Faculty Bibliography

OBJECTIVE:Automatic detection of interictal epileptiform discharges (IEDs, short as ``spikes'') from an epileptic brain can help predict seizure recurrence and support the diagnosis of epilepsy. Developing fast, reliable and robust detection methods for IEDs based on scalp or intracortical EEG may facilitate online seizure monitoring and closed-loop neurostimulation. APPROACH/METHODS:We developed a new deep learning approach, which employs a long short-term memory (LSTM) network architecture (``IEDnet'') and an auxiliary classifier generative adversarial network (AC-GAN), to train on both expert-annotated and augmented spike events from intracranial electroencephalography (iEEG) recordings of epilepsy patients. We validated our IEDnet with two real-world iEEG datasets, and compared IEDnet with the support vector machine (SVM) and random forest (RF) classifiers on their detection performances. MAIN RESULTS/RESULTS:IEDnet achieved excellent cross-validated detection performances in terms of both sensitivity and specificity, and outperformed SVM and RF. Synthetic spike samples augmented by AC-GAN further improved the detection performance. In addition, the performance of IEDnet was robust with respect to the sampling frequency and noise. Furthermore, we also demonstrated the cross-institutional generalization ability of IEDnet while testing between two datasets. SIGNIFICANCE/CONCLUSIONS:IEDnet achieves excellent detection performances in identifying interictal spikes. AC-GAN can produce augmented iEEG samples to improve supervised deep learning.

The frontal cortex, especially the anterior cingulate cortex area (ACA), is essential for exerting cognitive control after errors, but the mechanisms that enable modulation of attention to improve performance after errors are poorly understood. Here we demonstrate that during a mouse visual attention task, ACA neurons projecting to the visual cortex (VIS; ACA_VIS neurons) are recruited selectively by recent errors. Optogenetic manipulations of this pathway collectively support the model that rhythmic modulation of ACA_VIS neurons in anticipation of visual stimuli is crucial for adjusting performance following errors. 30-Hz optogenetic stimulation of ACA_VIS neurons in anesthetized mice recapitulates the increased gamma and reduced theta VIS oscillatory changes that are associated with endogenous post-error performance during behavior and subsequently increased visually evoked spiking, a hallmark feature of visual attention. This frontal sensory neural circuit links error monitoring with implementing adjustments of attention to guide behavioral adaptation, pointing to a circuit-based mechanism for promoting cognitive control.

Somatodendritic dopamine (DA) release from midbrain DA neurons activates D2 autoreceptors on these cells to regulate their activity. However, the source of autoregulatory DA remains controversial. Here, we test the hypothesis that D2 autoreceptors on a given DA neuron in the substantia nigra pars compacta (SNc) are activated primarily by DA released from that same cell, rather than from its neighbors. Voltage-clamp recording allows monitoring of evoked D2-receptor-mediated inhibitory currents (D2ICs) in SNc DA neurons as an index of DA release. Single-cell application of antibodies to Na⁺ channels via the recording pipette decreases spontaneous activity of recorded neurons and attenuates evoked D2ICs; antibodies to SNAP-25, a soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein, also decrease D2IC amplitude. Evoked D2ICs are nearly abolished by the light chain of botulinum neurotoxin A, which cleaves SNAP-25, whereas synaptically activated GABA_B-receptor-mediated currents are unaffected. Thus, somatodendritic DA release in the SNc autoinhibits the neuron that releases it.

Vagus nerve stimulation (VNS) suppresses inflammation and autoimmune diseases in preclinical and clinical studies. The underlying molecular, neurological, and anatomical mechanisms have been well characterized using acute electrophysiological stimulation of the vagus. However, there are several unanswered mechanistic questions about the effects of chronic VNS, which require solving numerous technical challenges for a long-term interface with the vagus in mice. Here, we describe a scalable model for long-term VNS in mice developed and validated in 4 research laboratories. We observed significant heart rate responses for at least 4 weeks in 60-90% of animals. Device implantation did not impair vagus-mediated reflexes. VNS using this implant significantly suppressed TNF levels in endotoxemia. Histological examination of implanted nerves revealed fibrotic encapsulation without axonal pathology. This model may be useful to study the physiology of the vagus and provides a tool to systematically investigate long-term VNS as therapy for chronic diseases modeled in mice.

Gamma oscillations are thought to coordinate the spike timing of functionally specialized neuronal ensembles across brain regions. To test this hypothesis, we optogenetically perturbed gamma spike timing in the rat medial (MEC) and lateral (LEC) entorhinal cortices and found impairments in spatial and object learning tasks, respectively. MEC and LEC were synchronized with the hippocampal dentate gyrus through high- and low-gamma-frequency rhythms, respectively, and engaged either granule cells or mossy cells and CA3 pyramidal cells in a task-dependent manner. Gamma perturbation disrupted the learning-induced assembly organization of target neurons. Our findings imply that pathway-specific gamma oscillations route task-relevant information between distinct neuronal subpopulations in the entorhinal-hippocampal circuit. We hypothesize that interregional gamma-time-scale spike coordination is a mechanism of neuronal communication.

