The consequences of the new European reclassification of non-invasive brain stimulation devices and the medical device regulations pose an existential threat to research and treatment: An invited opinion paper.

A significant amount of European basic and clinical neuroscience research includes the use of transcranial magnetic stimulation (TMS) and low intensity transcranial electrical stimulation (tES), mainly transcranial direct current stimulation (tDCS). Two recent changes in the EU regulations, the introduction of the Medical Device Regulation (MDR) (2017/745) and the Annex XVI have caused significant problems and confusions in the brain stimulation field. The negative consequences of the MDR for non-invasive brain stimulation (NIBS) have been largely overlooked and until today, have not been consequently addressed by National Competent Authorities, local ethical committees, politicians and by the scientific communities. In addition, a rushed bureaucratic decision led to seemingly wrong classification of NIBS products without an intended medical purpose into the same risk group III as invasive stimulators. Overregulation is detrimental for any research and for future developments, therefore researchers, clinicians, industry, patient representatives and an ethicist were invited to contribute to this document with the aim of starting a constructive dialogue and enacting positive changes in the regulatory environment.

Impact of Benzodiazepines and Illness Duration on Obsessive-Compulsive Disorder during COVID-19 in Italy: Exploring Symptoms' Evolutionary Benefits.

Obsessive-compulsive disorder (OCD) is believed to follow a waxing and waning course, often according to environmental stressors. During the COVID-19 pandemic, pre-existing OCD symptoms were reported to increase and to change from checking to washing behaviors, while new-onset symptoms were predominantly of the hoarding type. In the present study, we followed the evolution of OCD symptoms, anxiety, depression, and insights of illness in forty-six OCD patients throughout the pandemic. Clinical measures were collected at four different time points before and during the COVID-19 pandemic in Italy. Within-subject comparisons were used to compare clinical scale scores across time, and correlations were examined between patients' baseline characteristics and changes in clinical scores. We found that all clinical measures increased during the first Italian lockdown with respect to the pre-pandemic values. Anxiety decreased during the temporary elimination of restriction provisions, whereas the severity of OCD symptoms and insight returned to pre-pandemic values during the second mandatory lockdown. These results were observed only in two sub-groups of patients: those taking benzodiazepines and those with shorter illness duration. Our findings suggest the need for additional clinical attention to these specific sub-groups of OCD patients in case of particularly distressing circumstances while pointing to a possible adaptive role of their OCD symptoms when the environment requires a higher care of hygiene and an extraordinary supply of essential resources.

The Neurobiological Underpinnings of Obsessive-Compulsive Symptoms in Psychosis, Translational Issues for Treatment-Resistant Schizophrenia.

Almost 25% of schizophrenia patients suffer from obsessive-compulsive symptoms (OCS) considered a transdiagnostic clinical continuum. The presence of symptoms pertaining to both schizophrenia and obsessive-compulsive disorder (OCD) may complicate pharmacological treatment and could contribute to lack or poor response to the therapy. Despite the clinical relevance, no reviews have been recently published on the possible neurobiological underpinnings of this comorbidity, which is still unclear. An integrative view exploring this topic should take into account the following aspects: (i) the implication for glutamate, dopamine, and serotonin neurotransmission as demonstrated by genetic findings; (ii) the growing neuroimaging evidence of the common brain regions and dysfunctional circuits involved in both diseases; (iii) the pharmacological modulation of dopaminergic, serotoninergic, and glutamatergic systems as current therapeutic strategies in schizophrenia OCS; (iv) the recent discovery of midbrain dopamine neurons and dopamine D1- and D2-like receptors as orchestrating hubs in repetitive and psychotic behaviors; (v) the contribution of N-methyl-D-aspartate receptor subunits to both psychosis and OCD neurobiology. Finally, we discuss the potential role of the postsynaptic density as a structural and functional hub for multiple molecular signaling both in schizophrenia and OCD pathophysiology.

Depression and Anxiety Symptoms "Among the Waves" of the COVID-19 Pandemic in Obsessive Compulsive Disorder and Adjustment Disorder Patients.

