Combined Transcranial Magnetic Stimulation Research Articles

Combination of TMS and MRT to understand neurological diseases

Modern neuroimaging techniques, such as structural and functional magnetic resonance imaging (MRI) and non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS) are increasingly used in the neuroscientific research of neurological disorders, such as stroke, tinnitus and movement disorders. These methods offer a non-invasive approach and especially in combination, not only the opportunity to add to the pathophysiological understanding of these disorders but also to provide information about the functional recovery and the natural course of the disease in a predictive way. Based on such knowledge therapeutic approaches can be adapted in a patient-tailored fashion to achieve the best therapeutic effects. Furthermore, these methods might provide additional non-invasive information for neurosurgical interventions reducing perioperative interventional risks.In the present article these aspects will be discussed with a focus on the combination of MRI and TMS especially addressed for the topic of recovery from stroke.

Characterizing Long Interval Cortical Inhibition over the Time-Frequency Domain

ObjectiveLong-interval cortical inhibition (LICI) can be recorded from motor and non-motor regions of the cortex through combined transcranial magnetic stimulation (TMS) with electroencephalography (EEG). This study aimed to evaluate additional dimensions of LICI characteristics over an extended time-frequency and spatial domain. This was done by introducing two alternative measures of LICI signal amplitude: the Discrete Fourier Transform (DFT) and the Hilbert transform (HT). Both approaches estimate signal amplitude not taking into account the phase. In both cases LICI was measured as the difference between the unconditioned and conditioned activity evoked by the test pulse. Finally, we evaluated whether the topographical patterns of single and paired responses differed beyond the expected variations in amplitude.Materials and MethodsLICI was delivered as single and paired pulses to the motor cortex (MC) and dorsolateral prefrontal cortex (DLPFC) in 33 healthy subjects with TMS-EEG.ResultsSignificant differences (p<0.0001) between the unconditioned and conditioned evoked activity were found for both the DLPFC and MC using both methods (i.e., DFT and HT) after correcting for multiple comparisons in the time-frequency domain. The influence of inhibition was found to be significantly larger in space and time than previously considered. Single and paired conditions differ in intensity, but also in their topographic pattern (i.e., the specific spatiotemporal configuration of active sources).ConclusionSimilar results were found by both DFT and HT. The effect of inhibition across the cortex was also found to be complex and extended. In particular, it was found that LICI may be measured with high sensitivity in areas that were relatively distant from the stimulation site, which may have important practical applications. The analysis presented in this study overcomes some limitations of previous studies and could serve as a key reference for future studies examining TMS-indices of inhibition/excitation in healthy and diseased states.

Rapid Relief of Treatment Resistant Depression by Facilitated Ketamine Infusion: A Preliminary Report

Abstract By combining transcranial magnetic stimulation (TMS) with intravenous ketamine therapy, we sought to increase the therapeutic value of TMS and, at the same time, to improve the efficacy of intravenous ketamine therapy among depressed patients previously classified as non-responders. In this preliminary report, we provide evidence for a new and much more reliable method of treating patients with treatment resistant depression. Twenty-eight patients with various degrees of treatment unresponsive depression were treated with a combination of TMS and ketamine infusion. Of these patients, twenty received pretreatment for 3 days to 2 weeks involving intensive (thrice daily) rTMS treatment administered 6 or 7 days/week or priming TMS treatment immediately prior to the combination TMSketamine infusion combination therapy. Eight patients received neither pretreatment nor priming. All of the 28 patients who did fully participate in the first month of treatment experienced relief of psychiatric symptoms, and showed significant psychosocial recovery. In contrast to previous studies examining ketamine or rTMS individually, the positive outcomes presented here suggest a synergistic effect of the combination therapy of TMS and ketamine infusion.

