Cognitive Functions following Trigeminal Neuromodulation.

Vast scientific effort in recent years have been focused on the search for effective and safe treatments for cognitive decline. In this regard, non-invasive neuromodulation has gained increasing attention for its reported effectiveness in promoting the recovery of multiple cognitive domains after central nervous system damage. In this short review, we discuss the available evidence supporting a possible cognitive effect of trigeminal nerve stimulation (TNS). In particular, we ask that, while TNS has been widely and successfully used in the treatment of various neuropsychiatric conditions, as far as research in the cognitive field is concerned, where does TNS stand? The trigeminal nerve is the largest cranial nerve, conveying the sensory information from the face to the trigeminal sensory nuclei, and from there to the thalamus and up to the somatosensory cortex. On these bases, a bottom-up mechanism has been proposed, positing that TNS-induced modulation of the brainstem noradrenergic system may affect the function of the brain networks involved in cognition. Nevertheless, despite the promising theories, to date, the use of TNS for cognitive empowering and/or cognitive decline treatment has several challenges ahead of it, mainly due to little uniformity of the stimulation protocols. However, as the field continues to grow, standardization of practice will allow for data comparisons across studies, leading to optimized protocols targeting specific brain circuitries, which may, in turn, influence cognition in a designed manner.

Structural and Functional Brain Patterns Predict Formal Thought Disorder's Severity and Its Persistence in Recent-Onset Psychosis: Results From the PRONIA Study.

BACKGROUND: Formal thought disorder (FThD) is a core feature of psychosis, and its severity and long-term persistence relates to poor clinical outcomes. However, advances in developing early recognition and management tools for FThD are hindered by a lack of insight into the brain-level predictors of FThD states and progression at the individual level. METHODS: Two hundred thirty-three individuals with recent-onset psychosis were drawn from the multisite European Prognostic Tools for Early Psychosis Management study. Support vector machine classifiers were trained within a cross-validation framework to separate two FThD symptom-based subgroups (high vs. low FThD severity), using cross-sectional whole-brain multiband fractional amplitude of low frequency fluctuations, gray matter volume and white matter volume data. Moreover, we trained machine learning models on these neuroimaging readouts to predict the persistence of high FThD subgroup membership from baseline to 1-year follow-up. RESULTS: Cross-sectionally, multivariate patterns of gray matter volume within the salience, dorsal attention, visual, and ventral attention networks separated the FThD severity subgroups (balanced accuracy [BAC] = 60.8%). Longitudinally, distributed activations/deactivations within all fractional amplitude of low frequency fluctuation sub-bands (BACslow-5 = 73.2%, BACslow-4 = 72.9%, BACslow-3 = 68.0%), gray matter volume patterns overlapping with the cross-sectional ones (BAC = 62.7%), and smaller frontal white matter volume (BAC = 73.1%) predicted the persistence of high FThD severity from baseline to follow-up, with a combined multimodal balanced accuracy of BAC = 77%. CONCLUSIONS: We report the first evidence of brain structural and functional patterns predictive of FThD severity and persistence in early psychosis. These findings open up avenues for the development of neuroimaging-based diagnostic, prognostic, and treatment options for the early recognition and management of FThD and associated poor outcomes.

ERP and attachment dimensions as predictors of seeking care or food comfort in stressful situations.

In this study, we aimed to test the association of the Late Positive Potential (LPP) response and attachment dimensions in the choice of care/food pictures and its reaction time (RT) in threatening versus neutral conditions. Fifty-two participants (38 females, Mage 22.62) responded to the ECR questionnaire and were exposed to adequate visual stimuli, during EEG recording. Results showed that threatening stimuli increase the choice of care, decrease RT, and increase LPP magnitude in centro-parietal areas (Cpz, Pz, P3 and P4). Food choice was lower, with increased RT. Furthermore, larger LPP magnitude in centro-parietal cluster was associated with increased RT in the choice of care. Considering the dimensions of attachment, in threatening conditions, while anxiety was not associated with RT and care/food choice, avoidance was associated with an increase in care choice and RT. In conclusion, the specific association of increased RT in care choice with high LPP magnitude centro-parietal cluster may be explained in terms of a functional interference of these areas in the choice of care, but not of food. Further, we postulate that the increased RT of avoidant individuals may reflect a more articulated choice process.

