Unraveling the brain mechanisms of source monitoring with non-invasive brain stimulation: A systematic review.

Background/Objective: Source monitoring refers to the ability to determine the source of memories and encompasses three subprocesses: internal source monitoring, reality monitoring, and external source monitoring. Neuroimaging studies provide valuable insights about neural correlates of source monitoring, but the causal relationship between brain and behavior is lacking. This study aimed to identify brain circuits involved in source monitoring by synthesizing the effects of brain stimulation on source monitoring as a function of the targeted brain regions or circuits. Method: We conducted a systematic review of interventional studies that have examined the effects of brain stimulation on source monitoring across six databases. The principal outcome was the difference of source monitoring performance between active and control stimulation conditions. Results: 23 studies (920 healthy participants and 54 patients with schizophrenia) were included. Our findings revealed the involvement of i) the lateral prefrontal and temporoparietal cortices in internal source monitoring, ii) the medial prefrontal and temporoparietal cortices in reality monitoring, and iii) the precuneus and the left angular gyrus in external source monitoring. Conclusions: These findings deepen our understanding of the brain mechanisms of source monitoring and highlight specific stimulation targets to alleviate source monitoring deficits.

Mechanistic account of the left auditory cortex for tone-matching in schizophrenia: A pilot transcranial random noise stimulation (tRNS) sham-controlled study.

OBJECTIVE: Deficits in the ability to match tones following brief delay and their contribution to higher-order cognitive alterations have been repeatedly documented in schizophrenia. The aim was to explore if left fronto-temporal high-frequency transcranial random noise stimulation (hf-tRNS), with electrodes placed over brain regions involved in tone-matching would significantly modulate performances in participants with schizophrenia. METHODS: In a randomized, double-blind sham-controlled study, 10 participants with schizophrenia were allocated to receive ten sessions of either active or sham hf-tRNS. The anode was placed over the left prefrontal cortex and the cathode over the left temporoparietal junction. A tone-matching task was administered before and after the hf-tRNS. RESULTS: We calculated the changes in tone-matching performance before and after hf-tRNS session in each group. A significant between-group difference was observed for the difficult tone-matching conditions (W= 14.500, p = 0.032), with tone-matching improvement in the sham group and no improvement in the active group. DISCUSSION: hf-tRNS could disrupt the test-retest learning effect in the tone-matching task in individuals with schizophrenia. It is likely that this disruption resulted from cathodal-induced inhibition of the functional coupling between auditory cortical areas that correlates with tone-matching performance in patients. CONCLUSION: The findings contribute to our understanding of hf-tRNS effects on early auditory processing in schizophrenia.

The neural signature of reality-monitoring: A meta-analysis of functional neuroimaging studies.

Distinguishing imagination and thoughts from information we perceived from the environment, a process called reality-monitoring, is important in everyday situations. Although reality monitoring seems to overlap with the concept of self-monitoring, which allows one to distinguish self-generated actions or thoughts from those generated by others, the two concepts remain largely separate cognitive domains and their common brain substrates have received little attention. We investigated the brain regions involved in these two cognitive processes and explored the common brain regions they share. To do this, we conducted two separate coordinate-based meta-analyses of functional magnetic resonance imaging studies assessing the brain regions involved in reality- and self-monitoring. Few brain regions survived threshold-free cluster enhancement family-wise multiple comparison correction (p < .05), likely owing to the small number of studies identified. Using uncorrected statistical thresholds recommended by Signed Differential Mapping with Permutation of Subject Images, the meta-analysis of reality-monitoring studies (k = 9 studies including 172 healthy subjects) revealed clusters in the lobule VI of the cerebellum, the right anterior medial prefrontal cortex and anterior thalamic projections. The meta-analysis of self-monitoring studies (k = 12 studies including 192 healthy subjects) highlighted the involvement of a set of brain regions including the lobule VI of the left cerebellum and fronto-temporo-parietal regions. We showed with a conjunction analysis that the lobule VI of the cerebellum was consistently engaged in both reality- and self-monitoring. The current findings offer new insights into the common brain regions underlying reality-monitoring and self-monitoring, and suggest that the neural signature of the self that may occur during self-production should persist in memories.

Basic auditory processing and its relationship with symptoms in patients with schizophrenia: A systematic review.

