Harnessing Placebo Effects for the Treatment of Functional Cognitive Disorder: A Feasibility Pilot Study.

OBJECTIVE: Limited research has directly investigated whether and how placebo effects can be harnessed for the treatment of functional neurological disorder (FND), despite a long-standing and controversial history of interest in this area. METHODS: A small exploratory study was conducted with adults with a cognitive subtype of FND recruited from a single cognitive neurology center in the United States. Participants were given the expectation of receiving cranial stimulation that could benefit their memory symptoms; however, the intervention was sham transcranial magnetic stimulation (placebo). Outcomes included measures of short-term memory testing, subjective memory rating, and state anxiety before and after stimulation. After the study, the true objective and rationale for investigating placebo effects were explained in a scripted debriefing session. Acceptability of the study design and qualitative feedback were collected. Institutional ethics approval and signed consent were obtained. RESULTS: Three patients (female, N=2; male, N=1; average age=57 years) were recruited. Outcome data were analyzed descriptively at the patient level. Trends of improvement in subjective memory rating, but not objective cognitive test scores, and decreases in state anxiety were observed. After the debriefing session, all patients found the study design to be acceptable (ratings of 70%, 90%, and 100%), and two of the three patients believed that withholding mechanistic information about the intervention was needed to leverage placebo effects as treatment. CONCLUSIONS: In the first study to prospectively investigate the feasibility of harnessing placebo effects for the treatment of FND, promising preliminary findings were obtained, and methods and resources for use in larger future studies are offered.

A randomized sham-controlled trial of high-dosage accelerated intermittent theta burst rTMS in major depression: study protocol.

BACKGROUND: Intermittent theta burst stimulation (iTBS), a novel form of repetitive transcranial magnetic stimulation (rTMS), can be administered in 1/10th of the time of standard rTMS (~ 3 min vs. 37.5 min) yet achieves similar outcomes in depression. The brief nature of the iTBS protocol allows for the administration of multiple iTBS sessions per day, thus reducing the overall course length to days rather than weeks. This study aims to compare the efficacy and tolerability of active versus sham iTBS using an accelerated regimen in patients with treatment-resistant depression (TRD). As a secondary objective, we aim to assess the safety, tolerability, and treatment response to open-label low-frequency right-sided (1 Hz) stimulation using an accelerated regimen in those who do not respond to the initial week of treatment. METHODS: Over three years, approximately 230 outpatients at the Centre for Addiction and Mental Health and University of British Columbia Hospital, meeting diagnostic criteria for unipolar MDD, will be recruited and randomized to a triple blind sham-controlled trial. Patients will receive five consecutive days of active or sham iTBS, administered eight times daily at 1-hour intervals, with each session delivering 600 pulses of iTBS. Those who have not achieved response by the week four follow-up visit will be offered a second course of treatment, regardless of whether they initially received active or sham stimulation. DISCUSSION: Broader implementation of conventional iTBS is limited by the logistical demands of the current standard course consisting of 4-6 weeks of daily treatment. If our proposed accelerated iTBS protocol enables patients to achieve remission more rapidly, this would offer major benefits in terms of cost and capacity as well as the time required to achieve clinical response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04255784.

Characterizing the profiles of patients with acute concussion versus prolonged post-concussion symptoms in Ontario.

Identifying vulnerability factors for developing persisting concussion symptoms is imperative for determining which patients may require specialized treatment. Using cross-sectional questionnaire data from an Ontario-wide observational concussion study, we compared patients with acute concussion (≤ 14 days) and prolonged post-concussion symptoms (PPCS) (≥ 90 days) on four factors of interest: sex, history of mental health disorders, history of headaches/migraines, and past concussions. Differences in profile between the two groups were also explored. 110 patients with acute concussion and 96 patients with PPCS were included in our study. The groups did not differ on the four factors of interest. Interestingly, both groups had greater proportions of females (acute concussion: 61.1% F; PPCS: 66.3% F). Patient profiles, however, differed wherein patients with PPCS were significantly older, more symptomatic, more likely to have been injured in a transportation-related incident, and more likely to live outside a Metropolitan city. These novel risk factors for persisting concussion symptoms require replication and highlight the need to re-evaluate previously identified risk factors as more and more concussions occur in non-athletes and different risk factors may be at play.

