Non-invasive Brain Stimulation Protocols Research Articles

Gamma-induction in frontotemporal dementia (GIFTeD) randomized placebo-controlled trial: Rationale, noninvasive brain stimulation protocol, and study design.

IntroductionFrontotemporal dementia (FTD) is a neurodegenerative disorder for which there is no effective pharmacological treatment. Recently, interneuron activity responsible for fast oscillatory brain activity has been found to be impaired in a mouse model of FTD with consequent cognitive and behavioral alterations. In this study, we aim to investigate the safety, tolerability, and efficacy of a novel promising therapeutic intervention for FTD based on 40 Hz transcranial alternating current stimulation (tACS), a form of non‐invasive brain stimulation thought to engage neural activity in a frequency‐specific manner and thus suited to restore altered brain oscillatory patterns.MethodsThis is a multi‐site, randomized, double‐blind, placebo‐controlled trial on 50 patients with a diagnosis of behavioral variant FTD (bvFTD). Participants will be randomized to undergo either 30 days of 1‐hour daily tACS or Sham (placebo) tACS. The outcomes will be assessed at baseline, right after the intervention and at a 3‐ to 6‐months follow‐up. The primary outcome measures are represented by the safety and feasibility of tACS administration, which will be assessed considering the nature, frequency, and severity of adverse events as well as attrition rate, respectively. To assess secondary outcomes, participants will undergo extensive neuropsychological and behavioral assessments and fluorodeoxyglucose (FDG)–positron emission tomography (PET) scans to evaluate changes in brain metabolism, functional and structural magnetic resonance imaging (MRI), resting and evoked electroencephalography, as well as blood biomarkers to measure changes in neurodegenerative and neuroinflammatory markers.ResultsThe trial started in October 2020 and will end in October 2023. Study protocols have been approved by the local institutional review board (IRB) at each data‐collection site.DiscussionThis study will evaluate the safety and tolerability of 40 Hz tACS in bvFTD patients and its efficacy on gamma oscillatory activity, cognitive function, and brain glucose hypometabolism.

The Effects of Non-invasive Brain Stimulation on Impulsivity in People with Mental Disorders: a Systematic Review and Explanatory Meta-Analysis.

Impulsivity is a multi-faceted construct that underpins various mental health disorders. Impulsive behavior exacts a substantial health and economic burden, hence the importance of developing specific interventions to target impulsivity. Two forms of non-invasive brain stimulation, namely transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), have been used to modulate impulsivity. To date, no reviews have systematically examined their effects on modulating impulsivity in people with mental health disorders. We conducted a systematic review and meta-analysis of the literature from AMED, Embase, Medline and PsycINFO databases on the use of rTMS and tDCS to modulate impulsivity in people with mental health disorders. Results from 11 tDCS and 18 rTMS studies indicate that tDCS has a significant, albeit small, effect on modulating impulsivity (g = 0.29; 95% CI, 0.09 to 0.48; p = .004) whereas rTMS has no significant effect on impulsivity (g = -0.08; 95% Cl, -0.35 to 0.19; p = .550). Subgroup analyses identified the key parameters required to enhance the effects of tDCS and rTMS on impulsivity. Gender and stimulation intensity acted as significant moderators for effects of rTMS on impulsivity. There is insufficient evidence to support the use of tDCS or rTMS in clinical practice to reduce impulsivity in people with mental health disorders. The use of standardized non-invasive brain stimulation protocols and outcome measures in patients with the same diagnosis is advised to minimize methodological heterogeneity.

Understanding diaschisis models of attention dysfunction with rTMS

Visual attentive tracking requires a balance of excitation and inhibition across large-scale frontoparietal cortical networks. Using methods borrowed from network science, we characterize the induced changes in network dynamics following low frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) as an inhibitory noninvasive brain stimulation protocol delivered over the intraparietal sulcus. When participants engaged in visual tracking, we observed a highly stable network configuration of six distinct communities, each with characteristic properties in node dynamics. Stimulation to parietal cortex had no significant impact on the dynamics of the parietal community, which already exhibited increased flexibility and promiscuity relative to the other communities. The impact of rTMS, however, was apparent distal from the stimulation site in lateral prefrontal cortex. rTMS temporarily induced stronger allegiance within and between nodal motifs (increased recruitment and integration) in dorsolateral and ventrolateral prefrontal cortex, which returned to baseline levels within 15 min. These findings illustrate the distributed nature by which inhibitory rTMS perturbs network communities and is preliminary evidence for downstream cortical interactions when using noninvasive brain stimulation for behavioral augmentations.

