Faculty Bibliography

Due to shared hippocampal dysfunction, patients with Alzheimer's dementia and late-onset epilepsy (LOE) report memory decline. Multiple studies have described the epidemiological, pathological, neurophysiological, and behavioral overlap between Alzheimer's Disease and LOE, implying a bi-directional relationship. We describe the neurobiological decline occurring at different spatial in AD and LOE patients, which may explain why their phenotypes overlap and differ. We provide suggestions for clinical recognition of dual presentation and novel approaches for behavioral testing that reflect an "inside-out," or biologically-based approach to testing memory. New memory and language assessments could detect-and treat-memory impairment in AD and LOE at an earlier, actionable stage.

OBJECTIVE:Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. METHODS:Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12-60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1-weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. RESULTS:Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = -.007 to -.002, p = .0003). Each 10-year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = -.007 to -.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = -.014 to -.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. SIGNIFICANCE/CONCLUSIONS:This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.

RATIONALE/BACKGROUND:The International Classification of Cognitive Disorders in Epilepsy (IC-CoDE) was recently introduced as a consensus-based, empirically-driven taxonomy of cognitive disorders in epilepsy and has been effectively applied to patients with temporal lobe epilepsy (TLE). The purpose of this study was to apply the IC-CoDE to patients with frontal lobe epilepsy (FLE) using national multicenter data. METHODS:Neuropsychological data of 455 patients with FLE aged 16 years or older were available across four US-based sites. First, we examined test-specific impairment rates across sites using two impairment thresholds (1.0 and 1.5 standard deviations below the normative mean). Following the proposed IC-CoDE guidelines, patterns of domain impairment were determined based on commonly used tests within five cognitive domains (language, memory, executive functioning, attention/processing speed, and visuospatial ability) to construct phenotypes. Impairment rates and distributions across phenotypes were then compared with those found in patients with TLE for which the IC-CoDE classification was initially validated. RESULTS:The highest rates of impairment were found among tests of naming, verbal fluency, speeded sequencing and set-shifting, and complex figure copy. The following IC-CoDE phenotype distributions were observed using the two different threshold cutoffs: 23-40% cognitively intact, 24-29% single domain impairment, 13-20% bi-domain impairment, and 18-33% generalized impairment. Language was the most common single domain impairment (68% for both thresholds) followed by attention and processing speed (15-18%). Overall, patients with FLE reported higher rates of cognitive impairment compared with patients with TLE. CONCLUSIONS:These results demonstrate the applicability of the IC-CoDE to epilepsy syndromes outside of TLE. Findings indicated generally stable and reproducible phenotypes across multiple epilepsy centers in the U.S. with diverse sample characteristics and varied neuropsychological test batteries. Findings also highlight opportunities for further refinement of the IC-CoDE guidelines as the application expands.

BACKGROUND:Former American football players are at risk for chronic traumatic encephalopathy (CTE) which may have parkinsonism as a clinical feature. OBJECTIVE:Former football players were prospectively assessed for parkinsonism. METHODS:120 former professional football players, 58 former college football players, and 60 same-age asymptomatic men without repetitive head impacts, 45-74 years, were studied using the MDS-UPDRS to assess for parkinsonism, and the Timed Up and Go (TUG). Traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE, was adjudicated and includes parkinsonism diagnosis. Fisher's Exact Test compared groups on parkinsonism due to small cell sizes; analysis of covariance or linear regressions controlling for age and body mass index were used otherwise. RESULTS:Twenty-two (12.4%) football players (13.3% professional, 10.3% college) met parkinsonism criteria compared with two (3.3%) in the unexposed group. Parkinsonism was higher in professional (p = 0.037) but not college players (p = 0.16). There were no differences on the MDS-UPDRS Part III total scores. Scores on the individual MDS-UPDRS items were low. TUG times were longer in former professional but not college players compared with unexposed men (13.09 versus 11.35 s, p < 0.01). There were no associations between years of football, age of first exposure, position or level of play on motor outcomes. TES status was not associated with motor outcomes. CONCLUSIONS:Parkinsonism rates in this sample of football players was low and highest in the professional football players. The association between football and parkinsonism is inconclusive and depends on factors related to sample selection, comparison groups, and exposure characteristics.

