Elias P. Casula

Low-frequency rTMS inhibitory effects in the primary motor cortex: Insights from TMS-evoked potentials

The neuromodulatory effects of repetitive transcranial magnetic stimulation (rTMS) have been mostly investigated by peripheral motor-evoked potentials (MEPs). New TMS-compatible EEG systems allow a direct investigation of the stimulation effects through the analysis of TMS-evoked potentials (TEPs). We investigated the effects of 1-Hz rTMS over the primary motor cortex (M1) of 15 healthy volunteers on TEP evoked by single pulse TMS over the same area. A second experiment in which rTMS was delivered over the primary visual cortex (V1) of 15 healthy volunteers was conducted to examine the spatial specificity of the effects. Single-pulse TMS evoked four main components: P30, N45, P60 and N100. M1-rTMS resulted in a significant decrease of MEP amplitude and in a significant increase of P60 and N100 amplitude. There was no effect after V1-rTMS. 1-Hz rTMS appears to increase the amount of inhibition following a TMS pulse, as demonstrated by the higher N100 and P60, which are thought to originate from GABAb-mediated inhibitory post-synaptic potentials. Our results confirm the reliability of the TMS-evoked N100 as a marker of cortical inhibition and provide insight into the neuromodulatory effects of 1-Hz rTMS. The present finding could be of relevance for therapeutic and diagnostic purposes.

Somatosensory Temporal Discrimination Threshold Involves Inhibitory Mechanisms in the Primary Somatosensory Area

Somatosensory temporal discrimination threshold (STDT) is defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. Although STDT is altered in several neurological disorders, its neural bases are not entirely clear. We used continuous theta burst stimulation (cTBS) to condition the excitability of the primary somatosensory cortex in healthy humans to examine its possible contribution to STDT. Excitability was assessed using the recovery cycle of the N20 component of somatosensory evoked potentials (SEP) and the area of high-frequency oscillations (HFO). cTBS increased STDT and reduced inhibition in the N20 recovery cycle at an interstimulus interval of 5 ms. It also reduced the amplitude of late HFO. All three effects were correlated. There was no effect of cTBS over the secondary somatosensory cortex on STDT, although it reduced the N120 component of the SEP. STDT is assessed conventionally with a simple ascending method. To increase insight into the effect of cTBS, we measured temporal discrimination with a psychophysical method. cTBS reduced the slope of the discrimination curve, consistent with a reduction of the quality of sensory information caused by an increase in noise. We hypothesize that cTBS reduces the effectiveness of inhibitory interactions normally used to sharpen temporal processing of sensory inputs. This reduction in discriminability of sensory input is equivalent to adding neural noise to the signal. SIGNIFICANCE STATEMENT Precise timing of sensory information is crucial for nearly every aspect of human perception and behavior. One way to assess the ability to analyze temporal information in the somatosensory domain is to measure the somatosensory temporal discrimination threshold (STDT), defined as the shortest time interval necessary for a pair of tactile stimuli to be perceived as separate. In this study, we found that STDT depends on inhibitory mechanisms within the primary somatosensory area (S1). This finding helps interpret the sensory processing deficits in neurological diseases, such as focal dystonia and Parkinsons disease, and possibly prompts future studies using neurostimulation techniques over S1 for therapeutic purposes in dystonic patients.

Muscle and timing-specific functional connectivity between the dorsolateral prefrontal cortex and the primary motor cortex

The pFC has a crucial role in cognitive control, executive function, and sensory processing. Functional imaging, neurophysiological, and animal studies provide evidence for a functional connectivity between the dorsolateral pFC (DLPFC) and the primary motor cortex (M1) during free choice but not instructed choice selection tasks. In this study, twin coil, neuronavigated TMS was used to examine the precise timing of the functional interaction between human left DLPFC and ipsilateral M1 during the execution of a free/specified choice selection task involving the digits of the right hand. In a thumb muscle that was not involved in the task, a conditioning pulse to the left DLPFC enhanced the excitability of the ipsilateral M1 during free selection more than specified selection 100 msec after presentation of the cue; the opposite effect was seen at 75 msec. However, the difference between free and externally specified conditions disappeared when a task-specific muscle was investigated. In this case, the influence from DLPFC was dominated by task involvement rather than mode of selection, suggesting that other processes related to movement execution were also operating. Finally, we show that the effects were spatially specific because they were absent when an adjacent area of DLPFC was stimulated. These results reveal temporally and spatially selective interactions between BA 46 and M1 that are both task and muscle specific.

