Cerebral small vessel disease pathology in COVID-19 patients: A systematic review.

Cerebral small vessel disease (CSVD) is the leading cause of vascular cognitive impairment and is associated with COVID-19. However, contributing factors that often accompany CSVD pathology in COVID-19 patients may influence the incidence of cerebrovascular complications. Thus, a mechanism linking COVID-19 and CSVD has yet to be uncovered and differentiated from age-related comorbidities (i.e., hypertension), and medical interventions during acute infection. We aimed to evaluate CSVD in acute and recovered COVID-19 patients and to differentiate COVID-19-related cerebrovascular pathology from the above-mentioned contributing factors by assessing the localization of microbleeds and ischemic lesions/infarctions in the cerebrum, cerebellum, and brainstem. A systematic search was performed in December 2022 on PubMed, Web of Science, and Embase using a pre-established search criterion related to history of, or active COVID-19 with CSVD pathology in adults. From a pool of 161 studies, 59 met eligibility criteria and were included. Microbleeds and ischemic lesions had a strong predilection for the corpus callosum and subcortical/deep white matter in COVID-19 patients, suggesting a distinct CSVD pathology. These findings have important implications for clinical practice and biomedical research as COVID-19 may independently, and through exacerbation of age-related mechanisms, contribute to increased incidence of CSVD.

Gait variability predicts cognitive impairment in older adults with subclinical cerebral small vessel disease.

Introduction: Advanced methods of gait research, including approaches to quantify variability, and orderliness/regularity/predictability, are increasingly used to identify patients at risk for the development of cognitive impairment. Cerebral small vessel disease (CSVD) is highly prevalent in older adults and is known to contribute to the development of vascular cognitive impairment and dementia (VCID). Studies in preclinical models demonstrate that subclinical alterations precede CSVD-related cognitive impairment in gait coordination. In humans, CSVD also associates with gait abnormalities. The present study was designed to test the hypothesis that increased gait variability and gait asymmetry predict a decline in cognitive performance in older adults with CSVD. Methods: To test this hypothesis, we compared cognitive performance and gait function in patients with CSVD (age: 69.8 ± 5.3 years; n = 11) and age- and sex-matched control participants (age: 70.7 ± 5.8 years; n = 11). Based on imaging findings, patients with CSVD were identified [presence of white matter hyperintensities plus silent brain infarcts and/or microhemorrhages on magnetic resonance imaging (MRI) assessment]. Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Gait parameters were measured during the single and dual tasks, during which participants, in addition to the motor task, completed a series of mental arithmetic calculations. Spatial and temporal parameters of gait variability, symmetry, and permutation entropy were determined using a pressure-sensitive gait mat during single and dual cognitive task conditions. Results: Patients with CSVD exhibited lower performance in a visual learning test (p = 0.030) and in a sustained attention test (p = 0.007). CSVD also affected step time variability (p = 0.009) and step length variability (p = 0.017). Step lengths of CSVD participants were more asymmetric (p = 0.043) than that of controls, while the two groups were statistically similar regarding step time symmetry and entropy of step time and length. Gait variability was inversely associated with sustained attention, especially among CSVD patients, and this relationship was significantly different between the two groups. The association of sustained attention with gait symmetry was also significantly different between the two groups. Discussion: Our findings provide additional evidence in support of the concept that increased gait variability and asymmetry may predict cognitive impairment in older adults with CSVD.

Safer Stroke-Dx Instrument: Identifying Stroke Misdiagnosis in the Emergency Department.

