Trials Of Noninvasive Brain Stimulation Research Articles

The Role of Expectation and Beliefs on the Effects of Non-Invasive Brain Stimulation.

Non-invasive brain stimulation (NIBS) techniques are used in clinical and cognitive neuroscience to induce a mild magnetic or electric field in the brain to modulate behavior and cortical activation. Despite the great body of literature demonstrating promising results, unexpected or even paradoxical outcomes are sometimes observed. This might be due either to technical and methodological issues (e.g., stimulation parameters, stimulated brain area), or to participants’ expectations and beliefs before and during the stimulation sessions. In this narrative review, we present some studies showing that placebo and nocebo effects, associated with positive and negative expectations, respectively, could be present in NIBS trials, both in experimental and in clinical settings. The lack of systematic evaluation of subjective expectations and beliefs before and after stimulation could represent a caveat that overshadows the potential contribution of placebo and nocebo effects in the outcome of NIBS trials.

Intervention Effect of Non-Invasive Brain Stimulation on Cognitive Functions among People with Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aggregated and examined the treatment effect of non-invasive brain stimulation (NIBS) (transcranial direct current stimulation and transcranial magnetic stimulation) on cognitive functions in people with traumatic brain injury (TBI). A systematic search was conducted using databases (PubMed, Web of Science, Scopus, PsycINFO, EMBASE) for studies with keywords related to non-randomized and randomized control trials of NIBS among people with TBI. Nine out of 1790 NIBS studies with 197 TBI participants (103 active vs. 94 sham) that met the inclusion and exclusion criteria of the present study were finally selected for meta-analysis using Comprehensive Meta-Analysis software (version 3). Results showed that the overall effect of NIBS on cognition in people with TBI was moderately significant (g = 0.304, 95% CI = 0.055 to 0.553) with very low heterogeneity across studies (I2 = 0.000, Tau = 0.000). Specifically, significant and marginally significant moderate effect sizes were found for cognitive sub-domains including attention, memory, and executive function. The present findings suggest that NIBS is moderately effective in improving cognitive functions among people with TBI. In particular, NIBS may be used as an alternative and/or an adjunct treatment to the traditional approach in rehabilitating cognitive functions in people with TBI.

Pharmacological, psychological and non-invasive brain stimulation interventions for preventing depression after stroke.