Transcranial direct current stimulation (tDCS) is an emerging treatment for major depression. We recruited participants with moderate-to-severe major depressive episodes for an observational clinical trial using Soterix Medical's tDCS telehealth platform as a standard of care. The acute intervention consisted of 28 sessions (5 sessions/week, 6 weeks) of the left anodal dorsolateral prefrontal cortex (DLPFC) tDCS (2.0 mA × 30 min) followed by a tapering phase of weekly sessions for 4 weeks (weeks 7-10). The n = 16 completing participants had a significant reduction in depressive symptoms by week 2 of treatment [Montgomery-Åsberg Depression Rating Scale (MADRS), Baseline: 28.00 ± 4.35 vs. Week 2: 17.12 ± 5.32, p < 0.001] with continual improvement across each biweekly timepoint. Acute intervention responder and remission rates were 75 and 63% and 88 and 81% following the taper period (week 10).

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].

Abstract Background: Loss of hand dexterity is disabling and reduces quality of life. People living with progressive forms of MS have marked neurologic disabilities but limited rehabilitation options. Transcranial direct current stimulation (tDCS) is a method of noninvasive brain stimulation in which stimulation delivered during motor training can strengthen outcomes. We have established a remotely supervised tDCS (RS-tDCS) protocol that delivers multiple stimulation sessions paired with training to participants at home.
Objective(s): To evaluate a blinded randomized sham-controlled clinical trial of active vs. sham tDCS paired with manual dexterity training for people with progressive MS.
Method(s): We recruited right-hand dominant individuals with progressive MS and hand dexterity impairment. Participants completed 20 sessions of daily (M-F) manual dexterity and were randomized to either active (2.0 mA) or sham primary motor cortex (M1-SO) tDCS. Manual dexterity was measured with the Nine-Hole Peg Test (9HPT) and Dellon-Modified Moberg Pick-Up test (MMPUT) at baseline and study end and transformed to normative z-scores for comparison.
Result(s): Participants were n=60 with primary (32%) or secondary (68%) progressive MS (52% female, ages 37-72 years, and a median Expanded Disability Status Scale (EDSS) score of 5.0 [1.5-7.5]). The intervention was safe and well tolerated, with n=59/60 (98%) completing 18/20 daily sessions. Combining hands and tasks, the full group improved following the manual dexterity training (mean z-score improvement 1.64+/-9.53, p=0.016). Active tDCS led to greater improvement (mean z-score improvement 4.51+/-8.78, p=0.001). Analyzing those with right- or left-hand impairment at baseline, the active tDCS group had significant improvement on the 9HPT (Right: p=0.036, Left: p=0.028) and trended towards significant improvement for the MMPUT (Right: p=0.071, Left: p=0.079).
Conclusion(s): At-home manual dexterity training paired with tDCS is a safe, tolerable, and feasible intervention for people with progressive MS and hand impairment. Training outcomes are augmented with simultaneous M1-SO tDCS. Research Category and Technology and Methods Clinical Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: tDCS, motor training, multiple sclerosis, teleintervention
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Abstract Objectives: Evaluate feasibility and preliminary efficacy of remotely supervised transcranial Direct Current Stimulation (RS-tDCS) interventions for persistent post-traumatic headache (PPTH) secondary to mild TBI (mTBI).
Method(s): Veterans with PPTH completed a 28-day baseline observation of headache days and received either active or sham RS-tDCS paired with mindfulness meditation. This 4-week intervention of 20-minutes daily (M-F) RS-tDCS (anodal stimulation dlPFC) was monitored via VA Video Connect. Feasibility was determined by the number of participants completing >=80% of the intervention. Efficacy was measured by changes in number of moderate/severe headache days from baseline period to the end of treatment phase, and 4-week post-treatment follow-up. Secondary endpoints included total number of headache days, acute pain medication use, as well as headache- and mTBI-related disability.
Result(s): Twenty-six veterans (46.6+/-8.7 years) with PPTH completed baseline observations and were randomized to either active (n=13) or sham (n=13) treatment groups. A total of 22/25 (88%) participants fully completed either active (10/12) or sham (12/13) interventions (p=.0.59). Within-group analyses reveled significant reductions in moderate/severe headache days in the active (p=0.04) but not sham (p=0.54) groups. This resulted in a trend towards significant reductions in moderate/severe headache days in the active vs. sham groups (p = 0.07). Active participants also demonstrated a reduction in total number of headache days during treatment (p=0.04) where the sham group did not (p=0.70). There is statistically significant reduction in total number of headache days during treatment for active vs. sham participants (p=0.03). No significant differences were maintained during the 4-week post-treatment follow-up (p's>0.05).
Conclusion(s): RS-tDCS treatment feasible with high adherence and effective for veterans with PPTH. Findings suggest that active RS-tDCS via dlPFC reduce headache frequency and improve clinical outcomes. A larger phase II study is warranted to confirm these findings and inform evaluation for clinical use. Research Category and Technology and Methods Clinical Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: tDCS, Persistent Post-traumatic headache, Veterans, mTBI
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OBJECTIVES:Intra-individual variability (IIV), measured across repeated response times (RT) during continuous psychomotor tasks, is an early marker of cognitive change in the context of neurodegeneration. To advance IIV towards broader application in clinical research, we evaluated IIV from a commercial cognitive testing platform and compared it to the calculation approaches used in experimental cognitive studies. METHODS:-transformed standard deviation or "LSD"). We calculated IIV from the raw RTs using coefficient of variation (CoV), regression-based, and ex-Gaussian methods. The IIV from each calculation was then compared by rank across participants. RESULTS:A total of n = 120 participants with MS aged 20-72 (Mean ± SD, 48.99 ± 12.09) completed the baseline cognitive measures. For each task, the interclass correlation coefficient was generated. Each ICC showed that LSD, CoV, ex-Gaussian, and regression methods clustered strongly (Average ICC for DET: 0.95 with 95% CI [0.93, 0.96]; Average ICC for IDN: 0.92 with 95% CI [0.88 to 0.93]; Average ICC for ONB: 0.93 with 95% CI [0.90 to 0.94]). Correlational analyses indicated the strongest correlation between LSD and CoV for all tasks (rs ≥ 0.94). CONCLUSION:The LSD was consistent with research-based methods for IIV calculations. These findings support the use of LSD for the future measurement of IIV for clinical studies.

