A systematic review of TMS and neurophysiological biometrics in patients with schizophrenia

TMS for measuring excitatory and inhibitory processes in schizophrenia

SICI was reduced in patients with schizophrenia in 9 out of 11 studies that measured SICI. SICI is thought to reflect postsynaptic inhibition of corticospinal neurons mediated by α2 or α3 subunit–bearing GABA-A receptors.19^,40 A recent systematic review suggested that in schizophrenia, expression of GAD67 mRNA is diminished in a subset of parvalbumin-containing GABAergic interneurons in the primary motor cortex and dlPFC, accompanied by a decreased level of type 1 GABA transporter mRNA, which may result in a net increase or decrease in inhibitory tone on pyramidal cells.147 The reduction in SICI thus indicates that synaptic GABAergic inhibition of pyramidal neurons may be reduced to some extent in the motor cortex. Moreover, a single oral dose of haloperidol (D₂ receptor antagonist and agonist of ζ receptors) was shown to decrease SICI in healthy volunteers.148

The data for the effect of antipsychotic treatment on SICI are broadly suggestive that antipsychotic medications do not have a consistent impact on the reduced SICI observed in patients with schizophrenia. Other receptors that have been shown to play a role in modulating GABA-A receptor–mediated postsynaptic inhibition include presynaptic GABA-B autoreceptors, noradrenaline and ζ receptor systems.29^,77^,90^,149 Our results showed that reduced SICI is the most consistent finding among several studies using TMS to assess excitatory and inhibitory processes in schizophrenia. These results suggest impaired GABA-A–mediated cortical inhibition affecting the prodromal stage and persisting during the progression of the disease.

Most of the studies showed no statistically significant difference between patients and healthy controls in terms of motor threshold, in RMT or AMT (18 of 22 studies), MEP amplitude elicited by suprathreshold stimuli (7 of 9 studies) or ICF (8 of 9 studies). We also found no significant difference in the degree of LICI and SAI between patients and healthy controls, although only 1 study examined each measure. The results for the duration of CSP were inconclusive: of the 9 studies that delivered monophasic TMS pulses to the motor cortex and recorded responses from the surface of the hand muscle, 443^,86^,93^,95 detected no significant group difference (most or all patients were medicated; 6 patients were taking clozapine), 282^,96 reported shorter CSP duration in both medicated and unmedicated patients, and 352^,58^,94 reported longer CSP duration in patients (most or all were medicated; 2 patients were taking clozapine). However, we found greater consistency in the data for the effect of antipsychotic treatment, especially clozapine, on increasing CSP duration. This result might have important implications for the treatment of schizophrenia, because GABA-B–mediated inhibition might be involved in some of the benefits induced by drugs.

Interestingly, it has been shown that mice with a GABA-B1 deficit exhibited marked hyperlocomotion when exposed to a novel environment.150 In addition, loss of GABA-B activity resulted in a sustained moderate hyperdopaminergic state, which was phenotypically revealed by contextual hyperlocomotor activity. Taken together, these results suggest an association between deficits in GABA-B neurotransmission and an altered dopaminergic system, which might provide insights for therapeutic intervention.

Furthermore, CSP duration increases with stimulus intensity in a sigmoid fashion, and the actual effect of positive modulators of GABA-A receptors on CSP may depend on whether measurement is obtained in the low-or high-intensity range of the sigmoid curve, implying that different underlying processes may be at work for different intensity ranges.19^,151 Therefore, it is likely that antipsychotic treatment may interact with variations in stimulus intensity (from 120% AMT to 90% maximum stimulator output) to explain some of the inconsistencies related to CSP duration that we found.

