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.

Investigating the structural network underlying brain-immune interactions using combined histopathology and neuroimaging: a critical review for its relevance in acute and long COVID-19.

Current views on immunity support the idea that immunity extends beyond defense functions and is tightly intertwined with several other fields of biology such as virology, microbiology, physiology and ecology. It is also critical for our understanding of autoimmunity and cancer, two topics of great biological relevance and for critical public health considerations such as disease prevention and treatment. Central to this review, the immune system is known to interact intimately with the nervous system and has been recently hypothesized to be involved not only in autonomic and limbic bio-behaviors but also in cognitive function. Herein we review the structural architecture of the brain network involved in immune response. Furthermore, we elaborate upon the implications of inflammatory processes affecting brain-immune interactions as reported recently in pathological conditions due to SARS-Cov-2 virus infection, namely in acute and post-acute COVID-19. Moreover, we discuss how current neuroimaging techniques combined with ad hoc clinical autopsies and histopathological analyses could critically affect the validity of clinical translation in studies of human brain-immune interactions using neuroimaging. Advances in our understanding of brain-immune interactions are expected to translate into novel therapeutic avenues in a vast array of domains including cancer, autoimmune diseases or viral infections such as in acute and post-acute or Long COVID-19.

The role of benzodiazepines in common conditions: a narrative review focusing on lormetazepam.

This review aimed to examine the place of benzodiazepines, specifically lormetazepam, in the treatment of insomnia, including during pregnancy or in patients with psychodermatoses. PubMed was searched for the term "lormetazepam" in association with MeSH terms encompassing anxiety, insomnia/sleep disorders, pregnancy/gestation, and psychodermatoses/skin disorders. English-language articles up to 31 July 2022 were identified. Ad hoc searches for relevant literature were performed at later stages of review development. Multiple randomized, placebo-controlled studies have demonstrated that lormetazepam dose-dependently increases total sleep time, decreases wakefulness over a dosing range of 0.5-2.0 mg, and improves subjective assessments of sleep quality. Lormetazepam is as effective as other benzodiazepines in improving sleep duration and quality, but is better tolerated than the long-acting agents with minimal next-day effects. Benzodiazepines can be used as short-term monotherapy at the lowest effective dose during the second or third trimesters of pregnancy; lormetazepam is also a reasonable choice due to its limited transplacental passage. Insomnia associated with skin disorders or pregnancy can be managed by effective symptom control (especially itching), sleep hygiene, treatment of anxiety/depression, and a short course of hypnotics.

The definition of treatment resistance in anxiety disorders: a Delphi method-based consensus guideline.

Anxiety disorders are very prevalent and often persistent mental disorders, with a considerable rate of treatment resistance which requires regulatory clinical trials of innovative therapeutic interventions. However, an explicit definition of treatment-resistant anxiety disorders (TR-AD) informing such trials is currently lacking. We used a Delphi method-based consensus approach to provide internationally agreed, consistent and clinically useful operational criteria for TR-AD in adults. Following a summary of the current state of knowledge based on international guidelines and an available systematic review, a survey of free-text responses to a 29-item questionnaire on relevant aspects of TR-AD, and an online consensus meeting, a panel of 36 multidisciplinary international experts and stakeholders voted anonymously on written statements in three survey rounds. Consensus was defined as ≥75% of the panel agreeing with a statement. The panel agreed on a set of 14 recommendations for the definition of TR-AD, providing detailed operational criteria for resistance to pharmacological and/or psychotherapeutic treatment, as well as a potential staging model. The panel also evaluated further aspects regarding epidemiological subgroups, comorbidities and biographical factors, the terminology of TR-AD vs. "difficult-to-treat" anxiety disorders, preferences and attitudes of persons with these disorders, and future research directions. This Delphi method-based consensus on operational criteria for TR-AD is expected to serve as a systematic, consistent and practical clinical guideline to aid in designing future mechanistic studies and facilitate clinical trials for regulatory purposes. This effort could ultimately lead to the development of more effective evidence-based stepped-care treatment algorithms for patients with anxiety disorders.