Litigation, Performance Validity Testing, and Treatment Outcomes in Adults With Mild Traumatic Brain Injury.

OBJECTIVE: To investigate whether involvement in litigation and performance validity test (PVT) failure predict adherence to treatment and treatment outcomes in adults with persistent symptoms after mild traumatic brain injury (mTBI). SETTING: Outpatient concussion clinics in British Columbia, Canada. Participants were assessed at intake (average 12.9 weeks postinjury) and again following 3 to 4 months of rehabilitation. PARTICIPANTS: Adults who met the World Health Organization Neurotrauma Task Force definition of mTBI. Litigation status was known for 69 participants (n = 21 reported litigation), and 62 participants completed a PVT (n = 13 failed the Test of Memory Malingering) at clinic intake. DESIGN: Secondary analysis of a clinical trial (ClinicalTrials.gov #NCT03972579). MAIN MEASURES: Outcomes included number of completed sessions, homework adherence, symptoms (Rivermead Post Concussion Symptoms Questionnaire), disability ratings (World Health Organization Disability Assessment Schedule 2.0), and patient-rated global impression of change. RESULTS: We did not observe substantial differences in session and homework adherence associated with litigation or PVT failure. Disability and postconcussion symptoms generally improved with treatment. Involvement in litigation was associated with a smaller improvement in outcomes, particularly disability (B = 2.57, 95% confidence interval [CI] [0.25-4.89], P = .03) and patient-reported global impression of change (odds ratio [OR] = 4.19, 95% CI [1.40-12.57], P = .01). PVT failure was not associated with considerable differences in treatment outcomes. However, participants who failed the PVT had a higher rate of missing outcomes (31% vs 8%) and perceived somewhat less global improvement (OR = 3.47, 95% CI [0.86-14.04]; P = .08). CONCLUSION: Adults with mTBI who are in litigation or who failed PVTs tend to adhere to and improve following treatment. However, involvement in litigation may be associated with attenuated improvements, and pretreatment PVT failure may predict lower engagement in the treatment process.

Placebo Effects and Neuromodulation: Ethical Considerations and Recommendations.

Placebo-controlled trials are the gold standard of evaluating treatment efficacy in clinical research. Neuromodulation is emerging as an important treatment pathway for many neuropsychiatric conditions, and placebo control arms of these trials require careful design with unique considerations (e.g., sham devices that mimic active stimulation, blinding effectiveness). Inherent to placebo-controlled trials are ethical concerns, such as deception, and potential harm of not receiving the active treatment. In this article, we outline important ethical considerations of placebo-controlled trials across neuromodulation approaches and provide recommendations on how ethical principles can be adhered to going forward. We specifically address issues of autonomy and respect for persons, beneficence, and justice. Within the context of this ethical framework, we also discuss factors influencing placebo effects in neuromodulation, the importance of adequate blinding, and alternative trial designs that could be considered.

COVID-19 vaccination for the prevention and treatment of long COVID: A systematic review and meta-analysis.

Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295-0.987, p = 0.045, N = 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules.

Molecular and Biochemical Assessment of Gene Therapy in the Canine Model of Duchenne Muscular Dystrophy.

Mutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disease. Adeno-associated virus (AAV) mediated gene replacement, and CRISPR/Cas9-mediated genome editing hold the potential to treat DMD. Molecular and biochemical analyses are essential to determine gene transfer efficiency and therapeutic efficacy. In this chapter, we present a series of methods routinely used in our laboratory to extract and quantify DNA, RNA, and protein in gene therapy studies performed in the canine DMD model.

