Emotion dysregulation links pathological eating styles and psychopathological traits in bariatric surgery candidates.

Objectives: Approximately one-third of bariatric surgery patients experience weight regain or suboptimal weight loss within five years post-surgery. Pathological eating styles and psychopathological traits (e.g., emotion dysregulation) are recognized as potential hindrances to sustain weight loss efforts and are implicated in obesity development. A comprehensive understanding of these variables and their interplays is still lacking, despite their potential significance in developing more effective clinical interventions for bariatric patients. We investigate the prevalence of and interactions between pathological eating styles and psychopathological traits in this population. Materials and methods: 110 bariatric surgery candidates were characterized using the Binge Eating Scale (BES), Hamilton Depression/Anxiety Scales (HAM-D/A), Barratt Impulsiveness Scale (BIS-11), Experiences in Close Relationships (ECR), Difficulties in Emotion Regulation Scale (DERS). We analyzed these variables with multiple logistic regression analyses and network analysis. Results: Patients with pathological eating styles showed more pronounced anxiety/depressive symptoms and emotion dysregulation. Network analysis revealed strong connections between BES and DERS, with DERS also displaying robust connections with HAM-A/D and ECR scales. DERS and attention impulsivity (BIS-11-A) emerged as the strongest nodes in the network. Discussion: Our findings demonstrate the mediating role of emotion dysregulation between pathological eating styles and psychopathological traits, supporting existing literature on the association between psychopathological traits, insecure attachment styles, and pathological eating behaviors. This research emphasizes the significance of emotion regulation in the complex network of variables contributing to obesity, and its potential impact on bariatric surgery outcomes. Interventions focusing on emotion regulation may thus lead to improved clinical outcomes for bariatric patients.

Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: A systematic review and meta-analysis.

N-acetyl aspartate (NAA) is a marker of neuronal integrity and metabolism. Deficiency in neuronal plasticity and hypometabolism are implicated in Major Depressive Disorder (MDD) pathophysiology. To test if cerebral NAA concentrations decrease progressively over the MDD course, we conducted a pre-registered meta-analysis of Proton Magnetic Resonance Spectroscopy (1H-MRS) studies comparing NAA concentrations in chronic MDD (n = 1308) and first episode of depression (n = 242) patients to healthy controls (HC, n = 1242). Sixty-two studies were meta-analyzed using a random-effect model for each brain region. NAA concentrations were significantly reduced in chronic MDD compared to HC within the frontal lobe (Hedges' g = -0.330; p = 0.018), the occipital lobe (Hedges' g = -0.677; p = 0.007), thalamus (Hedges' g = -0.673; p = 0.016), and frontal (Hedges' g = -0.471; p = 0.034) and periventricular white matter (Hedges' g = -0.478; p = 0.047). We highlighted a gap of knowledge regarding NAA levels in first episode of depression patients. Sensitivity analyses indicated that antidepressant treatment may reverse NAA alterations in the frontal lobe. We highlighted field strength and correction for voxel grey matter as moderators of NAA levels detection. Future studies should assess NAA alterations in the early stages of the illness and their longitudinal progression.

Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Effect of Combined Levothyroxine (L-T4) and 3-Iodothyronamine (T1AM) Supplementation on Memory and Adult Hippocampal Neurogenesis in a Mouse Model of Hypothyroidism.