A machine learning approach on whole blood immunomarkers to identify an inflammation-associated psychosis onset subgroup.

Psychosis onset is a transdiagnostic event that leads to a range of psychiatric disorders, which are currently diagnosed through clinical observation. The integration of multimodal biological data could reveal different subtypes of psychosis onset to target for the personalization of care. In this study, we tested the existence of subgroups of patients affected by first-episode psychosis (FEP) with a possible immunopathogenic basis. To do this, we designed a data-driven unsupervised machine learning model to cluster a sample of 127 FEP patients and 117 healthy controls (HC), based on the peripheral blood expression levels of 12 psychosis-related immune gene transcripts. To validate the model, we applied a resampling strategy based on the half-splitting of the total sample with random allocation of the cases. Further, we performed a post-hoc univariate analysis to verify the clinical, cognitive, and structural brain correlates of the subgroups identified. The model identified and validated two distinct clusters: 1) a FEP cluster characterized by the high expression of inflammatory and immune-activating genes (IL1B, CCR7, IL12A and CXCR3); 2) a cluster consisting of an equal number of FEP and HC subjects, which did not show a relative over or under expression of any immune marker (balanced subgroup). None of the subgroups was related to specific symptoms dimensions or longitudinal diagnosis of affective vs non-affective psychosis. FEP patients included in the balanced immune subgroup showed a thinning of the left supramarginal and superiorfrontal cortex (FDR-adjusted p-values < 0.05). Our results demonstrated the existence of a FEP patients' subgroup identified by a multivariate pattern of immunomarkers involved in inflammatory activation. This evidence may pave the way to sample stratification in clinical studies aiming to develop diagnostic tools and therapies targeting specific immunopathogenic pathways of psychosis.

Short-term transcutaneous trigeminal nerve stimulation does not affect visual oddball task and paired-click paradigm ERP responses in healthy volunteers.

Recent research suggests that transcutaneous trigeminal nerve stimulation (TNS) may positively affect cognitive function. However, no clear-cut evidence is available yet, since the majority of it derives from clinical studies, and the few data on healthy subjects show inconsistent results. In this study, we report the effects of short-term TNS on event-related potentials (ERP) recorded during the administration of a simple visual oddball task and a paired-click paradigm, both considered useful for studying brain information processing functions. Thirty-two healthy subjects underwent EEG recording before and after 20 min of sham- or real-TNS, delivered bilaterally to the infraorbital nerve. The amplitude and latency of P200 and P300 waves in the simple visual oddball task and P50, N100 and P200 waves in the paired-click paradigm were measured before and after treatment. Our results show that short-term TNS did not alter any of the ERP parameters measured, suggesting that in healthy subjects, short-term TNS may not affect brain processes involved in cognitive functions such as pre-attentional processes, early allocation of attention and immediate memory. The perspective of having an effective, non-pharmacological, non-invasive, and safe treatment option for cognitive decline is particularly appealing; therefore, more research on the positive effects on cognition of TNS is definitely needed.

Association between Diffusion Tensor Imaging, inflammation and immunological alterations in unipolar and bipolar depression: A review.

Major Depressive Disorder (MDD) and Bipolar Disorder Depression (BDD) are common psychiatric illnesses characterized by structural and functional brain alterations and signs of neuroinflammation. In line with the neuroinflammatory pathogenesis of depressive syndromes, recent studies have demonstrated how white matter (WM) microstructural impairments detected by Diffusion Tensor Imaging, are correlated to peripheral immunomarkers in depressed patients. In this context, we performed a comprehensive systematic search on PubMed, Medline and Scopus of the original studies published till June 2022, exploring the association between immunomarkers and WM alteration patterns in patients affected by MDD or BDD. Overall, the studies included in this review showed a consistent association between blood proinflammatory and counter-regulatory immunomarkers, including regulatory T cells and natural killer cells markers, as well as measures of demyelination and dysmyelination in both MDD and BDD patients. These pathogenetic insights could outline an integrated clinical perspective to affective disorders, helping psychiatrists to develop novel biotype-to-phenotype models of depression and opening the way to tailored approaches in treatments.

