Pulse Transcranial Magnetic Stimulation Research Articles

Cortical responses to noninvasive perturbations enable individual brain fingerprinting

BackgroundIn recent years, it has become increasingly apparent that characterizing individual brain structure, connectivity and dynamics is essential for understanding brain function in health and disease. However, the majority of neuroimaging and brain stimulation research has characterized human brain function by averaging measurements from groups of subjects and providing population-level inferences. External perturbations applied directly to well-defined brain regions can reveal distinctive information about the state, connectivity and dynamics of the human brain at the individual level. ObjectivesIn a series of studies, we aimed to characterize individual brain responses to MRI-guided transcranial magnetic stimulation (TMS), and explore the reproducibility of the evoked effects, differences between brain regions, and their individual specificity. MethodsIn the first study, we administered single pulses of TMS to both anatomically (left dorsolateral prefrontal cortex- ‘L-DLPFC’, left Intra-parietal lobule- ‘L-IPL) and functionally (left motor cortex- ‘L-M1’, right default mode network- ‘R-DMN, right dorsal attention network- ‘R-DAN’) defined cortical nodes in the frontal, motor, and parietal regions across two identical sessions spaced one month apart in 24 healthy volunteers. In the second study, we extended our analyses to two independent data sets (n = 10 in both data sets) having different sham-TMS protocols. ResultsIn the first study, we found that perturbation-induced cortical propagation patterns are heterogeneous across individuals but highly reproducible within individuals, specific to the stimulated region, and distinct from spontaneous activity. Most importantly, we demonstrate that by assessing the spatiotemporal characteristics of TMS-induced brain responses originating from different cortical regions, individual subjects can be identified with perfect accuracy. In the second study, we demonstrated that subject specificity of TEPs is generalizable across independent data sets and distinct from non-transcranial neural responses evoked by sham-TMS protocols. ConclusionsPerturbation-induced brain responses reveal unique “brain fingerprints” that reflect causal connectivity dynamics of the stimulated brain regions, and may serve as reliable biomarkers of individual brain function.

Reliability of the TMS-conditioned monosynaptic reflex in the flexor carpi radialis muscle

A subthreshold pulse of transcranial magnetic stimulation (TMS) on the motor cortex can modulate the amplitude of the monosynaptic reflex (H-reflex) elicited in the flexor carpi radialis (FCR) muscle, a method known as TMS-conditioning of the H-reflex. The purpose of this study was to establish the intersession reliability of this method over the course of three sessions. Eleven healthy participants received either peripheral nerve stimulation (PNS), TMS or a combination of the two. The intensity of the PNS stimuli was set to evoke a monosynaptic response (H-reflex) corresponding to 10 % of the maximum motor response (Mmax), HM10 %. The conditioning effect of TMS on the monosynaptic reflex was assessed by delivering subthreshold cortical pulses at different conditioning-test intervals (from -7 ms to 7 ms) from peripheral nerve stimulation. The first interval at which facilitation could be observed was deemed early facilitation (EF). Using intraclass correlation coefficients (ICCs), we found excellent reliability for Mmax amplitudes (ICC = 0.98), HM10 % amplitudes (ICC = 0.85) and TMS-conditioned H-reflexes recorded at the interval following EF (EF + 2 ms) (ICC = 0.87). Good reliability (ICCs ranging from 0.67 to 0.77) was found for the other conditioning-test intervals. We conclude that TMS-conditioned H-reflexes are reliable parameters to assess the excitability of corticospinal circuits.

Network-level macroscale structural connectivity predicts propagation of transcranial magnetic stimulation

Information processing in the brain is mediated by structural white matter pathways and is highly dependent on topological brain properties. Here we combined transcranial magnetic stimulation (TMS) with high-density electroencephalography (EEG) and Diffusion Weighted Imaging (DWI), specifically looking at macroscale connectivity to understand whether regional, network-level or whole-brain structural properties are more responsible for stimulus propagation. Neuronavigated TMS pulses were delivered over two individually defined nodes of the default mode (DMN) and dorsal attention (DAN) networks in a group of healthy subjects, with test-retest reliability assessed 1-month apart. TMS-evoked activity was predicted by the modularity and structural integrity of the stimulated network rather than the targeted region(s) or the whole-brain connectivity, suggesting network-level structural connectivity as more relevant than local and global brain properties in shaping TMS signal propagation. The importance of network structural connectome was unveiled only by evoked activity, but not resting-state data. Future clinicals interventions might enhance target engagement by adopting DWI-guided, network-focused TMS.

