Faculty Bibliography

The Victoria Symptom Validity Test (VSVT) is a performance validity test (PVT) with over two decades of empirical backing, although methodological limitations within the extant literature restrict its clinical and research generalizability. Chief among these constraints includes limited consensus on the most accurate index within the VSVT and the most appropriate cut-scores within each VSVT validity index. The current systematic review synthesizes existing VSVT validation studies and provides additional cross-validation in an independent sample using a known-groups design. We completed a systematic search of the literature, identifying 17 peer-reviewed studies for synthesis (7 simulation designs, 7 differential prevalence designs, and 3 known-groups designs). The independent cross-validation sample consisted of 200 mixed clinical neuropsychiatric patients referred for outpatient neuropsychological evaluation. Across all indices, Total item accuracy produced the strongest psychometric properties at an optimal cut-score of ≤ 40 (62% sensitivity/88% specificity). However, ROC curve analyses for all VSVT indices yielded statistically significant areas under the curve (AUCs; .73-81), suggestive of moderate classification accuracy. Cut-scores derived using the independent cross-validation sample converged with some previous findings supporting cut-scores of ≤ 22 for Easy item accuracy and ≤ 40 for Total item accuracy, although divergent findings were noted for Difficult item accuracy. Overall, VSVT validity indicators have adequate diagnostic accuracy across populations, with the current study providing additional support for its use as a psychometrically sound PVT in clinical settings. However, caution is recommended among patients with certain verified clinical conditions (e.g., dementia) and those with pronounced working memory deficits due to concerns for increased risk of false positives.

Slowed information processing speed is among the earliest markers of cognitive impairment in multiple sclerosis (MS) and has been associated with white matter (WM) structural integrity. Localization of WM tracts associated with slowing, but not significant impairment, on specific cognitive tasks in pediatric and young age onset MS can facilitate early and effective therapeutic intervention. Diffusion tensor imaging data were collected on 25 MS patients and 24 controls who also underwent the Symbol Digit Modalities Test (SDMT) and the computer-based Cogstate simple and choice reaction time tests. Fractional anisotropy (FA), mean (MD), radial (RD) and axial (AD) diffusivities were correlated voxel-wise with processing speed measures. All DTI metrics of several white matter tracts were significantly different between groups (p < 0.05). Notably, higher MD, RD, and AD, but not FA, in the corpus callosum correlated with lower scores on both SDMT and simple reaction time. Additionally, all diffusivity metrics in the left corticospinal tract correlated negatively with SDMT scores, whereas only MD in the right superior fronto-occipital fasciculus correlated with simple reaction time. In conclusion, subtle slowing of processing speed is correlated with WM damage in the visual-motor processing pathways in patients with young age of MS onset.

De novo, heterozygous, loss of function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared to wild-type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome. This article is protected by copyright. All rights reserved.

Objective/UNASSIGNED:Evaluate whether the benefits of Mindfulness-Based Cognitive Therapy for Migraine (MBCT-M) on headache disability differs among people with episodic and chronic migraine (CM). Methods/UNASSIGNED:This is a planned secondary analysis of a randomized clinical trial. After a 30-day baseline, participants were stratified by episodic (6-14 d/mo) and CM (15-30 d/mo) and randomized to 8 weekly individual sessions of MBCT-M or wait list/treatment as usual (WL/TAU). Primary outcomes (Headache Disability Inventory; Severe Migraine Disability Assessment Scale [scores ≥ 21]) were assessed at months 0, 1, 2, and 4. Mixed models for repeated measures tested moderation with fixed effects of treatment, time, CM, and all interactions. Planned subgroup analyses evaluated treatment*time in episodic and CM. Results/UNASSIGNED:= 0.268). Conclusions/UNASSIGNED:MBCT-M is a promising treatment for reducing headache-related disability, with greater benefits in episodic than CM. Trial Registration Information/UNASSIGNED:ClinicalTrials.gov Identifier: NCT02443519. Classification of Evidence/UNASSIGNED:This study provides Class III evidence that MBCT-M reduces headache disability to a greater extent in people with episodic than CM.