Successful clozapine rechallenge after myopericarditis: a case report.

Clozapine-induced myocarditis and pericarditis are uncommon adverse effects of clozapine treatment. However, in most cases, they lead to clozapine discontinuation. Here, we describe a case of successful clozapine rechallenge after clozapine-induced myopericarditis. The patient, a 31-year-old male with treatment-resistant schizophrenia (TRS), developed dyspnea on exertion and chest pain on day 19 after the start of clozapine titration. An electrocardiogram (ECG) showed widespread, mild, convex ST interval elevation. While troponin levels were mildly elevated, the echocardiogram was unremarkable. A myopericarditis diagnosis was formulated, and clozapine was stopped, with a progressive resolution of clinical, laboratory and ECG abnormalities. After 6 months, a rechallenge with clozapine was attempted. A very slow titration scheme was adopted, along with close monitoring of clinical, laboratory and ECG parameters. Clozapine target dose was reached without the occurrence of any abnormality. Given the unique role of clozapine in the management of TRS, clozapine rechallenge may be considered after pericarditis, even with troponin levels elevation. Further studies are needed to update current clinical guidelines.

Factors Associated With Severity of Delirium Complicating COVID-19 in Intensive Care Units.

The clinical outcome of the disease provoked by the SARS-CoV-2 infection, COVID-19, is largely due to the development of interstitial pneumonia accompanied by an Acute Respiratory Distress Syndrome (ARDS), often requiring ventilatory support therapy in Intensive Care Units (ICUs). Current epidemiologic evidence is demonstrating that the COVID-19 prognosis is significantly influenced by its acute complications. Among these, delirium figures as one of the most frequent and severe, especially in the emergency setting, where it shows a significantly negative prognostic impact. In this regard, the aim of our study is to identify clinical severity factors of delirium complicating COVID-19 related-ARDS. We performed a comparative and correlation analysis using demographics, comorbidities, multisystemic and delirium severity scores and anti-delirium therapy in two cohorts of ARDS patients with delirium, respectively, due to COVID-19 (n = 40) or other medical conditions (n = 39). Our results indicate that delirium in COVID-19-related ARDS is more severe since its onset despite a relatively less severe systemic condition at the point of ICU admission and required higher dosages of antipsychotic and non-benzodiazepinic sedative therapy respect to non-COVID patients. Finally, the correlation analysis showed a direct association between the male gender and maximum dosage of anti-delirium medications needed within the COVID-19 group, which was taken as a surrogate of delirium severity. Overall, our results seem to indicate that pathogenetic factors specifically associated to severe COVID-19 are responsible for the high severity of delirium, paving the way for future research focused on the mechanisms of the cognitive alterations associated with COVID-19.

Zinc as a Neuroprotective Nutrient for COVID-19-Related Neuropsychiatric Manifestations: A Literature Review.

The outbreak of the pandemic associated with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) led researchers to find new potential treatments, including nonpharmacological molecules such as zinc (Zn2+). Specifically, the use of Zn2+ as a therapy for SARS-CoV-2 infection is based on several findings: 1) the possible role of the anti-inflammatory activity of Zn2+ on the aberrant inflammatory response triggered by COronaVIrus Disease 19 (COVID-19), 2) properties of Zn2+ in modulating the competitive balance between the host and the invading pathogens, and 3) the antiviral activity of Zn2+ on a number of pathogens, including coronaviruses. Furthermore, Zn2+ has been found to play a central role in regulating brain functioning and many disorders have been associated with Zn2+ deficiency, including neurodegenerative diseases, psychiatric disorders, and brain injuries. Within this context, we carried out a narrative review to provide an overview of the evidence relating to the effects of Zn2+ on the immune and nervous systems, and the therapeutic use of such micronutrients in both neurological and infective disorders, with the final goal of elucidating the possible use of Zn2+ as a preventive or therapeutic intervention in COVID-19. Overall, the results from the available evidence showed that, owing to its neuroprotective properties, Zn2+ supplementation could be effective not only on COVID-19-related symptoms but also on virus replication, as well as on COVID-19-related inflammation and neurological damage. However, further clinical trials evaluating the efficacy of Zn2+ as a nonpharmacological treatment of COVID-19 are required to achieve an overall improvement in outcome and prognosis.

