Nadia Bolognini

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.

Somatic and Motor Components of Action Simulation

Seminal studies in monkeys report that the viewing of actions performed by other individuals activates frontal and parietal cortical areas typically involved in action planning and execution. That mirroring actions might rely on both motor and somatosensory components is suggested by reports that action observation and execution increase neural activity in motor and in somatosensory areas. This occurs not only during observation of naturalistic movements but also during the viewing of biomechanically impossible movements that tap the afferent component of action, possibly by eliciting strong somatic feelings in the onlooker. Although somatosensory feedback is inherently linked to action execution, information on the possible causative role of frontal and parietal cortices in simulating motor and sensory action components is lacking. By combining low-frequency repetitive and single-pulse transcranial magnetic stimulation, we found that virtual lesions of ventral premotor cortex (vPMc) and primary somatosensory cortex (S1) suppressed mirror motor facilitation contingent upon observation of possible and impossible movements, respectively. In contrast, virtual lesions of primary motor cortex did not influence mirror motor facilitation. The reported double dissociation suggests that vPMc and S1 play an active, differential role in simulating efferent and afferent components of observed actions.

Neurophysiological and Behavioral Effects of tDCS Combined With Constraint-Induced Movement Therapy in Poststroke Patients

Background. Recovery of motor function after stroke may depend on a balance of activity in the neural network involving the affected and the unaffected motor cortices. Objective. To assess whether transcranial direct current stimulation (tDCS) can increase the training-induced recovery of motor functions. Methods. In an exploratory study, 14 patients with chronic stroke and mean Fugl-Meyer Upper Extremity Motor Assessment of 29 (range = 8-50) entered a double-blind sham-controlled study, aimed to investigate neurophysiological and behavioral effects of bihemispheric tDCS (cathodal stimulation of the unaffected motor cortex and anodal stimulation of the affected motor cortex), combined with constraint-induced movement therapy (CIMT). Results. Patients in both groups demonstrated gains on primary outcome measures, that is, Jebsen Taylor Hand Function Test, Handgrip Strength, Motor Activity Log Scale, and Fugl-Meyer Motor Score. Gains were larger in the active tDCS group. Neurophysiological measurements showed a reduction in transcallosal inhibition from the intact to the affected hemisphere and increased corticospinal excitability in the affected hemisphere only in the active tDCS/CIMT group. Such neurophysiological changes correlated with the magnitude of the behavioral gains. Both groups showed a reduction in corticospinal excitability of the unaffected hemisphere. Conclusions. CIMT alone appears effective in modulating local excitability but not in removing the imbalance in transcallosal inhibition. Bihemispheric tDCS may achieve this goal and foster greater functional recovery.

Proprioceptive Alignment of Visual and Somatosensory Maps in the Posterior Parietal Cortex

A touch on one hand can enhance the response to a visual stimulus delivered at a nearby location [1, 2], improving our interactions with the external world. In order to keep such visual-tactile spatial interactions effective, the brain updates the continuous postural changes, like those typically accompanying hand actions, through proprioception, thus maintaining the somatosensory and visual maps in spatial register [2, 3]. The posterior parietal cortex (PPC) might be critical for such a spatial remapping [4]; nevertheless, a direct causal demonstration of its involvement is lacking. Here, we found that unattended touches to one hand enhanced visual sensitivity for phosphenes induced by occipital trancranial magnetic stimulation (TMS) [5] when the touched hand was spatially coincident to the reported location of the phosphenes in external space. Notably, this spatially specific crossmodal facilitation was maintained after hand crossing, suggesting an efficient visual-tactile remapping. Critically, after 1 Hz repetitive TMS interference [6] over the PPC, but not over the primary somatosensory cortex, phosphene detection was still enhanced by spatially coincident touches with uncrossed hands, but it was enhanced by spatially noncoincident touches after hand crossing. This is the first causal evidence in humans that the PPC constantly updates the representation of the body in space in order to facilitate crossmodal interactions.

Brain polarization of parietal cortex augments training-induced improvement of visual-exploratory and attentional skills

Recent evidence suggests that behavioural gains induced by behavioural training are maximized when combined with techniques of cortical neuromodulation, such as transcranial Direct Current Stimulation (tDCS). Here we address the validity of this appealing approach by investigating the effect of coupling a multisensory visual field exploration training with tDCS of the posterior parietal cortex (PPC). The multisensory visual field exploration training consisted in the practice of visual search through the systematic audio-visual stimulation of the visual field. Neurologically unimpaired participants performed a bimodal exploration training for 30 min, while simultaneously receiving anodal-excitatory PPC tDCS or sham tDCS. In two different experiments, the left and the right hemisphere were stimulated. Outcome measures included visual exploration speed at different time intervals during the training, and the post-training effects on tests assessing visual scanning and visuo-spatial orienting. Results show that PPC tDCS applied to the right, but not to the left, hemisphere increases the training-induced behavioural improvement of visual exploration, as compared to sham tDCS. In addition, right PPC tDCS brings about an improvement of covert visual orienting, in a task different from the visual search practice. In an additional experiment, we confirm that right parietal tDCS by itself, even without the associated training, can lead to enhancement of visual search. Overall, anodal PPC tDCS is a promising technique to enhance visuo-spatial abilities, when combined to a visual field exploration training task.

