Faculty Bibliography

Rationale: Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is characterized by global developmental impairment and early-onset, refractory seizures. In a recent placebo-controlled study, ganaxolone reduced major motor seizure frequency (MMSF) in patients with CDD. Here we report further data at a minimum of 1-year in the open-label extension (OLE).
Method(s): Patients with CDD (aged 2-19 years) who completed the double-blind phase were eligible to receive ganaxolone in the OLE. Assessments included changes in MMSF from pre-randomization baseline to 3-month intervals in the OLE, responder rates (>=50% and >=75% MMSF reductions), Clinical Global Impression of Improvement (CGI-I), safety, and tolerability.
Result(s): Eighty-eight patients (87.1%; median age of 5; 79.5% female) continued into the OLE (101 were randomized to the double-blind study). Median baseline 28-day MMSF was 50.6. The 1-year retention rate was 70.5% with 26 discontinuations. At the time of analysis, 34 participants had discontinued due to lack of efficacy (n = 12), adverse event (n = 10), or withdrawal by caregiver (n = 10) as the most common reasons. During months 1-3, 4-6, 7-9, and 10-12, patients experienced a median reduction in MMSF of 24.7%, 32.1%, 30.0%, and 42.2%, respectively. During months 13-24, MMSF reductions ranged from 44.2% to 56.1%. At 1 year, 46.3% and 23.9% of patients experienced a >=50% and >=75% reduction in MMSF, respectively. In the OLE, clinicians and caregivers rated 60.6% and 72.5% of the patients, respectively, as improved at 1 year. The most commonly reported adverse events were seizure (22.7%), somnolence (20.5%), vomiting (18.2%), and pyrexia (17.0%). There was one death reported due to sepsis, but it was deemed unrelated to study treatment.
Conclusion(s): Reductions in MMSF at 1 year and beyond provide supportive evidence for the maintenance of effect of ganaxolone in seizures associated with CDD. Ganaxolone was generally well-tolerated in the OLE with safety findings consistent with the double-blind phase

OBJECTIVE:Identify molecular mechanisms in brain tissue of Rasmussen encephalitis (RE) when compared to people with non-RE epilepsy (PWE) and control cases using whole exome sequencing (WES), RNAseq, and proteomics. METHODS:Frozen brain tissue (ages 2-19 years) was obtained from control autopsy (n=14), surgical PWE (n=10), and surgical RE cases (n=27). We evaluated WES variants in RE associated with epilepsy, seizures, RE, and human leukocyte antigens (HLAs). Differential expression was evaluated by RNAseq (adjusted p<0.05) and label-free quantitative mass spectrometry (false discovery rate<5%) in the three groups. RESULTS:, z=5.61). Proteomics detected fewer altered targets. SIGNIFICANCE/CONCLUSIONS:In RE, we identified activated immune signaling pathways and immune cell type annotation enrichment that suggest roles of the innate and adaptive immune responses, as well as HLA variants that may increase vulnerability to RE. Follow up studies could evaluate cell type density and subregional localization associated with top targets, clinical history (neuropathology, disease duration), and whether modulating crosstalk between dendritic and natural killer cells may limit disease progression.

The utility of symptom (SVT) and performance (PVT) validity tests has been independently established in neuropsychological evaluations, yet research on the relationship between these two types of validity indices is limited to circumscribed populations and measures. This study examined the relationship between SVTs on the Minnesota Multiphasic Personality Inventory-2-Restructured Form (MMPI-2-RF) and PVTs in a mixed neuropsychiatric setting. This cross-sectional study included data from 181 diagnostically and demographically diverse patients with neuropsychiatric conditions referred for outpatient clinical neuropsychological evaluation at an academic medical center. All patients were administered a uniform neuropsychological battery, including the MMPI-2-RF and five PVTs (i.e., Dot Counting Test; Medical Symptom Validity Test; Reliable Digit Span; Test of Memory Malingering-Trial 1; Word Choice Test). Nonsignificant associations emerged between SVT and PVT performance. Although the Response Bias Scale was most predictive of PVT performance, MMPI-2-RF SVTs generally had low classification accuracy for predicting PVT performance. Neuropsychological test performance was related to MMPI-2-RF SVT status only when overreporting elevations were at extreme scores. The current study further supports that SVTs and PVTs measure unique and dissociable constructs among diverse patients with neuropsychiatric conditions, consistent with literature from other clinical contexts. Therefore, objective evidence of symptom overreporting on MMPI-2-RF SVTs cannot be interpreted as definitively indicating invalid performance on tests of neurocognitive abilities. As such, clinicians should include both SVTs and PVTs as part of a comprehensive neuropsychological evaluation as they provide unique information regarding performance and symptom validity.

