Efficacy and safety of ketamine and esketamine for unipolar and bipolar depression: an overview of systematic reviews with meta-analysis.

Background: Unipolar and bipolar depression present treatment challenges, with patients sometimes showing limited or no response to standard medications. Ketamine and its enantiomer, esketamine, offer promising alternative treatments that can quickly relieve suicidal thoughts. This Overview of Reviews (OoR) analyzed and synthesized systematic reviews (SRs) with meta-analysis on randomized clinical trials (RCTs) involving ketamine in various formulations (intravenous, intramuscular, intranasal, subcutaneous) for patients with unipolar or bipolar depression. We evaluated the efficacy and safety of ketamine and esketamine in treating major depressive episodes across various forms, including unipolar, bipolar, treatment-resistant, and non-resistant depression, in patient populations with and without suicidal ideation, aiming to comprehensively assess their therapeutic potential and safety profile. Methods: Following PRIOR guidelines, this OoR's protocol was registered on Implasy (ID:202150049). Searches in PubMed, Scopus, Cochrane Library, and Epistemonikos focused on English-language meta-analyses of RCTs of ketamine or esketamine, as monotherapy or add-on, evaluating outcomes like suicide risk, depressive symptoms, relapse, response rates, and side effects. We included studies involving both suicidal and non-suicidal patients; all routes and formulations of administration (intravenous, intramuscular, intranasal) were considered, as well as all available comparisons with control interventions. We excluded meta-analysis in which the intervention was used as anesthesia for electroconvulsive therapy or with a randomized ascending dose design. The selection, data extraction, and quality assessment of studies were carried out by pairs of reviewers in a blinded manner. Data on efficacy, acceptability, and tolerability were extracted. Results: Our analysis included 26 SRs and 44 RCTs, with 3,316 subjects. The intervention is effective and well-tolerated, although the quality of the included SRs and original studies is poor, resulting in low certainty of evidence. Limitations: This study is limited by poor-quality SRs and original studies, resulting in low certainty of the evidence. Additionally, insufficient available data prevents differentiation between the effects of ketamine and esketamine in unipolar and bipolar depression. Conclusion: While ketamine and esketamine show promising therapeutic potential, the current evidence suffers from low study quality. Enhanced methodological rigor in future research will allow for a more informed application of these interventions within the treatment guidelines for unipolar and bipolar depression. Systematic review registration: [https://inplasy.com/inplasy-2021-5-0049/], identifier (INPLASY202150049).

Mental Pain Correlates with Mind Wandering, Self-Reflection, and Insight in Individuals with Psychotic Disorders: A Cross-Sectional Study.

Understanding the cognitive processes that contribute to mental pain in individuals with psychotic disorders is important for refining therapeutic strategies and improving patient outcomes. This study investigated the potential relationship between mental pain, mind wandering, and self-reflection and insight in individuals diagnosed with psychotic disorders. We included individuals diagnosed with a 'schizophrenia spectrum disorder' according to DSM-5 criteria. Patients in the study were between 18 and 65 years old, clinically stable, and able to provide informed consent. A total of 34 participants, comprising 25 males and 9 females with an average age of 41.5 years (SD 11.5) were evaluated. The Psychache Scale (PAS), the Mind Wandering Deliberate and Spontaneous Scale (MWDS), and the Self-Reflection and Insight Scale (SRIS) were administered. Statistical analyses involved Spearman's rho correlations, controlled for potential confounders with partial correlations, and mediation and moderation analyses to understand the indirect effects of MWDS and SRIS on PAS and their potential interplay. Key findings revealed direct correlations between PAS and MWDS and inverse correlations between PAS and SRIS. The mediation effects on the relationship between the predictors and PAS ranged from 9.22% to 49.8%. The largest statistically significant mediation effect was observed with the SRIS-I subscale, suggesting that the self-reflection and insight component may play a role in the impact of mind wandering on mental pain. No evidence was found to suggest that any of the variables could function as relationship moderators for PAS. The results underscore the likely benefits of interventions aimed at reducing mind wandering and enhancing self-reflection in psychotic patients (e.g., metacognitive therapy, mindfulness). Further research will be essential to elucidate the underlying mechanisms.

Exploring Personal Recovery in Schizophrenia: The Role of Mentalization.

