Dynamic involvement of premotor and supplementary motor areas in bimanual pinch force control.

Many activities of daily living require quick shifts between symmetric and asymmetric bimanual actions. Bimanual motor control has been mostly studied during continuous repetitive tasks, while little research has been carried out in experimental settings requiring dynamic changes in motor output generated by both hands. Here, we performed functional magnetic resonance imaging (MRI) while healthy volunteers performed a visually guided, bimanual pinch force task. This enabled us to map functional activity and connectivity of premotor and motor areas during bimanual pinch force control in different task contexts, requiring mirror-symmetric or inverse-asymmetric changes in discrete pinch force exerted with the right and left hand. The bilateral dorsal premotor cortex showed increased activity and effective coupling to the ipsilateral supplementary motor area (SMA) in the inverse-asymmetric context compared to the mirror-symmetric context of bimanual pinch force control while the SMA showed increased negative coupling to visual areas. Task-related activity of a cluster in the left caudal SMA also scaled positively with the degree of synchronous initiation of bilateral pinch force adjustments, irrespectively of the task context. The results suggest that the dorsal premotor cortex mediates increasing complexity of bimanual coordination by increasing coupling to the SMA while SMA provides feedback about motor actions to the sensory system.

Multipulse transcranial magnetic stimulation of human motor cortex produces short-latency corticomotor facilitation via two distinct mechanisms.

Single-pulse transcranial magnetic stimulation (TMS) of the precentral hand representation (M1HAND) can elicit indirect waves in the corticospinal tract at a periodicity of ∼660 Hz, called I-waves. These descending volleys are produced by transsynaptic excitation of fast-conducting corticospinal axons in M1HAND. Paired-pulse TMS can induce short-interval intracortical facilitation (SICF) of motor evoked potentials (MEPs) at interpulse intervals that match I-wave periodicity. This study examined whether short-latency corticospinal facilitation engages additional mechanisms independently of I-wave periodicity. In 19 volunteers, one to four biphasic TMS pulses were applied to left M1HAND with interpulse intervals adjusted to the first peak or trough of the individual SICF curve at different intensities to probe the intensity-response relationship. Multipulse TMSHAND at individual peak latency facilitated MEP amplitudes and reduced resting motor threshold (RMT) compared with single pulses. Multipulse TMSHAND at individual trough latency also produced a consistent facilitation of MEPs and a reduction of RMT. Short-latency facilitation at trough latency was less pronounced, but the relative difference in facilitation decreased with increasing stimulus intensity. Increasing the pulse number had only a modest effect. Two mechanisms underlie short-latency facilitation caused by biphasic multipulse TMSHAND. One intracortical mechanism is related to I-wave periodicity and engages fast-conducting direct projections to spinal motoneurons. A second corticospinal mechanism does not rely on I-wave rhythmicity and may be mediated by slower-conducting indirect pyramidal tract projections from M1HAND to spinal interneurons. The latter mechanism deserves more attention in studies of the corticomotor system and its link to manual motor control using the MEP.NEW & NOTEWORTHY TMS pairs evoke SICF at interpulse intervals (IPIs) that match I-wave periodicity. Biphasic bursts with IPIs at the latency of the first peak facilitate MEPs and reduce corticomotor threshold. Bursts at the latency of the first trough facilitate MEPs and reduce corticomotor threshold to a lesser extent. TMS bursts facilitate corticomotor excitability via two mechanisms: SICF-dependently via fast-conducting direct projections from M1HAND to spinal motoneurons and SICF-independently, probably through slower-conducting indirect pyramidal tract projections.

Sense of agency as synecdoche: Multiple neurobiological mechanisms may underlie the phenomenon summarized as sense of agency.

