Assessment of Cortical Plasticity in Schizophrenia by Transcranial Magnetic Stimulation

Abualait, Turki; Alzahrani, Sultan; AlOthman, Ahmed; Alhargan, Fahad Abdulah; Altwaijri, Nouf; Khallaf, Rooa; Nasim, Eman; Bashir, Shahid

doi:https://doi.org/10.1155/2021/5585951

Neural Plasticity

On this page

Abstract Introduction Methods Discussion Conclusion Data Availability Conflicts of Interest Authors’ Contributions References Copyright Related Articles

Review Article | Open Access

Volume 2021 | Article ID 5585951 | https://doi.org/10.1155/2021/5585951

Assessment of Cortical Plasticity in Schizophrenia by Transcranial Magnetic Stimulation

Turki Abualait,¹Sultan Alzahrani,²Ahmed AlOthman,²Fahad Abdulah Alhargan,³Nouf Altwaijri,⁴Rooa Khallaf,²Eman Nasim,²and Shahid Bashir²

Academic Editor: Gabriela Delevati Colpo

Received23 Feb 2021

Revised18 Oct 2021

Accepted15 Nov 2021

Published02 Dec 2021

Abstract

Neural plasticity refers to the capability of the brain to modify its structure and/or function and organization in response to a changing environment. Evidence shows that disruption of neuronal plasticity and altered functional connectivity between distinct brain networks contribute significantly to the pathophysiological mechanisms of schizophrenia. Transcranial magnetic stimulation has emerged as a noninvasive brain stimulation tool that can be utilized to investigate cortical excitability with the aim of probing neural plasticity mechanisms. In particular, in pathological disorders, such as schizophrenia, cortical dysfunction, such as an aberrant excitatory-inhibitory balance in cortical networks, altered cortical connectivity, and impairment of critical period timing are very important to be studied using different TMS paradigms. Studying such neurophysiological characteristics and plastic changes would help in elucidating different aspects of the pathophysiological mechanisms underlying schizophrenia. This review attempts to summarize the findings of available TMS studies with diagnostic and characterization aims, but not with therapeutic purposes, in schizophrenia. Findings provide further evidence of aberrant excitatory-inhibitory balance in cortical networks, mediated by neurotransmitter pathways such as the glutamate and GABA systems. Future studies with combining techniques, for instance, TMS with brain imaging or molecular genetic typing, would shed light on the characteristics and predictors of schizophrenia.

1. Introduction

Schizophrenia is a complex chronic mental health disorder characterized by a positive and negative array of symptoms [1]. Diagnosis of schizophrenia is incomplete unless one of the positive symptoms is present: hallucinations, delusions, and disorganized speech or behaviors [2]. Despite numerous research in neuroimaging, epidemiology, and genetics, treatment of schizophrenia is still not optimal, and its exact etiologic factors remain elusive. For that reason, researchers are attempting to be more specific in treating only a single psychotic symptom [3, 4]. First- and second-generation antipsychotics are the first line of treatment for schizophrenia [5]. Unfortunately, the schizophrenia prognosis offers poor outcomes despite current treatment; patients often remain symptomatic, and 25%-33% of patients are treatment-resistant [6]. In addition, antipsychotics are associated with significant side effects, leading to additional complications in treating the disease [7].

Application of local stimulation of the neocortex based on a neurophysiological can enhance a greater understanding of the complex architecture of cortical anatomy and its correlation with brain functions. Such methods were applied some time ago to explore a wide range of cerebral functions such as sensory, motor, emotional, and subcortical vascular cognitive impairment [8].

Transcranial magnetic stimulation (TMS) is a “non-invasive method for brain stimulation using the magnetic field to stimulate nerve cells in the brain meninges, subsequently inducing an electric current in the brain tissues that produces neuronal depolarization and generate action potentials” [9]. Introduced in 1985 [10], the TMS has been applied to investigate cortical and spinal excitability, as well as treating neurological and psychiatric disorders [9].

TMS therapeutic effects are applied either through single-pulse TMS, repetitive pulse (rTMS), or theta-burst stimulation (TBS). A single pulse measures the motor threshold in an experimental setting [11]. However, rTMS assists in measuring diseases like major depressive disorder [12]. TMS measures cortical excitability by determining the motor threshold of each individual, which is only conducted through stimulation of the motor system using surface EMG electrodes placed over the motor cortex of the target muscle to obtain a muscle response potential (MEP). This investigation was initiated based on the motor corticospinal pathways [13]. Through the development of TMS techniques “paired-pulse,” it was possible to focus more on specific aspects of cortical excitability, such as inhibitory and facilitatory processes of the components of the motor system that causes various neuropsychiatric disorders [14]. I-wave facilitation and long-interval cortical inhibition (LICI) are some of the specific paired-pulse TMS paradigms. LICI helps to assess an initial suprathreshold stimulus combined with a suprathreshold second stimulus. The initial stimulus produces an inhibition of the evoked motor response to the second (test) stimulus when presented at an appropriate interstimulus interval (50–200 ms). The I-wave facilitation measures the descending I-wave volleys induced by magnetic stimulation [15].

TMS is investigated for the treatment of positive schizophrenic symptoms [16]. Neuronal networks of schizophrenic patients are impaired, especially patients not treated with antipsychotic therapy have impaired extrapyramidal motor disorders that include a general disturbance of fine motor skills, manual dexterity, the bimanual coordination deficits of antisaccade eye movements, and psychomotor speed [17]. In addition, cognitive, motor, neurophysiological, and neuropathological systems are responsible for schizophrenia, causing cortical inhibition.

These disorders are associated with an increased subcortical dopaminergic activity leading to decreased activation of inhibitory cortical afferents, ultimately increasing cortical excitability results. In morphological studies of neuropathological changes, the cortical inhibition is mediated by cortical GABAergic interneurons, closing the final inhibitory dysfunction [18, 19]. While schizophrenia was first treated by TMS over two decades ago, the current evidence still failed to provide a clear picture of the effect [20, 21].

The present study is aimed at reviewing and analyzing the current literature available on the efficacy and assessment of brain plasticity index in schizophrenia through TMS protocols.