Mood alterations, anxiety, and cognitive impairments associated with adult-onset hypothyroidism often persist despite replacement treatment. In rodent models of hypothyroidism, replacement does not bring 3-iodothyronamine (T1AM) brain levels back to normal. T1AM is a thyroid hormone derivative with cognitive effects. Using a pharmacological hypothyroid mouse model, we investigated whether augmenting levothyroxine (L-T4) with T1AM improves behavioural correlates of depression, anxiety, and memory and has an effect on hippocampal neurogenesis. Hypothyroid mice showed impaired performance in the novel object recognition test as compared to euthyroid mice (discrimination index (DI): 0.02 ± 0.09 vs. 0.29 ± 0.06; t = 2.515, p = 0.02). L-T4 and L-T4+T1AM rescued memory (DI: 0.27 ± 0.08 and 0.34 ± 0.08, respectively), while T1AM had no effect (DI: -0.01 ± 0.10). Hypothyroidism reduced the number of neuroprogenitors in hippocampal neurogenic niches by 20%. L-T4 rescued the number of neuroprogenitors (mean diff = 106.9 ± 21.40, t = 4.99, pcorr = 0.003), while L-T4+T1AM produced a 30.61% rebound relative to euthyroid state (mean diff = 141.6 ± 31.91, t = 4.44, pcorr = 0.004). We performed qPCR analysis of 88 genes involved in neurotrophic signalling pathways and found an effect of treatment on the expression of Ngf, Kdr, Kit, L1cam, Ntf3, Mapk3, and Neurog2. Our data confirm that L-T4 is necessary and sufficient for recovering memory and hippocampal neurogenesis deficits associated with hypothyroidism, while we found no evidence to support the role of non-canonical TH signalling.

T1AM/TAAR1 System Reduces Inflammatory Response and ß-Amyloid Toxicity in Human Microglial HMC3 Cell Line.

Microglial dysfunction is one of the hallmarks and leading causes of common neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD). All these pathologies are characterized by aberrant aggregation of disease-causing proteins in the brain, which can directly activate microglia, trigger microglia-mediated neuroinflammation, and increase oxidative stress. Inhibition of glial activation may represent a therapeutic target to alleviate neurodegeneration. Recently, 3-iodothyronamine (T1AM), an endogenous derivative of thyroid hormone (TH) able to interact directly with a specific GPCR known as trace amine-associated receptor 1 (TAAR1), gained interest for its ability to promote neuroprotection in several models. Nevertheless, T1AM's effects on microglial disfunction remain still elusive. In the present work we investigated whether T1AM could inhibit the inflammatory response of human HMC3 microglial cells to LPS/TNFα or ß-amyloid peptide 25-35 (Aß25-35) stimuli. The results of ELISA and qPCR assays revealed that T1AM was able to reduce microglia-mediated inflammatory response by inhibiting the release of proinflammatory factors, including IL-6, TNFα, NF-kB, MCP1, and MIP1, while promoting the release of anti-inflammatory mediators, such as IL-10. Notably, T1AM anti-inflammatory action in HMC3 cells turned out to be a TAAR1-mediated response, further increasing the relevance of the T1AM/TAAR1 system in the management of NDDs.

Functional correlates of subliminal stimulation in Posttraumatic Stress Disorder: Systematic review and meta-analysis.

Patients with Post-traumatic stress disorder (PTSD) exposed to traumatic reminders show hyperreactivity in brain areas (e.g., amygdala) belonging or related to the Innate Alarm System (IAS), allowing the rapid processing of salient stimuli. Evidence that IAS is activated by subliminal trauma-reminders could shed a new light on the factors precipitating and perpetuating PTSD symptomatology. Thus, we systematically reviewed studies investigating neuroimaging correlates of subliminal stimulation in PTSD. Twenty-three studies were selected from the MEDLINE and Scopus® databases for a qualitative synthesis, 5 of which allowed a further meta-analysis of fMRI data. The intensity of IAS responses to subliminal trauma-related reminders ranged from a minimum in healthy controls to a maximum in the PTSD patients with the most severe (e.g., dissociative) symptoms or the least responsiveness to treatment. Comparisons with other disorders (e.g., phobias) revealed contrasting results. Our findings demonstrate the hyperactivation of areas belonging or related to IAS in response to unconscious threats that should be integrated in diagnostic as well as in therapeutic protocols.

An automatic analysis framework for FDOPA PET neuroimaging.

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size.

Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders.

