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.

Characterising activity and diet compositions for dementia prevention: protocol for the ACTIVate prospective longitudinal cohort study.

INTRODUCTION: Approximately 40% of late-life dementia may be prevented by addressing modifiable risk factors, including physical activity and diet. Yet, it is currently unknown how multiple lifestyle factors interact to influence cognition. The ACTIVate Study aims to (1) explore associations between 24-hour time-use and diet compositions with changes in cognition and brain function; and (2) identify duration of time-use behaviours and the dietary compositions to optimise cognition and brain function. METHODS AND ANALYSIS: This 3-year prospective longitudinal cohort study will recruit 448 adults aged 60-70 years across Adelaide and Newcastle, Australia. Time-use data will be collected through wrist-worn activity monitors and the Multimedia Activity Recall for Children and Adults. Dietary intake will be assessed using the Australian Eating Survey food frequency questionnaire. The primary outcome will be cognitive function, assessed using the Addenbrooke's Cognitive Examination-III. Secondary outcomes include structural and functional brain measures using MRI, cerebral arterial pulse measured with diffuse optical tomography, neuroplasticity using simultaneous transcranial magnetic stimulation and electroencephalography, and electrophysiological markers of cognitive control using event-related potential and time frequency analyses. Compositional data analysis, testing for interactions between time point and compositions, will assess longitudinal associations between dependent (cognition, brain function) and independent (time-use and diet compositions) variables. CONCLUSIONS: The ACTIVate Study will be the first to examine associations between time-use and diet compositions, cognition and brain function. Our findings will inform new avenues for multidomain interventions that may more effectively account for the co-dependence between activity and diet behaviours for dementia prevention. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the University of South Australia's Human Research Ethics committee (202639). Findings will be disseminated through peer-reviewed manuscripts, conference presentations, targeted media releases and community engagement events. TRIAL REGISTRATION NUMBER: Australia New Zealand Clinical Trials Registry (ACTRN12619001659190).

Motor network connectivity predicts neuroplastic response following theta burst stimulation in healthy adults.

A patterned repetitive transcranial magnetic stimulation protocol, known as continuous theta burst stimulation (cTBS), can suppress corticospinal excitability via mechanisms that appear similar to long-term depression synaptic plasticity. Despite much potential, this technique is currently limited by substantial response variability. The purpose of this study was to investigate whether baseline resting state functional connectivity is a determinant of response to cTBS. Eighteen healthy young adults participated in up to three experimental sessions. Single-pulse transcranial magnetic stimulation was used to quantify change in corticospinal excitability following cTBS. Three minutes of resting electroencephalographic activity was recorded, and functional connectivity was estimated using the debiased weighted phase lag index across different frequency bands. Partial least squares regression identified models of connectivity between a seed region (C3) and the whole scalp that maximally accounted for variance in cTBS responses. There was no group-level effect of a single cTBS train or spaced cTBS trains on corticospinal excitability (p = 0.092). A low beta frequency band model of connectivity accounted for the largest proportion of variance in spaced cTBS response (R2 = 0.50). Based on the low beta frequency model, a-priori regions of interest were identified and predicted 39% of variance in response to spaced cTBS at a subsequent session. Importantly, weaker connectivity between the seed electrode (C3) and a cluster approximating a frontocentral region was associated with greater spaced cTBS response (p = 0.02). It appears M1-frontocentral networks may have an important role in determining the effects of cTBS on corticospinal excitability.

Can Transcranial Direct Current Stimulation Enhance Poststroke Motor Recovery? Development of a Theoretical Patient-Tailored Model.

New treatments that can facilitate neural repair and reduce persistent impairments have significant value in promoting recovery following stroke. One technique that has gained interest is transcranial direct current stimulation (tDCS) as early research suggested it could enhance plasticity and enable greater behavioral recovery. However, several studies have now identified substantial intersubject variability in response to tDCS and clinical trials revealed insufficient evidence of treatment effectiveness. A possible explanation for the varied and negative findings is that the physiologic model of stroke recovery that researchers have used to guide the application of tDCS-based treatments in stroke is overly simplistic and does not account for stroke heterogeneity or known determinants that affect the tDCS response. Here, we propose that tDCS could have a more clearly beneficial role in enhancing stroke recovery if greater consideration is given to individualizing treatment. By critically reviewing the proposed mechanisms of tDCS, stroke physiology across the recovery continuum, and known determinants of tDCS response, we propose a new, theoretical, patient-tailored approach to delivering tDCS after stroke. The proposed model includes a step-by-step principled selection strategy for identifying optimal neuromodulation targets and outlines key areas for further investigation. Tailoring tDCS treatment to individual neuroanatomy and physiology is likely our best chance at producing robust and meaningful clinical benefit for people with stroke and would therefore accelerate opportunities for clinical translation.