The COVID-19 pandemic and the associated restrictions caused great psychological suffering to the general population and psychiatric patients. We aimed to explore the course of depression and anxiety symptoms in obsessive compulsive disorder (OCD) patients, adjustment disorder (AD) patients, and participants without psychiatric disorders (control group, CG) across the different phases of the pandemic: the first lockdown, a temporary interruption of restrictions, and the second lockdown. Out of the 158 patients screened, we enrolled 46 OCD and 19 AD patients as well as 29 CG participants. The Beck Depression Inventory-II and the State-Trait Anxiety Inventory-Y were administered to all participants at each time point. The results showed different symptom severities among the groups throughout the whole study, with OCD patients always scoring higher than AD patients and the CG, and the AD patients always scoring higher than the CG. The symptom course within each group was different. OCD patients' symptoms sharply worsened during the first lockdown and then remained stable irrespective of the subsequent pandemic phases. In the AD and CG groups, symptoms waxed and waned following the fluctuations of the restriction provisions, with a complete return to the baseline when the restrictions were stopped only in the CG. These findings suggest that the influence of the pandemic and of the associated restrictions on depression and anxiety manifestations may vary depending on the particular pre-existing mental health status.

Effects of strict COVID-19 lockdown on patients with obsessive-compulsive disorder compared to a clinical and a nonclinical sample.

BACKGROUND: Symptoms of obsessive-compulsive disorder (OCD) have been reported to increase during the COVID-19 lockdowns because of the hygiene requirements related to the pandemic. Patients with adjustment disorder (AD) may, in turn, represent a vulnerable population for identifiable stressors. In this study, we aimed at assessing potential symptoms changes in OCD patients during the lockdown in comparison with AD patients as well as versus healthy controls (HC). METHODS: During the COVID-related lockdown, we enrolled 65 patients and 29 HC. Participants were tested with four clinical rating scales (Yale-Brown obsessive-compulsive scale and Brown Assessment of Beliefs Scale for OCD patients; Beck Depression Inventory-II and State-Trait Anxiety Inventory-Y for each group) that had been also administered just before the Italian lockdown. RESULTS: Our results showed that during the lockdown: (i) the symptoms of depression and anxiety increased in all groups, but this increase was most pronounced in HC (p < 0.001); (ii) OCD symptoms severity did not increase, but the insight worsened (p = 0.028); (iii) the proportion of OCD patients showing hygiene-related symptoms increased (p = 0.031 for obsessions of contamination), whereas that of patients with checking-related symptoms decreased. CONCLUSIONS: The lockdown-induced psychological distress apparently changed the characteristics and the pattern of OCD symptoms expression but not their overall severity. This evidence confirms the heterogeneity and changing nature of OCD symptoms, strongly depending on the environmental circumstances.

The effects of sustained COVID-19 emergency and restrictions on the mental health of subjects with serious mental illness: A prospective study.

Few longitudinal studies have so far investigated the impact of sustained COVID-19 among people with pre-existing psychiatric disorders. We conducted a prospective study involving people with serious mental illness (n = 114) and healthy controls (n = 41) to assess changes in the Perceived Stress Scale, Generalized Anxiety Disorder Scale, Patient Health Questionnaire, and Specific Psychotic Experiences Questionnaire scores 18 months after the COVID-19 pandemic outset. Subjects underwent interviews with a mental health professional in April 2020 and at the end of the local third wave (October 2021). A significant increase in perceived stress was found in healthy controls, especially females. Psychiatric patients showed a significant worsening of anxiety symptoms compared to baseline records (t = -2.3, p = 0.036). Patients who rejected vaccination had significantly higher paranoia scores compared to those willing to get vaccinated (U = 649.5, z = -2.02, p = 0.04). These findings indicate that COVID-19's sustained emergency may cause enduring consequences on mental health, soliciting further investigations.

Transcranial direct current stimulation for bipolar depression: systematic reviews of clinical evidence and biological underpinnings.

