In neurology, as in all branches of medicine, symptoms of disease and the resulting burden of illness and disability are not simply the consequence of the injury, inflammation or dysfunction of a ...given organ; they also reflect the consequences of the nervous system's attempt to adapt to the insult. This plastic response includes compensatory changes that prove adaptive for the individual, as well as changes that contribute to functional disability and are, therefore, maladaptive. In this context, brain stimulation techniques tailored to modulate individual plastic changes associated with neurological diseases might enhance clinical benefits and minimize adverse effects. In this Review, we discuss the use of two noninvasive brain stimulation techniques--repetitive transcranial magnetic stimulation and transcranial direct current stimulation--to modulate activity in the targeted cortex or in a dysfunctional network, to restore an adaptive equilibrium in a disrupted network for best behavioral outcome, and to suppress plastic changes for functional advantage. We review randomized controlled studies, in focal epilepsy, Parkinson's disease, recovery from stroke, and chronic pain, to illustrate these principles, and we present evidence for the clinical effects of these two techniques.
The development of mild cognitive impairment (MCI) and Alzheimer's disease (AD) may be associated with an inflammatory process. Inflammatory cytokines may be a surrogate for systemic inflammation ...leading to worsening neurological function. We aim to investigate the association between cognitive impairment and inflammation by pooling and analyzing the data from previously published studies.
We performed a systematic literature search on MEDLINE, PubMed, Embase, Web of Science, and Scopus for prospective longitudinal and cross-sectional studies evaluating the relationship between inflammation and cognitive functions.
A total of 79 articles were included in our systematic review and meta-analysis. Pooled estimates from cross-sectional studies have demonstrated an increased level of C-reactive protein (CRP) Hedges's g 0.35, 95% CI (0.16, 0.55),
< 0.05, IL-1β 0.94, 95% CI (-0.04, 1.92),
< 0.05, interleukin-6 (IL-6) 0.46, 95% CI (0.05, 0.88),
< 0.005, TNF alpha 0.22, 95% CI (-0.24, 0.68),
< 0.05, sTNFR-1 0.74, 95% CI (0.46, 1.02),
< 0.05 in AD compared to controls. Similarly, higher levels of IL-1β 0.17, 95% CI (0.05, 0.28),
< 0.05, IL-6 0.13, 95% CI (0.08, 0.18),
< 0.005, TNF alpha 0.28, 95% CI (0.07, 0.49),
< 0.05, sTNFR-1 0.21, 95% CI (0.05, 0.48),
< 0.05 was also observed in MCI vs. control samples. The data from longitudinal studies suggested that levels of IL-6 significantly increased the risk of cognitive decline OR = 1.34, 95% CI (1.13, 1.56). However, intermediate levels of IL-6 had no significant effect on the final clinical endpoint OR = 1.06, 95% CI (0.8, 1.32).
The data from cross-sectional studies suggest a higher level of inflammatory cytokines in AD and MCI as compared to controls. Moreover, data from longitudinal studies suggest that the risk of cognitive deterioration may increase by high IL-6 levels. According to our analysis, CRP, antichymotrypsin (ACT), Albumin, and tumor necrosis factor (TNF) alpha may not be good surrogates for neurological degeneration over time.
Transcranial direct current stimulation (tDCS) is a non-pharmacological intervention for depression. It has mixed results, possibly caused by study heterogeneity.
To assess tDCS efficacy and to ...explore individual response predictors.
Systematic review and individual patient data meta-analysis.
Data were gathered from six randomised sham-controlled trials, enrolling 289 patients. Active tDCS was significantly superior to sham for response (34% v. 19% respectively, odds ratio (OR) = 2.44, 95% CI 1.38-4.32, number needed to treat (NNT) = 7), remission (23.1% v. 12.7% respectively, OR = 2.38, 95% CI 1.22-4.64, NNT = 9) and depression improvement (B coefficient 0.35, 95% CI 0.12-0.57). Mixed-effects models showed that, after adjustment for other predictors and confounders, treatment-resistant depression and higher tDCS 'doses' were, respectively, negatively and positively associated with tDCS efficacy.
The effect size of tDCS treatment was comparable with those reported for repetitive transcranial magnetic stimulation and antidepressant drug treatment in primary care. The most important parameters for optimisation in future trials are depression refractoriness and tDCS dose.
We compared transcranial direct-current stimulation (tDCS) with a selective serotonin-reuptake inhibitor for the treatment of depression.
In a single-center, double-blind, noninferiority trial ...involving adults with unipolar depression, we randomly assigned patients to receive tDCS plus oral placebo, sham tDCS plus escitalopram, or sham tDCS plus oral placebo. The tDCS was administered in 30-minute, 2-mA prefrontal stimulation sessions for 15 consecutive weekdays, followed by 7 weekly treatments. Escitalopram was given at a dose of 10 mg per day for 3 weeks and 20 mg per day thereafter. The primary outcome measure was the change in the 17-item Hamilton Depression Rating Scale (HDRS-17) score (range, 0 to 52, with higher scores indicating more depression). Noninferiority of tDCS versus escitalopram was defined by a lower boundary of the confidence interval for the difference in the decreased score that was at least 50% of the difference in the scores with placebo versus escitalopram.