Neural oscillations represent an interplay between excitatory glutamatergic pyramidal neurons in the cortex and local circuit GABAergic interneurons (modulated by additional neurotransmitter systems such as dopamine, serotonin, noradrenaline, choline and metabotropic glutamate receptors) and thus may be particularly useful as indices of E/I balance across mental disorders.152^,153 TMS-elicited neural oscillations can provide such indices as oscillation inhibition and induction (or generation). Three studies99^,105^,106 assessed oscillations in the left primary motor cortex in schizophrenia using the LICI paradigm, indexing GABA-B receptor–mediated inhibition. Radhu and colleagues99 found significant within-group inhibition of both lower and higher frequencies in patients with schizophrenia and healthy controls, whereas Farzan and colleagues105 detected significant within-group inhibition of only δ, θ and α bands in patients and healthy controls. One of the reasons for the difference might have been their choice of region of interest (i.e., multiple EEG channels versus a single channel). Nevertheless, all 3 studies reported that LICI induced a similar level of attenuation on all frequency bands between patients and healthy controls, whether the outcome measure was ERSP99^,106 or area under the rectified curve for averaged EEG,105 suggesting that GABA-B receptor–mediated inhibition might be relatively intact in the motor cortex of patients with schizophrenia. This was consistent with findings that decreased expression of GABA-B receptor protein has been identified in the entorhinal cortex, hippocampus, inferior temporal cortex, prefrontal cortex and superior frontal cortex (Brodmann area 9) of the postmortem brains of people with schizophrenia,154^–156 but to our knowledge so far similar findings have not been reported for GABA-B receptor protein in the motor cortex.

Taking together the results for SICI and LICI, there seem to be inhibitory deficits mediated by GABA-A receptors, but not GABA-B receptors in the motor cortex of patients with schizophrenia. It is worth noting that of the 3 studies above, only Radhu and colleagues106 corrected for the excitatory effect of the conditioning pulse that superimposes early EEG responses elicited by the test pulse (by subtracting the single pulse from the paired pulse lined up to the conditioning pulse). The other 2 studies did not correct for this confound. As well, although both LICI and CSP duration may reflect motor cortical GABA-B receptor–mediated postsynaptic inhibition, 19 previous studies have shown differential modulation of LICI and CSP duration by drugs, disease and fatigue, which seems to imply that the mechanisms that underlie LICI and CSP are not identical29^,157^,158 and predictions for one cannot be made based on the other.

Two of the 3 studies that applied the LICI paradigm over the motor cortex reported oscillatory responses to single-pulse TMS stimuli in psychiatric patients and healthy controls. Farzan and colleagues105 reported no significant difference in area under the curve at channel C3 for any frequency after test pulses alone among patients with schizophrenia, patients with bipolar disorder and healthy controls. Ferrarelli and colleagues91 found no significant difference in global activation (global mean field power), amplitude change (ERSP) or intertrial phase synchrony (ITC) at any frequency after test pulses alone between patients with first-episode psychosis and healthy controls, but the patients showed significantly lower relative spectral power in the 27~33 Hz range (high β/low γ) in a cluster of frontocentral electrodes overlying the motor cortex. However, Ferrarelli and colleagues91 did not specify how they calculated relative spectral power except by saying that it was “the percentage of power in a given frequency.” We do not know whether the relative spectral power reflected traditional evoked power or a combination of evoked and induced power (like the ERSP), so it was more difficult to unambiguously interpret the meaning of this measure.152

Previous studies have shown a deficit in oscillation induction in the motor cortex of patients with schizophrenia in response to actively initiated movement and passive stimulation by TMS. Compared to healthy controls, patients treated with antipsychotics and likely with chronic schizophrenia (based on their average age of 42) demonstrated reduced intertrial coherence preceding a self-initiated button-press over the contralateral motor cortex (measured at FC3 and FC5) in the γ (36~45 Hz) and β (16~24 Hz) bands.159 Prepress neural synchrony is thought to represent the corollary discharge.159 On the other hand, in Ferrarelli and colleagues, 160 medicated patients with chronic schizophrenia (mean duration of illness 13 years) showed a slowing of natural frequency in the motor cortex compared to healthy controls after single-pulse TMS stimuli that corresponded to 110~115% RMT. The total ERSP (cumulated between 8–50 Hz and 20–300 ms) was also reduced in the patients. Data were calculated in the EEG channel closest to the TMS coil to reflect the activity of the targeted area.160 Considering the evidence from previous research, it is possible that GABA-A receptor–mediated inhibition is involved in the disturbance of the γ- and β-band oscillations observed in the motor cortex of patients with schizophrenia.152^,161^,162