Transcranial magnetic stimulation (TMS)/repetitive TMS in mild cognitive impairment and Alzheimer's disease

Several Transcranial Magnetic Stimulation (TMS) techniques can be applied to noninvasively measure cortical excitability and brain plasticity in humans. TMS has been used to assess neuroplastic changes in Alzheimer's disease (AD), corroborating findings that cortical physiology is altered in AD due to the underlying neurodegenerative process. In fact, many TMS studies have provided physiological evidence of abnormalities in cortical excitability, connectivity, and plasticity in patients with AD. Moreover, the combination of TMS with other neurophysiological techniques, such as high-density electroencephalography (EEG), makes it possible to study local and network cortical plasticity directly. Interestingly, several TMS studies revealed abnormalities in patients with early AD and even with mild cognitive impairment (MCI), thus enabling early identification of subjects in whom the cholinergic degeneration has occurred. Furthermore, TMS can influence brain function if delivered repetitively; repetitive TMS (rTMS) is capable of modulating cortical excitability and inducing long-lasting neuroplastic changes. Preliminary findings have suggested that rTMS can enhance performances on several cognitive functions impaired in AD and MCI. However, further well-controlled studies with appropriate methodology in larger patient cohorts are needed to replicate and extend the initial findings. The purpose of this paper was to provide an updated and comprehensive systematic review of the studies that have employed TMS/rTMS in patients with MCI and AD.

27. Modulation of motor cortex excitability and brain activation in professional pianists during music listening: A combined EEG and TMS study

Neuroimaging studies have reported mirroring motor activation to music listening in musicians. Actual corticospinal modulation remains to be clarified. We tested the motor cortex modulation in pianists while listening to well-known, predictable melodic sequences, using Transcranial Magnetic Stimulation (TMS) and electroencephalography (EEG). Two groups of subjects were studied: pianists (n = 10) and controls (n = 10). Participants listened to a melodic sequence containing the alternating repetition of a scale in two different octaves. Using a circular coil on the vertex, Motor Evoked Potentials (MEP) were recorded bilaterally on both hands at different time points, with 32 channels EEG monitoring. EEG event-related desynchronization (ERD) of the mu rhythm was assessed by comparing its spectral power during listening vs rest. Pianists, not controls, showed modulation of MEPs amplitude of right hand muscles according to the timing of their activation during actual performance. Left sensori-motor frontal mu ERD to the melodic sequence played with the right hand was present in 9 pianists vs 4 control. The dynamic auditory induced motor resonance to music listening observed in pianists suggests the presence of an audio-motor mirror system that can be related to the ability of musician to confer a gestural meaning to well-known melodies.

IS 26. Transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI)

The combination of transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) is a powerful multimodal approach to study human brain function. fMRI uses the blood oxygen level dependent (BOLD) signal to map changes in regional neural activity at high spatial resolution. When TMS is interleaved with fMRI (online approach), it is possible to assess how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. By manipulating the “neural state” of the cortical target area, one can examine how a change in context alters the regional and distributed BOLD response to TMS. TMS and fMRI can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped using fMRI. Alternatively, fMRI can be performed before TMS to localize brain areas that are involved in a given task. The temporospatial activation pattern obtained by neuroimaging can then be used to define the optimal site of stimulation for subsequent TMS. In this lecture, I will address some general methodologic issues that need to be taken into account when combining TMS and fMRI. I will then discuss how the combination of fMRI and TMS can be used to study the selection of actions in the human brain.