The Implication of Hinge 1 and Hinge 4 in Micro-Dystrophin Gene Therapy for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is a fatal muscle disease caused by dystrophin deficiency. Dystrophin consists of the amino terminus, central rod domain with 24 spectrin-like repeats and four hinges (H), cysteine-rich domain, and carboxyl terminus. Several highly abbreviated micro-dystrophins (µDys) are currently in clinical trials. They all carry H1 and H4. In this study, we investigated whether these two hinges are essential for µDy function in murine DMD models. Three otherwise identical µDys were engineered to contain H1 and/or H4 and were named H1/H4 (with both H1 and H4), ΔH1 (without H1), and ΔH4 (without H4). These constructs were packaged in adeno-associated virus serotype-9 and delivered to the tibialis anterior muscle of 3-month-old male mdx4cv mice (1E12 vector genome particles/muscle). Three months later, we detected equivalent µDys expression in total muscle lysate. However, only H1/H4 and ΔH1 showed correct sarcolemmal localization. ΔH4 mainly existed as sarcoplasmic aggregates. H1/H4 and ΔH1, but not ΔH4, fully restored the dystrophin-associated protein complex and significantly improved the specific muscle force. Eccentric contraction-induced force decline was best protected by H1/H4, followed by ΔH1, but not by ΔH4. Next, we compared H1/H4 and ΔH1 in 6-week-old male mdx mice by intravenous injection (1E13 vector genome particles/mouse). Four months postinjection, H1/H4 significantly outperformed ΔH1 in extensor digitorum longus muscle force measurements but two constructs yielded comparable electrocardiography improvements. We conclude that H4 is essential for µDys function and H1 facilitates force production. Our findings will help develop next-generation µDys gene therapy.

Neuromodulation Therapies in Pre-Clinical Models of Traumatic Brain Injury: Systematic Review and Translational Applications.

Traumatic brain injury (TBI) has been associated with several lasting impairments that affect quality of life. Pre-clinical models of TBI have been studied to further our understanding of the underlying short-term and long-term symptomatology. Neuromodulation techniques have become of great interest in recent years as potential rehabilitative therapies after injury because of their capacity to alter neuronal activity and neural circuits in targeted brain regions. This systematic review aims to provide an overlook of the behavioral and neurochemical effects of transcranial direct current stimulation (tDCS), transcranial magnetic stimulation (TMS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS) in pre-clinical TBI models. After screening 629 abstracts, 30 articles were pooled for review. These studies showed that tDCS, TMS, DBS, or VNS delivered to rodents restored TBI-induced deficits in coordination, balance, locomotor activity and improved cognitive impairments in memory, learning, and impulsivity. Potential mechanisms for these effects included neuroprotection, a decrease in apoptosis, neuroplasticity, and the restoration of neural circuit abnormalities. The translational value, potential applicability, and the interpretation of these findings in light of outcome data from clinical trials in patients with TBI are discussed.

A bovine antibody possessing an ultralong complementarity-determining region CDRH3 targets a highly conserved epitope in sarbecovirus spike proteins.

Broadly neutralizing antibodies have huge potential as novel antiviral therapeutics due to their ability to recognize highly conserved epitopes that are seldom mutated in viral variants. A subset of bovine antibodies possess an ultralong complementarity-determining region (CDR)H3 that is highly adept at recognizing such conserved epitopes, but their reactivity against Sarbecovirus Spike proteins has not been explored previously. Here, we use a SARS-naïve library to isolate a broadly reactive bovine CDRH3 that binds the receptor-binding domain of SARS-CoV, SARS-CoV-2, and all SARS-CoV-2 variants. We show further that it neutralizes viruses pseudo-typed with SARS-CoV Spike, but this is not by competition with angiotensin-converting enzyme 2 (ACE2) binding. Instead, using differential hydrogen-deuterium exchange mass spectrometry, we demonstrate that it recognizes the major site of vulnerability of Sarbecoviruses. This glycan-shielded cryptic epitope becomes available only transiently via interdomain movements of the Spike protein such that antibody binding triggers destruction of the prefusion complex. This proof of principle study demonstrates the power of in vitro expressed bovine antibodies with ultralong CDRH3s for the isolation of novel, broadly reactive tools to combat emerging pathogens and to identify key epitopes for vaccine development.

Registered clinical trials investigating treatment of long COVID: a scoping review and recommendations for research.