Modeling motor-evoked potentials from neural field simulations of transcranial magnetic stimulation

ObjectiveTo develop a population-based biophysical model of motor-evoked potentials (MEPs) following transcranial magnetic stimulation (TMS). MethodsWe combined an existing MEP model with population-based cortical modeling. Layer 2/3 excitatory and inhibitory neural populations, modeled with neural-field theory, are stimulated with TMS and feed layer 5 corticospinal neurons, which also couple directly but weakly to the TMS pulse. The layer 5 output controls mean motoneuron responses, which generate a series of single motor-unit action potentials that are summed to estimate a MEP. ResultsA MEP waveform was generated comparable to those observed experimentally. The model captured TMS phenomena including a sigmoidal input–output curve, common paired pulse effects (short interval intracortical inhibition, intracortical facilitation, long interval intracortical inhibition) including responses to pharmacological interventions, and a cortical silent period. Changes in MEP amplitude following theta burst paradigms were observed including variability in outcome direction. ConclusionsThe model reproduces effects seen in common TMS paradigms. SignificanceThe model allows population-based modeling of changes in cortical dynamics due to TMS protocols to be assessed in terms of changes in MEPs, thus allowing a clear comparison between population-based modeling predictions and typical experimental outcome measures.

Expected TMS excites the motor system less effectively than unexpected stimulation

The brain's response to sensory input is modulated by prediction. For example, sounds that are produced by one's own actions, or those that are strongly predicted by environmental cues, elicit an attenuated N1 component in the auditory evoked potential. It has been suggested that this form of sensory attenuation to stimulation produced by one's own actions is the reason we are unable to tickle ourselves. Here we examined whether the neural response to direct stimulation of the brain is attenuated by prediction in a similar manner. Transcranial magnetic stimulation (TMS) applied over primary motor cortex can be used to gauge the excitability of the motor system. Motor-evoked potentials (MEPs), elicited by TMS and measured in peripheral muscles, are larger when actions are being prepared and smaller when actions are voluntarily suppressed. We tested whether the amplitude of MEPs was attenuated under circumstances where the TMS pulse can be reliably predicted, even though control of the relevant motor effector was never required. Self-initiation of the TMS pulse and reliable cuing of the TMS pulse both produced attenuated MEP amplitudes, compared to those generated programmatically in an unpredictable manner. These results suggest that predictive coding may be governed by domain-general mechanisms responsible for all forms predictive learning. The findings also have important methodological implications for designing TMS experiments that control for the predictability of TMS pulses.

Simultaneous Transcranial Magnetic Stimulation and Functional Magnetic Resonance Imaging: Aspects of Technical Implementation

The simultaneous transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) offers a unique opportunity to non-invasively stimulate brain circuits while simultaneously monitoring changes in brain activity. However, to take advantage of this multimodal technique, some technical issues need to be considered/addressed. In this work, we evaluated technical issues associated with the setup and utilization of this multimodal tool, such as the use of a large single-channel radio frequency (rf) coil, and the artifacts induced by TMS when interleaved with the echo-planar imaging (EPI) sequence. We demonstrated that good image quality can be achieved with this rf coil and that the adoption of axial imaging orientation in conjunction with a safe interval of 100 ms, between the TMS pulse and imaging acquisition, is a suitable combination to eliminate potential image artifacts when using the combined TMS-fMRI technique in 3-T MRI scanners.

Brain Response Induced with Paired Associative Stimulation Is Related to Repetition Suppression of Motor Evoked Potential.

