United States

Opioids are a leading cause of overdose-related deaths in the US, accounting for 70.6% of fatalities in 2019 due primarily to respiratory depression. Epidural electrical stimulation (EES) has emerged as a novel approach for facilitating rhythmic movement such as respiration in humans and rodent models. To reveal the mechanism underpinning modulation of respiratory neural circuits, we compared the effects of dorsal and ventral cervical epidural electrical stimulation (D-CEES, V-CEES) on respiration after opioid-induced respiratory suppression or depression (OIRD) via administration of remifentanil in anesthetized patients undergoing medically necessary spinal cord surgery. We hypothesized that V-CEES activates ventral horn motoneurons while D-CEES recruits local spinal circuits and tracts to supraspinal structures. We enrolled 43 patients receiving opioids during ventral (n = 25) and dorsal (n = 18) cervical spinal surgery. EES was delivered to the spinal cord (C2-C7) for &lt;90 seconds at an optimal intensity (0.5-5mA) at 5Hz or 30Hz. The subjects’ vital signs were recorded intraoperatively. Electromyograms (EMG) were used to monitor respiratory and upper extremity muscles such as the diaphragm, laryngeal, intercostal, genioglossal, and deltoid muscles bilaterally. The anesthesia stage was measured via electroencephalogram (EEG). A pneumotach recorded each patient’s airway pressure. An independent anesthesiologist, tasked with ensuring patient safety, maintained a stable surgical plane of anesthesia via propofol in conjunction with minimal remifentanil prior to EES. We divided the responses into 2 states: ON- and OFF-State. The ON-State condition was defined as suppressed, but still present, respiration compared to baseline through an additional dose of remifentanil (0.001-.05mcg/kg/min). OFF-State condition was produced by dosing the subject with the lowest sufficient concentration of remifentanil (0.05-0.1mcg/kg/min) necessary to induce apnea. We observed four main differences between D- and V-CEES in regulating respiration in the presence of remifentanil: 1) D-CEES alone induced inspiratory phase resetting; 2) D-CEES induced longer lasting respiratory modulation after EES cessation; 3) D-CEES induced both frequency and tidal volume changes of respiration while V-CEES modulated the tidal volume more significantly; and 4) D-CEES respiratory modulation was inhibited more significantly during the OFF-state, while the most responsive spinal level to V-CEES, C6/7, maintained its respiratory modulation in both ON- and OFF-States. These observations suggest D- and V-CEES facilitate respiration via different neural circuits.


AMA Research Challenge 2023

Dorsal and Ventral Cervical Epidural Electrical Stimulation Opposes Opioid-Induced Respiratory Depression via Different Respiratory Neural Circuits

### Welcome to the 2023 Understanding Interventions/NSF CREST Annual Conference
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15th Conference on Understanding Interventions 2023 

This conference was established to facilitate dissemination and exchange of hypothesis-based research on interventions and initiatives that broaden participation in science and engineering research careers. The conference is designed to create a dialogue among behavioral/social science and education researchers, evaluators, and faculty in STEM (science, technology, engineering, and mathematics) fields who participate in intervention programs.

