 2018.

BACKGROUND:Post-traumatic headache (PTH) is associated with considerable disability and reduced health-related quality of life. Despite the very high prevalence of PTH, there are no evidence-based guidelines for PTH treatment. Thus, we found it timely to provide a systematic review of the current literature on acute and preventive pharmacological treatment of PTH using PubMed and Embase databases. FINDINGS/RESULTS:Included studies involved acute and preventive pharmacological treatment of headache attributed to traumatic injury to the head in adherence to the International Classification of Headache Disorders (ICHD) criteria. Of 1424 potentially relevant articles identified, 63 were retrieved for detailed evaluation and seven studies (one prospective and six retrospective) met the inclusion criteria. None of the seven included studies were randomized clinical trials (RCTs) or used a placebo-controlled study design. CONCLUSION/CONCLUSIONS:We found that there is a lack of high-quality evidence-based studies on the pharmacological treatment of PTH. Future studies are highly needed and must emphasize open-label studies with rigorous methodology or RCTs with a placebo-controlled design.

Retinopathy of prematurity (ROP) is a biphasic disease in which the first phase is characterized by high oxygen tension leading to vaso-obliteration in the retina. Pearson syndrome is a rare multisystem mitochondrial disease with a defect in cellular respiration. The authors describe a patient with Pearson syndrome and delayed onset of ROP at a postconceptual age of 42 weeks. The proposed mechanistic theory was the increased oxygen use associated with the metabolic impairments in Pearson syndrome counterbalancing the effects of supplemental oxygen during the vaso-obliterative stage of ROP. [J Pediatr Ophthalmol Strabismus. 2019;56:e60-e64.].

OBJECTIVE:To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS). METHODS:This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions. RESULTS:< 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID. CONCLUSION/CONCLUSIONS:Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.