Recovery is a broadly debated concept in the field of psychiatry research and in schizophrenia. Our study aims to understand the correlation between personal recovery from schizophrenia and factors such as mentalization, disability, quality of life, and antipsychotic side effects; Methods: Participants with schizophrenia (according to DSM-5 criteria) were consecutively recruited from the Psychiatry Unit of the University of Catania, Italy. Participants were assessed with the Recovery Assessment Scale (RAS), the Multidimensional Mentalizing Questionnaire (MMQ), the brief version of the WHO Disability Assessment Schedule (WHO-DAS), the EuroQoL-5 dimensions-5 levels, the Insight Orientation Scale (IOS) and the Glasgow Antipsychotic Side Effect Scale (GASS); Results: 81 patients were included. Our findings showed a positive correlation between RAS total scores and MMQ scores, especially in "good mentalizing" subdomains. IOS scores also had a positive association with RAS and MMQ scores. In contrast, poor mentalizing abilities negatively correlated with WHO-DAS 2.0 scores. While antipsychotic side effects influenced functioning, they did not impact perceived recovery. Conclusions: The study's results identified potential predictors of personal recovery from schizophrenia. These findings could contribute to creating tailored interventions to facilitate the recovery process.

Challenging the Pleiotropic Effects of Repetitive Transcranial Magnetic Stimulation in Geriatric Depression: A Multimodal Case Series Study.

BACKGROUND: Although the antidepressant potential of repetitive transcranial magnetic stimulation (rTMS), the pleiotropic effects in geriatric depression (GD) are poorly investigated. We tested rTMS on depression, cognitive performance, growth/neurotrophic factors, cerebral blood flow (CBF) to transcranial Doppler sonography (TCD), and motor-evoked potentials (MEPs) to TMS in GD. METHODS: In this case series study, six drug-resistant subjects (median age 68.0 years) underwent MEPs at baseline and after 3 weeks of 10 Hz rTMS on the left dorsolateral prefrontal cortex. The percentage change of serum nerve growth factor, vascular endothelial growth factor, brain-derived growth factor, insulin-like growth factor-1, and angiogenin was obtained. Assessments were performed at baseline, and at the end of rTMS; psychocognitive tests were also repeated after 1, 3, and 6 months. RESULTS: Chronic cerebrovascular disease was evident in five patients. No adverse/undesirable effect was reported. An improvement in mood was observed after rTMS but not at follow-up. Electrophysiological data to TMS remained unchanged, except for an increase in the right median MEP amplitude. TCD and neurotrophic/growth factors did not change. CONCLUSIONS: We were unable to detect a relevant impact of high-frequency rTMS on mood, cognition, cortical microcircuits, neurotrophic/growth factors, and CBF. Cerebrovascular disease and exposure to multiple pharmacological treatments might have contributed.

Transcranial Magnetic Stimulation for the Treatment of Gambling Disorder: A Systematic Review.

BACKGROUND: Gambling Disorder (GD) is a behavioral addiction listed within the diagnostic category of substance-related and addictive disorders. Recently, transcranial magnetic stimulation (TMS), which non-invasively stimulates the brain and has neuromodulatory properties, has emerged as an innovative treatment tool for GD, thus offering a new option for the management of this complex disorder. The present review explored the efficacy of TMS as a possible non-pharmacological treatment for GD. METHODS: An exhaustive search was performed across the MEDLINE, Web of Science, and EMBASE databases using a specific search string related to GD and TMS. A total of 20 papers were selected for full-text examination, out of which eight fulfilled the inclusion criteria and were therefore systematically analyzed in the present review. RESULTS: This review included eight studies: three randomized-controlled trials (RCTs), three non-controlled studies, one case series, and one case report. Two cross-over RCTs described a decrease in craving after high-frequency (excitatory), repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) and the medial prefrontal cortex (PFC), respectively; another study applying low-frequency (inhibitory) rTMS on the right DLPFC did not find any positive effect on craving. Among uncontrolled studies, one demonstrated the beneficial effect of high-frequency rTMS over the left DLPFC, while another showed the efficacy of a continuous theta burst stimulation protocol directed over the pre-supplementary motor area, bilaterally. CONCLUSION: The included studies showed the promising effect of excitatory stimulation over the left PFC. However, further investigation is needed, particularly in terms of standardizing stimulation protocols and psychometric assessments.

A Systematic Review on the Effect of Nutraceuticals on Antidepressant-Induced Sexual Dysfunctions: From Basic Principles to Clinical Applications.

