Regional Precuneus Cortical Hyperexcitability in Alzheimer's Disease Patients.

OBJECTIVE: Neuronal excitation/inhibition (E/I) imbalance is a potential cause of neuronal network malfunctioning in Alzheimer's disease (AD), contributing to cognitive dysfunction. Here, we used a novel approach combining transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to probe cortical excitability in different brain areas known to be directly involved in AD pathology. METHODS: We performed TMS-EEG recordings targeting the left dorsolateral prefrontal cortex (l-DLPFC), the left posterior parietal cortex (l-PPC), and the precuneus (PC) in a large sample of patients with mild-to-moderate AD (n = 65) that were compared with a group of age-matched healthy controls (n = 21). RESULTS: We found that patients with AD are characterized by a regional cortical hyperexcitability in the PC and, to some extent, in the frontal lobe, as measured by TMS-evoked potentials. Notably, cortical excitability assessed over the l-PPC was comparable between the 2 groups. Furthermore, we found that the individual level of PC excitability was associated with the level of cognitive impairment, as measured with Mini-Mental State Examination, and with corticospinal fluid levels of Aß42 . INTERPRETATION: Our data provide novel evidence that precuneus cortical hyperexcitability is a key feature of synaptic dysfunction in patients with AD. The current results point to the combined approach of TMS and EEG as a novel promising technique to measure hyperexcitability in patients with AD. This index could represent a useful biomarker to stage disease severity and evaluate response to novel therapies. ANN NEUROL 2023;93:371-383.

Motor potentials evoked by transcranial magnetic stimulation: interpreting a simple measure of a complex system.

Transcranial magnetic stimulation (TMS) is a non-invasive technique that is increasingly used to study the human brain. One of the principal outcome measures is the motor-evoked potential (MEP) elicited in a muscle following TMS over the primary motor cortex (M1), where it is used to estimate changes in corticospinal excitability. However, multiple elements play a role in MEP generation, so even apparently simple measures such as peak-to-peak amplitude have a complex interpretation. Here, we summarize what is currently known regarding the neural pathways and circuits that contribute to the MEP and discuss the factors that should be considered when interpreting MEP amplitude measured at rest in the context of motor processing and patients with neurological conditions. In the last part of this work, we also discuss how emerging technological approaches can be combined with TMS to improve our understanding of neural substrates that can influence MEPs. Overall, this review aims to highlight the capabilities and limitations of TMS that are important to recognize when attempting to disentangle sources that contribute to the physiological state-related changes in corticomotor excitability.

Standard intensities of transcranial alternating current stimulation over the motor cortex do not entrain corticospinal inputs to motor neurons.

Transcranial alternating current stimulation (TACS) is commonly used to synchronize a cortical area and its outputs to the stimulus waveform, but gathering evidence for this based on brain recordings in humans is challenging. The corticospinal tract transmits beta oscillations (∼21 Hz) from the motor cortex to tonically contracted limb muscles linearly. Therefore, muscle activity may be used to measure the level of beta entrainment in the corticospinal tract due to TACS over the motor cortex. Here, we assessed whether TACS is able to modulate the neural inputs to muscles, which would provide indirect evidence for TACS-driven neural entrainment. In the first part of the study, we ran simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results suggest that MNs are highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N = 10) in which TACS (at 1 mA) was delivered over the motor cortex at 21 Hz (beta stimulation), or at 7 Hz or 40 Hz (control conditions) while the abductor digiti minimi or the tibialis anterior muscle were tonically contracted. Muscle activity was measured using high-density electromyography, which allowed us to decompose the activity of pools of motor units innervating the muscles. By analysing motor unit pool activity, we observed that none of the TACS conditions could consistently alter the spectral contents of the common neural inputs received by the muscles. These results suggest that 1 mA TACS over the motor cortex given at beta frequencies does not entrain corticospinal activity. KEY POINTS: Transcranial alternating current stimulation (TACS) is commonly used to entrain the communication between brain regions. It is challenging to find direct evidence supporting TACS-driven neural entrainment due to the technical difficulties in recording brain activity during stimulation. Computational simulations of motor neuron pools receiving common inputs in the beta (∼21 Hz) band indicate that motor neurons are highly sensitive to corticospinal beta entrainment. Motor unit activity from human muscles does not support TACS-driven corticospinal entrainment.