P 194. The EEG correlates of the TMS induced EMG silent period in humans

Application of magnetic or electrical stimulation to the motor cortex can result in a period of electromyography (EMG) silence in a tonically active peripheral muscle. This period of EMG silence is referred to as the silent period (SP). The duration of SP shows intersubject variability and reflects the integrity of the cortical and corticospinal pathways. A non-invasive technique for assessing the duration of SP is the combination of Transcranial Magnetic Stimulation (TMS) with EMG. Utilizing TMS-EMG, several studies have reported on the shortening or lengthening of SP in neuropsychiatric disorders such as schizophrenia, bipolar disorder, depression, obsessive compulsive disorder, epilepsy, Parkinson’s disease, and stroke. However, cortical, corticospinal and peripheral components are difficult to disentangle from EMG alone. Here, we use the multimodal neuroimaging technique of TMS-EMG combined with concurrent electroencephalography (EEG) recording to further examine the cortical origin of SP and the cortical oscillatory activity that underlies SP genesis. We demonstrate that the duration of SP is related to the temporal characteristics of the cortical reactivity and the power of low frequency cortical oscillations (1–15 Hz) in both local and remote areas ipsilateral and contralateral to the stimulation site. We illustrate that, compared to EMG, the EEG indices of the SP provide additional information about the brain dynamics and propose that the EEG measures of SP may be used in future clinical and research investigations to more precisely delineate the mechanisms underlying inhibitory impairments.

P 11. Cortical inhibition within motor and frontal regions in alcohol dependence: A TMS–EEG study

Background Preclinical studies suggest that alterations within the frontal cortex play a critical role in the neurophysiology of alcohol dependence. The combination of transcranial magnetic stimulation and electroencephalography (TMS-EEG) allows a direct assessment of cortical excitability and inhibition within the frontal cortex in human subjects. We report the first application of TMS-EEG to measure these indices within the frontal cortices of patients with alcohol dependence. Methods Cortical inhibition was assessed in 12 patients with alcohol dependence and 14 healthy controls through single and paired-pulse transcranial magnetic stimulations (TMS) paradigms delivered to both the frontal and motor cortices. Long interval cortical inhibition (LICI) was used to index inhibition in the frontal cortex. Short intracortical inhibition (SICI) and cortical silent period (CSP) was used to index inhibition, while intracortical facilitation (ICF) measured facilitation, in the motor cortex. Cortical excitability was indexed by the resting motor threshold (RMT) and active motor threshold (AMT). Results The alcohol dependent group demonstrated deficits in LICI across both the left and right dorsolateral prefrontal cortex relative to healthy controls. The alcohol dependent group also exhibited reduced RMT and AMT. In terms of motor cortex inhibition, there were no significant differences in SICI, ICF or CSP, although increased intra-trial-variability in SICI was observed in the alcohol dependent group. Conclusions The current study provides the first direct evidence of reduced cortical inhibition that is specific to the frontal cortex of patients with alcohol dependence. Our study also revealed evidence of altered cortical excitability in the motor cortex of patients with alcohol dependence; however, the utility of using the motor cortex to index cortical alterations related to alcohol dependence remains unclear. Although these findings are preliminary, they provide critical neurophysiological evidence of disrupted cortical excitability within the frontal cortex of alcohol dependent patients.

