Imaging techniques document enhanced activity in multiple motor areas of the damaged and contralesional (intact) hemisphere (CON-H) after stroke. In the subacute stage, increased activity within motor areas in the CON-H during simple movements of the affected hand has been shown to correlate with poorer motor outcome. For those patients in the chronic stage who recovered well, the functional relevance of an increased activation within the CON-H is unclear. Using trains of repetitive transcranial magnetic stimulation (TMS) during performance of complex finger movements, we tested the behavioral relevance of regional functional magnetic resonance imaging (fMRI) activation within the CON-H for sequential finger movement performance of the recovered hand in seven patients who had experienced a subcortical stroke. TMS was navigated over fMRI activation maxima within anatomically preselected regions of the CON-H, and effects were compared with those of healthy controls. Stimulation over the dorsal premotor cortex (dPMC), the primary motor cortex (M1), and the superior parietal lobe (SPL) resulted in significant interference with recovered performance in patients. Interference with the dPMC and M1 induced timing errors only, SPL stimulation caused both timing and accuracy deficits. The present results argue for a persistent beneficial role of the dPMC, M1, and SPL of the CON-H on some aspects of effectively recovered complex motor behavior after subcortical stroke.

The functional neuroanatomy of executive function critically involves the dorsolateral prefrontal cortex. Transcranial direct current stimulation (tDCS) has been established as a noninvasive tool for transient modulation of cortical function. Here, we examined the effects of tDCS of the left dorsolateral prefrontal cortex on planning function by using the Tower of London task to evaluate performance during and after anodal, cathodal (1 mA, 15 min), and sham tDCS in 24 healthy volunteers. The key finding was a double dissociation of polarity and training phase: improved performance was found with cathodal tDCS applied during acquisition and early consolidation, when preceding anodal tDCS, but not in the later training session. In contrast, anodal tDCS enhanced performance when applied in the later sessions following cathodal tDCS. Our results indicate that both anodal and cathodal tDCS can improve planning performance as quantified by the Tower of London test. Most importantly, these data demonstrate training-phase-specific effects of tDCS. We propose that excitability decreasing cathodal tDCS mediates its early beneficial effect through noise reduction of neuronal activity, whereas a further adaptive configuration of specific neuronal connections is supported by excitability enhancing anodal tDCS in the later training phase by enhanced efficacy of active connections. This gain of function was sustained in a follow-up 6 and 12 months after training. In conclusion, the specific coupling of stimulation and training phase interventions may support the treatment of cognitive disorders involving frontal lobe functions.

Gait and balance disturbances typically emerge in advanced Parkinson’s disease with generally limited response to dopaminergic medication and subthalamic nucleus deep brain stimulation. Therefore, advanced programming with interleaved pulses was put forward to introduce concomittant nigral stimulation on caudal contacts of a subthalamic lead. Here, we hypothesized that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata improves axial symptoms compared with standard subthalamic nucleus stimulation. Twelve patients were enrolled in this 2 × 2 cross-over double-blind randomized controlled clinical trial and both the safety and efficacy of combined subthalamic nucleus and substantia nigra pars reticulata stimulation were evaluated compared with standard subthalamic nucleus stimulation. The primary outcome measure was the change of a broad-scaled cumulative axial Unified Parkinson’s Disease Rating Scale score (Scale II items 13–15, Scale III items 27–31) at ‘3-week follow-up’. Secondary outcome measures specifically addressed freezing of gait, balance, quality of life, non-motor symptoms and neuropsychiatric symptoms. For the primary outcome measure no statistically significant improvement was observed for combined subthalamic nucleus and substantia nigra pars reticulata stimulation at the ‘3-week follow-up’. The secondary endpoints, however, revealed that the combined stimulation of subthalamic nucleus and substantia nigra pars reticulata might specifically improve freezing of gait, whereas balance impairment remained unchanged. The combined stimulation of subthalamic nucleus and substantia nigra pars reticulata was safe, and of note, no clinically relevant neuropsychiatric adverse effect was observed. Patients treated with subthalamic nucleus and substantia nigra pars reticulata stimulation revealed no ‘global’ effect on axial motor domains. However, this study opens the perspective that concomittant stimulation of the substantia nigra pars reticulata possibly improves otherwise resistant freezing of gait and, therefore, highly warrants a subsequent phase III randomized controlled trial.