Effects of rTMS on the brain: is there value in variability?

The ability of repetitive transcranial magnetic stimulation (rTMS) to non-invasively induce neuroplasticity in the human cortex has opened exciting possibilities for its application in both basic and clinical research. Changes in the amplitude of motor evoked potentials (MEPs) elicited by single-pulse transcranial magnetic stimulation has so far provided a convenient model for exploring the neurophysiology of rTMS effects on the brain, influencing the ways in which these stimulation protocols have been applied therapeutically. However, a growing number of studies have reported large inter-individual variability in the mean MEP response to rTMS, raising legitimate questions about the usefulness of this model for guiding therapy. Although the increasing application of different neuroimaging approaches has made it possible to probe rTMS-induced neuroplasticity outside the motor cortex to measure changes in neural activity that impact other aspects of human behaviour, the high variability of rTMS effects on these measurements remains an important issue for the field to address. In this review, we seek to move away from the conventional facilitation/inhibition dichotomy that permeates much of the rTMS literature, presenting a non-standard approach for measuring rTMS-induced neuroplasticity. We consider the evidence that rTMS is able to modulate an individual's moment-to-moment variability of neural activity, and whether this could have implications for guiding the therapeutic application of rTMS.

Daily activities are associated with non-invasive measures of neuroplasticity in older adults.

OBJECTIVE: We aimed to determine the association between daily activities (sleep, sedentary behavior and physical activities) and neuroplasticity in older adults by measuring motor evoked potential amplitudes (MEPs) elicited after a single and spaced continuous theta burst stimulation (cTBS) paradigm, targeting the primary motor cortex. METHODS: MEPs were recorded from the right first dorsal interosseous muscle of 34 older adults (66.9 ± 4.5 years) by delivering single-pulse TMS before, between and at 0, 10, 20, 40 and 60 min after the application of spaced-cTBS separated by 10 min. Habitual activity was assessed by accelerometry for 24 h/day over 7-days. Multiple linear regression models determined if the time-use composition (sleep, sedentary behavior and physical activities) was associated with neuroplasticity response. RESULTS: More physical activity at the equal expense of sleep and sedentary behaviors was associated with greater motor cortical neuroplasticity. Associations appeared to be driven by more time spent in light- but not moderate-to-vigorous- physical activities. CONCLUSIONS: Engaging in light physical activity at the expense of sleep and sedentary behavior was associated with greater LTD-like motor cortex neuroplasticity (as measured with cTBS) in older adults. SIGNIFICANCE: These findings suggest the promotion of physical activity among older adults to support brain neuroplasticity.

Evidence for a Window of Enhanced Plasticity in the Human Motor Cortex Following Ischemic Stroke.

BACKGROUND: In preclinical models, behavioral training early after stroke produces larger gains compared with delayed training. The effects are thought to be mediated by increased and widespread reorganization of synaptic connections in the brain. It is viewed as a period of spontaneous biological recovery during which synaptic plasticity is increased. OBJECTIVE: To look for evidence of a similar change in synaptic plasticity in the human brain in the weeks and months after ischemic stroke. METHODS: We used continuous theta burst stimulation (cTBS) to activate synapses repeatedly in the motor cortex. This initiates early stages of synaptic plasticity that temporarily reduces cortical excitability and motor-evoked potential amplitude. Thus, the greater the effect of cTBS on the motor-evoked potential, the greater the inferred level of synaptic plasticity. Data were collected from separate cohorts (Australia and UK). In each cohort, serial measurements were made in the weeks to months following stroke. Data were obtained for the ipsilesional motor cortex in 31 stroke survivors (Australia, 66.6 ± 17.8 years) over 12 months and the contralesional motor cortex in 29 stroke survivors (UK, 68.2 ± 9.8 years) over 6 months. RESULTS: Depression of cortical excitability by cTBS was most prominent shortly after stroke in the contralesional hemisphere and diminished over subsequent sessions (P = .030). cTBS response did not differ across the 12-month follow-up period in the ipsilesional hemisphere (P = .903). CONCLUSIONS: Our results provide the first neurophysiological evidence consistent with a period of enhanced synaptic plasticity in the human brain after stroke. Behavioral training given during this period may be especially effective in supporting poststroke recovery.