Repetition suppression (RS), i.e., the reduction of neuronal activity upon repetition of an external stimulus, can be demonstrated in the motor system using transcranial magnetic stimulation (TMS). We evaluated the RS in relation to the neuroplastic changes induced by paired associative stimulation (PAS). An RS paradigm, consisting of 20 trains of four identical suprathreshold TMS pulses 1 s apart, was assessed for motor-evoked potentials (MEPs) in 16 healthy subjects, before and following (at 0, 10, and 20 min) a common PAS protocol. For analysis, we divided RS into two components: (1) the ratio of the second MEP amplitude to the first one in RS trains, i.e., the “dynamic” component, and (2) the mean of the second to fourth MEP amplitudes, i.e., the “stable” component. Following PAS, five subjects showed change in the dynamic RS component. However, nearly all the individuals (n = 14) exhibited change in the stable component (p < 0.05). The stable component was similar between subjects showing increased MEPs and those showing decreased MEPs at this level (p = 0.254). The results suggest the tendency of the brain towards a stable state, probably free from the ongoing dynamics, following PAS.

Impaired short-term visual paired associative plasticity in patients with migraine between attacks.

A common experimental neurophysiological method to study synaptic plasticity is pairing activity of somatosensory afferents and motor cortical circuits, so-called paired associative stimulation (PAS). Dysfunctional inhibitory and excitatory PAS mechanisms within the sensorimotor system were described in patients with migraine without aura (MO) between attacks. We have recently observed that the same bidirectional PAS rules also apply to the visual system. Here, we have tested whether dysfunctioning associative plasticity might characterize the visual system of patients with MO. In 14 patients with MO between attacks and in 15 healthy volunteers, we performed a previously validated visual PAS (vPAS) protocol by coupling 90 black-and-white checkerboard reversals with low-frequency transcranial magnetic stimulation pulses over the occipital cortex at 2 interstimulus intervals of -25/+25 ms around the visual-evoked potential (VEP) P1 latency. We recorded VEPs (600 sweeps) before, immediately after, and 10 min after each vPAS session. We analysed VEP N1-P1 amplitude and delayed habituation. Although vPAS-25 significantly enhanced and vPAS + 25 reduced VEP amplitude habituation in healthy volunteers, the same protocols did not significantly change VEP amplitude habituation in MO between attacks. We provide evidence for lack of habituation enhancing and habituation suppressing visual PAS mechanisms within the visual system in interictal migraine. This finding, in combination with those previously obtained studying the sensorimotor system, leads us to argue that migraine disease-related dysrhythmic thalamocortical activity prevents the occurrence of physiological bidirectional synaptic plasticity induced by vPAS.

Effects of tDCS on spontaneous spike activity in a healthy ambulatory rat model

BackgroundThe neurophysiological effects of transcranial direct current stimulation (tDCS) are typically described with respect to changes in cortical excitability, defined by using transcranial magnetic stimulation pulses to determine changes in motor evoked potentials. However, how individual cortical neurons change firing patterns under the influence of tDCS is largely unknown. While the relatively weak currents produced in the brain by tDCS may not be adequate to directly depolarize neuronal membranes, ongoing neuronal activity, combined with subthreshold changes in membrane polarization might be sufficient to alter the threshold for neural firing. ObjectivesThe purpose of this study was to determine the effects of tDCS on neurophysiological activity in motor cortex of freely moving, healthy rats. MethodsIn nine healthy, ambulatory rats, each studied under six different stimulation conditions varying in current intensity (maximum current density = 39.8 A/m2 at 0.4 mA) and polarity (anodal or cathodal), neural activity was analyzed in response to 20 min of tDCS applied through bone screws insulated from the overlying scalp. ResultsAfter analysis of 480 multi-unit channels that satisfied a rigid set of neurophysiological criteria, we found no systematic effect of tDCS stimulation condition on firing rate or firing pattern. Restricting the analysis to the most responsive units, subtle, but statistically significant changes occurred only in the highest intensity anodal condition. ConclusionsThese results confirm that at current densities typically used in human or animal tDCS studies, observed effects of tDCS are likely to occur via mechanisms other than direct neuronal depolarization.

