Treatment of depression with transcranial direct current stimulation (tDCS): A Review

Major Depression Disorder (MDD) is usually accompanied by alterations of cortical activity and excitability, especially in prefrontal areas. These are reflections of a dysfunction in a distributed cortico-subcortical, bihemispheric network. Therefore it is reasonable to hypothesize that altering this pathological state with techniques of brain stimulation may offer a therapeutic target. Besides repetitive transcranial magnetic stimulation, tonic stimulation with weak direct currents (tDCS) modulates cortical excitability for hours after the end of stimulation, thus, it is a promising non-invasive therapeutic option. Early studies from the 1960s suggested some efficacy of DC stimulation to reduce symptoms in depression, but mixed results and development of psychotropic drugs resulted in an early abandonment of this technique. In the last years tDCS protocols have been optimized. Application of the newly developed stimulation protocols in patients with major depression has shown promise in few pilot studies. Further studies are needed to identify the optimal parameters of stimulation and the clinical and patient characteristics that may condition response to tDCS.     

Non-invasive brain stimulation (rTMS and tDCS) in patients with aphasia: Mode of action at the cellular level

A high proportion of patients who have suffered a stroke also suffer from aphasia. Approximately half of those affected will remain in this state despite intensive language therapy. Non-invasive brain stimulation allows us to directly and focally stimulate areas of the brain. Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), methods used in the treatment of aphasia, are based on an imbalance of mutual interhemispheric inhibition. In open and sham-controlled studies, a low-frequency, 1 Hz stimulation of the non-lesioned hemisphere (the homologue of Broca's area) for a week or more significantly improved spontaneous speech and anomia in patients with non-fluent aphasia. These positive outcomes from rTMS stimulation developed slowly, often over months following treatment, and persisted. Effects of intermittent theta burst stimulation (iTBS) developed faster than the low-frequency stimulation, and high-activity enhancement was detected in the left hemisphere after the stimulation of Broca's region. Both types of tDCS stimulation resulted in improved comprehension and reduced anomia, their primary modes of action are distinct, however, both share a common site of action with regard to the balance that occurs between inhibitory and excitatory neurotransmitters (synaptic and non-synaptic). Both types of non-invasive stimulation prepare the lesioned brain for better outcome.     

A meta-analysis of non-invasive brain stimulation and autonomic functioning: Implications for brain-heart pathways to cardiovascular disease

Given the intrinsic connection between the brain and the heart, a recent body of research emerged with the aim to influence cardiovascular system functioning by non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Despite the implications of cardiovascular activity modulation for therapeutic purposes, such effects of NIBS have not yet been quantified. The aim of this study was to meta-analyze studies on NIBS effects on blood pressure (BP), heart rate (HR) and its variability (HRV). PubMed and Scopus databases were searched for English language studies conducted in humans. Twenty-nine studies were eligible for the analyses. Pooled effect sizes (Hedges’ g) were compared. Random effect models were used. NIBS was effective in reducing HR (g = 0.17) and enhancing HRV (g = 0.30). A marginal effect emerged for BP (g = 0.21). Significant moderators were the stimulation technique and the site of stimulation. Results show that NIBS affects cardiovascular and autonomic nervous system activity, confirming a potential pathogenic brain-heart pathway to cardiovascular disease.     

Plasticity induced by non-invasive transcranial brain stimulation: A position paper

Several techniques and protocols of non-invasive transcranial brain stimulation (NIBS), including transcranial magnetic and electrical stimuli, have been developed in the past decades. Non-invasive transcranial brain stimulation may modulate cortical excitability outlasting the period of non-invasive transcranial brain stimulation itself from several minutes to more than one hour. Quite a few lines of evidence, including pharmacological, physiological and behavioral studies in humans and animals, suggest that the effects of non-invasive transcranial brain stimulation are produced through effects on synaptic plasticity. However, there is still a need for more direct and conclusive evidence. The fragility and variability of the effects are the major challenges that non-invasive transcranial brain stimulation currently faces. A variety of factors, including biological variation, measurement reproducibility and the neuronal state of the stimulated area, which can be affected by factors such as past and present physical activity, may influence the response to non-invasive transcranial brain stimulation. Work is ongoing to test whether the reliability and consistency of non-invasive transcranial brain stimulation can be improved by controlling or monitoring neuronal state and by optimizing the protocol and timing of stimulation.     

