To identify the clinical efficacy of rhythmic transcranial magnetic stimulation (rTMS) in resistant schizophrenia.

The study included 44 male patients with resistant schizophrenia, divided into 4 groups: with depressive (group 1; n=11, 25.0%), with hallucinatory (group 2; n=12, 27.3%), with negative (group 3; n=11, 25.0%) and with delusional symptoms (group 4; n=10, 22.7%). Patients received rTMS, the parameters of which were determined depending on the typological variety, for 3 weeks (15 sessions). Psychometric assessment was carried with PANSS, CGI-S, CGI-I, SANS, CDSS, AHRS when included in the study (0 day), after stimulation (21 days) and by the end of the study (42 day) that allowed evaluation of both the severity of the therapeutic effect and its duration.

By the end of the course of stimulation, patients of the first three groups developed a distinct positive effect corresponding to a significant reduction in the total PANSS score: group 1 - 24.4% (p=0.002), group 2 - 8.3% (p=0.02), group 3 - 11.7% (p=0.001), which remained stable by day 42 in patients of the first (p=0.001) and second (p=0.005) groups. In patients with delusional symptoms (group 4), a subpsychotic state developed with a corresponding increase in the total PANSS score by 9.7% (p=0.007) requiring a course of relief therapy, which showed effectiveness by the end of the observation (day 42), indicating that resistance was overcome.

The study demonstrated the validity of rTMS as an adjuvant method of treatment in the resistant schizophrenia. To implement the potential of rTMS, it is necessary first of all to take into account the structural features of the condition, as well as to continue improving the stimulation technique itself (increasing the duration of the course, developing supportive courses).

Traditional therapeutic methods in psychiatry, such as psychopharmacology and psychotherapy help many people suffering from mental disorders, but in the long-term prove to be effective in a relatively small proportion of those affected. Therapeutically, resistant forms of mental disorders such as schizophrenia, major depressive disorder, and bipolar disorder lead to persistent distress and dysfunction in personal, social, and professional aspects. In an effort to address these problems, the translational approach in neuroscience has initiated the inclusion of novel or modified unconventional diagnostic and therapeutic techniques with promising results. For instance, neuroimaging data sets from multiple modalities provide insight into the nature of pathophysiological mechanisms such as disruptions of connectivity, integration, and segregation of neural networks, focusing on the treatment of mental disorders through instrumental biomedical methods such as electro-convulsive therapy (ECT), transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS) and deep brain stimulation (DBS). These methodologies have yielded promising results that have yet to be understood and improved to enhance the prognosis of the severe and persistent psychotic and affective disorders. The current review is focused on the translational approach in the management of schizophrenia and mood disorders, as well as the adaptation of new transdisciplinary diagnostic tools such as neuroimaging with concurrently administered psychopathological questionnaires and integration of the results into the therapeutic framework using various advanced instrumental biomedical tools such as ECT, TMS, tDCS and DBS.

Repetitive transcranial magnetic stimulation (rTMS), when applied to left dorsolateral prefrontal cortex (LDLPFC), reduces negative symptoms of schizophrenia, but has no effect on positive symptoms. In a small number of cases, it appears to worsen the severity of positive symptoms. It has been hypothesized that high-frequency rTMS of the LDLPFC might increase the dopaminergic neurotransmission by driving the activity of the left striatum in the basal ganglia (LSTR)-increasing striatal dopaminergic activity. This hypothesis relies on the assumption that either the frontal-striatal connection or the intrinsic frontal and/or striatal connections covary with the severity of positive symptoms. The current work aimed to evaluate this assumption by studying the association between positive and negative symptoms severity and the effective connectivity within the frontal and striatal network using dynamic causal modeling of resting state fMRI in a sample of 19 first episode psychosis subjects. We found that the total score of positive symptoms of schizophrenia is strongly associated with the frontostriatal circuitry. Stronger intrinsic inhibitory tone of LDLPFC and LSTR, as well as decreased bidirectional excitatory influence between the LDLPFC and the LSTR is related to the severity of positive symptoms, especially delusions. We interpret that an increase in striatal dopaminergic tone that underlies positive symptoms is likely associated with increased prefrontal inhibitory tone, strengthening the frontostriatal 'brake'. Furthermore, based on our model, we propose that lessening of positive symptoms could be achieved by means of continuous theta-burst or low-frequency (1 Hz) rTMS of the prefrontal area.

We reviewed the literature on transcranial magnetic stimulation and its uses and efficacy in schizophrenia. Multiple sources were examined on transcranial magnetic stimulation efficacy in relieving positive and negative symptoms of schizophrenia. Literature review was conducted via Ovid Medline and PubMed databases. We found multiple published studies and metaanalyses that give evidence that repetitive transcranial magnetic stimulation can have benefit in relieving positive and negative symptoms of schizophrenia, particularly auditory hallucinations. These findings should encourage the psychiatric community to expand research into other applications for which transcranial magnetic stimulation may be used to treat patients with psychiatric disability.

