Bidirectional effects on interhemispheric resting‐state functional connectivity induced by excitatory and inhibitory repetitive transcranial magnetic stimulation

Several recent studies using functional magnetic resonance imaging (fMRI) have shown that repetitive transcranial magnetic stimulation (rTMS) affects not only brain activity in stimulated regions but also resting‐state functional connectivity (RSFC) between the stimulated region and other remote regions. However, these studies have only demonstrated an effect of either excitatory or inhibitory rTMS on RSFC, and have not clearly shown the bidirectional effects of both types of rTMS. Here, we addressed this issue by performing excitatory and inhibitory quadripulse TMS (QPS), which is considered to exert relatively large and long‐lasting effects on cortical excitability. We found that excitatory rTMS (QPS with interstimulus intervals of 5 ms) decreased interhemispheric RSFC between bilateral primary motor cortices, whereas inhibitory rTMS (QPS with interstimulus intervals of 50 ms) increased interhemispheric RSFC. The magnitude of these effects on RSFC was significantly correlated with that of rTMS‐induced effects on motor evoked potential from the corresponding muscle. The bidirectional effects of QPS were also observed in the stimulation over prefrontal and parietal association areas. These findings provide evidence for the robust bidirectional effects of excitatory and inhibitory rTMSs on RSFC, and raise a possibility that QPS can be a powerful tool to modulate RSFC. Hum Brain Mapp 35:1896–1905, 2014. © 2013 Wiley Periodicals, Inc .     

Myoclonus and transcranial magnetic stimulation

The neural dysfunction at the origin of myoclonus may locate at various anatomical levels within the central nervous system, including the motor cortices. Transcranial magnetic stimulation (TMS) can be used to assess the balance between inhibitory and excitatory processes involved in the regulation of motor cortex activity and thereby, may be of value to determine the pathophysiological mechanisms of myoclonus. Using paired-pulse paradigms with various interstimulus intervals, TMS studies showed that intracortical inhibition (ICI) was reduced in progressive myoclonic epilepsy (PME). In contrast, ICI was decreased only for short interstimulus intervals in patients with juvenile myoclonic epilepsy (JME). Transcallosal inhibition and sensorimotor integration were also both altered in PME but not in JME. Actually, the loss of inhibitory regulation within the central nervous system might represent an intrinsic mechanism of myoclonus, whether of epileptic origin or not. Finally, the other TMS parameters of excitability (motor threshold, silent period, intracortical facilitation) were found normal in most cases of myoclonus. According to these observations, it was quite conceivable that the application of repetitive trains of TMS (rTMS) at inhibitory low-frequency (around 1 Hz) might be able to relieve myoclonus by restoring ICI. A few reported cases illustrate the efficacy of low-frequency rTMS to alleviate myoclonic symptoms. Therapeutic-like perspectives are opened for rTMS in these forms of myoclonus that are related to motor cortical hyperexcitability secondary to the loss of ICI.     

Magnetic stimulation of the central and peripheral nervous systems

Since 1985, when the technique of transcranial magnetic stimulation (TMS) was first developed, a wide range of applications in healthy and diseased subjects has been described. Comprehension of the physiological basis of motor control and cortical function has been improved. Modifications of the basic technique of measuring central motor conduction time (CMCT) have included measurement of the cortical silent period, paired stimulation in a conditioning test paradigm, repetitive transcranial magnetic stimulation (rTMS), and peristimulus time histograms (PSTH). These methods allow dissection of central motor excitatory versus inhibitory interplay on the cortical motor neuron and its presynaptic connections at the spinal cord, and have proven to be powerful investigational techniques. TMS can be used to assess upper and lower motor neuron dysfunction, monitor the effects of many pharmacological agents, predict stroke outcome, document the plasticity of the motor system, and assess its maturation and the effects of aging, as well as perform intraoperative monitoring. The recent use of rTMS in the treatment of depression and movement disorders is novel, and opens the way for other potential therapeutic applications.     

Motor cortical excitability studied with repetitive transcranial magnetic stimulation in patients with Huntington's disease.