Adult Avoidant Attachment, Attention Bias, and Emotional Regulation Patterns: An Eye-Tracking Study.

Proximity-seeking in distress situations is one of attachment theory's primary strategies; insecure individuals often also develop secondary strategies. The mechanisms implied in attachment deactivation constitute a key issue in the current debate related to their role in support-seeking. The main aim of this study is to investigate the attachment deactivation strategy and the processes of proximity/support-seeking under distress conditions by analyzing the attentional processes (i.e., an essential emotion-regulation strategy), using eye-tracking techniques. Seventy-two participants (45 female; Mage 23.9 ± 3.97) responded to the ECR-R questionnaire in order to identify their attachment style. They participated in an experimental situation in which they had to choose between pictures of care or pictures of food, following the presentation of threatening or neutral prime conditions (via the pictures' stimuli). Results showed that a care-consistency response pattern was the most frequent pattern of response, particularly under a threatening condition; on the contrary, only avoidant individuals showed a lower care-consistency response pattern by choosing food pictures. The overall findings demonstrate that avoidant individuals used the deactivation strategy to process comfort-related attachment pictures, suggesting that they considered these stimuli to be threatening. The implications for attachment theory and particularly for avoidant strategies are discussed.

Case Report: The Association Between Chromosomal Anomalies and Cluster A Personality Disorders: The Case of Two Siblings With 16p11.2 Deletion and a Review of the Literature.

Although several studies have shown the correlation between chromosomal rearrangements and the risk of developing psychotic disorders, such as schizophrenia, little attention has been given to identifying the genetic basis of pre-disposing personality so far. In this regard, a limited but significant number of studies seem to indicate an association between chromosomal anomalies and cluster A personality disorders (CAPD). Starting from the clinical description of two brothers affected by familial 16p11 deletion syndrome (OMIM #611913), both sharing cluster A and C personality traits, the aim of the present study is to critically review the literature regarding the correlation between chromosomal rearrangements and CAPD. A bibliographic search on PubMed has been conducted, and eight studies were finally included in our review. Most of the studies highlight the presence of schizotypal personality disorder in the 22q11.2 deletion syndrome, whose evolutionary course toward psychotic pictures is well-known. One study also identified a paranoid personality disorder in a patient with a deletion on chromosome 7q21.3. No studies have so far identified the presence of paranoid personality disorder in 16p11 deletion, as in the case of the two siblings we report, while its association with psychosis and autism is already known. Although further epidemiologic studies on broader populations are indicated, our observations might pave the way for the definition of new diagnostic subgroups of CAPD and psychotic disorders, in order to implement the clinical management of such complex conditions.

Classification of Psychoses Based on Immunological Features: A Machine Learning Study in a Large Cohort of First-Episode and Chronic Patients.

For several years, the role of immune system in the pathophysiology of psychosis has been well-recognized, showing differences from the onset to chronic phases. Our study aims to implement a biomarker-based classification model suitable for the clinical management of psychotic patients. A machine learning algorithm was used to classify a cohort of 362 subjects, including 160 first-episode psychosis patients (FEP), 70 patients affected by chronic psychiatric disorders (schizophrenia, bipolar disorder, and major depressive disorder) with psychosis (CRO) and 132 health controls (HC), based on mRNA transcript levels of 56 immune genes. Models distinguished between FEP, CRO, and HC and between the subgroup of drug-free FEP and HC with a mean accuracy of 80.8% and 90.4%, respectively. Interestingly, by using the feature importance method, we identified some immune gene transcripts that contribute most to the classification accuracy, possibly giving new insights on the immunopathogenesis of psychosis. Therefore, our results suggest that our classification model has a high translational potential, which may pave the way for a personalized management of psychosis.

Sexual Dimorphism in the Brain Correlates of Adult-Onset Depression: A Pilot Structural and Functional 3T MRI Study.