Functional magnetic resonance imaging (fMRI) studies on the sense of agency (SoA) have yielded heterogeneous findings identifying regional brain activity during tasks that probed SoA. In this review, we argue that the reason behind this between-study heterogeneity is a "synecdochic" way the field conceptualizes and studies SoA. Typically, a single feature is experimentally manipulated and then this is interpreted as covering all aspects of SoA. The purpose of this paper is to give an overview of the fMRI studies of SoA and attempt to provide meaningful categories whereby the heterogeneous findings may be classified. This classification is based on a separation of the experimental paradigms (Feedback Manipulations of ongoing movements, Action-Effect, and Sensory Attenuation) and type of report employed (implicit, explicit reports of graded or dichotic nature, and whether these concern self-other distinctions or sense of control). We only find that Feedback Manipulation and Action-Effect share common activation in supplementary motor area, insula and cerebellum in positive SoA and inferior frontal gyrus in the negative SoA, but observe large networks related to SoA only in Feedback Manipulation studies. To illustrate the advantages of this approach, we discuss the findings from an fMRI study which we conducted, within this framework.

Corticomuscular coherence is reduced in relation to dorsiflexion fatigability to the same extent in adults with cerebral palsy as in neurologically intact adults.

PURPOSE: Fatigue is frequent in adults with cerebral palsy (CP) and it is unclear whether this is due to altered corticospinal drive. We aimed to compare changes in corticospinal drive following sustained muscle contractions in adults with CP and neurologically intact (NI) adults. METHODS: Fourteen adults with CP [age 37.6 (10.1), seven females, GMFCS levels I-II] and ten NI adults [age 35.4 (10.3), 6 females] performed 1-min static dorsiflexion at 30% of maximal voluntary contraction (MVC) before and after a submaximal contraction at 60% MVC. Electroencephalography (EEG) and electromyography (EMG) from the anterior tibial muscle were analyzed to quantify the coupling, expressed by corticomuscular coherence (CMC). RESULTS: Adults with CP had lower MVCs but similar time to exhaustion during the relative load of the fatigability trial. Both groups exhibited fatigability-related changes in EMG median frequency and EMG amplitude. The CP group showed lower beta band (16-35 Hz) CMC before fatigability, but both groups decreased beta band CMC following fatigability. There was a linear correlation between decrease of beta band CMC and fatigability-related increase in EMG. CONCLUSION: Fatigability following static contraction until failure was related to decreased beta band CMC in both NI adults and adults with CP. Our findings indicate that compensatory mechanisms to fatigability are present in both groups, and that fatigability affects the corticospinal drive in the same way. We suggest that the perceived physical fatigue in CP is related to the high relative load of activities of daily living rather than any particular physiological mechanism.

Cerebellar - Premotor cortex interactions underlying visuomotor adaptation.

Visuomotor adaptation (VMA) is a form of motor learning essential for performing day to day routines. Theoretical models and empirical evidence suggest a specific cortico-striato-cerebellar loop that mediates early and late learning in VMA. Here, we investigated dynamic changes in neural activity and connectivity when learning a novel visuomotor rotation using fMRI. We found that motor cortical regions, parietal cortex and cerebellum are recruited in the early phase of VMA, gradually reduce their activity as learning reaches plateau and rebound when the visuomotor rotation is removed. At this phase, dubbed de-adaptation, individual performance correlated with activity in motor and parietal cortex such that stronger activity was associated with better performance. Theory suggests that VMA is governed by the cortico-striato-cerebellar network during the early phase of learning and by the cortico-cerebellar loop at later stages. We tested this hypothesis using dynamic causal modelling and found distinct modulation of a cerebellar to dorsal premotor cortex (dPMC) loop. Specifically, the cerebellar to dPMC connection was modulated during adaptation, suggesting a release of inhibition and net excitatory effect of cerebellum on dPMC. The modulation of cerebellar to dPMC connection during de-adaptation was specifically related to behavioral learning parameter: stronger release of inhibition of the cerebellar to dPMC connection was associated with better de-adaptation. We interpret these findings to reflect dynamic interactions between representation of movement in cerebellum and visuomotor integration in dPMC.

Beneficial effects of cerebellar tDCS on motor learning are associated with altered putamen-cerebellar connectivity: A simultaneous tDCS-fMRI study.