P 212. A novel high sensitivity MR-device for combined TMS/fMRI experiments

Introduction Studies with simultaneous functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) have become increasingly popular as the combination of these techniques allows investigation of TMS effects on the brain and could help answer unresolved questions concerning causality in fMRI ( Kobayashi, 2003 ). So far, experiments are being performed using rather large, standard MRI head coils, with the TMS positioned between head and MR coil, resulting in poor sensitivity for the MRI experiment, while also preventing visualization of activation spots directly below the TMS focus. Objective To gain sensitivity for combined TMS and fMRI experiments, we developed a dedicated, slim MR coil on a curved, form-fitted surface that can be placed between TMS and the head. This way, the TMS is close enough to the brain to achieve efficient stimulation, and the MR coil can provide far higher sensitivity than in the conventional arrangement due to its proximity to the head. This way, the TMS coil itself does not cause artifacts in the fMRI maps. Materials and methods This dedicated receive coil is designed for 3T MR systems, with a field of view of 15 cm and a target depth of 5.0–7.5 cm. It consists of seven hexagonally arranged loop elements of 6 cm diameter each. To decouple adjacent elements, loops were overlapped. The array is placed on a spherical support with a curvature to fit the average human head. An illustration of the device positioned for investigations in the dorsolateral prefrontal cortex is shown in ( Fig. 1 ). All elements of the MR coil are passively and actively detunable for decoupling from the MR system’s body coil during signal transmission. A second stage matching network ( Reykowski, 1995 ) connects the coil elements to low noise preamplifiers, additionally improving mutual decoupling between array elements. Preamplifiers are not placed directly on the coil, minimizing coil thickness to assure efficient TMS stimulation, and avoiding damage to the preamplifiers by TMS pulses. Results Mutual coupling between elements of the MR coil is below-9 dB for all channels. Additional-20 dB decoupling was achieved by preamplifier decoupling, minimizing noise correlation between elements, and thus, enabling parallel imaging with low g-factors. The dedicated MR coil is well isolated from the transmitting MR body coil, proven by field distortions well below 5%. This avoids image artifacts and ensures patient safety. A gradient echo image of a phantom acquired with one of the seven elements is shown in ( Fig. 2 ), demonstrating the high sensitivity of the basic elements in cortical areas. Conclusion A dedicated 7-channel MR coil array for simultaneous fMRI/TMS measurements is presented. Individual coil elements were efficiently decoupled from each other and from the transmit body coil. Due to the substantial gain in SNR and good isolation between channels, parallel imaging can also be implemented to speed up TMS-fMRI measurements. This novel hardware development will boost sensitivity of fMRI in combined fMRI/TMS experiments, enabling fast and high-resolution fMRI while efficiently and safety stimulating the brain with TMS.

The EEG correlates of the TMS-induced EMG silent period in humans

Application of magnetic or electrical stimulation to the motor cortex can result in a period of electromyography (EMG) silence in a tonically active peripheral muscle. This period of EMG silence is referred to as the silent period (SP). The duration of SP shows intersubject variability and reflects the integrity of cortical and corticospinal pathways. A non-invasive technique for assessing the duration of SP is the combination of Transcranial Magnetic Stimulation (TMS) with EMG. Utilizing TMS–EMG, several studies have reported on the shortening or lengthening of SP in neuropsychiatric disorders such as schizophrenia, bipolar disorder, depression, obsessive compulsive disorder, epilepsy, Parkinson's disease, and stroke. However, cortical, corticospinal and peripheral components are difficult to disentangle from EMG alone. Here, we use the multimodal neuroimaging technique of TMS–EMG combined with concurrent electroencephalography (EEG) recording to further examine the cortical origin of SP and the cortical oscillatory activity that underlies SP genesis. We demonstrate that the duration of SP is related to the temporal characteristics of the cortical reactivity and the power of delta to alpha oscillations in both local and remote areas ipsilateral and contralateral to the stimulation site, and beta oscillations locally. We illustrate that, compared to EMG, the EEG indices of the SP provide additional information about the brain dynamics and propose that the EEG measures of SP may be used in future clinical and research investigations to more precisely delineate the mechanisms underlying inhibitory impairments.

Cortical Inhibition, Excitation, and Connectivity in Schizophrenia: A Review of Insights From Transcranial Magnetic Stimulation

Schizophrenia (SCZ) is a debilitating mental illness with an elusive pathophysiology. Over the last decade, theories emphasizing cortical dysfunction have received increasing attention to explain the heterogeneous symptoms experienced in SCZ. Transcranial magnetic stimulation (TMS) is a noninvasive form of brain stimulation that is particularly suited to probing the fidelity of specific excitatory and inhibitory neuronal populations in conscious humans. In this study, we review the contribution of TMS in assessing inhibitory and excitatory neuronal populations and their long-range connections in SCZ. In addition, we discuss insights from combined TMS and electroencephalography into the functional consequences of impaired excitation/inhibition on cortical oscillations in SCZ.