Schizophrenia remains a major health burden, highlighting the need for new treatment approaches. We consider the potential for targeting the trace amine (TA) system. We first review genetic, preclinical, and clinical evidence for the role of TAs in the aetiopathology of schizophrenia. We then consider how the localisation and function of the trace amine-associated receptor 1 (TAAR1) position it to modulate key brain circuits for the disorder. Studies in rodents using Taar1 knockout (TAAR1-KO) and overexpression models show that TAAR1 agonism inhibits midbrain dopaminergic and serotonergic activity, and enhances prefrontal glutamatergic function. TAAR1 agonists also reduce hyperactivity, attenuate prepulse inhibition (PPI) deficits and social withdrawal, and improve cognitive measures in animal models. Finally, we consider findings from clinical trials of TAAR1 agonists and how this approach may address psychotic and negative symptoms, tolerability issues, and other unmet needs in the treatment of schizophrenia.

Trace amine-associated receptor 1 (TAAR1) agonists for psychosis: protocol for a living systematic review and meta-analysis of human and non-human studies.

BACKGROUND: There is an urgent need to develop more effective and safer antipsychotics beyond dopamine 2 receptor antagonists. An emerging and promising approach is TAAR1 agonism. Therefore, we will conduct a living systematic review and meta-analysis to synthesize and triangulate the evidence from preclinical animal experiments and clinical studies on the efficacy, safety, and underlying mechanism of action of TAAR1 agonism for psychosis. METHODS: Independent searches will be conducted in multiple electronic databases to identify clinical and animal experimental studies comparing TAAR1 agonists with licensed antipsychotics or other control conditions in individuals with psychosis or animal models for psychosis, respectively. The primary outcomes will be overall psychotic symptoms and their behavioural proxies in animals. Secondary outcomes will include side effects and neurobiological measures. Two independent reviewers will conduct study selection, data extraction using predefined forms, and risk of bias assessment using suitable tools based on the study design. Ontologies will be developed to facilitate study identification and data extraction. Data from clinical and animal studies will be synthesized separately using random-effects meta-analysis if appropriate, or synthesis without meta-analysis. Study characteristics will be investigated as potential sources of heterogeneity. Confidence in the evidence for each outcome and source of evidence will be evaluated, considering the summary of the association, potential concerns regarding internal and external validity, and reporting biases. When multiple sources of evidence are available for an outcome, an overall conclusion will be drawn in a triangulation meeting involving a multidisciplinary team of experts. We plan trimonthly updates of the review, and any modifications in the protocol will be documented. The review will be co-produced by multiple stakeholders aiming to produce impactful and relevant results and bridge the gap between preclinical and clinical research on psychosis. PROTOCOL REGISTRATION: PROSPERO-ID: CRD42023451628.

Applications of Mendelian randomization in psychiatry: a comprehensive systematic review.

Psychiatric diseases exact a heavy socioeconomic toll, and it is particularly difficult to identify their risk factors and causative mechanisms due to their multifactorial nature, the limited physiopathological insight, the many confounding factors, and the potential reverse causality between the risk factors and psychiatric diseases. These characteristics make Mendelian randomization (MR) a precious tool for studying these disorders. MR is an analytical method that employs genetic variants linked to a certain risk factor, to assess if an observational association between that risk factor and a health outcome is compatible with a causal relationship. We report the first systematic review of all existing applications and findings of MR in psychiatric disorders, aiming at facilitating the identification of risk factors that may be common to different psychiatric diseases, and paving the way to transdiagnostic MR studies in psychiatry, which are currently lacking. We searched Web of Knowledge, Scopus, and Pubmed databases (until 3 May 2022) for articles on MR in psychiatry. The protocol was preregistered in PROSPERO (CRD42021285647). We included methodological details and results from 50 articles, mainly on schizophrenia, major depression, autism spectrum disorders, and bipolar disorder. While this review shows how MR can offer unique opportunities for unraveling causal links in risk factors and etiological elements of specific psychiatric diseases and transdiagnostically, some methodological flaws in the existing literature limit reliability of results and probably underlie their heterogeneity. We highlight perspectives and recommendations for future works on MR in psychiatry.

Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer's disease.