Transcranial electrical stimulation motor threshold can estimate individualized tDCS dosage from reverse-calculation electric-field modeling

BackgroundUnique amongst brain stimulation tools, transcranial direct current stimulation (tDCS) currently lacks an easy or widely implemented method for individualizing dosage.ObjectiveWe developed a method of reverse-calculating electric-field (E-field) models based on Magnetic Resonance Imaging (MRI) scans that can estimate individualized tDCS dose. We also evaluated an MRI-free method of individualizing tDCS dose by measuring transcranial magnetic stimulation (TMS) motor threshold (MT) and single pulse, suprathreshold transcranial electrical stimulation (TES) MT and regressing it against E-field modeling. Key assumptions of reverse-calculation E-field modeling, including the size of region of interest (ROI) analysis and the linearity of multiple E-field models were also tested.MethodsIn 29 healthy adults, we acquired TMS MT, TES MT, and anatomical T1-weighted MPRAGE MRI scans with a fiducial marking the motor hotspot. We then computed a “reverse-calculated tDCS dose” of tDCS applied at the scalp needed to cause a 1.00 V/m E-field at the cortex. Finally, we examined whether the predicted E-field values correlated with each participant’s measured TMS MT or TES MT.ResultsWe were able to determine a reverse-calculated tDCS dose for each participant using a 5 × 5 x 5 voxel grid region of interest (ROI) approach (average = 6.03 mA, SD = 1.44 mA, range = 3.75–9.74 mA). The Transcranial Electrical Stimulation MT, but not the Transcranial Magnetic Stimulation MT, significantly correlated with the ROI-based reverse-calculated tDCS dose determined by E-field modeling (R² = 0.45, p < 0.001).ConclusionsReverse-calculation E-field modeling, alone or regressed against TES MT, shows promise as a method to individualize tDCS dose. The large range of the reverse-calculated tDCS doses between subjects underscores the likely need to individualize tDCS dose. Future research should further examine the use of TES MT to individually dose tDCS as an MRI-free method of dosing tDCS.     

Non-invasive brain stimulation and the autonomic nervous system

Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are non-invasive methods of brain stimulation (NIBS) that can induce significant effects on cortical and subcortical neural networks. Both methods are relatively safe if appropriate guidelines are followed, and both can exert neuromodulatory effects that may be applied to the investigation of the autonomic nervous system (ANS). In addition, ANS measures can shed important light onto the neurobiologic mechanisms of NIBS. Here we present a systematic review on studies testing NIBS and ANS simultaneously. We structure our findings into four broad (not mutually exclusive) categories: (i) studies in which ANS function was modified by NIBS versus those in which it was not; (ii) studies in which NIBS was used to understand ANS function, (iii) studies in which ANS was used to understand NIBS mechanisms and (iv) NIBS/ANS studies conducted in healthy subjects versus those in patients with neuropsychiatric diseases. Forty-four articles were identified and no conclusive evidence of the effects of NIBS on ANS was observed, mainly because of the heterogeneity of included studies. Based on a comprehensive summary of this literature we propose how NIBS might be further developed to enhance our understanding of the cortical mechanisms of autonomic regulation and perhaps to modulate autonomic activity for therapeutic purposes.     

Non pharmacological treatment for neuropathic pain: Invasive and non-invasive cortical stimulation

The use of medications in chronic neuropathic pain may be limited with regard to efficacy and tolerance. Therefore, non-pharmacological approaches, using electrical stimulation of the cortex has been proposed as an alternative. First, in the early nineties, surgically-implanted epidural motor cortex stimulation (EMCS) was proven to be effective to relieve refractory neuropathic pain. Later, non-invasive stimulation techniques were found to produce similar analgesic effects, at least by means of repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1). Following “high-frequency” rTMS (e.g., stimulation frequency ranging from 5 to 20 Hz) delivered to the precentral gyrus (e.g., M1 region), it is possible to obtain an analgesic effect via the modulation of several remote brain regions involved in nociceptive information processing or control. This pain reduction can last for weeks beyond the time of the stimulation, especially if repeated sessions are performed, probably related to processes of long-term synaptic plasticity. Transcranial direct current stimulation (tDCS), another form of transcranial stimulation, using low-intensity electrical currents, generally delivered by a pair of large electrodes, has also shown some efficacy to improve patients with chronic pain syndromes. The mechanism of action of tDCS differs from that of EMCS and rTMS, but the cortical target is the same, which is M1. Although the level of evidence of therapeutic efficacy in the context of neuropathic pain is lower for tDCS than for rTMS, interesting perspectives are opened by using at-home tDCS protocols for long-term management. Now, there is a scientific basis for recommending both EMCS and rTMS of M1 to treat refractory chronic neuropathic pain, but their application in clinical practice remains limited due to practical and regulatory issues.     