2. Methods

2.1. Search Strategy

We searched for studies published in the following electronic databases including the Cochrane Library, PubMed, EMBASE, and Web of Science, using the search terms as follows: e.g., “Schizophrenia” AND “transcranial magnetic stimulation “or “psychiatric Disorders” AND “TMS” or “schizophrenia” AND “brain plasticity Index” or paired pulse stimulation, from inception to September, 2021. In addition, combinations of Medical Subject Headings (MeSH) and text were used. One hundred and twenty-nine articles were selected. One author performed the initial selection of studies based on title and abstract. Then, each potentially eligible selected study was screened against the inclusion criteria. Finally, for 85 studies, three authors independently reviewed and evaluated the full-text articles to decide and determine whether these articles meet the predefined inclusion criteria. Any related disagreement was resolved by discussion. All selected studies collected from the search were critically examined. The studies for the review were grouped according to the paradigms and parameters examined in schizophrenia patients (Table 1).

2.2. Motor Threshold (MT)

The motor threshold (MT) is defined as the lowest intensity of TMS, required to provoke a predefined motor-evoked potential (MEP) with a peak-to-peak amplitude of 50 μV in at least 50% of pursued trials (in 5 of 10 trials) [22]. Minimum stimulation intensity that can elicit a motor response of a given amplitude is either from a muscle at rest, called resting motor threshold (RMT), or during a muscle contraction (almost 5-10% of the target muscle’s maximum contraction), named active motor threshold (AMT).

Moreover, medications such as carbamazepine and phenytoin increase the MT activities by changing the sodium channel properties which reflect the transsynaptic excitability of corticospinal response neurons, modulated by altering the presynaptic sodium/calcium channel conductivity [23]. Other substances, such as neuroleptics, antidepressants, or benzodiazepines, acting via the modulation of neurotransmitters offer lesser effects [24]. However, increasing evidence shows that changes in the MT glutamatergic transmission can cause MT activities [25].

Table 1 presents the outcomes of numerous studies reviewed aimed at investigating whether RMT changes in patients with schizophrenia compared to healthy control. From the table, few studies offer no differences in RMT between schizophrenic patients and first-degree relatives compared to healthy control [26]. Following the reported evidence, a significantly lower RMT in schizophrenic patients is noted compared to control subjects, which support the evidence that schizophrenia is linked to the deficits in cortical inhibition (CI) [8, 27, 28]. In addition, naturally occurring and drug-induced psychosis share a pathway that can base on dysfunctional glutamatergic mechanisms [27, 28]. Regarding inhibitory rTMS over the premotor cortex in the intervention with low frequency, some studies revealed a lack of increase in the RMT after stimulation in schizophrenic patients compared to controls. The observed TMS changes could be understood as intracortical motor’s primary alterations followed by cortical inhibition defects that might be attributed to antipsychotic medication effect, schizophrenia, or the interaction between the condition and medication [29–31]. The aberrant middle prefrontal-motor cortex connectivity mediates motor inhibitory biomarker in schizophrenia [30]. Therefore, schizophrenia patients display abnormal brain responses to rTMS applied to the premotor cortex that relate to minimized motor cortical inhibition [31–33]. A significant reduction of intracortical inhibition was observed in medicated patients compared with unmedicated patients and controls. This difference was more noticeable in the right hemisphere compared with the left [33]. Additionally, schizophrenia is attributed to a reversed pattern of interhemispheric corticospinal excitability [33]. Another study observed differences between the RMT in patients with schizophrenia treated with risperidone (increased RMT) compared to olanzapine (reduced RMT) [34]. Altogether, these studies provide evidence of impaired excitation/inhibition on cortical oscillations in schizophrenia and suggest that schizophrenia might be characterized by an imbalance of interhemispheric corticospinal excitability [31, 33, 35]. Therefore, there are selective alterations of interhemispheric facilitatory dPM–M1 connectivity in schizophrenia [35].

2.3. Motor-Evoked Potentials

Merton and Morton [36] note that MEPs during contraction (contracted-MEPs) are bigger in amplitude and shorter in latency than what MEPs attained during full muscular relaxation (relaxed-MEPs). Thus, muscles that act as prime movers for voluntary movement exert the greatest facilitation [37, 38]. MEPs have been noted to increase when a muscle group is in action due to reduced intracortical inhibition [39]. Other researchers have pinpointed that one of the fundamental findings in patients with schizophrenia is impaired cortical inhibition that mainly results from a dysfunction in the transmission of gamma-aminobutyric acid (GABA) [40, 41]. According to one study, 51 schizophrenic patients with control subjects showed an increase in stimulus intensity for maximum MEP (SI-max) with longer MEP latency and no change in amplitude. SI-max was calculated assuming that MEP size reaches the plateau phase of the curve, and this may affect MEP results [29]. In another study, on hand, preference and TMS asymmetry of cortical motor representation, its effect on MEP was tested, and it was found that the MEP threshold or size did not differ between the preferred and nonpreferred hands. However, the preferred limb had a significantly greater number of scalp stimulation sites that generated MEPs [42]. Du et al. elucidate that used magnetic stimulation markers to demonstrate that high MEPs during schizophrenia are due to abnormal connectivity between the motor cortex and other regions of the brain such as the middle prefrontal gyrus that is affected by schizophrenia [30].

Patients with schizophrenia who are medicine-free demonstrate a higher degree of enhanced I-wave inhibition than those taking medication thus implying that their cortical inhibitory GABAergic activity is impaired [15, 43]. Worth noting is that the main factors that influence MEP in schizophrenic patients are the state of medication and stage of illness. MEPs will be more elevated in patients who are not taking medication and those with advanced stages of schizophrenia [36]. Frank et al. conducted a study that demonstrated that medications such as anticonvulsants and antidepressants can significantly prolong the cortical salient period (CSP) thus controlling MEPs [44]. In another study, interhemispheric facilitation was decreased in schizophrenia, though no change was reported in MEP [35]. Furthermore, a study on the effects of antipsychotic medication responses to TMS of the motor cortex in schizophrenia involved group nine of drug naïve patients compared with a group of nine patients on established neuroleptic medication. There was no difference in TMS threshold strength or latency for inducing compound motor-evoked potentials (cMEPs) [45]. Alternatively, one study compared nine drug-free schizophrenic patients with nine healthy subjects, which revealed a reduction in the latency of MEP [46].