BACKGROUND: A considerable proportion of individuals report persistent, debilitating and disparate symptoms despite resolution of acute COVID-19 infection (i.e. long COVID). Numerous registered clinical trials investigating treatment of long COVID are expected to be completed in 2021-2022. The aim of this review is to provide a scope of the candidate treatments for long COVID. A synthesis of ongoing long COVID clinical trials can inform methodologic approaches for future studies and identify key research vistas. METHODS: Scoping searches were conducted on multiple national and international clinical trial registries. Interventional trials testing treatments for long COVID were selected. The search timeline was from database inception to 28 July 2021. RESULTS: This scoping review included 59 clinical trial registration records from 22 countries with a total projected enrolment of 6718. Considerable heterogeneity was exhibited amongst component records with respect to the characterization of long COVID (i.e. name, symptoms- including frequency, intensity, trajectory and duration- mode of ascertainment, and definition of acute phase). In addition, the majority of proposed interventions were non-pharmacological and either targeted multiple long COVID symptoms simultaneously, or focussed on treatment of respiratory/pulmonary sequelae. Multiple interventions targeted inflammation, as well as tissue oxygenation and cellular recovery, and several interventions were repurposed from analogous conditions. CONCLUSIONS: The results of this scoping review investigating ongoing clinical trials testing candidate treatments for long COVID suggest that a greater degree of definitional stringency and homogeneity is needed insofar as the characterization of long COVID and inclusion/exclusion criteria.

Neuromodulation Treatments for Mild Traumatic Brain Injury and Post-concussive Symptoms.

PURPOSE OF REVIEW: Mild traumatic brain injury (mTBI) can result in prolonged post-concussive symptoms (e.g., depression, headaches, cognitive impairment) that are debilitating and difficult to treat. This article reviews recent research on neuromodulation for mTBI. RECENT FINDINGS: Transcranial magnetic stimulation (TMS) is the most studied neuromodulation approach for mTBI (four studies for depression, four for headache, one for cognitive impairment, and two for global post-concussive symptoms) with promising results for post-concussive depression and headache. Transcranial direct current stimulation (tDCS) has also been evaluated (one study for post-traumatic headache, and three for cognitive impairment), with more mixed results overall. TMS appears to be a potentially promising neuromodulation treatment strategy for post-concussive symptoms; however, integration into clinical practice will require larger sham-controlled randomized trials with longer and more consistent follow-up periods. Future studies should also explore new stimulation protocols, personalized approaches, and the role of placebo effects.

Neuropsychiatric Treatment for Mild Traumatic Brain Injury: Nonpharmacological Approaches.

Postconcussive symptoms following mild traumatic brain injury (mTBI)/concussion are common, disabling, and challenging to manage. Patients can experience a range of symptoms (e.g., mood disturbance, headaches, insomnia, vestibular symptoms, and cognitive dysfunction), and neuropsychiatric management relies heavily on nonpharmacological and multidisciplinary approaches. This article presents an overview of current nonpharmacological strategies for postconcussive symptoms including psychoeducation; psychotherapy; vestibular, visual, and physical therapies; cognitive rehabilitation; as well as more novel approaches, such as neuromodulation. Ultimately, treatment and management of mTBI should begin early with appropriate psychoeducation/counseling, and be tailored based on core symptoms and individual goals.

Neuromodulation for the treatment of functional neurological disorder and somatic symptom disorder: a systematic review.

Functional neurological disorder and somatic symptom disorder are complex neuropsychiatric conditions that have been linked to circuit-based dysfunction of brain networks. Neuromodulation is a novel therapeutic strategy capable of modulating relevant brain networks, making it a promising potential candidate for the treatment of these patient populations. We conducted a systematic review of Medline, Embase and PsycINFO up to 4 March 2021. Trials investigating neuromodulation devices for the treatment of functional neurological disorder or somatic symptom disorder were selected. Extracted variables included study design, demographic and clinical characteristics, psychiatric comorbidity, neurostimulation protocols, clinical outcome measures and results. 404 studies were identified with 12 meeting inclusion criteria. 221 patients were treated in the included studies with mean study sample size of 18 (4-70). Five studies were randomised clinical trials. Functional motor symptoms (six weakness, four movement disorders) were the most studied subpopulations. Transcranial magnetic stimulation (TMS) was the most frequently used device (10 studies), followed by electroconvulsive therapy (one study) and direct-current stimulation (one study). Treatment protocols varied in intended therapeutic mechanism(s): eight studies aimed to modulate underlying network dysfunction, five aimed to demonstrate movement (one also leveraged the former) and three boosted their primary mechanism with enhanced suggestion/expectation. All but one study reported positive results; however, methodological/outcome heterogeneity, mixed study quality and small sample sizes precluded quantitative meta-analysis. Neuromodulation, particularly TMS for the treatment of functional motor symptoms, shows preliminary promise in a growing line of research. Larger, sham-controlled studies are needed to further establish efficacy and better understand therapeutic mechanisms.