Despite multiple available treatments for bipolar depression (BD), many patients face sub-optimal responses. Transcranial direct current stimulation (tDCS) has been advocated in the management of different conditions, including BD, especially in treatment-resistant cases. The optimal dose and timing of tDCS, the mutual influence with other concurrently administered interventions, long-term efficacy, overall safety, and biological underpinnings nonetheless deserve additional assessment. The present study appraised the existing clinical evidence about tDCS for bipolar depression, delving into the putative biological underpinnings with a special emphasis on cellular and molecular levels, with the ultimate goal of providing a translational perspective on the matter. Two separate systematic reviews across the PubMed database since inception up to August 8th 2022 were performed, with fourteen clinical and nineteen neurobiological eligible studies. The included clinical studies encompass 207 bipolar depression patients overall and consistently document the efficacy of tDCS, with a reduction in depression scores after treatment ranging from 18% to 92%. The RCT with the largest sample clearly showed a significant superiority of active stimulation over sham. Mild-to-moderate and transient adverse effects are attributed to tDCS across these studies. The review of neurobiological literature indicates that several molecular mechanisms may account for the antidepressant effect of tDCS in BD patients, including the action on calcium homeostasis in glial cells, the enhancement of LTP, the regulation of neurotrophic factors and inflammatory mediators, and the modulation of the expression of plasticity-related genes. To the best of our knowledge, this is the first study on the matter to concurrently provide a synthesis of the clinical evidence and an in-depth appraisal of the putative biological underpinnings, providing consistent support for the efficacy, safety, and tolerability of tDCS.

Psychiatric Symptoms in Parkinson's Disease Patients before and One Year after Subthalamic Nucleus Deep Brain Stimulation Therapy: Role of Lead Positioning and Not of Total Electrical Energy Delivered.

Parkinson's disease (PD) patients may experience neuropsychiatric symptoms, including depression, anxiety, sleep disturbances, psychosis, as well as behavioral and cognitive symptoms during all the different stages of the illness. Deep Brain Stimulation (DBS) therapy has proven to be successful in controlling the motor symptoms of PD and its possible correlation with the occurrence or worsening of neuropsychiatric symptoms has been reported. We aimed to assess the neuropsychiatric symptoms of 14 PD patients before and after one year of Subthalamic Nucleus (STN)-DBS and to correlate the possible changes to the lead placement and to the total electrical energy delivered. We assessed PD motor symptoms, depression, anxiety, apathy, impulsivity, and suicidality using clinician- and/or self-administered rating scales and correlated the results to the lead position using the Medtronic SuretuneTM software and to the total electrical energy delivered (TEED). At the 12-month follow-up, the patients showed a significant improvement in PD symptoms on the UPDRS (Unified Parkinson's disease Rating Scale) (−38.5%; p < 0.001) and in anxiety on the Hamilton Anxiety Rating Scale (HAM-A) (−29%; p = 0.041), with the most significant reduction in the physiological anxiety subscore (−36.26%; p < 0.001). A mild worsening of impulsivity was detected on the Barratt Impulsiveness Scale (BIS-11) (+9%; p = 0.048), with the greatest increase in the attentional impulsiveness subscore (+13.60%; p = 0.050). No statistically significant differences were found for the other scales. No correlation was found between TEED and scales' scores, while the positioning of the stimulating electrodes in the different portions of the STN was shown to considerably influence the outcome, with more anterior and/or medial lead position negatively influencing psychiatric symptoms.

Simultaneous Bilateral Frontal and Bilateral Cerebellar Transcranial Direct Current Stimulation in Treatment-Resistant Depression-Clinical Effects and Electrical Field Modelling of a Novel Electrodes Montage.

Depressive disorders are one of the leading causes of disability worldwide. Transcranial direct current stimulation (tDCS) is a safe, simple, non-invasive brain stimulation technique showing considerable effectiveness in improving depressive symptoms. Most studies to date have applied anodal tDCS to the left dorsolateral prefrontal cortex (DLPFC), in line with the hypothesis that depressed patients exhibit relative hypoactivity in the left DLPFC compared to the right. Considering the emerging role of the cerebellum in emotional processes, we aimed to study the effect of combining bilateral cerebellar tDCS with the commonly used bifrontal stimulation in patients with severe depression. This open-label pilot study entailed the simultaneous administration of bilateral cerebellar (anode over the left cerebellum, cathode over the right cerebellum) and bilateral frontal (anode over the left DLPFC, cathode over the right DLPFC) tDCS to patients (N = 12) with treatment-resistant depression. The 21-item Hamilton Depression Rating Scale (HDRS) and Beck's Depression Inventory-II (BDI-II) were selected as outcome measures. Electric fields distribution originating from this novel electrode montage was obtained by a computational method applied to a realistic human head model. We observed a 30% reduction of both clinician-rated and self-reported severity of depressive symptoms after only five days (10 sessions) of treatment. Younger age was associated with greater clinical improvement. Adverse events were similar to those of the conventional electrodes montage. The modelling studies demonstrated that the electric fields generated by each pair of electrodes are primarily distributed in the cortical areas under the electrodes. In conclusion, the cerebellum could represent a promising adjunctive target for tDCS interventions in patients with TRD, particularly for younger patients.

