A transcranial magnetic stimulation study of inhibitory deficits in the motor cortex in patients with schizophrenia

It has been proposed that inhibitory deficits play a crucial role in the pathophysiological process of schizophrenia as suggested by post-mortem, neuropsychological and neurophysiological evidence. We hypothesised that patients with schizophrenia would demonstrate abnormalities of cortical inhibition in the motor cortex with single and paired pulse transcranial magnetic stimulation (TMS). Patients with DSM-IV schizophrenia (n=22) and normal volunteers (n=21) participated in the study. Electromyographic recordings from the abductor pollicis brevis (APB) muscle were made during focal TMS stimulation to the contra-lateral motor cortex. The threshold intensity to produce a motor response, the size of the motor evoked potential, the duration of the silent period, and the cortical inhibition and facilitation to paired pulse TMS were measured. The patient group demonstrated a reduction in length of the silent period and a reduction in cortical inhibition with paired stimuli. No changes were found in motor threshold, motor evoked potential size, or cortical facilitation. The study demonstrated deficits of cortical inhibition in the motor cortex of patients with schizophrenia. These deficits appear to be of cortical origin. Their relationship to dysfunction in other cortical networks requires further elucidation.     

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.     

2011 CCNP Young Investigator Award paper: Inhibition of the cortex using transcranial magnetic stimulation in psychiatric populations: current and future directions

Several lines of evidence suggest that deficits in γ-aminobutyric acid (GABA) inhibitory neurotransmission are implicated in the pathophysiology of schizophrenia, bipolar disorder, major depressive disorder and obsessive–compulsive disorder. Cortical inhibition refers to a neurophysiological process, whereby GABA inhibitory interneurons selectively attenuate pyramidal neurons. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to measure cortical inhibition, excitability and plasticity in the cortex. These measures were traditionally specific to the motor cortex, which is an important limitation when nonmotor neurophysiological processes are of primary interest. Recently, TMS has been combined with electroencephalography (EEG) to derive such measurements directly from the cortex. This review focuses on neurophysiological studies related to inhibitory and excitatory TMS paradigms, linking dysfunctional GABAergic neurotransmission to disease states. We review evidence that suggests cortical inhibition deficits among psychiatric populations and demonstrate how each disorder has a specific neurophysiological response to treatment. We conclude by discussing the future directions of TMS combined with EEG, demonstrating the potential to identify biological markers of neuropsychiatric disorders.     

Motor Cortical Excitability Assessed by Transcranial Magnetic Stimulation in Psychiatric Disorders: A Systematic Review

BackgroundTranscranial magnetic stimulation (TMS) is a popular neurostimulation technique suitable for the investigation of inhibitory and facilitatory networks in the human motor system. In the last 20 years, several studies have used TMS to investigate cortical excitability in various psychiatric disorders, leading to a consequent improvement in pathophysiological understanding. However, little is known about the overlap and specificity of these findings across these conditions.ObjectiveTo provide a systematic review of TMS studies (1985–2013) focusing on motor cortical excitability in dementia, schizophrenia, affective disorders (major depression and bipolar), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), Tourette Syndrome (TS), substance abuse (alcohol, cocaine, cannabis, nicotine) and other disorders (borderline personality disorder, posttraumatic stress disorder (PTSD)).MethodsSystematic literature-based review.ResultsAcross disorders, patients displayed a general pattern of cortical disinhibition, while the most consistent results of reduced short-interval intracortical inhibition could be found in schizophrenia, OCD and Tourette Syndrome. In dementia, the most frequently reported finding was reduced short-latency afferent inhibition as a marker of cholinergic dysfunction.ConclusionsThe results of this systematic review indicate a general alteration in motor cortical inhibition in mental illness, rather than disease-specific changes. Changes in motor cortical excitability provide insight that can advance understanding of the pathophysiology underlying various psychiatric disorders. Further investigations are needed to improve the diagnostic application of these parameters.     

Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation

BACKGROUND: Cortical inhibition (CI) deficits have been proposed as a pathophysiologic mechanism in schizophrenia. This study employed 3 transcranial magnetic stimulation (TMS) paradigms to assess CI in patients with schizophrenia. Paired-pulse TMS involves stimulating with a lower-intensity pulse a few milliseconds before a higher-intensity pulse, thereby inhibiting the size of the motor evoked potential produced by the higher-intensity pulse. In the cortical silent period paradigm, inhibition is reflected by the silent period duration (ie, the duration of electromyographic activity cessation following a TMS-induced motor evoked potential). Transcallosal inhibition involves stimulation of the contralateral motor cortex several milliseconds prior to stimulation of the ipsilateral motor cortex, inhibiting the size of the motor evoked potential produced by ipsilateral stimulation. METHODS: We measured CI using these 3 paradigms in 15 unmedicated patients with schizophrenia (14 medication-naive and 1 medication-free for longer than 1 year) (13 were in the transcallosal inhibition paradigm), 15 medicated patients with schizophrenia (11 taking olanzapine, 1 risperidone, 1 quetiapine, 1 methotrimeprazine + perphenazine, 1 quetiapine + loxapine), and 15 healthy controls. RESULTS: Unmedicated patients demonstrated significant CI deficits compared with healthy controls across all inhibitory paradigms whereas medicated patients did not (at all inhibitory intervals, paired-pulse TMS: controls = 59.9%, medicated = 44.3%, unmedicated = 28.7%; cortical silent period: controls = 55.0 milliseconds, medicated = 60.4 milliseconds, unmedicated = 39.7 milliseconds; transcallosal inhibition: controls = 33.6%, medicated = 23.7%, unmedicated = 10.4%; P<.05). CONCLUSIONS: These results suggest that schizophrenia is associated with deficits in CI and that antipsychotic medications may increase CI.     

Applications of transcranial magnetic stimulation (TMS) in child and adolescent psychiatry

Transcranial magnetic stimulation (TMS) is emerging as a new treatment and neurophysiological research tool for psychiatric disorders. Recent publications suggest that this modality will also serve as a treatment and research tool in child and adolescent psychiatry. Current reports on therapeutic trials of repetitive transcranial magnetic stimulation (rTMS) in adolescents have primarily focused on depression. However, other pilot work involves the treatment of attention-deficit/hyperactivity disorder (ADHD), autism and schizophrenia. Neurophysiological studies typically utilize single and paired-pulse TMS paradigms which index cortical excitability and inhibition. Initial studies have focused on ADHD, autism, and depression. General knowledge regarding TMS among child and adolescent psychiatrists is lacking. The aim of this review is to provide an overview of TMS in the context of child and adolescent psychiatry, discuss recent therapeutic and neurophysiological studies, and examine relevant ethical considerations.     

Transcranial Magnetic Stimulation in the investigation and treatment of schizophrenia: a review

Transcranial Magnetic Stimulation (TMS) is a non-invasive method of stimulating the brain that is increasingly being used in neuropsychiatric research and clinical psychiatry. This review examines the role of TMS in schizophrenia research as a diagnostic and a therapeutic resource. After a brief overview of TMS, we describe the application of TMS to schizophrenia in studies of cortical excitability and inhibition, and we discuss the potential confounding role of neuroleptic medications. Based on these studies, it appears that some impairment of cortical inhibition may be present in schizophrenic subjects. We then review attempts to employ TMS for treating different symptoms of schizophrenia. Some encouraging results have been obtained, such as the reduction of auditory hallucinations after slow TMS over auditory cortex and an improvement of psychotic symptoms after high frequency TMS over left prefrontal cortex. However, these results need to be confirmed using better placebo conditions. Future studies are likely to employ TMS in combination with functional brain imaging to examine the effects produced by the stimulated area on activity in other brain regions. Such studies may reveal impaired effective connectivity between specific brain areas, which could identify these regions as targets for selective stimulation with therapeutic doses of TMS.     

Inhibition of the cortex using transcranial magnetic stimulation in psychiatric populations: current and future directions

Several lines of evidence suggest that deficits in γ-aminobutyric acid (GABA) inhibitory neurotransmission are implicated in the pathophysiology of schizophrenia, bipolar disorder, major depressive disorder and obsessive-compulsive disorder. Cortical inhibition refers to a neurophysiological process, whereby GABA inhibitory interneurons selectively attenuate pyramidal neurons. Transcranial magnetic stimulation (TMS) represents a noninvasive technique to measure cortical inhibition, excitability and plasticity in the cortex. These measures were traditionally specific to the motor cortex, which is an important limitation when nonmotor neurophysiological processes are of primary interest. Recently, TMS has been combined with electroencephalography (EEG) to derive such measurements directly from the cortex. This review focuses on neurophysiological studies related to inhibitory and excitatory TMS paradigms, linking dysfunctional GABAergic neurotransmission to disease states. We review evidence that suggests cortical inhibition deficits among psychiatric populations and demonstrate how each disorder has a specific neurophysiological response to treatment. We conclude by discussing the future directions of TMS combined with EEG, demonstrating the potential to identify biological markers of neuropsychiatric disorders.     

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.     