2.4. Paired-Pulse Paradigms

Corticocortical excitability can be more directly examined by using paired-pulse TMS in which two consecutive TMS stimuli are applied to the brain at different interstimulus intervals (ISIs). The conditioning stimulus (CS) with approximately 80-95% of the RMT is the first, where the cortex of the actual test stimulus (TS) is set at 110-120% of RMT. Thus, the neuromodulatory effect of the CS on the amplitude of TMS-evoked MEPs depends mostly on two factors: the intensity of CS and TS and the interstimulus interval (ISIs) between both types of stimuli [47].

An ISI of 1-5 ms is “short” and produces inhibitory effects with a lower MEP amplitude. An ISI in the interval of 8-20 ms demonstrates facilitatory effects with the MEP amplitude over 1 mV (amplitude height of the TS without previous CS). When using the bilateral stimulation (dual-pulse technique), a significant reduction of the contralateral MEP amplitude was remarked in the untreated schizophrenic patients, revealing that the antipsychotic treatment may repeal the increased transcallosal inhibition (TCI) in schizophrenia [27]. First-degree relatives of schizophrenics were unrelated to the differences in the duration and latency of the ipsilateral CSP, revealing the transcallosal inhibition and the single-pulse technique [26].

2.4.1. Intracortical Inhibition

Intracortical inhibition can identify changes in variable conditions. Administering GABA-A receptor agonists such as lorazepam primarily caused cortical inhibition [48] and might suppress the I-wave facilitation, which is difficult to be detected [23].

2.4.2. Short Interval Intracortical Inhibition (SICI)

A study explored important aspects of the pathophysiological mechanisms using the paired-pulse method, in which ( schizophrenic patients) served as subjects and half were untreated [49]. However, a decrease is noted in cortical inhibition, only significant in the untreated patients compared to controls and no difference in the facilitation [49, 50]. In the treated patients, an inclination to reduced inhibition is perceived compared to the untreated schizophrenia patients [27, 33]. In another study ( schizophrenic patients), it demonstrates primarily less cortical inhibition in schizophrenic patients [51]. However, a study revealed significantly less cortical inhibition after treating schizophrenic patients with antipsychotic drugs when compared to controls [31]. Moreover, subjects at ultrahigh risk of psychosis exhibited a prolonged CSP with no change in SICI compared to healthy controls, whereas patients with schizophrenia showed a prolonged CSP and a diminished SICI [40].

Compared to the controls before and after administering 1 Hz rTMS on schizophrenic patients, there was less cortical inhibition [31]. However, in prepost comparison for the control group, as anticipated by the inhibitory rTMS, a surge of cortical inhibition was noted [31]. Moreover, the post-rTMS patients had an amplitude of MEPs at rest, which was significantly lower, suggesting a lower modulation of excitability in schizophrenia [32]. In another study, in which the schizophrenics were untreated, no significant differences in cortical excitability were observed with the paired-pulse method as compared with healthy controls [28].

Another study used resting-state functional connectivity to report if SICI was linked to functional connectivity between motor and prefrontal areas and symptoms in schizophrenia (rsFC), which included 24 schizophrenia-spectrum patients and 30 healthy controls. The study indicated that the left middle prefrontal gyrus-motor cortex rsFC was linked to both cortical inhibition and schizophrenia symptoms as stronger the rsFC indicates stronger the motor cortical inhibition [30]. A study examined the changes in SICI to the ultrahigh risk of psychosis (UHR), schizophrenia patients (SZ), and healthy controls. When SZ were compared to healthy controls and SZ patients with UHR individuals, there was a reduced inhibition. In contrast, there was no difference in SICI between UHR subjects and healthy controls [40]. Multiple papers tested the changes in SICI in schizophrenia patients and healthy controls result and have reported a consistent decrease in SICI. A hypothesis might be proposed that changes in SICI develop at all stages of schizophrenia [30, 39, 41, 42, 52]. Compared to literature, only one study found that unmedicated schizophrenia patients had higher SICIs than medicated patients did, for which the researchers were unable to explain [43]. Moreover, a study done on drug-free patients with acute psychosis before and after 3 weeks of treatment did not reveal any changes in SICI. In interpreting this data, it is critical to consider that the absence of the control group might explain the lack of change [44].

2.4.3. Intracortical Facilitation

If the interstimulus interval between the 2 pulses is long, i.e., 9-25 ms, a facilitatory effect is observed, referred to as intracortical facilitation (ICF) [40, 43, 45–56]. ICF can constitute more facilitation and weaker inhibition. In approximately 10 ms, the latency of NMDA receptor-mediated excitatory postsynaptic potentials can occur. Regarding the time course of ICF, some studies [40, 49–51, 57] highlight the importance of glutamatergic transmission of ICF. Typically, NMDA receptor antagonists and GABAA agonists mostly decrease ICF [58]. One study showed acceptable reliability of ICF in schizophrenic patients but poor reliability in healthy subjects [59]. Another study noted that when comparing schizophrenic patients with controls, reducing facilitation is noted based on P60 and N100 ICF. Moreover, the ICF is correlated with the positive and negative total score, representing the pathophysiology of the schizophrenia symptoms, possibly associated with the prefrontal GABA and glutamatergic dysfunctions [60]. Several studies investigated ICF among schizophrenic patients. As one study included 16 ultrahigh risk of psychosis (UHR), 17 schizophrenia patients, and 28 healthy controls investigated, the primary motor cortex did not reveal any changes in the ICF [40]. A similar discovery was made as a one-study test of 24 drug-free schizophrenia patients with acute psychosis before and after starting quetiapine for 3 weeks was unable to detect a significant change in ICF [45]. Another study included 43 unmedicated schizophrenia patients and 38 medicated schizophrenia patients with 32 healthy controls, which failed to show any different ICF changes [43]. This is in line with two studies that compared neuroleptic-naive first-episode schizophrenia patients to healthy controls and found no difference in ICF [28, 41].

This is opposite to two studies that found there is a difference in ICF, as one study involved 13 schizophrenia patients and 13 controls of ICF measured after changing their antipsychotic and were followed up for 8-weeks. ICF measurements were done at baseline and 8 weeks posttreatment. The study reported significantly lower ICF at 8 weeks compared to baseline; this could be attributed to the interstimulus interval which was between 7 and 30 ms, and previous studies have been cross-sectional in design, and this might explain the lack of change in ICF between healthy controls and schizophrenia patients [53]. Another study that measured ICF in the context-based action observation in schizophrenia included 39 schizophrenia patients and 28 healthy controls, which revealed a diminished ICF in schizophrenia patients compared to controls. This could be due to schizophrenia patients having difficulty evaluating and interpreting social cues [39].