A total of 245 patients underwent randomization, with 91 being assigned to escitalopram, 94 to tDCS, and 60 to placebo. In the intention-to-treat analysis, the mean (±SD) decrease in the score from baseline was 11.3±6.5 points in the escitalopram group, 9.0±7.1 points in the tDCS group, and 5.8±7.9 points in the placebo group. The lower boundary of the confidence interval for the difference in the decrease for tDCS versus escitalopram (difference, -2.3 points; 95% confidence interval CI, -4.3 to -0.4; P=0.69) was lower than the noninferiority margin of -2.75 (50% of placebo minus escitalopram), so noninferiority could not be claimed. Escitalopram and tDCS were both superior to placebo (difference vs. placebo, 5.5 points 95% CI, 3.1 to 7.8; P<0.001 and 3.2 points 95% CI, 0.7 to 5.5; P=0.01, respectively). Patients receiving tDCS had higher rates of skin redness, tinnitus, and nervousness than did those in the other two groups, and new-onset mania developed in 2 patients in the tDCS group. Patients receiving escitalopram had more frequent sleepiness and obstipation than did those in the other two groups.
In a single-center trial, tDCS for the treatment of depression did not show noninferiority to escitalopram over a 10-week period and was associated with more adverse events. (Funded by Fundação de Amparo à Pesquisa do Estado de São Paulo and others; ELECT-TDCS ClinicalTrials.gov number, NCT01894815 .).
•Cranial Electrotherapy Stimulation is a descendant of Electrosleep.•Transcutaneous Cranial Electrical Stimulation is a descendant of Electroanesthesia.•There is a need for better reporting of ...dosages and devices used.•There is a shift to basic dosages in contemporary approaches.
Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.
Several clinical studies on major depressive disorder (MDD) have shown that blood brain-derived neurotrophic factor (BDNF) – a factor used to index neuroplasticity – is associated with depression ...response; however, the results are mixed. The purpose of our study was to evaluate whether BDNF levels are correlated with improvement of depression. We performed a systematic review and meta-analysis of the literature, searching Medline, Cochrane Central, SciELO databases and reference lists from retrieved articles for clinical studies comparing mean BDNF blood levels in depressed patients pre- and post-antidepressant treatments or comparing depressed patients with healthy controls. Two reviewers independently searched for eligible studies and extracted outcome data using a structured form previously elaborated. Twenty articles, including 1504 subjects, met our inclusion criteria. The results showed that BDNF levels increased significantly after antidepressant treatment (effect size 0.62, 95% CI 0.36–0.88, random effects model). In addition, there was a significant correlation between changes in BDNF level and depression scores changes (p=0.02). Moreover, the results were robust according to the sensitivity analysis and Begg's funnel plot results did not suggest publication bias. Finally, there was a difference between pre-treatment patients and healthy controls (effect size 0.91, 95% CI 0.70–1.11) and a small but significant difference between treated patients and healthy controls (effect size 0.34, 95% CI 0.02–0.66). Our results show that BDNF levels are associated with clinical changes in depression; supporting the notion that depression improvement is associated with neuroplastic changes.
Therapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited ...and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.
Today, several pharmaceutic and non-pharmaceutic approaches exist to treat psychiatric and neurological diseases. Because of the lack of treatment procedures that are medication free and without ...severe side effects, transcranial direct current stimulation (tDCS) and aerobic exercise (AE) have been tested to explore the potential for initiating and modulating neuroplasticity in the human brain. Both tDCS and AE could support cognition and behavior in the clinical and non-clinical context to improve the recovery process within neurological or psychiatric conditions or to increase performance. As these techniques still lack meaningful effects, although they provide multiple beneficial opportunities within disease and health applications, there is emerging interest to find improved tDCS and AE protocols. Since multimodal approaches could provoke synergetic effects, a few recent studies have begun to combine tDCS and AE within different settings such as in cognitive training in health or for treatment purposes within clinical settings, all of which show superior effects compared to single technique applications. The beneficial outcomes of both techniques depend on several parameters and the understanding of neural mechanisms that are not yet fully understood. Recent studies have begun to directly combine tDCS and AE within one session, although their interactions on the behavioral, neurophysiological and neurochemical levels are entirely unclear. Therefore, this review: (a) provides an overview of acute behavioral, neurophysiological, and neurochemical effects that both techniques provoke within only one single application in isolation; (b) gives an overview regarding the mechanistic pathways; and (c) discusses potential interactions and synergies between tDCS and AE that might be provoked when directly combining both techniques. From this literature review focusing primarily on the cognitive domain in term of specific executive functions (EFs; inhibition, updating, and switching), it is concluded that a direct combination of tDCS and AE provides multiple beneficial opportunities for synergistic effects. A combination could be useful within non-clinical settings in health and for treating several psychiatric and neurologic conditions. However, there is a lack of research and there are several possibly interacting moderating parameters that must be considered and more importantly must be systematically investigated in the future.
•tDCS in this population of subjects is not associated with adverse effects.•There was a specific tDCS effect on executive function.•Dorsolateral prefrontal tDCS is not associated with motor function ...improvement.
Non-motor symptoms in patients with Parkinson's disease (PD) are often poorly recognized, significantly impair quality of life and cause severe disability. Currently, there is limited evidence to guide treatment of associated psychiatric and cognitive problems. Non-invasive brain stimulation techniques have emerged as non-pharmacological alternatives to target cognitive symptoms without worsening motor function. In this context, we conducted a multicenter, sham controlled, double-blinded study to assess the immediate and long-term effects of ten consecutive sessions of transcranial direct current stimulation (tDCS) over the anode on the right dorsolateral prefrontal cortex (DLPFC) (n=5), left DLPFC (n=6) or sham (n=7). We assessed cognitive functions, depressive symptoms and motor functions in 18 PD patients at baseline, at the end of the 2-week stimulation sessions and at 1-month follow-up. Our results showed that active stimulation of both left and right DLPFC resulted in prolonged improvements in Trail Making Test B, an established test to measure executive function, compared to sham tDCS at the 1-month follow-up. These results suggest the existence of a beneficial long-term effect on executive functions in PD patients following active tDCS over the DLPFC. Thus, our findings encourage further investigation exploring tDCS as an adjuvant therapy for cognitive and behavioral treatment in PD.
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