Faculty Bibliography

BACKGROUND:Extended interval dosing (EID; average dosing interval approximately every 6 weeks) of natalizumab is associated with significantly lower risk of progressive multifocal leukoencephalopathy than standard interval dosing (SID; every 4 weeks) in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies, though limited, suggest that natalizumab effectiveness is generally maintained in patients who switch to EID after initiation of stable treatment with SID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a collaborative, multicenter learning health system that generates real-world clinical and MRI data using highly standardized acquisition protocols. We compared MRI outcomes in MS PATHS patients treated with natalizumab EID versus SID. We also compared MRI outcomes in patients treated with natalizumab (EID and/or SID) versus injectable MS platform therapy. METHODS:Natalizumab infusion data from the TOUCH Prescribing Program database and MS PATHS MRI assessment data from seven US sites as of July 23, 2020, were used to identify patients with relapsing-remitting MS who had received natalizumab EID or SID in the interval between two MRI scans (an MRI segment). Patients who received injectable platform MS therapy between two MRI scans were also identified. MRI data were used to determine the incidence rate and odds of developing new or enlarging T2 lesions, annualized percentage change in T2 lesion volume (T2LV), and annualized percentage change in brain parenchymal fraction (BPF). MRI outcomes were compared for 1) natalizumab EID treatment versus natalizumab SID treatment, 2) natalizumab treatment (EID + SID) versus platform therapy, and 3) natalizumab EID versus platform therapy. Propensity score-based weighting or matching were used to balance covariates at the start of MRI segments for all comparisons. RESULTS:The MRI outcomes observed with natalizumab EID treatment did not differ significantly from those observed with natalizumab SID treatment. The odds ratio for any new or enlarging T2 lesion was 1.07 (95% confidence interval [CI]: 0.93, 1.24; p = 0.355), and the rate ratio (95% CI) for new or enlarging T2 lesions was 1.62 (0.93, 2.82; p = 0.090). Differences (95% CI) between EID and SID patients in mean annualized percentage change in T2LV and BPF were 1.56% (-3.77%, 6.90%; p = 0.566) and -0.11% (-0.25%, -0.10%; p = 0.096), respectively. Conversely, when MRI outcomes in natalizumab and platform therapy patients were compared, there were significant differences favoring natalizumab in all assessments: the odds of any new or enlarging T2 lesion (odds ratio: 0.69 [95% CI: 0.64, 0.75]; p<0.001), the incidence rate of new or enlarging T2 lesions (rate ratio: 0.47 [95% CI: 0.37, 0.61]; p<0.001), annualized percentage change (decrease) in T2LV (difference: -3.68% [95% CI: -7.06%, -0.30%]; p = 0.033), and annualized percentage change (increase) in BPF (difference: 0.22% [95% CI: 0.16%, 0.29%]; p<0.001). Results of the subgroup comparison of natalizumab EID patients with platform therapy patients were similar to those of the overall-natalizumab-group-versus-platform-therapy comparison. CONCLUSIONS:The results indicate that natalizumab EID and SID provide comparable real-world effectiveness on quantitative MRI metrics. These data further demonstrate that natalizumab EID can provide superior real-world effectiveness to injectable platform therapy on quantitative MRI metrics.

Background: Remotely-supervised transcranial direct current stimulation (RS-tDCS) is a telerehabilitation protocol that provides access to tDCS treatment to participants with aphasia in their homes using real-time monitoring via videoconference and overcomes barriers associated with in-person tDCS treatment of neurological disease. Aims: Two feasibility studies for participants with aphasia are presented herein that investigate (1) RS-tDCS procedural implementation, acceptability, and demand, and (2) acceptability of ten repeated consecutive RS-tDCS sessions. Methods & Procedures: Thirteen participants with aphasia were enrolled in Study 1: (1) seven participants with stroke-induced latent aphasia, (2) four participants with stroke-induced clinically diagnosed aphasia, and (3) two participants with logopenic variant primary progressive aphasia (lvPPA). Four supervisors (1 certified speech-language pathologist [SLP], 3 graduate SLPs-in-training) were trained to supervise RS-tDCS and also provided survey responses. All participants participated in RS-tDCS training and a virtual simulation of home delivery. Two participants with stroke-induced aphasia (1 latent aphasia, 1 clinically diagnosed aphasia) were enrolled in 10 consecutive sessions of RS-tDCS alongside computerized treatment in their home for Study 2. Outcomes & Results: This work provides preliminary evidence for the feasibility of RS-tDCS for people with stable and progressive aphasia of varying severity and typology and includes both participant and clinician perspectives. Importantly, no major barriers to use of RS-tDCS were revealed for people with aphasia, though eHelpers were required for two participants. Conclusions: This work confirms that remotely supervised at-home tDCS studies can be used to enable much-needed efficacy trials, with sufficient sample size, power, and dosing considerations, that will determine the clinical efficacy of tDCS as a treatment adjuvant to aphasia treatment.