Major Depressive Disorder (MDD) is a disabling illness affecting more than 5% of the elderly population. Higher female prevalence and sex-specific symptomatology have been observed, suggesting that biologically-determined dimensions might affect the disease onset and outcome. Rumination and executive dysfunction characterize adult-onset MDD, but sex differences in these domains and in the related brain mechanisms are still largely unexplored. The present pilot study aimed to explore any interactions between adult-onset MDD and sex on brain morphology and brain function during a Go/No-Go paradigm. We hypothesized to detect diagnosis by sex effects on brain regions involved in self-referential processes and cognitive control. Twenty-four subjects, 12 healthy (HC) (mean age 68.7 y, 7 females and 5 males) and 12 affected by adult-onset MDD (mean age 66.5 y, 5 females and 7 males), underwent clinical evaluations and a 3T magnetic resonance imaging (MRI) session. Diagnosis and diagnosis by sex effects were assessed on regional gray matter (GM) volumes and task-related functional MRI (fMRI) activations. The GM volume analyses showed diagnosis effects in left mid frontal cortex (p < 0.01), and diagnosis by sex effects in orbitofrontal, olfactory, and calcarine regions (p < 0.05). The Go/No-Go fMRI analyses showed MDD effects on fMRI activations in left precuneus and right lingual gyrus, and diagnosis by sex effects on fMRI activations in right parahippocampal gyrus and right calcarine cortex (p < 0.001, ≥ 40 voxels). Our exploratory results suggest the presence of sex-specific brain correlates of adult-onset MDD-especially in regions involved in attention processing and in the brain default mode-potentially supporting cognitive and symptom differences between sexes.

The role of vitamin D in bipolar disorder: Epidemiology and influence on disease activity.

BACKGROUND: Although many studies found an association between psychiatric disorders, especially major depressive disorder, and vitamin D deficiency, little is still known about the association between vitamin D and bipolar disorder (BD). Therefore, the present review aims at providing an overview of the available literature exploring the role of vitamin D in BD patients in different phases of the disease. METHODS: From a bibliographic research in PubMed until April 2020, we collected ten original studies that fulfilled our inclusion criteria. RESULTS: No significant differences in vitamin D levels between BD patients and other psychiatric disorders were found by most of the studies. In the majority of the studies, the average values of vitamin D in BD population were sub-threshold for vitamin D deficiency. Moreover, although an association between vitamin D levels and clinical symptomatology was observed in BD patients, it cannot be considered a specific marker of this disorder but a common characteristic shared with other psychiatric disorders, including schizophrenia and major depressive disorder. Finally, vitamin D supplementation was associated with a reduction in both depressive and manic symptoms. LIMITATIONS: Few studies with small and heterogeneous populations. Methodological heterogeneity in terms of vitamin D measurement and threshold. CONCLUSIONS: The results showed that vitamin D status does not differ between BD and other psychiatric conditions. However, given the correlation between vitamin D levels and depressive or manic symptoms, we could hypothesize that an adequate vitamin D status could positively affect the mood balance thanks to its immunomodulatory activity.

Augmentation with Atypical Antipsychotics for Treatment-Resistant Depression.

BACKGROUND: Treatment-resistant depression (TRD) is considered a common clinical condition often associated with relevant suicidal ideation and characterized by a severe functional impairment lifetime. Among the available drugs for the TRD treatment, second-generation antipsychotics (SGAs) have been reported as effective. In this context, the aim of this study was to review the clinical studies evaluating the efficacy of SGAs as add-on therapy in TRD. METHODS: A comprehensive search on PubMed, Medline and PsychINFO of all randomized clinical trials (RCTs) assessing the augmentation with antipsychotics in TRD, published from January 2000 until March 2020, was performed. Sixteen RCTs studies met the inclusion criteria. RESULTS: The reviewed studies showed that the add-on therapy with aripiprazole could be beneficial in the treatment of TRD. Furthermore, RCTs on quetiapine augmentation support its use in TRD, especially when comorbid anxiety or insomnia are present. The effects of risperidone and olanzapine as add-on in TRD were less studied, but preliminary data indicated an efficacy respect to placebo, making them a possible therapeutic option in TRD. LIMITATIONS: The lack of consistency in the definition of TRD together with the small sample sizes and the heterogeneity of antipsychotics dosages used in the reviewed RCTs may have limited the strength of evidences obtained. CONCLUSION: Overall, the available RCTs studies seem to support the hypothesis that the augmentation with SGAs, in particular aripiprazole and quetiapine, is a valid therapeutic option for TRD. However, to improve the therapeutic outcome of patients with TRD, larger and more homogeneous RCTs are needed.

