Right ventrolateral and left dorsolateral 10 Hz transcranial magnetic stimulation as an add-on treatment for bipolar I and II depression: a double-blind, randomised, three-arm, sham-controlled study.

OBJECTIVES: Despite the clinical importance of bipolar depression (BDE), effective treatment options are still limited. Transcranial magnetic stimulation (rTMS) has proven of moderate efficacy in major depression, but the evidence remains inconclusive for BDE. METHODS: A 4-week, double-blind, randomised, parallel-group, sham-controlled study (trial ID ISRCTN77188420) explored the benefits of 10 Hz MRI-guided right ventrolateral (RVL) rTMS and left dorsolateral (LDL) rTMS as add-on treatments for BDE. Outcome measures included changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) score, self-assessment, response and remission rates, and side effects. RESULTS: Sixty patients were randomly assigned to study groups, and forty-six completed the double-blind phase. The mean change from baseline to Week 4 in MADRS was greater in both active groups compared to the sham, yet differences did not achieve significance (RVL vs sham: -4.50, 95%CI -10.63 to 1.64, p = 0.3; LDL vs sham: -4.07, 95%CI -10.24 to 2.10, p = 0.4). None of the other outcome measures yielded significant results. CONCLUSIONS: While not demonstrating the superiority of either 10 Hz rTMS over sham, with the limited sample size, we can not rule out a moderate yet clinically meaningful effect. Further well-powered studies are essential to elucidate the role of rTMS in managing BDE.

Transcranial direct current stimulation (tDCS) in the treatment of neuropsychiatric symptoms of long COVID.

The study aimed to assess the efficacy of transcranial direct current stimulation (tDCS) in the treatment of neuropsychiatric (NP) symptoms of the post-acute sequelae of SARS-CoV-2 infection (PASC), known as the long COVID. A double-blind, randomized, sham-controlled study compared the efficacy and safety of prefrontal cortex active tDCS to sham-tDCS in treating NP-PASC. Patients diagnosed with NP-PASC, with a Fatigue Impact Scale (FIS) score ≥ 40, were eligible for the study. Twenty tDCS sessions were administered within four weeks, with continuous, end-of-treatment, and follow-up measurements. The primary outcome was a change in the FIS at the end-of-treatment, analyzed in the intention-to-treat population. Data from 33 patients assigned to active (n = 16) or sham-tDCS (n = 17) were analyzed. After the treatment, a decrease in the FIS score was more pronounced in the sham than in the active group, yet the intergroup difference was insignificant (11.7 [95% CI -11.1 to 34.5], p = 0.6). Furthermore, no significant intergroup differences were observed regarding anxiety, depression, quality of life, and cognitive performance. The small cohort sample, differences in baseline FIS scores between groups (non-stratified randomization), or chosen stimulation parameters may have influenced our findings. However, it might also be possible that the expected mechanism of action of tDCS is insufficient to treat these conditions.

Transcranial alternating current stimulation in affecting cognitive impairment in psychiatric disorders: a review.

Transcranial alternating current stimulation (tACS) is a non-invasive brain stimulation method that, through its manipulation of endogenous oscillations, can affect cognition in healthy adults. Given the fact that both endogenous oscillations and cognition are impaired in various psychiatric diagnoses, tACS might represent a suitable intervention. We conducted a search of Pubmed and Web of Science databases and reviewed 27 studies where tACS is used in psychiatric diagnoses and cognition change is evaluated. TACS is a safe and well-tolerated intervention method, suitable for multiple-sessions protocols. It can be administered at home, individualized according to the patient''s anatomical and functional characteristics, or used as a marker of disease progression. The results are varying across diagnoses and applied protocols, with some protocols showing a long-term effect. However, the overall number of studies is small with a great variety of diagnoses and tACS parameters, such as electrode montage or used frequency. Precise mechanisms of tACS interaction with pathophysiological processes are only partially described and need further research. Currently, tACS seems to be a feasible method to alleviate cognitive impairment in psychiatric patients; however, a more robust confirmation of efficacy of potential protocols is needed to introduce it into clinical practise.

Towards causal mechanisms of consciousness through focused transcranial brain stimulation.