Predicting the Severity of Lockdown-Induced Psychiatric Symptoms with Machine Learning.

During the COVID-19 pandemic, an increase in the incidence of psychiatric disorders in the general population and an increase in the severity of symptoms in psychiatric patients have been reported. Anxiety and depression symptoms are the most commonly observed during large-scale dramatic events such as pandemics and wars, especially when these implicate an extended lockdown. The early detection of higher risk clinical and non-clinical individuals would help prevent the new onset and/or deterioration of these symptoms. This in turn would lead to the implementation of public policies aimed at protecting vulnerable populations during these dramatic contingencies, therefore optimising the effectiveness of interventions and saving the resources of national healthcare systems. We used a supervised machine learning method to identify the predictors of the severity of psychiatric symptoms during the Italian lockdown due to the COVID-19 pandemic. Via a case study, we applied this methodology to a small sample of healthy individuals, obsessive-compulsive disorder patients, and adjustment disorder patients. Our preliminary results show that our models were able to predict depression, anxiety, and obsessive-compulsive symptoms during the lockdown with up to 92% accuracy based on demographic and clinical characteristics collected before the pandemic. The presented methodology may be used to predict the psychiatric prognosis of individuals under a large-scale lockdown and thus supporting the related clinical decisions.

Efficacy and safety of transcranial direct current stimulation as an add-on treatment for obsessive-compulsive disorder: a randomized, sham-controlled trial.

Obsessive-compulsive disorder (OCD) is a frequent, disabling disorder with high rates of treatment resistance. Transcranial direct current stimulation (tDCS) is a safe, tolerable noninvasive neuromodulation therapy with scarce evidence for OCD. This double-blind, randomized, and sham-controlled study investigates the efficacy of tDCS as add-on treatment for treatment-resistant OCD (failure to respond to at least one previous pharmacological treatment). On 20 consecutive weekdays (4 weeks), 43 patients with treatment-resistant OCD underwent 30 min active or sham tDCS sessions, followed by a 8 week follow-up. The cathode was positioned over the supplementary motor area (SMA) and the anode over the left deltoid. The primary outcome was the change in baseline Y-BOCS score at week 12. Secondary outcomes were changes in mood and anxiety and the occurrence of adverse events. Response was evaluated considering percent decrease of baseline Y-BOCS scores and the Improvement subscale of the Clinical Global Impression (CGI-I) between baseline and week 12. Patients that received active tDCS achieved a significant reduction of OCD symptoms than sham, with mean (SD) Y-BOCS score changes of 6.68 (5.83) and 2.84 (6.3) points, respectively (Cohen's d: 0.62 (0.06-1.18), p = 0.03). We found no between-group differences in responders (four patients in the active tDCS and one in the sham group). Active tDCS of the SMA was not superior to sham in reducing symptoms of depression or anxiety. Patients in both groups reported mild adverse events. Our results suggest that cathodal tDCS over the SMA is an effective add-on strategy in treatment-resistant OCD.

Cerebellar Transcranial Direct Current Stimulation in Children with Autism Spectrum Disorder: A Pilot Study on Efficacy, Feasibility, Safety, and Unexpected Outcomes in Tic Disorder and Epilepsy.