2.4.4. Long Interval Cortical Inhibition

Long-interval intracortical inhibition (LICI) refers to suppression of cortical neuronal firing, following a paired-pulse TMS, mediated in part by the primary inhibitory neurotransmitter of the central nervous system; gamma-aminobutyric acid (GABA) receptor B. LICI can be measured either from motor-evoked potentials (MEPs) in the interossei muscles of the hand or directly recorded from the cortex using a concomitant electroencephalography (EEG) method.

Several studies examined the prefrontal cortex, motor cortex TMS-EMG LICI in patients with schizophrenia (SCZ). In a study including 18 SCZ patients (9 were medicated with antipsychotics) and 18 HC, Fitzgerald et al., in a study including 18 patients with schizophrenia (9 were medicated with antipsychotics) and 18 healthy controls, showed that there was no significant difference across both groups related to LICI, suggesting that no influence of neuroleptic medication [15]. Similarly, a cross-sectional study including 54 patients with schizophrenia and 45 healthy controls failed to find a significant LICI difference in patients compared to healthy participants. In addition, there was no significant correlation between LICI and social cognition outcome measures in both groups [61].

It is noteworthy to mention that the studies investigating LICI in the motor cortex of patients with schizophrenia failed to exhibit any significant correlation between LICI changes and neural correlates of schizophrenia symptoms. However, studies examining LICI in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia revealed significant findings. This suggests that altered inhibitory process related to DLPFC, and not to motor cortex, might be underlying the deficits of cognitive function that exist in patients with schizophrenia [61–66].

2.4.5. Cortical Silent Period (CSP)

The application of TMS can assist in studying the transcallosal connection between primary motor cortices (M1) in both human hemispheres, which include transcallosal inhibition (TCI) and facilitation (TCF) with onset latency, typically (30-40 ms). Moreover, the latency and duration of the TCI are known as the transcortical conduction time (transcallosal conduction time, TCT) [50]. The resulting phenomenon is called a cortical silent period (CSP) or a contralateral silent period. By comparing the ipsilateral and contralateral CSP, the contralateral CSP measures the breaking of the target muscle activity of the contralateral side, as per the anatomy of the motor system (pyramidal tract crossing) [48]. The control loops and mechanisms, which produced the CSP principles, are intricate. This involves pallidus, having different cortical and subcortical (globus, the thalamus) structures, facilitated by GABA-B receptors and offered a vital role in neural modulation [67] and via the posterior midbody of the corpus callosum [68].

A previously early study, on the CSP in schizophrenia, revealed no significant differences in the duration of CSP between schizophrenic patients and controls [46]. However, a longer initial latency (onset latency) in treated patients was recorded [45, 56, 69]. Multiple studies reported a consistent shorter CSP in patients without medication effects (risperidone and olanzapine) [34, 39, 52, 70, 71]. On contrary, a different study found a shorter CSP when compared to controls, shown only in the untreated patients. On the other hand, a prolonged CSP is shown in the neuroleptic-treated patients [27, 48]. Another paper found a longer CSP in schizophrenic patients regardless of the application of antipsychotic medication when compared to the control [28]. Another similar study demonstrates a significant CSP prolongation after rTMS in untreated and treated patients compared to controls [31]. One study that explored first-degree relatives of schizophrenia showed no differences in the CSP compared to controls [26].

3. Therapeutic Application of TMS

TMS is a noninvasive procedure that uses a magnetic field to stimulate nerve cells of the brain. For the past few decades, TMS has been established as a potential treatment for schizophrenia. TSM enhances casual relationships between the brain and behavior. Furthermore, rTMS is known for its positive effects on neuroplasticity. Given its neuroprotective effects, rTMS can benefit patients with various neuropsychiatric disorders in a short period [1, 14–21, 24–30, 42, 72–76], which include, mood disorders such as depression, schizophrenia, anxiety, dysphemia, autism, substance use disorders, attention-deficit/hyperactivity disorder, and monosymptomatic nocturnal enuresis. The outcomes of a meta-analysis conducted by Freitas et al. showed a significant and moderate effect of rTMS on the negative and positive schizophrenia symptoms. However, the sham-controlled studies revealed that these symptoms demonstrate a small nonsignificant effect [77].

4. Discussion

Investigating cortical excitability (motor-neural transmission, ipsilateral recurrence and contralateral CSP, short- or long-latency-intracortical inhibition, and interhemispheric inhibition) can measure cortical inhibition. In patients with schizophrenia, TMS is an auspicious approach to record changes in cortical excitability and to elucidate the underlying pathophysiological mechanisms of the schizophrenia [77–79].

Methodological issues can cause measurement inaccuracies (Table 1). In addition, distinct characteristics and the existing physiological arousal significantly influence the measurement results, such as age [27, 32–34], handedness [75], vigilance [9], state of relaxation [28], gender and time during the menstrual cycle [63], and expectation [13, 14, 68, 72, 76–81]. Lack of compulsory uniform definitions may lead to the formation of automated measuring methods, in which the silent period shows an improvement [78].

Increased MEP is a major observation among patients with schizophrenia due to interference in the cortical inhibitory mechanism [36–39]. MEP is further increased in the absence of medication and when the disease has progressed [36]. Researchers have indicated that dysfunction in the transmission of the inhibitory neurotransmitter GABA and disrupted connections between the motor cortex and other brain regions are the most likely mechanisms [30, 40, 41].

In several lines of evidence, cortical inhibition was observed in schizophrenic patients compared to controls [15, 26–28]. This finding is consistent with the proposed increase in subcortical dopaminergic activity and decrease cortical GABAergic activity. Furthermore, the ICF role in the pathophysiology of schizophrenia needs to be clarified more as a potential indicator to the decrease or increase in the cortical inhibition in a longitudinal study for drug-naive first-episode schizophrenia patients who begin new antipsychotic drug treatment [53].