Sexual dysfunctions are common side effects reported by patients during antidepressant treatment. When they occur, patients often discontinue psychopharmacological therapy, with a negative impact on the underlying psychiatric disease. Recently, great attention has been paid to the use of nutraceuticals in the management of psychiatric disorders, although a systematic review on their effects as a treatment option for antidepressant-induced sexual dysfunctions (AISD) is lacking. Here, we conducted a systematic search in the following databases: MEDLINE (through PubMed), EMBASE, PsycINFO, Cochrane Central Register of Controlled Trials, and Web of Science. We searched eligible studies among parallel or crossover randomized controlled trials (RCTs) in adult populations. After this process, a total of 10 articles that evaluated the effect of six different nutraceuticals versus placebo were included: Maca Root, S-adenosyl-L-methionine (SAMe), Rosa Damascena, Ginkgo Biloba, Saffron, and Yohimbine. Overall, a high dose of Maca Root and the use of SAMe or Saffron may improve AISD. Additionally, the administration of Rosa Damascena seemed to be more effective in men than in women, whereas no evidence of effects emerged for Gingko Biloba and Yohimbine. Given the mixed results still available, future RCTs should consider larger samples and confounding factors, such as depressive status and individual vulnerability.

Exploration of mood spectrum symptoms during a major depressive episode: The impact of contrapolarity-Results from a transdiagnostic cluster analysis on an Italian sample of unipolar and bipolar patients.

BACKGROUND: Subthreshold hypomania during a major depressive episode challenges the bipolar-unipolar dichotomy. In our study we employed a cross-diagnostic cluster analysis - to identify distinct subgroups within a cohort of depressed patients. METHODS: A k-means cluster analysis- based on the domain scores of the Mood Spectrum Self-Report (MOODS-SR) questionnaire-was performed on a data set of 300 adults with either bipolar or unipolar depression. After identifying groups, between-clusters comparisons were conducted on MOODS-SR domains and factors and on a set of sociodemographic, clinical and psychometric variables. RESULTS: Three clusters were identified: one with intermediate depressive and poor manic symptomatology (Mild), one with severe depressive and poor manic symptomatology (Moderate), and a third one with severe depressive and intermediate manic symptomatology (Mixed). Across the clusters, bipolar patients were significantly less represented in the Mild one, while the DSM-5 "Mixed features" specifier did not differentiate the groups. When compared to the other patients, those of Mixed cluster exhibited a stronger association with most of the illness-severity, quality of life, and outcomes measures considered. After performing pairwise comparisons significant differences between "Mixed" and "Moderate" clusters were restricted to: current and disease-onset age, psychotic ideation, suicidal attempts, hospitalization numbers, impulsivity levels and comorbidity for Cluster B personality disorder. CONCLUSIONS: In the present study, a clustering approach based on a spectrum exploration of mood symptomatology led to the identification of three transdiagnostic groups of patients. Consistent with our hypothesis, the magnitude of subthreshold (hypo)manic symptoms was related to a greater clinical severity, regardless of the main categorical diagnosis.

Mixed Depression: A Mini-Review to Guide Clinical Practice and Future Research Developments.

The debate on mixed states (MS) has been intense for decades. However, several points remain controversial from a nosographic, diagnostic, and therapeutic point of view. The different perspectives that have emerged over the years have turned into a large, but heterogeneous, literature body. The present review aims to summarize the evidence on MS, with a particular focus on mixed depression (MxD), in order to provide a guide for clinicians and encourage the development of future research on the topic. First, we review the history of MS, focusing on their different interpretations and categorizations over the centuries. In this section, we also report alternative models to traditional nosography. Second, we describe the main clinical features of MxD and list the most reliable assessment tools. Finally, we summarize the recommendations provided by the main international guidelines for the treatment of MxD. Our review highlights that the different conceptualizations of MS and MxD, the variability of clinical pictures, and the heterogeneous response to pharmacological treatment make MxD a real challenge for clinicians. Further studies are needed to better characterize the phenotypes of patients with MxD to help clinicians in the management of this delicate condition.

Family interventions for relapse prevention in schizophrenia: a systematic review and network meta-analysis.