Opioids are a leading cause of overdose-related deaths in the US, accounting for 70.6% of fatalities in 2019 due primarily to respiratory depression. Epidural electrical stimulation (EES) has emerged as a novel approach for facilitating rhythmic movement such as respiration in humans and rodent models. To reveal the mechanism underpinning modulation of respiratory neural circuits, we compared the effects of dorsal and ventral cervical epidural electrical stimulation (D-CEES, V-CEES) on respiration after opioid-induced respiratory suppression or depression (OIRD) via administration of remifentanil in anesthetized patients undergoing medically necessary spinal cord surgery. We hypothesized that V-CEES activates ventral horn motoneurons while D-CEES recruits local spinal circuits and tracts to supraspinal structures. We enrolled 43 patients receiving opioids during ventral (n = 25) and dorsal (n = 18) cervical spinal surgery. EES was delivered to the spinal cord (C2-C7) for <90 seconds at an optimal intensity (0.5-5mA) at 5Hz or 30Hz. The subjects’ vital signs were recorded intraoperatively. Electromyograms (EMG) were used to monitor respiratory and upper extremity muscles such as the diaphragm, laryngeal, intercostal, genioglossal, and deltoid muscles bilaterally. The anesthesia stage was measured via electroencephalogram (EEG). A pneumotach recorded each patient’s airway pressure. An independent anesthesiologist, tasked with ensuring patient safety, maintained a stable surgical plane of anesthesia via propofol in conjunction with minimal remifentanil prior to EES. We divided the responses into 2 states: ON- and OFF-State. The ON-State condition was defined as suppressed, but still present, respiration compared to baseline through an additional dose of remifentanil (0.001-.05mcg/kg/min). OFF-State condition was produced by dosing the subject with the lowest sufficient concentration of remifentanil (0.05-0.1mcg/kg/min) necessary to induce apnea. We observed four main differences between D- and V-CEES in regulating respiration in the presence of remifentanil: 1) D-CEES alone induced inspiratory phase resetting; 2) D-CEES induced longer lasting respiratory modulation after EES cessation; 3) D-CEES induced both frequency and tidal volume changes of respiration while V-CEES modulated the tidal volume more significantly; and 4) D-CEES respiratory modulation was inhibited more significantly during the OFF-state, while the most responsive spinal level to V-CEES, C6/7, maintained its respiratory modulation in both ON- and OFF-States. These observations suggest D- and V-CEES facilitate respiration via different neural circuits.

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Introduction: Increasing frailty is a significant determinant of perioperative morbidity and mortality within neurosurgical literature. This study investigates the predictive value of the modified frailty index 5 (mFI-5) for postoperative morbidity and mortality following surgical drainage of chronic subdural hematoma (cSDH).

METHODS: A retrospective cohort study was performed on patients who underwent surgical evacuation of a cSDH. The mFI-5 score was calculated for each patient and used to stratify patients: prefrail (mFI-5<2), frail (mFI-5 [ 2), and
severely frail (mFI-5>2). Multivariate Cox proportional hazards (CPH) regression analysis were used to identify factors associated with our primary outcomes: overall
survival and 30-day readmission. Secondary outcomes included nonhome discharge, length of stay, hematoma accumulation, development of new postoperative neurologic deficits, resolution of preoperative neurologic deficits, and a modified Rankin score >2 at discharge.

RESULTS: 118 patients with a mean age of 74.4 +/- 11.9 years were analyzed. All baseline demographics were similar across the 3 groups. On multivariate analysis,
severely frail patients (N [ 24, 20.3%) had increased rates of 30-day readmission (hazard ratio [HR] 4.3, CPH regression P value<0.001) and postoperative mortality (HR 3.1, CPH regression P value<0.01) compared to the prefrail cohort. Severely frail patients had increased rates of nonhome disposition (HR 9.6, CPH regression P value<0.001), development of new postoperative neurologic deficits (HR 2.75, CPH regression P value [ 0.03), and hematoma reaccumulation (HR 4.07, CPH regression
P value [ 0.004). A novel scoring system accounting for patient age and frailty was predictive of 90-day mortality (area under the curve 0.77).

CONCLUSIONS: Frailty, measured by the mFI-5, and our novel scoring system holds a predictive value regarding outcomes for patients undergoing surgical drainage of a
cSDH.

Utility of the mfi-5 Score in Outcome Prediction for Patients with Chronic
Subdural Hematoma