Non-invasive transcranial stimulation of cerebellum and primary motor cortex (M1) has been shown to enhance motor learning. However, the mechanisms by which stimulation improves learning remain largely unknown. Here, we sought to shed light on the neural correlates of transcranial direct current stimulation (tDCS) during motor learning by simultaneously recording functional magnetic resonance imaging (fMRI). We found that right cerebellar tDCS, but not left M1 tDCS, led to enhanced sequence learning in the serial reaction time task. Performance was also improved following cerebellar tDCS compared to sham in a sequence production task, reflecting superior training effects persisting into the post-training period. These behavioral effects were accompanied by increased learning-specific activity in right M1, left cerebellum lobule VI, left inferior frontal gyrus and right inferior parietal lobule during cerebellar tDCS compared to sham. Despite the lack of group-level changes comparing left M1 tDCS to sham, activity increase in right M1, supplementary motor area, and bilateral middle frontal cortex, under M1 tDCS, was associated with better sequence performance. This suggests that lack of group effects in M1 tDCS relate to inter-individual variability in learning-related activation patterns. We further investigated how tDCS modulates effective connectivity in the cortico-striato-cerebellar learning network. Using dynamic causal modelling, we found altered connectivity patterns during both M1 and cerebellar tDCS when compared to sham. Specifically, during cerebellar tDCS, negative modulation of a connection from putamen to cerebellum was decreased for sequence learning only, effectively leading to decreased inhibition of the cerebellum. These results show specific effects of cerebellar tDCS on functional activity and connectivity in the motor learning network and may facilitate the optimization of motor rehabilitation involving cerebellar non-invasive stimulation.

Directed connectivity between primary and premotor areas underlying ankle force control in young and older adults.

The control of ankle muscle force is an integral component of walking and postural control. Aging impairs the ability to produce force steadily and accurately, which can compromise functional capacity and quality of life. Here, we hypothesized that reduced force control in older adults would be associated with altered cortico-cortical communication within a network comprising the primary motor area (M1), the premotor cortex (PMC), parietal, and prefrontal regions. We examined electroencephalographic (EEG) responses from fifteen younger (20-26 â€‹yr) and fifteen older (65-73 â€‹yr) participants during a unilateral dorsiflexion force-tracing task. Dynamic Causal Modelling (DCM) and Parametric Empirical Bayes (PEB) were used to investigate how directed connectivity between contralateral M1, PMC, parietal, and prefrontal regions was related to age group and precision in force production. DCM and PEB analyses revealed that the strength of connections between PMC and M1 were related to ankle force precision and differed by age group. For young adults, bidirectional PMC-M1 coupling was negatively related to task performance: stronger backward M1-PMC and forward PMC-M1 coupling was associated with worse force precision. The older group exhibited deviations from this pattern. For the PMC to M1 coupling, there were no age-group differences in coupling strength; however, within the older group, stronger coupling was associated with better performance. For the M1 to PMC coupling, older adults followed the same pattern as young adults - with stronger coupling accompanied by worse performance - but coupling strength was lower than in the young group. Our results suggest that bidirectional M1-PMC communication is related to precision in ankle force production and that this relationship changes with aging. We argue that the observed differences reflect compensatory reorganization that counteracts age-related sensorimotor declines and contributes to maintaining performance.

Getting to grips with endoscopy - Learning endoscopic surgical skills induces bi-hemispheric plasticity of the grasping network.

Endoscopic surgery requires skilled bimanual use of complex instruments that extend the peri-personal workspace. To delineate brain structures involved in learning such surgical skills, 48 medical students without surgical experience were randomly assigned to five training sessions on a virtual-reality endoscopy simulator or to a non-training group. Brain activity was probed with functional MRI while participants performed endoscopic tasks. Repeated task performance in the scanner was sufficient to enhance task-related activity in left ventral premotor cortex (PMv) and the anterior Intraparietal Sulcus (aIPS). Simulator training induced additional increases in task-related activation in right PMv and aIPS and reduced effective connectivity from left to right PMv. Skill improvement after training scaled with stronger task-related activation of the lateral left primary motor hand area (M1-HAND). The results suggest that a bilateral fronto-parietal grasping network and left M1-HAND are engaged in bimanual learning of tool-based manipulations in an extended peri-personal space.

Centre-surround organization of fast sensorimotor integration in human motor hand area.