Revisiting benzodiazepines (GABA Enhancers):A transdiagnostic and precision medicine approach.

Since the mid 1980's, there has been an increased focus on the side effects of benzodiazepines (GABA enhancers), and as a result there has been a decrease in their use. We have systematically reviewed recent studies of GABA enhancers in psychiatry, and highlight evidence of their utility which may impact their negative conceptualization in clinical practice. We propose a new perspective on the appropriate use of these medications and describeclinical reasoning underpinning the use of benzodiazepine (GABA enhancers) based on their effect on specific receptors. A translational approach, involving a more comprehensive characterization of GABA receptors and their neuroscience-based mechanisms allows for a more precise use of this medication class. By adopting a precision person-centered approach, instead of a categorical approach, supports the prescribing of GABA enhancers when a cross-cutting transdiagnostic assessment shows anxiety symptoms associated with clinical impairment.

From 'mental fog' to post-acute COVID-19 syndrome's executive function alteration: Implications for clinical approach.

A common symptom of the neuropsychiatric Post-Acute COVID-19 syndrome (neuro-PACS) is the so called 'brain fog'. Patients describe the brain fog as problems with attention, memory and mental fatigue. Brain fog is experienced by 9-55% of people for months after having contracted SARS-CoV-2 virus. Several theories have been proposed to explain PACS's brain fog, including a neuroinflammatory hypothesis, but the hypothesis remains to be proven. Here, we examined inflammatory and immunological blood profile in a cohort of patients with PACS to investigate the association between executive functions and blood inflammatory markers. Executive function was assessed by the Trail Making Test (TMT) Part A and Part B, as well as the Barkley Deficits in Executive Functioning Scale (BDEFS), in 71 patients (36 men), average age of 40 years (range: 15-82, SD: 15.7). Impairment in executive functioning (BDEFS scores and TMT B scores) correlated with increased levels of Interleukin-6 (IL-6), fibrinogen and ferritin. Moreover, elevated levels of Il-6, fibrinogen, ferritin, tumor necrosis factor-alpha and C-reactive protein have been observed in PACS. These findings demonstrate that PACS is characterized by the presence of an immuno-inflammatory process, which is associated with diminished executive functioning. Here, we argue in favour of a shift from the non-descriptive definition of 'mental fog' to a characterization of a subtype of PACS, associated with alteration in executive functioning. Implication for clinical settings and prevention are discussed.

Postinfectious Inflammation, Autoimmunity, and Obsessive-Compulsive Disorder: Sydenham Chorea, Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infection, and Pediatric Acute-Onset Neuropsychiatric Disorder.

Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

PANDAS/PANS in the COVID-19 Age: Autoimmunity and Epstein-Barr Virus Reactivation as Trigger Agents?

COVID-19 impacted the entire world's population, frequently resulting in long-lasting neuropsychiatric complications. Furthermore, social distancing, lockdowns and fear for one's personal health worsen individual psychological wellbeing, especially in children and adolescents. Herein, we discuss the results of studies that specifically reported data about the impact of the COVID-19 pandemic or infection on children with Pediatric Acute-Onset Neuropsychiatric Disorders (PANS). Furthermore, we present the cases of five adolescents with PANS whose symptomatology increased following SARS-CoV-2 infection. What emerged from this study was that COVID-19 resulted in the exacerbation of obsessions, tics, anxiety and mood symptoms and decreased wellbeing. Moreover, new symptoms, as well as new PANS cases, are reported to have arisen after COVID-19 infection. Here, we hypothesize that the pathogenic mechanisms of silent viruses, such as the Epstein-Barr virus, are related to neuroinflammation, immune responses and reactivation, with additional roles played by social-isolation-related inflammatory processes. The discussion of PANS, which represents a model of immune-mediated neuropsychiatric manifestations, is particularly relevant, with the aim of uncovering the mechanisms that lead to neuropsychiatric Post-Acute COVID-19 Syndrome (PACS). Prospects for future studies and treatment implications are discussed.

Peripheral control of psychiatric disorders: Focus on OCD. Are we there yet?