BACKGROUND: Missed or delayed diagnosis of acute stroke, or false-negative stroke (FNS), at initial emergency department (ED) presentation occurs in ≈9% of confirmed stroke patients. Failure to rapidly diagnose stroke can preclude time-sensitive treatments, resulting in higher risks of severe sequelae and disability. In this study, we developed and tested a modified version of a structured medical record review tool, the Safer Dx Instrument, to identify FNS in a subgroup of hospitalized patients with stroke to gain insight into sources of ED stroke misdiagnosis. METHODS: We conducted a retrospective cohort study at 2 unaffiliated comprehensive stroke centers. In the development and confirmatory cohorts, we applied the Safer Stroke-Dx Instrument to report the prevalence and documented sources of ED diagnostic error in FNS cases among confirmed stroke patients upon whom an acute stroke was suspected by the inpatient team, as evidenced by stroke code activation or urgent neurological consultation, but not by the ED team. Inter-rater reliability and agreement were assessed using interclass coefficient and kappa values (κ). RESULTS: Among 183 cases in the development cohort, the prevalence of FNS was 20.2% (95% CI, 15.0-26.7). Too narrow a differential diagnosis and limited neurological examination were common potential sources of error. The interclass coefficient for the Safer Stroke-Dx Instrument items ranged from 0.42 to 0.91, and items were highly correlated with each other. The κ for diagnostic error identification was 0.90 (95% CI, 0.821-0.978) using the Safer Stroke-Dx Instrument. In the confirmatory cohort of 99 cases, the prevalence of FNS was 21.2% (95% CI, 14.2-30.3) with similar sources of diagnostic error identified. CONCLUSIONS: Hospitalized patients identified by stroke codes and requests for urgent neurological consultation represent an enriched population for the study of diagnostic error in the ED. The Safer Stroke-Dx Instrument is a reliable tool for identifying FNS and sources of diagnostic error.

Motor cortex transcranial direct current stimulation effects on knee osteoarthritis pain in elderly subjects with dysfunctional descending pain inhibitory system: A randomized controlled trial.

BACKGROUND: Although evidence has indicated a positive effect of transcranial direct current stimulation (tDCS) on reducing pain, few studies have focused on the elderly population with knee osteoarthritis (KOA). OBJECTIVE: To evaluate whether tDCS reduces KOA pain in elderly individuals with a dysfunctional descending pain inhibitory system (DPIS). METHODS: In a double-blind trial, individuals ≥ 60 years with KOA pain and a dysfunctional DPIS, we randomly assigned patients to receive 15 daily sessions of 2 mA tDCS over the primary motor cortex (anode) and contralateral supraorbital area (cathode) (M1-SO) for 20 min or sham tDCS. Change in pain perception indexed by the Brief Pain Inventory (BPI) at the end of intervention was the primary outcome. Secondary outcomes included: disability, quantitative sensory testing, pain pressure threshold and conditioned pain modulation (CPM). Subjects were followed-up for 2 months. RESULTS: Of the 104 enrolled subjects, with mean (SD) age of 73.9 (8.01) years and 88 (84.6%) female, 102 finished the trial. In the intention-to-treat analysis, the active tDCS group had a significantly greater reduction in BPI compared to the sham group (difference, 1.59; 95% CI, 0.95 to 2.23; P < 0.001; Cohen's d, 0.58); and, also a significantly greater improvement in CPM-pressure in the knee (P = 0.01) and CPM-pain in the hand (P = 0.01). These effects were not sustained at follow-up. The intervention was well tolerated, with no severe adverse effects. CONCLUSION: M1-SO tDCS is associated with a moderate effect size in reducing pain in elderly patients with KOA after 15 daily sessions of stimulation. This intervention has also shown to modulate the DPIS.

Risk factors of pain, physical function, and health-related quality of life in elderly people with knee osteoarthritis: A cross-sectional study.