EEG responses induced by cerebellar TMS at rest and during visuomotor adaptation.

BACKGROUND: Connections between the cerebellum and the cortex play a critical role in learning and executing complex behaviours. Dual-coil transcranial magnetic stimulation (TMS) can be used non-invasively to probe connectivity changes between the lateral cerebellum and motor cortex (M1) using the motor evoked potential as an outcome measure (cerebellar-brain inhibition, CBI). However, it gives no information about cerebellar connections to other parts of cortex. OBJECTIVES: We used electroencephalography (EEG) to investigate whether it was possible to detect activity evoked in any areas of cortex by single-pulse TMS of the cerebellum (cerebellar TMS evoked potentials, cbTEPs). A second experiment tested if these responses were influenced by the performance of a cerebellar-dependent motor learning paradigm. METHODS: In the first series of experiments, TMS was applied over either the right or left cerebellar cortex, and scalp EEG was recorded simultaneously. Control conditions that mimicked auditory and somatosensory inputs associated with cerebellar TMS were included to identify responses due to non-cerebellar sensory stimulation. We conducted a follow-up experiment that evaluated whether cbTEPs are behaviourally sensitive by assessing individuals before and after learning a visuomotor reach adaptation task. RESULTS: A TMS pulse over the lateral cerebellum evoked EEG responses that could be distinguished from those caused by auditory and sensory artefacts. Significant positive (P80) and negative peaks (N110) over the contralateral frontal cerebral area were identified with a mirrored scalp distribution after left vs. right cerebellar stimulation. The P80 and N110 peaks were replicated in the cerebellar motor learning experiment and changed amplitude at different stages of learning. The change in amplitude of the P80 peak was associated with the degree of learning that individuals retained following adaptation. Due to overlap with sensory responses, the N110 should be interpreted with caution. CONCLUSIONS: Cerebral potentials evoked by TMS of the lateral cerebellum provide a neurophysiological probe of cerebellar function that complements the existing CBI method. They may provide novel insight into mechanisms of visuomotor adaptation and other cognitive processes.

Reply to: "Reflecting the causes of variability of EEG responses elicited by cerebellar TMS".

In their commentary on our recently published paper about electroencephalographic responses induced by cerebellar transcranial magnetic stimulation (Fong et al., 2023), Gassmann and colleagues (Gassmann et al., 2023b) try to explain the differences between our results and their own previous work on the same topic. We agree with them that many of the differences arise from our use of a different magnetic stimulation coil. However, two unresolved questions remain. (1) Which method is most likely to achieve optimal activation of cerebellar output? (2) To what extent are the evoked cerebellar responses contaminated by concomitant sensory input? We highlight the role of careful experimental design and of combining electrophysiological and behavioural data to obtain reliable TMS-EEG data.

Decreased Frontal Gamma Activity in Alzheimer Disease Patients.

OBJECTIVE: In Alzheimer disease (AD) animal models, synaptic dysfunction has recently been linked to a disorder of high-frequency neuronal activity. In patients, a clear relation between AD and oscillatory activity remains elusive. Here, we attempt to shed light on this relation by using a novel approach combining transcranial magnetic stimulation and electroencephalography (TMS-EEG) to probe oscillatory activity in specific hubs of the frontoparietal network in a sample of 60 mild-to-moderate AD patients. METHODS: Sixty mild-to-moderate AD patients and 21 age-matched healthy volunteers (HVs) underwent 3 TMS-EEG sessions to assess cortical oscillations over the left dorsolateral prefrontal cortex, the precuneus, and the left posterior parietal cortex. To investigate the relations between oscillatory activity, cortical plasticity, and cognitive decline, AD patients underwent a TMS-based neurophysiological characterization and a cognitive evaluation at baseline. The latter was repeated after 24 weeks to monitor clinical evolution. RESULTS: AD patients showed a significant reduction of frontal gamma activity as compared to age-matched HVs. In addition, AD patients with a more prominent decrease of frontal gamma activity showed a stronger impairment of long-term potentiation-like plasticity and a more pronounced cognitive decline at subsequent follow-up evaluation at 24 weeks. INTERPRETATION: Our data provide novel evidence that frontal lobe gamma activity is dampened in AD patients. The current results point to the TMS-EEG approach as a promising technique to measure individual frontal gamma activity in patients with AD. This index could represent a useful biomarker to predict disease progression and to evaluate response to novel pharmacological therapies. ANN NEUROL 2022;92:464-475.