Depression is an important consequence of stroke that influences recovery yet often is not detected, or is inadequately treated. This is an update and expansion of a Cochrane Review first published in 2004 and previously updated in 2008. The primary objective is to test the hypothesis that pharmacological, psychological therapy, non-invasive brain stimulation, or combinations of these interventions reduce the incidence of diagnosable depression after stroke. Secondary objectives are to test the hypothesis that pharmacological, psychological therapy, non-invasive brain stimulation or combinations of these interventions reduce levels of depressive symptoms and dependency, and improve physical functioning after stroke. We also aim to determine the safety of, and adherence to, the interventions. We searched the Specialised Register of Cochrane Stroke and the Cochrane Depression Anxiety and Neurosis (last searched August 2018). In addition, we searched the following databases; Cochrane Central Register of Controlled Trials, CENTRAL (the Cochrane Library, 2018, Issue 8), MEDLINE (1966 to August 2018), Embase (1980 to August 2018), PsycINFO (1967 to August 2018), CINAHL (1982 to August 2018) and three Web of Science indexes (2002 to August 2018). We also searched reference lists, clinical trial registers (World Health Organization International Clinical Trials Registry Platform (WHO ICTRP); to August 2018 and ClinicalTrials.gov; to August 2018), conference proceedings; we also contacted study authors. Randomised controlled trials (RCTs) comparing: 1) pharmacological interventions with placebo; 2) one of various forms of psychological therapy with usual care and/or attention control; 3) one of various forms of non-invasive brain stimulation with sham stimulation or usual care; 4) a pharmacological intervention and one of various forms of psychological therapy with a pharmacological intervention and usual care and/or attention control; 5) non-invasive brain stimulation and pharmacological intervention with a pharmacological intervention and sham stimulation or usual care; 6) pharmacological intervention and one of various forms of psychological therapy with placebo and psychological therapy; 7) pharmacological intervention and non-invasive brain stimulation with placebo plus non-invasive brain stimulation; 8) non-invasive brain stimulation and one of various forms of psychological therapy versus non-invasive brain stimulation plus usual care and/or attention control; and 9) non-invasive brain stimulation and one of various forms of psychological therapy versus sham brain stimulation or usual care plus psychological therapy, with the intention of preventing depression after stroke. Review authors independently selected studies, assessed risk of bias, and extracted data from all included studies. We calculated mean difference (MD) or standardised mean difference (SMD) for continuous data and risk ratio (RR) for dichotomous data with 95% confidence intervals (CIs). We assessed heterogeneity using the I2 statistic and assessed the certainty of evidence using GRADE. We included 19 RCTs (21 interventions), with 1771 participants in the review. Data were available for 12 pharmacological trials (14 interventions) and seven psychological trials. There were no trials of non-invasive brain stimulation compared with sham stimulation or usual care, a combination of pharmacological intervention and one of various forms of psychological therapy with placebo and psychological therapy, or a combination of non-invasive brain stimulation and a pharmacological intervention with a pharmacological intervention and sham stimulation or usual care to prevent depression after stroke. Treatment effects were observed on the primary outcome of meeting the study criteria for depression at the end of treatment: there is very low-certainty evidence from eight trials (nine interventions) that pharmacological interventions decrease the number of people meeting the study criteria for depression (RR 0.50, 95% CI 0.37 to 0.68; 734 participants) compared to placebo. There is very low-certainty evidence from two trials that psychological interventions reduce the proportion of people meeting the study criteria for depression (RR 0.68, 95% CI 0.49 to 0.94, 607 participants) compared to usual care and/or attention control. Eight trials (nine interventions) found no difference in death and other adverse events between pharmacological intervention and placebo groups (RR 1.25, 95% CI 0.32 to 4.91; 496 participants) based on very low-certainty evidence. Five trials found no difference in psychological intervention and usual care and/or attention control groups for death and other adverse events (RR 1.18, 95% CI 0.73 to 1.91; 975 participants) based on very low-certainty evidence. The available evidence suggests that pharmacological interventions and psychological therapy may prevent depression and improve mood after stroke. However, there is very low certainty in these conclusions because of the very low-certainty evidence. More trials are required before reliable recommendations can be made about the routine use of such treatments after stroke.

Pharmacological, psychological, and non-invasive brain stimulation interventions for treating depression after stroke.

Pharmacological, psychological, and non-invasive brain stimulation interventions for treating depression after stroke.

Noninvasive brain stimulation for Parkinson's disease

In advanced Parkinson's disease (PD), the emergence of symptoms refractory to conventional therapy poses therapeutic challenges. The success of deep-brain-stimulation (DBS) and advances in the understanding of PD pathophysiology have raised interest in noninvasive brain stimulation as an alternative therapeutic tool. The rationale for its use draws from the concept that reversing abnormalities in brain activity and physiology thought to cause the clinical deficits may restore normal functioning. Currently the best evidence in support of this concept comes from DBS, which improves motor deficits, and modulates brain activity and motor cortex physiology, though whether a causal interaction exists remains largely undetermined. Most trials of noninvasive brain stimulation in PD have applied repetitive transcranial magnetic stimulation (rTMS) targeting the motor cortex. The current studies suggest a possible therapeutic potential of rTMS and transcranial direct current stimulation (tDCS), but clinical effects so far have been small and negligible regarding functional independence/quality-of-life. Approaches to potentiate the efficacy of rTMS include increasing stimulation intensity and novel stimulation parameters, which derive their rationale from studies on brain physiology. These novel parameters intend to simulate normal firing patterns or to act on the hypothesized role of oscillatory activity in the motor cortex and basal ganglia in motor control and its contribution to the pathogenesis of motor disorders.

Coordinate-Based Meta-Analysis of the Default Mode and Salience Network for Target Identification in Non-Invasive Brain Stimulation of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Networks.