Neurostimulation and Reach-to-Grasp Function Recovery Following Acquired Brain Injury: Insight From Pre-clinical Rodent Models and Human Applications.

Reach-to-grasp is an evolutionarily conserved motor function that is adversely impacted following stroke and traumatic brain injury (TBI). Non-invasive brain stimulation (NIBS) methods, such as transcranial magnetic stimulation and transcranial direct current stimulation, are promising tools that could enhance functional recovery of reach-to-grasp post-brain injury. Though the rodent literature provides a causal understanding of post-injury recovery mechanisms, it has had a limited impact on NIBS protocols in human research. The high degree of homology in reach-to-grasp circuitry between humans and rodents further implies that the application of NIBS to brain injury could be better informed by findings from pre-clinical rodent models and neurorehabilitation research. Here, we provide an overview of the advantages and limitations of using rodent models to advance our current understanding of human reach-to-grasp function, cortical circuitry, and reorganization. We propose that a cross-species comparison of reach-to-grasp recovery could provide a mechanistic framework for clinically efficacious NIBS treatments that could elicit better functional outcomes for patients.

P18 Novel non-invasive brain stimulation protocol to rapidly ensure the safety of inpatients with depression & suicidality

P18 Novel non-invasive brain stimulation protocol to rapidly ensure the safety of inpatients with depression & suicidality

Non-Invasive Cerebellar Stimulation in Neurodegenerative Ataxia: A Literature Review.

Cerebellar ataxias are a heterogenous group of degenerative disorders for which we currently lack effective and disease-modifying interventions. The field of non-invasive brain stimulation has made much progress in the development of specific stimulation protocols to modulate cerebellar excitability and try to restore the physiological activity of the cerebellum in patients with ataxia. In light of limited evidence-based pharmacologic and non-pharmacologic treatment options for patients with ataxia, several different non-invasive brain stimulation protocols have emerged, particularly employing repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) techniques. In this review, we summarize the most relevant rTMS and tDCS therapeutic trials and discuss their implications in the care of patients with degenerative ataxias.

Does non-invasive brain stimulation modulate emotional stress reactivity?

Excessive emotional responses to stressful events can detrimentally affect psychological functioning and mental health. Recent studies have provided evidence that non-invasive brain stimulation (NBS) targeting the prefrontal cortex (PFC) can affect the regulation of stress-related emotional responses. However, the reliability and effect sizes have not been systematically analyzed. In the present study, we reviewed and meta-analyzed the effects of repetitive transcranial magnetic (rTMS) and transcranial direct current stimulation (tDCS) over the PFC on acute emotional stress reactivity in healthy individuals. Forty sham-controlled single-session rTMS and tDCS studies were included. Separate random effects models were performed to estimate the mean effect sizes of emotional reactivity. Twelve rTMS studies together showed no evidence that rTMS over the PFC influenced emotional reactivity. Twenty-six anodal tDCS studies yielded a weak beneficial effect on stress-related emotional reactivity (Hedges’ g = −0.16, CI95% = [−0.33, 0.00]). These findings suggest that a single session of NBS is insufficient to induce reliable, clinically significant effects but also provide preliminary evidence that specific NBS methods can affect emotional reactivity. This may motivate further research into augmenting the efficacy of NBS protocols on stress-related processes.

Review: Non-Invasive Brain Stimulation in Behavioral Addictions: Insights from Direct Comparisons With Substance Use Disorders.