Confirmed through imaging and TMS technique, schizophrenia patients are suspected to have other neurophysiological and neuropsychological considerations, impaired by interhemispheric transfer [80]. Despite the heterogeneity of the results for the assessment of cortical plasticity with TMS methods, a promising investigation tool is required.

5. Conclusion

TMS is an auspicious noninvasive method that can be used to study detailed aspects of cortico-motor-neural excitability in schizophrenia on a pathophysiological basis, with a focus on detecting inhibitory dysfunction (paired-pulse method, transcallosal inhibition, or cortical silent period). Combining it with other methods, like molecular genetic typing, neuropsychological examination, structural and functional imaging including magnetic resonance-volumetric, event-related potentials, and functional magnetic resonance imaging techniques, might contribute to an understanding of future neurobiological vulnerability about schizophrenia population.

Data Availability

The data used to support the findings of this study are included in the article.

Conflicts of Interest

All authors declare that there is no conflict of interest regarding the publication of this work.

Authors’ Contributions

All listed authors developed different substantial activities. All participated in drafting and writing the manuscript. Each author participated sufficiently in writing and reviewing the manuscript. All authors read and approved the final manuscript.

References

Schizophrenia, “Schizophrenia - symptoms, diagnosis and treatment,” BMJ Best Practice, 2020, Available from: https://bestpractice.bmj.com/topics/en-gb/406.
View at: Google Scholar
D. E. Battle, “Diagnostic and Statistical Manual of Mental Disorders (DSM),” Codas, vol. 25, no. 2, pp. 91-92, 2021.
View at: Google Scholar
S. Winkelbeiner, M. Cavelti, A. Federspiel et al., “Decreased blood flow in the right insula and middle temporal gyrus predicts negative formal thought disorder in schizophrenia,” Schizophrenia Research, vol. 201, pp. 432–434, 2018.
View at: Publisher Site | Google Scholar
P. Homan, P. Vermathen, C. van Swam et al., “Magnetic resonance spectroscopy investigations of functionally defined language areas in schizophrenia patients with and without auditory hallucinations,” NeuroImage, vol. 94, no. 94, pp. 23–32, 2014.
View at: Publisher Site | Google Scholar
G. A. Keepers, L. J. Fochtmann, J. M. Anzia et al., “The American Psychiatric Association practice guideline for the treatment of patients with schizophrenia,” The American Journal of Psychiatry, vol. 177, no. 9, pp. 868–872, 2020.
View at: Publisher Site | Google Scholar
A. Essali, N. al-Haj Haasan, C. Li, J. Rathbone, and Cochrane Schizophrenia Group, “Clozapine versus typical neuroleptic medication for schizophrenia,” Cochrane Database of Systematic Reviews, vol. 21, p. 1, 2009.
View at: Publisher Site | Google Scholar
S. Leucht, C. Corves, D. Arbter, R. R. Engel, C. Li, and J. M. Davis, “Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis,” Lancet, vol. 373, no. 9657, pp. 31–41, 2009.
View at: Publisher Site | Google Scholar
J. P. Lefaucheur, N. André-Obadia, A. Antal et al., “Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS),” Clinical Neurophysiology, vol. 125, no. 11, pp. 2150–2206, 2014.
View at: Publisher Site | Google Scholar
I. Griskova, J. Höppner, O. Ruksenas, and K. Dapsys, “Transcranial magnetic stimulation: the method and application,” Medicina, vol. 42, no. 10, pp. 798–804, 2006.
View at: Google Scholar
A. T. Barker, R. Jalinous, and I. L. Freeston, “Non-invasive magnetic stimulation of human motor cortex,” Lancet, vol. 11, no. 1, pp. 106-107, 1985.
View at: Google Scholar
A. Valero-Cabré, J. L. Amengual, C. Stengel, A. Pascual-Leone, and O. A. Coubard, “Transcranial magnetic stimulation in basic and clinical neuroscience: a comprehensive review of fundamental principles and novel insights,” Neuroscience and Biobehavioral Reviews, vol. 83, pp. 381–404, 2017.
View at: Publisher Site | Google Scholar
C. Baeken, A. K. Brem, M. Arns et al., “Repetitive transcranial magnetic stimulation treatment for depressive disorders: current knowledge and future directions,” Current Opinion in Psychiatry, vol. 32, no. 5, pp. 409–415, 2019.
View at: Publisher Site | Google Scholar
F. Maeda and A. Pascual-Leone, “Transcranial magnetic stimulation: studying motor neurophysiology of psychiatric disorders,” Psychopharmacology, vol. 168, no. 4, pp. 359–376, 2003.
View at: Publisher Site | Google Scholar
L. Kiers, D. Cros, K. H. Chiappa, and J. Fang, “Variability of motor potentials evoked by transcranial magnetic stimulation,” Electroencephalography and Clinical Neurophysiology, vol. 89, no. 6, pp. 415–423, 1993.
View at: Publisher Site | Google Scholar
P. B. Fitzgerald, T. J. Brown, N. A. Marston et al., “A transcranial magnetic stimulation study of abnormal cortical inhibition in schizophrenia,” Psychiatry Research, vol. 118, no. 3, pp. 197–207, 2003.
View at: Publisher Site | Google Scholar
O. Rosenberg, Y. Roth, M. Kotler, A. Zangen, and P. Dannon, “Deep transcranial magnetic stimulation for the treatment of auditory hallucinations: a preliminary open-label study,” Annals of General Psychiatry, vol. 10, no. 1, p. 3, 2011.
View at: Publisher Site | Google Scholar
Y. L. R. Chen, Y. H. E. Chen, and F. L. Mak, “Soft neurological signs in schizophrenic patients and their nonpsychotic siblings,” The Journal of Nervous and Mental Disease, vol. 188, no. 2, pp. 84–89, 2000.
View at: Publisher Site | Google Scholar