Using the short-latency afferent inhibition (SAI) paradigm, transcranial magnetic stimulation (TMS) of the primary motor hand area (M1HAND) can probe how sensory input from limbs modulates corticomotor output in humans. Here we applied a novel TMS mapping approach to chart the spatial representation of SAI in human hand-knob. We hypothesized SAI is somatotopically expressed in M1HAND depending on both the site of peripheral electrical nerve stimulation and the cortical spot targeted by TMS within M1HAND. The left index or little finger was stimulated 23 ms before focal single-pulse TMS of the right M1HAND. Using frameless stereotaxy, we applied biphasic-TMS pulses at seven stimulation positions above right M1HAND and recorded the motor evoked potentials (MEPs) from relaxed left first-dorsal-interosseous (FDI) and abductor-digiti-minimi (ADM) muscles. Homotopic stimulation of the finger close to the muscle targeted by TMS revealed a somatotopic expression of afferent inhibition matching the somatotopic representation of unconditioned MEPs (homotopic SAI). Conversely, heterotopic stimulation of a finger distant to the muscle targeted by TMS induced short-latency afferent facilitation (SAF) of MEPs in M1HAND. Like homotopic SAI, heterotopic SAF was somatotopically expressed in M1HAND. Together, the results provide first-time evidence that fast sensorimotor integration involves centre-inhibition and surround-facilitation in human M1HAND.

Modulation of fronto-parietal connections during the rubber hand illusion.

Accumulating evidence suggests that parieto-frontal connections play a role in adjusting body ownership during the Rubber Hand Illusion (RHI). Using a motor version of the rubber hand illusion paradigm, we applied single-site and dual-site transcranial magnetic stimulation (TMS) to investigate cortico-spinal and parietal-frontal connectivity during perceived rubber hand ownership. Healthy volunteers received a conditioning TMS pulse over left anterior intraparietal sulcus (aIPS) and a test TMS pulse over left primary motor cortex (M1). Motor Evoked Potentials (MEPs) were recorded at rest and during three RHI conditions: (i) agency and ownership, (ii) agency but no ownership and (iii) neither agency nor ownership. Parietal-motor communication differed among experimental conditions. The induction of action ownership was associated with an inhibitory parietal-to-motor connectivity, which was comparable to the aIPS-to-M1 inhibition present at rest. This aIPS-to-M1 inhibition disappeared during movement conditions not inducing ownership. Cortico-spinal excitability was not significantly modulated during the motor RHI as indicated by the task-constant MEP amplitude elicited by the M1 test pulse alone. Our results indicate that the perceived ownership over the rubber hand is associated with normal parietal-motor communication. This communication is disturbed if the sensorimotor conflict between one's own hand and the rubber hand is not resolved.

Combining non-invasive transcranial brain stimulation with neuroimaging and electrophysiology: Current approaches and future perspectives.

Non-invasive transcranial brain stimulation (NTBS) techniques such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (TCS) are important tools in human systems and cognitive neuroscience because they are able to reveal the relevance of certain brain structures or neuronal activity patterns for a given brain function. It is nowadays feasible to combine NTBS, either consecutively or concurrently, with a variety of neuroimaging and electrophysiological techniques. Here we discuss what kind of information can be gained from combined approaches, which often are technically demanding. We argue that the benefit from this combination is twofold. Firstly, neuroimaging and electrophysiology can inform subsequent NTBS, providing the required information to optimize where, when, and how to stimulate the brain. Information can be achieved both before and during the NTBS experiment, requiring consecutive and concurrent applications, respectively. Secondly, neuroimaging and electrophysiology can provide the readout for neural changes induced by NTBS. Again, using either concurrent or consecutive applications, both "online" NTBS effects immediately following the stimulation and "offline" NTBS effects outlasting plasticity-inducing NTBS protocols can be assessed. Finally, both strategies can be combined to close the loop between measuring and modulating brain activity by means of closed-loop brain state-dependent NTBS. In this paper, we will provide a conceptual framework, emphasizing principal strategies and highlighting promising future directions to exploit the benefits of combining NTBS with neuroimaging or electrophysiology.

Transcranial brain stimulation: closing the loop between brain and stimulation.

