The double-blind sham-controlled study of high-frequency rTMS (20 Hz) for negative symptoms in schizophrenia: negative results

The high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) over the prefrontal cortex is a promising method for the treatment of negative symptoms of schizophrenia. Using double-blind sham-controlled parallel design, we evaluated the effect of HF-rTMS over the left dorsolateral prefrontal cortex (DLPFC) on negative symptoms in patients with schizophrenia. Sixteen schizophrenia patients with predominantly negative symptoms on stable antipsychotic medication were treated with 20 Hz rTMS (90% of motor threshold, 2000 stimuli per session) over ten days within 2 weeks with six weeks follow-up. The effect was assessed using PANSS, CGI, MADRS and neuropsychological tests. We failed to find any significant effect of active rTMS. Sham rTMS showed a trend for improvement over time on positive and negative subscales of PANSS and MADRS. Between-group comparisons failed to reveal any significant differences on any rating scales except a positive subscale of PANSS after 8 weeks. Results from our study did not confirm that HF-rTMS over the left DLPCF affects the negative symptoms of schizophrenia and alternative rTMS approaches are discussed.     

奥氮平联合重复经颅磁刺激或改良电休克治疗精神分裂症的疗效分析

目的:比较抗精神病药物奥氮平联合复经颅磁刺激(rTMS)或改良电休克(MECT)治疗精神分裂症的疗效。方法:将84例精神分裂症患者随机分为rTMS组(42例)与MECT组(42例),两组分别在奥氮平的基础上联合MECT或rTMS进行治疗。在治疗2、4、8周末后,采用阳性症状和阴性症状量表PANSS、治疗时出现症状量表TESS评估临床治疗效果及不良反应,同时采用修订韦氏记忆量表(WMS-RC)和威斯康星卡片分类测验(WCST)评定认知功能。结果:治疗后,两组总有效率比较无统计学差异(P0.05)。两组治疗后PANSS总分、阳性症状、阴性症状和一般病理分值均显著低于治疗前(P0.05,P0.01),但组间比较无统计学差异(P0.05)。两组TESS评分及不良反应的发生情况比较无统计学差异(P0.05)。与治疗前相比,两组患者治疗后认知功能均显著改善(P0.05,P0.01),且rTMS联合组在改善患者记忆功能、执行能力方面效果优于MTCT组(P0.05)。结论:奥氮平联合MECT或rTMS对精神分裂症状的疗效相当,但联合rTMS可更显著改善患者的认知功能。     

重复经颅磁刺激对慢性精神分裂症患者认知功能影响的初步研究

目的:探讨重复经颅磁刺激(rTMS)对慢性精神分裂症患者认知功能的影响。方法:100例慢性精神分裂症患者,按照随机数字表法分为rTMS真刺激组和伪刺激组,每组各50例。采用阳性与阴性症状量表(PANSS)及副反应量表(TESS)评估患者治疗前后精神症状及不良反应;采用威斯康星卡片分类测验(WCST)及可重复的成套神经心理状态测量(RBANS)评价患者治疗前后认知功能。结果:治疗后,rTMS真刺激组PANSS总分、阳性量表分、阴性量表分、一般精神病理量表分均明显降低(P0.05),且均明显低于伪刺激组(P0.05),两组治疗前后及组间TESS评分无明显差异(P0.05);rTMS真刺激组WCST中的概念化水平百分数明显高于伪刺激组(P0.05),总时间及错误思考时间短于伪刺激组(P0.05);rTMS真刺激组RBANS中视觉广度与延迟记忆成绩明显提高(P0.05),且视觉广度明显高于伪刺激组(P0.05);rTMS真刺激组2例患者首次治疗后出现轻度不适症状,随访3个月所有患者均无不适主诉。结论:rTMS治疗对慢性精神分裂症患者的部分认知功能有一定的改善作用,且安全性较高,值得进一步研究。     

Repetitive transcranial magnetic stimulation in a patient suffering from depression and rheumatoid arthritis: evidence for immunomodulatory effects

Repetitive transcranial magnetic stimulation (rTMS) has been suggested as antidepressive treatment strategy. The mechanism of action by which the antidepressive effect is brought about remains unclear at present. Here, we report findings in a patient suffering from recurrent major depression and rheumatoid arthritis. Improvement of depressive symptoms during 20 Hz rTMS of the left dorsolateral prefrontal cortex was repeatedly associated with a systemic inflammatory reaction, suggesting that rTMS induced an immunomodulatory effect.     

Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment

In humans, phencyclidine (PCP), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reproduces a schizophrenia-like psychosis including positive symptoms, negative symptoms and cognitive dysfunction. Thus, the glutamatergic neuronal dysfunction hypothesis is one of the main explanatory hypotheses and PCP-treated animals have been utilized as an animal model of schizophrenia. The adult rodents treated with PCP repeatedly exhibit hyperlocomotion as an index of positive symptoms, a social behavioral deficit in a social interaction test and enhanced immobility in a forced swimming test as indices of negative symptoms. They also show a sensorimotor gating deficits and cognitive dysfunctions in several learning and memory tests. Some of these behavioral changes endure after withdrawal from repeated PCP treatment. Furthermore, repeated PCP treatment induces some neurochemical and neuroanatomical changes. On the other hand, the exposure to viral or environmental insult in the second trimester of pregnancy increases the probability of subsequently developing schizophrenia as an adult. NMDA receptor has been implicated in controlling the structure and plasticity of developing brain circuitry. Based on neurodevelopment hypothesis of schizophrenia, schizophrenia model rats treated with PCP at the perinatal stage is developed. Perinatal PCP treatment impairs neuronal development and induces long-lasting schizophrenia-like behaviors in adult period. Many findings suggest that these PCP animal models would be useful for evaluating novel therapeutic candidates and for confirming pathological mechanisms of schizophrenia.     

The Loudness Dependence of Auditory Evoked Potentials (LDAEP) as an Indicator of Serotonergic Dysfunction in Patients with Predominant Schizophrenic Negative Symptoms

Besides the influence of dopaminergic neurotransmission on negative symptoms in schizophrenia, there is evidence that alterations of serotonin (5-HT) system functioning also play a crucial role in the pathophysiology of these disabling symptoms. From post mortem and genetic studies on patients with negative symptoms a 5-HT dysfunction is documented. In addition atypical neuroleptics and some antidepressants improve negative symptoms via serotonergic action. So far no research has been done to directly clarify the association between the serotonergic functioning and the extent of negative symptoms. Therefore, we examined the status of brain 5-HT level in negative symptoms in schizophrenia by means of the loudness dependence of auditory evoked potentials (LDAEP). The LDAEP provides a well established and non-invasive in vivo marker of the central 5-HT activity. We investigated 13 patients with schizophrenia with predominant negative symptoms treated with atypical neuroleptics and 13 healthy age and gender matched controls with a 32-channel EEG. The LDAEP of the N1/P2 component was evaluated by dipole source analysis and single electrode estimation at Cz. Psychopathological parameters, nicotine use and medication were assessed to control for additional influencing factors. Schizophrenic patients showed significantly higher LDAEP in both hemispheres than controls. Furthermore, the LDAEP in the right hemisphere in patients was related to higher scores in scales assessing negative symptoms. A relationship with positive symptoms was not found. These data might suggest a diminished central serotonergic neurotransmission in patients with predominant negative symptoms.     

Trait and state positive emotional experience in schizophrenia: a meta-analysis

Background

Prior meta-analyses indicated that people with schizophrenia show impairment in trait hedonic capacity but retain their state hedonic experience (valence) in laboratory-based assessments. Little is known about what is the extent of differences for state positive emotional experience (especially arousal) between people with schizophrenia and healthy controls. It is also not clear whether negative symptoms and gender effect contribute to the variance of positive affect.

Methods and Findings

The current meta-analysis examined 21 studies assessing state arousal experience, 40 studies measuring state valence experience, and 47studies assessing trait hedonic capacity in schizophrenia. Patients with schizophrenia demonstrated significant impairment in trait hedonic capacity (Cohen’s d = 0.81). However, patients and controls did not statistically differ in state hedonic (valence) as well as exciting (arousal) experience to positive stimuli (Cohen’s d = −0.24 to 0.06). They also reported experiencing relatively robust state aversion and calmness to positive stimuli compared with controls (Cohen’s d = 0.75, 0.56, respectively). Negative symptoms and gender contributed to the variance of findings in positive affect, especially trait hedonic capacity in schizophrenia.

Conclusions

Our findings suggest that schizophrenia patients have no deficit in state positive emotional experience but impairment in “noncurrent” hedonic capacity, which may be mediated by negative symptoms and gender effect.     