Background
Freezing of gait (FoG) is a symptom of Parkinson Disease (PD) that can interrupt daily life and cause devastating falls. Previous research has demonstrated benefits of cueing on FoG. Many cue modalities are not ideal for real-world applications, affecting social interaction or requiring adherence to cadences. Non-rhythmic, spatial augmented reality (AR) cues are promising in their versatility and user-friendliness but have not proven effective in reducing FoG, possibly due to field-of-view (FOV) limitations of AR headsets or suboptimal control of how cues are displayed. We designed a clinical trial and a novel cue to study how to best utilize non-rhythmic spatial AR cues to treat FoG.
Methods
In this single-center, crossover, unblinded study, 36 PD patients will complete walking tasks in an AR environment projected by the Magic Leap 2 (ML2), a recently released AR headset with a larger FOV than prior models. An AR cue consisting of two concentric circles (designed for use when walking straight or turning) with radii based on stride length will be presented in several randomized variations: constant, user hand-triggered as-needed, user eye-triggered as-needed, examiner-triggered as-needed. AR strategies will be compared to a proven physical cue and a control (no cue) condition. FoG and gait parameters will be compared between the test arms.
Results
So far, fifteen participants have completed the trials. 86.7% said they would use the cue on a daily, real-world basis. The preferred condition varied widely between individuals. The “no cue” condition was never selected as preferred but was selected most frequently as the least preferred. Averaging results across the group, time spent in FoG was lowest in AR cue conditions and highest in the physical cue condition. The top two AR cue conditions per individual significantly reduced time in FoG compared to the physical and no cue conditions. Intermittent and constant AR cueing achieved statistically similar outcomes.
Conclusion
The most effective and preferred manner of AR cueing varies per individual. Visuospatial AR cues can decrease time spent in FoG and perform as well as or better than physical cues.


Optimizing Augmented Reality Cueing Strategies for Freezing of Gait in PD: The ELIMINATE FoG Study

Rationale: 
Our pilot study has shown that electrical stimulation of specific brain regions through responsive neurostimulation (RNS) can improve memory consolidation [1]. This study aims to reinforce and investigate whether responsive neurostimulation (RNS) devices can improve memory function through the administration of verbal and non-verbal learning tasks. We hypothesize that direct cortical stimulation with RNS could improve memory. 

Methods:
In an outpatient setting, a verbal learning task (Hopkins Verbal Learning Test-Revised) was administered to patients with RNS implants in various brain regions (hippocampal, temporal, and insular) [2]. For the verbal task, patients read a list of 12 semantically related words and tried to recall the list in the 3 different trials, along with a delayed recall and recognition trial performed 20 minutes later. True or sham stimulations were administered to patients through Neuropace.

Results:
Most of the 34 participants were right-handed (88.2%) with the remainder being left-handed (11.8%). Of the two RNS electrodes, 44.1% had the first electrode in the hippocampus. Only 28 patients had RNS data collected. A paired two-sided t-test with an alpha level of .05 was performed for all statistical tests. Although current results show no statistical significance, there still is a trend for patients who underwent electrical stimulation at the time of learning to perform better on recall than those who had sham stimulations, especially in the delayed recall trial. ​

Conclusion:
The pilot study found that RNS stimulation can improve memory encoding; however, the smaller sample size prompted continuing investigation and analysis of RNS impact on memory. The current results show a trend for improvement of memory with electrical stimulation during verbal tasks. We plan to acquire more data to more effectively interpret the effects of RNS on memory. 


The Impact of Brain Stimulation on Verbal Memory

Background/ Objectives: 
Migraines are the second leading cause of disability worldwide. However, there is a paucity of research focused on the clinical presentation of chronic migraines (CM) in Native Hawaiians and other Pacific Islanders (NHOPI). This study aims to identify possible differences in the clinical presentation of CM in NHOPI in contrast to other Ethnocultural racial groups in Hawaii.
Methods:
A retrospective case-control study was conducted to examine the relationship between demographics, comorbidities, and chronic migraines. Data from a single neurological care center in Hawaii were used to identify adults aged ≥18 years diagnosed with CM between 2018-2023. Adults with CM were matched for age and sex to 3 controls (patients with radiculopathy who did not present with CM). 
Results:
Overall, 309 CM patients and 964 matched controls were identified for analysis. NHOPI populations accounted for 24.9% of CM and 26% of radiculopathy patients. NHOPIs, on average, were diagnosed with CM or radiculopathy 2-3 years earlier (p=0.07) and had a higher average BMI than their White counterparts (p<0.01). Among NHOPIs, CM cases were more likely to have public insurance coverage (p=0.04), hyperlipidemia (p<0.01), diabetes (p=0.02), and insomnia (p=0.01). They were also more likely to be on more medications than White patients (p<0.001). 
Conclusion:
NHOPI CM patients were more likely to be diagnosed earlier than White patients and had higher BMIs, as well as higher rates of hyperlipidemia, insomnia, diabetes, and polypharmacy. These findings have important implications for understanding underlying comorbidities among NHOPI CM patients and developing targeted interventions.