The Vividness of Motor Imagery Is Correlated With Corticospinal Excitability During Combined Motor Imagery and Action Observation.

The present study aimed to investigate the relationship between motor imagery (MI) assessment (ability and quality) and neurophysiological assessment [transcranial magnetic stimulation (TMS)-induced motor-evoked potentials (MEPs)] during combined MI and action observation (AO; MI + AO). Sixteen subjects completed an MI task playing the piano with both hands, and neurophysiological assessment was performed during the MI task. The Movement Imagery Questionnaire-Revised was adopted to evaluate MI ability, while the visual analogue scale (VAS) was adopted to evaluate MI quality. A TMS pulse was delivered during the MI task, and MEPs were subsequently recorded in the abductor pollicis brevis (APB). We found a significant positive correlation between the VAS score and the TMS-induced MEPs (ρ = 0.497, p < 0.001). These findings suggest that the VAS score could potentially reflect the corticospinal excitability during MI + AO, particularly in complex MI tasks.

Enabling and promoting walking rehabilitation by paired associative stimulation after incomplete paraplegia: a case report

IntroductionPaired associative stimulation (PAS) is a combination of transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) and induces plastic changes in the human corticospinal tract. We have previously shown that PAS consisting of TMS pulses given at 100% of stimulator output and high-frequency PNS is beneficial for motor rehabilitation of patients with a chronic incomplete spinal cord injury (SCI). The therapeutic possibilities of this PAS variant for walking rehabilitation of paraplegic patients are unexplored.Case presentationA 47-year old man with traumatic incomplete paraplegia (AIS D, neurological level T7) received PAS to his left leg for 3 months at 12 months post injury (PAS1) and for an additional 3 months at 24 months post injury (PAS2). The right leg had normal AIS scores and was not stimulated. Before PAS, the patient was nonambulatory, could not stand without weight support, and was consequently not eligible for conventional walking rehabilitation. After PAS1, the patient could stand for 1.5 min and take 13 steps (24 steps in follow up) on parallel bars without weight support and was enrolled into conventional walking rehabilitation. He achieved independent walking ability with a rollator. During PAS2, walking distance increased 2.4 times faster than during the preceding year. The left leg AIS score and spinal cord independence measure mobility subscore increased. No adverse effects were detected.DiscussionThis is the first report of PAS with a high-frequency peripheral component that enabled and promoted walking rehabilitation. Together with previous reports on this technique, this result encourages further research into its therapeutic potential and mechanism.

Extinguishing Exogenous Attention via Transcranial Magnetic Stimulation

Orienting covert exogenous (involuntary) attention to a target location improves performance in many visual tasks [1, 2]. It is unknown whether early visual cortical areas are necessary for this improvement. To establish a causal link between these areas and attentional modulations, we used transcranial magnetic stimulation (TMS) to briefly alter cortical excitability and determine whether early visual areas mediate the effect of exogenous attention on performance. Observers performed an orientation discrimination task. After a peripheral valid, neutral, or invalid cue, two cortically magnified gratings were presented, one in the stimulated region and the other in the symmetric region in the opposite hemifield. Observers received two successive TMS pulses around their occipital pole while the stimuli were presented. Shortly after, a response cue indicated the grating whose orientation observers had to discriminate. The response cue either matched-target stimulated-or did not match-distractor stimulated-the stimulated side. Grating contrast was varied to measure contrast response functions (CRF) for all combinations of attention and TMS conditions. When the distractor was stimulated, exogenous attention yielded response gain-performance benefits in the valid-cue condition and costs in the invalid-cue condition compared with the neutral condition at the high contrast levels. Crucially, when the target was stimulated, this response gain was eliminated. Therefore, TMS extinguished the effect of exogenous attention. These results establish a causal link between early visual areas and the modulatory effect of exogenous attention on performance.