PURPOSE OF REVIEW: To discuss recent strategies for boosting the efficacy of noninvasive transcranial brain stimulation to improve human brain function. RECENT FINDINGS: Recent research exposed substantial intra- and inter-individual variability in response to plasticity-inducing transcranial brain stimulation. Trait-related and state-related determinants contribute to this variability, challenging the standard approach to apply stimulation in a rigid, one-size-fits-all fashion. Several strategies have been identified to reduce variability and maximize the plasticity-inducing effects of noninvasive transcranial brain stimulation. Priming interventions or paired associative stimulation can be used to 'standardize' the brain-state and hereby, homogenize the group response to stimulation. Neuroanatomical and neurochemical profiling based on magnetic resonance imaging and spectroscopy can capture trait-related and state-related variability. Fluctuations in brain-states can be traced online with functional brain imaging and inform the timing or other settings of transcranial brain stimulation. State-informed open-loop stimulation is aligned to the expression of a predefined brain state, according to prespecified rules. In contrast, adaptive closed-loop stimulation dynamically adjusts stimulation settings based on the occurrence of stimulation-induced state changes. SUMMARY: Approaches that take into account trait-related and state-related determinants of stimulation-induced plasticity bear considerable potential to establish noninvasive transcranial brain stimulation as interventional therapeutic tool.

Induction of motor associative plasticity in the posterior parietal cortex-primary motor network.

There is anatomical and functional connectivity between the primary motor cortex (M1) and posterior parietal cortex (PPC) that plays a role in sensorimotor integration. In this study, we applied corticocortical paired-associative stimuli to ipsilateral PPC and M1 (parietal ccPAS) in healthy right-handed subjects to test if this procedure could modulate M1 excitability and PPC-M1 connectivity. One hundred and eighty paired transcranial magnetic stimuli to the PPC and M1 at an interstimulus interval (ISI) of 8 ms were delivered at 0.2 Hz. We found that parietal ccPAS in the left hemisphere increased the excitability of conditioned left M1 assessed by motor evoked potentials (MEPs) and the input-output curve. Motor behavior assessed by the Purdue pegboard task was unchanged compared with controls. At baseline, conditioning stimuli over the left PPC potentiated MEPs from left M1 when ISI was 8 ms. This interaction significantly attenuated at 60 min after left parietal ccPAS. Additional experiments showed that parietal ccPAS induced plasticity was timing-dependent, was absent if ISI was 100 ms, and could also be seen in the right hemisphere. Our results suggest that parietal ccPAS can modulate M1 excitability and PPC-M1 connectivity and is a new approach to modify motor excitability and sensorimotor interaction.

Older and younger adults differ in time course of skill acquisition but not in overall improvement in a bimanual visuomotor tracking task.

Manual motor performance declines with age, but the extent to which age influences the acquisition of new skills remains a topic of debate. Here, we examined whether older healthy adults show less training-dependent performance improvements during a single session of a bimanual pinch task than younger adults. We also explored whether physical and cognitive factors, such as grip strength or motor-cognitive ability, are associated with performance improvements. Healthy younger (n = 16) and older (n = 20) adults performed three training blocks separated by short breaks. Participants were tasked with producing visually instructed changes in pinch force using their right and left thumb and index fingers. Task complexity was varied by shifting between bimanual mirror-symmetric and inverse-asymmetric changes in pinch force. Older adults generally displayed higher visuomotor force tracking errors during the more complex inverse-asymmetric task compared to younger adults. Both groups showed a comparable net decrease in visuomotor force tracking error over the entire session, but their improvement trajectories differed. Young adults showed enhanced visuomotor tracking error only in the first block, while older adults exhibited a more gradual improvement over the three training blocks. Furthermore, grip strength and performance on a motor-cognitive test battery scaled positively with individual performance improvements during the first block in both age groups. Together, the results show subtle age-dependent differences in the rate of bimanual visuomotor skill acquisition, while overall short-term learning ability is maintained.

Dopamine D2 receptor density in the limbic striatum is related to implicit but not explicit movement sequence learning.