OBJECTIVE: TMS techniques have provided controversial information on motor cortical function in Huntington's disease (HD). We investigated the excitability of motor cortex in patients with HD using repetitive transcranial magnetic stimulation (rTMS). METHODS: Eleven patients with HD, and 11 age-matched healthy subjects participated in the study. The clinical features of patients with HD were evaluated with the United Huntington's Disease Rating Scale (UHDRS). rTMS was delivered with a Magstim Repetitive Magnetic Stimulator through a figure-of-8 coil placed over the motor area of the first dorsal interosseus (FDI) muscle. Trains of 10 stimuli were delivered at 5 Hz frequency and suprathreshold intensity (120% resting motor threshold) with the subjects at rest and during voluntary contraction of the target muscle. RESULTS: In healthy subjects at rest, rTMS produced motor evoked potentials (MEPs) that increased in amplitude over the course of the trains. Conversely in patients, rTMS left the MEP size almost unchanged. In both groups, during voluntary contraction rTMS increased the silent period (SP) duration. CONCLUSIONS: Because rTMS modulates motor cortical excitability by activating cortical excitatory and inhibitory interneurons these findings suggest that in patients with HD the excitability of facilitatory intracortical interneurones is decreased. SIGNIFICANCE: We suggest that depressed excitability of the motor cortex in patients with HD reflects a disease-related weakening of cortical facilitatory mechanisms.     

Suprathreshold 0.3 Hz repetitive TMS prolongs the cortical silent period: potential implications for therapeutic trials in epilepsy.

OBJECTIVE: To investigate the after-effects of 0.3 Hz repetitive transcranial magnetic stimulation (rTMS) on excitatory and inhibitory mechanisms at the primary motor cortex level, as tested by single-pulse TMS variables. METHODS: In 9 healthy subjects, we studied a wide set of neurophysiological and behavioral variables from the first dorsal interosseous before (Baseline), immediately after (Post 1), and 90 min after (Post 2) the end of a 30 min long train of 0.3 Hz rTMS delivered at an intensity of 115% resting motor threshold (RMT). Variables under investigation were: maximal M wave, F wave, and peripheral silent period after ulnar nerve stimulation; RMT, amplitude and stimulus-response curve of the motor evoked potential (MEP), and cortical silent period (CSP) following TMS; finger-tapping speed. RESULTS: The CSP was consistently lengthened at both Post 1 and Post 2 compared with Baseline. The other variables did not change significantly. CONCLUSIONS: These findings suggest that suprathreshold 0.3 Hz rTMS produces a relatively long-lasting enhancement of the inhibitory mechanisms responsible for the CSP. These effects differ from those, previously reported, of 0.9-1 Hz rTMS, which reduces the excitability of the circuits underlying the MEP and does not affect the CSP. This provides rationale for sham-controlled trials aiming to assess the therapeutic potential of 0.3 Hz rTMS in epilepsy.     

Reduction of cortical excitability and increase of thalamic activity in a low-frequency rTMS treatment for chronic tinnitus

Low-frequency repetitive transcranial magnetic stimulation (rTMS) has received increasing attention for the treatment of tinnitus, but its therapeutic mechanisms are unclear. We performed low-frequency rTMS treatment for a patient with chronic tinnitus and examined changes of cortical excitability and cerebral blood flow using paired-pulse TMS and single-photon emission computed tomography. After the rTMS treatment, tinnitus loudness was decreased, cortical excitability was reduced, and blood flow in the thalamus was increased. Our results suggest that low-frequency rTMS treatment reduces tinnitus loudness by an inhibitory effect on the cortical excitability and a remote activation effect on the thalamus through the corticothalamic networks.     

Stimulus intensity and coil characteristics influence the efficacy of rTMS to suppress cortical excitability.