Low-intensity repetitive paired associative stimulation targeting the motor hand area at theta frequency causes a lasting reduction in corticospinal excitability

ObjectiveSub-motor threshold 5 Hz repetitive paired associative stimulation (5 Hz-rPAS25ms) produces a long-lasting increase in corticospinal excitability. Assuming a spike-timing dependent plasticity-like (STDP-like) mechanism, we hypothesized that 5 Hz-rPAS at a shorter inter-stimulus interval (ISI) of 15 ms (5 Hz-rPAS15ms) would exert a lasting inhibitory effect on corticospinal excitability. Methods20 healthy volunteers received two minutes of 5 Hz-rPAS15ms. Transcranial magnetic stimulation (TMS) was applied over the motor hotspot of the right abductor pollicis brevis muscle at 90% active motor threshold. Sub-motor threshold peripheral electrical stimulation was given to the left median nerve 15 ms before each TMS pulse. We assessed changes in mean amplitude of the unconditioned motor evoked potential (MEP), short-latency intracortical inhibition (SICI), intracortical facilitation (ICF), short-latency afferent inhibition (SAI), long-latency afferent inhibition (LAI), and cortical silent period (CSP) before and for 60 minutes after 5-Hz rPAS15ms. ResultsSubthreshold 5-Hz rPAS15ms produced a 20–40% decrease in mean MEP amplitude along with an attenuation in SAI, lasting at least 60 minutes. A follow-up experiment revealed that MEP facilitation was spatially restricted to the target muscle. ConclusionsSubthreshold 5-Hz rPAS15ms effectively suppresses corticospinal excitability. Together with the facilitatory effects of subthreshold 5-Hz rPAS25ms (Quartarone et al., J Physiol 2006;575:657–670), the results show that sub-motor threshold 5-Hz rPAS induces STDP-like bidirectional plasticity in the motor cortex. SignificanceThe results of the present study provide a new short-time paradigm of long term depression (LTD) induction in human sensory-motor cortex.

Effects of transcranial magnetic stimulation on the performance of the activities of daily living and attention function after stroke: a randomized controlled trial

Objective: We aimed to interrogate the effects of transcranial magnetic stimulation (TMS) on the performance in activities of daily living (ADL) and attention function after stroke. Design: Randomized controlled trial. Setting: Inpatient rehabilitation hospital. Subjects: We randomized 62 stroke patients with attention dysfunction who were randomly assigned into two groups, and two dropped out from each group. The TMS group (n = 29) and a sham group (n = 29), whose mean (SD) was 58.12 (6.72) years. A total of 33 (56.9%) patients had right hemisphere lesion while the rest 25 (43.1%) patients had left hemisphere lesion. Interventions: Patients in the TMS group received 10 Hz, 700 pulses of TMS, while those in the sham group received sham TMS for four weeks. All the participants underwent comprehensive cognitive training. Main measures: At baseline, and end of the four-week treatment, the performance in the activities of daily living was assessed by Functional Independence Measure (FIM). On the other side, attention dysfunction was screened by Mini-Mental State Examination (MMSE), while the attention function was assessed by the Trail Making Test-A (TMT-A), Digit Symbol Test (DST) and Digital Span Test (DS). Results: Our data showed a significant difference in the post-treatment gains in motor of Functional Independence Measure (13.00 SD 1.69 vs 4.21 SD 2.96), cognition of Functional Independence Measure (4.69 SD 1.56 vs 1.52 SD 1.02), total of Functional Independence Measure (17.69 SD 2.36 vs 5.72 SD 3.12), Mini-Mental State Examination (3.07 SD 1.36 vs 1.21 SD 0.62), time taken in Trail Making Test-A (96.67 SD 25.18 vs 44.28 SD 19.45), errors number in Trail Making Test-A (2.72 SD 1.03 vs 0.86 SD 1.03), Digit Symbol Test (3.76 SD 1.09 vs 0.76 SD 0.87) or Digital Span Test (1.69 SD 0.54 vs 0.90 SD 0.72) between the TMS group and the sham group (P < 0.05). Conclusions: Taken together, we demonstrate that TMS improves the performance in the activities of daily living and attention function in patients with stroke.

A Causal Role of Area hMST for Self-Motion Perception in Humans.