Examining motor evoked potential amplitude and short-interval intracortical inhibition on the up-going and down-going phases of a transcranial alternating current stimulation (tacs) imposed alpha oscillation.

Many brain regions exhibit rhythmical activity thought to reflect the summed behaviour of large populations of neurons. The endogenous alpha rhythm has been associated with phase-dependent modulation of corticospinal excitability. However, whether exogenous alpha rhythm, induced using transcranial alternating current stimulation (tACS) also has a phase-dependent effect on corticospinal excitability remains unknown. Here, we triggered transcranial magnetic stimuli (TMS) on the up- or down-going phase of a tACS-imposed alpha oscillation and measured motor evoked potential (MEP) amplitude and short-interval intracortical inhibition (SICI). There was no significant difference in MEP amplitude or SICI when TMS was triggered on the up- or down-going phase of the tACS-imposed alpha oscillation. The current study provides no evidence of differences in corticospinal excitability or GABAergic inhibition when targeting the up-going (peak) and down-going (trough) phase of the tACS-imposed oscillation.

The Role of Alpha Power in the Suppression of Anticipated Distractors During Verbal Working Memory.

As working memory (WM) is limited in capacity, it is important to direct neural resources towards processing task-relevant information while ignoring distractors. Neural oscillations in the alpha frequency band (8-12 Hz) have been suggested to play a role in the inhibition of task-irrelevant information during WM, although results are mixed, possibly due to differences in the type of WM task employed. Here, we examined the role of alpha power in suppression of anticipated distractors of varying strength using a modified Sternberg task where the encoding and retention periods were temporally separated. We recorded EEG while 20 young adults completed the task and found: (1) slower reaction times in strong distractor trials compared to weak distractor trials; (2) increased alpha power in posterior regions from baseline prior to presentation of a distractor regardless of condition; and (3) no differences in alpha power between strong and weak distractor conditions. Our results suggest that parieto-occipital alpha power is increased prior to a distractor. However, we could not find evidence that alpha power is further modulated by distractor strength.

Obesity is Associated with Reduced Plasticity of the Human Motor Cortex.

Obesity is characterised by excessive body fat and is associated with several detrimental health conditions, including cardiovascular disease and diabetes. There is some evidence that people who are obese have structural and functional brain alterations and cognitive deficits. It may be that these neurophysiological and behavioural consequences are underpinned by altered plasticity. This study investigated the relationship between obesity and plasticity of the motor cortex in people who were considered obese (n = 14, nine males, aged 35.4 ± 14.3 years) or healthy weight (n = 16, seven males, aged 26.3 ± 8.5 years). A brain stimulation protocol known as continuous theta burst transcranial magnetic stimulation was applied to the motor cortex to induce a brief suppression of cortical excitability. The suppression of cortical excitability was quantified using single-pulse transcranial magnetic stimulation to record and measure the amplitude of the motor evoked potential in a peripheral hand muscle. Therefore, the magnitude of suppression of the motor evoked potential by continuous theta burst stimulation was used as a measure of the capacity for plasticity of the motor cortex. Our results demonstrate that the healthy-weight group had a significant suppression of cortical excitability following continuous theta burst stimulation (cTBS), but there was no change in excitability for the obese group. Comparing the response to cTBS between groups demonstrated that there was an impaired plasticity response for the obese group when compared to the healthy-weight group. This might suggest that the capacity for plasticity is reduced in people who are obese. Given the importance of plasticity for human behaviour, our results add further emphasis to the potentially detrimental health effects of obesity.

Age-related decline of neuroplasticity to intermittent theta burst stimulation of the lateral prefrontal cortex and its relationship with late-life memory performance.

OBJECTIVE: Advanced age is accompanied by a deterioration in memory performance that can profoundly influence activities of daily living. However, the neural processes responsible for age-related memory decline are not fully understood. Here, we used transcranial magnetic stimulation (TMS) in combination with electroencephalography (EEG) to assess age-related changes in neuroplasticity in the human prefrontal cortex. METHODS: TMS-evoked cortical potentials (TEPs) were recorded before and following the neuroplasticity-inducing intermittent theta burst stimulation (iTBS), applied to the left lateral prefrontal cortex in healthy young (n = 33, mean age 22 ± 3 years) and older adults (n = 33, mean age 68 ± 7 years). RESULTS: iTBS increased the amplitude of the positive TEP component at 60 ms after the TMS pulse (P60) in young, but not older adults. This age-related decline in P60 plasticity response was associated with poorer visuospatial associative (but not working) memory performance in older adults. CONCLUSIONS: These findings suggest that neuroplasticity in the human lateral prefrontal cortex is reduced in older relative to young adults, and this may be an important factor in age-related memory decline. SIGNIFICANCE: This may have important implications for the early detection of cognitive decline and dementia.