Treatment models developed for substance use disorders (SUDs) are often applied to behavioral addictions (BAs), even though the correspondence between these forms of addiction is unclear. This is also the case for noninvasive brain stimulation (NIBS) techniques being investigated as potential treatment interventions for SUDs and BAs. to contribute to the development of more effective NIBS protocols for BAs. Two literature searches using PubMed and Google Scholar were conducted identifying a total of 35 studies. The first search identified 25 studies examining the cognitive and neurophysiological overlap between BAs and SUDs. The second search yielded 10 studies examining the effects of NIBS in BAs. Impulsivity and cravings show behavioral and neurophysiologic overlaps between BAs and SUDs, however, other outcomes like working-memory abilities or striatal connectivity, differ between BAs and SUDs. The most-employed NIBS target in BAs was dorsolateral prefrontal cortex (DLPFC), which was associated with a decrease in cravings, and less frequently with a reduction of addiction severity. Direct comparisons between BAs and SUDs revealed discrepancies between behavioral and neurophysiological outcomes, but overall, common and distinctive characteristics underlying each disorder. The lack of complete overlap between BAs and SUDs suggests that investigating the cognitive and neurophysiological features of BAs to create individual NIBS protocols that target risk-factors associated specifically with BAs, might be more effective than transferring protocols from SUDs to BAs. Individualizing NIBS protocols to target specific risk-factors associated with each BA might help to improve treatment interventions for BAs. (Am J Addict 2019;00:1-23).

Neuronavigated theta burst stimulation for chronic aphasia: two exploratory case studies

ABSTRACTThe present study reports the findings of a 10-day neuronavigated continuous theta burst stimulation (cTBS) over the right pars triangularis for two individuals with chronic aphasia after a single left hemispheric stroke. Baseline language and quality of life measures were collected prior to the treatment study, post-treatment and at 3-month follow up. Therapy was tolerated well by both participants and no side effects were noticed during and after treatment. Results from one individual showed potential for positive change in performance in comprehension and expressive language both post-treatment and at the follow-up stage. Also, a trend towards improvement post-treatment was noticed in discourse and sentence productivity, and grammatical accuracy. In the follow up stage, grammatical accuracy showed a trend towards improvement; discourse productivity decreased and; sentence productivity skills showed mixed results. Results from the other participant showed potential for positive change in comprehension post-treatment, that was maintained at the follow-up stage. However, a decline in expressive language post-treatment and at follow-up, stronger post-treatment, was noticed. Regarding quality of life measurements, participant one appeared to have improved as his performance increased in the overall, physical and communication domains, but decreased slightly in the psychosocial domain. The second participant improved in the physical and communication domains and declined overall and in the psychosocial domains. Findings from this study indicate that cTBS over the right pars triangularis may have the potential to improve various language skills in patients suffering from chronic aphasia post-stroke. However, the potential benefits of this fast, non-invasive brain stimulation protocol on improvement of language abilities post-stroke need further exploration.

Evidence for Cognitive Placebo and Nocebo Effects in Healthy Individuals

Inactive interventions can have significant effects on cognitive performance. Understanding the generation of these cognitive placebo/nocebo effects is crucial for evaluating the cognitive impacts of interventional methods, such as non-invasive brain stimulation (NIBS). We report both cognitive placebo and nocebo effects on reward-based learning performance induced using an active sham NIBS protocol, verbal suggestions and conditioning in 80 healthy participants. Whereas our placebo manipulation increased both expected and perceived cognitive performance, nocebo had a detrimental effect on both. Model-based analysis suggests manipulation-specific strategic adjustments in learning-rates: Participants in the placebo group showed stronger learning from losses and reduced behavioral noise, participants in the nocebo group showed stronger learning from gains and increased behavioral noise. We conclude that experimentally induced expectancy can impact cognitive functions of healthy adult participants. This has important implications for the use of double-blind study designs that can effectively maintain blinding in NIBS studies.

Head models of healthy and depressed adults forsimulating the electric fields of non-invasive electric brain stimulation.