PROBLEM/OBJECTIVE:Physician-scientists are individuals trained in both clinical practice and scientific research. Often, the goal of physician-scientist training is to address pressing questions in biomedical research. The established pathways to formally train such individuals are, mainly, MD-PhD programs and physician-scientist track residencies. Although graduates of these pathways are well equipped to be physician-scientists, numerous factors, including funding and length of training, discourage application to such programs and impede success rates. APPROACH/METHODS:To address some of the pressing challenges in training and retaining burgeoning physician-scientists, New York University Grossman School of Medicine formed the Accelerated MD-PhD-Residency Pathway in 2016. This pathway builds on the previously established accelerated three-year MD pathway to residency at the same institution. The Accelerated MD-PhD-Residency Pathway conditionally accepts MD-PhD trainees to a residency position at the same institution through the National Resident Matching Program. OUTCOMES/RESULTS:Since its inception, 2 students have joined the Accelerated MD-PhD-Residency Pathway, which provides protected research time in their chosen residency. The pathway reduces the time to earn an MD and PhD by one year and reduces the MD training phase to three years, reducing the cost and lowering socioeconomic barriers. Remaining at the same institution for residency allows for the growth of strong research collaborations and mentoring opportunities, which foster success. NEXT STEPS/UNASSIGNED:The authors and institutional leaders plan to increase the number of trainees that are accepted into the Accelerated MD-PhD-Residency Pathway and track the success of these students through residency and into practice to determine if the pathway is meeting its goal of increasing the number of practicing physician-scientists. The authors hope this model can serve as an example to leaders at other institutions who may wish to adopt this pathway for the training of their MD-PhD students.

BACKGROUND: Primary hyperoxaluria (PH) is a family of rare genetic disorders affecting 1-3 per 1 million persons globally. PH causes hepatic oxalate overproduction leading to increased urinary oxalate excretion, that can result in frequent kidney stone events, progression to end-stage kidney disease (ESKD) and then other systemic morbidities.
OBJECTIVE(S): To assess the burden of PH among patients and caregivers with respect to healthcare resource utilization (HRU), quality of life (QoL) and work productivity.
METHOD(S): An IRB-approved web survey was conducted among adults (>= 18 years) with PH, and caregivers of children (< 17 years) with PH in the US. Participants were asked about their or their child's medical care, HRU and QoL. The Kidney Disease Quality of Life (KDQOL-36TM: range 0-100, higher score = better QOL) and Work Productivity and Activity Impairment (WPAI: range 0-100%, higher score = more impairment) questionnaires were administered. Descriptive statistics summarized the responses.
RESULT(S): Patient sample (n = 21) comprised 7 adults (median age 42 years) and 14 children (median age 8 years). Patients' HRU consisted of visits to nephrologists (81%), urologists (67%) and ophthalmologists (10%). 33% visited the emergency room and 29% were hospitalized. Patients on dialysis (n = 5) spent a median of 24 hours per week receiving dialysis. PH complications included kidney stone events (95%), pain (71%, nearly all moderate-severe) and nephrocalcinosis (48%). 48% of all patients experienced PH-related anxiety. Adult patients' mean KDQOL-36TM domain scores (burden, symptoms/problems and effects of kidney disease) were 38 (SD = 23), 77 (SD = 23) and 65 (SD = 26), respectively. Employed adult patients (n = 4) reported 25% presenteeism (reduced productivity at work) on average based on the WPAI. Children missed a median of 15 hours/month of school due to their PH. Caregivers (n = 13) experienced moderate-severe anxiety about the possibility of future PH-related outcomes (i.e., kidney stones [54%], kidney disease progression [62%] and ESKD [62%]) for their child. Employed caregivers (n = 9) reported 28% presenteeism on average based on the WPAI.
CONCLUSION(S): This research quantifies the burden of PH in terms of HRU, QoL and productivity for patients and caregivers. Patients experienced considerable clinical sequalae associated with PH, such as kidney stones and pain, which appear to negatively affect these outcomes. Numerous clinician visits indicated an intensive level of care. Further, PH burden goes beyond the patient, as evidenced by caregiver burden, including anxiety and impact on work productivity

PURPOSE/OBJECTIVE:The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA. METHODS:Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations. RESULTS:The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others. CONCLUSIONS:Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.

We describe 4 cases of spinal cord ischemia resulting in paraplegia after peripheral venoarterial extracorporeal membrane oxygenation for cardiogenic shock. This is an uncommon, but possibly underreported, complication with significant irreversible long-term morbidity. While causes are likely multifactorial, it is possible that thrombosis may occur at the level of the mixing cloud due to turbulent flow. Additional studies will be needed to elucidate the true incidence of this complication and investigate whether flow dynamics may potentiate clot formation.