Faculty Bibliography

BACKGROUND:Evidence suggests that adverse childhood experiences (ACEs) predict cognitive dysfunction, possibly through direct (e.g., brain structure/function changes) and indirect (e.g., increased psychopathology risk) pathways. However, extant studies have focused on young and older adults, with limited understanding of how ACEs affect cognitive health in midadulthood. OBJECTIVE:This study compared psychiatric and cognitive differences between adults at high- and low-risk of adverse health outcomes based on the ACE risk classification scheme. PARTICIPANTS AND SETTING/METHODS: METHOD/METHODS:Patients were divided into high and low ACE groups based on the number of ACEs endorsed. Subsequently, a series of one-way analyses of variances were conducted to compare high versus low ACE groups on the Test of Premorbid Functioning, Wechsler Adult Intelligence Scale-Fourth Edition Digit Span Test, Trail Making Test-Parts A and B, Rey Auditory Verbal Learning Test, Beck Depression Inventory-II, and Beck Anxiety Inventory scores. RESULTS:Significant group differences were detected for anxiety and depression with the high ACE group endorsing significantly greater depression and anxiety symptoms relative to the low ACE group. High and low ACE groups did not significantly differ on any cognitive measures. CONCLUSIONS:Results indicate that an individual's psychological health, but not cognitive functioning, is impacted by the level of ACE exposure. Study findings highlight the importance of including ACE measures in neuropsychological evaluations, as it will aid in case conceptualization and tailoring treatment recommendations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

PURPOSE OF REVIEW/OBJECTIVE:Chronic headaches are a significant source of disability worldwide. Despite the development of conventional strategies, a subset of patients remain refractory and/or experience side effects following these treatments. Hence, occipital nerve stimulation (ONS) should be considered as an alternative strategy for intractable chronic headaches. This review aims to provide a comprehensive overview of the effectiveness, safety, mechanisms and practical application of ONS for the treatment of headache disorders. RECENT FINDINGS/RESULTS:Overall response rate of ONS is 35.7-100%, 17-100%, and 63-100% in patients with cluster headache, chronic migraine and occipital neuralgia respectively. Regarding the long-term effectivity in all groups, 41.6-88.0% of patients remain responders after ≥ 18.3 months. The most frequently reported adverse events include lead migration/fracture (13%) and local pain (7.3%). Based on our results, ONS can be considered a safe and effective treatment for chronic intractable headache disorders. To support more widespread application of ONS, additional research with larger sample sizes should be conducted.

Cenobamate has demonstrated efficacy in patients with treatment-resistant epilepsy, including patients who continued to have seizures after epilepsy surgery. This article provides recommendations for cenobamate use in patients referred for epilepsy surgery evaluation. A panel of six senior epileptologists from the United States and Europe with experience in presurgical evaluation of patients with epilepsy and in the use of antiseizure medications (ASMs) was convened to provide consensus recommendations for the use of cenobamate in patients referred for epilepsy surgery evaluation. Many patients referred for surgical evaluation may benefit from ASM optimization; both ASM and surgical treatment should be individualized. Based on previous clinical studies and the authors' clinical experience with cenobamate, a substantial proportion of patients with treatment-resistant epilepsy can become seizure-free with cenobamate. We recommend a cenobamate trial and ASM optimization in parallel with presurgical evaluations. Cenobamate can be started before phase two monitoring, especially in patients who are found to be suboptimal surgery candidates. As neurostimulation therapies are generally palliative, we recommend trying cenobamate before vagus nerve stimulation (VNS), deep brain stimulation, or responsive neurostimulation (RNS). In surgically remediable cases (mesial temporal sclerosis, benign discrete lesion in non-eloquent cortex, cavernous angioma, etc.), cenobamate use should not delay imminent surgery; however, a patient may decide to defer or even cancel surgery should they achieve sustained seizure freedom with cenobamate. This decision should be made on an individual, case-by-case basis based on seizure etiology, patient preferences, potential surgical risks (mortality and morbidity), and likely surgical outcome. The addition of cenobamate after unsuccessful surgery or palliative neuromodulation may also be associated with better outcomes.

Alzheimer's disease (AD) is a devastating, age-associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ-targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD-related pathologies, such as NFTs, are not directly targeted. A non-mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD-related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. ANN NEUROL 2024.