Synaptic dysfunction is an early mechanism in Alzheimer's disease that involves progressively larger areas of the brain over time. However, how it starts and propagates is unknown. Here we show that amyloid-ß released by microglia in association with large extracellular vesicles (Aß-EVs) alters dendritic spine morphology in vitro, at the site of neuron interaction, and impairs synaptic plasticity both in vitro and in vivo in the entorhinal cortex-dentate gyrus circuitry. One hour after Aß-EV injection into the mouse entorhinal cortex, long-term potentiation was impaired in the entorhinal cortex but not in the dentate gyrus, its main target region, while 24 h later it was also impaired in the dentate gyrus, revealing a spreading of long-term potentiation deficit between the two regions. Similar results were obtained upon injection of extracellular vesicles carrying Aß naturally secreted by CHO7PA2 cells, while neither Aß42 alone nor inflammatory extracellular vesicles devoid of Aß were able to propagate long-term potentiation impairment. Using optical tweezers combined to time-lapse imaging to study Aß-EV-neuron interaction, we show that Aß-EVs move anterogradely at the axon surface and that their motion can be blocked through annexin-V coating. Importantly, when Aß-EV motility was inhibited, no propagation of long-term potentiation deficit occurred along the entorhinal-hippocampal circuit, implicating large extracellular vesicle motion at the neuron surface in the spreading of long-term potentiation impairment. Our data indicate the involvement of large microglial extracellular vesicles in the rise and propagation of early synaptic dysfunction in Alzheimer's disease and suggest a new mechanism controlling the diffusion of large extracellular vesicles and their pathogenic signals in the brain parenchyma, paving the way for novel therapeutic strategies to delay the disease.

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies.

Trace amine-associated receptor 1 (TAAR1) has emerged as a promising therapeutic target for neuropsychiatric disorders due to its ability to modulate monoaminergic and glutamatergic neurotransmission. In particular, agonist compounds have generated interest as potential treatments for schizophrenia and other psychoses due to TAAR1-mediated regulation of dopaminergic tone. Here, we review unmet needs in schizophrenia, the current state of knowledge in TAAR1 circuit biology and neuropharmacology, including preclinical behavioral, imaging, and cellular evidence in glutamatergic, dopaminergic and genetic models linked to the pathophysiology of psychotic, negative and cognitive symptoms. Clinical trial data for TAAR1 drug candidates are reviewed and contrasted with antipsychotics. The identification of endogenous TAAR1 ligands and subsequent development of small-molecule agonists has revealed antipsychotic-, anxiolytic-, and antidepressant-like properties, as well as pro-cognitive and REM-sleep suppressing effects of TAAR1 activation in rodents and non-human primates. Ulotaront, the first TAAR1 agonist to progress to randomized controlled clinical trials, has demonstrated efficacy in the treatment of schizophrenia, while another, ralmitaront, is currently being evaluated in clinical trials in schizophrenia. Coupled with the preclinical findings, this provides a rationale for further investigation and development of this new pharmacological class for the treatment of schizophrenia and other psychiatric disorders.

Portable technologies for digital phenotyping of bipolar disorder: A systematic review.

BACKGROUND: Bias-prone psychiatric interviews remain the mainstay of bipolar disorder (BD) assessment. The development of digital phenotyping promises to improve BD management. We present a systematic review of the evidence about the use of portable digital devices for the identification of BD, BD types and BD mood states and for symptom assessment. METHODS: We searched Web of KnowledgeSM, Scopus ®, IEEE Xplore, and ACM Digital Library databases (until 5/1/2021) for articles evaluating the use of portable/wearable digital devices, such as smartphone apps, wearable sensors, audio and/or visual recordings, and multimodal tools. The protocol is registered in PROSPERO (CRD42020200086). RESULTS: We included 62 studies (2325 BD; 724 healthy controls, HC): 27 using smartphone apps, either for recording self-assessments (n = 10) or for passively gathering metadata (n = 7) or both (n = 10); 15 using wearable sensors for physiological parameters; 17 analysing audio and/or video recordings; 3 using multiple technologies. Two thirds of the included studies applied artificial intelligence (AI)-based approaches. They achieved fair to excellent classification performances. LIMITATIONS: The included studies had small sample sizes and marked heterogeneity. Evidence of overfitting emerged, limiting generalizability. The absence of clear guidelines about reporting classification performances, with no shared standard metrics, makes results hardly interpretable and comparable. CONCLUSIONS: New technologies offer a noteworthy opportunity to BD digital phenotyping with objectivity and high granularity. AI-based models could deliver important support in clinical decision-making. Further research and cooperation between different stakeholders are needed for addressing methodological, ethical and socio-economic considerations.