Transcranial direct current stimulation (tDCS) for depression in pregnancy: A pilot randomized controlled trial

BackgroundDepression in pregnancy negatively affects maternal-child health. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation treatment for depression, has not been evaluated in pregnancy.ObjectiveTo conduct a pilot randomized controlled trial (RCT) to evaluate tDCS for antenatal depression.MethodsIn this pilot RCT in Toronto, Ontario (October 2014 to December 2016), adult pregnant women 14–32 weeks gestation with major depressive disorder who had declined antidepressant medication were considered for inclusion. Participants were randomly assigned 1:1 to tDCS or sham-control. Active tDCS comprised 30-min sessions of 2 mAmp direct current delivered over the dorsolateral prefrontal cortex, 5 days per week, for 3 weeks. Sham was administered similarly, but with current turned off after 30 s. Main outcomes were feasibility, acceptability, and protocol adherence. Maternal Montgomery Asperg Depression Rating Scale (MADRS) was measured post-treatment and at 4 and 12 weeks postpartum.ResultsOf 20 women randomized, 16 completed treatment and provided data (124 tDCS, 122 sham sessions). Views of treatment were positive with no serious adverse events. Post-treatment estimated marginal mean MADRS scores were 11.8 (standard error, SE 2.66) for tDCS and 15.4 (SE 2.51) for sham (p = 0.34). At 4 weeks postpartum, 75.0% of tDCS women were remitted versus 12.5% sham-control (p = 0.04).ConclusionsResults support proceeding to a definitive RCT to evaluate tDCS for antenatal depression. The preliminary efficacy estimates immediately post-treatment and in the postpartum, are encouraging with respect to the potential use of tDCS to improve treatment rates in this population. The trial was registered at: clinical trials.gov (NCT02116127).     

Electrified minds: Transcranial direct current stimulation (tDCS) and Galvanic Vestibular Stimulation (GVS) as methods of non-invasive brain stimulation in neuropsychology—A review of current data and future implications

Transcranial direct current stimulation (tDCS) is a noninvasive, low-cost and easy-to-use technique that can be applied to modify cerebral excitability. This is achieved by weak direct currents to shift the resting potential of cortical neurons. These currents are applied by attaching two electrodes (usually one anode and one cathode) to distinct areas of the skull. Galvanic Vestibular Stimulation (GVS) is a variant of tDCS where the electrodes are attached to the mastoids behind the ears in order to stimulate the vestibular system. tDCS and GVS are safe when standard procedures are used. We describe the basic physiological mechanisms and application of these procedures. We also review current data on the effects of tDCS and GVS in healthy subjects as well as clinical populations. Significant effects of such stimulation have been reported for motor, visual, somatosensory, attentional, vestibular and cognitive/emotional function as well as for a range of neurological and psychiatric disorders. Moreover, both techniques may induce neuroplastic changes which make them promising techniques in the field of neurorehabilitation. A number of open research questions that could be addressed with tDCS or GVS are formulated in the domains of sensory and motor processing, spatial and nonspatial attention including neglect, spatial cognition and body cognition disorders, as well as novel treatments for various neuropsychological disorders. We conclude that the literature suggests that tDCS and GVS are exciting and easily applicable research tools for neuropsychological as well as clinical-therapeutic investigations.     

tDCS possibly stimulates glial cells

Objective

Explore the possibility that transcranial direct current stimulation (tDCS) of the brain affects glial cells.

Methods

Cable theory is used to estimate roughly transmembrane potential in neurons and glial cells. tDCS is additionally compared to neuronal stimulation techniques for which the mechanisms are well known.

Results

Theoretical calculations indicated that tDCS can affect the glial transmembrane potential. The change is similar to what is physiologically observed in astrocytes during neuronal activation. In neurons, transmembrane potential changes are much weaker than the threshold for eliciting action potentials.

Conclusions

Based on simplified cable theory, tDCS may affect glial cells’ transmembrane potential and thereby the balance of neurotransmitters. No physiological evidence or proof is available, however.

Significance

It is an exciting possibility that tDCS could manipulate glial cells because they are active participants in brain function, and have multiple essential roles in the human brain. This approach may change greatly the therapeutic potential of tDCS, and also affects the safety considerations.     

Serum levels of carbamazepine and cortical excitability by magnetic brain stimulation

Abstract. We investigated the correlation between serum levels of carbamazepine (CBZ) and motor excitability studied by different parameters of transcranial magnetic stimulation (TMS) in patients at the beginning of antiepileptic treatment. A total of 10 patients with complex partial seizures following stroke were treated with loading doses of CBZ. Motor evoked potential (MEP) was recorded from the thenar eminence (TE) muscles of the unaffected arm. In all patients, we studied rest and active motor threshold (rMT, aMT), MEP amplitude and cortical silent period (CSP). In three patients, intracortical inhibition (ICI) and intracortical facilitation (ICF) were measured using paired TMS at short interstimulus intervals (1–25 ms). The recording sessions were performed before treatment and after 7, 15 and 60 days (SD=16 days). Serum level of CBZ were monitored at each recording session. We observed a progressive increase in rMT and aMT until the serum levels of CBZ reached a steady state condition. No significant changes were observed in MEP amplitude, CSP, ICI and ICF. This study documents the increase of both motor threshold and drug serum levels in patients treated with loading doses of CBZ, suggesting a relationship between drug metabolism and the effect on motor cortical excitability.     