OBJECTIVE: Low-frequency repetitive transcranial magnetic stimulation (rTMS) can reduce cortical excitability. Here we examined whether inhibitory after effects of low-frequency rTMS are influenced by stimulus intensity, the type of TMS coil and re-afferent sensory stimulation. METHODS: In fifteen healthy volunteers, we applied 900 biphasic pulses of 1Hz rTMS to the left primary motor cortex (M1) at an intensity that was 10% below or 15% above resting motor threshold. For rTMS, we used two different figure-of-eight shaped coils (Magstim or Medtronic coil) attached to the same stimulator. We recorded motor evoked potentials (MEPs) evoked with the same set-up used for rTMS (MEP-rTMS) before and twice after rTMS. Using a different TMS setup, we also applied monophasic pulses to the M1 in order to assess the effects of rTMS on corticospinal excitability, intracortical paired-pulse excitability and the duration of the cortical silent period (CSP). In a control experiment, the same measurements were performed after 15min of 1Hz repetitive electrical nerve stimulation (rENS) of the right ulnar nerve. RESULTS: Analysis of variance revealed an interaction between intensity, coil and time of measurement (p<0.035), indicating that the effect of 1Hz rTMS on MEP-rTMS amplitude depended on the intensity and the type of coil used for rTMS. Suppression of corticospinal excitability was strongest after suprathreshold 1Hz rTMS with the Medtronic coil (p<0.01 for both post-rTMS measurements relative to pre-intervention baseline). Regardless of the type of coil, suprathreshold but not subthreshold rTMS transiently prolonged the CSP and attenuated paired-pulse facilitation. Suprathreshold 1Hz rENS also induced a short-lasting inhibition of MEP-rTMS. CONCLUSIONS: Both the stimulation intensity and the type of TMS coil have an impact on the after effects of 1Hz rTMS. Re-afferent feedback activation may at least in part account for the stronger suppression of corticospinal excitability by suprathreshold 1Hz rTMS. SIGNIFICANCE: These data should be considered when rTMS is used as a therapeutic means.     

Contribution of transcranial magnetic stimulation in restless legs syndrome: pathophysiological insights and therapeutical approaches

Transcranial magnetic stimulation (TMS) may offer a reliable means to characterize significant pathophysiologic and neurochemical aspects of restless legs syndrome (RLS). Namely, TMS has revealed specific patterns of changes in cortical excitability and plasticity, in particular dysfunctional inhibitory mechanisms and sensorimotor integration, which are thought to be part of the pathophysiological mechanisms of RLS rather than reflect a non-specific consequence of sleep architecture alteration.If delivered repetitively, TMS is able to transiently modulate the neural activity of the stimulated and connected areas. Some studies have begun to therapeutically use repetitive TMS (rTMS) to improve sensory and motor disturbances in RLS. High-frequency rTMS applied over the primary motor cortex or the supplementary motor cortex, as well as low-frequency rTMS over the primary somatosensory cortex, seem to have transient beneficial effects. However, further studies with larger patient samples, repeated sessions, an optimized rTMS setup, and clinical follow-up are needed in order to corroborate preliminary results.Thus, we performed a systematic search of all the studies that have used TMS and rTMS techniques in patients with RLS.     

Intensity-dependent effects of 1 Hz rTMS on human corticospinal excitability.

OBJECTIVES: This study explored whether the effects of repetitive transcranial magnetic stimulation (rTMS) on corticospinal excitability are dependent on the stimulation intensity and examined the effect of rTMS on inhibitory function.METHODS: Nine normal volunteers received 15min of 1Hz rTMS at 85 and 115% of the resting motor threshold (RMT). Cortical excitability was measured before and after rTMS.RESULTS: rTMS at both intensities produced an increase in the RMT but only 115% stimulation reduced the size of motor evoked potentials (MEPs). rTMS had no effects on the cortical silent period or cortical inhibition measured with paired pulse TMS.CONCLUSIONS: The effects of 1Hz rTMS on motor cortex excitability are partially dependent on stimulus intensity and the effects of rTMS on motor thresholds and MEP size may differ.     

Non-linear input-output properties of the cortical networks mediating TMS-induced short-interval intracortical inhibition in humans

The effects of transcranial magnetic stimulation (TMS) on post-discharge histograms of single motor units in the first dorsal interosseous have been tested to estimate the input-output properties of cortical network-mediating short-interval intracortical inhibition (SICI) to pyramidal cells of the human primary motor cortex. SICI was studied using the paired pulse paradigm (2-ms interval): test TMS intensity was varied to evoke peaks of different size in post-discharge histograms, reflecting the corticospinal excitatory post-synaptic potential in the relevant spinal motoneuron, and conditioning TMS intensity was constant (0.6 × the resting motor threshold). Navigated brain stimulation was used to monitor the coil position. A linear relationship was observed between test peak size and test TMS intensity, reflecting linear summation of excitatory inputs induced by TMS. SICI was estimated using the difference between conditioned (produced by the paired pulses) and test peaks (produced by the isolated test pulse). Although the conditioning intensity (activating cortical inhibitory interneurons mediating SICI) was kept constant throughout the experiments, the level of SICI changed with the test peak size, in a non-linear fashion, suggesting that low-threshold cortical neurons (excitatory interneurons/pyramidal cells) are less sensitive to SICI than those of higher threshold. These findings provide the first experimental evidence, under physiological conditions, for non-linear input/output properties of a complex cortical network. Consequently, changes in the recruitment gain of cortical inhibitory interneurons can greatly modify the excitability of pyramidal cells and their response to afferent inputs.     

