Marine Mondino

Examining transcranial direct-current stimulation (tDCS) as a treatment for hallucinations in schizophrenia.

OBJECTIVE Some 25%–30% of patients with schizophrenia have auditory verbal hallucinations that are refractory to antipsychotic drugs. Outcomes in studies of repetitive transcranial magnetic stimulation suggest the possibility that application of transcranial direct-current stimulation (tDCS) with inhibitory stimulation over the left temporo-parietal cortex and excitatory stimulation over the left dorsolateral prefrontal cortex could affect hallucinations and negative symptoms, respectively. The authors investigated the efficacy of tDCS in reducing the severity of auditory verbal hallucinations as well as negative symptoms. METHOD Thirty patients with schizophrenia and medication-refractory auditory verbal hallucinations were randomly allocated to receive 20 minutes of active 2-mA tDCS or sham stimulation twice a day on 5 consecutive weekdays. The anode was placed over the left dorsolateral prefrontal cortex and the cathode over the left temporo-parietal cortex. RESULTS Auditory verbal hallucinations were robustly reduced by tDCS relative to sham stimulation, with a mean diminution of 31% (SD=14; d=1.58, 95% CI=0.76–2.40). The beneficial effect on hallucinations lasted for up to 3 months. The authors also observed an amelioration with tDCS of other symptoms as measured by the Positive and Negative Syndrome Scale (d=0.98, 95% CI=0.22–1.73), especially for the negative and positive dimensions. No effect was observed on the dimensions of disorganization or grandiosity/excitement. CONCLUSIONS Although this study is limited by the small sample size, the results show promise for treating refractory auditory verbal hallucinations and other selected manifestations of schizophrenia.

Effects of Fronto-Temporal Transcranial Direct Current Stimulation on Auditory Verbal Hallucinations and Resting-State Functional Connectivity of the Left Temporo-Parietal Junction in Patients With Schizophrenia

Auditory verbal hallucinations (AVH) in patients with schizophrenia are associated with abnormal hyperactivity in the left temporo-parietal junction (TPJ) and abnormal connectivity between frontal and temporal areas. Recent findings suggest that fronto-temporal transcranial Direct Current stimulation (tDCS) with the cathode placed over the left TPJ and the anode over the left prefrontal cortex can alleviate treatment-resistant AVH in patients with schizophrenia. However, brain correlates of the AVH reduction are unclear. Here, we investigated the effect of tDCS on the resting-state functional connectivity (rs-FC) of the left TPJ. Twenty-three patients with schizophrenia and treatment-resistant AVH were randomly allocated to receive 10 sessions of active (2 mA, 20min) or sham tDCS (2 sessions/d for 5 d). We compared the rs-FC of the left TPJ between patients before and after they received active or sham tDCS. Relative to sham tDCS, active tDCS significantly reduced AVH as well as the negative symptoms. Active tDCS also reduced rs-FC of the left TPJ with the left anterior insula and the right inferior frontal gyrus and increased rs-FC of the left TPJ with the left angular gyrus, the left dorsolateral prefrontal cortex and the precuneus. The reduction of AVH severity was correlated with the reduction of the rs-FC between the left TPJ and the left anterior insula. These findings suggest that the reduction of AVH induced by tDCS is associated with a modulation of the rs-FC within an AVH-related brain network, including brain areas involved in inner speech production and monitoring.

Fronto-temporal transcranial Direct Current Stimulation (tDCS) reduces source-monitoring deficits and auditory hallucinations in patients with schizophrenia

n 15 13 Gender (male/female) 6/9 6/7 1 Handedness (right-/left-handed) 13/2 10/3 0.6 Age (years) 36.5 (9.6) 39.2 (9.0) 0.4 Education (years) 12.8 (3.1) 11.9 (2.2) 0.4 Illness duration (years) 10.5 (8.8) 11.4 (7.8) 0.4 Olanzapine equivalent dose (mg/day) 27.3 (20.0) 34.0 (32.1) 0.6 PANSS score Total 68.9 (12.7) 75.4 (13.0) 0.8 Positive subscale 18.7 (4.1) 20.2 (4.5) 0.4 Negative subscale 19.3 (5.5) 19.5 (5.6) 1 General psychopathology subscale 31.7 (7.4) 35.7 (6.8) 0.2 AVH frequency (range 0–9) 6.14 (2.7) 5.46 (3.1) 0.6 Source-monitoring performances Total confusions (range 0–16) 3.87 (1.6) 3.54 (2.8) 0.24 Covert/overt speech misattributions (range 0–8) 1.73 (1.1) 1.69 (1.4) 0.8

Efficacy and safety of bifocal tDCS as an interventional treatment for refractory schizophrenia.