Patients with autism spectrum disorder (ASD) display distinctive neurophysiological characteristics associated with significant cognitive, emotional, and behavioral symptoms. Transcranial direct current stimulation (tDCS) applied to the frontal or temporoparietal lobes has demonstrated potential to reduce the severity of ASD-related symptoms. Recently, the cerebellum has been identified as a brain area involved in ASD pathophysiology. In this open-label pilot study, seven ASD patients aged between 9 and 13 years underwent 20 daily sessions of 20 min cathodal stimulation of the right cerebellar lobe. At the end of the treatment, the Aberrant Behavior Checklist (ABC) scores showed a 25% mean reduction in global severity of symptoms, with a more pronounced reduction in the "social withdrawal and lethargy" (-35%), "hyperactivity and noncompliance" (-26%), and "irritability, agitation, and crying" (-25%) subscales. Minor and no improvement were observed in the "stereotypic behavior" (-18%) and "inappropriate speech" (-0%) subscales, respectively. Improvements were not detected in the two patients who were taking psychotropic drugs during the study. Clinical response showed a symptom-specific time course. Quality of sleep and mood improved earlier than hyperactivity and social withdrawal. The treatment was generally accepted by patients and well tolerated. No serious adverse events were reported. Stimulation also appeared to markedly reduce the severity of tics in a patient with comorbid tic disorder and led to the disappearance of a frontal epileptogenic focus in another patient with a history of seizures. In conclusion, cerebellar tDCS is safe, feasible, and potentially effective in the treatment of ASD symptoms among children. Strategies to improve recruitment and retention are discussed.

Functional connectivity changes and symptoms improvement after personalized, double-daily dosing, repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: A pilot study.

BACKGROUND: intrusive thoughts and compulsive behaviors that characterize obsessive compulsive disorder (OCD) are associated to aberrant resting state functional connectivity (rsFC) patterns within the cortico-striatal-thalamo-cortical (CSTC) circuits. A high percentage of OCD patients do not respond to conventional pharmacological treatments or psychotherapy. In these patients, inhibitory repetitive transcranial magnetic stimulation (rTMS) of the Supplementary Motor Area (SMA) resulted in a significant clinical benefit. METHODS: In the current study, we applied a novel protocol of 1-week MRI-guided individualized double-daily sessions of rTMS treatment (1-Hz; 110% of resting Motor Threshold/7200 pulses/day), to bilateral SMA in 9 OCD patients. We tested its (i) feasibility-safety, (ii) clinical efficacy and (iii) rsFC related changes. RESULTS: Patients reported no side effects during and after rTMS. Personalized rTMS treatment led to a significant improvement of OCD symptoms (average 25%; p = .005) and persistence of benefit up to 3-month follow-up. rsFC analysis revealed a significant reduction of connectivity patterns between bilateral SMA and subcortical regions, specifically in the basal ganglia and thalamus. Additional analysis showed that OCD symptoms severity correlates with a higher connectivity pattern between bilateral SMA and subcortical regions. CONCLUSIONS: rTMS double-daily sessions are safe, feasible and effective in OCD. The clinical outcomes, that are consistent with those found in our previous RCT, are linked to a decreased connectivity between SMA and subcortical brain areas implicated in control over obsessions and maladaptive compulsive behavior.

Cost-utility analysis of transcranial direct current stimulation (tDCS) in non-treatment-resistant depression: the DISCO randomised controlled study protocol.

INTRODUCTION: Depression is among the most widespread psychiatric disorders in France. Psychiatric disorders are associated with considerable social costs, amounting to €22.6 billion for treatment and psychotropic medication in 2011. Treatment as usual (TAU), mainly consisting of pharmacotherapy and psychotherapy, is effective for only a third of patients and in most cases fails to prevent treatment resistance and chronicity. Transcranial direct current stimulation (tDCS) consists in a non-invasive and painless application of low-intensity electric current to the cerebral cortex through the scalp. Having proved effective in depressed patients, it could be used in combination with TAU to great advantage. The objective is to compare, for the first time ever, the cost-utility of tDCS-TAU and of TAU alone for the treatment of a depressive episode that has been refractory to one or two drug treatments. METHODS AND ANALYSIS: This paper, based on the DISCO study protocol, focuses on the design of a prospective, randomised, controlled, open-label multicentre economic study to be conducted in France. It will include 214 patients with unipolar or bipolar depression, assigning them to two parallel arms: group A (tDCS-TAU) and group B (TAU alone). The primary outcome is the incremental cost-effectiveness ratio, that is, the ratio of the difference in cost between each strategy to the difference in their effects. Their effects will be expressed as numbers of quality-adjusted life-years, determined through administration of the EuroQol Five-Dimension questionnaire over a 12-month period to patients (EQ-5D-5L). Expected benefits are the reduction of treatment resistance and suicidal ideation as well as social and professional costs of depression. Should depression-related costs fall significantly, tDCS might be considered an efficient treatment for depression. ETHICS AND DISSEMINATION: This protocol has been approved by a French ethics committee, the CPP--Est IV (Comité de Protection des Personnes-Strasbourg). Data are to be published in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: RCB 2018-A00474-51; NCT03758105.