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.Key words: GABA, cortical inhibition, NMDA, connectivity     

Repetitive transcranial magnetic stimulation (rTMS): insights into the treatment of Parkinson's disease by cortical stimulation.

Repetitive transcranial magnetic stimulation (rTMS) is a potent tool that can be used to modify activity of targeted cortical areas. Significant clinical effects have been obtained in patients with Parkinson's disease (PD) by stimulating different cortical regions with rTMS at inhibitory (low) or excitatory (high) frequency. These effects were thought to result from plastic changes in motor cortical networks. Actually cortical dysfunction has been documented in PD by neuroimaging and neurophysiologic studies showing either hypo- or hyper-activation of various brain areas. In addition, cortical excitability studies using transcranial magnetic stimulation disclosed significant alterations in intracortical facilitatory or inhibitory processes according to the resting state or to phases of movement preparation or execution. These observations clearly support the therapeutic potential of cortical neuromodulation in PD. Motor cortex stimulation could impact on any station within the cortico-basal ganglia-thalamo-cortical loops that are involved in motor control, providing alleviation of parkinsonian symptoms. Depending on the target, cortical stimulation might improve motor performance or other symptoms associated with PD, like depression. Clinical application of rTMS to treat PD patients is limited by the short duration of the effects beyond the time of stimulation, even if long-lasting improvements have been observed after repeated rTMS sessions. In any case, the place of cortical stimulation in the therapeutic management of PD patients remains to be determined, as an alternative or a complementary technique to deep brain stimulation. The rTMS technique could be used to better define the targets and the parameters of stimulation subsequently applied in chronic epidural stimulation.     

Motor cortex stimulation for Parkinson's disease and dystonia: lessons from transcranial magnetic stimulation? A review of the literature

INTRODUCTION: Over the last few years, deep brain stimulation techniques, with targets such as the subthalamic nucleus or the pallidum, have bee found to be beneficial in the treatment of Parkinson's disease and dystonia. Conversely, therapeutic strategies of cortical stimulation have not yet been validated in these diseases, although they are known to be associated with various cortical dysfunctions. Transcranial magnetic stimulation (TMS) is a valuable tool for non-invasive study of the role played by the motor cortex in the pathophysiology of movement disorders, in particular by assessing various cortical excitability determinants using single or paired pulse paradigms. In addition, repetitive TMS (rTMS) trains can be used to study the effects of transient activity changes of a targeted cortical area. BACKGROUND: Studies with TMS revealed significant motor cortex excitability changes, particularly regarding intracortical inhibitory pathways, both in Parkinson's disease and in dystonia, and these changes can be distinguished owing to the resting state or to the phases of movement preparation or execution. However, more specific correlation between electrophysiological features and clinical symptoms remains to be established. In addition, the stimulation of various cortical targets by rTMS protocols applied at low or high frequencies have induced some clear clinical effects. PERSPECTIVES: The TMS effects are and will remain applied in movement disorders to better understand the role played by the motor cortex, to assess various types of treatment and appraise the therapeutic potential of cortical stimulation. CONCLUSION: TMS provides evidence for motor cortex dysfunction in Parkinson's disease or dystonia. Moreover, rTMS results have opened new perspectives for therapeutic strategies of implanted cortical stimulation. By these both aspects, TMS techniques show their usefulness in the assessment of movement disorders.     

Transcranial magnetic stimulation: a new investigational and treatment tool in psychiatry

Transcranial magnetic stimulation (TMS) is a new investigational technique used to explore various neural processes and treat a variety of neuropsychiatric illnesses. The most notable advantage of TMS is its ability to directly stimulate the cortex with little effect on intervening tissue. Single-pulse stimulation techniques can measure cortical inhibition, facilitation, connectivity, reactivity, and cortical plasticity, providing valuable insights into the cortical physiology. Repetitive TMS (rTMS) is currently being used to investigate cognitive processes and as a treatment tool in disorders such as depression and schizophrenia. Both TMS and rTMS are safe and well tolerated. The most serious side effect of high-frequency rTMS is seizures. TMS represents an exciting new frontier in neuroscience research, providing insights into the pathophysiology and treatment of various neuropsychiatric disorders.     

