Roberta Ferrucci

Clinical research with transcranial direct current stimulation (tDCS): Challenges and future directions

BACKGROUND Transcranial direct current stimulation (tDCS) is a neuromodulatory technique that delivers low-intensity, direct current to cortical areas facilitating or inhibiting spontaneous neuronal activity. In the past 10 years, tDCS physiologic mechanisms of action have been intensively investigated giving support for the investigation of its applications in clinical neuropsychiatry and rehabilitation. However, new methodologic, ethical, and regulatory issues emerge when translating the findings of preclinical and phase I studies into phase II and III clinical studies. The aim of this comprehensive review is to discuss the key challenges of this process and possible methods to address them. METHODS We convened a workgroup of researchers in the field to review, discuss, and provide updates and key challenges of tDCS use in clinical research. MAIN FINDINGS/DISCUSSION We reviewed several basic and clinical studies in the field and identified potential limitations, taking into account the particularities of the technique. We review and discuss the findings into four topics: (1) mechanisms of action of tDCS, parameters of use and computer-based human brain modeling investigating electric current fields and magnitude induced by tDCS; (2) methodologic aspects related to the clinical research of tDCS as divided according to study phase (ie, preclinical, phase I, phase II, and phase III studies); (3) ethical and regulatory concerns; and (4) future directions regarding novel approaches, novel devices, and future studies involving tDCS. Finally, we propose some alternative methods to facilitate clinical research on tDCS.

Effects of transcranial direct current stimulation on working memory in patients with Parkinson's disease

OBJECTIVES Cognitive impairment is a common feature in Parkinsons disease (PD) and is an important predictor of quality of life. Past studies showed that some aspects of cognition, such as working memory, can be enhanced following dopaminergic therapy and transcranial magnetic stimulation. The aim of our study was to investigate whether another form of noninvasive brain stimulation, anodal transcranial direct current stimulation (tDCS), which increases cortical excitability, is associated with a change in a working memory task performance in PD patients. METHODS We studied 18 patients (12 men and 6 women) with idiopathic PD. The patients performed a three-back working memory task during active anodal tDCS of the left dorsolateral prefrontal cortex (LDLPFC), anodal tDCS of the primary motor cortex (M1) or sham tDCS. In addition, patients underwent two different types of stimulation with different intensities: 1 and 2 mA. RESULTS The results of this study show a significant improvement in working memory as indexed by task accuracy, after active anodal tDCS of the LDLPFC with 2 mA. The other conditions of stimulation: sham tDCS, anodal tDCS of LDLPFC with 1 mA or anodal tDCS of M1 did not result in a significant task performance change. CONCLUSION tDCS may exert a beneficial effect on working memory in PD patients that depends on the intensity and site of stimulation. This effect might be explained by the local increase in the excitability of the dorsolateral prefrontal cortex.

Improved naming after transcranial direct current stimulation in aphasia

Transcranial direct current stimulation (tDCS) has been proposed as an adjuvant technique to improve functional recovery after ischaemic stroke. This study evaluated the effect of tDCS over the left frontotemporal areas in eight chronic non-fluent post-stroke aphasic patients. The protocol consisted of the assessment of picture naming (accuracy and response time) before and immediately after anodal or cathodal tDCS (2 mA, 10 minutes) and sham stimulation. Whereas anodal tDCS and sham tDCS failed to induce any changes, cathodal tDCS significantly improved the accuracy of the picture naming task by a mean of 33.6% (SEM 13.8%).

Transcranial direct current stimulation improves recognition memory in Alzheimer disease

Objective: To evaluate the cognitive effect of transcranial direct current stimulation (tDCS) over the temporoparietal areas in patients with Alzheimer disease (AD). Methods: In 10 patients with probable AD, we delivered anodal tDCS (AtDCS), cathodal tDCS (CtDCS), and sham tDCS (StDCS) over the temporoparietal areas in three sessions. In each session recognition memory and visual attention were tested at baseline (prestimulation) and 30 minutes after tDCS ended (poststimulation). Results: After AtDCS, accuracy of the word recognition memory task increased (prestimulation: 15.5 ± 0.9, poststimulation: 17.9 ± 0.8, p = 0.0068) whereas after CtDCS it decreased (15.8 ± 0.6 vs 13.2 ± 0.9, p = 0.011) and after StDCS it remained unchanged (16.3 ± 0.7 vs 16.0 ± 1.0, p = 0.75). tDCS left the visual attention-reaction times unchanged. Conclusion: Transcranial direct current stimulation (tDCS) delivered over the temporoparietal areas can specifically affect a recognition memory performance in patients with Alzheimer disease (AD). Because tDCS is simple, safe and inexpensive, our finding prompts studies using repeated tDCS, in conjunction with other therapeutic interventions for treating patients with AD.