"We are all in this together" - we often hear this phrase when we want to flag up a problem that is not for a single individual but concerns us all. A similar reflection has been recently made in the field of mental disorders where brain-centric scientists have started to zoom out their brain-focused graphical representations of the mechanisms regulating psychiatric diseases to include other organs or mediators that did not belong historically to the world of neuroscience. The brain itself - that has long been seen as a master in command secluded in its fortress (the blood brain barrier), has now become a collection of Airbnb(s) where all sorts of cells come in and out and sometimes even rearrange the furniture! Under this new framework of reference, mental disorders have become multisystem pathologies where different biological systems - not just the CNS -contribute 'all together' to the development and severity of the disease. In this narrative review article, we will focus on one of the most popular biological systems that has been shown to influence the functioning of the CNS: the immune system. We will specifically highlight the two main features of the immune system and the CNS that we think are important in the context of mental disorders: plasticity and memory.

Neurodevelopmental Disorders (NDDs): Beyond the Clinical Definition and Translational Approach.

Neurodevelopmental disorders (NDDs) are complex and heterogeneous disorders that affect the growth and development of the brain and are often associated with impairments in cognitive and motor functions, communication, and adaptive behavior [...].

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part I: Anxiety disorders.

AIM: This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders (published in 2002, revised in 2008). METHOD: A consensus panel of 33 international experts representing 22 countries developed recommendations based on efficacy and acceptability of available treatments. In total, 1007 RCTs for the treatment of these disorders in adults, adolescents, and children with medications, psychotherapy and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medications. RESULT: This paper, Part I, contains recommendations for the treatment of panic disorder/agoraphobia (PDA), generalised anxiety disorder (GAD), social anxiety disorder (SAD), specific phobias, mixed anxiety disorders in children and adolescents, separation anxiety and selective mutism. Selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are first-line medications. Cognitive behavioural therapy (CBT) is the first-line psychotherapy for anxiety disorders. The expert panel also made recommendations for patients not responding to standard treatments and recommendations against interventions with insufficient evidence. CONCLUSION: It is the goal of this initiative to provide treatment guidance for these disorders that has validity throughout the world.

World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for treatment of anxiety, obsessive-compulsive and posttraumatic stress disorders - Version 3. Part II: OCD and PTSD.

AIM: This is the third version of the guideline of the World Federation of Societies of Biological Psychiatry (WFSBP) Task Force for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Posttraumatic Stress Disorders which was published in 2002 and revised in 2008. METHOD: A consensus panel of 34 international experts representing 22 countries developed recommendations based on efficacy and acceptability of the treatments. In this version, not only medications but also psychotherapies and other non-pharmacological interventions were evaluated, applying the same rigorous methods that are standard for the assessment of medication treatments. RESULT: The present paper (Part II) contains recommendations based on published randomised controlled trials (RCTs) for the treatment of OCD (n = 291) and PTSD (n = 234) in children, adolescents, and adults. The accompanying paper (Part I) contains the recommendations for the treatment of anxiety disorders.For OCD, first-line treatments are selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioural therapy (CBT). Internet-CBT was also superior to active controls. Several second-line medications are available, including clomipramine. For treatment-resistant cases, several options are available, including augmentation of SSRI treatment with antipsychotics and other drugs.Other non-pharmacological treatments, including repetitive transcranial magnetic stimulation (rTMS), deep brain stimulation (DBS) and others were also evaluated.For PTSD, SSRIs and the SNRI venlafaxine are first-line treatments. CBT is the psychotherapy modality with the best body of evidence. For treatment-unresponsive patients, augmentation of SSRI treatment with antipsychotics may be an option. CONCLUSION: OCD and PTSD can be effectively treated with CBT and medications.

ADHD-Gaming Disorder Comorbidity in Children and Adolescents: A Narrative Review.