The first81 of 2 studies investigating the reaction of the premotor cortex to single-pulse TMS stimuli in patients with schizophrenia and healthy volunteers reported reduced amplitude (ERSP) and intertrial phase synchrony (ITC) of γ-band oscillations between 12 and 100 ms after TMS in the right premotor cortex of patients. In the second study, consistent with this finding that γ oscillations may be impaired in the premotor cortex of patients, Canali and colleagues107 reported that between 20 and 300 ms after TMS, the left premotor cortex of patients with schizophrenia, bipolar disorder and major depressive disorder oscillated at slower frequencies (11~27 Hz, high α/β) relative to healthy controls (21~50 Hz, high β/γ) in response to TMS perturbation, suggesting a deficit in evoked or induced higher-frequency oscillations in the premotor cortex of patients with schizophrenia.

The main findings of the 3 studies that assessed LICI of the dlPFC were that the inhibition of γ oscillations by the LICI paradigm in schizophrenia was less effective than in healthy controls, regardless of whether the outcome measure was the area under the rectified curve for average EEG105 or ERSP;99^,106 as well, the inhibition of other frequency bands (δ, θ, α and β) may also be impaired in schizophrenia. This was consistent with a finding of lower expression of GABA-B receptor subunits in the postmortem superior frontal cortex (Brodmann area 9) of patients with schizophrenia relative to healthy controls, suggesting that slow inhibitory signals mediated by metabotropic GABA-B receptors could be reduced in the dlPFC of patients with schizophrenia.154^,155 Furthermore, patients with schizophrenia showed an impaired LICI of γ oscillations (measured by area under the curve) and other frequency bands (measured by ERSP) compared to patients with bipolar disorder1^,105 and obsessive–compulsive disorder, 99 respectively, but no significant difference was found between the latter 2 groups of patients and healthy controls. This finding suggests that reduced suppression of neural oscillations by LICI in the dlPFC of patients with schizophrenia could be a specific endophenotype for the disorder.

Although disinhibition of the motor cortex has been a ubiquitous finding in psychiatric illnesses, independent of medication status,17^,163^,164 the overall pattern of these GABAergic deficits may differ across disorders with no specific pattern of inhibitory deficits for each disorder and little evidence for GABAergic deficits in the dlPFC across different psychiatric illnesses. The reported impairments in evoked and induced frontal oscillatory activity, especially in the γ band, have been thought to contribute to deficits in cognition, such as working memory and cognitive control.109^,165^–167 Our findings show abnormalities in γ oscillations in this clinical population, such as a deficit of GABA-B receptor–mediated inhibition of γ induced by LICI over the dlPFC,105 and deficits in γ synchronization over the premotor cortex.113 These findings might suggest selective γ impairment in this population. It has been consistently shown that inhibition of spiking parvalbumin interneurons induces suppression of γ oscillatory activity, 168 and postmortem studies show reduction of GAD67 in this subclass of GABAergic interneurons in patients with schizophrenia.12 In addition, because cortical inhibition determines the spread of cortical activation along the cortical surface, 169 the excessive propagation of TMS-induced oscillations (i.e., increased cortical conductivity) found in this population might be because of deficient cortical inhibition.85

The findings of the 2 studies by Noda and colleagues97^,108 indicate that GABA-A receptor function (assessed by SICI) and the function of a low-threshold excitatory cortical circuit that may involve glutamatergic or noradrenergic receptor activation (assessed by ICF) may be impaired in the dlPFC of patients with schizophrenia relative to healthy controls. Central cholinergic activity (assessed by SAI) may also differ between patients and healthy controls because the paradigm induced differential modulation of N100 (in the dlPFC) and P180 (in the motor cortex) amplitudes in the 2 groups. SAI increased GABA-B receptor–mediated inhibition in healthy controls, but it produced the opposite effect in the dlPFC of patients. If P180 amplitude reflects neuronal membrane excitability, 170^,171 SAI made the neuronal membrane in the motor cortex of patients more excitable than that of healthy controls.