Bi-directional Modulation of Somatosensory Mismatch Negativity with Transcranial Direct Current Stimulation: An event Related Potential Study

Sensory mismatch negativity is impaired in patients with cerebellar lesions, suggesting that the cerebellum may play an important role in this form of sensory processing. Anodal transcranial direct current stimulation over the right cerebellar hemisphere increased the amplitude of sensory mismatch negativity to stimuli delivered to the right hand while cathodal transcranial direct current stimulation reduced it. The cerebellum appears to be an important node in the network mediating sensory mismatch negativity, and tDCS is a useful method with which to manipulate sensory mismatch negativity for experimental studies.

Spike-timing-dependent plasticity in the human dorso-lateral prefrontal cortex.

Changes in the synaptic strength of neural connections are induced by repeated coupling of activity of interconnected neurons with precise timing, a phenomenon known as spike-timing-dependent plasticity (STDP). It is debated if this mechanism exists in large-scale cortical networks in humans. We combined transcranial magnetic stimulation (TMS) with concurrent electroencephalography (EEG) to directly investigate the effects of two paired associative stimulation (PAS) protocols (fronto-parietal and parieto-frontal) of pre and post-synaptic inputs within the human fronto-parietal network. We found evidence that the dorsolateral prefrontal cortex (DLPFC) has the potential to form robust STDP. Long-term potentiation/depression of TMS-evoked cortical activity is prompted after that DLPFC stimulation is followed/preceded by posterior parietal stimulation. Such bidirectional changes are paralleled by sustained increase/decrease of high-frequency oscillatory activity, likely reflecting STDP responsivity. The current findings could be important to drive plasticity of damaged cortical circuits in patients with cognitive or psychiatric disorders.

Cerebellar theta burst stimulation modulates the neural activity of interconnected parietal and motor areas

Voluntary movement control and execution are regulated by the influence of the cerebellar output over different interconnected cortical areas, through dentato-thalamo connections. In the present study we applied transcranial magnetic stimulation (TMS) and electroencephalography (EEG) to directly assess the effects of cerebellar theta-burst stimulation (TBS) over the controlateral primary motor cortex (M1) and posterior parietal cortex (PPC) in a group of healthy volunteers. We found a TBS-dependent bidirectional modulation over TMS-evoked activity; specifically, cTBS increased whereas iTBS decreased activity between 100 and 200 ms after TMS, in a similar manner over both M1 and PPC areas. On the oscillatory domain, TBS induced specific changes over M1 natural frequencies of oscillation: TMS-evoked alpha activity was decreased by cTBS whereas beta activity was enhanced by iTBS. No effects were observed after sham stimulation. Our data provide novel evidence showing that the cerebellum exerts its control on the cortex likely by impinging on specific set of interneurons dependent on GABA-ergic activity. We show that cerebellar TBS modulates cortical excitability of distant interconnected cortical areas by acting through common temporal, spatial and frequency domains.

TMS-evoked long-lasting artefacts: A new adaptive algorithm for EEG signal correction

OBJECTIVE During EEG the discharge of TMS generates a long-lasting decay artefact (DA) that makes the analysis of TMS-evoked potentials (TEPs) difficult. Our aim was twofold: (1) to describe how the DA affects the recorded EEG and (2) to develop a new adaptive detrend algorithm (ADA) able to correct the DA. METHODS We performed two experiments testing 50 healthy volunteers. In experiment 1, we tested the efficacy of ADA by comparing it with two commonly-used independent component analysis (ICA) algorithms. In experiment 2, we further investigated the efficiency of ADA and the impact of the DA evoked from TMS over frontal, motor and parietal areas. RESULTS Our results demonstrated that (1) the DA affected the EEG signal in the spatiotemporal domain; (2) ADA was able to completely remove the DA without affecting the TEP waveforms; (3). ICA corrections produced significant changes in peak-to-peak TEP amplitude. CONCLUSIONS ADA is a reliable solution for the DA correction, especially considering that (1) it does not affect physiological responses; (2) it is completely data-driven and (3) its effectiveness does not depend on the characteristics of the artefact and on the number of recording electrodes. SIGNIFICANCE We proposed a new reliable algorithm of correction for long-lasting TMS-EEG artifacts.

