Antoni Valero-Cabré

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.

Modulation of input-output curves by low and high frequency repetitive transcranial magnetic stimulation of the motor cortex.

OBJECTIVES Exploring the modulatory effects of different frequencies of repetitive transcranial magnetic stimulation (rTMS) on the excitability of the motor cortex as measured by the input-output curve technique (I-O curve). METHODS Sixteen healthy subjects participated in this experiment. On two different sessions, conducted 1 week apart, rTMS was applied either at a frequency of 20 or 1 Hz at 90% of individual motor threshold (MT) for a total of 1600 pulses each. Before and after rTMS, the cortical excitability was assessed by measuring MT and the size of motor evoked potentials (MEPs) collected at different intensities of stimulation. RESULTS The analysis on the whole population showed a significant decrease of cortical excitability after 1 Hz rTMS and an increase after 20 Hz rTMS. A subsequent cluster analysis pointed out the presence of two distinct groups of subjects with opposite responses at the same frequency of stimulation. Significant variations on MT were found for both groups only for the facilitatory effect irrespective of the frequency of stimulation. CONCLUSIONS The results provide further insight into interindividual differences in the effects of rTMS and suggest the existence of subpopulations with specific patterns of response to rTMS.

Disruption of Primary Motor Cortex before Learning Impairs Memory of Movement Dynamics

Although multiple lines of evidence implicate the primary motor cortex (M1) in motor learning, the precise role of M1 in the adaptation to novel movement dynamics and in the subsequent consolidation of a memory of those dynamics remains unclear. Here we used repetitive transcranial magnetic stimulation (rTMS) to dissociate the contribution of M1 to these distinct aspects of motor learning. Subjects performed reaching movements in velocity-dependent force fields over three epochs: a null-field baseline epoch, a clockwise-field learning epoch (15 min after the baseline epoch), and a clockwise-field retest epoch (24 h after the learning epoch). Half of the subjects received 15 min of 1 Hz rTMS to M1 between the baseline and learning epochs. Subjects given rTMS performed identically to control subjects during the learning epoch. However, control subjects performed with significantly less error than rTMS subjects in the retest epoch on the following day. These results suggest that M1 is not critical to the network supporting motor adaptation per se but that, within this network, M1 may be important for initiating the development of long-term motor memories.

Biophysical foundations underlying TMS: Setting the stage for an effective use of neurostimulation in the Cognitive Neurosciences

Transcranial Magnetic Stimulation (TMS) induces electrical currents in the brain to stimulate neural tissue. This article reviews our present understanding of TMS methodology, focusing on its biophysical foundations. We concentrate on how the laws of electromagnetic induction apply to TMS; addressing issues such as the location, area (i.e., focality), depth, and mechanism of TMS. We also present a review of the present limitations and future potential of the technique.

Dorsal and Ventral Parietal Contributions to Spatial Orienting in the Human Brain

Influential functional magnetic resonance imaging (fMRI)-based models have involved a dorsal frontoparietal network in the orienting of both endogenous and exogenous attention, and a ventral system in attentional reorienting to task-relevant events. Nonetheless, given the low temporal resolution and susceptibility to epiphenomenal activations of fMRI, such depictions remain highly debated. We hereby benefited from the high temporal resolution and causal power of event-related transcranial magnetic stimulation to explore the implications of key dorsal and ventral parietal regions in those two types of attention. We provide for the first time causal evidence of right intraparietal sulcus involvement in both types of attentional orienting, while we link the temporoparietal junction with the orienting of exogenous but not endogenous spatial attention.

Impact of repetitive transcranial magnetic stimulation of the parietal cortex on metabolic brain activity: a 14C-2DG tracing study in the cat

Transcranial magnetic stimulation (TMS) is increasingly utilized in clinical neurology and neuroscience. However, detailed knowledge of the impact and specificity of the effects of TMS on brain activity remains unresolved. We have used 14C-labeled deoxyglucose (14C-2DG) mapping during repetitive TMS (rTMS) of the posterior and inferior parietal cortex in anesthetized cats to study, with exquisite spatial resolution, the local and distant effects of rTMS on brain activity. High-frequency rTMS decreases metabolic activity at the primary site of stimulation with respect to homologue areas in the unstimulated hemisphere. In addition, rTMS induces specific distant effects on cortical and subcortical regions known to receive substantial efferent projections from the stimulated cortex. The magnitude of this distal impact is correlated with the strength of the anatomical projections. Thus, in the anesthetized animal, the impact of rTMS is upon a distributed network of structures connected to the primary site of application.

Superior muscle reinnervation after autologous nerve graft or poly-L-lactide-?-caprolactone (PLC) tube implantation in comparison to silicone tube repair