F. M. Benes, “Model generation and testing to probe neural circuitry in the cingulate cortex of postmortem schizophrenic brain,” Schizophrenia Bulletin, vol. 24, no. 2, pp. 219–230, 1998.
View at: Publisher Site | Google Scholar
F. M. Benes, “Cortical pathology: a new generation of quantitative microscopic studies,” in The Neuropathology of Schizophrenia: Progress and Interpretation, P. J. Harrison and G. W. Roberts, Eds., pp. 81–104, Oxford University Press, New York, 2000.
View at: Google Scholar
R. E. Hoffman, N. N. Boutros, R. M. Berman et al., “Transcranial magnetic stimulation of left temporoparietal cortex in three patients reporting hallucinated "voices",” Biological Psychiatry, vol. 46, no. 1, pp. 130–132, 1999.
View at: Publisher Site | Google Scholar
T. Marzouk, S. Winkelbeiner, H. Azizi, A. K. Malhotra, and P. Homan, “Transcranial magnetic stimulation for positive symptoms in schizophrenia: a systematic review,” Neuropsychobiology, vol. 79, no. 6, pp. 384–396, 2020.
View at: Publisher Site | Google Scholar
R. M. Rossini, A. Berardelli, G. Deuschl et al., “Applications of magnetic cortical stimulation. The International Federation of Clinical Neurophysiology,” Electroencephalography and Clinical Neurophysiology. Supplement, vol. 171, no. 52, pp. 171–185, 1999.
View at: Google Scholar
U. Ziemann, S. Lönnecker, B. J. Steinhoff, and W. Paulus, “Effects of antiepileptic drugs on motor cortex excitability in humans: a transcranial magnetic stimulation study,” Annals of Neurology, vol. 40, no. 3, pp. 367–378, 1996.
View at: Publisher Site | Google Scholar
U. Ziemann and M. Hallett, “Basic neurophysiological studies with TMS,” in Transcranial Magnetic Stimulation in Neuropsychiatry, M. S. George and R. H. Belmaker, Eds., vol. 1, pp. 45–98, American Psychiatric Press, Washington DC, 2000.
View at: Google Scholar
V. D. Lazzaro, A. Oliviero, P. Profice et al., “Ketamine increases human motor cortex excitability to transcranial magnetic stimulation,” The Journal of Physiology, vol. 547, no. 2, pp. 485–496, 2003.
View at: Publisher Site | Google Scholar
M. C. Saka, E. C. Atbasoglu, H. D. Özgüven, H. Ö. Sener, and E. Özay, “Cortical inhibition in first-degree relatives of schizophrenic patients assessed with transcranial magnetic stimulation,” The International Journal of Neuropsychopharmacology, vol. 8, no. 4, pp. 595–599, 2005.
View at: Publisher Site | Google Scholar
Z. J. Daskalakis, B. K. Christensen, R. Chen, P. B. Fitzgerald, R. B. Zipursky, and S. Kapur, “Evidence for impaired cortical inhibition in schizophrenia using transcranial magnetic stimulation,” Archives of General Psychiatry, vol. 59, no. 4, pp. 347–354, 2002.
View at: Publisher Site | Google Scholar
P. Eichhammer, R. Wiegand, A. Kharraz, B. Langguth, H. Binder, and G. Hajak, “Cortical excitability in neuroleptic-naive first-episode schizophrenic patients,” Schizophrenia Research, vol. 67, no. 2-3, pp. 253–9, 2004.
View at: Publisher Site | Google Scholar
E. Soubasi, E. Chroni, P. Gourzis, A. Zisis, S. Beratis, and P. Papathanasopoulos, “Cortical motor neurophysiology of patients with schizophrenia: a study using transcranial magnetic stimulation,” Psychiatry Research, vol. 176, no. 2-3, pp. 132–136, 2010.
View at: Publisher Site | Google Scholar
X. du, F. S. Choa, J. Chiappelli et al., “Aberrant middle prefrontal-motor cortex connectivity mediates motor inhibitory biomarker in schizophrenia,” Biological Psychiatry, vol. 85, no. 1, pp. 49–59, 2019.
View at: Publisher Site | Google Scholar
P. B. Fitzgerald, T. L. Brown, N. A. Marston et al., “Reduced plastic brain responses in schizophrenia: a transcranial magnetic stimulation study,” Schizophrenia Research, vol. 71, no. 1, pp. 17–26, 2004.
View at: Publisher Site | Google Scholar
T. Oxley, P. B. Fitzgerald, T. L. Brown, A. de Castella, Z. Jeff Daskalakis, and J. Kulkarni, “Repetitive transcranial magnetic stimulation reveals abnormal plastic response to premotor cortex stimulation in schizophrenia,” Biological Psychiatry, vol. 56, no. 9, pp. 628–633, 2004.
View at: Publisher Site | Google Scholar
A. Pascual-Leone, D. S. Manoach, R. Birnbaum, and D. C. Goff, “Motor cortical excitability in schizophrenia,” Biological Psychiatry, vol. 52, no. 1, pp. 24–31, 2002.
View at: Publisher Site | Google Scholar
P. B. Fitzgerald, T. L. Brown, Z. J. Daskalakis, and J. Kulkarni, “A transcranial magnetic stimulation study of the effects of olanzapine and risperidone on motor cortical excitability in patients with schizophrenia,” Psychopharmacology, vol. 162, no. 1, pp. 74–81, 2002.
View at: Publisher Site | Google Scholar
M. Ribolsi, F. Mori, V. Magni et al., “Impaired inter-hemispheric facilitatory connectivity in schizophrenia,” Clinical Neurophysiology, vol. 122, no. 3, pp. 512–517, 2011.
View at: Publisher Site | Google Scholar
P. A. Merton and H. B. Morton, “Stimulation of the cerebral cortex in the intact human subject,” Nature, vol. 285, no. 5762, pp. 227–227, 1980.
View at: Publisher Site | Google Scholar
P. M. Rossini and S. Rossi, “Clinical applications of motor evoked potentials,” Electroencephalography and Clinical Neurophysiology, vol. 106, no. 3, pp. 180–194, 1998.
View at: Publisher Site | Google Scholar
C. Tomberg and M. D. Caramia, “Prime mover muscle in finger lift or finger flexion reaction times: identification with transcranial magnetic stimulation,” Electroencephalography and Clinical Neurophysiology, vol. 81, no. 4, pp. 319–322, 1991.
View at: Publisher Site | Google Scholar