OnabotulinumtoxinA (onabotA) is approved in the US for 12 therapeutic indications. Real-world data on onabotA multi-indication use are limited, often leading to delayed or reduced treatment. This study provides real-world evidence on the safety of onabotA when treating multiple indications concomitantly. SYNCHRONIZE was a multicenter, retrospective, chart-review study evaluating onabotA's safety for adults treated for ≥2 therapeutic indications within a 3-month period. The primary outcome was treatment-emergent adverse events (TEAEs) within 6 months post-treatment. A total of 279 patients were included. The most common concomitant indications treated were cervical dystonia and chronic migraine (43.4%). The average 3-month cumulative dose for multiple indications was 282.2 U. The treatment interval for multiple indications was ≤24 h for most patients (62.4%). Overall, 28.7% of patients reported ≥1 TEAE with no apparent trends in TEAEs and dose interval or cumulative dose. Reported TEAEs included UTI (5.7%), neck pain (5.0%), and headache (4.3%). No patient had a lack of effect according to clinical objective measurements. SYNCHRONIZE described the real-world safety of onabotA for patients treated concomitantly for ≥2 indications within a 3-month period. TEAEs were generally consistent with the known safety profiles of individual indications. No new safety signals were identified).

Nilotinib, a tyrosine kinase inhibitor that targets the Abelson tyrosine kinase (c-Abl) signaling pathway, is FDA-approved to treat chronic myeloid leukemia. Nilotinib has properties indicative of a possible utility in neuroprotection that have prompted exploration of repurposing the drug for the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD). AD is a progressive age-related neurodegenerative disorder characterized by the deposition of extracellular amyloid-β plaques and intracellular neurofibrillary tangles. It is incurable and affects approximately 50 million patients worldwide. Nilotinib reduces c-Abl phosphorylation, amyloid-β levels, and dopaminergic neuron degeneration in preclinical AD models. This study explores the effects of nilotinib on amyloid processing and mitochondrial functioning in the SH-SY5Y human neuroblastoma cell line. SH-SY5Y cells were exposed to nilotinib (1, 5, and 10 µM). Real-time PCR and immunoblot analysis were performed to quantify the expression of genes pertaining to amyloid-β processing and neuronal health. Nilotinib did not significantly change APP, BACE1, or ADAM10 mRNA levels. However, BACE1 protein was significantly increased at 1 µM, and ADAM10 was increased at 10 µM nilotinib without affecting APP protein expression. Further, nilotinib treatment did not affect the expression of genes associated with neuronal health and mitochondrial functioning. Taken together, our findings do not support the efficacy of nilotinib treatment for neuroprotection.

DHPS deficiency syndrome is an ultra-rare neurodevelopmental disorder (NDD) which results from biallelic mutations in the gene encoding the enzyme deoxyhypusine synthase (DHPS). DHPS is essential to synthesize hypusine, a rare amino acid formed by post-translational modification of a conserved lysine in eukaryotic initiation factor 5 A (eIF5A). DHPS deficiency syndrome causes epilepsy, cognitive and motor impairments, and mild facial dysmorphology. In mice, a brain-specific genetic deletion of Dhps at birth impairs eIF5A^HYP-dependent mRNA translation. This alters expression of proteins required for neuronal development and function, and phenotypically models features of human DHPS deficiency. We studied the role of DHPS in early brain development using a zebrafish loss-of-function model generated by knockdown of dhps expression with an antisense morpholino oligomer (MO) targeting the exon 2/intron 2 (E2I2) splice site of the dhps pre-mRNA. dhps knockdown embryos exhibited dose-dependent developmental delay and dysmorphology, including microcephaly, axis truncation, and body curvature. In dhps knockdown larvae, electrophysiological analysis showed increased epileptiform activity, and confocal microscopy analysis revealed reduced arborisation of GABAergic neurons. Our findings confirm that hypusination of eIF5A by DHPS is needed for early brain development, and zebrafish with an antisense knockdown of dhps model features of DHPS deficiency syndrome.