Revisiting interhemispheric imbalance in chronic stroke: A tDCS study

Objective

Chronic 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.

Pinging the brain with transcranial magnetic stimulation reveals cortical reactivity in time and space

BackgroundSingle-pulse transcranial magnetic stimulation (TMS) elicits an evoked electroencephalography (EEG) potential (TMS-evoked potential, TEP), which is interpreted as direct evidence of cortical reactivity to TMS. Thus, combining TMS with EEG can be used to investigate the mechanism underlying brain network engagement in TMS treatment paradigms. However, controversy remains regarding whether TEP is a genuine marker of TMS-induced cortical reactivity or if it is confounded by responses to peripheral somatosensory and auditory inputs. Resolving this controversy is of great significance for the field and will validate TMS as a tool to probe networks of interest in cognitive and clinical neuroscience.ObjectiveHere, we delineated the cortical origin of TEP by spatially and temporally localizing successive TEP components, and modulating them with transcranial direct current stimulation (tDCS) to investigate cortical reactivity elicited by single-pulse TMS and its causal relationship with cortical excitability.MethodsWe recruited 18 healthy participants in a double-blind, cross-over, sham-controlled design. We collected motor-evoked potentials (MEPs) and TEPs elicited by suprathreshold single-pulse TMS targeting the left primary motor cortex (M1). To causally test cortical and corticospinal excitability, we applied tDCS to the left M1.ResultsWe found that the earliest TEP component (P25) was localized to the left M1. The following TEP components (N45 and P60) were largely localized to the primary somatosensory cortex, which may reflect afferent input by hand-muscle twitches. The later TEP components (N100, P180, and N280) were largely localized to the auditory cortex. As hypothesized, tDCS selectively modulated cortical and corticospinal excitability by modulating the pre-stimulus mu-rhythm oscillatory power.ConclusionTogether, our findings provide causal evidence that the early TEP components reflect cortical reactivity to TMS.     

Caloric vestibular stimulation and postural control in patients with spatial neglect following stroke

The impact of spatial neglect remains a substantial challenge to patients undergoing rehabilitation following stroke. Beyond the relatively well-described implications for visuospatial function, neglect is increasingly shown to have a negative impact on the wider aspects of sensori-motor performance with corresponding implications for activities including gait and balance. Caloric vestibular stimulation (CVS) administered to the contralesional ear has previously been shown to improve performance in patients with spatial neglect. Here, in Experiment One, we investigated the effect of CVS on clinical measures of spatial neglect and postural control in three groups of patients following stroke; left brain damaged patients (LBD, n?=?6), right brain damaged patients without neglect (RBD–, n?=?6), and right brain damaged patients with neglect (RBD+?, n?=?6). While post-stimulation scores demonstrated an improvement for participants with spatial neglect, further analysis of postural scores indicated that improvement was selective for asymmetrical activities, with symmetrical activities remaining unchanged. We interpret these results with reference to the related problem of extinction which predicts that activities demanding synchronous bilateral activity (symmetrical activities) would cause greater difficulties for patients with neglect. In Experiment Two, we tested a further six RBD+ patients on the same measures following CVS to the ipsilesional (right) ear. There was no significant improvement in perceptual or postural scores. Our findings are supportive of previous studies that demonstrate improvement in perception and movement for patients with spatial neglect following contralesional CVS and suggest that these improvements may have clinical benefits.     

The Uncertain Outcome of Prefrontal tDCS

BackgroundTranscranial direct current stimulation (tDCS) is increasingly used in research and clinical settings, and the dorsolateral prefrontal cortex (DLPFC) is often chosen as a target for stimulation. While numerous studies report modulation of cognitive abilities following DLPFC stimulation, the wide array of cognitive functions that can be modulated makes it difficult to predict its precise outcome.ObjectiveThe present review aims at identifying and characterizing the various cognitive domains affected by tDCS over DLPFC.MethodsArticles using tDCS over DLPFC indexed in PubMed and published between January 2000 and January 2014 were included in the present review.ResultstDCS over DLPFC affects a wide array of cognitive functions, with sometimes apparent conflicting results.ConclusionPrefrontal tDCS has the potential to modulate numerous cognitive functions simultaneously, but to properly interpret the results, a clear a priori hypothesis is necessary, careful technical consideration are mandatory, further insights into the neurobiological impact of tDCS are needed, and consideration should be given to the possibility that some behavioral effects may be partly explained by parallel modulation of related functions.