Pierre Vassiliadis

Deep brain stimulation needs high focality in deep parts of the brain; hence, it has largely relied on invasive surgical approaches in clinical populations. Transcranial temporal interference stimulation (tTIS) has emerged as a method for focal non-invasive electrical deep brain stimulation. First developed and validated through computational modelling and rodent work, tTIS is now being translated to humans for targeting deep brain regions such as the hippocampus or striatum. Here we present current evidence for tTIS-based neuromodulation, describe the underlying mechanisms and discuss future developments of this technology. We highlight key opportunities and challenges for fundamental neuroscience, as well as for the design of interventions in neuropsychiatric disorders. We suggest that a multidisciplinary research effort is now required to further validate the use of tTIS in multiple applications, understand its underlying principles and optimize the technology in the view of wider scientific and clinical deployment.

Motor learning is shaped by motivational context: punishment can accelerate initial learning, whereas reward enhances memory retention. Yet it remains unclear whether the dissociable effects of reward and punishment observed in laboratory tasks generalize to complex real-world skills. Here, we tested this idea using a naturalistic motor task—basketball free-throw shooting. Sixty-eight participants trained under four motivational contexts that differed only in how points were awarded for each pair of consecutive shots: control (standard scoring), reward (bonus points for two consecutive successful shots), punishment (penalty for two consecutive missed shots), or mixed (both bonus and penalty). Performance was assessed before training, immediately after, and 1 and 3 days later. Punishment and mixed schedules significantly improved early acquisition, resulting in higher accuracy immediately after training compared to the control and reward conditions. This advantage emerged during the first training block, indicating a rapid motivational influence on performance. In contrast, reward selectively enhanced offline consolidation: three days after training, the reward group showed the largest gains in accuracy, outperforming both the control and punishment groups. The mixed schedule produced quick early gains similar to punishment, but achieved smaller long-term improvements than reward. Consistent with these findings, individual punishment sensitivity was associated with gains in acquisition, while reward sensitivity correlated with offline improvements. Together, these findings demonstrate dissociable effects of motivational valence on the acquisition and consolidation of a complex real-world motor skill. More generally, they position motivational interventions as simple and cost-effective strategies to enhance rehabilitation and sports training.

Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric condition often resistant to conventional treatments such as cognitive behavioral therapy and pharmacotherapy. For treatment-refractory cases, neuromodulation techniques offer promising alternatives. This review provides an overview of recent advances in three major neuromodulation strategies: transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS). DBS has demonstrated robust efficacy across several brain targets, though clinical outcomes are influenced by interindividual variability in fiber anatomy, lead positioning, correct parameter adjustments, and symptomatology. Recent efforts focus on connectivity-based targeting, patient-specific imaging, and the development of closed-loop systems guided by electrophysiological and neuroimaging biomarkers. rTMS, a noninvasive neuromodulation technique, shows therapeutic potential but lacks consensus on optimal parameters and cortical targets, despite FDA approval of certain stimulation protocols. tDCS, while the most accessible modality, presents inconclusive evidence due to small sample sizes and heterogeneity in electrode montages. Overall, these neuromodulation techniques are rapidly evolving and hold considerable promise, but further high-quality studies are needed to standardize stimulation protocols, validate reliable biomarkers and tailor interventions to individual patient profiles. Personalized neuromodulation may represent the future of therapeutic strategies in OCD.

From rodents to humans, animals constantly face a central question: is the reward worth the effort? Effort and reward sensitivity in such situations vary substantially across individuals and ultimately shape goal-directed behavior. Yet, the brain mechanisms underlying this variability across individuals remain unclear. Here, we combined computational modeling of effort and reward sensitivity during decision-making with whole-brain diffusion MRI in 45 healthy participants to identify white matter substrates of individual sensitivity. A data-driven, cluster-based analysis of fractional anisotropy and mean diffusivity revealed 12 clusters: five linked to effort sensitivity, all within tracts connected to major frontal valuation nodes (e.g., supplementary motor area [SMA], dorsal anterior cingulate cortex [dACC], orbitofrontal cortex [OFC]), and seven linked to reward sensitivity, spanning frontal valuation, fronto-parietal, and sensorimotor networks. The strongest associations involved two SMA-connected clusters, one shared across effort and reward sensitivity and another consistent across both microstructural metrics. Critically, microstructural features from the five effort-related and seven reward-related clusters reliably predicted individual effort and reward sensitivity in out-of-sample machine learning analyses, respectively, whereas randomly sampled clusters did not. SMA-connected tracts were the dominant predictors in these decoding analyses, with additional contributions from fronto-parietal and sensorimotor pathways for reward sensitivity. These findings reveal a distributed white matter architecture underlying inter-individual differences in effort and reward sensitivity, with SMA pathways emerging as central hubs. They demonstrate that localized white matter microstructure can robustly predict these individual differences, offering a framework to forecast the impact of lesions or interventions on goal-directed behavior, including apathy and impulsivity. SIGNIFICANCE STATEMENT: Why do some people give up easily when faced with high effort demands, while others persist even when rewards are small? Such differences in effort and reward sensitivity shape goal-directed behavior, yet their neural basis is unclear. Using diffusion MRI and computational modeling, we show that white matter microstructure in specific pathways reliably predicts individual differences in these sensitivities. Tracts connected to the supplementary motor area emerged as central hubs, with additional contributions from fronto-parietal and sensorimotor networks. These results demonstrate that variability in effort and reward sensitivity is rooted not only in brain activity but also in structural connectivity, providing a framework to anticipate how white matter lesions or interventions may alter goal-directed behavior, including apathy and impulsivity.