Cerebellar transcranial direct current stimulation impairs the practice-dependent proficiency increase in working memory

How the cerebellum is involved in the practice and proficiency of non-motor functions is still unclear. We tested whether transcranial direct current stimulation (tDCS) over the cerebellum (cerebellar tDCS) induces after-effects on the practice-dependent increase in the proficiency of a working memory (WM) task (Sternberg test) in 13 healthy subjects. We also assessed the effects of cerebellar tDCS on visual evoked potentials (VEPs) in four subjects and compared the effects of cerebellar tDCS on the Sternberg test with those elicited by tDCS delivered over the prefrontal cortex in five subjects. Our experiments showed that anodal or cathodal tDCS over the cerebellum impaired the practice-dependent improvement in the reaction times in a WM task. Because tDCS delivered over the prefrontal cortex induced an immediate change in the WM task but left the practice-dependent proficiency unchanged, the effects of cerebellar tDCS are structure-specific. Cerebellar tDCS left VEPs unaffected, its effect on the Sternberg task therefore seems unlikely to arise from visual system involvement. In conclusion, tDCS over the cerebellum specifically impairs the practice-dependent proficiency increase in verbal WM.

Transcranial direct current stimulation in severe, drug-resistant major depression.

BACKGROUND Though antidepressant drugs are the treatment of choice for severe major depression, a number of patients do not improve with pharmacologic treatment. This study aimed to assess the effects of transcranial direct current stimulation (tDCS) in patients with severe, drug-resistant depression. METHODS Fourteen hospitalized patients aged 37-68, with severe major depressive disorder according to DSM-IV.TR criteria, drug resistant, with high risk of suicide and referred for ECT were included. Mood was evaluated using the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HDRS) and the Visual Analogue Scale (VAS). We also administered cognitive tasks to evaluate the possible cognitive effects on memory and attention. tDCS was delivered over the dorsolateral prefrontal cortex (DLPC) (2 mA, 20 min, anode left, cathode right) twice a day. RESULTS After five days of treatment although cognitive performances remained unchanged, the BDI and HDRS scores improved more than 30% (BDI p=0.001; HDRS p=0.017). The mood improvement persisted and even increased at four (T2) weeks after treatment ended. The feeling of sadness and mood as evaluated by VAS improved after tDCS (Sadness p=0.007; Mood p=0.036). CONCLUSIONS We conclude that frontal tDCS is a simple, promising technique that can be considered in clinical practice as adjuvant treatment for hospitalized patients with severe, drug-resistant major depression.

Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS)

A group of European experts was commissioned by the European Chapter of the International Federation of Clinical Neurophysiology to gather knowledge about the state of the art of the therapeutic use of transcranial direct current stimulation (tDCS) from studies published up until September 2016, regarding pain, Parkinsons disease, other movement disorders, motor stroke, poststroke aphasia, multiple sclerosis, epilepsy, consciousness disorders, Alzheimers disease, tinnitus, depression, schizophrenia, and craving/addiction. The evidence-based analysis included only studies based on repeated tDCS sessions with sham tDCS control procedure; 25 patients or more having received active treatment was required for Class I, while a lower number of 10-24 patients was accepted for Class II studies. Current evidence does not allow making any recommendation of Level A (definite efficacy) for any indication. Level B recommendation (probable efficacy) is proposed for: (i) anodal tDCS of the left primary motor cortex (M1) (with right orbitofrontal cathode) in fibromyalgia; (ii) anodal tDCS of the left dorsolateral prefrontal cortex (DLPFC) (with right orbitofrontal cathode) in major depressive episode without drug resistance; (iii) anodal tDCS of the right DLPFC (with left DLPFC cathode) in addiction/craving. Level C recommendation (possible efficacy) is proposed for anodal tDCS of the left M1 (or contralateral to pain side, with right orbitofrontal cathode) in chronic lower limb neuropathic pain secondary to spinal cord lesion. Conversely, Level B recommendation (probable inefficacy) is conferred on the absence of clinical effects of: (i) anodal tDCS of the left temporal cortex (with right orbitofrontal cathode) in tinnitus; (ii) anodal tDCS of the left DLPFC (with right orbitofrontal cathode) in drug-resistant major depressive episode. It remains to be clarified whether the probable or possible therapeutic effects of tDCS are clinically meaningful and how to optimally perform tDCS in a therapeutic setting. In addition, the easy management and low cost of tDCS devices allow at home use by the patient, but this might raise ethical and legal concerns with regard to potential misuse or overuse. We must be careful to avoid inappropriate applications of this technique by ensuring rigorous training of the professionals and education of the patients.