Conscious experience represents one of the most elusive problems of empirical science, namely neuroscience. The main objective of empirical studies of consciousness has been to describe the minimal sets of neural events necessary for a specific neuronal state to become consciously experienced. The current state of the art still does not meet this objective but rather consists of highly speculative theories based on correlates of consciousness and an ever-growing list of knowledge gaps. The current state of the art is defined by the limitations of past stimulation techniques and the emphasis on the observational approach. However, looking at the current stimulation technologies that are becoming more accurate, it is time to consider an alternative approach to studying consciousness, which builds on the methodology of causal explanations via causal alterations. The aim of this methodology is to move beyond the correlates of consciousness and focus directly on the mechanisms of consciousness with the help of the currently focused brain stimulation techniques, such as geodesic transcranial electric neuromodulation. This approach not only overcomes the limitations of the correlational methodology but will also become another firm step in the following science of consciousness.

The effect of low-frequency rTMS on auditory hallucinations, EEG source localization and functional connectivity in schizophrenia.

BACKGROUND: Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) diminishes auditory hallucinations (AHs). The aims of our study were a) to assess the efficacy of LF-rTMS in a randomized, sham-controlled double-blind alignment, b) to identify the electrophysiological changes accompanying the LF-rTMS, and c) to identify the influence of LF-rTMS on brain functional connectivity (FC). METHODS: Nineteen schizophrenia patients with antipsychotic-resistant AHs were randomized to either active (n = 10) or sham (n = 9) LF-rTMS administered over the left temporo-parietal region for ten days. The clinical effect was assessed by the Auditory Hallucination Rating Scale (AHRS). The localization of the differences in electrical activity was identified by standardized low resolution brain electromagnetic tomography (sLORETA) and FC was measured by lagged phase synchronization. RESULTS: AHRS scores were significantly improved for patients receiving active rTMS compared to the sham (median reduction: 40 % vs 12 %; p = 0.01). sLORETA revealed a decrease of alpha-2, beta-1,-2 bands in the left hemisphere in the active group. Active rTMS led to a decrease of the lagged phase connectivity in beta bands originating in areas close to the site of stimulation, and to a prevailing increase of alpha-2 FC. No significant differences in current density or FC were observed in the sham group. LIMITATIONS: Limitations to our study included the small group sizes, and the disability of LORETA to assess subcortical neuronal activity. CONCLUSIONS: LF-rTMS attenuated AHs and induced a decrease of higher frequency bands on the left hemisphere. The FC changes support the assumption that LF-rTMS is linked to the modulation of cortico-cortical coupling.

A Literature Mini-Review of Transcranial Direct Current Stimulation in Schizophrenia.

Transcranial direct current stimulation (tDCS) is a non-invasive neurostimulation method that utilizes the effect of low-current on brain tissue. In recent years, the effect of transcranial direct current stimulation has been investigated as a therapeutic modality in various neuropsychiatric indications, one of them being schizophrenia. This article aims to provide an overview of the potential application and effect of tDCS in treating patients with schizophrenia. A literature search was performed using the PubMed, Web of Science, and Google Scholar databases for relevant research published from any date until December 2021. Eligible studies included those that used randomized controlled parallel-group design and focused on the use of transcranial direct current stimulation for the treatment of positive, negative, or cognitive symptoms of schizophrenia. Studies were divided into groups based on the focus of research and an overview is provided in separate sections and tables in the article. The original database search yielded 705 results out of which 27 randomized controlled trials met the eligibility criteria and were selected and used for the purpose of this article. In a review of the selected trials, transcranial direct current stimulation is a safe and well-tolerated method that appears to have the potential as an effective modality for the treatment of positive and negative schizophrenic symptoms and offers promising results in influencing cognition. However, ongoing research is needed to confirm these conclusions and to further specify distinct application parameters.

Modulating Inhibitory Control Processes Using Individualized High Definition Theta Transcranial Alternating Current Stimulation (HD θ-tACS) of the Anterior Cingulate and Medial Prefrontal Cortex.