V. I. Bagewadi, U. M. Mehta, S. S. Naik et al., “Diminished modulation of motor cortical reactivity during context-based action observation in schizophrenia,” Schizophrenia Research, vol. 204, pp. 222–229, 2019.
View at: Publisher Site | Google Scholar
Y. Tang, T. Zhang, B. Edelman et al., “Prolonged cortical silent period among drug-naive subjects at ultra-high risk of psychosis,” Schizophrenia Research, vol. 160, no. 1-3, pp. 124–130, 2014.
View at: Publisher Site | Google Scholar
A. Hasan, T. Wobrock, C. Grefkes et al., “Deficient inhibitory cortical networks in antipsychotic-naive subjects at risk of developing first-episode psychosis and first-episode schizophrenia patients: a cross-sectional study,” Biological Psychiatry, vol. 72, no. 9, pp. 744–751, 2012.
View at: Publisher Site | Google Scholar
J. M. Abarbanel, T. Lemberg, U. Yaroslavski, N. Grisam, and R. H. Belmaker, “Electrophysiological responses to transcranial magnetic stimulation in depression and schizophrenia,” Biological Psychiatry, vol. 40, no. 2, pp. 148–150, 1996.
View at: Publisher Site | Google Scholar
M. Schecklmann, C. Weidler, P. Eichhammer, G. Hajak, and B. Langguth, “Increased short-interval intracortical inhibition in un-medicated patients with schizophrenia,” Brain Stimulation, vol. 11, no. 5, pp. 1080–1082, 2018.
View at: Publisher Site | Google Scholar
E. Frank, M. Landgrebe, T. B. Poeppl et al., “Antipsychotic treatment with quetiapine increases the cortical silent period,” Schizophrenia Research, vol. 156, no. 1, pp. 128–132, 2014.
View at: Publisher Site | Google Scholar
N. Davey, B. Puri, H. Lewis, S. W. Lewis, and P. H. Ellaway, “Effects of antipsychotic medication on electromyographic responses to transcranial magnetic stimulation of the motor cortex in schizophrenia,” Journal of Neurology, Neurosurgery, and Psychiatry, vol. 63, no. 4, pp. 468–473, 1997.
View at: Publisher Site | Google Scholar
B. K. Puri, N. J. Davey, P. H. Ellaway, and S. W. Lewis, “An investigation of motor function in schizophrenia using transcranial magnetic stimulation of the motor cortex,” The British Journal of Psychiatry, vol. 169, no. 6, pp. 690–695, 1996.
View at: Publisher Site | Google Scholar
T. V. Ilić, F. Meintzschel, U. Cleff, D. Ruge, K. R. Kessler, and U. Ziemann, “Short-interval paired-pulse inhibition and facilitation of human motor cortex: the dimension of stimulus intensity,” The Journal of Physiology, vol. 545, no. 1, pp. 153–167, 2002.
View at: Publisher Site | Google Scholar
P. Eichhammer, B. Langguth, J. Müller, and G. Hajak, “Die neuronale Ebene der Motorik: Bestimmung der kortikalen Exzitabilität durch TMS,” Psychiatrische Praxis, vol. 32, no. 1, pp. 43–46, 2005.
View at: Publisher Site | Google Scholar
E. V. Evins, S. M. Fitzgerald, L. Wine, R. Rosselli, and D. C. Goff, “Placebo-controlled trial of glycine added to clozapine in schizophrenia,” The American Journal of Psychiatry, vol. 157, no. 5, pp. 826–828, 2000.
View at: Publisher Site | Google Scholar
M. Bajbouj, J. Gallinat, L. Niehaus, U. E. Lang, S. Roricht, and B. U. Meyer, “Abnormalities of inhibitory neuronal mechanisms in the motor cortex of patients with schizophrenia,” Pharmacopsychiatry, vol. 37, no. 2, pp. 74–80, 2004.
View at: Publisher Site | Google Scholar
B. Boroojerdi, R. Töpper, H. Foltys, and U. Meincke, “Transcallosal inhibition and motor conduction studies in patients with schizophrenia using transcranial magnetic stimulation,” The British Journal of Psychiatry, vol. 175, no. 4, pp. 375–379, 1999.
View at: Publisher Site | Google Scholar
N. Radhu, L. G. Dominguez, T. A. Greenwood et al., “Investigating cortical inhibition in first-degree relatives and probands in schizophrenia,” Scientific Reports, vol. 7, no. 1, 2017.
View at: Publisher Site | Google Scholar
M. I. Yıldız, C. Temuçin, and A. Ertuğru, “The relationship of the change in symptoms and cognitive functions with the change in cortical inhibition parameters measured by transcranial magnetic stimulation: an eight-week follow-up study,” Türk Psikiyatri Dergisi, vol. 26, no. 3, pp. 167–171, 2015.
View at: Google Scholar
S. M. McClintock, C. Freitas, L. Oberman, S. H. Lisanby, and A. Pascual-Leone, “Transcranial magnetic stimulation: a neuroscientific probe of cortical function in schizophrenia,” Biological Psychiatry, vol. 70, no. 1, pp. 19–27, 2011.
View at: Publisher Site | Google Scholar
Z. J. Daskalakis, B. K. Christensen, R. Chen, P. B. Fitzgerald, R. B. Zipursky, and S. Kapur, “Effect of antipsychotics on cortical inhibition using transcranial magnetic stimulation,” Psychopharmacology, vol. 170, no. 3, pp. 255–262, 2003.
View at: Publisher Site | Google Scholar
A. Ahlgrén-Rimpiläinen, H. Lauerma, S. Kähkönen, and I. Rimpiläinen, “Disrupted central inhibition after transcranial magnetic stimulation of motor cortex in schizophrenia with long-term antipsychotic treatment,” Psychiatry, vol. 2013, pp. 1–9, 2013.
View at: Publisher Site | Google Scholar
K. Rosenkranz and J. C. Rothwell, “Differential effect of muscle vibration on intracortical inhibitory circuits in humans,” The Journal of Physiology, vol. 551, no. 2, pp. 649–660, 2003.
View at: Publisher Site | Google Scholar
H. Russmann, J. C. Lamy, E. A. Shamim, S. Meunier, and M. Hallett, “Associative plasticity in intracortical inhibitory circuits in human motor cortex,” Clinical Neurophysiology, vol. 120, no. 6, pp. 1204–1212, 2009.
View at: Publisher Site | Google Scholar
L. Säisänen, P. Julkunen, E. Niskanen et al., “Short- and intermediate-interval cortical inhibition and facilitation assessed by navigated transcranial magnetic stimulation,” Journal of Neuroscience Methods, vol. 195, no. 2, pp. 241–248, 2011.