During the past decade, it became clear that the electric field elicited by non-invasive brain stimulation (NIBS) techniques such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) are substantially influenced by variations in individual head and brain anatomy. In addition to structural variations in the healthy, several psychiatric disorders are characterized by anatomical alterations that are likely to further constrain the intracerebral effects of NIBS. Here, we present high-resolution realistic head models derived from structural magnetic resonance imaging data of 19 healthy adults and 19 patients diagnosed with major depressive disorder (MDD). By using a freely available software package for modelling the electric fields induced by different NIBS protocols, we show that our head models are well-suited for assessing inter-individual and between-group variability in the magnitude and focality of tDCS-induced electric fields for two protocols targeting the left dorsolateral prefrontal cortex.

Head models of healthy and depressed adults for simulating the effects of non-invasive brain stimulation

During the past decade, it became clear that the effects of non-invasive brain stimulation (NIBS) techniques such as transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) are substantially influenced by variations in individual head and brain anatomy. In addition to structural variations in the healthy, several psychiatric disorders are characterized by anatomical alterations that are likely to further constrain the intracerebral effects of NIBS. Here, we present high-resolution realistic head models derived from structural magnetic resonance imaging data of 19 healthy adults and 19 patients diagnosed with major depressive disorder (MDD). By using a freely available software package for modelling the effects of different NIBS protocols, we show that our head models are well-suited for assessing inter-individual and between-group variability in the magnitude and focality of tDCS-induced electric fields for two protocols targeting the left dorsolateral prefrontal cortex.

Profiles of women in science: Prof. Lisa Marshall of the University of Lübeck, Lübeck, Germany.

Profiles of women in science: Prof. Lisa Marshall of the University of Lübeck, Lübeck, Germany.

Cluster analysis and subgrouping to investigate inter-individual variability to non-invasive brain stimulation: a systematic review.

Cluster analysis and other subgrouping techniques have risen in popularity in recent years in non-invasive brain stimulation research in the attempt to investigate the issue of inter-individual variability - the issue of why some individuals respond, as traditionally expected, to non-invasive brain stimulation protocols and others do not. Cluster analysis and subgrouping techniques have been used to categorise individuals, based on their response patterns, as responder or non-responders. There is, however, a lack of consensus and consistency on the most appropriate technique to use. This systematic review aimed to provide a systematic summary of the cluster analysis and subgrouping techniques used to date and suggest recommendations moving forward. Twenty studies were included that utilised subgrouping techniques, while seven of these additionally utilised cluster analysis techniques. The results of this systematic review appear to indicate that statistical cluster analysis techniques are effective in identifying subgroups of individuals based on response patterns to non-invasive brain stimulation. This systematic review also reports a lack of consensus amongst researchers on the most effective subgrouping technique and the criteria used to determine whether an individual is categorised as a responder or a non-responder. This systematic review provides a step-by-step guide to carrying out statistical cluster analyses and subgrouping techniques to provide a framework for analysis when developing further insights into the contributing factors of inter-individual variability in response to non-invasive brain stimulation.

No Interaction between tDCS Current Strength and Baseline Performance: A Conceptual Replication.

Several recent studies have reported non-linear effects of transcranial direct current stimulation (tDCS), which has been attributed to an interaction between the stimulation parameters (e.g., current strength, duration) and the neural state of the cortex being stimulated (e.g., indexed by baseline performance ability, age) (see Fertonani and Miniussi, 2016). We have recently described one such non-linear interaction between current strength and baseline performance on a visuospatial attention (landmark) task (Benwell et al., 2015). In this previous study, we induced a small overall rightward shift of spatial attention across 38 participants using bi-hemispheric tDCS applied for 20 min (concurrent left posterior parietal (P5) anode and right posterior parietal (P6) cathode) relative to a sham protocol. Importantly, this shift in bias was driven by a state-dependent interaction between current intensity and the discrimination sensitivity of the participant at baseline (pre-stimulation) for the landmark task. Individuals with high discrimination sensitivity (HDS) shifted rightward in response to low- (1 mA) but not high-intensity (2 mA) tDCS, whereas individuals with low discrimination sensitivity (LDS) shifted rightward with high- but not low-intensity stimulation. However, in Benwell et al. (2015) current strength was applied as a between-groups factor, where half of the participants received 1 mA and half received 2 mA tDCS, thus we were unable to compare high and low-intensity tDCS directly within each individual. Here we aimed to replicate these findings using a within-group design. Thirty young adults received 15 min of 1 and 2 mA tDCS, and a sham protocol, each on different days, to test the concept of an interaction between baseline performance and current strength. We found no overall rightward shift of spatial attention with either current strength, and no interaction between performance and current strength. These results provide further evidence of low replicability of non-invasive brain stimulation protocols, and the need for further attempts to replicate the key experimental findings within this field.