Subacute Thyroiditis During the SARS-CoV-2 Pandemic.

CONTEXT: Acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been related to subacute thyroiditis (SAT). OBJECTIVE: We compared SAT cases during the SARS-CoV-2 pandemic to those observed in the previous years. METHODS: A cross-sectional, retrospective study was conducted at the Endocrinology Unit of University Hospital of Pisa, Italy. We included all patients observed from January 2016 to December 2020 because of an untreated SAT, who had developed the disease within 15 days prior to the visit. SAT cases from 2016 to 2019 (N = 152) are referred to as pre-SARS-CoV-2, while 2020 SAT patients are classified as pos-SARS-CoV-2 (N = 18) or neg-SARS-CoV-2 (N = 28), according to positive or negative SARS-CoV-2 testing performed up to 45 days from SAT onset. RESULTS: While during 2016-2019, most SAT cases were observed in the third quarter, in 2020, 2 peaks were seen, superimposable to the SARS-CoV-2 outbreaks in the second and the fourth quarters. In the second and fourth quarters of 2020, we observed higher levels of free thyroxine (FT4), C-reactive protein (CRP), and thyroglobulin (Tg) compared with the same quarters of the years 2016-2019. Pos-SARS-CoV-2 patients had higher FT4 (28.4 vs 24.1 nmol/L), CRP (8.5 vs 3.6 mg/L), and Tg (155 vs 60 µg/L) (P < 0.05 for all) and more frequently had hypothyroidism (13/15 vs 30/152 at 3 months) (P < 0.001) than pre-SARS-CoV-2 patients. Neg-SARS-CoV-2 patients showed a clinical picture intermediate between the other 2 groups. CONCLUSION: The SARS-CoV-2 pandemic has caused a shift in the annual timing and severity of SAT cases.

Unconscious processing of subliminal stimuli in panic disorder: A systematic review and meta-analysis.

Attentional biases to threat exist in panic disorder (PD), probably related to altered subliminal processing. We systematically reviewed studies investigating subliminal processing in PD. Studies were retrieved from MEDLINE and Scopus®. We meta-analytically compared PD (n = 167) and healthy controls (HC, n = 165) for processing of masked panic-related and neutral words. We also compared subliminal and supraliminal presentations of panic-related words relative to neutral words within PD subjects and HC. We found a significantly enhanced Stroop interference to masked panic-related words in PD vs HC (Hedges' g = 0.60, p = 0.03; Q = 14.83, I2 = 66.3 %, p = 0.01). While both PD subjects and HC tended to be slower to respond to supraliminal threat words than to neutral words, PD subjects only showed a marginally significant slower response to subliminal panic-related words vs neutral words. Findings remain inconclusive regarding comparison to other mental disorders, neural correlates, and the effect of psychotherapy. Even if possibly flawed by methodological weaknesses, our findings support the existence of a sensitivity to subliminal threat cues in PD, which could be targeted to improve treatment.

Developing and Validating an Individualized Clinical Prediction Model to Forecast Psychotic Recurrence in Acute and Transient Psychotic Disorders: Electronic Health Record Cohort Study.