There is a dearth of experimental data validating direct model predictions of induced brain current flow or relating these predictions to experimental/clinical outcomes. And there has been no comprehensive effort to differentiate the impact on modeling techniques in regard to their clinical use. Moreover, most modeling studies are published as ‘‘case’’ reports with single head analysis and thus have limited consideration of variance across individualsd even as increasingly precise patient-specific models illustrate the impact of idiosyncratic anatomic differences. Modeling results can be presented phenomenologically, with current flow maps used by clinicians as a ‘‘look-up table’’ predicting activated and spared regions (given the caveats outlined above). But the applied value of a model follows specific predictions explaining existing data (in ways not obvious) and/or suggesting experimentally testable outcomes (notably when unexpected). In either case explicating hypotheses, including specifying to which populations they apply and underlying assumptions, provides practical insight into clinical decisions. The increased exploration of tDCS to treat diverse neuropsychiatric diseases and the desire to rationally optimize tDCS dose requires an understanding of which brain regions are targeted. Even working within existing unknown tDCS mechanisms, forward models thus serve as a key framework in developing electrical stimulation strategies and elucidating study outcomes–and indeed may thus provide a substrate for explaining the mechanisms.

Efficacy of Cathodal Transcranial Direct Current Stimulation Over the Left Orbitofrontal Cortex in a Patient With Treatment-Resistant Obsessive-Compulsive Disorder.

Obsessive-compulsive disorder (OCD) is a disabling and frequent neuropsychiatric disorder. Forty percent to 60% of patients with OCD fail to respond to available treatments. Neuroimaging studies have highlighted an association between the severity of obsessive and compulsive symptoms and an increased activity of the left orbitofrontal cortex (OFC) in patients with OCD. Transcranial direct current stimulation (tDCS) is a powerful and easy-to-use tool to modulate brain activity. Cathodal tDCS (c-tDCS) is assumed to decrease cortical excitability in the targeted brain region. We hypothesized that c-tDCS applied over the left OFC alleviates symptoms in patients with treatment-resistant OCD. We report here the case of a patient who received 10 sessions (2 mA, 20 minutes) of c-tDCS. The tDCS sessions were delivered twice a day with a 2-hour interval, with the cathode (35 cm²) placed over the left OFC and the anode (100 cm²) placed over the contralateral occipital region. No adverse event was reported. One month after the completion of the tDCS sessions, we observed a 26% reduction in severity of obsessive and compulsive symptoms measured using the Yale-Brown Obsessive Compulsive Scale scores. These findings are consistent with a previous study reporting a similar reduction in obsessive and compulsive symptoms after a low-frequency repetitive transcranial magnetic stimulation was given to the left OFC. Our results indicate that c-tDCS applied over the left OFC may be a suitable and safe treatment in patients with treatment-resistant OCD.

Low- vs High-Frequency Repetitive Transcranial Magnetic Stimulation as an Add-On Treatment for Refractory Depression.

Objectives: Repetitive transcranial magnetic stimulation (rTMS) seems to be effective as an antidepressant, however, some confusion remains about the best parameters to apply and the efficacy of its association with pharmacological antidepressant treatments. Method: In a single blind randomized study 14 patients with unipolar resistant depression to one antidepressant treatment were enrolled to receive, in combination with venlafaxine (150 mg), either 20 sessions of 10 Hz rTMS (2000 pulses per session) applied over the left dorsolateral prefrontal cortex (DLPFC) or 20 sessions of 1 Hz rTMS (120 stimulations per sessions) applied over the right DLPFC. Results: A similar antidepressant effect was observed in both groups with a comparable antidepressant delay of action (2 weeks) and a comparable number of responders (MADRS < 15) after 4 weeks of daily rTMS sessions (66 vs 50%). Conclusion: Low- and high- frequency rTMS seems to be effective as an add-on treatment to venlafaxine as monotherapy in pharmacological refractory major depression (stage 1). Due to its short duration (one session of 1 Hz rTMS lasts 4 min vs 16 for 10 Hz rTMS) and its safety, low frequency rTMS may be a useful alternative treatment for patients with refractory depression.