The GABA-B receptor–mediated inhibitory signals may be involved in modulating the evoked or induced oscillatory activity in the motor cortex and dlPFC. There are a few caveats related to the original studies included in the review: although 3 studies99^,105^,106 chose the Talairach coordinates of (x,y,z = −50, 30, 36) and 2 studies97^,108 administered TMS paradigms at the F5 electrode site for stimulation of the dlPFC, stimulation of the premotor cortex was generally not associated with specific coordinates or electrode sites. Only 5 of 9 TMS-EEG studies81^,85^,91^,105^,107 used masking noise or sham TMS to control for the confounding effect of auditory-evoked potentials on the cortical EEG responses to TMS. Finally, all but 1 of the TMS-EEG studies tested fewer than 20 patients with schizophrenia, so the findings of these studies were based on relatively small sample sizes.

Effect of antipsychotic medications on TMS-EMG and TMS-EEG measures

Antipsychotic treatment seemed to have no effect on RMT,96^,98^,104^,129 AMT,96^,129 MEP amplitudes elicited by single-pulse suprathreshold stimuli (usually with an intensity that was set to produce 1 mV MEPs),96^,104^,129 ICF87^,96^,130^,131 or LICI,98 indicating that the lack of difference observed between patients and healthy controls on these measures in the motor cortex was not likely to be due to the effect of antipsychotics. One study showed that medication may have reduced interhemispheric facilitation, but not inhibitory connectivity, between the left dorsal premotor cortex and the right motor cortex.129 The findings for medication effects on SICI were inconclusive; antipsychotic treatment seemed to enhance SICI in 1 study130 but reduced it in another.96 Interestingly, of the 4 studies that compared unmedicated patients to healthy controls,87^,96^,130^,131 3 reported no significant difference in SICI between groups.87^,96^,131 Thus, the extent to which reduced SICI in medicated patients with chronic schizophrenia can be attributed to medication effect or chronic illness remains to be determined.

Certain antipsychotics may enhance GABA-A receptor–mediated neurotransmission: olanzapine and haloperidol increased the density of benzodiazepine-sensitive GABA-A receptors in rat prefrontal cortex without altering the total population of GABA-A receptors after 28 days of drug infusion, suggesting that prolonged antipsychotic administration resulted in a “reshuffling” of GABA-A receptor subtypes.172 Acute administration of olanzapine and clozapine increased the neuroactive steroid allopregnanolone (a potent positive allosteric modulator of GABA-A receptors) in rat cerebral cortex in a dose-dependent manner.173 These studies demonstrate the potential of antipsychotics to influence GABA-A receptor function and hence SICI. SICI was not correlated with illness duration in patients with schizophrenia,45^,60 although those who had a relatively short duration of illness (e.g., less than 3 years) or treatment (i.e., not longer than 6 weeks continuously) also showed reduced SICI in the motor cortex compared to healthy controls.46^,60^,174 Therefore, the decrease in SICI in schizophrenia may have been independent of illness and treatment duration.

As already mentioned, one of our most consistent findings was the effect of clozapine on CSP duration. This is noteworthy because of the unique place of clozapine in the antipsychotic armamentarium as the only medication licensed for use in treatment-refractory schizophrenia. Although it is clear that clozapine does not exert its unique effect via dopaminergic receptor antagonism (as observed in all other antipsychotic medications), its mechanism of action remains unclear. Clozapine was shown to increase CSP duration in patients with schizophrenia in 4 of 4 studies (2 were longitudinal). 87^,90^,95^,131 Therefore, the effect of clozapine on CSP duration suggests that clozapine may exert part of its antipsychotic effects by improving GABA-B–mediated inhibition. However, the current review did not find a significant correlation between CSP and symptom ratings, suggesting that further studies would be needed to clarify the role of GABA-B in treatment-refractory schizophrenia and the mechanism underlying clozapine’s unique efficacy.6 Interestingly, clozapine had no effect on RMT, MEP amplitudes elicited by single-pulse suprathreshold stimuli, SICI or ICF.44^,87^,95