Regulatory considerations for the clinical and research use of transcranial direct current stimulation (tDCS): Review and recommendations from an expert panel

Abstract The field of transcranial electrical stimulation (tES) has experienced significant growth in the past 15 years. One of the tES techniques leading this increased interest is transcranial direct current stimulation (tDCS). Significant research efforts have been devoted to determining the clinical potential of tDCS in humans. Despite the promising results obtained with tDCS in basic and clinical neuroscience, further progress has been impeded by a lack of clarity on international regulatory pathways. Therefore, a group of research and clinician experts on tDCS were convened to review the research and clinical use of tDCS. This report reviews the regulatory status of tDCS and summarizes the results according to research, off-label, and compassionate use of tDCS in the following countries: Australia, Brazil, France, Germany, India, Iran, Italy, Portugal, South Korea, Taiwan, and the US. Research use, off label treatment, and compassionate use of tDCS are employed in most of the countries reviewed in this study. It is critical that a global or local effort is organized to pursue definite evidence to either approve and regulate or restrict the use of tDCS in clinical practice on the basis of adequate randomized controlled treatment trials.

Transcranial Magnetic Stimulation: Disrupting Neural Activity to Alter and Assess Brain Function

Transcranial magnetic stimulation (TMS), first successfully demonstrated in 1985 ([Barker et al., 1985][1]), is a very safe, when following current safety guidelines ([Rossi et al., 2009][2]), and noninvasive method for affecting brain function. It relies upon the properties of electromagnetic

Enhancing multisensory spatial orienting by brain polarization of the parietal cortex

Transcranial direct current stimulation (tDCS) is a noninvasive brain stimulation technique that induces polarity‐specific excitability changes in the human brain, therefore altering physiological, perceptual and higher‐order cognitive processes. Here we investigated the possibility of enhancing attentional orienting within and across different sensory modalities, namely visual and auditory, by polarization of the posterior parietal cortex (PPC), given the putative involvement of this area in both unisensory and multisensory spatial processing. In different experiments, we applied anodal or sham tDCS to the right PPC and, for control, anodal stimulation of the right occipital cortex. Using a redundant signal effect (RSE) task, we found that anodal tDCS over the right PPC significantly speeded up responses to contralateral targets, regardless of the stimulus modality. Furthermore, the effect was dependant on the nature of the audiovisual enhancement, being stronger when subserved by a probabilistic mechanism induced by blue visual stimuli, which probably involves processing in the PPC. Hence, up‐regulating the level of excitability in the PPC by tDCS appears a successful approach for enhancing spatial orienting to unisensory and crossmodal stimuli. Moreover, audiovisual interactions mostly occurring at a cortical level can be selectively enhanced by anodal PPC tDCS, whereas multisensory integration of stimuli, which is also largely mediated at a subcortical level, appears less susceptible to polarization of the cortex.

Motor and parietal cortex stimulation for phantom limb pain and sensations.

&NA; Anodal transcranial direct current stimulation of the motor cortex induces relief from phantom limb pain, whereas cathodal stimulation of the parietal cortex reduces nonpainful phantom‐limb sensations. &NA; Limb amputation may lead to chronic painful sensations referred to the absent limb, ie phantom limb pain (PLP), which is likely subtended by maladaptive plasticity. The present study investigated whether transcranial direct current stimulation (tDCS), a noninvasive technique of brain stimulation that can modulate neuroplasticity, can reduce PLP. In 2 double‐blind, sham‐controlled experiments in subjects with unilateral lower or upper limb amputation, we measured the effects of a single session of tDCS (2 mA, 15 min) of the primary motor cortex (M1) and of the posterior parietal cortex (PPC) on PLP, stump pain, nonpainful phantom limb sensations and telescoping. Anodal tDCS of M1 induced a selective short‐lasting decrease of PLP, whereas cathodal tDCS of PPC induced a selective short‐lasting decrease of nonpainful phantom sensations; stump pain and telescoping were not affected by parietal or by motor tDCS. These findings demonstrate that painful and nonpainful phantom limb sensations are dissociable phenomena. PLP is associated primarily with cortical excitability shifts in the sensorimotor network; increasing excitability in this system by anodal tDCS has an antalgic effect on PLP. Conversely, nonpainful phantom sensations are associated to a hyperexcitation of PPC that can be normalized by cathodal tDCS. This evidence highlights the relationship between the level of excitability of different cortical areas, which underpins maladaptive plasticity following limb amputation and the phenomenology of phantom limb, and it opens up new opportunities for the use of tDCS in the treatment of PLP.

Seeing touch in the somatosensory cortex: A TMS study of the visual perception of touch

Recent studies suggest the existence of a visuo‐tactile mirror system, comprising the primary (SI) and secondary (SII) somatosensory cortices, which matches observed touch with felt touch. Here, repetitive transcranial magnetic stimulation (rTMS) was used to determine whether SI or SII play a functional role in the visual processing of tactile events. Healthy participants performed a visual discrimination task with tactile stimuli (a finger touching a hand) and a control task (a finger moving without touching). During both tasks, rTMS was applied over either SI or SII, and to the occipital cortex. rTMS over SI selectively reduced subject performance for interpreting whether a contralateral visual tactile stimulus contains a tactile event, whereas SII stimulation impaired visual processing regardless of the tactile component. These findings provide evidence for a multimodal sensory‐motor system with mirror properties, where somatic and visual properties of action converge. SI, a cortical area traditionally viewed as modality‐specific, is selectively implicated in the visual processing of touch. These results are in line with the existence of a sensory mirror system mediating the embodied simulation concept. Hum Brain Mapp, 2011.