Previous studies in the macaque monkey have provided clear causal evidence for an involvement of the medial-superior-temporal area (MST) in the perception of self-motion. These studies also revealed an overrepresentation of contraversive heading. Human imaging studies have identified a functional equivalent (hMST) of macaque area MST. Yet, causal evidence of hMST in heading perception is lacking. We employed neuronavigated transcranial magnetic stimulation (TMS) to test for such a causal relationship. We expected TMS over hMST to induce increased perceptual variance (i.e., impaired precision), while leaving mean heading perception (accuracy) unaffected. We presented 8 human participants with an optic flow stimulus simulating forward self-motion across a ground plane in one of 3 directions. Participants indicated perceived heading. In 57% of the trials, TMS pulses were applied, temporally centered on self-motion onset. TMS stimulation site was either right-hemisphere hMST, identified by a functional magnetic resonance imaging (fMRI) localizer, or a control-area, just outside the fMRI localizer activation. As predicted, TMS over area hMST, but not over the control-area, increased response variance of perceived heading as compared with noTMS stimulation trials. As hypothesized, this effect was strongest for contraversive self-motion. These data provide a first causal evidence for a critical role of hMST in visually guided navigation.

Cortico-cortical connectivity: the road from basic neurophysiological interactions to therapeutic applications.

Transcranial magnetic stimulation (TMS) based methods are emerging as a unique approach to evaluate in real-time brain electrical activity in healthy and pathological conditions. By applying TMS pulses in two different bran areas within a short temporal frame of few milliseconds, it is possible to investigate their physiological interactions. These paradigms, collectively termed dual-site TMS, have been inspired by Professor John Rothwell's work, based on the idea that applying a conditioning stimulus over a cortical area may activate putative pathways projecting onto a second target area, thus providing a unique opportunity to test the causal effects between interconnected brain areas. This review highlights the most important features of dual-coil TMS protocols, mainly pioneered in Professor John Rothwell's lab. In the first part, I reviewed development of dual-site TMS protocols leading to the discovery of a distributed system of short-latency interactions within the human parieto-frontal network, likely mediated by direct anatomical pathways. In the second part, the physiological role of these dual-site TMS evoked pathways is considered, describing how these functional interactions are not fixed but vary depending on the brain activation, the condition and on the precise time window in which they are explored. Then, I reviewed recent advances showing that the repeated coupling of interconnected neuronal populations, by means of dual-coil TMS, is able to induce spike-time-dependent plasticity and to determine selective potentiation of physiological connectivity between two human brain regions. Finally, the therapeutic implications of these novel discoveries are discussed, pointing to multi-site TMS as a novel tool to identify early features of synaptic dysfunctions, to monitor disease progression and potentially to provide novel therapeutic approaches by reshaping plasticity in different neurological and psychiatric conditions.

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

ObjectiveAdvanced 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. MethodsTMS-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). ResultsiTBS 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. ConclusionsThese 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. SignificanceThis may have important implications for the early detection of cognitive decline and dementia.

Motor potential evoked by transcranial magnetic stimulation depends on the placement protocol of recording electrodes: a pilot study

Objective: There seems to be no consensus in the literature regarding the protocol of surface electromyography (sEMG) electrode placement for recording motor evoked potentials (MEP) in transcranial magnetic stimulation (TMS) applications. Thus, the aim of this study was to investigate the effect on the MEP amplitude bytwo different protocols for electrode placement. Methods: sEMG electrodes were placed on three upper arm muscles (biceps brachii, flexor carpi radialis, and flexor pollicis brevis) of six right-handed subjects following two different protocols (1 and 2), which varied according to the interelectrode distance and location relative to the muscle. TMS pulses were applied to the hotspot of biceps brachii, while sEMGwas recorded from the two protocols and for each muscle simultaneously. Main Results: Greater MEP amplitudes were obtained for Protocol 1 compared to Protocol 2 (P < 0.05). Significance: Different electrode placement protocols may result in distinct MEP amplitudes, which should be taken into account when adjusting the intensity on single and repetitive TMS sessions.