Processing of basic auditory features, one of the earliest stages of auditory perception, has been the focus of considerable investigations in schizophrenia. Although numerous studies have shown abnormalities in pitch perception in schizophrenia, other basic auditory features such as intensity, duration, and sound localization have been less explored. Additionally, the relationship between basic auditory features and symptom severity shows inconsistent results, preventing concrete conclusions. Our aim was to present a comprehensive overview of basic auditory processing in schizophrenia and its relationship with symptoms. We conducted a systematic review according to the PRISMA guidelines. PubMed, Embase, and PsycINFO databases were searched for studies exploring auditory perception in schizophrenia compared to controls, with at least one behavioral task investigating basic auditory processing using pure tones. Forty-one studies were included. The majority investigated pitch processing while the others investigated intensity, duration and sound localization. The results revealed that patients have a significant deficit in the processing of all basic auditory features. Although the search for a relationship with symptoms was limited, auditory hallucinations experience appears to have an impact on basic auditory processing. Further research may examine correlations with clinical symptoms to explore the performance of patient subgroups and possibly implement remediation strategies.

Twice daily low frequency rTMS for treatment-resistant auditory hallucinations

Background: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a therapeutic solution in patients with treatment-resistant auditory verbal hallucinations. However, the optimal stimulation parameters remain unclear, especially for patients with clozapine-resistant symptoms. Method: In an open label retrospective study, we investigated whether parameters of stimulation that were useful in patients with major depressive disorder would help schizophrenia patients with treatment-resistant auditory verbal hallucinations. Fourteen participants, including 9 under clozapine, received 30 sessions of 1 Hz rTMS over 3 weeks (360 pulses per sessions delivered with 60 s ‘on’ and 30 s ‘off’ at 110% of the resting motor threshold, 2 sessions per day). Stimulations were applied over the left temporoparietal junction (T3-P3 according to 10/20 system). Results: After rTMS, a significant decrease of auditory verbal hallucinations was observed (−38.7% ± 31.8, p = 0.003) on the Auditory Hallucination Rating Scale. The beneficial effects were also significant in the 9 patients who were also receiving clozapine (−34.9% ± 28.4, p = 0.01). Conclusions: Low frequency rTMS, 30 sessions over 3 weeks, appears to be a suitable approach to decrease treatment-resistant auditory verbal hallucinations, including in patients with clozapine-resistant symptoms. Results from the current retrospective study in the clinical settings need to be confirmed by large-scale randomized sham-controlled trials. (AU)

Twice daily low frequency rTMS for treatment-resistant auditory hallucinations.

Background: Repetitive transcranial magnetic stimulation (rTMS) has emerged as a therapeutic solution in patients with treatment-resistant auditory verbal hallucinations. However, the optimal stimulation parameters remain unclear, especially for patients with clozapine-resistant symptoms. Method: In an open label retrospective study, we investigated whether parameters of stimulation that were useful in patients with major depressive disorder would help schizophrenia patients with treatment-resistant auditory verbal hallucinations. Fourteen participants, including 9 under clozapine, received 30 sessions of 1 Hz rTMS over 3 weeks (360 pulses per sessions delivered with 60 s 'on' and 30 s 'off' at 110% of the resting motor threshold, 2 sessions per day). Stimulations were applied over the left temporoparietal junction (T3-P3 according to 10/20 system). Results: After rTMS, a significant decrease of auditory verbal hallucinations was observed (-38.7% ± 31.8, p = 0.003) on the Auditory Hallucination Rating Scale. The beneficial effects were also significant in the 9 patients who were also receiving clozapine (-34.9% ± 28.4, p = 0.01). Conclusions: Low frequency rTMS, 30 sessions over 3 weeks, appears to be a suitable approach to decrease treatment-resistant auditory verbal hallucinations, including in patients with clozapine-resistant symptoms. Results from the current retrospective study in the clinical settings need to be confirmed by large-scale randomized sham-controlled trials.

Case report: accelerated cathodal HD-tDCS over the right dorsolateral prefrontal cortex in hoarding disorder.