Revisiting interhemispheric imbalance in chronic stroke: A tDCS study

ObjectiveChronic stroke patients with moderate-severe motor impairment may have an increased reliance on contralesional vs ipsilesional motor areas to control the paretic arm. We hypothesised that increasing contralesional excitability with anodal transcranial direct current stimulation (a-tDCS) would benefit motor performance in patients with moderate-severe impairment. MethodsTen patients with motor impairment at the chronic stage after stroke received a-tDCS, cathodal (c-tDCS) and sham with the target electrode over contralesional motor cortex (M1). Motor performance was quantified from the circularity and size of planar movements made with the paretic arm. Contralateral and ipsilateral corticospinal excitability was inferred using transcranial magnetic stimulation. Corticospinal tract integrity and basal GABA concentration were assessed with magnetic resonance imaging and spectroscopy. ResultsAnodal tDCS increased contralesional corticomotor excitability evident from motor evoked potentials in both wrist extensors (both P<0.043). Cathodal tDCS did not affect corticomotor excitability (P>0.37). The effect of tDCS on motor performance with the paretic limb was negatively associated with ipsilesional GABA concentration after c-tDCS (P=0.001). ConclusionsFurther investigation of noninvasive brain stimulation protocols that facilitate contralesional M1 is warranted. SignificanceThe inter-hemispheric imbalance model of stroke recovery may not apply to patients with more severe impairment.

Valeriana officinalis Root Extract Modulates Cortical Excitatory Circuits in Humans

Background:Valeriana officinalis extract (VE) is a popular herbal medicine used for the treatment of anxiety and sleep disorders. Although the anxiolytic and sedative effects are mainly attributed to the modulation of GABA-ergic transmission, the mechanism of action has not been fully investigated in humans. Noninvasive brain stimulation protocols can be used to elucidate the mechanisms of action of psychoactive substances at the cortical level in humans. In this study, we investigated the effects of a single dose of VE on cortical excitability as assessed with transcranial magnetic stimulation (TMS). Methods: Fifteen healthy volunteers participated in a double-blind, randomized, cross-over, placebo-controlled study. Subjects were required to take either 900 mg of VE (valerenic acid 0.8%) or placebo (an equal dose of vitamin E). Motor cortex excitability was studied by single and paired TMS before and at 1 h and 6 h after the oral administration. Cortical excitability was assessed using different TMS parameters: resting motor threshold, motor-evoked potential amplitude, cortical silent period, short-interval intracortical inhibition, and intracortical facilitation. Furthermore, we assessed sensorimotor integration by short-latency and long-latency afferent inhibition. Results: We found a significant reduction in ICF, without any significant changes in other TMS measures of motor cortex excitability. The amount of ICF returned to baseline value 6 h after the intake of the VE. Conclusion: A single oral dose of VE modulates intracortical facilitatory circuits. Our results in healthy subjects could be predictive markers of treatment response in patients and further support the use of pharmaco-TMS to investigate the neuropsychiatric effects of herbal therapies in humans.

Hypericum perforatum extract modulates cortical plasticity in humans.