Recovery after peripheral nerve injury depends not only on the amount of reinnervation, but also on its accuracy. The rat sciatic nerve was subjected to an 8 mm long gap lesion repaired either by autograft (AG, n = 6) or tubulization with impermeable silicone tube (SIL, n = 6) or permeable tube of poly‐L‐lactide‐ϵ‐caprolactone (PLC, n = 8). Recordings of the compound muscle action potential (CMAP) from gastrocnemius (mGC), tibialis anterior (mTA) and plantar (mPL) muscles were performed 90 days after injury to assess the amount of muscle reinnervation. The CMAP amplitude achieved in mGC, mTA and mPL was similar in after nerve autograft (39%, 42%, 22% of control values) and PLC tube implantation (37%, 36%, 24%) but lower with SIL tube (29%, 30%, 14%). The nerve fascicles projecting into each of these muscles were then transected and retrograde tracers (Fluoro Gold, Fast Blue, DiI) were applied to quantify the percentage of motoneurons with single or multiple branches to different targets. The total number of labeled motoneurons for the three muscles did not differ in autografted rats (1186 ± 56; mean ± SEM) with respect to controls (1238 ± 82), but was reduced with PLC tube (802 ± 101) and SIL tube (935 ± 213). The percentage of neurons with multiple projections was lower after autograft and PLC tube (6%) than with SIL tube (10%). Considering the higher CMAP amplitude and lower number of neurons with multiple projections, PLC nerve conduits seem superior to SIL tubes and a suitable alternative to autografts for the repair of long gaps. J. Neurosci. Res. 63:214–223, 2001.

Peripheral and spinal motor reorganization after nerve injury and repair.

Functional recovery after peripheral nerve injury depends on the amount as well as on the accuracy of reinnervation by regenerative axons. In this study, the rat sciatic nerve was subjected to crush injury or complete transection repaired by either (1) straight nerve suture, (2) crossed nerve suture of tibial and peroneal fascicles, or (3) silicone tubulization leaving a gap of 4 mm. The compound muscle action potentials (CMAP) of gastrocnemius, tibialis anterior and plantar muscles were recorded 90 days post operation to assess functional reinnervation and Fast Blue, Fluoro Gold and DiI were applied to the nerve branches projecting into these muscles to quantify morphological reinnervation. The CMAP amplitude achieved in gastrocnemius, tibialis anterior and plantar muscles was higher after nerve crush (86%, 82%, 65% of control) than after any surgical nerve repair (straight suture: 49%, 53%, 32%; crossed suture: 56%, 50%, 31%; silicone tube: 42%, 44%, 25%). The total number of labeled motoneurons, however, did not significantly differ between groups (control: 1238 +/- 82, crush: 1048 +/- 49, straight suture: 1175 +/- 106, crossed suture: 1085 +/- 84, silicone tube: 1250 +/- 182). The volume occupied by labeled motoneurons within the spinal cord was larger after surgical nerve repair than in crush or normal control animals, and fewer neurons showed abnormal multiple projections after crush (2.5%) or straight suture (2.2%) than following crossed suture (5%) or silicone tube (6%). In conclusion, nerve repair with a silicone tube leaving a short gap does not increase accuracy of reinnervation.

H reflex restitution and facilitation after different types of peripheral nerve injury and repair

This study addresses the restitution of monosynaptic H reflex after nerve injuries and their role in the recovery of walking. Adult rats were submitted to sciatic crush, complete section repaired by aligned or crossed fascicular suture, or an 8-mm resection repaired by autograft or tube repair. The sciatic nerve was stimulated proximal to the injury site and the M and H waves were recorded from gastrocnemius (GCm) and plantar (PLm) muscles at monthly intervals during 3 months postoperation. Walking track tests were also carried out and the sciatic functional index (SFI) calculated to assess gait recovery. The M and H waves reappeared in all the animals at the end of the follow-up. The H/M amplitude ratio increased during the first stages of regeneration and tended to decrease to control values as muscle reinnervation progressed. However, final values of the H/M ratio for the PLm remained significantly higher in all the groups except that with a nerve crush. The walking track pattern showed an appreciable recovery only after crush injury. Final SFI values correlated positively with the M wave amplitude and negatively with the H/M ratio. In conclusion, H reflex is facilitated after peripheral nerve injury and regeneration and tends to return to normal excitability with time. Changes in the H reflex circuitry and excitability correlated positively with the deficient recovery of walking pattern after severe nerve injury.

Functional Impact of Axonal Misdirection after Peripheral Nerve Injuries followed by Graft or Tube Repair

Accuracy of reinnervation is one of the main factors conditioning functional recovery after brain, spinal, or peripheral axonal damage. Using the peripheral nerve as an experimental model, we studied the amount of inaccurate muscle reinnervation and its consequences on walking. Adult rats were submitted to an 8-mm resection of the sciatic nerve repaired by autograft (AG, n = 9), silicone (SIL, n = 13) or poly-L-lactate-epsilon-caprolactone (PLC, n = 11) single guides, and fascicular tubulization of peroneal and tibial branches with a dual silicone tube (FSIL, n = 9). At the end of follow-up, the sciatic nerve and its tibial and peroneal fascicles were dissected and stimulated by means of a suction electrode. In control rats, gastrocnemius and plantar muscles are fully innervated by the tibial fascicle and the tibialis anterior muscle by the peroneal nerve. None of the groups had noticeable recovery of locomotion assessed by the walking track index (SFI around -70 in all groups). After resection, all animals of groups AG, SIL, and PLC showed aberrant muscle reinnervation by axons from a non-corresponding fascicle, whereas in group FSIL only one of six regenerated animals showed misdirected activity. The proportion of inaccurate muscle activation was similar in group AG (47% for gastrocnemius, 54% for tibialis anterior, and 44% for plantar muscles) and in group SIL (42%, 42%, and 42%), and reduced in group PLC (26%, 38%, and 27%). In conclusion, fascicular silicone tubulization allowed the highest degree of accuracy but the lowest recovery, whereas resorbable PLC guides provided for the best balance between amount and accuracy of reinnervation after nerve resection.