Translating preclinical findings in clinically relevant new antipsychotic targets: focus on the glutamatergic postsynaptic density. Implications for treatment resistant schizophrenia.

There is a growing interest in new molecular targets for antipsychotic therapy. Multiple signal transduction systems have been recently implicated in the pathophysiology of schizophrenia. However, the weight of each specific mechanism remains controversial. A need for a more vigorous approach to the pharmacotherapy of schizophrenia arises from the bedside: about 30-40% of patients do not respond to antipsychotic therapy. Postsynaptic Density (PSD) proteins have recently attracted attention for their role in signal transduction modulation and for their potential implication in psychosis and cognition. The involvement of PSD in the pathophysiology of schizophrenia is supported by post mortem studies, preclinical animal models, modulation by antipsychotics, and association of PSD genes with schizophrenia in GWAS. Taken together, these studies underline the role of PSD modulation, its effects on striatal function and its relationship with motor, executive- and cognitive-like functions suggesting a potential role of PSD proteins as a l target of novel intervention in the treatment of refractory psychosis.

Smoking relapse risk is increased among individuals in recovery.

BACKGROUND: The prevalence of cigarette smoking among individuals with a history of substance use disorders (SUDs) remains up to four times higher than those without a history of SUDs. More than half of individuals who attain sustained remission from SUDs will die of tobacco-related diseases. The aim of this secondary data analysis was to compare the risk for smoking relapse among smokers with no history of SUDs and smokers in recovery from SUDs after multi-component, cognitive-behavioral treatment for tobacco dependence. METHODS: Participants were randomized to receive 6 sessions of multicomponent cognitive-behavioral therapy (adapted for lower socioeconomic groups or standard), 8 weeks of nicotine patches, and were followed for 6 months in the parent randomized clinical trial. Participants passed a urine drug test prior to enrollment. Recovery was assessed at baseline by self-report to the question, "Do consider yourself in recovery from drugs or alcohol?" Relapse was defined as any smoking for 7 consecutive days. RESULTS: Participants were primarily lower SES and identified as racial and/or ethnic minorities. Cox proportional hazards models revealed that the risk of smoking relapse following tobacco dependence treatment was greater among smokers in long-term (HR: 1.44; 95% CI: 1.01, 2.05) and short-term (HR: 1.98; 95% CI: 1.30, 3.03) recovery than for smokers with no history of SUDs. CONCLUSIONS: Our findings indicate that smokers in recovery from SUDs have 1.5-2 times the risk of relapse than smokers with no history of SUDs. More effective relapse prevention interventions are needed for this vulnerable, high-risk group of smokers.

Transcranial direct current stimulation in obsessive-compulsive disorder: an update in electric field modeling and investigations for optimal electrode montage.

Introduction: Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation intervention that has been investigated for several psychiatric disorders, including Obsessive-Compulsive Disorder (OCD). As there are several candidate brain regions for targeting OCD relevant networks, clinical studies using tDCS have considerably varied in terms of the electrode montages used. Computer modeling of electric field currents induced by tDCS can help guiding the research of relevant targets for OCD. In this review, the authors used this tool to investigate targeted brain areas from previous studies of tDCS in OCD. Areas covered: A literature search for articles with the keywords 'tDCS', 'Transcranial Direct Current Stimulation' and 'Obsessive Compulsive Disorder' was conducted to identify relevant publications. For comparing different electrode montages, electric field (EF) models were performed using high-resolution brain scan templates. Authors found 13 studies mostly showing an improvement in OCD symptoms. The electrode montages varied considerably between studies. Nonetheless, two main patterns of EFs could be identified: 'focal montages', with EFs concentrated in the prefrontal cortex, and 'diffuse montages', with widespread EFs over cortical areas. Expert opinion: Electric field simulation can guide future clinical trials in psychiatry, using personalized tDCS montages with distinct electrode positioning according to clusters of symptoms.