Attention Deficit/Hyperactivity Disorder (ADHD) is a neurobiological condition characterized by developmentally inadequate levels of inattention, hyperactivity, and impulsivity, and a neurobiological disruption in brain neurotransmitters and circuitry causing abnormal responses to rewards. Playing electronic games generates a biological response that activates the neuronal circuits linked to pleasure and reward, and there is a growing attention to this type of activity, which can also turn into a mental health condition. The existence and the boundaries between the functional and the dysfunctional are still a source of debate, with the recognition of 'Internet Gaming Disorder' (IGD) as a condition belonging to the broader area of addiction requiring more in-depth study with respect to the DSM-5, while 'Gaming Disorder' (GD) was officially recognized as a new diagnosis by the World Health Organization (WHO) in the updated revision of the International Classification of Diseases (ICD-11). Notwithstanding, the suggested criteria for the diagnosis of Gaming Disorder are still debated. Since ADHD has been reported as a risk factor for developing addictions, this narrative review aims to provide the current state-of-the art of the knowledge about the comorbidity between ADHD and Gaming Disorder. For this aim, a literature search was conducted using a combination of specific keywords and the results are discussed within the R-Do-C framework and dimensions, and implications for treatment are considered.

Transcranial direct current stimulation in combination with cognitive training in individuals with mild cognitive impairment: a controlled 3-parallel-arm study.

OBJECTIVE: Several studies showed that transcranial direct current stimulation (tDCS) enhances cognition in patients with mild cognitive impairment (MCI), however, whether tDCS leads to additional gains when combined with cognitive training remains unclear. This study aims to compare the effects of a concurrent tDCS-cognitive training intervention with either tDCS or cognitive training alone on a group of patients with MCI. METHODS: The study was a 3-parallel-arm study. The intervention consisted of 20 daily sessions of 20 minutes each. Patients (n = 62) received anodal tDCS to the left dorsolateral prefrontal cortex, cognitive training on 5 cognitive domains (orientation, attention, memory, language, and executive functions), or both. To examine intervention gains, we examined global cognitive functioning, verbal short-term memory, visuospatial memory, and verbal fluency pre- and post-intervention. RESULTS: All outcome measures improved after the intervention in the 3 groups. The improvement in global cognitive functioning and verbal fluency was significantly larger in patients who received the combined intervention. Instead, the intervention gain in verbal short-term memory and visuospatial memory was similar across the 3 groups. DISCUSSION: tDCS, regardless of the practicalities, could be an efficacious treatment in combination with cognitive training given the increased effectiveness of the combined treatment. CONCLUSIONS: Future studies will need to consider individual differences at baseline, including genetic factors and anatomical differences that impact the electric field generated by tDCS and should also consider the feasibility of at-home treatments consisting of the application of tDCS with cognitive training.

Efficacy of a vegetal mixture composed of Zingiber officinale, Echinacea purpurea, and Centella asiatica in a mouse model of neuroinflammation: In vivo and ex vivo analysis.

Experimental evidence suggests that neuroinflammation is a key pathological event of many diseases affecting the nervous system. It has been well recognized that these devastating illnesses (e.g., Alzheimer's, Parkinson's, depression, and chronic pain) are multifactorial, involving many pathogenic mechanisms, reason why pharmacological treatments are unsatisfactory. The purpose of this study was to evaluate the efficacy of a vegetal mixture capable of offering a multiple approach required to manage the multifactoriality of neuroinflammation. A mixture composed of Zingiber officinale (150 mg kg-1), Echinacea purpurea (20 mg kg-1), and Centella asiatica (200 mg kg-1) was tested in a mouse model of systemic neuroinflammation induced by lipopolysaccharide (LPS, 1 mg kg-1). Repeated treatment with the vegetal mixture was able to completely counteract thermal and mechanical allodynia as reported by the Cold plate and von Frey tests, respectively, and to reduce the motor impairments as demonstrated by the Rota rod test. Moreover, the mixture was capable of neutralizing the memory loss in the Passive avoidance test and reducing depressive-like behavior in the Porsolt test, while no efficacy was shown in decreasing anhedonia as demonstrated by the Sucrose preference test. Finally, LPS stimulation caused a significant increase in the activation of glial cells, of the central complement proteins and of inflammatory cytokines in selected regions of the central nervous system (CNS), which were rebalanced in animals treated with the vegetal mixture. In conclusion, the vegetal mixture tested thwarted the plethora of symptoms evoked by LPS, thus being a potential candidate for future investigations in the context of neuroinflammation.