Other widely used antipsychotic medications include risperidone and olanzapine, and risperidone monotherapy also increased CSP duration with no effect on RMT in a before-and-after treatment study with a group of medication-naive patients with first-episode schizophrenia.132 However, olanzapine and risperidone exerted differential effects on RMT in a cross-sectional study.133 Depending on the transcallosal inhibition paradigm, TMS stimulation can activate inhibitory interneurons in the contralateral motor cortex via a pathway across the corpus callosum, producing a silent period in the ipsilateral tonic hand muscle (single-pulse transcallosal inhibition), or it can inactivate the inhibitory neurons in the contralateral cortex (i.e., an anti-inhibitory effect), reducing the silent period in the ipsilateral tonic hand muscle (dual-pulse transcallosal inhibition).133 Compared to risperidone, treatment with olanzapine might have led to increased inhibitory activity and a stronger anti-inhibitory effect in the contralateral motor cortex during single-pulse and dual-pulse transcallosal inhibition paradigms, respectively.133 Also, although group comparisons (olanzapine v. risperidone v. healthy controls) in Fitzgerald and colleagues133 could not tell us whether olanzapine and risperidone monotherapy had changed SICI, ICF and CSP duration in patients, the lack of statistical difference between the 2 medication groups suggest that the antipsychotics might have a similar effect on the 3 TMS indices.

None of the TMS-EMG indices evaluated in this review was significantly correlated with antipsychotic dose, suggesting that if antipsychotic treatment had an effect on the indices it was not dose-dependent. Finally, antipsychotic medications seemed to have no effect on any of the TMS-EEG outcomes we evaluated, including both the oscillatory responses to single-pulse stimuli and the SAI, SICI, ICF and LICI effects on TMS-EEG activity. However, these findings came from only 8 studies that performed cross-sectional group comparisons (2 studies91^,97) or correlational analyses between antipsychotic doses and TMS-EEG activity (6 studies81^,97^,99^,105^–107). The differences in the study samples (e.g., patients with first-episode or chronic schizophrenia), stimulation paradigms and outcome measures could also have influenced EEG responses to TMS in these studies.

Relationship between TMS measures and symptom severity

The MEP amplitude elicited by suprathreshold single-pulse stimuli was positively correlated with PANSS negative subscale ratings in 2 studies.54^,87 MEP amplitude is thought to reflect trans-synaptic activation of corticospinal neurons through a complex network of excitatory circuits.19 Thus, this correlation suggests that increased excitability of this system might be associated with more severe negative symptoms. Our findings also reported significant associations between symptom severity and SICI and ICF.

ICF is a net facilitation: it reflects the activity of an excitatory motor cortical circuit that is distinct from the SICI network but is closely linked to its function.19 Hence, correlations with SICI and ICF can be discussed together: reduced SICI and increased ICF (i.e., less inhibition and more excitation) were associated with more severe positive symptoms; increased SICI and reduced facilitatory modulation of N100 amplitude by ICF (i.e., more inhibition and less excitation) were associated with less overall symptom severity; and decreased ICF was related to less general psychopathology and more negative symptoms. General psychopathology may reflect deficits in cognition such as disorientation, poor attention, lack of insight and active social avoidance.175 It seems that less inhibition and more excitation might contribute to greater positive symptoms, deficits in cognition and overall symptom severity. One study also found that decreased ICF was associated with greater negative symptoms. 54 However, it should be noted that half of the studies did not find a significant correlation between PANSS scores and SICI (3 of 6 studies)60^,84^,96 and ICF (3 of 7 studies),84^,96,¹⁹⁰ indicating that the relationship between symptoms and TMS neurophysiology needs further research.

Most of the relevant studies (6 of 8)84^,95^,96^,100^,130^,132 found no correlation between CSP duration and symptom ratings as assessed with the PANSS. Moreover, 2 studies found that less severe negative symptoms were associated with more facilitatory connection between the left dorsal premotor cortex and right motor cortex,129 and between the right posterior parietal cortex and right motor cortex.104 Finally, 4 studies examined the correlations between TMS-elicited oscillations and symptom ratings.85^,91^,106^,107 Because they assessed different aspects of TMS-evoked or-induced oscillations (i.e., propagation or global conductivity of signal power, frontal β/γ power, inhibition of γ and overall power by LICI, and natural frequency) in different brain regions (entire brain, motor cortex, dlPFC and premotor cortex, respectively; all in the sensor space) and different patient populations (first-episode psychosis or chronic schizophrenia), it was difficult to ascribe any consistent effects.