Chronic Migraine and Comorbidity Characterization: A Focus on Native Hawaiians and Other Pacific Islanders


Background: Rett Syndrome (RTT) is a progressive X-linked neurodevelopmental disorder affecting 1 in 10,000 live female births, caused by deletions in the methyl-CpG binding protein 2 gene (MECP2). It is characterized by developmental regression, stereotypical hand movements, motor dysfunction, language impairments and seizures. Retrospective case reports have indicated atypical pain perception in patients with RTT. Yet, studies in patients and the MeCP2-/+ heterozygous (Het) mouse model of RTT have been inconclusive, with both hypoalgesia and hyperalgesia reported. Since the MeCP2 protein is a critical transcriptional repressor factor expressed in sensory neurons, mechanisms have been speculated for the modulation of pain by MeCP2. However, few studies have explored its role in atypical pain perception with a translational model of RTT. A better characterization of abnormal pain behavior in an RTT model is critical for future mechanistic studies to provide better care for these patients. 

Methods: MeCP2-/+ female mice and age-matched wild-type (WT) female littermates were used. Two different ages were evaluated: 6-8 weeks (pre-symptomatic) and 4 months (symptomatic) when the RTT phenotype was present and consistent. Phenotype was assessed using a neurobehavioral score (looking at paw clench, respiratory pattern, and mobility) along with Catwalk Gait analysis. Pain sensitivity and thresholds were assessed to mechanical (Von Frey test) and heat (Hargreaves test) stimuli.

Results: MeCP2-/+ mice showed variation in their sensitivity to pain as their disease progressed. Pre-symptomatic mice were hypersensitive to both mechanical and thermal pain, shown by increased responses to tactile stimulus on Von Frey filament testing and decreased paw withdrawal latency on thermal Hargreaves testing. However, with the progression of disease phenotype, MeCP2-/+ mice became hyposensitive to both mechanical and thermal pain. These changes appeared to be independent of their motor ability.

Conclusion: MeCP2-/+ female mice represent a useful preclinical RTT model and exhibit abnormal pain behavior, with initial hyperalgesia and eventual hypoalgesia that appears to be independent of motor function. Since MeCP2 overexpression has been associated with increased pain tolerance, lack of MeCP2 in the Het female mice may contribute to the early pain hypersensitivity. Future studies are needed to explore the cellular and molecular mechanisms involved in this altered pain sensation during the progression of RTT and for developing stage-dependent therapeutic targets.

Changes in pain sensitivity with the progression of Rett Syndrome in MeCP2-/+ female mice

Introduction: Diagnostic criteria for Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) are clinical, and determining specific etiology can be difficult even for experienced clinicians. Despite this, it is more important than ever to distinguish the two given the recent advent of novel therapies targeting disease-specific pathophysiologic mechanisms. Since clinical presentation can be nuanced, healthcare providers are increasingly turning to imaging and other biomarkers to aid in diagnosis of FTD and AD, and automated software tools like Neuroreader (NR) have been developed to provide objective, reliable volumetric data from brain imaging. Further, volumetric indices specifically between anterior and posterior brain areas have proved useful in distinguishing types of dementia in research cohorts. However, existing indices can be complicated to use and require further validation in the clinical setting. The objective of this study is to provide initial validation for the use of a simplified, easy-to-use anterior-posterior index (API) from NR data in distinguishing FTD and AD in a clinical cohort.
Methods: A retrospective chart review was completed to gather demographics, memory diagnoses over time, and cognitive screening and NR data in patients at a large academic medical center with a diagnosis of FTD or AD.
We then derived a simplified API to reflect NR data: API=((logV_A/V_P)⁡-μ)/σ where V_A is weighted volume of frontal and temporal lobes and V_P of parietal and occipital lobes derived from NR data. μ and σ are the mean and standard deviation of logV_A/V_P computed for AD patients only. Receiver operating curves (ROC) and 2 separate regression analyses (API and the parietal lobe) assessed the efficacy of the API vs. single brain areas in predicting the diagnosis of AD vs FTD as it was determined clinically using current diagnostic criteria.
Results: 39 patients with FTD and 78 patients with AD were included. The samples are similar in terms of demographics, cognitive testing score, and MRI type. The API had an excellent performance in distinguishing AD from FTD with an area under the curve (AUC) of 0.82 in addition to a positive association with diagnostic classification on logistic regression analysis (B=1.491, p<0.001). Most brain areas in isolation performed poorly, with the exception of the parietal lobe which had an AUC of 0.70, indicating an acceptable performance.
Conclusion: The API biomarker can successfully distinguish AD and FTD with an excellent level of performance, performing better than any studied brain area alone. The results of our study validate the API in a clinical setting and indicate that it could be a useful diagnostic tool for clinicians when distinguishing AD from FTD.