Effects of Low Frequency Prefrontal Repetitive Transcranial Magnetic Stimulation on the N2 Amplitude in a GoNogo Task

During the last decade, repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex has become established as a treatment for various mental diseases. The rational of prefrontal stimulation has been adapted from the mode of action known from rTMS using motor-evoked potentials though little is known about the precise effect of rTMS at prefrontal sites. The objective of the current study is to investigate the inhibitory effect of prefrontal 1 Hz rTMS by stimulating the generators of event-related potentials (ERP) which are located in the prefrontal cortex. Thus, 1 Hz rTMS was applied offline over the left dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal cortex (MPFC) in 18 healthy subjects who subsequently underwent a GoNogo task. Both active conditions were compared to sham rTMS within a randomized and counterbalanced cross-over design in one day. ERPs were recorded during task performance and the N2 and the P3 were analysed. After 1 Hz rTMS of the left DLPFC (but not of the MPFC), an inhibitory effect on the N2 amplitude was observed, which was related to inhibitory control. In contrast, after 1 Hz rTMS of the MPFC (but not at the left DLPFC) a trend towards an increased P3 amplitude was found. There was no significant modulation of latencies and behavioural data. The results argue in favour of an inhibitory effect of 1 Hz rTMS on N2 amplitudes in a GoNogo task. Our findings suggest that rTMS may mildly modulate prefrontally generated ERP immediately after stimulation, even where behavioural effects are not measurable. Thus, combined rTMS-ERP approaches need to be further established in order to serve as paradigms in experimental neuroscience and clinical research.     

Pregnenolone Rescues Schizophrenia-Like Behavior in Dopamine Transporter Knockout Mice

Pregnenolone belongs to a class of endogenous neurosteroids in the central nervous system (CNS), which has been suggested to enhance cognitive functions through GABA_A receptor signaling by its metabolites. It has been shown that the level of pregnenolone is altered in certain brain areas of schizophrenic patients, and clozapine enhances pregnenolone in the CNS in rats, suggesting that pregnenolone could be used to treat certain symptoms of schizophrenia. In addition, early phase proof-of-concept clinical trials have indicated that pregnenolone is effective in reducing the negative symptoms and cognitive deficits of schizophrenia patients. Here, we evaluate the actions of pregnenolone on a mouse model for schizophrenia, the dopamine transporter knockout mouse (DAT KO). DAT KO mice mirror certain symptoms evident in patients with schizophrenia, such as the psychomotor agitation, stereotypy, deficits of prepulse inhibition and cognitive impairments. Following acute treatment, pregnenolone was found to reduce the hyperlocomotion, stereotypic bouts and pre-pulse inhibition (PPI) deficits in DAT KO mice in a dose-dependent manner. At 60 mg/kg of pregnenolone, there were no significant differences in locomotor activities and stereotypy between wild-type and DAT KO mice. Similarly, acute treatment of 60 mg/kg of pregnenolone fully rescued PPI deficits of DAT KO mice. Following chronic treatment with pregnenolone at 60 mg/kg, the cognitive deficits of DAT KO mice were rescued in the paradigms of novel object recognition test and social transmission of food preference test. Pregnenolone thus holds promise as a therapeutic candidate in schizophrenia.     

TMS evidence for the involvement of the right occipital face area in early face processing

Extensive research has demonstrated that several specialized cortical regions respond preferentially to faces. One such region, located in the inferior occipital gyrus, has been dubbed the occipital face area (OFA). The OFA is the first stage in two influential face-processing models, both of which suggest that it constructs an initial representation of a face, but how and when it does so remains unclear. The present study revealed that repetitive transcranial magnetic stimulation (rTMS) targeted at the right OFA (rOFA) disrupted accurate discrimination of face parts but had no effect on the discrimination of spacing between these parts. rTMS to left OFA had no effect. A matched part and spacing discrimination task that used house stimuli showed no impairment. In a second experiment, rTMS to rOFA replicated the face-part impairment but did not produce the same effect in an adjacent area, the lateral occipital cortex. A third experiment delivered double pulses of TMS separated by 40 ms at six periods after stimulus presentation during face-part discrimination. Accuracy dropped when pulses were delivered at 60 and 100 ms only. These findings indicate that the rOFA processes face-part information at an early stage in the face-processing stream.     