Data on the precise mechanisms of the complex interactions of factors related to clinical impact of knee osteoarthritis (KOA) in the elderly population remain limited. To find predictors that explain pain intensity, physical function, and quality of life in elderly KOA subjects, we performed a cross-sectional analysis of the baseline data from a randomized trial. The trial included 104 subjects (aged ≥60) with KOA pain and dysfunctional endogenous pain-inhibitory system activity assessed by conditioned pain modulation (CPM). Three multiple linear regression models were performed to understand the independent predictors of Brief Pain Inventory (BPI), WOMAC function subscale (WOMACFunc), and SF-12 physical subscale (SF12-PCS). Model 1 showed that BPI pain score was predicted by low CPM response, high von-Frey light touch threshold, worse radiological severity as indexed by Kellgren-Lawrence grade (KL), high von-Frey punctate pain intensity and high levels of anxiety (adjusted R2 = 27.1%, F (6,95) = 7.27, P < 0.0001). In model 2, von-Frey light touch threshold, KL, depressive symptoms indexed by Beck Depression Inventory (BDI), level of sleepiness and pain pressure threshold were risk factors for SF12-PCS (adjusted R2 = 31.9%, F (5,96) = 10.5, P < 0.0001). Finally, model 3 showed that WOMACFunc was predicted by BDI, KL and BPI (adjusted R2 = 41%, F (3,98) = 24.42, P < 0.0001). Our data provides an interesting framework to understand the predictors of KOA pain in the elderly and highlights how its related outcomes are affected by disease-specific factors, somatosensory dysfunction and emotional factors.

Intracortical Inhibition in the Affected Hemisphere in Limb Amputation.

Phantom limb pain (PLP) affects up to 80% of amputees. Despite the lack of consensus about the etiology and pathophysiology of phantom experiences, previous evidence pointed out the role of changes in motor cortex excitability as an important factor associated with amputation and PLP. In this systematic review, we investigated changes in intracortical inhibition as indexed by transcranial magnetic stimulation (TMS) in amputees and its relationship to pain. Four electronic databases were screened to identify studies using TMS to measure cortical inhibition, such as short intracortical inhibition (SICI), long intracortical inhibition (LICI) and cortical silent period (CSP). Seven articles were included and evaluated cortical excitability comparing the affected hemisphere with the non-affected hemisphere or with healthy controls. None of them correlated cortical disinhibition and clinical parameters, such as the presence or intensity of PLP. However, most studies showed decreased SICI in amputees affected hemisphere. These results highlight that although SICI seems to be changed in the affected hemisphere in amputees, most of the studies did not investigate its clinical correlation. Thus, the question of whether they are a valid diagnostic marker remains unanswered. Also, the results were highly variable for both measurements due to the heterogeneity of study designs and group comparisons in each study. Although these results underscore the role of inhibitory networks after amputation, more studies are needed to investigate the role of a decreased inhibitory drive in the motor cortex to the cause and maintenance of PLP.

Motor Cortex Reorganization in Limb Amputation: A Systematic Review of TMS Motor Mapping Studies.

Purpose: The purpose of this systematic review is to evaluate motor cortex reorganization in amputees as indexed by transcranial magnetic stimulation (TMS) cortical mapping and its relationship with phantom limb pain (PLP). Methods: Pubmed database were systematically searched. Three independent researchers screened the relevant articles, and the data of motor output maps, including the number of effective stimulation sites, center of gravity (CoG) shift, and their clinical correlations were extracted. We calculated a pooled CoG shift for motor cortex TMS mapping. Results: The search yielded 468 articles, 11 were included. Three studies performed correlation between the cortical changes and PLP intensity, and only one study compared cortical mapping changes between amputees with pain and without pain. Results showed (i) enlarged excitable area and a shift of CoG of neighboring areas toward the deafferented limb area; (ii) no correlation between motor cortex reorganization and level of pain and (iii) greater cortical reorganization in patients with PLP compared to amputation without pain. Conclusion: Our review supports the evidence for cortical reorganization in the affected hemisphere following an amputation. The motor cortex reorganization could be a potential clinical target for prevention and treatment response of PLP.

Neural and Genetic Bases for Human Ability Traits.

The judgement of human ability is ubiquitous, from school admissions to job performance reviews. The exact make-up of ability traits, however, is often narrowly defined and lacks a comprehensive basis. We attempt to simplify the spectrum of human ability, similar to how five personality traits are widely believed to describe most personalities. Finding such a basis for human ability would be invaluable since neuropsychiatric disease diagnoses and symptom severity are commonly related to such differences in performance. Here, we identified four underlying ability traits within the National Institutes of Health Toolbox normative data (n = 1, 369): (1) Motor-endurance, (2) Emotional processing, (3) Executive and cognitive function, and (4) Social interaction. We used the Human Connectome Project young adult dataset (n = 778) to show that Motor-endurance and Executive and cognitive function were reliably associated with specific brain functional networks (r 2 = 0.305 ± 0.021), and the biological nature of these ability traits was also shown by calculating their heritability (31 and 49%, respectively) from twin data.