Consensus paper of the WFSBP Task Force on Biological Markers: Criteria for biomarkers and endophenotypes of schizophrenia part I: Neurophysiology

The neurophysiological components that have been proposed as biomarkers or as endophenotypes for schizophrenia can be measured through electroencephalography (EEG) and magnetoencephalography (MEG), transcranial magnetic stimulation (TMS), polysomnography (PSG), registration of event-related potentials (ERPs), assessment of smooth pursuit eye movements (SPEM) and antisaccade paradigms. Most of them demonstrate deficits in schizophrenia, show at least moderate stability over time and do not depend on clinical status, which means that they fulfil the criteria as valid endophenotypes for genetic studies. Deficits in cortical inhibition and plasticity measured using non-invasive brain stimulation techniques seem promising markers of outcome and prognosis. However the utility of these markers as biomarkers for predicting conversion to psychosis, response to treatments, or for tracking disease progression needs to be further studied.     

Reduced cortical inhibition in first-episode schizophrenia

Disturbances in cortico-cortical and cortico-subcortical circuits in schizophrenia have been described by previous neuroimaging and electrophysiological studies. Transcranial magnetic stimulation (TMS) provides a neurophysiological technique for the measurement of cortical excitability, especially of the motoneural system. Previous studies using paired-pulse TMS to investigate short-interval cortical inhibition (SICI) and intracortical facilitation (ICF), mainly involving chronic schizophrenia patients, have been inconsistent and only one study in first-episode patients has been conducted so far. We assessed SICI (interstimulus interval, ISI, 3 milliseconds, ms) and ICF (ISI 7 ms) in 29 first-episode schizophrenia patients (FE-SZ) with limited exposure to antipsychotic treatment against measures of 28 healthy controls (HC). Amplitudes of motor evoked potentials (MEPs) were measured from the left and right first dorsal interosseus muscle (FDI). The conditioning stimulus was set at 80% intensity of resting motor threshold (RMT) and the test stimulus (TS) was set at an intensity that produced an MEP amplitude of about 1 mV. For SICI conditions, FE-SZ demonstrated significantly higher MEP amplitudes from left motor cortex (right FDI) compared to HC, and for MEPs from right motor cortex (left FDI) a similar trend was observable (FE-SZ 41% vs. HC 21% of TS, p=0.017 for left motor cortex, and FE-SZ 59% vs. HC 31% of TS, p=0.059 for right motor cortex; Mann-Whitney U-test). No significant difference in MEPs could be detected for ICF on either hemisphere. In addition, there was no difference in left and right RMT comparing patients and control subjects. Our result of a reduced SICI in a large sample of well characterized first-episode schizophrenia patients suggests that a GABAergic deficit may be involved in schizophrenic pathophysiology, already early in the disease course, supporting the intracortical dysconnectivity hypothesis.     

Somatotopic blocking of sensation with navigated transcranial magnetic stimulation of the primary somatosensory cortex

We demonstrate that spatially accurate and selective stimulation is crucial when cortical functions are studied by the creation of temporary lesions with transcranial magnetic stimulation (TMS). Previously, the interpretation of the TMS results has been hampered by inaccurate knowledge of the site and strength of the induced electric current in the brain. With a Navigated Brain Stimulation (NBS) system, which provides real-time magnetic resonance image (MRI)-guided targeting of the TMS-induced electric field, we found that TMS of a spatially restricted cortical S1 thenar area is sufficient to abolish sensation from a weak electric stimulation of the corresponding skin area. We demonstrate that with real-time navigation, TMS can be repeatably directed at millimeter-level precision to a target area defined on the MRI. The stimulation effect was temporally and spatially specific: the greatest inhibition of sensation occurred when TMS was applied 20 ms after the cutaneous test stimulus and the TMS effect was sensitive to 8-13 mm displacements of the induced electric field pattern. The results also indicate that TMS selectively to S1 is sufficient to abolish perception of cutaneous stimulation of the corresponding skin area.     