A Novel Paired Somatosensory-Cerebellar Stimulation Induces Plasticity on Cerebellar-Brain Connectivity.

The cerebellum receives and integrates a large amount of sensory information that is important for motor coordination and learning. The aim of the present work was to investigate whether peripheral nerve and cerebellum paired associative stimulation (cPAS) could induce plasticity in both the cerebellum and the cortex. In a cross-over design, we delivered right median nerve electrical stimulation 25 or 10 ms before applying transcranial magnetic stimulation over the cerebellum. We assessed changes in motor evoked potentials (MEP), somatosensory evoked potentials (SEP), short-afferent inhibition (SAI), and cerebellum-brain inhibition (CBI) immediately, and 30 min after cPAS. Our results showed a significant reduction in CBI 30 minutes after cPAS, with no discernible changes in MEP, SEP, and SAI. Notably, cPAS10 did not produce any modulatory effects on these parameters. In summary, cPAS25 demonstrated the capacity to induce plasticity effects in the cerebellar cortex, leading to a reduction in CBI. This novel intervention may be used to modulate plasticity mechanisms and motor learning in healthy individuals and patients with neurological conditions.

Consensus Paper: Novel Directions and Next Steps of Non-invasive Brain Stimulation of the Cerebellum in Health and Disease.

The cerebellum is involved in multiple closed-loops circuitry which connect the cerebellar modules with the motor cortex, prefrontal, temporal, and parietal cortical areas, and contribute to motor control, cognitive processes, emotional processing, and behavior. Among them, the cerebello-thalamo-cortical pathway represents the anatomical substratum of cerebellum-motor cortex inhibition (CBI). However, the cerebellum is also connected with basal ganglia by disynaptic pathways, and cerebellar involvement in disorders commonly associated with basal ganglia dysfunction (e.g., Parkinson's disease and dystonia) has been suggested. Lately, cerebellar activity has been targeted by non-invasive brain stimulation (NIBS) techniques including transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) to indirectly affect and tune dysfunctional circuitry in the brain. Although the results are promising, several questions remain still unsolved. Here, a panel of experts from different specialties (neurophysiology, neurology, neurosurgery, neuropsychology) reviews the current results on cerebellar NIBS with the aim to derive the future steps and directions needed. We discuss the effects of TMS in the field of cerebellar neurophysiology, the potentials of cerebellar tDCS, the role of animal models in cerebellar NIBS applications, and the possible application of cerebellar NIBS in motor learning, stroke recovery, speech and language functions, neuropsychiatric and movement disorders.

Altered motor cortex physiology and dysexecutive syndrome in patients with fatigue and cognitive difficulties after mild COVID-19.

BACKGROUND AND PURPOSE: Fatigue and cognitive difficulties are reported as the most frequently persistent symptoms in patients after mild SARS-CoV-2 infection. An extensive neurophysiological and neuropsychological assessment of such patients was performed focusing on motor cortex physiology and executive cognitive functions. METHODS: Sixty-seven patients complaining of fatigue and/or cognitive difficulties after resolution of mild SARS-CoV-2 infection were enrolled together with 22 healthy controls (HCs). Persistent clinical symptoms were investigated by means of a 16-item questionnaire. Fatigue, exertion, cognitive difficulties, mood and 'well-being' were evaluated through self-administered tools. Utilizing transcranial magnetic stimulation of the primary motor cortex (M1) resting motor threshold, motor evoked potential amplitude, cortical silent period duration, short-interval intracortical inhibition, intracortical facilitation, long-interval intracortical inhibition and short-latency afferent inhibition were evaluated. Global cognition and executive functions were assessed with screening tests. Attention was measured with computerized tasks. RESULTS: Post COVID-19 patients reported a mean of 4.9 persistent symptoms, high levels of fatigue, exertion, cognitive difficulties, low levels of well-being and reduced mental well-being. Compared to HCs, patients presented higher resting motor thresholds, lower motor evoked potential amplitudes and longer cortical silent periods, concurring with reduced M1 excitability. Long-interval intracortical inhibition and short-latency afferent inhibition were also impaired, indicating altered GABAB -ergic and cholinergic neurotransmission. Short-interval intracortical inhibition and intracortical facilitation were not affected. Patients also showed poorer global cognition and executive functions compared to HCs and a clear impairment in sustained and executive attention. CONCLUSIONS: Patients with fatigue and cognitive difficulties following mild COVID-19 present altered excitability and neurotransmission within M1 and deficits in executive functions and attention.