GABAergic inhibitory neurons are the principal source of inhibition in the brain. Traditionally, their role in maintaining the balance of excitation-inhibition has been emphasized. Beyond homeostatic functions, recent circuit mapping and functional manipulation studies have revealed a wide range of specific roles that GABAergic circuits play in dynamically tilting excitation-inhibition coupling across spatio-temporal scales. These span from gating of compartment- and input-specific signaling, gain modulation, shaping input-output functions and synaptic plasticity, to generating signal-to-noise contrast, defining temporal windows for integration and rate codes, as well as organizing neural assemblies, and coordinating inter-regional synchrony. GABAergic circuits are thus instrumental in controlling single-neuron computations and behaviorally-linked network activity. The activity dependent modulation of sensory and mnemonic information processing by GABAergic circuits is pivotal for the formation and maintenance of episodic memories in the hippocampus. Here, we present an overview of the local and long-range GABAergic circuits that modulate the dynamics of excitation-inhibition and disinhibition in the main output area of the hippocampus CA1, which is crucial for episodic memory. Specifically, we link recent findings pertaining to GABAergic neuron molecular markers, electrophysiological properties, and synaptic wiring with their function at the circuit level. Lastly, given that area CA1 is particularly impaired during early stages of Alzheimer's disease, we emphasize how these GABAergic circuits may contribute to and be involved in the pathophysiology.

BACKGROUND:Children with familial dysautonomia (FD) are smaller and grow more slowly than the general population. It is unknown whether this abnormal growth is due to comorbidities that patients with FD live with, or if it is a direct effect of the disease-causing homozygous ELP-1 mutations. Here, we created growth curves for weight, height, and body mass index (BMI) in male and female children with FD to monitor the nutritional status of patients with FD. METHODS:We used the New York University (NYU) FD Registry which includes data from 680 individuals with FD who were followed longitudinally since birth. We generated sex-specific FD growth charts for three age ranges (birth to 36 months, 2 to 20 years, and 2 to 40 years) and compared them to the general population. We generated Kaplan-Meier curves to test the hypothesis that FD patients with low BMI had shorter survival than the rest of the cohort. RESULTS:Growth charts generated from 591 individuals with FD show that these patients grow more slowly, reach less height, and gain less weight than the general population. The impact of FD on height was more pronounced in girls than in boys. However, both groups showed markedly low weights, which resulted in low BMI. Low weight, but not height, is already evident at birth. In a subpopulation of FD patients, we found that treatment with growth hormone or spinal fusion surgery helped patients achieve the expected growth characteristic of FD patients, but these treatments did not lead FD patients to achieve the growth pattern of the general population. Contrary to our hypothesis, low BMI had no impact on patient survival. CONCLUSIONS:Pediatric patients with FD have lower height, weight, and BMI compared to the general pediatric population, but this does not appear to affect survival. Growth curves specific to the FD population are an important tool to monitor growth and nutritional status in pediatric patients with FD when the general population growth curves are of limited use.