The accurate choice of the site of non-invasive brain stimulation (NIBS) is an important factor in trial design. Based on the observation that Alzheimer's disease (AD) and behavioral frontotemporal dementia (bvFTD) affect specific large-scale networks, i.e., the default mode network (DMN) and the salience network (SN), respectively, we aimed to identify population-average coordinates of these networks that could be used as potential targets in NIBS trials aiming to modulate these circuits. Asystematic literature search of resting-state functional MRI studies reporting DMN and SN stereotactic coordinates was performed according to PRISMA guidelines. Coordinate-based meta-analyses were conducted to identify consistent nodes of the DMN and SN using GingerALE BrainMap software and the activation likelihood estimation method. DMN coordinates mapped primarily to mesial areas (posterior cingulate cortex/precuneus [Brodmann Area - BA 23/31] and medial prefrontal cortex [BA 9/10/32]). More superficial areas mapped to the bilateral parietal (angular gyrus [BA 39]), temporal (middle gyrus [BA 21]) and dorsolateral prefrontal (superior gyrus [BA 8]) cortex. SN coordinates mapped primarily to mesial and deep frontal areas (anterior insula, anterior cingulate cortex [BA 24/32]), but more superficial areas mapped to the bilateral parietal (supramarginal gyrus [BA 40]) and the right dorsolateral prefrontal (middle gyrus [BA 9/10]) cortex. NIBS should target the bilateral angular, the middle temporal cortex, or superior frontal gyri in AD for DMN modulation, and the right middle frontal or supramarginal gyri in bvFTD for SN modulation.

T002 Non-invasive brain stimulation for Parkinson’s disease

In advanced Parkinson’s disease (PD), the emergence of symptoms refractory to conventional therapy poses a therapeutic challenge. The success of deep brain stimulation(DBS) and advances in the understanding of the pathophysiology of PD have raised interest in non-invasive brain stimulation as an alternative therapeutic tool. The rationale for its use draws from the concept that reversing abnormalities in brain activity and physiology thought to cause the clinical deficits may restore normal functioning. Currently the best evidence in support of this concept comes from DBS, which improves motor deficits, and modulates brain activity and motor cortex physiology, though whether a causal interaction exists remains largely undetermined. Most trials of non-invasive brain stimulation in PD have applied repetitive trans-cranial magnetic stimulation(rTMS) targeting the primary motor cortex and cortical areas of the motor circuit. The current studies suggest a possible therapeutic potential of rTMS and transcranial direct current stimulation (tDCS), but clinical effects so far have been small and negligible regarding functional independence and quality of life. Approaches to potentiate the efficacy of rTMS include increasing stimulation intensity and novel stimulation parameters, which derive their rationale from studies on brain physiology. These novel parameters intend to simulate normal firing patterns or to act on the hypothesized role of oscillatory activity in the motor cortex and basal ganglia in motor control and its contribution to the pathogenesis of motor disorders. There may be a diagnostic potential of TMS in better characterizing individual traits in the perspective of personalized medicine.

Brain networks stimulation in dementia: insights from functional imaging.

Noninvasive brain stimulation (NIBS) is increasingly used in the field of dementia as a therapeutic option; however, evidence of clinical efficacy is limited, and the mechanism of action remains unknown. This review summarizes how functional imaging could contribute to the design of targeted and effective NIBS interventions for dementia. Resting-state functional magnetic resonance imaging (fMRI) has largely contributed to understanding brain dysfunction in dementia by identifying disease-specific networks. Resting-state fMRI might inform on a number of factors critical for the conduction of effective NIBS trials, such as definition of stimulation paradigms and choice of the stimulation target. In addition, fMRI may contribute to the understanding of the mechanisms of action of NIBS, and provide a tool to monitor treatment efficacy. Functional imaging is a promising approach for the development of hypothesis-driven, targeted stimulation approaches in the field of dementia.

Challenges in Recruitment for the Study of Noninvasive Brain Stimulation in Stroke: Lessons from Deep Brain Stimulation