N-acetyl-aspartate level is decreased in the prefrontal cortex in subjects at-risk for schizophrenia

Reduced N-acetyl-aspartate (NAA) levels have been reported in the prefrontal cortex (PFC) in patients with schizophrenia using proton magnetic resonance spectroscopy. However, it is unclear whether this NAA reduction predates the illness onset and is reported in subjects at-risk for developing schizophrenia (HRS). The aim of this study was to assess NAA levels in the PFC in HRS. We hypothesized that HRS display lower NAA levels than healthy controls in the PFC. Studies assessing levels of NAA/Creatine (NAA/Cr) in the PFC in HRS were extracted from literature. Meta-analysis tools were used to compute effect sizes of nine selected studies meeting our inclusion criteria (clinical and/or genetic HRS, groups of HRS, and healthy controls matched for age and gender, spectral acquisition in the PFC). We reported that HRS exhibited a significant lower NAA/Cr level (2.15 ± 0.29; n = 208) than healthy controls (2.21 ± 0.32; n = 234) in the PFC with a medium pooled effect size [Hedges’s g = −0.42; 95% confidence interval: (−0.61; −0.23); p < 0.0001] corresponding to an average 5.7% of NAA/Cr decrease. Secondary analysis revealed that this reduction was observed in young HRS (<40 years old) who have not reached the peak age of risk for schizophrenia (−11%, g = −0.82, p < 0.00001) but not in old HRS (>40 years old) who have already passed the peak age (g = 0.11, p = 0.56), when they are compared with their matched healthy controls. Our findings suggest that the NAA/Cr reduction in the PFC reported in patients with schizophrenia is observable only in HRS who have not passed the peak age of risk for schizophrenia. NAA/Cr level in the PFC could therefore be considered as a biological vulnerability marker of schizophrenia.

Transcranial Direct Current Stimulation for Obsessive-Compulsive Disorder: A Systematic Review

Despite the advances in psychopharmacology and established psychotherapeutic interventions, more than 40% of patients with obsessive-compulsive disorder (OCD) do not respond to conventional treatment approaches. Transcranial direct current stimulation (tDCS) has been recently proposed as a therapeutic tool to alleviate treatment-resistant symptoms in patients with OCD. The aim of this review was to provide a comprehensive overview of the current state of the art and future clinical applications of tDCS in patients with OCD. A literature search conducted on the PubMed database following PRISMA guidelines and completed by a manual search yielded 12 results: eight case reports, three open-label studies (with 5, 8, and 42 participants), and one randomized trial with two active conditions (12 patients). There was no sham-controlled study. A total of 77 patients received active tDCS with a large diversity of electrode montages mainly targeting the dorsolateral prefrontal cortex, the orbitofrontal cortex or the (pre-) supplementary motor area. Despite methodological limitations and the heterogeneity of stimulation parameters, tDCS appears to be a promising tool to decrease obsessive-compulsive symptoms as well as comorbid depression and anxiety in patients with treatment-resistant OCD. Further sham-controlled studies are needed to confirm these preliminary results.

N-Acetyl-Aspartate in the dorsolateral prefrontal cortex in men with schizophrenia and auditory verbal hallucinations: A 1.5 T Magnetic Resonance Spectroscopy Study

Auditory verbal hallucinations (AVH) in patients with schizophrenia are linked to abnormalities within a large cerebral network including frontal and temporal regions. Whilst abnormalities of frontal speech production and temporal speech perception regions have been extensively studied, alterations of the dorsolateral prefrontal cortex (DLPFC), a region critically involved in the pathophysiology of schizophrenia, have rarely been studied in relation to AVH. Using 1.5 T proton magnetic resonance spectroscopy, this study examined the relationship between right and left DLPFCs N-AcetylAspartate (NAA) levels and the severity of AVH in patients with schizophrenia. Twenty-seven male patients with schizophrenia were enrolled in this study, 15 presented daily treatment-resistant AVH (AVH+) and 12 reported no AVH (no-AVH). AVH+ patients displayed higher NAA levels in the right DLPFC than no-AVH patients (p = 0.033). In AVH+ patients, NAA levels were higher in the right DLPFC than in the left (p = 0.024). No difference between the right and left DLPFC was observed in no-AVH patients. There was a positive correlation between NAA levels in the right DLPFC and the severity of AVH (r = 0.404, p = 0.037). Despite limited by magnetic field strength, these results suggest that AVH may be associated with increased NAA levels in the right DLPFC in schizophrenia.