Elevated motor threshold in drug-free, cocaine-dependent patients assessed with transcranial magnetic stimulation.

BACKGROUND: Transcranial magnetic stimulation (TMS) provides a noninvasive method of examining cortical inhibitory and excitatory processes and cortical excitability in awake subjects. There is evidence from clinical and electroencephalographic (EEG) data that cortical excitability may be abnormal in some psychiatric populations. Chronic cocaine abuse influences a number of neurotransmitters that are involved in the excitatory/inhibitory balance of the cerebral cortex. This pilot study was conducted to ascertain the possible utility of TMS in examining cortical excitability in a population of chronic cocaine abusers. METHODS: The right and left motor thresholds of ten cocaine-dependent subjects, according to DSM-IV, and ten normal control subjects were examined using single pulse TMS. RESULTS: The resting motor thresholds resulting from stimulation of the right or the left motor cortical regions were significantly elevated in cocaine-dependent subjects compared with matched control subjects. CONCLUSIONS: These pilot data suggest that chronic cocaine use significantly alters cortical excitability in the direction of increased inhibition or decreased excitability. We hypothesize that this observation reflects adaptation to those effects of cocaine intoxication that promote cortical excitability and seizures.     

A comparative study of the effects of repetitive paired transcranial magnetic stimulation on motor cortical excitability

OBJECTIVES: Various methods of application of repetitive transcranial magnetic stimulation (TMS) have been evaluated for their potential capacity to alter motor cortical excitability. Initial research suggests that the repetitive application of paired TMS pulses (repetitive paired pulse TMS (rppTMS)) may have greater effects on cortical excitability, perhaps through the facilitation of I-wave interaction. We aimed to compare the post-train effects of 15 min trains of rppTMS to investigate the potential therapeutic application of this technique as well as to compare it to a standard high frequency repetitive TMS paradigm. METHODS: Ten normal subjects received three 15 min sessions of rppTMS, 5 Hz high frequency rTMS and sham TMS in randomised order. rppTMS consisted of a single train of 180 pulse pairs (0.2 Hz, 1.5 ms inter-stimulus interval, supra-threshold intensity) administered over 15 min. The rTMS condition involved 750 pulses provided in 5s 5 Hz trains with a 25s inter-train interval at 90% of the RMT. Motor evoked potential size and cortical silent period duration were assessed before and after each session. RESULTS: There were no significant changes in cortical excitability produced by any of the stimulation conditions. Five hertz rTMS produced an increase in cortical silent period duration (p=0.004) which was not affected by rppTMS. CONCLUSIONS: Fifteen minutes trains of 1.5ms rppTMS do not substantially increase post train cortical excitability. Repetitive brief trains of 5Hz rTMS also do not alter excitability but appear to effect cortical inhibition.     

Modulation of motor cortex excitability in obsessive-compulsive disorder: An exploratory study on the relations of neurophysiology measures with clinical outcome

Low-frequency repetitive transcranial magnetic stimulation (rTMS) to supplementary motor area (SMA) showed clinical benefit in obsessive-compulsive disorder (OCD). Here we tested whether clinical improvement was associated with enhanced cortical inhibition as measured by single and paired-pulse TMS variables. In 18 OCD patients receiving 4 weeks of either active or sham rTMS in a double-blind randomized trial, we assessed bilateral resting and active motor thresholds (RMT and AMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). We tested correlations between changes in Yale-Brown Obsessive Compulsive Scale-Self-report (Y-BOCS-SR), Clinical Global Impression-Severity subscale (CGI-S) and cortical excitability measures. Active rTMS increased right hemisphere RMT whose change correlated with Y-BOCS-SR improvement. Baseline RMT hemispheric asymmetry, defined as the difference between left and right hemispheres RMT, and its normalization after active rTMS correlated with Y-BOCS-SR and CGI-S improvements. Active rTMS also increased right hemisphere SICI whose change correlated with Y-BOCS-SR and CGI-S at week 4, and with normalization of baseline RMT hemispheric asymmetry. Treatment-induced changes in cortical excitability measures are consistent with an inhibitory action of SMA rTMS on dysfunctional motor circuits in OCD. Correlations of neurophysiology measures with therapeutic outcome are supportive of the role of SMA in the modulation of OCD symptoms.     