The association between SICI and working memory performance, as assessed by different tasks, was a relatively consistent finding. Increased working memory capacity was related to increased SICI in the left motor cortex of medicated patients with recent-onset schizophrenia (duration of illness less than 3 years), and in the left dlPFC in medicated patients with chronic schizophrenia.60^,108 As well, when data from patients and healthy controls were pooled, increased SICI in the motor cortex was associated with better working memory task accuracy on the 3-back condition of the n-back task.93 Taken together, these results might imply a relationship between impaired GABA-A receptor–mediated inhibition and working memory deficits in schizophrenia. As well, more enhancement in SICI in the motor cortex of medicated patients with chronic schizophrenia was associated with more improvement in performance on the delayed recall of words in a verbal learning test,90 which is a sensitive measure for the diagnosis of amnestic mild cognitive impairment and early Alzheimer disease.176 However, the increase in SICI in the same group of patients was related to less improvement in executive function, including task switching and response inhibition (assessed by the time taken to complete the word-colour subtest of the Stroop test).90 These correlations are consistent with the relationship between γ oscillations and working memory.

Lower GABA-B receptor–mediated inhibition (as reflected by a lower degree of LICI in 1 study143 and reduced N100 amplitude in another97) in the left dlPFC might also contribute to poorer working memory capacity and executive function (assessed by the Stroop task and the Trail-Making Test) in patients with schizophrenia.108^,143 Noda and colleagues97 also showed that central cholinergic activity induced by the SAI paradigm increased N100 amplitude in the dlPFC of healthy controls, whereas cholinergic activity might be impaired in patients with schizophrenia, leading to suppression of the N100 amplitude in the dlPFC.

Social cognition is closely related to the negative symptoms of schizophrenia and forms an important deficit that prevents people from engaging in social activities and work. A key aspect of social cognition is the ability to infer the intentions of other people, and the mirror neuron system has been proposed to underpin this important function. Mirror neurons are neurons that fire both when we act and when we observe the same action performed by others.177 Mirror neuron activity has been indexed by increased MEP amplitude in response to suprathreshold single-pulse stimuli (with or without a reduced SICI and increased ICF) while observing an action. 78^,145^,146 Three studies76^,145^,146 demonstrated that the mirror neuron system may be impaired in the motor cortex of patients with schizophrenia during action observation, whether the action is embedded in a social context or not. This suggests that an impaired mirror neuron system may be a potential marker of poorer social cognition and warrants further investigation for its effect on social networks and functioning.

Relationship between TMS measures and illness duration

The TMS-EMG and TMS-EEG measures evaluated the current review were not associated with duration of illness in schizophrenia, except in 1 study,104 which reported a significant correlation between illness duration and facilitatory connection between the right posterior parietal and right motor cortices in a group of patients with chronic schizophrenia (70% of whom were medicated). Thus, the findings of this review do not support the premise that illness duration may itself induce physiologic changes in the brain.

TMS-elicited plasticity and effective connectivity in schizophrenia

In medicated patients with chronic schizophrenia relative to healthy controls, prolonged duration of transcallosal inhibition evoked by the single-pulse transcallosal inhibition paradigm, indexing functional connectivity in schizophrenia, may hint at functional impairment of transcallosal motor pathways in schizophrenia that might result from structural changes of the relevant callosal fibres.79^,80^,178 The facilitatory parietomotor connection in the right hemisphere may also be reduced in both medicated and unmedicated patients with chronic schizophrenia.104 One study81 showed that signal propagation of TMS-elicited neural activity in patients with schizophrenia (most of whom were medicated) was limited to the premotor and motor areas along the midline in both hemispheres in the first 100 ms after TMS of the right premotor cortex, suggesting defective interactions among cortical areas in chronic schizophrenia. Another study83 found that higher average global voltage 400~750 ms after TMS of the left motor cortex in patients with chronic schizophrenia (most of whom were medicated) may be driven by increased total power in the δ and β or γ bands between 400~800 ms in many EEG channels. Such prolonged activation relative to healthy controls may suggest increased interhemispheric functional connectivity between homologous motor areas and extended to bilateral temporoparietal regions in patients with schizophrenia.85 These studies showed that functional connectivity in patients with chronic schizophrenia may be disrupted in both time and space (including interhemispheric and within-hemisphere connections). This finding supports a contemporary theory that schizophrenia symptoms arise as a consequence of functional neural dysconnectivity rather than because of a specific regional deficit or lesion.179