Prolonged visual memory enhancement after direct current stimulation in Alzheimer's disease

BACKGROUND Immediately after patients with Alzheimers disease (AD) receive a single anodal transcranial direct current stimulation (tDCS) session their memory performance improves. Whether multiple tDCS sessions improve memory performance in the longer term remains unclear. OBJECTIVE In this study we aimed to assess memory changes after five consecutive sessions of anodal tDCS applied over the temporal cortex in patients with AD. METHODS A total of 15 patients were enrolled in two centers. Cognitive functions were evaluated before and after therapeutic tDCS. tDCS was delivered bilaterally through two scalp anodal electrodes placed over the temporal regions and a reference electrode over the right deltoid muscle. The stimulating current was set at 2 mA intensity and was delivered for 30 minutes per day for 5 consecutive days. RESULTS After patients received tDCS, their performance in a visual recognition memory test significantly improved. We found a main effect of tDCS on memory performance, i.e., anodal stimulation improved it by 8.99% from baseline, whereas sham stimulation decreased it by 2.62%. tDCS failed to influence differentially general cognitive performance measures or a visual attention measure. CONCLUSIONS Our findings show that after patients with AD receive anodal tDCS over the temporal cerebral cortex in five consecutive daily sessions their visual recognition memory improves and the improvement persists for at least 4 weeks after therapy. These encouraging results provide additional support for continuing to investigate anodal tDCS as an adjuvant treatment for patients with AD.

Transcranial direct current stimulation (tDCS) in unipolar vs. bipolar depressive disorder

Transcranial direct current stimulation (tDCS) is a non-invasive method for brain stimulation. Although pilot trials have shown that tDCS yields promising results for major depressive disorder (MDD), its efficacy for bipolar depressive disorder (BDD), a condition with high prevalence and poor treatment outcomes, is unknown. In a previous study we explored the effectiveness of tDCS for MDD. Here, we expanded our research, recruiting patients with MDD and BDD. We enrolled 31 hospitalized patients (24 women) aged 30-70 years 17 with MDD and 14 with BDD (n = 14). All patients received stable drug regimens for at least two weeks before enrollment and drug dosages remained unchanged throughout the study. We applied tDCS over the dorsolateral prefrontal cortex (anodal electrode on the left and cathodal on the right) using a 2 mA-current for 20 min, twice-daily, for 5 consecutive days. Depression was measured at baseline, after 5 tDCS sessions, one week later, and one month after treatment onset. We used the scales of Beck (BDI) and Hamilton-21 items (HDRS). All patients tolerated treatment well without adverse effects. After the fifth tDCS session, depressive symptoms in both study groups diminished, and the beneficial effect persisted at one week and one month. In conclusion, our preliminary study suggests that tDCS is a promising treatment for patients with MDD and BDD.2.

Non-invasive Cerebellar Stimulation—a Consensus Paper

The field of neurostimulation of the cerebellum either with transcranial magnetic stimulation (TMS; single pulse or repetitive (rTMS)) or transcranial direct current stimulation (tDCS; anodal or cathodal) is gaining popularity in the scientific community, in particular because these stimulation techniques are non-invasive and provide novel information on cerebellar functions. There is a consensus amongst the panel of experts that both TMS and tDCS can effectively influence cerebellar functions, not only in the motor domain, with effects on visually guided tracking tasks, motor surround inhibition, motor adaptation and learning, but also for the cognitive and affective operations handled by the cerebro-cerebellar circuits. Verbal working memory, semantic associations and predictive language processing are amongst these operations. Both TMS and tDCS modulate the connectivity between the cerebellum and the primary motor cortex, tuning cerebellar excitability. Cerebellar TMS is an effective and valuable method to evaluate the cerebello-thalamo-cortical loop functions and for the study of the pathophysiology of ataxia. In most circumstances, DCS induces a polarity-dependent site-specific modulation of cerebellar activity. Paired associative stimulation of the cerebello-dentato-thalamo-M1 pathway can induce bidirectional long-term spike-timing-dependent plasticity-like changes of corticospinal excitability. However, the panel of experts considers that several important issues still remain unresolved and require further research. In particular, the role of TMS in promoting cerebellar plasticity is not established. Moreover, the exact positioning of electrode stimulation and the duration of the after effects of tDCS remain unclear. Future studies are required to better define how DCS over particular regions of the cerebellum affects individual cerebellar symptoms, given the topographical organization of cerebellar symptoms. The long-term neural consequences of non-invasive cerebellar modulation are also unclear. Although there is an agreement that the clinical applications in cerebellar disorders are likely numerous, it is emphasized that rigorous large-scale clinical trials are missing. Further studies should be encouraged to better clarify the role of using non-invasive neurostimulation techniques over the cerebellum in motor, cognitive and psychiatric rehabilitation strategies.