Cerebellar-Motor Cortex Connectivity: One or Two Different Networks?

Anterior-posterior (AP) and posterior-anterior (PA) pulses of transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) appear to activate distinct interneuron networks that contribute differently to two varieties of physiological plasticity and motor behaviors (Hamada et al., 2014). The AP network is thought to be more sensitive to online manipulation of cerebellar (CB) activity using transcranial direct current stimulation. Here we probed CB-M1 interactions using cerebellar brain inhibition (CBI) in young healthy female and male individuals. TMS over the cerebellum produced maximal CBI of PA-evoked EMG responses at an interstimulus interval of 5 ms (PA-CBI), whereas the maximum effect on AP responses was at 7 ms (AP-CBI), suggesting that CB-M1 pathways with different conduction times interact with AP and PA networks. In addition, paired associative stimulation using ulnar nerve stimulation and PA TMS pulses over M1, a protocol used in human studies to induce cortical plasticity, reduced PA-CBI but not AP-CBI, indicating that cortical networks process cerebellar inputs in distinct ways. Finally, PA-CBI and AP-CBI were differentially modulated after performing two different types of motor learning tasks that are known to process cerebellar input in different ways. The data presented here are compatible with the idea that applying different TMS currents to the cerebral cortex may reveal cerebellar inputs to both the premotor cortex and M1. Overall, these results suggest that there are two independent CB-M1 networks that contribute uniquely to different motor behaviors.SIGNIFICANCE STATEMENT Connections between the cerebellum and primary motor cortex (M1) are essential for performing daily life activities, as damage to these pathways can result in faulty movements. Therefore, developing and understanding novel approaches to probe this pathway are critical to advancing our understanding of the pathophysiology of diseases involving the cerebellum. Here, we show evidence for two distinct cerebellar-cerebral interactions using cerebellar stimulation in combination with directional transcranial magnetic stimulation (TMS) over M1. These distinct cerebellar-cerebral interactions respond differently to physiological plasticity and to distinct motor learning tasks, which suggests they represent separate cerebellar inputs to the premotor cortex and M1. Overall, we show that directional TMS can probe two distinct cerebellar-cerebral pathways that likely contribute to independent processes of learning.

Dissecting two distinct interneuronal networks in M1 with transcranial magnetic stimulation.

Interactions from both inhibitory and excitatory interneurons are necessary components of cortical processing that contribute to the vast amount of motor actions executed by humans daily. As transcranial magnetic stimulation (TMS) over primary motor cortex is capable of activating corticospinal neurons trans-synaptically, studies over the past 30 years have provided how subtle changes in stimulation parameters (i.e., current direction, pulse width, and paired-pulse) can elucidate evidence for two distinct neuronal networks that can be probed with this technique. This article provides a brief review of some fundamental studies demonstrating how these networks have separable excitatory inputs to corticospinal neurons. Furthermore, the findings of recent investigations will be discussed in detail, illustrating how each network's sensitivity to different brain states (i.e., rest, movement preparation, and motor learning) is dissociable. Understanding the physiological characteristics of each network can help to explain why interindividual responses to TMS exist, while also providing insights into the role of these networks in various human motor behaviors.

The association between apathy and frailty in older adults: a new investigation using data from the Mapt study.

INTRODUCTION: Apathy is a behavioral syndrome that has been suggested to share similar neuro-physiological pathways with frailty. OBJECTIVE: To investigate the cross-sectional association between apathy and frailty using original data from dementia-free, community-dwelling older adults. METHOD: A cross-sectional analysis was performed to test the association between frailty (according to Fried's frailty phenotype) and apathy (defined by three items from Geriatric Depression Scale) using data from MAPT, a 3-year, randomized, multicenter, placebo-controlled trial among community-dwelling, dementia-free participants (1.679 individuals with mean age of 75 years). RESULTS: The ordinal logistic regression showed that apathetic individuals had a two-fold more probability to be rated as frail (OR 2.20, 95% CI 1.7-2.9), when adjusting for confounders. Apathetic individuals display a two-fold more likelihood to be rated as pre-frail (RRR 2.1; 95% CI 1.5-2.8) and a three-fold higher probability to be rated as frail (RRR 3.5, 95% CI 1.8-6.9) compared to robust participants. CONCLUSION: Although data on the associations between apathy and frailty are scarce, these conditions potentially shares physiological mechanisms and were found to be closely associated. Temporal association between frailty and apathy deserve to be further investigated.