View at: Publisher Site | Google Scholar
F. Ferrarelli, R. E. Kaskie, B. Graziano, C. C. Reis, and A. G. Casali, “Abnormalities in the evoked frontal oscillatory activity of first-episode psychosis: a TMS/EEG study,” Schizophrenia Research, vol. 206, pp. 436–439, 2019.
View at: Publisher Site | Google Scholar
R. D. Webler, C. Hamady, C. Molnar et al., “Decreased interhemispheric connectivity and increased cortical excitability in unmedicated schizophrenia: a prefrontal interleaved TMS fMRI study,” Brain Stimulation, vol. 13, no. 5, pp. 1467–1475, 2020.
View at: Publisher Site | Google Scholar
K. Udupa, Z. Ni, C. Gunraj, and R. Chen, “Effect of long interval interhemispheric inhibition on intracortical inhibitory and facilitatory circuits,” The Journal of Physiology, vol. 588, no. 14, pp. 2633–2641, 2010.
View at: Publisher Site | Google Scholar
T. Wobrock, M. Schneider, D. Kadovic et al., “Reduced cortical inhibition in first-episode schizophrenia,” Schizophrenia Research, vol. 105, no. 1-3, pp. 252–261, 2008.
View at: Publisher Site | Google Scholar
U. Ziemann, “TMS and drugs,” Clinical Neurophysiology, vol. 115, no. 8, pp. 1717–1729, 2004.
View at: Publisher Site | Google Scholar
X. Du and L. E. Hong, “Test-retest reliability of short-interval intracortical inhibition and intracortical facilitation in patients with schizophrenia,” Psychiatry Research, vol. 267, pp. 575–581, 2018.
View at: Publisher Site | Google Scholar
K. J. Werhahn, E. Kunesch, S. Noachtar, R. Benecke, and J. Classen, “Differential effects on motorcortical inhibition induced by blockade of GABA uptake in humans,” The Journal of Physiology, vol. 517, no. 2, pp. 591–597, 1999.
View at: Publisher Site | Google Scholar
B. U. Meyer, S. Röricht, and C. Woiciechowsky, “Topography of fibers in the human corpus callosum mediating interhemispheric inhibition between the motor cortices,” Annals of Neurology, vol. 43, no. 3, pp. 360–369, 1998.
View at: Publisher Site | Google Scholar
W. J. Triggs, B. Subramanium, and F. Rossi, “Hand preference and transcranial magnetic stimulation asymmetry of cortical motor representation,” Brain Research, vol. 835, no. 2, pp. 324–329, 1999.
View at: Publisher Site | Google Scholar
W. Strube, T. Wobrock, T. Bunse et al., “Impairments in motor-cortical inhibitory networks across recent-onset and chronic schizophrenia: a cross-sectional TMS study,” Behavioural Brain Research, vol. 264, no. 264, pp. 17–25, 2014.
View at: Publisher Site | Google Scholar
P. B. Fitzgerald, T. L. Brown, Z. J. Daskalakis, A. deCastella, and J. Kulkarni, “A study of transcallosal inhibition in schizophrenia using transcranial magnetic stimulation,” Schizophrenia Research, vol. 56, no. 3, pp. 199–209, 2002.
View at: Publisher Site | Google Scholar
T. Kujirai, M. D. Caramia, J. C. Rothwell et al., “Corticocortical inhibition in human motor cortex,” The Journal of Physiology, vol. 471, no. 1, pp. 501–519, 1993.
View at: Publisher Site | Google Scholar
M. León Ruiz, M. Sospedra, S. Arce Arce, J. Tejeiro-Martínez, and J. Benito-León, “Evidencias actuales sobre las potenciales aplicaciones terapeuticas de la estimulacion magnetica transcraneal en la esclerosis multiple: Revision sistematica de la literatura,” Neurology, vol. 10, no. 18, p. 30153, 2020.
View at: Publisher Site | Google Scholar
C. Freitas, F. Fregni, and A. Pascual-Leone, “Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia,” Schizophrenia Research, vol. 108, no. 1-3, pp. 11–24, 2009.
View at: Publisher Site | Google Scholar
B. P. Blum and J. J. Mann, “The GABAergic system in schizophrenia,” The International Journal of Neuropsychopharmacology, vol. 5, no. 2, pp. 159–179, 2002.
View at: Publisher Site | Google Scholar
P. Eichhammer, B. Langguth, M. Zowe et al., “GABA-B-assoziierte neuropsychiatrische Erkrankungen,” Psychiatrische Praxis, vol. 31, no. S1, pp. 44–46, 2004.
View at: Publisher Site | Google Scholar
M. L. Phillips, P. W. Woodruff, and A. S. David, “Stroop interference and facilitation in the cerebral hemispheres in schizophrenia,” Schizophrenia Research, vol. 20, no. 1-2, pp. 57–68, 1996.
View at: Publisher Site | Google Scholar
J. P. Brasil-Neto, L. G. Cohen, and M. Hallett, “Central fatigue as revealed by postexercise decrement of motor evoked potentials,” Muscle & Nerve, vol. 17, no. 7, pp. 713–719, 1994.
View at: Publisher Site | Google Scholar
M. J. Smith, J. C. Keel, B. D. Greenberg et al., “Menstrual cycle effects on cortical excitability,” Neurology, vol. 53, no. 9, pp. 2069–2072, 1999.
View at: Publisher Site | Google Scholar
A. P. Strafella and T. Paus, “Modulation of cortical excitability during action observation: a transcranial magnetic stimulation study,” NeuroReport, vol. 11, no. 10, pp. 2289–2292.
View at: Publisher Site | Google Scholar
Z. J. Daskalakis, G. F. Molnar, B. K. Christensen, A. Sailer, P. B. Fitzgerald, and R. Chen, “An automated method to determine the transcranial magnetic stimulation-induced contralateral silent period,” Clinical Neurophysiology, vol. 114, no. 5, pp. 938–944, 2003.
View at: Publisher Site | Google Scholar
J. Höppner, E. Kunesch, A. Großmann et al., “Dysfunction of transcallosally mediated motor inhibition and callosal morphology in patients with schizophrenia,” Acta Psychiatrica Scandinavica, vol. 104, no. 3, pp. 227–235, 2001.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2021 Turki Abualait et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

534

Downloads

749

Citations