Recruitment challenges in stroke neurorecovery clinical trials.

There are multiple available treatments to enhance stroke rehabilitation, although few interventions have confirmed significant clinical improvements on motor function in pivotal Randomized Clinical Trials. Development of large Randomized Clinical Trials is limited by several barriers and low enrollment rate is considered an important factor. Consequently, most of the evidence comes from small sample size studies, often leading to limited conclusions. According to the National Institute of Health (NIH), about 80% of clinical trials in the United States do not achieve their timelines, increasing research costs and postponing regulatory approval of new therapies. Given that the success of a Randomized Clinical Trial is dependent on enrolling an adequate number of subjects, effective strategies to enhance recruitment rates are highly desirable. In addition, given the resources and time limitations, it is important to understand which strategies are most cost-effective. In this manuscript, we summarize and discuss nine recruitment strategies used in an NIH R21 sponsored clinical trial, including medical records review and online advertising, among others. In addition, we developed an index to compare the time spent benefit of each approach and guide the allocation of the recruitment efforts. For this trial, online advertising and referral from health care professionals other than physicians were the strategies with greater time-benefit, leading to the largest number of stroke subjects enrolled.

Transcranial Direct Current Stimulation as a Therapeutic Tool for Chronic Pain.

Transcranial direct current stimulation (tDCS) modulates spontaneous neuronal activity that can generate long-term neuroplastic changes. It has been used in numerous therapeutic trials showing significant clinical effects especially when combined with other behavioral therapies. One area of intensive tDCS research is chronic pain. Since the initial tDCS trials for chronic pain treatment using current parameters of stimulation, more than 60 clinical trials have been published testing its effects in different pain syndromes. However, as the field moves in the direction of clinical application, several aspects need to be taken into consideration regarding tDCS effectiveness and parameters of stimulation. In this article, we reviewed the evidence of tDCS effects for the treatment of chronic pain and critically analyzed the literature pertaining its safety and efficacy, and how to optimize tDCS clinical effects in a therapeutic setting. We discuss optimization of tDCS effects in 3 different domains: (i) parameters of stimulation, (ii) combination therapies, and (iii) subject selection. This article aims to provide insights for the development of future tDCS clinical trials.

Transcranial direct current stimulation in individuals with spinal cord injury: Assessment of autonomic nervous system activity.

BACKGROUND: We hypothesized in this study that transcranial direct current stimulation (tDCS) of primary motor cortex could exert top-down modulation over subcortical systems associated with autonomic control and thus be useful to revert some of the dysfunctional changes found in the autonomic nervous system (ANS) of subjects with spinal cord injuries (SCI). OBJECTIVE: To explore the acute effect of tDCS on ANS indexed by Heart Rate Variability (HRV) in individuals with SCI and analyze whether this effect depends on the gender, degree, level and time of injury. METHODS: In this randomized, placebo-controlled, crossover, double-blinded study, 18 adults with SCI (32.9±7.9 years old) were included; the intervention consisted of a single 12-minute session of active tDCS (anodal, 2 mA) and a control session of sham tDCS applied over Cz (bihemispheric motor cortex). HRV was calculated using spectral analysis. Low-frequency (LF), high-frequency (HF), and LF/HF ratio variables were evaluated before, during, and post tDCS. RESULTS: A two-way repeated measures ANOVA showed that after active (anodal) stimulation, LF/HF ratio was significantly increased (P = 0.013). There was a trend for an interaction between time and stimulation for both LF and HF (P = 0.052). Paired exploratory t-tests reported effects on the difference of time [post-pre] between stimulation conditions for LF (P = 0.052), HF (P = 0.052) and LF/HF (P = 0.003). CONCLUSION: Anodal tDCS of the motor cortex modulated ANS activity in individuals with SCI independent of gender, type and time of lesion. These changes were in the direction of normalization of ANS parameters, thus confirming our initial hypothesis that an enhancement of cortical excitability by tDCS could at least partially restore some of the dysfunctional activity in the ANS system of subjects with SCI.