La stimulation magnétique transcrânienne répétée : vers un nouvel outil thérapeutique en psychiatrie

Transcranial magnetic stimulation (TMS) is a technique used for investigation of the tics, when repeatedly applied, has a therapeutic potential, notably in psychiatry. The physiological and neuroendocrine effects induced by repeated TMS treatment in an animal model are similar to those caused by antidepressants in man. In particular, TMS appears to modify the release of neuromediators (serotonin, dopamine) involved in depressive states. Because of these properties, repeated TMS has been proposed as a potential treatment for depression. Several randomized studies have now evaluated its effects in this regard and for the most part show statistically significant results, although the findings are sometimes modest at the clinical level. However, the therapeutic effects depend on various parameters which are generally not taken into account, such as cortical excitability and regional cerebral metabolism, Apart from depression, the trials focus on a limited number of disorders. In schizophrenia, the use of TMS has permitted abnormalities in cortical excitability to be demonstated and an improvement of the symptomatology, e.g. by suppressing the perception of auditory hallucinations. Parkinson?s disease, nervous twitch and Gilles de la Tourette syndome, obsessive-compulsive disorders and mania have also been the focus of promising albeit preliminary trials. Wider randomized studies should now assess the different parameters involved in the therapeutic effects, so that the treatment procedure can be optimized and the physiopathology of various neuropsychiatric disorders better understood.     

Cortical inhibition in motor and non-motor regions: a combined TMS-EEG study

A number of studies using paired pulse transcranial magnetic stimulation (TMS) have demonstrated that cortical inhibition (CI) of the motor cortex can be recorded and also gauged through surface electromyography. However, recording CI from other brain regions that are more directly related with the pathophysiology of some neurologic and psychiatric disorders (e.g., dorsolateral prefrontal cortex (DLPFC) in schizophrenia) was previously fraught with technical difficulties. This study was therefore designed to examine, through a combination of TMS with EEG, whether CI could be measured directly from the motor cortex, DLPFC, and another non-motor region. To index CI, long interval cortical inhibition (LICI; a TMS paradigm) was used in the motor cortex and DLPFC in 14 healthy subjects, and in the parietal lobe in 5 of those subjects. In the motor cortex, LICI resulted in a significant suppression in mean cortical evoked activity on EEG (37.31 +/- 47.51%). In the DLPFC, LICI resulted in a significant suppression (32.45 +/- 47.86%) in mean cortical evoked activity and did not correlate with LICI in the motor cortex although they did not significantly differ. In the parietal lobe, LICI resulted in significant suppression (47.76 +/- 44.70%) in mean cortical evoked activity. In conclusion, CI in the dorsolateral prefrontal cortex, motor cortex and parietal cortex were similar at 120% of motor threshold. These data suggest that CI can be recorded by combining TMS with EEG and may facilitate future research attempting to ascertain the role of CI in the pathophysiology of several neurologic and psychiatric disorders.     

Changes of inhibitory interneurons during transcallosal stimulations

Summary The present study was performed in order to determine the influence of ipsilateral transcranial magnetic stimulations (TMS) on the silent period evoked by contralateral cortical stimulations. Ipsilateral TMS preceded the contralateral magnetic or electrical cortex stimulation by 0–50ms. In all subjects, the duration of the silent period was decreased in interstimulus intervals of 20–30ms when using magnetic ipsi- and contralateral stimuli. No change in the silent period was seen with ipsilateral magnetic and contralateral electrical stimulations. Decreases of motor evoked potential amplitudes were an inconsistant phenomenon.The results indicate that ipsilateral TMS in activate inhibitory cortical interneurons, probably via transcallosal pathways. Different time courses and different degrees of inhibition indicate that motor excitation and inhibition may be mediated by different neuronal circuits.     

Transcranial magnetic stimulation techniques in clinical investigation

Transcranial magnetic stimulation (TMS) is a technique that can activate cortical motor areas and the corticospinal tract without causing the subject discomfort. Since TMS was introduced, numerous applications of the technique have been developed for the evaluation of neurologic diseases. Standard TMS applications (central motor conduction time, threshold and amplitude of motor evoked potentials) allow the evaluation of motor conduction in the CNS. Conduction studies provide specific information in neurologic conditions characterized by clinical and subclinical upper motor neuron involvement. In addition, they have proved useful in monitoring motor abnormalities and the recovery of motor function. TMS also gives information on the pathophysiology of the processes underlying the various clinical conditions. More complex TMS applications (paired-pulse stimulation, silent period, ipsilateral silent period, input-output curve, and evaluation of central fatigue) allow investigation into the mechanisms of diseases causing changes in the excitability of cortical motor areas. These techniques are also useful in monitoring the effects of neurotrophic drugs on cortical activity. TMS applications have an important place among the investigative tools to study patients with motor disorders.     