Increased frontal midline theta activity generated by the anterior cingulate cortex (ACC) is induced by conflict processing in the medial frontal cortex (MFC). There is evidence that theta band transcranial alternating current stimulation (θ-tACS) modulates ACC function and alters inhibitory control performance during neuromodulation. Multi-electric (256 electrodes) high definition θ-tACS (HD θ-tACS) using computational modeling based on individual MRI allows precise neuromodulation targeting of the ACC via the medial prefrontal cortex (mPFC), and optimizes the required current density with a minimum impact on the rest of the brain. We therefore tested whether the individualized electrode montage of HD θ-tACS with the current flow targeted to the mPFC-ACC compared with a fixed montage (non-individualized) induces a higher post-modulatory effect on inhibitory control. Twenty healthy subjects were randomly assigned to a sequence of three HD θ-tACS conditions (individualized mPFC-ACC targeting; non-individualized MFC targeting; and a sham) in a double-blind cross-over study. Changes in the Visual Simon Task, Stop Signal Task, CPT III, and Stroop test were assessed before and after each session. Compared with non-individualized θ-tACS, the individualized HD θ-tACS significantly increased the number of interference words and the interference score in the Stroop test. The changes in the non-verbal cognitive tests did not induce a parallel effect. This is the first study to examine the influence of individualized HD θ-tACS targeted to the ACC on inhibitory control performance. The proposed algorithm represents a well-tolerated method that helps to improve the specificity of neuromodulation targeting of the ACC.

Effects of deep transcranial magnetic stimulation (dTMS) on cognition.

Deep transcranial magnetic stimulation (dTMS) is a modern non-invasive brain stimulation method demonstrated as effective in the treatment of major depression and obsessive-compulsive disorder (OCD). This review aims to survey present knowledge concerning the cognitive function changes identified in dTMS research. A systematic literature search in PubMed and Google Scholar was performed and 23 out of 64 studies on dTMS and cognitive functioning were included in the review. Ten studies were conducted with patients with affective disorders, six with healthy participants, two with schizophrenia patients, two with OCD patients, and one study each with patients suffering from central neuropathic pain, autistic disorder, and attention deficit hyperactivity disorder. The best outcomes were obtained after 20 sessions of high-frequency dTMS with OCD patients, where, in addition to clinical improvement, patients showed amelioration of cognitive functions, specifically in cognitive control domains. The studies on patients with depression appear to show inconsistent results, from cognitive improvement in open-label studies to no improvement versus sham dTMS in controlled trials. Experimental research in healthy volunteers suggests an influence of dTMS on memory and self-agency, and also contain contradictory results. Most studies did not demonstrate a significant improvement in cognitive functioning. However, randomized sham-controlled trials with larger groups of medication-free patients and inclusion of functional imaging or electrophysiological recording connected with dTMS application are necessary for more detailed and confident conclusions concerning the effect of dTMS on cognitive functions.

Repetitive transcranial magnetic stimulation (rTMS) for schizophrenia patients treated with clozapine.

OBJECTIVES: Biological strategies to improve treatment efficacy in clozapine-treated patients are urgently needed. Repetitive transcranial magnetic stimulation (rTMS) merits consideration as intervention for patients with persistent auditory hallucinations (AH) or negative symptoms (NS) not responding sufficiently to clozapine treatment. METHODS: Data from 10 international RCTs of rTMS for patients being treated with clozapine were pooled. Two levels of symptomatic response were defined: improvement of ≥20% and ≥50% on study-specific primary endpoint scales. Changes in the positive and negative syndrome scale (PANSS) from baseline to endpoint assessment were also analysed. RESULTS: Analyses of 131 patients did not reveal a significant difference for ≥20% and ≥50% response thresholds for improvement of AH, negative or total symptoms between active and sham rTMS groups. The number needed to treat (NNT) for an improvement in persistent AH was nine following active rTMS. PANSS scores did not improve significantly from baseline to endpoint between active and sham groups in studies investigating NS and AH. CONCLUSIONS: rTMS as a treatment for persistent symptoms in clozapine-treated patients did not show a beneficial effect of active compared to sham treatment. For AH, the size of the NNTs indicates a possible beneficial effect of rTMS.

The Antidepressant Effect of Ketamine Is Dampened by Concomitant Benzodiazepine Medication.