Impaired Representation of Time in Schizophrenia Is Linked to Positive Symptoms and Cognitive Demand

Time processing critically relies on the mesencephalic dopamine system and striato-prefrontal projections and has thus been suggested to play a key role in schizophrenia. Previous studies have provided evidence for an acceleration of the internal clock in schizophrenia that may be linked to dopaminergic pathology. The present study aimed to assess the relationship between altered time processing in schizophrenia and symptom manifestation in 22 patients and 22 controls. Subjects were required to estimate the time needed for a visual stimulus to complete a horizontal movement towards a target position on trials of varying cognitive demand. It was hypothesized that patients – compared to controls – would be less accurate at estimating the movement time, and that this effect would be modulated by symptom manifestation and task difficulty. In line with the notion of an accelerated internal clock due to dopaminergic dysregulation, particularly patients with severe positive symptoms were expected to underestimate movement time. However, if altered time perception in schizophrenia was better explained in terms of cognitive deficits, patients with severe negative symptoms should be specifically impaired, while generally, task performance should correlate with measures of processing speed and cognitive flexibility. Patients underestimated movement time on more demanding trials, although there was no link to disease-related cognitive dysfunction. Task performance was modulated by symptom manifestation. Impaired estimation of movement time was significantly correlated with PANSS positive symptom scores, with higher positive symptom scores associated with stronger underestimation of movement time. The present data thus support the notion of a deficit in anticipatory and predictive mechanisms in schizophrenia that is modulated both by symptom manifestation and by cognitive demand.     

Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial

Schizophrenia is a chronic, complex and heterogeneous mental disorder, with pathological features of disrupted neuronal excitability and plasticity within limbic structures of the brain. These pathological features manifest behaviorally as positive symptoms (including hallucinations, delusions and thought disorder), negative symptoms (such as social withdrawal, apathy and emotional blunting) and other psychopathological symptoms (such as psychomotor retardation, lack of insight, poor attention and impulse control). Altered glutamate neurotransmission has for decades been linked to schizophrenia, but all commonly prescribed antipsychotics act on dopamine receptors. LY404039 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors and has shown antipsychotic potential in animal studies. With data from rodents, we provide new evidence that mGlu2/3 receptor agonists work by a distinct mechanism different from that of olanzapine. To clinically test this mechanism, an oral prodrug of LY404039 (LY2140023) was evaluated in schizophrenic patients with olanzapine as an active control in a randomized, three-armed, double-blind, placebo-controlled study. Treatment with LY2140023, like treatment with olanzapine, was safe and well-tolerated; treated patients showed statistically significant improvements in both positive and negative symptoms of schizophrenia compared to placebo (P < 0.001 at week 4). Notably, patients treated with LY2140023 did not differ from placebo-treated patients with respect to prolactin elevation, extrapyramidal symptoms or weight gain. These data suggest that mGlu2/3 receptor agonists have antipsychotic properties and may provide a new alternative for the treatment of schizophrenia.     

Short and Long Term Effects of Left and Bilateral Repetitive Transcranial Magnetic Stimulation in Schizophrenia Patients with Auditory Verbal Hallucinations: A Randomized Controlled Trial

Background

Repetitive transcranial magnetic stimulation of the left temporo-parietal junction area has been studied as a treatment option for auditory verbal hallucinations. Although the right temporo-parietal junction area has also shown involvement in the genesis of auditory verbal hallucinations, no studies have used bilateral stimulation. Moreover, little is known about durability effects. We studied the short and long term effects of 1 Hz treatment of the left temporo-parietal junction area in schizophrenia patients with persistent auditory verbal hallucinations, compared to sham stimulation, and added an extra treatment arm of bilateral TPJ area stimulation.

Methods

In this randomized controlled trial, 51 patients diagnosed with schizophrenia and persistent auditory verbal hallucinations were randomly allocated to treatment of the left or bilateral temporo-parietal junction area or sham treatment. Patients were treated for six days, twice daily for 20 minutes. Short term efficacy was measured with the Positive and Negative Syndrome Scale (PANSS), the Auditory Hallucinations Rating Scale (AHRS), and the Positive and Negative Affect Scale (PANAS). We included follow-up measures with the AHRS and PANAS at four weeks and three months.

Results

The interaction between time and treatment for Hallucination item P3 of the PANSS showed a trend for significance, caused by a small reduction of scores in the left group. Although self-reported hallucination scores, as measured with the AHRS and PANAS, decreased significantly during the trial period, there were no differences between the three treatment groups.