BACKGROUND:Disorders of consciousness (DoC) are frequently encountered in both, acute and chronic brain injuries. In many countries, early withdrawal of life-sustaining treatments is common practice for these patients even though the accuracy of predicting recovery is debated and delayed recovery can be seen. In this review, we will discuss theoretical concepts of consciousness and pathophysiology, explore effective strategies for management, and discuss the accurate prediction of long-term clinical outcomes. We will also address research challenges. MAIN TEXT/METHODS:DoC are characterized by alterations in arousal and/or content, being classified as coma, unresponsive wakefulness syndrome/vegetative state, minimally conscious state, and confusional state. Patients with willful modulation of brain activity detectable by functional MRI or EEG but not by behavioral examination is a state also known as covert consciousness or cognitive motor dissociation. This state may be as common as every 4th or 5th patient without behavioral evidence of verbal command following and has been identified as an independent predictor of long-term functional recovery. Underlying mechanisms are uncertain but intact arousal and thalamocortical projections maybe be essential. Insights into the mechanisms underlying DoC will be of major importance as these will provide a framework to conceptualize treatment approaches, including medical, mechanical, or electoral brain stimulation. CONCLUSIONS:We are beginning to gain insights into the underlying mechanisms of DoC, identifying novel advanced prognostication tools to improve the accuracy of recovery predictions, and are starting to conceptualize targeted treatments to support the recovery of DoC patients. It is essential to determine how these advancements can be implemented and benefit DoC patients across a range of clinical settings and global societal systems. The Curing Coma Campaign has highlighted major gaps knowledge and provides a roadmap to advance the field of coma science with the goal to support the recovery of patients with DoC.

INTRODUCTION AND PROBLEM STATEMENT/UNASSIGNED:A chief resident's role incorporates administrative, academic, and interpersonal responsibilities essential to managing a successful residency program. However, rising chief residents receive little formal exposure to leadership training. OBJECTIVES/UNASSIGNED:To (1) define leadership styles; (2) understand the effect of cultural competence on leadership styles; (3) learn effective methods to advocate as the chief resident; (4) provide effective peer feedback; (5) provide effective supervisor feedback; (6) learn effective conflict management; (7) ensure psychological safety. METHODS AND CURRICULUM DESCRIPTION/UNASSIGNED:We developed a 1-day curriculum combining didactics and simulation activities for our program's rising chief residents. Implementation of our curricular design included a morning session focusing on small groups and didactic-based lectures on specific topics pertinent to leadership, along with a debriefing of a psychometric evaluation tool administered before the curriculum day. The simulation activity consisted of 3 group objective structured clinical examination (G-OSCE) scenarios: (1) providing a struggling junior trainee with feedback; (2) debriefing an adverse clinical outcome as the team leader; (3) navigating a challenging situation with a supervising physician. Standardized participants were surveyed for specific objectives. Learners completed precurricular and postcurricular surveys on their familiarity and preparedness for their chief year. RESULTS AND ASSESSMENT DATA/UNASSIGNED:= 0.421), learner-reported use of wellness resources was noted to be reduced after the curricular intervention and remains a result of further interest for exploration. DISCUSSION AND LESSONS LEARNED/UNASSIGNED:A 1-day leadership development curriculum combining didactics and simulation is an effective means of preparing rising chief residents to succeed in their transition to this leadership role.

OBJECTIVE/UNASSIGNED:This study investigates speech decoding from neural signals captured by intracranial electrodes. Most prior works can only work with electrodes on a 2D grid (i.e., Electrocorticographic or ECoG array) and data from a single patient. We aim to design a deep-learning model architecture that can accommodate both surface (ECoG) and depth (stereotactic EEG or sEEG) electrodes. The architecture should allow training on data from multiple participants with large variability in electrode placements and the trained model should perform well on participants unseen during training. APPROACH/UNASSIGNED:We propose a novel transformer-based model architecture named SwinTW that can work with arbitrarily positioned electrodes, by leveraging their 3D locations on the cortex rather than their positions on a 2D grid. We train both subject-specific models using data from a single participant as well as multi-patient models exploiting data from multiple participants. MAIN RESULTS/UNASSIGNED:The subject-specific models using only low-density 8x8 ECoG data achieved high decoding Pearson Correlation Coefficient with ground truth spectrogram (PCC=0.817), over N=43 participants, outperforming our prior convolutional ResNet model and the 3D Swin transformer model. Incorporating additional strip, depth, and grid electrodes available in each participant (N=39) led to further improvement (PCC=0.838). For participants with only sEEG electrodes (N=9), subject-specific models still enjoy comparable performance with an average PCC=0.798. The multi-subject models achieved high performance on unseen participants, with an average PCC=0.765 in leave-one-out cross-validation. SIGNIFICANCE/UNASSIGNED:The proposed SwinTW decoder enables future speech neuroprostheses to utilize any electrode placement that is clinically optimal or feasible for a particular participant, including using only depth electrodes, which are more routinely implanted in chronic neurosurgical procedures. Importantly, the generalizability of the multi-patient models suggests the exciting possibility of developing speech neuroprostheses for people with speech disability without relying on their own neural data for training, which is not always feasible.