The Use of an Anterior-Posterior Atrophy Index to Distinguish Alzheimer’s Disease from Frontotemporal Disorders: An Automated Volumetric MRI Study

Background Patient-proxies often provide informed consent for neurocritical care research. Informed consent success depends on research staff availability, rapport-building time between patients-proxy, language barriers, health literacy, cultural biases that affect patient comprehension, proxy's distress with acute brain injury news, and perceived patient choices. Pandemic-related visitor restrictions made proxy consents harder to obtain. Two clinical trials highlight the importance of remote e-consent and proposed solutions.
Methods Consent workflow description for Study A utilizing multiple modality e-consent with remote investigators compared to Study B using in-person dedicated staff when remote e-consent was not allowed.
Results 
Study A contacted 51 of 70 eligible patients. Only one consent was obtained in-person during the 3-month recruitment period when IRB only allowed in-person consents. After remote e-consent approval, 50 patient proxies were mailed consent to sign after patient discharge, taking 6 hours of remote-investigator time. Only one returned signed form after 21 days. 49 proxies were phoned by Doximity over 6 months, taking 3.5 min/eligible subject with one redial every month (average 4 calls/subject), with 17 rejected, 11 unreachable. 8/21 phone proxies received DocuSign®-based consent emails and returned signed forms in average 36 days (4 hrs-144 days). Mail yielded 2% and email-based DocuSign consent 38%, compared to 1% in-person. 
Study B: Of 81 eligible over 6 months, 50 consented in-person or by-mail through 3 in-house investigators with a 62% success rate, with average of 48 minutes/consent (15–50 minutes), and 2 consents received by-mail. Getting consent in-person while patient was hospitalized, meeting proxies in parking lots when visiting premises for unrelated purposes, and dedicated unit staff increased success rate.
Conclusion 
Email-based DocuSign® e-consent through remote investigators can overcome pandemic-induced visitor limitations. Our institutional Digital Communications Governance Committee is exploring HIPAA-compliant text-based messaging solutions using cloud-based communication platform (Twilio®) to facilitate remote consenting access.


Pandemic-Induced Challenges in Consenting Patients andProposed Solutions for Neurocritical Care Trials