The global assessment of OCD.

Obsessive Compulsive Disorder (OCD) is a common mental disorder that often causes great sufferance, with substantial impairment in social functioning and quality of life and affects family and significant relationships. Notwithstanding its severity, OCD is often not adequately diagnosed, or it is diagnosed with delay, leading often to a long latency between onset of the OCD symptoms and the start of adequate treatments. Several factors contribute to the complexity of OCD's clinical picture: early age of onset, chronic course, heterogeneity of symptoms, high rate of comorbidity with other psychiatric disorders, slow or partial response to therapy. Therefore, it is of primary importance for clinicians involved in diagnosing OCD, to assess all aspects of the disorder. This narrative review focuses on the global assessment of OCD, highlighting crucial areas to explore, pointing out the clinical features which are relevant for the treatment of the disorder, and giving an overview of the psychometric tools that can be useful during the screening procedure.

Advances in problematic usage of the internet research - A narrative review by experts from the European network for problematic usage of the internet.

Global concern about problematic usage of the internet (PUI), and its public health and societal costs, continues to grow, sharpened in focus under the privations of the COVID-19 pandemic. This narrative review reports the expert opinions of members of the largest international network of researchers on PUI in the framework of the European Cooperation in Science and Technology (COST) Action (CA 16207), on the scientific progress made and the critical knowledge gaps remaining to be filled as the term of the Action reaches its conclusion. A key advance has been achieving consensus on the clinical definition of various forms of PUI. Based on the overarching public health principles of protecting individuals and the public from harm and promoting the highest attainable standard of health, the World Health Organisation has introduced several new structured diagnoses into the ICD-11, including gambling disorder, gaming disorder, compulsive sexual behaviour disorder, and other unspecified or specified disorders due to addictive behaviours, alongside naming online activity as a diagnostic specifier. These definitions provide for the first time a sound platform for developing systematic networked research into various forms of PUI at global scale. Progress has also been made in areas such as refining and simplifying some of the available assessment instruments, clarifying the underpinning brain-based and social determinants, and building more empirically based etiological models, as a basis for therapeutic intervention, alongside public engagement initiatives. However, important gaps in our knowledge remain to be tackled. Principal among these include a better understanding of the course and evolution of the PUI-related problems, across different age groups, genders and other specific vulnerable groups, reliable methods for early identification of individuals at risk (before PUI becomes disordered), efficacious preventative and therapeutic interventions and ethical health and social policy changes that adequately safeguard human digital rights. The paper concludes with recommendations for achievable research goals, based on longitudinal analysis of a large multinational cohort co-designed with public stakeholders.

"A Theta Burst Stimulation on Pre-SMA: Proof-of-Concept of Transcranial Magnetic Stimulation in Gambling Disorder".

Gambling Disorder (GD) is a condition constituting a public health concern, with a burden of harm which is much greater than that of drug addiction. Patients with GD are generally reluctant to pharmacologic treatment and seem to prefer nonpharmacological interventions. Therefore, this proof-of-concept study aimed to investigate the feasibility of continuous Theta Burst Stimulation (cTBS) on the pre-SMA in six patients (5 males, 1 female), aged 30-64 years, with a DSM-5 diagnosis of Gambling Disorder and no comorbid mood disorders. Participants received over 10 sessions of Continuous TBS (cTBS) over pre-SMA bilaterally and have been evaluated using rating scales, including the PG-YBOCS and the CGI, before treatment (T0), at day 10 of treatment (T1) and at day 30 after treatment (T2); cTBS intervention was safe and without side effects. Since the design of our study does not allow us to draw conclusions on the effectiveness of the intervention with respect to the improvement of the functioning of the subject with GD, a more in-depth study, including a sham condition, neurocognitive measures of disinhibition and decision making, and collecting follow-up data on the sustained effect of TBS over a longer period is ongoing.