Human motor skill acquisition is improved by performance feedback, and coupling such feedback with extrinsic reward (such as money) can enhance skill learning. However, the neurophysiology underlying such behavioral effect is unclear. To bridge this gap, we assessed the effects of reward on multiple forms of motor plasticity during skill learning. Sixty-five healthy participants divided into three groups performed a pinch-grip skill task with sensory feedback only, sensory and reinforcement feedback, or both feedback coupled with an extrinsic monetary reward during skill training. To probe motor plasticity, we applied transcranial magnetic stimulation at rest, on the left primary motor cortex before, at an early-training time point, and after training in the three groups and measured motor-evoked potentials from task-relevant muscle of the right arm. This allowed us to evaluate the amplitude and variability of corticospinal output, GABAergic short-intracortical inhibition, and use-dependent plasticity before training and at two additional time points (early and end training). At the behavioral level, monetary reward accelerated skill learning. In parallel, corticospinal output became less variable early on during training in the presence of extrinsic reward. Interestingly, this effect was particularly pronounced for participants who were more sensitive to reward, as evaluated in an independent questionnaire. Other measures of motor excitability remained comparable across groups. These findings highlight that a mechanism underlying the benefit of reward on motor skill learning is the fine-tuning of early-training resting-state corticospinal variability.

Over the past decade, research has shown that the primary motor cortex (M1), the brain’s main output for movement, also responds to rewards. These reward signals may shape motor output in its final stages, influencing movement invigoration and motor learning. In this Perspective, we highlight the functional roles of M1 reward signals and propose how they could guide advances in neurotechnologies for movement restoration, specifically brain-computer interfaces and non-invasive brain stimulation. Understanding M1 reward signals may open new avenues for enhancing motor control and rehabilitation.

Because of the depth of the hippocampal-entorhinal complex (HC-EC) in the brain, understanding of its role in spatial navigation via neuromodulation was limited in humans. Here, we aimed to better elucidate this relationship in healthy volunteers, using transcranial temporal interference electric stimulation (tTIS), a noninvasive technique allowing to selectively neuromodulate deep brain structures. We applied tTIS to the right HC-EC in either continuous or intermittent theta-burst stimulation patterns (cTBS or iTBS), compared to a control condition, during a virtual reality–based spatial navigation task and concomitant functional magnetic resonance imaging. iTBS improved spatial navigation performance, correlated with hippocampal activity modulation, and decreased grid cell–like activity in EC. Collectively, these data provide the evidence that human HC-EC activity can be directly and noninvasively modulated leading to changes of spatial navigation behavior. These findings suggest promising perspectives for patients suffering from cognitive impairment such as following traumatic brain injury or dementia.

SUMMARY: Apathy is a syndrome characterized by a disruption in effort-reward decision-making, accompanied by structural and functional changes in a related fronto-basal ganglia (BG) network. While activity changes in the primary motor cortex (M1) during effort and reward valuation have been repeatedly observed, previous work on apathy has largely overlooked the connections between the fronto-BG network and M1, potentially missing key circuits in the apathy network. This study addresses this gap by investigating structural and effective connectivity in fronto-M1, fronto-BG-M1, and intra-M1 circuits in relation to apathy in 45 healthy subjects. Behavior was assessed using a battery of apathy-related questionnaires and computational modeling of effort and reward valuation in a decision-making task. Fronto-motor circuits were examined through a combination of MRI-derived tractography and paired-pulse transcranial magnetic stimulation, which probed structural and effective connectivity, respectively. The data reveal that apathy scores are associated with both structural and effective connectivity in fronto-M1 and fronto-BG-M1 circuits. Circuits originating from the supplementary motor area primarily index effort valuation, while connectivity in intra-M1 GABAergic circuits correlates exclusively with reward valuation. These findings suggest that distinct fronto-motor circuits are linked to different dimensions of motivated behavior and may constitute specific neuromodulation targets for patients suffering from apathy.