Cerebellar-M1 Connectivity Changes Associated with Motor Learning Are Somatotopic Specific.

One of the functions of the cerebellum in motor learning is to predict and account for systematic changes to the body or environment. This form of adaptive learning is mediated by plastic changes occurring within the cerebellar cortex. The strength of cerebellar-to-cerebral pathways for a given muscle may reflect aspects of cerebellum-dependent motor adaptation. These connections with motor cortex (M1) can be estimated as cerebellar inhibition (CBI): a conditioning pulse of transcranial magnetic stimulation delivered to the cerebellum before a test pulse over motor cortex. Previously, we have demonstrated that changes in CBI for a given muscle representation correlate with learning a motor adaptation task with the involved limb. However, the specificity of these effects is unknown. Here, we investigated whether CBI changes in humans are somatotopy specific and how they relate to motor adaptation. We found that learning a visuomotor rotation task with the right hand changed CBI, not only for the involved first dorsal interosseous of the right hand, but also for an uninvolved right leg muscle, the tibialis anterior, likely related to inter-effector transfer of learning. In two follow-up experiments, we investigated whether the preparation of a simple hand or leg movement would produce a somatotopy-specific modulation of CBI. We found that CBI changes only for the effector involved in the movement. These results indicate that learning-related changes in cerebellar-M1 connectivity reflect a somatotopy-specific interaction. Modulation of this pathway is also present in the context of interlimb transfer of learning.SIGNIFICANCE STATEMENT Connectivity between the cerebellum and motor cortex is a critical pathway for the integrity of everyday movements and understanding the somatotopic specificity of this pathway in the context of motor learning is critical to advancing the efficacy of neurorehabilitation. We found that adaptive learning with the hand affects cerebellar-motor cortex connectivity, not only for the trained hand, but also for an untrained leg muscle, an effect likely related to intereffector transfer of learning. Furthermore, we introduce a novel method to measure cerebellar-motor cortex connectivity during movement preparation. With this technique, we show that, outside the context of learning, modulation of cerebellar-motor cortex connectivity is somatotopically specific to the effector being moved.

Cerebellar direct current stimulation enhances on-line motor skill acquisition through an effect on accuracy.

The cerebellum is involved in the update of motor commands during error-dependent learning. Transcranial direct current stimulation (tDCS), a form of noninvasive brain stimulation, has been shown to increase cerebellar excitability and improve learning in motor adaptation tasks. Although cerebellar involvement has been clearly demonstrated in adaptation paradigms, a type of task that heavily relies on error-dependent motor learning mechanisms, its role during motor skill learning, a behavior that likely involves error-dependent as well as reinforcement and strategic mechanisms, is not completely understood. Here, in humans, we delivered cerebellar tDCS to modulate its activity during novel motor skill training over the course of 3 d and assessed gains during training (on-line effects), between days (off-line effects), and overall improvement. We found that excitatory anodal tDCS applied over the cerebellum increased skill learning relative to sham and cathodal tDCS specifically by increasing on-line rather than off-line learning. Moreover, the larger skill improvement in the anodal group was predominantly mediated by reductions in error rate rather than changes in movement time. These results have important implications for using cerebellar tDCS as an intervention to speed up motor skill acquisition and to improve motor skill accuracy, as well as to further our understanding of cerebellar function.

Laterality Differences in Cerebellar-Motor Cortex Connectivity.

Lateralization of function is an important organizational feature of the motor system. Each effector is predominantly controlled by the contralateral cerebral cortex and the ipsilateral cerebellum. Transcranial magnetic stimulation studies have revealed hemispheric differences in the stimulation strength required to evoke a muscle response from the primary motor cortex (M1), with the dominant hemisphere typically requiring less stimulation than the nondominant. The current study assessed whether the strength of the connection between the cerebellum and M1 (CB-M1), known to change in association with motor learning, have hemispheric differences and whether these differences have any behavioral correlate. We observed, in right-handed individuals, that the connection between the right cerebellum and left M1 is typically stronger than the contralateral network. Behaviorally, we detected no lateralized learning processes, though we did find a significant effect on the amplitude of reaching movements across hands. Furthermore, we observed that the strength of the CB-M1 connection is correlated with the amplitude variability of reaching movements, a measure of movement precision, where stronger connectivity was associated with better precision. These findings indicate that lateralization in the motor system is present beyond the primary motor cortex, and points to an association between cerebellar M1 connectivity and movement execution.