Hypericum perforatum (HYP) extract is one of the most commonly used complementary alternative medicines (CAMs) for the treatment of mild-to-moderate depression. Non-invasive brain stimulation protocols can be used to investigate the effect of psychoactive substances on the human brain. In this study, we explored the effect of a single dose of HYP extract (WS 5570) intake on corticospinal excitability and plasticity in humans. Twenty-eight healthy subjects were required to intake 900mg of either HYP extract or placebo. Cortical excitability was assessed using single and paired transcranial magnetic stimulation (TMS). The electrophysiological parameters of motor threshold, recruitment of motor-evoked potentials (MEPs), cortical silent period (CSP), short interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were tested before and 2 and 5h after the oral intake. Spinal and neuromuscular excitability and peripheral nerve excitability were measured by F response and M-wave. Cortical plasticity was induced using transcranial direct current stimulation (tDCS). Subjects received either HYP extract or placebo before anodal and cathodal tDCS of the primary motor cortex. Plasticity was assessed by MEP amplitudes. HYP extract reversed cathodal tDCS-induced long-term depression (LTD)-like plasticity into facilitation, as compared to placebo. HYP extract did not have a significant effect on anodal tDCS-induced plasticity and TMS measures of motor cortex and spinal/neuromuscular excitability. Our findings suggest that a single oral dose of HYP extract modulates cortical plasticity in healthy subjects and provide new insight into its possible mechanism of action in humans.

The therapeutic use of non-invasive brain stimulation in multiple sclerosis – a review

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system and a leading cause of disability in young adults. Many disabling symptoms in MS, such as spasticity, pain, depression and cognitive deficits are not fully controlled by drug treatment. Non-invasive brain stimulation (NIBS) techniques can be used as tools for modulating altered cortical excitability and plasticity MS patients, providing an improvement in disabling symptoms affecting such patients. This review reported and summarized some of the most interesting and promising recent achievements regarding the therapeutic use of NIBS in MS patients. We reviewed the clinical application of transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), emphasizing their effect on clinical symptoms and signs that are commonly involved in MS patients. In addition, we shortly described new NIBS protocols, such as transcranial alternating current stimulation and transcranial focused ultrasound stimulation as potential and innovative therapeutic options to be applied in future studies in MS patients. We reviewed twenty-one studies covering six main clinical domains. Most of such studies focused on fatigues (33.3%), motor performance (19%) and spasticity (19%), sparse results were about pain (9.5%), cognitive abilities (9.5%), sensory deficit (4.8%) and bladder function (4.8%). The most promising results have been published for the improvement of motor (i.e. hand dexterity) and cognitive performances (i.e. attention and working memory) by applying rTMS or tDCS alone or in association with motor/cognitive training, for pain's treatment by using tDCS. There are still no official recommendations for the therapeutic use of tDCS or rTMS in MS. The huge inter-individual variability of NIBS efficacy is still a big challenge which needs to be solved. However, well-designed studies, deeper knowledge about pathomechanisms underlying MS, and the combination of such techniques with motor and cognitive rehabilitation might results in higher effectiveness of NIBS.

Oscillatory Activities in Neurological Disorders of Elderly: Biomarkers to Target for Neuromodulation.

Non-invasive brain stimulation (NIBS) has been under investigation as adjunct treatment of various neurological disorders with variable success. One challenge is the limited knowledge on what would be effective neuronal targets for an intervention, combined with limited knowledge on the neuronal mechanisms of NIBS. Motivated on the one hand by recent evidence that oscillatory activities in neural systems play a role in orchestrating brain functions and dysfunctions, in particular those of neurological disorders specific of elderly patients, and on the other hand that NIBS techniques may be used to interact with these brain oscillations in a controlled way, we here explore the potential of modulating brain oscillations as an effective strategy for clinical NIBS interventions. We first review the evidence for abnormal oscillatory profiles to be associated with a range of neurological disorders of elderly (e.g., Parkinson’s disease (PD), Alzheimer’s disease (AD), stroke, epilepsy), and for these signals of abnormal network activity to normalize with treatment, and/or to be predictive of disease progression or recovery. We then ask the question to what extent existing NIBS protocols have been tailored to interact with these oscillations and possibly associated dysfunctions. Our review shows that, despite evidence for both reliable neurophysiological markers of specific oscillatory dis-functionalities in neurological disorders and NIBS protocols potentially able to interact with them, there are few applications of NIBS aiming to explore clinical outcomes of this interaction. Our review article aims to point out oscillatory markers of neurological, which are also suitable targets for modification by NIBS, in order to facilitate in future studies the matching of technical application to clinical targets.