Hoarding disorder is an under-recognized condition characterized by the excessive acquisition of possessions and difficulty in disposing of them, which can have dramatic consequences. As hoarding disorder is difficult to treat and associated with high levels of disability in all areas of functioning, there appears to be a critical need to develop novel, tailored therapeutic strategies. Non-invasive brain stimulation techniques hold promise as potential therapeutic interventions for various psychiatric conditions and as a tool to modulate impulsivity when applied over the dorsolateral prefrontal cortex (DLPFC). Therefore, we hypothesized that delivering accelerated cathodal high-definition direct transcranial stimulation (HD-tDCS) over the right DLPFC could be a suitable approach to alleviate symptoms in patients with hoarding disorder. In a case report, we observed beneficial clinical effects on acquisition and depressive symptoms after 15 sessions of three daily 20-min sessions. Accelerated cathodal HD-tDCS over the right DLPFC appears to be a safe and appropriate intervention for patients with hoarding disorder. However, randomized, sham-controlled trials are needed to further validate these encouraging findings.

High-Frequency Transcranial Random Noise Stimulation for Auditory Hallucinations of Schizophrenia: A Case Series.

Transcranial electrical stimulation has been proposed as a noninvasive therapeutic approach for reducing treatment-resistant symptoms of schizophrenia-in particular, auditory hallucinations. However, the high variability observed in the clinical response leaves much room to optimize the stimulation parameters and strengthen its benefits. We proposed to investigate the effects of high-frequency transcranial random noise stimulation (hf-tRNS), which is supposed to induce larger effects than conventional direct current stimulation. Here, we present an initial case series of ten patients with schizophrenia who underwent 10 sessions of 20 min hf-tRNS (2 mA, 100-500 Hz, 1 mA offset), with the anode placed over the left dorsolateral prefrontal cortex and the cathode over the left temporoparietal junction. Patients showed a significant reduction in auditory hallucinations after the hf-tRNS sessions (-36.1 +/- 21.8%, p = 0.0059). In this preliminary, open-label study conducted in ten patients with treatment-resistant symptoms of schizophrenia, frontotemporal hf-tRNS was shown to induce a substantial improvement in auditory hallucinations. Additional sham-controlled studies are needed to further evaluate hf-tRNS as a treatment for schizophrenia.

Digitalized transcranial electrical stimulation: A consensus statement.

OBJECTIVE: Although relatively costly and non-scalable, non-invasive neuromodulation interventions are treatment alternatives for neuropsychiatric disorders. The recent developments of highly-deployable transcranial electric stimulation (tES) systems, combined with mobile-Health technologies, could be incorporated in digital trials to overcome methodological barriers and increase equity of access. The study aims are to discuss the implementation of tES digital trials by performing a systematic scoping review and strategic process mapping, evaluate methodological aspects of tES digital trial designs, and provide Delphi-based recommendations for implementing digital trials using tES. METHODS: We convened 61 highly-productive specialists and contacted 8 tES companies to assess 71 issues related to tES digitalization readiness, and processes, barriers, advantages, and opportunities for implementing tES digital trials. Delphi-based recommendations (>60% agreement) were provided. RESULTS: The main strengths/opportunities of tES were: (i) non-pharmacological nature (92% of agreement), safety of these techniques (80%), affordability (88%), and potential scalability (78%). As for weaknesses/threats, we listed insufficient supervision (76%) and unclear regulatory status (69%). Many issues related to methodological biases did not reach consensus. Device appraisal showed moderate digitalization readiness, with high safety and potential for trial implementation, but low connectivity. CONCLUSIONS: Panelists recognized the potential of tES for scalability, generalizability, and leverage of digital trials processes; with no consensus about aspects regarding methodological biases. SIGNIFICANCE: We further propose and discuss a conceptual framework for exploiting shared aspects between mobile-Health tES technologies with digital trials methodology to drive future efforts for digitizing tES trials.

Recent advances in noninvasive brain stimulation for schizophrenia.

PURPOSE OF REVIEW: Noninvasive brain stimulation has emerged in the last three decades as a promising treatment for patients with antipsychotic-resistant symptoms of schizophrenia. This review updates the latest progress in the use of noninvasive brain stimulation to treat schizophrenia symptoms. RECENT FINDINGS: Several recently published randomized-controlled trials support a long-lasting clinical effect of stimulation techniques on schizophrenia symptoms. In addition, efforts have been made in recent months to improve efficacy through several optimization strategies. Studies have tested new parameters of stimulation, such as theta burst stimulation, and alternative cortical or subcortical targets and have reported encouraging results. New forms of electrical stimulations such as alternating and random noise stimulation, have also been studied and have shown clinical and cognitive usefulness for patients. Accelerated stimulation protocols, and prospects could arise with deeper stimulation strategies. SUMMARY: Using brain stimulation to treat symptoms of schizophrenia seems promising and the great flexibility of the stimulation parameters leaves much room for developing optimization strategies and improving its effectiveness. Further studies need to identify the optimal parameters to maximize response rate.