Motor cortex synchronization influences the rhythm of motor performance in premanifest huntington's disease: M1 Synchronization and Motor Performance

Background: In Huntingtons disease there is evidence of structural damage in the motor system, but it is still unclear how to link this to the behavioral disorder of movement. One feature of choreic movement is variable timing and coordination between sequences of actions. We postulate this results from desynchronization of neural activity in cortical motor areas.

Variability and Predictors of Response to Continuous Theta Burst Stimulation: A TMS-EEG Study

Continuous theta-burst stimulation (cTBS) is a repetitive transcranial magnetic stimulation paradigm reported to decrease the excitability of the stimulated cortical area and which is thought to reflect a form of inhibitory synaptic plasticity. However, since its introduction, the effect of cTBS has shown a remarkable variability in its effects, which are often quantified by measuring the amplitude of motor evoked potentials (MEPs). Part of this inconsistency in experimental results might be due to an intrinsic variability of TMS effects caused by genetic or neurophysiologic factors. However, it is also possible that MEP only reflect the excitability of a sub-population of output neurons; resting EEG power and measures combining TMS and electroencephalography (TMS-EEG) might represent a more thorough reflection of cortical excitability. The aim of the present study was to verify the robustness of several predictors of cTBS response, such as I wave recruitment and baseline MEP amplitude, and to test cTBS after-effects on multiple neurophysiologic measurements such as MEP, resting EEG power, local mean field power (LMFP), TMS-related spectral perturbation (TRSP), and inter-trial phase clustering (ITPC). As a result, we were not able to confirm either the expected decrease of MEP amplitude after cTBS or the ability of I wave recruitment and MEP amplitude to predict the response to cTBS. Resting EEG power, LMFP, TRSP, and ITPC showed a more consistent trend toward a decrease after cTBS. Overall, our data suggest that the effect of cTBS on corticospinal excitability is variable and difficult to predict with common electrophysiologic markers, while its effect might be clearer when probed with combined TMS and EEG.

Effects of pulse width, waveform and current direction in the cortex: A combined cTMS-EEG study

BACKGROUND the influence of pulse width, pulse waveform and current direction on transcranial magnetic stimulation (TMS) outcomes is of critical importance. However, their effects have only been investigated indirectly with motor-evoked potentials (MEP). By combining TMS and EEG it is possible to examine how these factors affect evoked activity from the cortex and compare that with the effects on MEP. OBJECTIVE we used a new controllable TMS device (cTMS) to vary systematically pulse width, pulse waveform and current direction and explore their effects on global and local TMS-evoked EEG response. METHODS In 19 healthy volunteers we measured (1) resting motor threshold (RMT) as an estimate of corticospinal excitability; (2) global mean field power (GMFP) as an estimate of global cortical excitability; and (3) local mean field power (LMFP) as an estimate of local cortical excitability. RESULTS RMT was lower with monophasic posterior-to-anterior (PA) pulses that have a longer pulse width (p < 0.001). After adjusting for the individual motor threshold of each pulse type we found that (a) GMFP was higher with monophasic pulses (p < 0.001); (b) LMFP was higher with longer pulse width (p = 0.015); (c) early TEP polarity was modulated depending on the current direction (p = 0.01). CONCLUSIONS Despite normalizing stimulus intensity to RMT, we found that local and global responses to TMS vary depending on pulse parameters. Since EEG responses can vary independently of the MEP, titrating parameters of TMS in relation to MEP threshold is not a useful way of ensuring that a constant set of neurons is activated within a cortical area.