A large body of literature suggests that motor sequence learning involves dopamine-modulated plastic processes in the basal ganglia. Sequence learning can occur both implicitly, without conscious awareness and intention to learn, and explicitly, i.e., under conscious control. Here, we investigated whether individual differences in implicit and explicit sequence learning of movement sequences in a group of 15 healthy participants are related to dopamine D2 receptor densities in functional subregions of the striatum. Sequence learning was assessed using the serial reaction time task, and measures of implicit and explicit knowledge were estimated using a process dissociation procedure. Correlation analyses were performed between these measures and D2 receptor densities, which had been measured previously with positron emission tomography. Striatal D2 densities were negatively related to measures of sequence learning. In the limbic subregion, D2 densities were specifically related to implicit but not explicit learning. These findings suggest that individual differences in striatal DA function underlie differences in sequence learning ability and support that implicit and explicit sequence learning depend on partly distinct neural circuitry. The findings are also in line with the general view that implicit learning systems are evolutionarily primitive and tend to rely more on phylogenetically old neural circuitry than does explicit learning and cognition.

Patient-tailored transcranial direct current stimulation to improve stroke rehabilitation: study protocol of a randomized sham-controlled trial.

BACKGROUND: Many patients do not fully regain motor function after ischemic stroke. Transcranial direct current stimulation (TDCS) targeting the motor cortex may improve motor outcome as an add-on intervention to physical rehabilitation. However, beneficial effects on motor function vary largely among patients within and across TDCS trials. In addition to a large heterogeneity of study designs, this variability may be caused by the fact that TDCS was given as a one-size-fits-all protocol without accounting for anatomical differences between subjects. The efficacy and consistency of TDCS might be improved by a patient-tailored design that ensures precise targeting of a physiologically relevant area with an appropriate current strength. METHODS: In a randomized, double-blinded, sham-controlled trial, patients with subacute ischemic stroke and residual upper-extremity paresis will receive two times 20 min of focal TDCS of ipsilesional primary motor hand area (M1-HAND) during supervised rehabilitation training three times weekly for 4 weeks. Anticipated 60 patients will be randomly assigned to active or sham TDCS of ipsilesional M1-HAND, using a central anode and four equidistant cathodes. The placement of the electrode grid on the scalp and current strength at each cathode will be personalized based on individual electrical field models to induce an electrical current of 0.2 V/m in the cortical target region resulting in current strengths between 1 and 4 mA. Primary endpoint will be the difference in change of Fugl-Meyer Assessment of Upper Extremity (FMA-UE) score between active TDCS and sham at the end of the intervention. Exploratory endpoints will include UE-FMA at 12 weeks. Effects of TDCS on motor network connectivity and interhemispheric inhibition will be assessed with functional MRI and transcranial magnetic stimulation. DISCUSSION: The study will show the feasibility and test the efficacy of personalized, multi-electrode anodal TDCS of M1-HAND in patients with subacute stroke patients with upper-extremity paresis. Concurrent multimodal brain mapping will shed light into the mechanisms of action of therapeutic personalized TDCS of M1-HAND. Together, the results from this trial may inform future personalized TDCS studies in patients with focal neurological deficits after stroke.

Timing-dependent modulation of the posterior parietal cortex-primary motor cortex pathway by sensorimotor training.

Interplay between posterior parietal cortex (PPC) and ipsilateral primary motor cortex (M1) is crucial during execution of movements. The purpose of the study was to determine whether functional PPC-M1 connectivity in humans can be modulated by sensorimotor training. Seventeen participants performed a sensorimotor training task that involved tapping the index finger in synchrony to a rhythmic sequence. To explore differences in training modality, one group (n = 8) learned by visual and the other (n = 9) by auditory stimuli. Transcranial magnetic stimulation (TMS) was used to assess PPC-M1 connectivity before and after training, whereas electroencephalography (EEG) was used to assess PPC-M1 connectivity during training. Facilitation from PPC to M1 was quantified using paired-pulse TMS at conditioning-test intervals of 2, 4, 6, and 8 ms by measuring motor-evoked potentials (MEPs). TMS was applied at baseline and at four time points (0, 30, 60, and 180 min) after training. For EEG, task-related power and coherence were calculated for early and late training phases. The conditioned MEP was facilitated at a 2-ms conditioning-test interval before training. However, facilitation was abolished immediately following training, but returned to baseline at subsequent time points. Regional EEG activity and interregional connectivity between PPC and M1 showed an initial increase during early training followed by a significant decrease in the late phases. The findings indicate that parietal-motor interactions are activated during early sensorimotor training when sensory information has to be integrated into a coherent movement plan. Once the sequence is encoded and movements become automatized, PPC-M1 connectivity returns to baseline.