Characterization of Young and Old Adult Brains: An EEG Functional Connectivity Analysis.

Brain connectivity studies have reported that functional networks change with older age. We aim to (1) investigate whether electroencephalography (EEG) data can be used to distinguish between individual functional networks of young and old adults; and (2) identify the functional connections that contribute to this classification. Two eyes-open resting-state EEG recording sessions with 64 electrodes for each of 22 younger adults (19-37 years) and 22 older adults (63-85 years) were conducted. For each session, imaginary coherence matrices in delta, theta, alpha, beta and gamma bands were computed. A range of machine learning classification methods were utilized to distinguish younger and older adult brains. A support vector machine (SVM) classifier was 93% accurate in classifying the brains by age group. We report decreased functional connectivity with older age in delta, theta, alpha and gamma bands, and increased connectivity with older age in beta band. Most connections involving frontal, temporal, and parietal electrodes, and more than half of connections involving occipital electrodes, showed decreased connectivity with older age. Slightly less than half of the connections involving central electrodes showed increased connectivity with older age. Functional connections showing decreased strength with older age were not significantly different in electrode-to-electrode distance than those that increased with older age. Most of the connections used by the classifier to distinguish participants by age group belonged to the alpha band. Findings suggest a decrease in connectivity in key networks and frequency bands associated with attention and awareness, and an increase in connectivity of the sensorimotor functional networks with aging during a resting state.

Transcranial Magnetic Stimulation-EEG Biomarkers of Poststroke Upper-Limb Motor Function.

BACKGROUND: Motor evoked potentials obtained with transcranial magnetic stimulation (TMS) can provide valuable information to inform stroke neurophysiology and recovery but are difficult to obtain in all stroke survivors due to high stimulation thresholds. OBJECTIVE: To determine whether transcranial magnetic stimulation evoked potentials (TEPs) evoked using a lower stimulus intensity, below that necessary for recording motor evoked potentials, could serve as a marker of poststroke upper-limb motor function and were different compared to healthy adults. METHODS: Eight chronic stroke survivors (66 ± 21 years) and 15 healthy adults (53 ± 10 years) performed a motor function task using a customized grip-lift manipulandum. TMS was applied to the lesioned motor cortex, with TEPs recorded using simultaneous high-definition electroencephalography (EEG). RESULTS: Stroke participants demonstrated greater hold ratio with the manipulandum. Cluster-based statistics revealed larger P30 amplitude in stroke participants, with significant clusters over frontal (P = .016) and parietal-occipital electrodes (P = .023). There was a negative correlation between the N45 peak amplitude and hold ratio in stroke participants (r = -.83, P = .02), but not controls. CONCLUSIONS: TEPs can be recorded using lower stimulus intensities in chronic stroke. The global P30 TEP response differed between stroke participants and healthy controls, with results suggesting that the TEP can be used as a biomarker of upper-limb behavior.

Visuomotor task acquisition is reduced by priming paired associative stimulation in older adults.

Transcranial magnetic stimulation may represent an effective means for improving motor function in the elderly. The aim of this study was therefore to investigate the effects of paired associative stimulation (PAS; a plasticity-inducing transcranial magnetic stimulation paradigm) on acquisition of a novel visuomotor task in young and older adults. Fourteen young (20.4 ± 0.6 years) and 13 older (69.0 ± 1.6 years) adults participated in 3 experimental sessions during which training was preceded (primed) by PAS. Within each session, the interstimulus interval used for PAS was set at either the N20 latency plus 5 ms (PASLTP), the N20 latency minus 10 ms (PASLTD), or a constant 100 ms (PASControl). After training, the level of motor skill was not different between PAS conditions in young subjects (all p-values > 0.2), but was reduced by both PASLTP (p = 0.02) and PASLTD (p = 0.0001) in older subjects. Consequently, priming PAS was detrimental to skill acquisition in older adults, possibly suggesting a need for interventions that are optimized for use in elderly populations.

Transcranial Magnetic Stimulation-Electroencephalography Measures of Cortical Neuroplasticity Are Altered after Mild Traumatic Brain Injury.