Cannabinoids, Inner Ear, Hearing, and Tinnitus: A Neuroimmunological Perspective.

Cannabis has been used for centuries for recreational and therapeutic purposes. Whereas, the recreative uses are based on the psychotropic effect of some of its compounds, its therapeutic effects range over a wide spectrum of actions, most of which target the brain or the immune system. Several studies have found cannabinoid receptors in the auditory system, both at peripheral and central levels, thus raising the interest in cannabinoid signaling in hearing, and especially in tinnitus, which is affected also by anxiety, memory, and attention circuits where cannabinoid effects are well described. Available studies on animal models of tinnitus suggest that cannabinoids are not likely to be helpful in tinnitus treatment and could even be harmful. However, the pharmacology of cannabinoids is very complex, and most studies focused on neural CB1R-based responses. Cannabinoid effects on the immune system (where CB2Rs predominate) are increasingly recognized as essential in understanding nervous system pathological responses, and data on immune cannabinoid targets have emerged in the auditory system as well. In addition, nonclassical cannabinoid targets (such as TRP channels) appear to play an important role in the auditory system as well. This review will focus on neuroimmunological mechanisms for cannabinoid effects and their possible use as protective and therapeutic agents in the ear and auditory system, especially in tinnitus.

Transcutaneous trigeminal nerve stimulation modulates the hand blink reflex.

The hand-blink reflex (HBR) is a subcortical response, elicited by the electrical stimulation of the median nerve, whose magnitude is specifically modulated according to the spatial properties of the defensive peripersonal space (DPPS) of the face. For these reasons, the HBR is commonly used as a model to assess the DPPS of the face. Little is known on the effects induced by the activation of cutaneous afferents from the face on the DPPS of the face. Therefore, we tested the effect of non-painful transcutaneous trigeminal nerve stimulation (TNS) on the amplitude of the HBR. Fifteen healthy participants underwent HBR recording before and after 20 min of sham- and real-TNS delivered bilaterally to the infraorbital nerve in two separate sessions. The HBR was recorded bilaterally from the orbicularis oculi muscles, following non-painful median nerve stimulation at the wrist. The HBR amplitude was assessed in the "hand-far" and "hand-near" conditions, relative to the hand position in respect to the face. The amplitudes of the hand-far and hand-near HBR were measured bilaterally before and after sham- and real-TNS. Real-TNS significantly reduced the magnitude of the HBR, while sham-TNS had no significant effect. The inhibitory effect of TNS was of similar extent on both the hand-far and hand-near components of the HBR, which suggests an action exerted mainly at brainstem level.

Neurocognitive impact of ketamine treatment in major depressive disorder: A review on human and animal studies.

BACKGROUND: Most recent evidence support a rapid and sustained antidepressant effect of subanesthetic dose of intravenous ketamine in patients with major depressive disorder (MDD). However, clinical and animal studies investigating the effects of intravenous ketamine on specific functional domains disrupted by depression reported conflicting results. Therefore, the aim of this review is to provide an overview of the recent findings exploring the cognitive effects of ketamine in depression. METHODS: After a bibliographic search on PubMed, Medline and PsycInfo, we retrieved 11 original studies meeting our research criteria, 7 in humans with MDD or Treatment Resistant Disorder and 4 using rats models for depression. RESULTS: Overall the results showed that a) ketamine reduced activation and normalized connectivity measures of several brain regions related to depressive behaviors and reversed deficits in cognitive flexibility and coping response strategy in rats with depressive features, and b) ketamine leads to a no significant impairment on neurocognitive functions in most of the studies, with only three studies observing improvements in speed of processing, verbal learning, sustained attention and response control, verbal and working memory. LIMITATIONS: The methodological heterogeneity, in terms of neuropsychological tests used and cognitive domain explored, of the studies included. CONCLUSIONS: Most of the studies included showed no significant cognitive impairments in MDD patients after ketamine treatment. Furthermore, the results of the fMRI studies considered suggest that ketamine may have a normalizing effect on brain functions during attentional and emotional processing in MDD patients. However, further studies are needed to confirm these preliminary evidences.