Efficacy of Transcranial Direct Current Stimulation to Improve Insight in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND AND HYPOTHESIS: Impaired insight into the illness and its consequences is associated with poor outcomes in schizophrenia. While transcranial direct current stimulation (tDCS) may represent a potentially effective treatment strategy to relieve various symptoms of schizophrenia, its impact on insight remains unclear. To investigate whether tDCS would modulate insight in patients with schizophrenia, we undertook a meta-analysis based on results from previous RCTs that investigated the clinical efficacy of tDCS. We hypothesize that repeated sessions of tDCS will be associated with insight improvement among patients. STUDY DESIGN: PubMed and ScienceDirect databases were systematically searched to identify RCTs that delivered at least 10 tDCS sessions in patients with schizophrenia. The primary outcome was the change in insight score, assessed by the Positive and Negative Syndrome Scale (PANSS) item G12 following active tDCS sessions as opposed to sham stimulation. Effect sizes were calculated for all studies and pooled using a random-effects model. Meta-regression and subgroup analyses were conducted. STUDY RESULTS: Thirteen studies (587 patients with schizophrenia) were included. A significant pooled effect size (g) of -0.46 (95% CI [-0.78; -0.14]) in favor of active tDCS was observed. Age and G12 score at baseline were identified as significant moderators, while change in total PANSS score was not significant. CONCLUSIONS: Ten sessions of active tDCS with either frontotemporoparietal or bifrontal montage may improve insight into the illness in patients with schizophrenia. The effect of this treatment could contribute to the beneficial outcomes observed in patients following stimulation.

Serum Mature BDNF Level Is Associated with Remission Following ECT in Treatment-Resistant Depression.

The search for a biological marker predicting the future failure or success of electroconvulsive therapy (ECT) remains highly challenging for patients with treatment-resistant depression. Evidence suggests that Brain-Derived Neurotrophic Factor (BDNF), a protein known to be involved in brain plasticity mechanisms, can play a key role in both the clinical efficacy of ECT and the pathophysiology of depressive disorders. We hypothesized that mature BDNF (mBDNF), an isoform of BDNF involved in the neural plasticity and survival of neural networks, might be a good candidate for predicting the efficacy of ECT. Total BDNF (tBDNF) and mBDNF levels were measured in 23 patients with severe treatment-resistant depression before (baseline) they received a course of ECT. More precisely, tBDNF and mBDNF measured before ECT were compared between patients who achieved the criteria of remission after the ECT course (remitters, n = 7) and those who did not (non-remitters, n = 16). We found that at baseline, future remitters displayed significantly higher mBDNF levels than future non-remitters (p = 0.04). No differences were observed regarding tBDNF levels at baseline. The multiple logistic regression model controlled for age and sex revealed that having a higher baseline mBDNF level was significantly associated with future remission after ECT sessions (odd ratio = 1.38; 95% confidence interval = 1.07-2.02, p = 0.04). Despite the limitations of the study, current findings provide additional elements regarding the major role of BDNF and especially the mBDNF isoform in the clinical response to ECT in major depression.

Examining transcranial random noise stimulation as an add-on treatment for persistent symptoms in schizophrenia (STIM'Zo): a study protocol for a multicentre, double-blind, randomized sham-controlled clinical trial.