Noninvasive brain stimulation (NIBS) can augment functional recovery following stroke; however, the technique lacks regulatory approval. Low enrollment in NIBS clinical trials is a key roadblock. Here, we pursued evidence to support the prevailing opinion that enrollment in trials of NIBS is even lower than enrollment in trials of invasive, deep brain stimulation (DBS). We compared 2 clinical trials in stroke conducted within a single urban hospital system, one employing NIBS and the other using DBS, (1) to identify specific criteria that generate low enrollment rates for NIBS and (2) to devise strategies to increase recruitment with guidance from DBS. Notably, we found that enrollment in the NIBS case study was 5 times lower (2.8%) than the DBS trial (14.5%) (χ(2) = 20.815, P < .0001). Although the number of candidates who met the inclusion criteria was not different (χ(2) = .04, P < .841), exclusion rates differed significantly between the 2 studies (χ(2) = 21.354, P < .0001). Beyond lack of interest, higher exclusion rates in the NIBS study were largely due to exclusion criteria that were not present in the DBS study, including restrictions for recurrent strokes, seizures, and medications. Based on our findings, we conclude and suggest that by (1) establishing criteria specific to each NIBS modality, (2) adjusting exclusion criteria based on guidance from DBS, and (3) including patients with common contraindications based on a probability of risk, we may increase enrollment and hence significantly impact the feasibility and generalizability of NIBS paradigms, particularly in stroke.

Non-invasive brain stimulation for Parkinson's disease: Current concepts and outlook 2015.

In advanced Parkinson's disease (PD), the emergence of symptoms refractory to conventional therapy poses a therapeutic challenge. The success of deep brain stimulation (DBS) and advances in the understanding of the pathophysiology of PD have raised interest in non-invasive brain stimulation as an alternative therapeutic tool. The rationale for its use draws from the concept that reversing abnormalities in brain activity and physiology thought to cause the clinical deficits may restore normal functioning. Currently the best evidence in support of this concept comes from DBS, which improves motor deficits, and modulates brain activity and motor cortex physiology, though whether a causal interaction exists remains largely undetermined. Most trials of non-invasive brain stimulation in PD have applied repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex and cortical areas of the motor circuit. Published studies suggest a possible therapeutic potential of rTMS and transcranial direct current stimulation (tDCS), but clinical effects so far have been small and negligible regarding functional independence and quality of life. Approaches to potentiate the efficacy of rTMS, including increasing stimulation intensity and novel stimulation parameters, derive their rationale from studies of brain physiology. These novel parameters simulate normal firing patterns or act on the hypothesized role of oscillatory activity in the motor cortex and basal ganglia in motor control. There may also be diagnostic potential of TMS in characterizing individual traits for personalized medicine.

OP29 – 2815: Brain stimulation and constraint for perinatal stroke hemiparesis: The PLASTIC CHAMPS trial

Objective Perinatal stroke causes hemiparetic cerebral palsy and lifelong disability. Constraint-induced movement therapy (CIMT) can improve motor function in congenital hemiparesis and adult stroke. Repetitive transcranial magnetic stimulation (rTMS) may improve motor function in adult stroke. The two have not been formally tested in perinatal stroke hemiparesis. Methods PLASTIC CHAMPS ( www.clinicaltrials.gov/NCT01189058 ) was a blinded, controlled, factorial trial of rTMS and CIMT in perinatal stroke hemiparesis. Children 6–18 years participated in a 2 week, goal-directed, peer-supported, motor learning camp. Subjects were randomized to daily inhibitory rTMS (1Hz, 1200 stimulations) over contralesional primary motor cortex, CIMT, both or neither. Primary outcomes were the Assisting Hand Assessment (AHA) and Canadian Occupational Performance Measure (COPM) at 1 week, 2 months, and 6 months. Additional outcomes included the Melbourne Assessment, quality-of-life, safety and tolerability. Corticospinal tract arrangement was defined using single-pulse TMS. Intent-to-treat analysis assessed change across treatment groups over time (ANOVA, linear mixed effects model). Results All forty-five children completed the trial (median 11.4 years). Across all subjects, COPM performance and satisfaction scores increased >100% with sustained, maximal gains at 6 months (p 5 logit units). Combined rTMS+CIMT resulted in larger AHA gains at all time points (6 months p=0.006). CIMT alone increased AHA at 2 months (p=0.007), rTMS alone increased AHA at 1 week (p=0.002). Neither treatment decreased unaffected hand function. Affected hand function did not decrease with rTMS in children with ipsilateral corticospinal tract arrangements. Procedures were well tolerated. Conclusion Children with hemiparesis participating in intensive, psychosocial rehabilitation programs perceive marked and sustained increases in goal-specific function. Non-invasive brain stimulation trials are feasible in children with CP. Contralesional inhibitory rTMS may enhance motor learning therapy in children with perinatal stroke.