Deficient neural plasticity was reported in 4 studies that assessed motor cortical plasticity in patients with schizophrenia. 44^,45^,89^,96 Patients with chronic schizophrenia (most of whom were medicated) in Strube and colleagues89 showed a deficit in focal long-term potentiation–like plasticity induced by paired associative stimulation, which emulates spike-timing-dependent plasticity.52^,180 Another study43 reported deficient anodal tDCS-induced nonfocal long-term potentiation–like plasticity in patients with multiple psychotic episodes (most of them medicated) but not in those with a single episode (recent-onset schizophrenia; most of them medicated), suggesting “a neurodegenerative process of cortical plasticity in patients with schizophrenia.” However, a recent meta-analysis reported that illness duration might not influence motor cortical plasticity in schizophrenia, and that altered plasticity may predate the manifestation of clinical symptoms.181 Furthermore, Hasan and colleagues45 speculated that patients with chronic schizophrenia might have disturbed GABAergic neurotransmission because tDCS enhanced SICI only in those with recent-onset schizophrenia. Still, no significant difference in SICI was found among those with recent-onset schizophrenia, multi-episode schizophrenia or healthy controls before tDCS administration in that study, and SICI was not correlated with the number of psychotic episodes or duration of psychosis in patients with schizophrenia. The third study96 found that a 15-minute train of low-frequency repetitive TMS increased RMT and decreased CSP duration in healthy controls but not in medicated and unmedicated patients with chronic schizophrenia; however, the change in MEP amplitudes did not differ significantly among groups when controlling for multiple comparisons. The fourth study131 demonstrated that medicated and unmedicated patients had an equal deficit in orienting post-training thumb movements in the direction of training compared to healthy controls, indicating that the mechanisms involved in use-dependent reorganization of cortical synaptic connections may be disrupted in schizophrenia.

Although the studies used change in MEP amplitude to index plasticity, it is important to note that before the administration of the plasticity paradigms (i.e., paired associative stimulation, anodal tDCS and rTMS), there was no significant difference in MEP amplitude among their respective participant groups, implying that the excitability of the motor cortex may not differ between patients and healthy controls. This may suggest that dysfunction may arise only as a consequence of dynamic change secondary to increased load or demand placed on the neural connectivity in the system. Indeed, tDCS to enhance neural plasticity and connectivity has been a feature of more recent novel interventions to improve cognitive symptoms in schizophrenia.182 Both NMDA receptor function and dopaminergic transmission have been implicated as essential components in long-term potentiation and use-dependent motor learning; GABAergic and cholinergic activity may also play a role in modulating plasticity.45^,89^,131

Risk of bias

For the subscales “measurement of exposure” and “blinding of outcome assessments,” details about blinding during data collection and analysis were not available in most of the studies and we were unable to judge whether the presumed absence of blinding in these studies may have affected the results. For the assessment of “selective outcome reporting,” we did not find the preregistered experimental protocol for any of the included studies, so formal assessment was not possible and we based our judgment on whether the outcomes and analyses defined in the hypotheses and methods sections (particularly the statistical analyses) were described in the results section of the studies.

Limitations

We aimed to review the literature on TMS-EMG and TMS-EEG in schizophrenia. The included studies were heterogeneous with respect to TMS paradigms and outcome measures, research questions and analyses, and participant samples, precluding a meta-analysis of the findings. Moreover, although the current review was set to include only those with a diagnosis of schizophrenia or schizoaffective disorder, one of the included studies91 examined patients with first-episode psychosis. As well, the various studies adopted different methods and criteria for excluding participants who might also have had substance abuse. Some studies used urine tests but others did not, and the time periods for which substance use was excluded before study participation differed. One of the studies83 screened the healthy controls for substance abuse and we assumed they did the same for patients with schizophrenia. Most of the patients included in the current review were medicated and had chronic schizophrenia. Most of the studies used cross-sectional group comparisons and had small patient sample sizes (less than 30). Longitudinal studies with larger samples may be needed to investigate changes in the brain associated with treatment effects and disease progression by following up participants from prodrome to schizophrenia diagnosis, or even longer.