BACKGROUND: One out of three patients with schizophrenia failed to respond adequately to antipsychotics and continue to experience debilitating symptoms such as auditory hallucinations and negative symptoms. The development of additional therapeutic approaches for these persistent symptoms constitutes a major goal for patients. Here, we develop a randomized-controlled trial testing the efficacy of high-frequency transcranial random noise stimulation (hf-tRNS) for the treatment of resistant/persistent symptoms of schizophrenia in patients with various profiles of symptoms, cognitive deficits and illness duration. We also aim to investigate the biological and cognitive effects of hf-tRNS and to identify the predictors of clinical response. METHODS: In a randomized, double-blind, 2-arm parallel-group, controlled, multicentre study, 144 patients with schizophrenia and persistent symptoms despite the prescription of at least one antipsychotic treatment will be randomly allocated to receive either active (n = 72) or sham (n = 72) hf-tRNS. hf-tRNS (100-500 Hz) will be delivered for 20 min with a current intensity of 2 mA and a 1-mA offset twice a day on 5 consecutive weekdays. The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left temporoparietal junction. Patients' symptoms will be assessed prior to hf-tRNS (baseline), after the 10 sessions, and at 1-, 3- and 6-month follow-up. The primary outcome will be the number of responders defined as a reduction of at least 25% from the baseline scores on the Positive and Negative Syndrome Scale (PANSS) after the 10 sessions. Secondary outcomes will include brain activity and connectivity, source monitoring performances, social cognition, other clinical (including auditory hallucinations) and biological variables, and attitude toward treatment. DISCUSSION: The results of this trial will constitute a first step toward establishing the usefulness of hf-tRNS in schizophrenia whatever the stage of the illness and the level of treatment resistance. We hypothesize a long-lasting effect of active hf-tRNS on the severity of schizophrenia symptoms as compared to sham. This trial will also have implications for the use of hf-tRNS as a preventive intervention of relapse in patients with schizophrenia. TRIAL REGISTRATION: ClinicalTrials.gov NCT02744989. Prospectively registered on 20 April 2016.

Neuroanatomical correlates of reality monitoring in patients with schizophrenia and auditory hallucinations.

BACKGROUND: Reality-monitoring process enables to discriminate memories of internally generated information from memories of externally derived information. Studies have reported impaired reality-monitoring abilities in schizophrenia patients with auditory hallucinations (AHs), specifically with an exacerbated externalization bias, as well as alterations in neural activity within frontotemporoparietal areas. In healthy subjects, impaired reality-monitoring abilities have been associated with reduction of the paracingulate sulcus (PCS). The current study aimed to identify neuroanatomical correlates of reality monitoring in patients with schizophrenia. METHODS: Thirty-five patients with schizophrenia and AHs underwent a reality-monitoring task and a 3D anatomical MRI scan at 1.5 T. PCS lengths were measured separately for each hemisphere, and whole-brain voxel-based morphometry analyses were performed using the Computational Anatomy Toolbox (version 12.6) to evaluate the gray-matter volume (GMV). Partial correlation analyses were used to investigate the relationship between reality-monitoring and neuroanatomical outcomes (PCS length and GMV), with age and intracranial volume as covariates. RESULTS: The right PCS length was positively correlated with reality-monitoring accuracy (Spearman's ρ = 0.431, p = 0.012) and negatively with the externalization bias (Spearman's ρ = -0.379, p = 0.029). Reality-monitoring accuracy was positively correlated with GMV in the right angular gyrus, whereas externalization bias was negatively correlated with GMV in the left supramarginal gyrus/superior temporal gyrus, in the right lingual gyrus and in the bilateral inferior temporal/fusiform gyri (voxel-level p < 0.001 and cluster-level p < 0.05, FDR-corrected). CONCLUSIONS: Reduced reality-monitoring abilities were significantly associated with shorter right PCS and reduced GMV in temporal and parietal regions of the reality-monitoring network in schizophrenia patients with AHs.

Frontotemporal Transcranial Direct Current Stimulation Decreases Serum Mature Brain-Derived Neurotrophic Factor in Schizophrenia.

Although transcranial direct current stimulation (tDCS) shows promise as a treatment for auditory verbal hallucinations in patients with schizophrenia, mechanisms through which tDCS may induce beneficial effects remain unclear. Evidence points to the involvement of neuronal plasticity mechanisms that are underpinned, amongst others, by brain-derived neurotrophic factor (BDNF) in its two main forms: pro and mature peptides. Here, we aimed to investigate whether tDCS modulates neural plasticity by measuring the acute effects of tDCS on peripheral mature BDNF levels in patients with schizophrenia. Blood samples were collected in 24 patients with schizophrenia before and after they received a single session of either active (20 min, 2 mA, n = 13) or sham (n = 11) frontotemporal tDCS with the anode over the left prefrontal cortex and the cathode over the left temporoparietal junction. We compared the tDCS-induced changes in serum mature BDNF (mBDNF) levels adjusted for baseline values between the two groups. The results showed that active tDCS was associated with a significantly larger decrease in mBDNF levels (mean -20% ± standard deviation 14) than sham tDCS (-8% ± 21) (F = 5.387; p = 0.030; η2 = 0.205). Thus, mature BDNF may be involved in the beneficial effects of frontotemporal tDCS observed in patients with schizophrenia.