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Background: Tinnitus has been shown to respond to modulations of cortical activity by high-frequency and low-frequency repetitive transcranial magnetic stimulation (rTMS). Objective: To determine the tinnitus-attenuating effects of a 2-week daily regimen of rTMS, navigated to the maximum of tinnitus-related increase in regional cerebral blood flow. Methods: Six patients with chronic tinnitus were enrolled in this sham-controlled crossover study and treated with 262 weeks of suprathreshold 1 Hz rTMS (30 min) applied to the region with maximal tinnitus-related increase in regional cerebral blood flow delineated by functional imaging with [ 15 O]H 2 O positron emission tomography and a control area. Tinnitus-related distress was assessed before and after each treatment and 2 weeks after the end of the 4-week course of stimulation using a validated tinnitus questionnaire. Additional self-assessment scores of tinnitus change, loudness and annoyance were obtained. Results: In five of six patients, rTMS induced greater reduction of the tinnitus questionnaire score than sham stimulation. In two patients, all parameters measured (tinnitus change score, tinnitus loudness, tinnitus annoyance) showed unequivocal improvement. At the group level, the degree of response in the tinnitus questionnaire score was correlated with tinnitus-associated activation of the anterior cingulate cortex. Two weeks after the final stimulation, tinnitus had returned to baseline in all patients but one. Conclusion: Tinnitus can be attenuated by low-frequency rTMS navigated to each person's maximum tinnitusrelated cortical hyperactivity. The effects are only moderate; interindividual responsiveness varies and the attenuation seems to wear off within 2 weeks after the last stimulation session. Notably, tinnitus-related anterior cingulate cortex activation seems to predict the response to rTMS treatment.

Recent data suggest that chronic tinnitus is a "phantom auditory perception" caused by maladaptive neuroplasticity and subsequent hyperactivity in an extended neuronal network including the primary auditory cortex, higher-order association areas, and parts of the limbic system. It was suggested that attenuation of this tinnitus-associated hyperactivity may offer a rational option for lasting tinnitus reduction. Here, we tested the hypothesis that tinnitus loudness can be attenuated by low-frequency repetitive transcranial magnetic stimulation (rTMS) individually navigated to cortical areas with excessive tinnitus-related activity as assessed by [(15)O]H(2)O positron-emission tomography (PET). Nine patients with chronic tinnitus underwent this combined functional imaging and rTMS-study. Group analysis of the PET data showed tinnitus-related increases of regional cerebral blood flow in the left middle and inferior temporal as well as right temporoparietal cortex and posterior cingulum. Repetitive TMS was performed at 1 Hz and 120% of the motor threshold for 5, 15, and 30 min, navigated to the individual maximum of tinnitus-related cortical hyperactivity. A noncortical stimulation site with the same distance to the ear served as sham control. Tinnitus loudness was reduced after temporoparietal, PET-guided low-frequency rTMS. This reduction, lasting up to 30 min, was dependent on the number of stimuli applied, differed from sham stimulation, and was negatively correlated with the length of the medical history of tinnitus in our patients. These data show the feasibility and effectiveness of rTMS guided by individual functional imaging to induce a lasting, dose-dependent attenuation of tinnitus. Of note, these effects were related to stimulation of cortical association areas, not primary auditory cortex, emphasizing the crucial role of higher-order sensory processing in the pathophysiology of chronic tinnitus.

It has been proposed that tinnitus is associated with an irregular activation of the temporoparietal cortex. If this activity is a functionally relevant component of the tinnitus-related network, a virtual temporary lesion of this area should result in transient reduction of tinnitus. To test this hypothesis, we applied 10Hz repetitive transcranial magnetic stimulation to eight scalp and four control positions in 14 patients with chronic tinnitus. Stimulation of left temporoparietal cortex significantly reduced tinnitus (Friedman analysis of variance, p < 0.05; compared with control), indicating that secondary auditory areas can be critical for tinnitus perception, perhaps as a consequence of maladaptive cortical reorganization.

Transcranial direct current stimulation (tDCS) to the dorsolateral prefrontal cortex (dlPFC) can modulate working memory (WM) performance. However, evidence regarding the enhancement of WM training, its sustainability and transferability is ambiguous. Since WM functioning appears to be lateralized in respect to stimulus characteristics, this study examined the difference between task-congruent (spatial-right, verbal-left), task-incongruent (spatial-left, verbal-right) and sham tDCS in regards to the efficacy of WM training. In a randomized, sham-controlled experiment, 71 healthy adults trained on a spatial or verbal adaptive n-back task. After a baseline session, anodal or sham tDCS (1 mA) to the right or left dlPFC was applied during the next three training sessions. Sustainability of training gains and near-transfer (verbal or spatial 3-back task) were tested in a fourth training and a follow-up session. Compared to sham stimulation, we found a steeper learning curve when WM training was combined with task-congruent tDCS. This advantage was also present compared to task-incongruent tDCS. Moreover, these effects lasted for up to nine months and transferred to the respective untrained task. These long-lasting, transferable, task-specific effects demonstrate a behaviorally relevant and sustainable facilitation of neuroplastic processes by tDCS that could be harnessed for the treatment of disorders associated with deficient WM.