Repetition suppression in the cortical motor and auditory systems resemble each other – A combined TMS and evoked potential study

Repetition suppression (RS) in cortical sensory systems optimizes the size of neuronal ensemble reacting to repetitive stimuli such as sounds. Recently RS has also been demonstrated to occur with mental imaging of movement. We studied the existence of RS in the motor system using transcranial magnetic stimulation (TMS). Six healthy subjects participated in this study. TMS was focused on the primary motor cortex with neuronavigation and RS was studied by measuring the motor-evoked potentials from the contralateral first dorsal interosseous muscle. At the same time, we measured TMS-induced cortical responses using electroencephalography (EEG). For a comparison baseline, we evaluated RS by recording EEG responses to sounds with the same stimulation protocol as with TMS. Each stimulus train included four identical stimuli repeated at 1-s intervals, and the stimulation trains were repeated at 20-s intervals. The response amplitude was reduced significantly (p<.01) after the first stimulus in all stimulus trains. This suggests that RS may be a general mechanism for adaptation of neuronal population responses in the human cortex.

Combined rTMS to the auditory cortex and prefrontal cortex for tinnitus control in patients with depression: a pilot study

Conclusion: The study showed that combined repetitive transcranial magnetic stimulation (rTMS) on the auditory cortex and prefrontal cortex has more benefit than rTMS on the auditory cortex alone for tinnitus control in patients with depression. Further studies for the most optimal combination of stimulation on both areas are needed. Objective: Recent studies suggest that the neuronal network changes of chronic tinnitus are beyond the auditory pathway. There is increasing evidences for the application of rTMS on multiple brain cortices in addition to the auditory cortex for the treatment of tinnitus. Sequential rTMS was performed on the auditory cortex alone as well as the auditory cortex combined with prefrontal cortex in patients with both chronic tinnitus and depression. Methods: Patients who presented with chronic tinnitus of more than 1 year were enrolled in the present study (seven males, four females; mean age 54 years). To select the site for the rTMS, PET CT was performed. Patients received the first rTMS on the primary auditory cortex for 5 days and on the primary auditory cortex and prefrontal cortex in the second application after tinnitus relapse. The Tinnitus Handicap Inventory (THI), visual analog scale (VAS), and Beck Depression Inventory (BDI) were evaluated before and after rTMS. Results: The mean THI score of the eight patients with depression changed from 77.5 ± 15 to 61.8 ± 20.1 after the second rTMS. There was statistical significance only for the second rTMS. The VAS score changed from 8.6 ± 1.6 to 6.3 ± 1.8 after the first rTMS and from 7.6 ± 2.4 to 4.6 ± 2.7 after the second rTMS, showing statistically significant changes both times. The THI changes after the second rTMS were greater than after the first rTMS, and the changes in VAS score showed a similar pattern. The changes in BDI score, which indicates the severity of depression, showed a variable pattern after rTMS. Patients with mild depression (10≤ BDI score <16, n = 4) showed significant improvement of THI with the second combined rTMS (ΔTHI = 24.5) as compared with the first rTMS on the auditory area (ΔTHI = 6). In contrast, combined rTMS did not show any better improvement on THI (ΔTHI = 6.5) than the first rTMS on the auditory cortex (ΔTHI = 7) in patients without depression (BDI <10, n = 3) and patients with moderate to severe depression (BDI ≥16, n = 4).

TMS-evoked changes in brain-state dynamics quantified by using EEG data

To improve our understanding of the combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) method in general, it is important to study how the dynamics of the TMS-modulated brain activity differs from the dynamics of spontaneous activity. In this paper, we introduce two quantitative measures based on EEG data, called mean state shift (MSS) and state variance (SV), for evaluating the TMS-evoked changes in the brain-state dynamics. MSS quantifies the immediate TMS-elicited change in the brain state, whereas SV shows whether the rate at which the brain state changes is modulated by TMS. We report a statistically significant increase for a period of 100–200 ms after the TMS pulse in both MSS and SV at the group level. This indicates that the TMS-modulated brain state differs from the spontaneous one. Moreover, the TMS-modulated activity is more vigorous than the natural activity.