Acute and transient psychotic disorders (ATPDs) include short-lived psychotic episodes with a high probability of developing psychotic recurrences. Clinical care for ATPD is currently limited by the inability to predict outcomes. Real-world electronic health record (EHR)-based retrospective cohort study STROBE/RECORD compliant included all individuals accessing the South London and Maudsley NHS Trust between 2006 and 2017 and receiving a first diagnosis of ATPD (F23, ICD-10). After imputing missing data, stepwise and LASSO Cox regression methods employing a priori predictors (n = 23) were compared to develop and internally validate an individualized risk prediction model to forecast the risk of psychotic recurrences following TRIPOD guidelines. The primary outcome was prognostic accuracy (area under the curve [AUC]). 3018 ATPD individuals were included (average age = 33.75 years, 52.7% females). Over follow-up (average 1042 ± 1011 days, up to 8 years) there were 1160 psychotic recurrences (events). Stepwise (n = 12 predictors) and LASSO (n = 17 predictors) regression methods yielded comparable prognostic accuracy, with an events per variable ratio >100 for both models. Both models showed an internally validated adequate prognostic accuracy from 4 years follow-up (AUC 0.70 for both models) and good calibration. A refined model was adapted in view of the new ICD-11 criteria on 307 subjects with polymorphic ATPD, showing fair prognostic accuracy at 4 years (AUC: stepwise 0.68; LASSO 0.70). This study presents the first clinically based prediction model internally validated to adequately predict long-term psychotic recurrence in individuals with ATPD. The model can be automatable in EHRs, supporting further external validations and refinements to improve its prognostic accuracy.

Tele-Mental Health for Reaching Out to Patients in a Time of Pandemic: Provider Survey and Meta-analysis of Patient Satisfaction.

BACKGROUND: The COVID-19 pandemic threatened to impact mental health by disrupting access to care due to physical distance measures and the unexpected pressure on public health services. Tele-mental health was rapidly implemented to deliver health care services. OBJECTIVE: The aims of this study were (1) to present state-of-the-art tele-mental health research, (2) to survey mental health providers about care delivery during the pandemic, and (3) to assess patient satisfaction with tele-mental health. METHODS: Document clustering was applied to map research topics within tele-mental health research. A survey was circulated among mental health providers. Patient satisfaction was investigated through a meta-analysis of studies that compared satisfaction scores between tele-mental health and face-to-face interventions for mental health disorders, retrieved from Web of Knowledge and Scopus. Hedges g was used as the effect size measure, and effect sizes were pooled using a random-effect model. Sources of heterogeneity and bias were examined. RESULTS: Evidence on tele-mental health has been accumulating since 2000, especially regarding service implementation, depressive or anxiety disorders, posttraumatic stress disorder, and special populations. Research was concentrated in a few countries. The survey (n=174 respondents from Italy, n=120 international) confirmed that, after the onset of COVID-19 outbreak, there was a massive shift from face-to-face to tele-mental health delivery of care. However, respondents held skeptical views about tele-mental health and did not feel sufficiently trained and satisfied. Meta-analysis of 29 studies (n=2143) showed that patients would be equally satisfied with tele-mental health as they are with face-to-face interventions (Hedges g=-0.001, 95% CI -0.116 to 0.114, P=.98, Q=43.83, I2=36%, P=.03) if technology-related issues were minimized. CONCLUSIONS: Mental health services equipped with tele-mental health will be better able to cope with public health crises. Both providers and patients need to be actively engaged in digitization, to reshape their reciprocal trust around technological innovations.

T1AM-TAAR1 signalling protects against OGD-induced synaptic dysfunction in the entorhinal cortex.

Abnormalities in thyroid hormones (TH) availability and/or metabolism have been hypothesized to contribute to Alzheimer's disease (AD) and to be a risk factor for stroke. Recently, 3-iodothyronamine (T1AM), an endogenous amine putatively derived from TH metabolism, gained interest for its ability to promote learning and memory in the mouse. Moreover, T1AM has been demonstrated to rescue the ß-Amyloid dependent LTP impairment in the entorhinal cortex (EC), a brain area crucially involved in learning and memory and early affected during AD. In the present work, we have investigated the effect of T1AM on ischemia-induced EC synaptic dysfunction. In EC brain slices exposed to oxygen-glucose deprivation (OGD), we demonstrated that the acute perfusion of T1AM (5 µM) was capable of preventing ischemia-induced synaptic depression and that this protective effect was mediated by the trace amine-associated receptor 1 (TAAR1). Moreover, we demonstrated that activation of the BDNF-TrkB signalling is required for T1AM action during ischemia. The protective effect of T1AM was more evident when using EC slices from transgenic mutant human APP (mhAPP mice) that are more vulnerable to the effect of OGD. Our results confirm that the TH derivative T1AM can rescue synaptic function after transient ischemia, an effect that was also observed in a Aß-enriched environment.