Transcranial electrical stimulation (tES) comprises noninvasive neuromodulation techniques that deliver low-amplitude electrical currents to targeted brain regions with the goal of modifying neural activities. Expanding evidence from the past decade, specifically using transcranial direct current simulation and transcranial alternating current stimulation, presents promising applications of tES as a treatment for psychiatric disorders. In this review, the authors discuss the basic technical aspects and mechanisms of action of tES in the context of clinical research and practice and review available evidence for its clinical use, efficacy, and safety. They also review recent advancements in use of tES for the treatment of depressive disorders, schizophrenia, substance use disorders, and obsessive-compulsive disorder. Findings largely support growing evidence for the safety and efficacy of tES in the treatment of patients with resistance to existing treatment options, particularly demonstrating promising treatment outcomes for depressive disorders. Future directions of tES research for optimal application in clinical settings are discussed, including the growing home-based, patient-friendly methods and the potential pairing with existing pharmacological or psychotherapeutic treatments for enhanced outcomes. Finally, neuroimaging advancements may provide more specific mapping of brain networks, aiming at more precise tES therapeutic targeting in the treatment of psychiatric disorders.

Since the outbreak of the COVID-19 pandemic, races across academia and industry have been initiated to identify and develop disease modifying or preventative therapeutic strategies has been initiated. The primary focus has been on pharmacological treatment of the immune and respiratory system and the development of a vaccine. The hyperinflammatory state ("cytokine storm") observed in many cases of COVID-19 indicates a prognostically negative disease progression that may lead to respiratory distress, multiple organ failure, shock, and death. Many critically ill patients continue to be at risk for significant, long-lasting morbidity or mortality. The human immune and respiratory systems are heavily regulated by the central nervous system, and intervention in the signaling of these neural pathways may permit targeted therapeutic control of excessive inflammation and pulmonary bronchoconstriction. Several technologies, both invasive and non-invasive, are available and approved for clinical use, but have not been extensively studied in treatment of the cytokine storm in COVID-19 patients. This manuscript provides an overview of the role of the nervous system in inflammation and respiration, the current understanding of neuromodulatory techniques from preclinical and clinical studies and provides a rationale for testing non-invasive neuromodulation to modulate acute systemic inflammation and respiratory dysfunction caused by SARS-CoV-2 and potentially other pathogens. The authors of this manuscript have co-founded the International Consortium on Neuromodulation for COVID-19 to advocate for and support studies of these technologies in the current coronavirus pandemic.

OBJECTIVE:To compare clinical and imaging features of multiple sclerosis (MS) severity between Black Americans (BA) and White Americans (WA) and evaluate the role of socioeconomic status. METHODS:We compared BA and WA participants in the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort with respect to MS characteristics including self-reported disability, objective neurologic function assessments, and quantitative brain MRI measurements, after covariate adjustment (including education level, employment, or insurance as socioeconomic indicators). In a subgroup, we evaluated within-race, neighborhood-level indicators of socioeconomic status (SES) using 9-digit ZIP codes. RESULTS:Of 1,214 BAs and 7,530 WAs with MS, BAs were younger, had lower education level, and were more likely to have Medicaid insurance or be disabled or unemployed than WAs. BAs had worse self-reported disability (1.47-fold greater odds of severe vs. mild disability, 95% CI 1.18, 1.86) and worse performances on tests of cognitive processing speed (-5.06 fewer correct, CI -5.72, -4.41), walking (0.66 seconds slower, 95% CI 0.36, 0.96) and manual dexterity (2.11 seconds slower, 95% CI 1.69, 2.54). BAs had more brain MRI lesions and lower overall and gray matter brain volumes, including reduced thalamic (-0.77 mL, 95% CI -0.91, -0.64), cortical (-30.63 mL, 95% CI -35.93, -25.33), and deep (-1.58 mL, 95% CI -1.92, -1.23) gray matter volumes. While lower SES correlated with worse neuroperformance scores in WAs, this association was less clear in BA. CONCLUSION/CONCLUSIONS:We observed a greater burden of disease in BAs with MS relative to WAs with MS, despite adjustment for SES indicators. Beyond SES, future longitudinal studies should also consider roles of other societal constructs (e.g., systemic racism). Such studies will be important for identifying prognostic factors and optimal treatment strategies among BAs with MS is warranted.

Pediatric-onset multiple sclerosis (POMS), representing approximately 5% of all MS cases, affects the central nervous system during its ongoing development. POMS is most commonly diagnosed during adolescence but can occur in younger children as well. For pediatric patients with MS, it is critical to manage the full impact of the disease and monitor for any effects on school and social functioning. Disease management includes not only disease-modifying therapies but also strategies to optimize wellbeing. We review the interventions with the highest evidence of ability to improve the disease course and quality of life in POMS. High levels of vitamin D and a diet low in saturated fat are associated with lower relapse rates. Exercise ameliorates fatigue and sleep. Behavioral strategies for sleep hygiene and mood regulation can also improve fatigue and perceived health. POMS management should be addressed holistically, including assessing overall symptom burden as well as the psychological and functional impact of the disease.