Mapping the After-effects of Theta Burst Stimulation on the Human Auditory Cortex with Functional Imaging

Auditory cortex pertains to the processing of sound, which is at the basis of speech or music-related processing1. However, despite considerable recent progress, the functional properties and lateralization of the human auditory cortex are far from being fully understood. Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that can transiently or lastingly modulate cortical excitability via the application of localized magnetic field pulses, and represents a unique method of exploring plasticity and connectivity. It has only recently begun to be applied to understand auditory cortical function 2. An important issue in using TMS is that the physiological consequences of the stimulation are difficult to establish. Although many TMS studies make the implicit assumption that the area targeted by the coil is the area affected, this need not be the case, particularly for complex cognitive functions which depend on interactions across many brain regions 3. One solution to this problem is to combine TMS with functional Magnetic resonance imaging (fMRI). The idea here is that fMRI will provide an index of changes in brain activity associated with TMS. Thus, fMRI would give an independent means of assessing which areas are affected by TMS and how they are modulated 4. In addition, fMRI allows the assessment of functional connectivity, which represents a measure of the temporal coupling between distant regions. It can thus be useful not only to measure the net activity modulation induced by TMS in given locations, but also the degree to which the network properties are affected by TMS, via any observed changes in functional connectivity. Different approaches exist to combine TMS and functional imaging according to the temporal order of the methods. Functional MRI can be applied before, during, after, or both before and after TMS. Recently, some studies interleaved TMS and fMRI in order to provide online mapping of the functional changes induced by TMS 5-7. However, this online combination has many technical problems, including the static artifacts resulting from the presence of the TMS coil in the scanner room, or the effects of TMS pulses on the process of MR image formation. But more importantly, the loud acoustic noise induced by TMS (increased compared with standard use because of the resonance of the scanner bore) and the increased TMS coil vibrations (caused by the strong mechanical forces due to the static magnetic field of the MR scanner) constitute a crucial problem when studying auditory processing. This is one reason why fMRI was carried out before and after TMS in the present study. Similar approaches have been used to target the motor cortex 8,9, premotor cortex 10, primary somatosensory cortex 11,12 and language-related areas 13, but so far no combined TMS-fMRI study has investigated the auditory cortex. The purpose of this article is to provide details concerning the protocol and considerations necessary to successfully combine these two neuroscientific tools to investigate auditory processing. Previously we showed that repetitive TMS (rTMS) at high and low frequencies (resp. 10 Hz and 1 Hz) applied over the auditory cortex modulated response time (RT) in a melody discrimination task 2. We also showed that RT modulation was correlated with functional connectivity in the auditory network assessed using fMRI: the higher the functional connectivity between left and right auditory cortices during task performance, the higher the facilitatory effect (i.e. decreased RT) observed with rTMS. However those findings were mainly correlational, as fMRI was performed before rTMS. Here, fMRI was carried out before and immediately after TMS to provide direct measures of the functional organization of the auditory cortex, and more specifically of the plastic reorganization of the auditory neural network occurring after the neural intervention provided by TMS. Combined fMRI and TMS applied over the auditory cortex should enable a better understanding of brain mechanisms of auditory processing, providing physiological information about functional effects of TMS. This knowledge could be useful for many cognitive neuroscience applications, as well as for optimizing therapeutic applications of TMS, particularly in auditory-related disorders.

Mapping the After-effects of Theta Burst Stimulation on the Human Auditory Cortex with Functional Imaging