I-wave origin and modulation

The human motor cortex can be activated by transcranial magnetic stimulation (TMS) evoking a high-frequency repetitive discharge of corticospinal neurones. The exact physiologic mechanisms producing the corticospinal activity still remain unclear because of the complexity of the interactions between the currents induced in the brain and the circuits of cerebral cortex, composed of multiple excitatory and inhibitory neurons and axons of different size, location, orientation and function. The aim of current paper is to evaluate whether the main characteristics of the activity evoked by single- and paired-pulse and repetitive TMS, can be accounted by the interaction of the induced currents in the brain with the key anatomic features of a simple cortical circuit composed of the superficial population of excitatory pyramidal neurons of layers II and III, the large pyramidal neurons in layer V, and the inhibitory GABA cells. This circuit represents the minimum architecture necessary for capturing the most essential cortical input-output operations of neocortex. The interaction between the induced currents in the brain and this simple model of cortical circuitry might explain the characteristics and nature of the repetitive discharge evoked by TMS, including its regular and rhythmic nature and its dose-dependency and pharmacologic modulation. The integrative properties of the circuit also provide a good framework for the interpretation of the changes in the cortical output produced by paired and repetitive TMS.     

The diagnostic and therapeutic application of transcranial magnetic stimulation

The functional abnormalities of the central motor structures and its contribution of rigidity, tremor and bradykinesia in Parkinson's disease seem mainly due to the degeneration of the nigro-striatal pathway. Transcranial magnetic stimulation (TMS) of the motor cortex may provide useful data on the pathophysiology of motor dysfunction in Parkinson's disease. Recent reviews on the basic mechanisms of TMS in Parkinson's disease show reduced inhibitory motor network at the cortical and spinal level. The observed changes are thought to be in relation with a dysfunction of subcortico-cortical and subcortico-spinal pathways. The abnormalities of the central motor function seem to be modified by several clinical related factors as prevalence of cardinal Parkinson's disease signs (e.g. rigidity versus tremor or bradykinesia), L-dopa therapy ('on/off' states) and laterality of the Parkinson's disease signs. Observations made using TMS give new pathophysiological insights in functioning of the central motor structures in Parkinson's disease and started new form of TMS - repetitive TMS (rTMS) as a treatment of the Parkinson's disease motor signs. A few studies using rTMS with repetition rate of 0.2, 1, and 5 Hz showed improvement of motor signs in the Parkinson's disease patients. Although these results support the beneficial effects of rTMS on parkinsonian symptoms, long-term studies with large numbers of subjects should be conducted to assess the efficacy of the rTMS on Parkinson's disease in future.     

Reduced plastic brain responses in schizophrenia: a transcranial magnetic stimulation study

BACKGROUND: Abnormalities in brain plasticity, possibly related to abnormal cortical inhibition (CI), have been proposed to underlie the pathophysiology of schizophrenia. Transcranial magnetic stimulation (TMS) provides a dynamic method for non-invasive study of plastic processes in the human brain. We aimed to determine whether patients with schizophrenia would exhibit an abnormal response to repetitive TMS (rTMS) applied to the motor cortex and whether this would relate to deficient cortical inhibition. METHODS: Measures of motor cortical excitability and cortical inhibition were made before and after a single 15-min train of 1-Hz rTMS applied to the motor cortex in medicated and unmedicated patients with schizophrenia as well as healthy controls. RESULTS: All three groups had equal motor cortical excitability prior to rTMS, although both patient groups had a shorter cortical silent period (CSP) and less cortical inhibition than the control group. Cortical excitability, as assessed by motor threshold levels, did not reduce in both medicated and unmedicated patients in response to rTMS as was seen in the control group. Significant differences were also seen between the groups in response to the rTMS for motor-evoked potential (MEP) size and cortical silent period duration. CONCLUSIONS: Both medicated and medication free patients with schizophrenia demonstrated reduced brain responses to rTMS and deficits in cortical inhibition.