The differential modulation of the ventral premotor-motor interaction during movement initiation is deficient in patients with focal hand dystonia.

A major feature of focal hand dystonia (FHD) pathophysiology is the loss of inhibition. One inhibitory process, surround inhibition, for which the cortical mechanisms are still unknown, is abnormal in FHD. As the ventral premotor cortex (PMv) plays a key role in the sensorimotor processing involved in shaping finger movements and has many projections onto the primary motor cortex (M1), we hypothesized that the PMv-M1 connections might play a role in surround inhibition. A paired-pulse transcranial magnetic stimulation paradigm was used in order to evaluate and compare the PMv-M1 interactions during different phases (rest, preparation and execution) of an index finger movement in patients with FHD and controls. A sub-threshold conditioning pulse (80% resting motor threshold) was applied to the PMv at 6 ms before M1 stimulation. The right abductor pollicis brevis, a surround muscle, was the target muscle. In healthy controls, the results showed that PMv stimulation induced an ipsilateral ventral premotor-motor inhibition at rest. This cortico-cortical interaction changed into an early facilitation (100 ms before movement onset) and turned back to inhibition 50 ms later. In patients with FHD, this PMv-M1 interaction and its modulation were absent. Our results show that, although the ipsilateral ventral premotor-motor inhibition does not play a key role in the genesis of surround inhibition, PMv has a dynamic influence on M1 excitability during the early steps of motor execution. The impaired cortico-cortical interactions observed in patients with FHD might contribute, at least in part, to the abnormal motor command.

Short periods of bipolar anodal TDCS induce no instantaneous dose-dependent increase in cerebral blood flow in the targeted human motor cortex.

Anodal transcranial direct current stimulation (aTDCS) of primary motor hand area (M1-HAND) can enhance corticomotor excitability, but it is still unknown which current intensity produces the strongest effect on intrinsic neural firing rates and synaptic activity. Magnetic resonance imaging (MRI) combined with pseudo-continuous Arterial Spin Labeling (pcASL MRI) can map regional cortical blood flow (rCBF). The measured rCBF signal is sensitive to regional changes in neuronal activity due to neurovascular coupling. Therefore, concurrent TDCS and pcASL MRI may reveal the relationship between current intensity and TDCS-induced changes in overall firing rates and synaptic activity in the cortical target. Here we employed pcASL MRI to map acute rCBF changes during short-duration aTDCS of left M1-HAND. Using the rCBF response as a proxy for regional neuronal activity, we investigated if short-duration aTDCS produces an instantaneous dose-dependent rCBF increase in the targeted M1-HAND that may be useful for individual dosing. Nine healthy right-handed participants received 30 s of aTDCS at 0.5, 1.0, 1.5, and 2.0 mA with the anode placed over left M1-HAND and cathode over the right supraorbital region. Concurrent pcASL MRI at 3 T probed TDCS-related rCBF changes in the targeted M1-HAND. Movement-induced rCBF changes were also assessed. Apart from a subtle increase in rCBF at 0.5 mA, short-duration aTDCS did not modulate rCBF in the M1-HAND relative to no-stimulation periods. None of the participants showed a dose-dependent increase in rCBF during aTDCS, even after accounting for individual differences in TDCS-induced electrical field strength. In contrast, finger movements led to robust activation of left M1-HAND before and after aTDCS. Short-duration bipolar aTDCS does not produce consistant instantaneous dose-dependent rCBF increases in the targeted M1-HAND at conventional intensity ranges. Therefore, the regional hemodynamic response profile to short-duration aTDCS may not be suited to inform individual dosing of TDCS intensity.

Transcranial magnetic stimulation of the brain: What is stimulated? - A consensus and critical position paper.

Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.