Background
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. Pupillometry is a noninvasive method to assess for preserved midbrain function. Specifically, poor pupil reactivity has been shown to be an early predictor of neurological deterioration and can signify impending herniation hours before clinical symptoms arise. In patients with TBI, absent pupil reactivity can stratify severity and prognosticate outcome. However, abnormal pupil phenotypes over the first 72 hours in mild, moderate, and severe TBI patients is poorly characterized. We calculated the incidence and burden of abnormal pupil phenotypes and investigated their relationship to unfavorable patient outcome at discharge (death or disposition to hospice or long-term care).
Methods
We performed a single-center retrospective observational study of 137 TBI patients with quantitative pupil measurements using the Neuroptics pupillometer. We calculated the median Neurologic Pupil Index (a metric of pupil reactivity ranging from 0-5) over 72 hours and compared cumulative burdens of abnormal pupil phenotypes (unilateral poor pupil reactivity and bilateral poor pupil reactivity) for mild, moderate, and severe TBI patients using ANOVA tests. We then used logistic regression to test the association of median average NPi and bilateral poor pupil reactivity burden with death or disposition to hospice or long-term care adjusting for age, sex, black race, TBI severity, and penetrating v. blunt injury. 
Results
Of 137 patients, 97 were male and median age was 59 [25th percentile 38, 75th percentile 72], of whom 49 (36%) had unfavorable outcomes. Fifty patients had mild TBI, 21 had moderate and 66 had severe TBI. Unilateral poor pupil reactivity occurred in 12 (24%), 6 (29%) and 32 (48%) patients with mild, moderate, and severe TBI. Bilateral poor pupil reactivity occurred in 3 (6%), 2 (10%), and 19 (29%) patients with mild, moderate, and severe TBI. After adjusting for confounders, median NPi over 72 hours was inversely associated with unfavorable outcome (0.22 [0.07-0.51]; p=0.004), while burden of bilateral poor pupil reactivity was associated with unfavorable outcomes (1.23 [1.08-1.45]; p=0.004).
Conclusion
Lower median NPi and higher burden of bilateral poor pupil reactivity over 72 hours in TBI patients is associated with unfavorable outcomes in TBI patients.

Prognostic Pupil Reactivity Markers within the first 72 hours of Traumatic Brain Injury

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig disease, is a fatal neurodegenerative disease affecting motor neurons in the brain and spinal cord. Progressive muscle weakness, atrophy, and spasticity characterize the condition, which eventually leads to paralysis and respiratory failure. There is currently no cure for ALS, and the standard of care is supportive, with riluzole being one of the few FDA approved medications that has been shown to slightly slow disease progression along with Radicava (edaravone) and RELYVRIO (AMX0035) approved in 2022 with Qalsody (tofersen) being approved in 2023. With limited options for medications, the use of mesenchymal stem cells (MSCs) in the treatment of ALS is a new area of research in regenerative medicine. MSCs are multipotent stem cells that can differentiate into a variety of cell types, including neurons, and have immunomodulatory and anti-inflammatory properties, making them an appealing therapy for neurodegenerative diseases such as ALS. This review examines the safety and efficacy of MSC therapy for ALS in three Phase II randomized controlled trials. The trials involved administering MSCs via various routes, including intrathecal and intravenous, and assessing outcomes such as survival, disease progression, and quality of life. 


Mesenchymal Stem Cell Therapy for Amyotrophic Lateral Sclerosis: A Narrative Review


Background 
Benefits of early skin-to-skin contact (SSC) are widely documented, including improved breastfeeding outcomes. While promoting immediate SSC is standard practice for vaginal birth, it happens less often after cesarean birth.  It is not known how changes in hospital practices and staff shortages during the COVID-19 pandemic have influenced the practice of SSC in the operating room.  This study aims to identify the relationship between SSC after cesarean birth and breastfeeding and compare SSC rates before and during the COVID-19 pandemic. 
Methods 
This was a retrospective, cohort chart review. Sample was 244 subjects who had scheduled cesarean deliveries at term during April-October 2019 and April-October 2020. Primary outcome was exclusive breastfeeding on discharge. Secondary outcomes were time to initiate breastfeeding, exclusive breastfeeding at postpartum visit and rate of SSC in the OR in 2019 compared to 2020. 
Results 
SSC in the first 3 days after birth was associated with feeding type on discharge (p<0.001) and/or at the postpartum visit (p=0.04). The study did not identify a statistically significant association between location of SSC and feeding type either on discharge (p=0.55) or at the postpartum visit (p=0.55). Infants who had SSC in the OR had significantly earlier initiation of breastfeeding (p<0.001). There was an increase in SSC in the OR between 2019 and 2020 (27% and 39%, respectively).  
Conclusion 
SSC practices after cesarean birth are associated with breastfeeding outcomes. Knowledge of this relationship will be important for optimizing surrounding SSC practices and breastfeeding support in the future.

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Utility of the mfi-5 Score in Outcome Prediction for Patients with Chronic Subdural Hematoma

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