Thorough assessment of performance validity has become an established standard of practice in neuropsychological assessment. While there has been a large focus on the development and cross-validation of embedded performance validity tests (PVTs) in recent years, new freestanding PVTs have also been developed, including the Word Choice Test (WCT) as part of the Advanced Clinical Solutions Effort System. And, while the WCT's general utility for identifying invalid performance has been demonstrated in the ensuing decade since its initial publication, optimal cut-scores and associated psychometric properties have varied widely across studies. This study sought to synthesize the existing diagnostic accuracy literature regarding the WCT via a systematic review and to conduct a meta-analysis to determine the performance validity cut-score that best maximizes sensitivity while maintaining acceptable specificity. A systematic search of the literature resulted in 14 studies for synthesis, with eight of those available for meta-analysis. Meta-analytic results revealed an optimal cut-score of ≤ 42 with 54% sensitivity and 93% specificity for identifying invalid neuropsychological test performance. Collectively, the WCT demonstrated adequate diagnostic accuracy as a PVT across a variety of populations. Recommendations for future studies are also provided.

INTRODUCTION/BACKGROUND:Levodopa/carbidopa intestinal gel (LCIG; carbidopa/levodopa enteral suspension) has been widely used and studied for the treatment of motor fluctuations in levodopa-responsive patients with advanced Parkinson's disease (PD) when other treatments have not given satisfactory results. Reduction in 'off'-time is a common primary endpoint in studies of LCIG, and it is important to assess the durability of this response. This systematic literature review was conducted to qualitatively summarise the data on the long-term effects of LCIG therapy on 'off'-time. METHODS:Studies were identified by searching PubMed, EMBASE and Ovid on 30 September 2019. Studies were included if they reported on patients with PD, had a sample size of ≥ 10, LCIG was an active intervention and 'off'-time was reported for ≥ 12 months after initiation of LCIG treatment. Randomised clinical trials, retrospective and prospective observational studies, and other interventional studies were included for selection. Data were collected on: 'off'-time (at pre-specified time periods and the end of follow-up), study characteristics, Unified Parkinson's Disease Rating Scale (UPDRS) II, III and IV total scores, dyskinesia duration, quality of life scores, non-motor symptoms and safety outcomes. RESULTS:Twenty-seven studies were included in this review. The improvement in 'off'-time observed shortly after initiating LCIG was maintained and was statistically significant at the end of follow-up in 24 of 27 studies. 'Off'-time was reduced from baseline to end of follow-up by 38-84% and was accompanied by a clinically meaningful improvement in quality of life. Stratified analysis of 'off'-time demonstrated mean relative reductions of 47-82% at 3-6 months and up to 83% reduction at 3-5 years of follow-up. Most studies reported significant improvements in activities of daily living and motor complications. Most frequent adverse events were related to the procedure or the device. CONCLUSION/CONCLUSIONS:In one of the largest qualitative syntheses of published LCIG studies, LCIG treatment was observed to provide a durable effect in reducing 'off'-time. INFOGRAPHIC/UNASSIGNED:Video Abstract.

Migraine is a prevalent primary headache disorder and is usually considered as benign. However, structural and functional changes in the brain of individuals with migraine have been reported. High frequency of white matter abnormalities, silent infarct-like lesions, and volumetric changes in both gray and white matter in individuals with migraine compared to controls have been demonstrated. Functional magnetic resonance imaging (MRI) studies found altered connectivity in both the interictal and ictal phase of migraine. MR spectroscopy and positron emission tomography studies suggest abnormal energy metabolism and mitochondrial dysfunction, as well as other metabolic changes in individuals with migraine. In this review, we provide a brief overview of neuroimaging studies that have helped us to characterize some of these changes and discuss their limitations, including small sample sizes and poorly defined control groups. A better understanding of alterations in the brains of patients with migraine could help not only in the diagnosis but may potentially lead to the optimization of a targeted anti-migraine therapy.