BACKGROUND:and purpose: Fatigue is among the most common persistent symptoms following post-acute sequelae of Sars-COV-2 infection (PASC). The current study investigated the potential therapeutic effects of High-Definition transcranial Direct Current Stimulation (HD-tDCS) associated with rehabilitation program for the management of PASC-related fatigue. METHODS:Seventy patients with PASC-related fatigue were randomized to receive 3 mA or sham HD-tDCS targeting the left primary motor cortex (M1) for 30 min paired with a rehabilitation program. Each patient underwent 10 sessions (2 sessions/week) over five weeks. Fatigue was measured as the primary outcome before and after the intervention using the Modified Fatigue Impact Scale (MFIS). Pain level, anxiety severity and quality of life were secondary outcomes assessed, respectively, through the McGill Questionnaire, Hamilton Anxiety Rating Scale (HAM-A) and WHOQOL. RESULTS:Active HD-tDCS resulted in significantly greater reduction in fatigue compared to sham HD-tDCS (mean group MFIS reduction of 22.11 points vs 10.34 points). Distinct effects of HD-tDCS were observed in fatigue domains with greater effect on cognitive (mean group difference 8.29 points; effect size 1.1; 95% CI 3.56-13.01; P < .0001) and psychosocial domains (mean group difference 2.37 points; effect size 1.2; 95% CI 1.34-3.40; P < .0001), with no significant difference between the groups in the physical subscale (mean group difference 0.71 points; effect size 0.1; 95% CI 4.47-5.90; P = .09). Compared to sham, the active HD-tDCS group also had a significant reduction in anxiety (mean group difference 4.88; effect size 0.9; 95% CI 1.93-7.84; P < .0001) and improvement in quality of life (mean group difference 14.80; effect size 0.7; 95% CI 7.87-21.73; P < .0001). There was no significant difference in pain (mean group difference -0.74; no effect size; 95% CI 3.66-5.14; P = .09). CONCLUSION/CONCLUSIONS:An intervention with M1 targeted HD-tDCS paired with a rehabilitation program was effective in reducing fatigue and anxiety, while improving quality of life in people with PASC.