Conclusion

We did not find convincing evidence for the efficacy of left-sided rTMS, compared to sham rTMS. Moreover, bilateral rTMS was not superior over left rTMS or sham in improving AVH. Optimizing treatment parameters may result in stronger evidence for the efficacy of rTMS treatment of AVH. Moreover, future research should consider investigating factors predicting individual response.

Trial Registration

Dutch Trial Register NTR1813     

重复经颅磁刺激对卒中后抑郁的治疗效果及机制

卒中后抑郁（post-stroke depression,PSD）是并发于脑血管病的一种情感障碍疾病，发病率高，预后差。重复经颅磁刺激（repetitive transcranial magnetic stimulation,r TMS）是通过磁场变化在大脑中产生感应电流来刺激皮层的非创伤性脑刺激技术，是临床上治疗PSD的一种重要非药物治疗方法，可以显著改善PSD患者的抑郁症状。但目前rTMS的作用机制不明确。本文总结了PSD治疗中有效的rTMS刺激方案，并结合PSD的单胺类神经递质相关致病假说及PSD的临床治疗手段，探索了rTMS通过对单胺类神经递质的调控参与PSD治疗的可能机制。rTMS刺激诱导的皮层单胺类递质释放增加、葡萄糖代谢上升、皮层兴奋性增加，提高了单胺类神经递质和脑源性神经营养因子（brain-derived neurotrophic factor,BDNF）水平，进而引发前额叶抑制功能上升、与下游脑区连接改变、脑网络功能的调整，可能是rTMS治疗PSD的重要机制之一。     

Modulation of monoamine transporter expression and function by repetitive transcranial magnetic stimulation

Repetitive transcranial magnetic stimulation (rTMS) is a new tool for the treatment of neuropsychiatric disorders. However, the mechanisms underlying the effects of rTMS are still unclear. In this study, we analyzed mRNA expression changes of monoamine transporter (MAT) genes, which are targets for antidepressants and psychostimulants. Following a 20-day rTMS treatment, these genes were found to be differentially expressed in the mouse brain. Down-regulation of serotonin transporter (SERT) mRNA levels and the subsequent decrease in serotonin uptake and binding were observed after chronic rTMS. In contrast to the SERT changes, increased mRNA levels of dopamine transporter (DAT) and norepinephrine transporter (NET) were observed. For NET, but not DAT, there were accompanying changes in uptake and binding. Similar effect on NET was observed in PC12 cells stimulated by rTMS for 15 days. These results indicate that modulation of MATs by chronic rTMS may be one therapeutic mechanism for the treatment of neuropsychiatric disorders.     

不同频率重复经颅磁刺激治疗脑卒中后失语症的效果观察

目的:探讨不同频率重复经颅磁刺激(Repeated transcranial magnetic stimulation,r TMS)治疗脑卒中后失语症的临床效果。方法:选取2015年10月至2018年10月我院收治的脑卒中后失语症患者80例,采用随机数字表法将患者分为两组,低频组患者给予低频r TMS治疗,高频组患者给予高频r TMS治疗。比较两组患者治疗后的西方失语成套测验(Western Aphasia Battery,WAB)各项评分,治疗前后日常生活交流能力检查(Communicative abilities in daily living test,CADL)评分、视图命名得分及命名反应时间的变化。结果:治疗后,两组患者的自发语言、听理解、命名、复述和失语商(Aphasia quotient,AQ)评分比较均无统计学差异(P0.05);两组CADL评分和视图命名得分均较治疗前显著升高(P0.05),但两组间比较无统计学差异(P0.05);两组命名反应时间均较治疗前显著缩短,且高频组显著短于低频组(P0.05)。结论:高频r TMS与低频r TMS均可显著改善脑卒中后失语症患者的自发语言、听理解、命名、复述及日常生活交流能力,但高频r TMS在缩短命名反应时间方面具有更好的效果。     

A Neuronal Network Model for Simulating the Effects of Repetitive Transcranial Magnetic Stimulation on Local Field Potential Power Spectra

Repetitive transcranial magnetic stimulation (rTMS) holds promise as a non-invasive therapy for the treatment of neurological disorders such as depression, schizophrenia, tinnitus, and epilepsy. Complex interdependencies between stimulus duration, frequency and intensity obscure the exact effects of rTMS stimulation on neural activity in the cortex, making evaluation of and comparison between rTMS studies difficult. To explain the influence of rTMS on neural activity (e.g. in the motor cortex), we use a neuronal network model. The results demonstrate that the model adequately explains experimentally observed short term effects of rTMS on the band power in common frequency bands used in electroencephalography (EEG). We show that the equivalent local field potential (eLFP) band power depends on stimulation intensity rather than on stimulation frequency. Additionally, our model resolves contradictions in experiments.     