Biological Markers in Noninvasive Brain Stimulation Trials in Major Depressive Disorder

The therapeutic effects of transcranial magnetic stimulation (TMS) and transcranial direct current stimulation in patients with major depression have shown promising results; however, there is a lack of mechanistic studies using biological markers (BMs) as an outcome. Therefore, our aim was to review noninvasive brain stimulation trials in depression using BMs. The following databases were used for our systematic review: MEDLINE, Web of Science, Cochrane, and SCIELO. We examined articles published before November 2012 that used TMS and transcranial direct current stimulation as an intervention for depression and had BM as an outcome measure. The search was limited to human studies written in English. Of 1234 potential articles, 52 articles were included. Only studies using TMS were found. Biological markers included immune and endocrine serum markers, neuroimaging techniques, and electrophysiological outcomes. In 12 articles (21.4%), end point BM measurements were not significantly associated with clinical outcomes. All studies reached significant results in the main clinical rating scales. Biological marker outcomes were used as predictors of response, to understand mechanisms of TMS, and as a surrogate of safety. Functional magnetic resonance imaging, single-photon emission computed tomography, positron emission tomography, magnetic resonance spectroscopy, cortical excitability, and brain-derived neurotrophic factor consistently showed positive results. Brain-derived neurotrophic factor was the best predictor of patients' likeliness to respond. These initial results are promising; however, all studies investigating BMs are small, used heterogeneous samples, and did not take into account confounders such as age, sex, or family history. Based on our findings, we recommend further studies to validate BMs in noninvasive brain stimulation trials in MDD.

Randomized, proof-of-principle clinical trial of active transcranial magnetic stimulation in chronic migraine

High-frequency repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex (rTMS-DLPFC) is an effective treatment for depression. Preliminary studies indicated beneficial effects of rTMS-DLPFC on pain relief in patients treated for depression, and in patients with chronic migraine. In this randomized, double-blind, parallel-group, single-center, proof-of-principle clinical trial, we tested the hypothesis that 23 sessions of active rTMS-DLPFC delivered over eight weeks would be feasible, safe and superior to sham rTMS to decrease the number of headache days in 18 patients with chronic migraine without severe depression. Per-protocol analysis was performed. rTMS-DLPFC applied over eight weeks was feasible and safe in patients with chronic migraine. Contrary to our primary hypothesis, the number of headache days decreased significantly more in the sham group than in the group treated with active rTMS-DLPFC at eight weeks. Average decrease in headache days was >50% in the sham group, indicating a powerful placebo response. Pain intensity improved in both groups to a similar extent. Positive results of M1 stimulation in other studies, and the absence of significant benefits of active high-frequency rTMS of the DLPFC in the present study, point to M1 as a more promising target than the DLPFC, for larger trials of noninvasive brain stimulation in patients with chronic migraine.

P 168. TMS neurophysiology and interventional rTMS in children with perinatal stroke: Safety and tolerability in the PLASTIC CHAMPS trial