Auditory cortex pertains to the processing of sound, which is at the basis of speech or music-related processing. However, despite considerable recent progress, the functional properties and lateralization of the human auditory cortex are far from being fully understood. Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that can transiently or lastingly modulate cortical excitability via the application of localized magnetic field pulses, and represents a unique method of exploring plasticity and connectivity. It has only recently begun to be applied to understand auditory cortical function. An important issue in using TMS is that the physiological consequences of the stimulation are difficult to establish. Although many TMS studies make the implicit assumption that the area targeted by the coil is the area affected, this need not be the case, particularly for complex cognitive functions which depend on interactions across many brain regions. One solution to this problem is to combine TMS with functional Magnetic resonance imaging (fMRI). The idea here is that fMRI will provide an index of changes in brain activity associated with TMS. Thus, fMRI would give an independent means of assessing which areas are affected by TMS and how they are modulated. In addition, fMRI allows the assessment of functional connectivity, which represents a measure of the temporal coupling between distant regions. It can thus be useful not only to measure the net activity modulation induced by TMS in given locations, but also the degree to which the network properties are affected by TMS, via any observed changes in functional connectivity. Different approaches exist to combine TMS and functional imaging according to the temporal order of the methods. Functional MRI can be applied before, during, after, or both before and after TMS. Recently, some studies interleaved TMS and fMRI in order to provide online mapping of the functional changes induced by TMS. However, this online combination has many technical problems, including the static artifacts resulting from the presence of the TMS coil in the scanner room, or the effects of TMS pulses on the process of MR image formation. But more importantly, the loud acoustic noise induced by TMS (increased compared with standard use because of the resonance of the scanner bore) and the increased TMS coil vibrations (caused by the strong mechanical forces due to the static magnetic field of the MR scanner) constitute a crucial problem when studying auditory processing. This is one reason why fMRI was carried out before and after TMS in the present study. Similar approaches have been used to target the motor cortex, premotor cortex, primary somatosensory cortex and language-related areas, but so far no combined TMS-fMRI study has investigated the auditory cortex. The purpose of this article is to provide details concerning the protocol and considerations necessary to successfully combine these two neuroscientific tools to investigate auditory processing. Previously we showed that repetitive TMS (rTMS) at high and low frequencies (resp. 10 Hz and 1 Hz) applied over the auditory cortex modulated response time (RT) in a melody discrimination task. We also showed that RT modulation was correlated with functional connectivity in the auditory network assessed using fMRI: the higher the functional connectivity between left and right auditory cortices during task performance, the higher the facilitatory effect (i.e. decreased RT) observed with rTMS. However those findings were mainly correlational, as fMRI was performed before rTMS. Here, fMRI was carried out before and immediately after TMS to provide direct measures of the functional organization of the auditory cortex, and more specifically of the plastic reorganization of the auditory neural network occurring after the neural intervention provided by TMS. Combined fMRI and TMS applied over the auditory cortex should enable a better understanding of brain mechanisms of auditory processing, providing physiological information about functional effects of TMS. This knowledge could be useful for many cognitive neuroscience applications, as well as for optimizing therapeutic applications of TMS, particularly in auditory-related disorders.

Measuring GABAergic Inhibitory Activity with TMS-EEG and Its Potential Clinical Application for Chronic Pain

Chronic pain is debilitating disorder in which the underlying pathophysiology is still unknown. Impaired cortical inhibition is one mechanism that is associated with chronic pain. Cortical inhibition refers to a neurophysiological process in which gamma-aminobutyric acid (GABA) inhibitory interneurons selectively attenuate the activity of pyramidal neurons in the cortex. Previous studies have capitalized on the ability of transcranial magnetic stimulation (TMS) to index cortical inhibition by stimulating the motor cortex and measuring the resulting peripheral motor evoked potentials with electromyography. Chronic pain has been shown to induce changes in cortical inhibition within the motor cortex using TMS. Electroencephalography (EEG) studies also demonstrate that gamma (30-50Hz) oscillations in the prefrontal and somatosensory cortex are associated with the experience of pain. As gamma oscillations are mediated by GABA, the combination of TMS with EEG allows for the examination of the relationship between cortical inhibition, gamma and chronic pain. In this paper, we summarize the evidence of impaired GABAergic and gamma oscillations in chronic pain patients. We then demonstrate TMS-EEG as a reliable method in which to record cortical inhibition directly from the prefrontal cortex to examine the modulatory effect of GABAB receptor inhibition on cortical oscillations. Finally, the modulation of GABA and gamma oscillations with repetitive TMS will be suggested as the possible mechanism through which rTMS exerts its therapeutic effects in the treatment of pain. The aim of this paper, therefore, is to present the TMS-EEG as a potential method through which to better classify, diagnose and treat chronic pain.