The contribution of transcranial magnetic stimulation in the diagnosis and in the management of dementia

Transcranial magnetic stimulation (TMS) is emerging as a promising tool to non-invasively assess specific cortical circuits in neurological diseases. A number of studies have reported the abnormalities in TMS assays of cortical function in dementias. A PubMed-based literature review on TMS studies targeting primary and secondary dementia has been conducted using the key words “transcranial magnetic stimulation” or “motor cortex excitability” and “dementia” or “cognitive impairment” or “memory impairment” or “memory decline”. Cortical excitability is increased in Alzheimer’s disease (AD) and in vascular dementia (VaD), generally reduced in secondary dementias. Short-latency afferent inhibition (SAI), a measure of central cholinergic circuitry, is normal in VaD and in frontotemporal dementia (FTD), but suppressed in AD. In mild cognitive impairment, abnormal SAI may predict the progression to AD. No change in cortical excitability has been observed in FTD, in Parkinson’s dementia and in dementia with Lewy bodies. Short-interval intracortical inhibition and controlateral silent period (cSP), two measures of gabaergic cortical inhibition, are abnormal in most dementias associated with parkinsonian symptoms. Ipsilateral silent period (iSP), which is dependent on integrity of the corpus callosum is abnormal in AD. While single TMS measure owns low specificity, a panel of measures can support the clinical diagnosis, predict progression and possibly identify earlier the “brain at risk”. In dementias, TMS can be also exploited to select and evaluate the responders to specific drugs and, it might become a rehabilitative tool, in the attempt to restore impaired brain plasticity.     

Neural noise and cortical inhibition in schizophrenia

BackgroundNeural information processing is subject to noise and this leads to variability in neural firing and behavior. Schizophrenia has been associated with both more variable motor control and impaired cortical inhibition, which is crucial for excitatory/inhibitory balance in neural commands.HypothesisIn this study, we hypothesized that impaired intracortical inhibition in motor cortex would contribute to task-related motor noise in schizophrenia.MethodsWe measured variability of force and of electromyographic (EMG) activity in upper limb and hand muscles during a visuomotor grip force-tracking paradigm in patients with schizophrenia (N = 25), in unaffected siblings (N = 17) and in healthy control participants (N = 25). Task-dependent primary motor cortex (M1) excitability and inhibition were assessed using transcranial magnetic stimulation (TMS).ResultsDuring force maintenance patients with schizophrenia showed increased variability in force and EMG, despite similar mean force and EMG magnitudes. Compared to healthy controls, patients with schizophrenia also showed increased M1 excitability and reduced cortical inhibition during grip-force tracking. EMG variability and force variability correlated negatively to cortical inhibition in patients with schizophrenia. EMG variability also correlated positively to negative symptoms. Siblings had similar variability and cortical inhibition compared to controls. Increased EMG and force variability indicate enhanced motor noise in schizophrenia, which relates to reduced motor cortex inhibition.ConclusionThe findings suggest that excessive motor noise in schizophrenia may arise from an imbalance of M1 excitation/inhibition of GABAergic origin. Thus, higher motor noise may provide a useful marker of impaired cortical inhibition in schizophrenia.     

Motor cortex excitability in restless legs syndrome

BACKGROUND AND PURPOSE: A review of the literature shows that the transcranial magnetic stimulation (TMS) is a useful neurophysiological tool to investigate the pathophysiology of the restless legs syndrome (RLS). In this study we used TMS to define motor cortical excitability in RLS subjects. PATIENTS AND METHODS: Six RLS patients and two healthy control subjects underwent TMS (single and paired) examination using two protocols: (1) the evaluation of motor cortical excitability changes occurring at various times after a repetitive finger movement task; (2) the evaluation of the time course of intracortical motor activity tested with pairs of magnetic stimuli applied at inter-stimulus intervals of 1-6 ms. RESULTS: Subjects affected by RLS do not show the normal fluctuations of motor cortical excitability usually found after a bimanual finger movement task. The intracortical inhibition was reduced in RLS subjects. CONCLUSIONS: These results compared with the other studies suggest a modification in the central circuits and suppose a reduction or alteration in the cortical plasticity.     

BOLD fMRI response to direct stimulation (transcranial magnetic stimulation) of the motor cortex shows no decline with age

Previous studies using BOLD fMRI to examine age-related changes in cortical activation used tasks that relied on peripheral systems to activate the brain. They were unable to distinguish between alterations due to age-related changes in the periphery and actual changes in cortical physiology. Transcranial magnetic stimulation (TMS), which allows direct, noninvasive stimulation of cortical neurons, was interleaved with BOLD fMRI to study 6 young and 5 old subjects. Three different tasks were compared: direct stimulation by TMS, indirect active stimulation produced by a motor task, and indirect passive stimulation produced by hearing the TMS coil discharge.Direct neuronal stimulation by TMS produced similar fMRI signal increases in both groups, suggesting that cortical physiology itself may not necessarily decline with age.