Perinatal stroke causes hemiplegic cerebral palsy and lifelong disability. TMS can define neurophysiology and central therapeutic targets while rTMS carries therapeutic potential in adult stroke but have not been applied to the more plastic developing brain. Ipsilateral projections from the unlesioned hemisphere to the affected hand are prominent in this population and the effects of non-lesioned inhibitory rTMS are unknown. PLASTIC CHAMPS is a randomized, blinded, factorial clinical trial of rTMS and constraint therapy (CIMT) to enhance upper extremity function in children (6–18 years) with perinatal stroke hemiparesis. Thirty-five children (mean age 11.25 y, 20 males) attended a 2-week intensive motor learning camp, randomized 1:1 to daily non-lesioned M1 inhibitory (1 Hz, 1200 stimulations) rTMS or sham. TMS neurophysiology mapping lasting 90–120 min (baseline and 1 week post-camp) included RMT, AMT, stimulus response curves, iSP, SICI, ICF, and IHI. Primary safety outcomes were decreased function in: (1) affected hand in children with ipsilateral projections (Assisting Hand Assessment (AHA), Melbourne Assessment (MA)) and (2) unaffected hand in all children (grip strength [GS], pinch strength [PS]). The Pediatric TMS Tolerability Evaluation was administered at 4 timepoints: 2 TMS neurophysiology sessions (pre and post camp) and 2 rTMS treatments (days 1 and 10). This measure characterizes any adverse events and subjectively ranks TMS against 7 common childhood experiences. Differences in hand function and tolerability scores were compared between rTMS and sham and over time (paired t -tests, ANOVA). TMS and rTMS procedures were well tolerated with no serious adverse events and no drop-outs. Affected hand function in children with ispsilateral projections did not decrease between rTMS and sham (AHA no change, MA increased). Unaffected hand function did not decrease with rTMS (GS and PS same). TMS and rTMS tolerability scores were favourable, scoring better than “a long car ride” on average. All side effects were mild, brief (minutes), and self-limiting with none requiring medication. Headache was common (43% during 1st TMS session) but resolved with removal of the swim cap used for mapping. Headache rates decreased (20%) with the same protocol 3 weeks later. Headache was uncommon during rTMS (11%) with tolerance (0% at 2nd session) and comparable rates between rTMS and sham. Other side-effects (neck pain, tingling, nausea, presyncope) were infrequent (<5% on final TMS session). Non-invasive brain stimulation trials are safe and feasible in children with perinatal stroke. Inhibitory rTMS over the non-lesioned M1 does not negatively affect normal hand function or affected hand function in children with ipsilateral projections. Headaches are common but mild and self-limiting.

Clinical trial design in non-invasive brain stimulation psychiatric research

Major depressive disorder (MDD) trials - investigating either non-pharmacological or pharmacological interventions - have shown mixed results. Many reasons explain this heterogeneity, but one that stands out is the trial design due to specific challenges in the field. We aimed therefore to review the methodology of non-invasive brain stimulation (NIBS) trials and provide a framework to improve clinical trial design. We performed a systematic review for randomized, controlled MDD trials whose intervention was transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) in MEDLINE and other databases from April 2002 to April 2008. We created an unstructured checklist based on CONSORT guidelines to extract items such as power analysis, sham method, blinding assessment, allocation concealment, operational criteria used for MDD, definition of refractory depression and primary study hypotheses. Thirty-one studies were included. We found that the main methodological issues can be divided in to three groups: (1) issues related to phase II/small trials, (2) issues related to MDD trials and, (3) specific issues of NIBS studies. Taken together, they can threaten study validity and lead to inconclusive results. Feasible solutions include: estimating the sample size a priori; measuring the degree of refractoriness of the subjects; specifying the primary hypothesis and statistical tests; controlling predictor variables through stratification randomization methods or using strict eligibility criteria; adjusting the study design to the target population; using adaptive designs and exploring NIBS efficacy employing biological markers. In conclusion, our study summarizes the main methodological issues of NIBS trials and proposes a number of alternatives to manage them.

Fibromyalgia: From treatment to rehabilitation

Fibromyalgia is a clinical syndrome of chronic widespread pain and reduced pain thresholds to palpation. The pathophysiology remains unknown, but there is increasing evidence that peripheral and central sensitization cause an amplification of sensory impulses that may alter pain perception in fibromyalgia patients. Interventions to treat fibromyalgia should aim at different targets simultaneously in order to reduce peripheral and central sensitization. There are both pharmacologic and non-pharmacologic approaches with evidence for effectiveness in the treatment of fibromyalgia and its associated symptoms. Evidence from randomized trials and meta-analyses shows that partial and short-term improvements in fibromyalgia symptoms can be achieved with low doses of antidepressants and with physical activity such as aerobic and strengthening exercises. A multidimensional approach which emphasizes education and integration of exercise and cognitive behavior therapy improves quality of life and reduces pain, fatigue and depressive symptoms when measured on a short term basis. More recently, trials have shown the neuromodulators gabapentin and pregabalin to be effective in reducing pain and improving quality of sleep in fibromyalgia. In addition, small trials of noninvasive brain stimulation have also shown benefits in reducing pain in fibromyalgia. It is essential to keep in mind that some important clinical conditions can mimic and overlap with fibromyalgia and should always be ruled out by a complete history, physical examination and appropriate laboratory testing.