BACKGROUND/UNASSIGNED:Currently, there are no FDA approved therapies for persistent post-traumatic headache (PPTH) secondary to traumatic brain injury (TBI). As such neither headache nor TBI specialists have an effective means to manage PPTH. Thus, the objective of the present pilot trial was to evaluate the feasibility and preliminary efficacy of a four-week at-home remotely supervised transcranial direct current stimulation (RS-tDCS) intervention for veterans with PPTH. METHODS/UNASSIGNED: = 13) RS-tDCS, with anodal stimulation over left dlPFC and cathodal over occipital pole. Following a four-week baseline, participants completed 20-sessions of active or sham RS-tDCS with real-time video monitoring over a period of four-weeks. Participants were assessed again at the end of the intervention and at four-weeks post-intervention. Primary outcomes were overall adherence rate (feasibility) and change in moderate-to-severe headache days per month (efficacy). Secondary outcomes were changes in total number of headache days, and PPTH-related functional outcomes. RESULTS/UNASSIGNED: = 0.03), compared to sham during-treatment (-4.0 ± 5.2 vs. 1.5 ± 3.8), and 4-week follow-up (-2.1 ± 7.2 vs. -0.2 ± 4.4). CONCLUSION/UNASSIGNED:The current results indicate our RS-tDCS paradigm provides a safe and effective means for reducing the severity and number of headache days in veterans with PPTH. High treatment adherence rate and the remote nature of our paradigm indicate RS-tDCS may be a feasible means to reduce PPTH, especially for veterans with limited access to medical facilities.Clinical Trial Registration: ClinicalTrials.gov, identifier [NCT04012853].

BACKGROUND/UNASSIGNED:Extreme Lateral Lumbar Interbody Fusions (XLIF), Oblique Lateral Interbody Fusion (OLIF,) and Lateral Lumbar Interbody Fusion (LLIF) were largely developed to provide indirect lumbar decompressions for spinal stenosis, deformity, and/or instability. METHODS/UNASSIGNED:Here, we have reviewed and updated the incidence of intraoperative errors attributed to XLIF, OLIF, and LLIF. Specifically, we focused on how often these procedures caused new neurological deficits, major vessel, visceral, and other injuries, including those warranting secondary surgery. RESULTS/UNASSIGNED:Performing XLIF, OLIF, and LLIF can lead to significant intraoperative surgical errors that include varying rates of; new neurological injuries (i.e. iliopsoas motor deficits (4.3-19.7-33.6-40%), proximal hip/upper thigh sensory loss/dysesthesias (5.1% to 21.7% to 40%)), life-threatneing vascular injuries (i.e., XLIF (0% - 0.4%-1.8%), OLIF (3.2%), and LLIF (2%) involving the aorta, iliac artery, inferior vena cava, iliac vein, and segmental arteries), and bowel/viscarl injuries (0.03%-0.4%) leading to reoperations (i.e., XLIF (1.8%) vs. LLIF (3.8%) vs. XLIF/LLIF/OLIF 2.2%)). CONCLUSION/UNASSIGNED:Varying reports documented that XLIF, OLIF and LLIF caused up to a 40% incidence of new sensory/motor deficits, up to a 3.2% incidence of major vascular insults, a 0.4% frequency of visceral/bowel perforations, and a 3.8% need for reoperations. These high frequencies of intraoperative surgical errors attributed to XLIF, OLIF, and LLIF should prompt reconsideration of whether these procedures are "safe."

INTRODUCTION/UNASSIGNED:Extracting regularities from ongoing stimulus streams to form predictions is crucial for adaptive behavior. Such regularities exist in terms of the content of the stimuli and their timing, both of which are known to interactively modulate sensory processing. In real-world stimulus streams such as music, regularities can occur at multiple levels, both in terms of contents (e.g., predictions relating to individual notes vs. their more complex groups) and timing (e.g., pertaining to timing between intervals vs. the overall beat of a musical phrase). However, it is unknown whether the brain integrates predictions in a manner that is mutually congruent (e.g., if "beat" timing predictions selectively interact with "what" predictions falling on pulses which define the beat), and whether integrating predictions in different timing conditions relies on dissociable neural correlates. METHODS/UNASSIGNED:= 20) performing a repetition detection task. RESULTS/UNASSIGNED:Our results reveal that temporal predictions based on beat or interval timing modulated mismatch responses to violations of "what" predictions happening at the predicted time points, and that these modulations were shared between types of temporal predictions in terms of the spatiotemporal distribution of EEG signals. Effective connectivity analysis using dynamic causal modeling showed that the integration of "what" and "when" predictions selectively increased connectivity at relatively late cortical processing stages, between the superior temporal gyrus and the fronto-parietal network. DISCUSSION/UNASSIGNED:Taken together, these results suggest that the brain integrates different predictions with a high degree of mutual congruence, but in a shared and distributed cortical network. This finding contrasts with recent studies indicating separable mechanisms for beat-based and memory-based predictive processing.