STRATEGIES TO ENHANCE RECRUITMENT METHODS IN PHANTOM LIMB PAIN CLINICAL TRIALS.

Phantom Limp Pain (PLP) was first described in 1551. To date, its mechanisms and novel interventions remain mostly untested. Only limited conclusions can be drawn from few and small randomized clinical trials (RCTs) on PLP. In this scenario, recruitment strategies are crucial in order to overcome inherent challenges to recruit PLP subjects for clinical trials. Although there are many methods to enhance recruitment and also retention, in this article we discuss these methods based on a common topic: dissemination. We summarize and discuss 10 strategies of recruitment related to the dissemination of information based on the notion that an increase in trial awareness may lead to both increased recruitment and also increased external generalizability. In addition, in our discussion we included insights based on our experience recruiting PLP patients for our large NIH-sponsored clinical trial. Although specific regulatory considerations need to be considered when choosing the methods of recruitment, which may vary across different countries and Institutional Review Boards (IRBs), these strategies may be applicable to most of research settings.

Optimizing Rehabilitation for Phantom Limb Pain Using Mirror Therapy and Transcranial Direct Current Stimulation: A Randomized, Double-Blind Clinical Trial Study Protocol.

BACKGROUND: Despite the multiple available pharmacological and behavioral therapies for the management of chronic phantom limb pain (PLP) in lower limb amputees, treatment for this condition is still a major challenge and the results are mixed. Given that PLP is associated with maladaptive brain plasticity, interventions that promote cortical reorganization such as non-invasive brain stimulation and behavioral methods including transcranial direct current stimulation (tDCS) and mirror therapy (MT), respectively, may prove to be beneficial to control pain in PLP. Due to its complementary effects, a combination of tDCS and MT may result in synergistic effects in PLP. OBJECTIVE: The objective of this study is to evaluate the efficacy of tDCS and MT as a rehabilitative tool for the management of PLP in unilateral lower limb amputees. METHODS: A prospective, randomized, placebo-controlled, double-blind, factorial, superiority clinical trial will be carried out. Participants will be eligible if they meet the following inclusion criteria: lower limb unilateral traumatic amputees that present PLP for at least 3 months after the amputated limb has completely healed. Participants (N=132) will be randomly allocated to the following groups: (1) active tDCS and active MT, (2) sham tDCS and active MT, (3) active tDCS and sham MT, and (4) sham tDCS and sham MT. tDCS will be applied with the anodal electrode placed over the primary motor cortex (M1) contralateral to the amputation side and the cathode over the contralateral supraorbital area. Stimulation will be applied at the same time of the MT protocol with the parameters 2 mA for 20 minutes. Pain outcome assessments will be performed at baseline, before and after each intervention session, at the end of MT, and in 2 follow-up visits. In order to assess cortical reorganization and correlate with clinical outcomes, participants will undergo functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) before and after the intervention. RESULTS: This clinical trial received institutional review board (IRB) approval in July of 2015 and enrollment started in December of 2015. To date 2 participants have been enrolled. The estimate enrollment rate is about 30 to 35 patients per year; thus we expect to complete enrollment in 4 years. CONCLUSIONS: This factorial design will provide relevant data to evaluate whether tDCS combined with MT is more effective than each therapy alone, as well as with no intervention (sham/sham) in patients with chronic PLP after unilateral lower limb amputation. In addition, this randomized clinical trial will help to investigate the neurophysiological mechanisms underlying the disease, which could potentially provide relevant findings for further management of this chronic condition and also help to optimize the use of this novel intervention. TRIAL REGISTRATION: Clinicaltrials.gov NCT02487966; https://clinicaltrials.gov/ct2/show/NCT02487966 (Archived by WebCite at http://www.webcitation.org/6i3GrKMyf).