The impact of TMS and PNS frequencies on MEP potentiation in PAS with high-frequency peripheral component.

Paired associative stimulation (PAS) combines transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) to induce plastic changes in the corticospinal tract. PAS employing single 0.2-Hz TMS pulses synchronized with the first pulse of 50–100 Hz PNS trains potentiates motor-evoked potentials (MEPs) in a stable manner in healthy participants and enhances voluntary motor output in spinal cord injury (SCI) patients. We further investigated the impact of settings of this PAS variant on MEP potentiation in healthy subjects. In experiment 1, we compared 0.2-Hz vs 0.4-Hz PAS. In experiment 2, PNS frequencies of 100 Hz, 200 Hz, and 400 Hz were compared. In experiment 3, we added a second TMS pulse. When compared with 0.4-Hz PAS, 0.2-Hz PAS was significantly more effective after 30 minutes (p = 0.05) and 60 minutes (p = 0.014). MEP potentiation by PAS with 100-Hz and 200-Hz PNS did not differ. PAS with 400-Hz PNS was less effective than 100-Hz (p = 0.023) and 200-Hz (p = 0.013) PNS. Adding an extra TMS pulse rendered PAS strongly inhibitory. These negative findings demonstrate that the 0.2-Hz PAS with 100-Hz PNS previously used in clinical studies is optimal and the modifications employed here do not enhance its efficacy.

M11. ALTERED TRANSCRANIAL MAGNETIC STIMULATION ELECTROENCEPHALOGRAPHIC MARKERS IN SCHIZOPHRENIA

BackgroundCortical inhibition is a neurophysiological process in which cortical gamma-aminobutyric acid (GABA) inhibitory interneurons modulate the activity of pyramidal neurons in the cerebral cortex. Multiple lines of evidence, including neurophysiological and neuropathological, report that individuals with schizophrenia have deficits in cortical inhibition. Combining transcranial magnetic stimulation (TMS) with electroencephalography is a reliable approach to measure inhibitory processes in the cortex. The overall waveform produced by TMS-EEG may index cortical reactivity as a whole and previous investigations have linked the N45 component peak and the N100 component peak with GABA-A and GABA-B inhibitory neurotransmission, respectively. The aim of this study was to stimulate the DLPFC with TMS and examine resultant differences in the TMS-EEG waveform peaks between patients with schizophrenia and healthy subjects. We hypothesized that individuals with schizophrenia will have smaller TMS-evoked potentials, specifically the amplitudes of the N100 and N45 components, those previously related to GABA-ergic inhibition.MethodsWe applied TMS over the left DLPFC and recorded EEG activity in 48 healthy subjects (mean age: 33.8±5.3) and 46 patients with schizophrenia (mean age: 43.3±6.4). Monophasic TMS pulses were administered using a 7-cm figure-of-8 coil, and two Magstim 200 stimulators connected via a Bistim module. Single pulse TMS was administered over the left DLPFC with 100 total pulses, which were delivered every 5s. Resultant waveforms were extracted and analyzed through custom MATLAB scripts. The TMS-evoked potential waveform was examined through Global Mean Field Amplitude (GMFA) analysis of waveform peaks in each the two groups. Normality of the distribution of each variable was assessed and a Mann Whitney U test was then performed for each variable of interest to assess differences between groups.ResultsIndividuals in the schizophrenia group demonstrated smaller measures of cortical inhibition in the DLPFC. Specifically, smaller amplitudes of the N45 (U=724.00, p=0.004) and N100 peaks (U=831.00, p=0.039), although the overall AUC of the waveform did not differ between groups (U=969.00, p=0.307). Further analysis is underway to examine medication and symptom cluster effects.DiscussionThese results demonstrate novel findings of deficits in both GABA-A and GABA-B associated measures of cortical inhibition as indexed by single pulse TMS-EEG. This reinforces previous evidence from different research modalities demonstrating overall GABAergic inhibitory deficits in schizophrenia, and specifically provides new support which confirms recent findings of aberrant GABA-Aergic inhibitory neurotransmission in schizophrenia.