Lower speech connectedness linked to incidence of psychosis in people at clinical high risk.

BACKGROUND: Formal thought disorder is a cardinal feature of psychotic disorders, and is also evident in subtle forms before psychosis onset in individuals at clinical high-risk for psychosis (CHR-P). Assessing speech output or assessing expressive language with speech as the medium at this stage may be particularly useful in predicting later transition to psychosis. METHOD: Speech samples were acquired through administration of the Thought and Language Index (TLI) in 24 CHR-P participants, 16 people with first-episode psychosis (FEP) and 13 healthy controls. The CHR-P individuals were then followed clinically for a mean of 7 years (s.d. = 1.5) to determine if they transitioned to psychosis. Non-semantic speech graph analysis was used to assess the connectedness of transcribed speech in all groups. RESULTS: Speech was significantly more disconnected in the FEP group than in both healthy controls (p < .01) and the CHR-P group (p < .05). Results remained significant when IQ was included as a covariate. Significant correlations were found between speech connectedness measures and scores on the TLI, a manual assessment of formal thought disorder. In the CHR-P group, lower scores on two measures of speech connectedness were associated with subsequent transition to psychosis (8 transitions, 16 non-transitions; p < .05). CONCLUSION: These findings support the utility and validity of speech graph analysis methods in characterizing speech connectedness in the early phases of psychosis. This approach has the potential to be developed into an automated, objective and time-efficient way of stratifying individuals at CHR-P according to level of psychosis risk.

ACE2 in the Era of SARS-CoV-2: Controversies and Novel Perspectives.

Angiotensin-converting enzyme 2 (ACE2) is related to ACE but turned out to counteract several pathophysiological actions of ACE. ACE2 exerts antihypertensive and cardioprotective effects and reduces lung inflammation. ACE2 is subjected to extensive transcriptional and post-transcriptional modulation by epigenetic mechanisms and microRNAs. Also, ACE2 expression is regulated post-translationally by glycosylation, phosphorylation, and shedding from the plasma membrane. ACE2 protein is ubiquitous across mammalian tissues, prominently in the cardiovascular system, kidney, and intestine. ACE2 expression in the respiratory tract is of particular interest, in light of the discovery that ACE2 serves as the initial cellular target of severe acute respiratory syndrome (SARS)-coronaviruses, including the recent SARS-CoV2, responsible of the COronaVIrus Disease 2019 (COVID-19). Since the onset of the COVID-19 pandemic, an intense effort has been made to elucidate the biochemical determinants of SARS-CoV2-ACE2 interaction. It has been determined that SARS-CoV2 engages with ACE2 through its spike (S) protein, which consists of two subunits: S1, that mediates binding to the host receptor; S2, that induces fusion of the viral envelope with the host cell membrane and delivery of the viral genome. Owing to the role of ACE2 in SARS-CoV2 pathogenicity, it has been speculated that medical conditions, i.e., hypertension, and/or drugs, i.e., ACE inhibitors and angiotensin receptor blockers, known to influence ACE2 density could alter the fate of SARS-CoV-2 infection. The debate is still open and will only be solved when results of properly designed experimental and clinical investigations will be made public. An interesting observation is, however that, upon infection, ACE2 activity is reduced either by downregulation or by shedding. These events might precipitate the so-called "cytokine storm" that characterizes the most severe COVID-19 forms. As evidence accumulates, ACE2 appears a druggable target in the attempt to limit virus entry and replication. Strategies aimed at blocking ACE2 with antibodies, small molecules or peptides, or at neutralizing the virus by competitive binding with exogenously administered ACE2, are currently under investigations. In this review, we will present an overview of the state-of-the-art knowledge on ACE2 biochemistry and pathophysiology, outlining open issues in the context of COVID-19 disease and potential experimental and clinical developments.