While the potential long-term side effects of mild traumatic brain injury (mTBI) are becoming increasingly recognized, the associated neurophysiological mechanisms remain poorly understood. However, changes in cortical inhibitory function and neuroplasticity have been suggested as possible contributing factors. The current study applied transcranial magnetic stimulation (TMS) in conjunction with electroencephalography (combined TMS-EEG) to investigate further the effects of mTBI on these processes. In 17 patients with a history of mTBI and 15 healthy control subjects with no mTBI history, paired-pulse TMS-EEG measures of short- (SICI) and long-interval intracortical inhibition (LICI) were used to assess intracortical inhibitory function. Single-pulse TMS-EEG was used to assess neuroplastic changes in cortical excitability after application of continuous theta burst stimulation (cTBS, a plasticity inducing TMS paradigm). Inhibition of the TMS-evoked EEG potential after application of SICI and LICI was not different between groups. In contrast, the inhibitory effects of cTBS on both P30 (p < 0.05) and N45 (p = 0.04) TEP components was significantly increased in patients, with the modulation of N45 in patients significantly related to the time since injury (p = 0.04). While these results provide further evidence that inhibitory circuits involving γ-aminobutyric acid (GABA) are modified after mTBI, they place greater emphasis on the plasticity of inhibitory networks involving the GABAA receptor subtype.

Intermittent single-joint fatiguing exercise reduces TMS-EEG measures of cortical inhibition.

Fatiguing intermittent single-joint exercise causes an increase in corticospinal excitability and a decrease in intracortical inhibition when measured with peripherally recorded motor evoked potentials (MEPs) after transcranial magnetic stimulation (TMS). Combined TMS and electroencephalography (TMS-EEG) allows for more direct recording of cortical responses through the TMS-evoked potential (TEP). The aim of this study was to investigate the changes in the excitatory and inhibitory components of the TEP during fatiguing single-joint exercise. Twenty-three young (22 ± 2 yr) healthy subjects performed intermittent 30-s maximum voluntary contractions of the right first dorsal interosseous muscle, followed by a 30-s relaxation period repeated for a total of 15 min. Six single-pulse TMSs and one peripheral nerve stimulation (PNS) to evoke maximal M wave (Mmax) were applied during each relaxation period. A total of 90 TMS pulses and 5 PNSs were applied before and after fatiguing exercise to record MEP and TEP. The amplitude of the MEP (normalized to Mmax) increased during fatiguing exercise ( P < 0.001). There were no changes in local and global P30, N45, and P180 of TEPs during the development of intermittent single-joint exercise-induced fatigue. Global analysis, however, revealed a decrease in N100 peak of the TEP during fatiguing exercise compared with before fatiguing exercise ( P = 0.02). The decrease in N100 suggests a fatigue-related decrease in global intracortical GABAB-mediated inhibition. The increase in corticospinal excitability typically observed during single-joint fatiguing exercise may be mediated by a global decrease in intracortical inhibition. NEW & NOTEWORTHY Fatiguing intermittent single-joint exercise causes an increase in corticospinal excitability and a decrease in intracortical inhibition when measured with transcranial magnetic stimulation (TMS)-evoked potentials from the muscle. The present study provides new and direct cortical evidence, using TMS-EEG to demonstrate that during single-joint fatiguing exercise there is a global decrease in intracortical GABAB-mediated inhibition.

Reaction Time Predicts Brain-Computer Interface Aptitude.

There is evidence that 15-30% of the general population cannot effectively operate brain-computer interfaces (BCIs). Thus the BCI performance predictors are critically required to pre-screen participants. Current neurophysiological and psychological tests either require complicated equipment or suffer from subjectivity. Thus, a simple and objective BCI performance predictor is desirable. Neurofeedback (NFB) training involves performing a cognitive task (motor imagery) instructed via sensory stimuli and re-adjusted through ongoing real-time feedback. A simple reaction time (SRT) test reflects the time required for a subject to respond to a defined stimulus. Thus, we postulated that individuals with shorter reaction times operate a BCI with rapidly updated feedback better than individuals with longer reaction times. Furthermore, we investigated how changing the feedback update interval (FUI), i.e., modification of the feedback provision frequency, affects the correlation between the SRT and BCI performance. Ten participants attended four NFB sessions with FUIs of 16, 24, 48, and 96 ms in a randomized order. We found that: 1) SRT is correlated with the BCI performance with FUIs of 16 and 96 ms; 2) good and poor performers elicit stronger ERDs and control BCIs more effectively (i.e., produced larger information transfer rates) with 16 and 96 ms FUIs, respectively. Our findings suggest that SRT may be used as a simple and objective surrogate for BCI aptitude with FUIs of 16 and 96 ms. It also implies that the FUI customization according to participants SRT measure may enhance the BCI performance.