Intermittent theta burst stimulation for negative symptoms of schizophrenia-A double-blind, sham-controlled pilot study.

Optimal noninvasive brain stimulation parameters for the treatment of negative symptoms of schizophrenia remain unclear. Here, we aimed to investigate the clinical and biological effects of intermittent theta burst transcranial magnetic stimulation (iTBS) in patients with treatment-resistant negative symptoms of schizophrenia (NCT00875498). In a randomized sham-controlled 2-arm study, 22 patients with schizophrenia and treatment-resistant negative symptoms received 20 sessions of either active (n = 12) or sham (n = 10) iTBS. Sessions were delivered twice a day on 10 consecutive working days. Negative symptom severity was assessed 5 times using the Scale for the Assessment of Negative Symptoms (SANS): before iTBS, after iTBS, and 1, 3, and 6 months after iTBS. As a secondary objective, we explored the acute effects of iTBS on functional connectivity of the left dorsolateral prefrontal cortex (DLPFC) using seed-based resting-state functional connectivity MRI (rsFC fMRI) images acquired before and after iTBS. Active iTBS over the left DLPFC significantly decreased negative symptoms severity compared to sham iTBS (F(3,60) = 3.321, p = 0.026). Post hoc analyses revealed that the difference between groups was significant 6 months after the end of stimulation sessions. Neuroimaging revealed an increase in rsFC between the left DLPFC and a brain region encompassing the right lateral occipital cortex and right angular gyrus and a right midbrain region that may encompass dopamine neuron cell bodies. Thus, iTBS over the left DLPFC can alleviate negative symptoms of schizophrenia. The effect might be driven by significant modulation of dopamine transmission.

Impaired self-recognition in individuals with no full-blown psychotic symptoms represented across the continuum of psychosis: a meta-analysis.

BACKGROUND: Impairments in self-recognition (i.e. recognition of own thoughts and actions) have been repeatedly shown in individuals with schizophrenia. According to classical clinical characterizations, schizophrenia is included in a continuum encompassing a large range of genetic statuses, psychotic states and symptoms. The current meta-analysis aims to determine whether self-recognition is affected by individuals within the psychosis continuum. METHOD: Three populations were considered: people with an at-risk mental state for psychosis (ARMS), hallucination-prone individuals and unaffected relatives of patients with schizophrenia. Eleven studies contrasted self-recognition between these three populations (n = 386) and healthy controls (n = 315) and four studies used correlational analysis to estimate comparable effects (n = 629). Eligible studies used experimental paradigms including source-monitoring and self-monitoring. RESULTS: We observed significantly reduced self-recognition accuracy in these populations [g = -0.44 (-0.71 to -0.17), p = 0.002] compared to controls. No influence of the type of population, experimental paradigm or study design was observed. CONCLUSION: The present analysis argues for self-recognition deficits in populations with no full-blown psychotic symptoms represented across the continuum of psychosis.

Improvement of Insight with Non-Invasive Brain Stimulation in Patients with Schizophrenia: A Systematic Review.

Patients with schizophrenia are often unaware of their condition and the consequences of their illness. This lack of insight results in impaired functioning, treatment non-adherence and poor prognosis. Here, we aimed to investigate the effects of non-invasive brain stimulation (NIBS) on two forms of insight, clinical and cognitive, in patients with schizophrenia. We conducted a systematic review of the literature registered in the PROSPERO database (CRD42020220323) according to PRISMA guidelines. The literature search was conducted in Medline and Web of Science databases based on studies published up until October 2020 that included pre-NIBS and post-NIBS measurements of clinical and/or cognitive insight in adults with schizophrenia. A total of 14 studies were finally included, and their methodological quality was assessed by using the QualSyst tool. Despite the lack of well-conducted large randomized-controlled studies using insight as the primary outcome, the available findings provide preliminary evidence that NIBS can improve clinical insight in patients with schizophrenia, with a majority of studies using transcranial direct current stimulation with a left frontotemporal montage. Further studies should investigate the effect of NIBS on insight as a primary outcome and how these effects on insight could translate into clinical and functional benefits in patients with schizophrenia.