Adolescents with anxiety disorders exhibit excessive emotional and somatic arousal. Neuroimaging studies have shown abnormal cerebral cortical activation and connectivity in this patient population. The specific role of cerebellar output circuitry, specifically the dentate nuclei (DN), in adolescent anxiety disorders remains largely unexplored. Resting-state functional connectivity analyses have parcellated the DN, the major output nuclei of the cerebellum, into three functional territories (FTs) that include default-mode, salience-motor, and visual networks. The objective of this study was to understand whether FTs of the DN are implicated in adolescent anxiety disorders. Forty-one adolescents (mean age 15.19 ± 0.82, 26 females) with one or more anxiety disorders and 55 age- and gender-matched healthy controls completed resting-state fMRI scans and a self-report survey on anxiety symptoms. Seed-to-voxel functional connectivity analyses were performed using the FTs from DN parcellation. Brain connectivity metrics were then correlated with State-Trait Anxiety Inventory (STAI) measures within each group. Adolescents with an anxiety disorder showed significant hyperconnectivity between salience-motor DN FT and cerebral cortical salience-motor regions compared to controls. Salience-motor FT connectivity with cerebral cortical sensorimotor regions was significantly correlated with STAI-trait scores in HC (R² = 0.41). Here, we report DN functional connectivity differences in adolescents diagnosed with anxiety, as well as in HC with variable degrees of anxiety traits. These observations highlight the relevance of DN as a potential clinical and sub-clinical marker of anxiety.

BACKGROUND AND PURPOSE/OBJECTIVE:Indirect consequences of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic include those related to failure of patients to seek or receive timely medical attention for seemingly unrelated disease. We report our experience with stroke code imaging during the early pandemic months of 2020. MATERIALS AND METHODS/METHODS:Retrospective review of stroke codes during the 2020 pandemic and both 2020 and matched 2019 prepandemic months was performed. Patient variables were age, sex, hospital location, and severity of symptoms based on the NIHSS. We reviewed the results of CT of the head, CTA, CTP, and MR imaging examinations and classified a case as imaging-positive if any of the imaging studies yielded a result that related to the clinical indication for the study. Both year-to-year and sequential comparisons were performed between pandemic and prepandemic months. RESULTS:= .03). CONCLUSIONS:During our pandemic period, there was a significantly decreased number of stroke codes but simultaneous increases in positivity rates, symptom severity, and inpatient codes. We postulate that this finding reflects the documented reluctance of patients to seek medical care during the pandemic, with the shift toward a greater proportion of inpatient stroke codes potentially reflecting the neurologic complications of the virus itself.

OBJECTIVE:Diazepam nasal spray (Valtoco), indicated for acute treatment of frequent seizure activity (seizure clusters) in patients with epilepsy ≥6 years of age, is designed to be a rapid, noninvasive, socially acceptable route of administration. This interim analysis evaluated the safety profile of diazepam nasal spray in patients with and without concomitant use of benzodiazepines, with use of a second dose for a seizure cluster as a proxy for effectiveness. METHODS:A long-term, phase 3, open-label safety study enrolled patients with epilepsy who had seizures despite a stable antiseizure medication regimen. RESULTS:Among 175 patients enrolled by October 31, 2019, a total of 158 were treated with diazepam nasal spray (aged 6-65 years; 53.8% female). Of those, 119 (75.3%) received concomitant benzodiazepines (60, chronic; 59, intermittent); 39 (24.7%) did not. Use of a second dose was similar in patients using chronic concomitant benzodiazepines (second dose in 11.1% [144/1299]) and those with no concomitant benzodiazepines (second dose in 10.3% [41/398]). Treatment emergent adverse events (TEAEs) occurred for 80.0% with chronic use of concomitant benzodiazepines and 61.5% without. Cardiorespiratory depression was not reported, and no serious TEAEs were treatment related. Study retention was high: 83.3% in the chronic benzodiazepine group and 76.9% in the no-benzodiazepine group. Findings were similar in a sub-analysis of patients who were (n = 44) or were not (n = 75) taking clobazam. SIGNIFICANCE/CONCLUSIONS:This analysis of patients from a long-term study shows a similar safety profile of diazepam nasal spray in patients with and without concomitant benzodiazepines, and consistent with the established profile for diazepam. Use of a single dose of diazepam nasal spray and high study retention rates suggest the effectiveness of diazepam nasal spray in patients irrespective of chronic daily benzodiazepine use. Results were similar in the clobazam sub-analysis. These results support the safety and effectiveness of diazepam nasal spray in patients with concomitant benzodiazepine use.