The Cerebellum and the Motor Cortex: Multiple Networks Controlling Multiple Aspects of Behavior.

The cerebellum and its thalamic projections to the primary motor cortex (M1) are well known to play an essential role in executing daily actions. Anatomic investigations in animals and postmortem humans have established the reciprocal connections between these regions; however, how these pathways can shape cortical activity in behavioral contexts and help promote recovery in neuropathological conditions remains not well understood. The present review aims to provide a comprehensive description of these pathways in animals and humans and discuss how novel noninvasive brain stimulation (NIBS) methods can be used to gain a deeper understanding of the cerebellar-M1 connections. In the first section, we focus on recent animal literature that details how information sent from the cerebellum and thalamus is integrated into an broad network of cortical motor neurons. We then discuss how NIBS approaches in humans can be used to reliably assess the connectivity between the cerebellum and M1. Moreover, we provide the latest perspectives on using advanced NIBS approaches to investigate and modulate multiple cerebellar-cortical networks involved in movement behavior and plasticity. Finally, we discuss how these emerging methods have been used in translation research to produce long-lasting modifications of cerebellar-thalamic-M1 to restore cortical activity and motor function in neurologic patients.

Using TMS-EEG to assess the effects of neuromodulation techniques: a narrative review.

Over the past decades, among all the non-invasive brain stimulation (NIBS) techniques, those aiming for neuromodulatory protocols have gained special attention. The traditional neurophysiological outcome to estimate the neuromodulatory effect is the motor evoked potential (MEP), the impact of NIBS techniques is commonly estimated as the change in MEP amplitude. This approach has several limitations: first, the use of MEP limits the evaluation of stimulation to the motor cortex excluding all the other brain areas. Second, MEP is an indirect measure of brain activity and is influenced by several factors. To overcome these limitations several studies have used new outcomes to measure brain changes after neuromodulation techniques with the concurrent use of transcranial magnetic stimulation (TMS) and electroencephalogram (EEG). In the present review, we examine studies that use TMS-EEG before and after a single session of neuromodulatory TMS. Then, we focused our literature research on the description of the different metrics derived from TMS-EEG to measure the effect of neuromodulation.

Alzheimer disease and neuroplasticity.

Alzheimer's disease (AD) is considered the most harmful form of dementia in the elderly population. At present, there are no effective treatments and this is likely due to the incomplete understanding of the pathophysiology. Recent data indicate that synaptic dysfunction could be a central element of AD pathophysiology. It was found that a synaptic breakdown is an early event that heralds neuronal degeneration. Transcranial magnetic stimulation (TMS) has been recently introduced as a novel approach to identify the early signatures of synaptic dysfunction characterizing AD pathophysiology. In this chapter, we review the new neurophysiologic signatures of AD that have been emphasized by TMS studies. We show how TMS measurement of neuroplasticity identified long-term potentiation (LTP)-like cortical plasticity as a key element of AD synaptic dysfunction. These measurements are useful to increase the accuracy of differential diagnosis, predict disease progression, and anticipate response to therapy. Moreover, enhancing neuroplasticity holds as a promising therapeutic approach to improve cognition in AD. In recent years, studies showed treatments with multiple sessions of rTMS can influence cognition in people with neurodegenerative diseases. In the second part of this chapter, we also consider novel therapeutic approaches based on the clinical use of rTMS.

Comparing the effects of focal and conventional tDCS on motor skill learning: A proof of principle study.

Transcranial direct current stimulation (tDCS) has emerged as a promising intervention in clinical and behavioral neuroscience; however, the response variability to this technique has limited its impact, partly due to the widespread of current flow with conventional methods. Here, we investigate whether a more targeted, focal approach over the primary motor cortex (M1) is advantageous for motor learning and targeting specific neuronal populations. Our preliminary results show that focal stimulation leads to enhanced skill learning and differentially recruits distinct pathways to M1. This finding suggests that focal tDCS approaches may improve the outcomes of future studies aiming to enhance behavior.