Placebo effects and neuromodulation for depression: a meta-analysis and evaluation of shared mechanisms.

There is growing evidence that placebo effects can meaningfully modulate the brain. However, there has been little consideration of whether these changes may overlap with regions/circuits targeted by depression treatments and what the implications of this overlap would be on measuring efficacy in placebo-controlled clinical trials. In this systematic review and meta-analysis, we searched PubMed/Medline and Google Scholar for functional MRI and PET neuroimaging studies of placebo effects. Studies recruiting both healthy subjects and patient populations were included. Neuroimaging coordinates were extracted and included for Activation Likelihood Estimation (ALE) meta-analysis. We then searched for interventional studies of transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) for depression and extracted target coordinates for comparative spatial analysis with the placebo effects maps. Of 1169 articles identified, 34 neuroimaging studies of placebo effects were included. There were three significant clusters of activation: left dorsolateral prefrontal cortex (DLPFC) (x = -41, y = 16, z = 34), left sub-genual anterior cingulate cortex (sgACC)/ventral striatum (x = -8, y = 18, z = -15) and the right rostral anterior cingulate cortex (rACC) (x = 4, y = 42, z = 10). There were two significant deactivation clusters: right basal ganglia (x = 20, y = 2, z = 7) and right dorsal anterior cingulate cortex (dACC) (x = 1, y = -5, z = 45). TMS and DBS targets for depression treatment overlapped with the left DLPFC cluster and sgACC cluster, respectively. Our findings identify a common set of brain regions implicated in placebo effects across healthy individuals and patient populations, and provide evidence that these regions overlap with depression treatment targets. We model the statistical impacts of this overlap and demonstrate critical implications on measurements of clinical trial efficacy for this field.

Feasibility of Concussion Rehabilitation Approaches Tailored to Psychological Coping Styles: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the feasibility of a clinical trial involving participants with concussion randomized to treatments designed to address fear avoidance or endurance coping, which are risk factors for disability. A secondary objective was to evaluate whether each treatment could affect selective change on targeted coping outcomes. DESIGN: Randomized controlled trial. SETTING: Outpatient concussion clinics. PARTICIPANTS: Adults (N=73, mean age=42.5y) who had persistent postconcussion symptoms and high avoidance or endurance behavior were enrolled at a mean of 12.9 weeks post injury. Ten participants did not complete treatment. INTERVENTIONS: Participants were randomized to an interdisciplinary rehabilitation program delivered via videoconferencing and tailored to avoidance coping (graded exposure therapy [GET]) or endurance coping (operant condition-based pacing strategies plus mindfulness training [Pacing+]). MAIN OUTCOME MEASURES: Feasibility outcomes included screening efficiency, accrual, credibility, treatment fidelity, adherence, and retention. Avoidance was measured with the Fear Avoidance Behavior after Traumatic Brain Injury Questionnaire and endurance behavior with the Behavioral Response to Illness Questionnaire. RESULTS: Screening efficiency, or the proportion of clinic patients who were assessed for eligibility, was 44.5% (275 of 618). A total of 65.8% (73 of 111) of eligible patients were randomized (37 to GET, 36 to Pacing+), meeting accrual targets; 91.7% (55 of 60) of participants perceived treatment as credible. Therapists covered a mean of 96.8% of essential prescribed elements, indicating excellent fidelity. The majority (71.2%; 47 of 66) of participants consistently attended treatment sessions and completed between-session homework. Retention was strong, with 65 of 73 (89%) randomized participants completing the outcome assessment. GET was associated with greater posttreatment reductions in avoidance behavior compared with Pacing+ (Cohen's drepeated measures, 0.81), whereas the treatment approach-specific effect of Pacing+ on endurance behavior was less pronounced (Cohen's drepeated measures, 0.39). CONCLUSIONS: These findings support a future efficacy-focused clinical trial. GET has the potential to selectively reduce fear avoidance behavior after concussion, and, via this mechanism, to prevent or reduce disability.