Inhibitory deficits in the dorsolateral prefrontal cortex in psychopathic offenders

Often typified as cunning social predators, psychopathic offenders show a persistent pattern of impulsive and reckless behavior, the pathophysiology of which has been related to dysfunction in the dorsolateral prefrontal cortex (DLPFC). That is, the DLPFC is important for the regulatory control of impulses and emotion as well as working memory and psychopathic offenders show impairments in all three dimensions. In the present study, we used combined transcranial magnetic stimulation and electroencephalography to compare the physiology of the DLPFC in 13 psychopathic offenders and 15 healthy subjects vis à vis excitability and inhibition. In addition, working memory performance was measured through the letter–number sequencing test. Results showed that compared to healthy subjects, psychopathic offenders had inhibition not excitability deficits in the DLPFC that was accompanied by deficits in working memory performance. In healthy controls and psychopathic offenders working memory performance correlated with the extent of inhibition over the DLPFC. Taken together, these findings suggest that psychopathic offenders suffer from dysfunctional inhibitory neurotransmission in the DLPFC and impaired working memory which may account for the behavioral impairments associated with this disorder.

Cortical mechanisms of loss of consciousness: insight from TMS/EEG studies.

In a recent series of experiments we recorded the electroencephalogram (EEG) response to a direct cortical stimulation in humans during wakefulness, NREM sleep, REM sleep and anesthesia by means of a combination of transcranial magnetic stimulation (TMS) and high-density EEG (hd-EEG). TMS/hd-EEG measurements showed that, while during wakefulness and REM sleep the brain is able to sustain long-range specific patterns of activation, during NREM sleep and Midazolam-induced anesthesia, when consciousness fades, this ability is lot: the thalamocortical system, despite being active and reactive, either breaks down in causally independent modules (producing a local slow wave), or it bursts into an explosive and non-specific response (producing a global EEG slow wave). We hypothesize that, like spontaneous sleep slow waves, the slow waves triggered by TMS during sleep and anaesthesia are due to bistability between upand down-states in thalamocortical circuits. In this condition, the inescapable occurrence of a silent, down state after an initial activation impairs the ability of thalamocortical circuits to sustain long-range, differentiated patterns of activation, a theoretical requisite for consciousness. According to animal experiments and computer simulations, thalamocortical bistability may result from increased K-currents, from alterations of the balance between excitation and inhibition and from partial cortical de-afferentation. We hypothesize that these factor may play an important role in determining loss, and recovery, of consciousness also in brain-injured subjects. If this is the case, some types of brain lesions may impair information transmission, above and beyond the associated anatomical disconnection, by inducing bistability in portions of the thalamocortical system that are otherwise healthy.

Frontal and parietal theta burst TMS impairs working memory for visual-spatial conjunctions

In tasks that selectively probe visual or spatial working memory (WM) frontal and posterior cortical areas show a segregation, with dorsal areas preferentially involved in spatial (e.g. location) WM and ventral areas in visual (e.g. object identity) WM. In a previous fMRI study [1], we showed that right parietal cortex (PC) was more active during WM for orientation, whereas left inferior frontal gyrus (IFG) was more active during colour WM. During WM for colour-orientation conjunctions, activity in these areas was intermediate to the level of activity for the single task preferred and non-preferred information. To examine whether these specialised areas play a critical role in coordinating visual and spatial WM to perform a conjunction task, we used theta burst transcranial magnetic stimulation (TMS) to induce a functional deficit. Compared to sham stimulation, TMS to right PC or left IFG selectively impaired WM for conjunctions but not single features. This is consistent with findings from visual search paradigms, in which frontal and parietal TMS selectively affects search for conjunctions compared to single features, and with combined TMS and functional imaging work suggesting that parietal and frontal regions are functionally coupled in tasks requiring integration of visual and spatial information. Our results thus elucidate mechanisms by which the brain coordinates spatially segregated processing streams and have implications beyond the field of working memory.