The rapid antidepressant effect of ketamine has become a breakthrough in the research and treatment of depression. Although predictive and modulating factors of the response to ketamine are broadly studied, little is known about optimal concurrent medication protocols. Concerning gamma-aminobutyric acid neurotransmission being a shared target for both ketamine and benzodiazepines (BZD), we evaluated the influence of BZD on the antidepressant effect of a single ketamine infusion in depressed patients. Data from 47 patients (27 females) with major depression (MADRS ≥ 20, ≥ 1 prior nonresponse to antidepressant treatment in current episode) who participated in two previous studies (EudraCT Number: 2009-010625-39 and 2013-000952-17) entered the analysis. All of the subjects were given an infusion of a subanesthetic dose of racemic ketamine (0.54 mg per kg) as an add-on medication to ongoing antidepressant treatment. Thirteen patients (28%) reached ≥ 50% reduction in MADRS within one week after ketamine administration. Nineteen (40%) patients took concomitant benzodiazepines on a daily basis. The doses of BZDs were significantly higher in nonresponders (p=0.007). ROC analysis distinguished responders from nonresponders by a criterion of >8mg of diazepam equivalent dose (DZ equivalent) with a sensitivity of 80% and a specificity of 85% (p<0.001). RM-ANOVA revealed a different time pattern of response to ketamine between the BZD+ (>8mg of DZ equivalent) and BZD- (≤8mg of DZ equivalent) groups, with a significantly worse outcome in BZD+ on day 3 (p=0.04) and day 7 (p=0.02). The results of the study indicate that concomitant benzodiazepine treatment in higher doses may attenuate ketamine's antidepressant effect. The pathophysiological, clinical and methodological implications of this finding should be considered in future research and ketamine treatment.

Prolonged Continuous Theta Burst Stimulation of the Motor Cortex Modulates Cortical Excitability But not Pain Perception.

Over the past decade, theta-burst stimulation (TBS) has become a focus of interest in neurostimulatory research. Compared to conventional repetitive transcranial magnetic stimulation (rTMS), TBS produces more robust changes in cortical excitability (CE). There is also some evidence of an analgesic effect of the method. Previously published studies have suggested that different TBS parameters elicit opposite effects of TBS on CE. While intermittent TBS (iTBS) facilitates CE, continuous TBS (cTBS) attenuates it. However, prolonged TBS (pTBS) with twice the number of stimuli produces the opposite effect. In a double-blind, placebo-controlled, cross-over study with healthy subjects (n = 24), we investigated the effects of various pTBS (cTBS, iTBS, and placebo TBS) over the right motor cortex on CE and pain perception. Changes in resting motor thresholds (RMTs) and absolute motor-evoked potential (MEP) amplitudes were assessed before and at two time-points (0-5 min; 40-45 min) after pTBS. Tactile and thermal pain thresholds were measured before and 5 min after application. Compared to the placebo, prolonged cTBS (pcTBS) transiently increased MEP amplitudes, while no significant changes were found after prolonged iTBS. However, the facilitation of CE after pcTBS did not induce a parallel analgesic effect. We confirmed that pcTBS with twice the duration converts the conventional inhibitory effect into a facilitatory one. Despite the short-term boost of CE following pcTBS, a corresponding analgesic effect was not demonstrated. Therefore, the results indicate a more complex regulation of pain, which cannot be explained entirely by the modulation of excitability.

Relationship of ketamine's antidepressant and psychotomimetic effects in unipolar depression.

OBJECTIVES: Ketamine and other NMDA (N-methyl-D-aspartate) antagonists produce fast-acting antidepressant-like effects, although the underlying mechanism is unclear. Furthermore, high affinity NMDA antagonists such as ketamine are associated with psychotomimetic effects. To date the link between the antidepressant and psychotomimetic effects of ketamine has not been explored. We examined the relationship between the antidepressant and psychotomimetic effects of a single ketamine infusion in subjects diagnosed with major depressive disorder. METHODS: In a double-blind, cross-over, placebo-controlled, two weeks clinical trial we studied the effects of ketamine (0.54 mg/kg within 30 min) in a group of 27 hospitalized depressive patients. RESULTS: Higher intensity of psychotomimetic symptoms, measured using BPRS, during ketamine administration correlated with alleviation in mood ratings during the following week with maximum on day seven. Ketamine was superior to placebo in all visits (day 1, 4, and 7) assessed by MADRS with effect size (Cohen´s d) of 0.62, 0.57, and 0.44 respectively. There was no significant correlation between ketamine and nor-ketamine plasma levels and MADRS score change at any study time point. CONCLUSION: The substantial relationship between ketamine's antidepressant and psychotomimetic effects was found. This relationship could be mediated by the initial steps of ketamine's action, trough NMDA receptors, shared by both ketamine's clinical effects.

Individualized rTMS neuronavigated according to regional brain metabolism ((18)FGD PET) has better treatment effects on auditory hallucinations than standard positioning of rTMS: a double-blind, sham-controlled study.

Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS) of the left temporo-parietal cortex (LTPC) has been proposed as a useful therapeutic method for auditory hallucinations (AHs). Stereotactic neuronavigation enables the magnetic coil to be targeted according to the individual parameters obtained from neuroimaging. Individualized rTMS neuronavigated according to 18-fluorodeoxyglucose positron emission tomography ((18)FDG PET) allows us to focus the coil explicitly on a given area with detected maxima of specific abnormalities, thus presuming a higher therapeutic effect of the method. The objective of this study is to test clinical efficacy of neuronavigated LF-rTMS administered according to the local maxima of (18)FDG PET uptake of LTPC and to compare it with treatment effects of standard and sham rTMS. In a double-blind, sham-controlled design, patients with AHs underwent a 10-day series of LF-rTMS using (1) (18)FDG PET-guided "neuronavigation," (2) "standard" anatomically guided positioning, and (3) sham coil. The effect of different rTMS conditions was assessed by the Auditory Hallucinations Rating Scale (AHRS) and the Positive and Negative Syndrome Scale (PANSS). Fifteen patients were randomized to a treatment sequence and ten of them completed all three treatment conditions. The intention-to-treat analysis of AHRS score change revealed superiority of the (18)FDG PET-guided rTMS over both the standard and the sham rTMS. The analyses of the PANSS scores failed to detect significant difference among the treatments. Our data showed acute efficacy of (18)FDG PET-guided rTMS in the treatment of AHs. Neuronavigated rTMS was found to be more effective than standard, anatomically guided rTMS.

Genetic variation in FOXP2 alters grey matter concentrations in schizophrenia patients.

FOXP2, the first gene known to be involved in the development of speech and language, can be considered to be, a priori, a candidate gene in schizophrenia, given the mounting evidence that the underlying core deficit in this disease could be a failure of structures relevant to normal language processing. To investigate the potential link between grey matter concentration (GMC) changes in patients with schizophrenia and the FOXP2 rs2396753 polymorphism previously reported to be associated with hallucinations in schizophrenia, we analysed high-resolution anatomical magnetic resonance images of 40 genotyped patients with schizophrenia and 36 healthy controls, using optimised voxel-based morphometry (VBM). Here we show that the common SNP rs2396753 (C>A) gene variant of the FOXP2 gene has significant effects on GMC in patients with schizophrenia, within regions of the brain known to be affected by this disease. Our data suggest that GMC reductions in schizophrenia may be driven by C allele carriers of the FOXP2 gene variant.

Repetitive transcranial magnetic stimulation (rTMS) in major depressive episode during pregnancy.

Sir: For women diagnosed with Recurrent depressive disorder, pregnancy poses a major treatment challenge. Apart from antidepressants, the most commonly used biological therapeutical method is ECT (electroconvulsive therapy). We believe that similar efficacy can be achieved using rTMS as a safer option with substantially less side effects. So far, only a few case-reports reporting the use of rTMS for treatment of pregnant patients with depression were published.

Effect of low-frequency rTMS on electromagnetic tomography (LORETA) and regional brain metabolism (PET) in schizophrenia patients with auditory hallucinations.

BACKGROUND: Auditory hallucinations are characteristic symptoms of schizophrenia with high clinical importance. It was repeatedly reported that low frequency (

Regional brain metabolism as the predictor of performance on the Trail Making Test in schizophrenia. A 18FDG PET covariation study.

OBJECTIVES: With the aim to indicate the functional anatomical substrate of cognitive dysfunction in schizophrenia we evaluated the relationship between resting brain metabolism and performance on the Trail Making Test (TMT). As the prerequisite analysis we compared the performance in Part A and B of the TMT between schizophrenic patients and controls. Resting brain metabolism was investigated by (18)FDG positron emission tomography (PET) as the probe for the relative regional synaptic strength and density. METHODS: (18)FDG PET data were analyzed by SPM99 with TMT A and B as the covariate (p< or =0.001). RESULTS: Schizophrenic patients (N=42) had worse performance in both TMT A and B compared to controls (N=42). In schizophrenic subjects (18)FDG PET did not predict the performance on Part A (psychomotor speed) but predicted that for Part B (set-shifting and flexibility) of the TMT. The (18)FDG uptake in the superior, middle and inferior frontal gyruses bilaterally was associated with better performance in the TMT B. The negative covariation between 18FDG uptake and time spent in the TMT B was detected in the temporal and parietal cortices, pre- and postcentral gyruses, precuneus limbic regions (anterior cingulate, uncus) and the pons. CONCLUSIONS: Our data indicate that hypometabolism in the frontal lobes and hypermetabolism in the temporo-parieto-limbic regions is the neurobiological basis for deficient TMT B performance in schizophrenia.

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.