Aberrant Interference of Auditory Negative Words on Attention in Patients with Schizophrenia

Previous research suggests that deficits in attention-emotion interaction are implicated in schizophrenia symptoms. Although disruption in auditory processing is crucial in the pathophysiology of schizophrenia, deficits in interaction between emotional processing of auditorily presented language stimuli and auditory attention have not yet been clarified. To address this issue, the current study used a dichotic listening task to examine 22 patients with schizophrenia and 24 age-, sex-, parental socioeconomic background-, handedness-, dexterous ear-, and intelligence quotient-matched healthy controls. The participants completed a word recognition task on the attended side in which a word with emotionally valenced content (negative/positive/neutral) was presented to one ear and a different neutral word was presented to the other ear. Participants selectively attended to either ear. In the control subjects, presentation of negative but not positive word stimuli provoked a significantly prolonged reaction time compared with presentation of neutral word stimuli. This interference effect for negative words existed whether or not subjects directed attention to the negative words. This interference effect was significantly smaller in the patients with schizophrenia than in the healthy controls. Furthermore, the smaller interference effect was significantly correlated with severe positive symptoms and delusional behavior in the patients with schizophrenia. The present findings suggest that aberrant interaction between semantic processing of negative emotional content and auditory attention plays a role in production of positive symptoms in schizophrenia. (224 words)     

Cerebral responses of healthy humans to rhythmic transcranial magnetic stimulation of different intensities

The effect of rhythmic transcranial magnetic stimulation (rTMS) of different intensities (single superthreshold rTMS more intense than 1.2 T and subthreshold one with an intensity of 70–80% of the motor threshold) of sagittal premotor cortical areas on the human functional activity was estimated in eight volunteers on the basis of combined EEG, neuropsychological, and hemodynamic examinations. The objectives of the study included the selection of the frequency of activating stimulation and revision of the objective EEG criteria of rTMS efficiency. It has been demonstrated that analysis of the EEG response to photostimulation at different frequencies is efficient in selecting the rTMS frequency. The EEG coherence is one of the most informative characteristics of the rTMS effect on central neurodynamics. The functional effects of stimulation (activating or inhibitory) have been shown to depend on the initial level of intercentral coherent relationships It has been found that rTMS of the sagittal premotor cortex causes definite changes in the functional activity of a healthy brain different from those caused by placebo. These changes are greater in the left hemisphere (in the form of intrahemispheric changes in coherence and depend on the stimulation intensity (superor subthreshold) and the initial state. The vascular factor has been shown to play an important role in the formation of cerebral responses to rTMS.     

The effect of repetitive transcranial magnetic stimulation on gamma oscillatory activity in schizophrenia

Background

Gamma (γ) oscillations (30–50 Hz) have been shown to be excessive in patients with schizophrenia (SCZ) during working memory (WM). WM is a cognitive process that involves the online maintenance and manipulation of information that is mediated largely by the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS) represents a non-invasive method to stimulate the cortex that has been shown to enhance cognition and γ oscillatory activity during WM.

Methodology and Principal Findings

We examined the effect of 20 Hz rTMS over the DLPFC on γ oscillatory activity elicited during the N-back task in 24 patients with SCZ compared to 22 healthy subjects. Prior to rTMS, patients with SCZ elicited excessive γ oscillatory activity compared to healthy subjects across WM load. Active rTMS resulted in the reduction of frontal γ oscillatory activity in patients with SCZ, while potentiating activity in healthy subjects in the 3-back, the most difficult condition. Further, these effects on γ oscillatory activity were found to be specific to the frontal brain region and were absent in the parieto-occipital brain region.

Conclusions and Significance

We suggest that this opposing effect of rTMS on γ oscillatory activity in patients with SCZ versus healthy subjects may be related to homeostatic plasticity leading to differential effects of rTMS on γ oscillatory activity depending on baseline differences. These findings provide important insights into the neurophysiological mechanisms underlying WM deficits in SCZ and demonstrated that rTMS can modulate γ oscillatory activity that may be a possible avenue for cognitive potentiation in this disorder.