Towards Targeted Brain Stimulation in Stroke: Connectivity as a Biomarker of Response.

Stroke is a leading cause of adult disability. New treatments capable of assisting recovery hold significant potential to improve quality of life for many stroke survivors. Transcranial direct current stimulation is one technique that has received much attention due to its potential to promote neuroplasticity and enhance recovery. However, current evidence suggests this is not a one-size-fits-all treatment with indication that responses are highly variable. Using electroencephalography, Hordacre et al recently demonstrated that connectivity between the ipsilesional motor cortex, ipsilesional parietal cortex, and contralesional frontotemporal cortex was a strong predictor of the neurophysiological response to anodal transcranial direct current stimulation applied to the ipsilesional motor cortex in people with chronic ischemic stroke. Based on this outcome, we discuss the potential for connectivity to be used as a biomarker to target transcranial direct current stimulation. This includes identification of a connectivity threshold which could be used to select stroke survivors who are likely to respond to this potentially beneficial neuromodulatory treatment. Furthermore, we discuss treatment approaches for those identified as unlikely to benefit from ipsilesional anodal transcranial direct current stimulation based on connectivity profile. This represents an important progression towards targeting transcranial direct current stimulation for best treatment outcome based on individual connectivity characteristics.

Simulation of electromyographic recordings following transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a technique that enables noninvasive manipulation of neural activity and holds promise in both clinical and basic research settings. The effect of TMS on the motor cortex is often measured by electromyography (EMG) recordings from a small hand muscle. However, the details of how TMS generates responses measured with EMG are not completely understood. We aim to develop a biophysically detailed computational model to study the potential mechanisms underlying the generation of EMG signals following TMS. Our model comprises a feed-forward network of cortical layer 2/3 cells, which drive morphologically detailed layer 5 corticomotoneuronal cells, which in turn project to a pool of motoneurons. EMG signals are modeled as the sum of motor unit action potentials. EMG recordings from the first dorsal interosseous muscle were performed in four subjects and compared with simulated EMG signals. Our model successfully reproduces several characteristics of the experimental data. The simulated EMG signals match experimental EMG recordings in shape and size, and change with stimulus intensity and contraction level as in experimental recordings. They exhibit cortical silent periods that are close to the biological values and reveal an interesting dependence on inhibitory synaptic transmission properties. Our model predicts several characteristics of the firing patterns of neurons along the entire pathway from cortical layer 2/3 cells down to spinal motoneurons and should be considered as a viable tool for explaining and analyzing EMG signals following TMS. NEW & NOTEWORTHY A biophysically detailed model of EMG signal generation following transcranial magnetic stimulation (TMS) is proposed. Simulated EMG signals match experimental EMG recordings in shape and amplitude. Motor-evoked potential and cortical silent period properties match experimental data. The model is a viable tool to analyze, explain, and predict EMG signals following TMS.

The effect of stimulation interval on plasticity following repeated blocks of intermittent theta burst stimulation.

This study assessed the effect of interval duration on the direction and magnitude of changes in cortical excitability and inhibition when applying repeated blocks of intermittent theta burst stimulation (iTBS) over motor cortex. 15 participants received three different iTBS conditions on separate days: single iTBS; repeated iTBS with a 5 minute interval (iTBS-5-iTBS); and with a 15 minute interval (iTBS-15-iTBS). Changes in cortical excitability and short-interval cortical inhibition (SICI) were assessed via motor-evoked potentials (MEPs) before and up to 60 mins following stimulation. iTBS-15-iTBS increased MEP amplitude for up to 60 mins post stimulation, whereas iTBS-5-iTBS decreased MEP amplitude. In contrast, MEP amplitude was not altered by single iTBS. Despite the group level findings, only 53% of individuals showed facilitated MEPs following iTBS-15-iTBS, and only 40% inhibited MEPs following iTBS-5-iTBS. Modulation of SICI did not differ between conditions. These results suggest interval duration between spaced iTBS plays an important role in determining the direction of plasticity on excitatory, but not inhibitory circuits in human motor cortex. While repeated iTBS can increase the magnitude of MEP facilitation/inhibition in some individuals compared to single iTBS, the response to repeated iTBS appears variable between individuals in this small sample.