Investigators are urgently searching for options to treat negative symptoms in schizophrenia because these symptoms are disabling and do not respond adequately to antipsychotic or psychosocial treatment. Meta-analyses based on small proof-of-principle trials suggest efficacy of repetitive transcranial magnetic stimulation (rTMS) for the treatment of negative symptoms and call for adequately powered multicenter trials. This study evaluated the efficacy of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex for the treatment of predominant negative symptoms in schizophrenia.

A multicenter randomized, sham-controlled, rater-blinded and patient-blinded trial was conducted from 2007-2011. Investigators randomly assigned 175 patients with schizophrenia with predominant negative symptoms and a high-degree of illness severity into two treatment groups. After a 2-week pretreatment phase, 76 patients were treated with 10-Hz rTMS applied 5 days per week for 3 weeks to the left dorsolateral prefrontal cortex (added to the ongoing treatment), and 81 patients were subjected to sham rTMS applied similarly.

There was no statistically significant difference in improvement in negative symptoms between the two groups at day 21 (p = .53, effect size = .09) or subsequently through day 105. Also, symptoms of depression and cognitive function showed no differences in change between groups. There was a small, but statistically significant, improvement in positive symptoms in the active rTMS group (p = .047, effect size = .30), limited to day 21.

Application of active 10-Hz rTMS to the left dorsolateral prefrontal cortex was well tolerated but was not superior compared with sham rTMS in improving negative symptoms; this is in contrast to findings from three meta-analyses.

The great majority of studies on repetitive transcranial magnetic stimulation (rTMS) as a therapeutic tool for auditory verbal hallucinations (AVH) have used 1-Hz stimulation with inconsistent results. Recently, it has been suggested that 20-Hz rTMS has strong therapeutic effects. It is conceivable that this 20-Hz stimulation is more effective than 1-Hz stimulation. The aim of this preliminary study is to investigate the efficacy of 20-Hz rTMS compared with 1-Hz rTMS as a treatment for AVH. Eighteen schizophrenia patients with medication-resistant AVH were randomized over two treatment groups. Each group received either 20 min of 1-Hz rTMS or 13 trains of 20-Hz rTMS daily over 1 week. After week 1, patients received a follow-up treatment once a week for 3 weeks. Stimulation location was based on individual AVH-related activation patterns identified with functional magnetic resonance imaging. Severity of AVH was monitored with the Auditory Hallucination Rating Scale (AHRS). Both groups showed a decrease in AVH after week 1 of rTMS. This decrease was significant for the 20-Hz group and the 1-Hz group. When the two treatment types were compared, no treatment type was superior. Based on these results we cannot conclude whether high frequency rTMS is more effective against AVH than is traditional 1-Hz rTMS. More research is needed to optimize stimulation parameters and to investigate potential target locations for stimulation.

This study sought to determine the moderators in the treatment effect of repetitive transcranial magnetic stimulation (rTMS) on negative symptoms in schizophrenia. We performed a meta-analysis of prospective studies on the therapeutic application of rTMS in schizophrenia assessing the effects of both low-frequency and high-frequency rTMS on negative symptoms. Results indicate that rTMS is effective in alleviating negative symptoms in schizophrenia. The effect size was moderate (0.63 and 0.53, respectively). The effect size of rTMS on negative symptoms in sham-controlled trials was 0.80 as measured by the SANS and 0.41 as measured by the PANSS. A longer duration of illness was associated with poorer efficacy of rTMS on negative symptoms. A 10 Hz setting, at least 3 consecutive weeks of treatment, treatment site at the left dorsolateral prefrontal cortex (DLPFC) and a 110% motor threshold (MT) were found to be the best rTMS parameters for the treatment of negative symptoms. The results of our meta-analysis suggest that rTMS is an effective treatment option for negative symptoms in schizophrenia. The moderators of rTMS on negative symptoms included duration of illness, stimulus frequency, duration of illness, position and intensity of treatment as well as the type of outcome measures used.

Despite recent advances in understanding the molecular mechanisms of autism spectrum disorders (ASD), the current treatments for these disorders are mostly focused on behavioral and educational approaches. The considerable clinical and molecular heterogeneity of ASD present a significant challenge to the development of an effective treatment targeting underlying molecular defects. Deficiency of SHANK family genes causing ASD represent an exciting opportunity for developing molecular therapies because of strong genetic evidence for SHANK as causative genes in ASD and the availability of a panel of Shank mutant mouse models. In this article, we review the literature suggesting the potential for developing therapies based on molecular characteristics and discuss several exciting themes that are emerging from studying Shank mutant mice at the molecular level and in terms of synaptic function.

Several studies demonstrated in experimental models and in humans synaptic plasticity impairment in some neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and schizophrenia. Recently new neurophysiological tools, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, have been introduced in experimental and clinical settings for studying physiology of the brain and modulating cortical activity. These techniques use noninvasive transcranial electrical or magnetic stimulation to modulate neurons activity in the human brain. Cortical stimulation might enhance or inhibit the activity of cortico-subcortical networks, depending on stimulus frequency and intensity, current polarity, and other stimulation parameters such as the configuration of the induced electric field and stimulation protocols. On this basis, in the last two decades, these techniques have rapidly become valuable tools to investigate physiology of the human brain and have been applied to treat drug-resistant neurological and psychiatric diseases. Here we describe these techniques and discuss the mechanisms that may explain these effects.