BACKGROUND: Family interventions are efficacious for relapse prevention in schizophrenia. Multiple different models have been developed. We aimed to compare the efficacy, acceptability, and tolerability of family interventions for relapse prevention in schizophrenia. METHODS: In this systematic review and network meta-analysis, we searched for randomised controlled trials that investigated family intervention models aimed at preventing relapse in patients with schizophrenia. We searched EMBASE, MEDLINE, PsycINFO, BIOSIS, CENTRAL, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform up to Jan 20, 2020 and PubMed up to July 15, 2021. We included blinded and open-label randomised controlled trials in which at least 80% of patients had schizophrenia spectrum disorders. We excluded studies in which all patients were acutely ill, had a concurrent medical or psychiatric disorder, or were prodromal or "at risk of psychosis". Study selection and data extraction were done by two independent reviewers. Data were extracted about overall, positive, negative, and depressive symptoms of schizophrenia, quality of life, adherence, overall functioning, family burden, expressed emotion, and discontinuations due to inefficacy. The primary outcome was relapse, measured with operationalised criteria, psychiatric hospital admissions, or clinical judgement. We did a frequentist, random-effects, network meta-analysis to calculate odds ratios ([ORs]; dichotomous outcomes) or standardised mean differences (continuous outcomes) with 95% CIs. The study protocol was registered with PROSPERO, CRD42020169951. FINDINGS: We identified 28 395 studies through the database search and 334 from references of previous studies. We compared 11 family intervention models tested on a total of 90 randomised controlled trials with 10 340 participants (3579 females and 5632 males with sex indicated; median age 31 years [range 14-65]) in the network meta-analysis. Ethnicity data were not available. All interventions, with the exception of crisis-oriented interventions and family psychoeducation with two sessions or fewer, reduced the relapse rate significantly when compared with treatment as usual at the primary timepoint of 12 months. ORs compared with treatment as usual ranged from 0·18 (95% CI 0·12-0·27) for family psychoeducation alone to 0·63 (0·42-0·94) for community-based interventions involving family members. The results were robust in various sensitivity and subgroup analyses. The confidence in the estimates ranged from moderate to very low for different comparisons. INTERPRETATION: Almost all family intervention models were efficacious in preventing relapse in schizophrenia. Family psychoeducation alone, without behavioural or skills training, was superior to the more complex models. Our results suggest that in contexts where there are financial constraints, family psychoeducation alone should be implemented. FUNDING: German Ministry for Education and Research.

Which mixed depression model? A comparison between DSM-5-defined mixed features and Koukopoulos' criteria.

BACKGROUND: The criteria of the Diagnostic and Statistical Manual of Mental Disorders 5th edition "with mixed features specifier" (DSM-5 MFS) are considered controversial since they include only typical manic symptoms. By contrast, Koukopoulos developed an alternative model of mixed depression (MxD) focusing primarily on the excitatory component. OBJECTIVE: To compare DSM-5 MFS and Koukopoulos' MxD (KMxD) in terms of prevalence, associated clinical variables, and discriminative capacity for bipolar depression in patients with major depressive episode (MDE). METHODS: A total of 300 patients with MDE-155 with major depressive disorder and 145 with bipolar disorder (BD)-were recruited. The discriminative capacity of DSM-5 MFS and KMxD criteria for BD was estimated using the area under the curves of receiver operating characteristic (ROC_AUC). The clinical variables associated with these two diagnostic constructs were assessed by performing a logistic regression. RESULTS: A total of 44 and 165 patients met the DSM-5 MFS and KMxD criteria, respectively. The ROC_AUCs and their confidence intervals for BD according to DSM-5 MFS and KMxD were 77.0% (72.0%-82.1%) and 71.9% (66.2%-77.7%), respectively. The optimal thresholds (combining sensitivity and specificity measures) for BD diagnosis were ≥1 (77%/68%) for DSM-5 MFS and ≥3 symptoms (78%/66%) for KMxD. However, considering the DSM-5 MFS cut-off (≥3 symptoms), the specificity (97%) increased at the expense of sensitivity (26%). CONCLUSIONS: KMxD and DSM-5-MFS showed an overlapping discriminative capacity for bipolar depression. The current diagnostic threshold of DSM-5 MFS did not prove to be very inclusive, if compared with the greater diagnostic sensitivity of KMxD, which also yielded better association with clinical variables related to mixedness.

Acute social and somatic stress alters cortical metaplasticity probed with non-invasive brain stimulation in humans.

Studying the neuronal mechanisms that govern the cortical adaptations to acute stress is critical for understanding the development of neuropsychiatric diseases. Homeostatic plasticity stabilizes the neural activity in which a previous synaptic event drives subsequent synaptic plasticity. In this study, we evaluated the effect of acute stress induced with the socially evaluated cold pressor test (SECPT) on cortical metaplasticity in humans using a non-invasive brain stimulation protocol. After being exposed to the SECPT and control stress conditions, 30 healthy participants were tested for cortical metaplasticity assessed with changes in the amplitude of the motor evoked potential (MEP) induced by a single-pulse transcranial magnetic stimulation (TMS). Cortical metaplasticity was induced by combining priming with cathodal tDCS (cTDCS) followed by a sub-threshold 1-Hz repetitive stimulation (rTMS) test session. Our results showed that SECPT induced cardiovascular adaptations (increase in systolic, diastolic blood pressure, and heart rate), indicating that SECPT effectively induced acute stress. Also, in our experiments stimulation of subjects with 1-Hz rTMS after they had undergone the SECPT condition induced inhibition of MEP whereas 1-Hz rTMS administered after the control condition induced a facilitatory (physiologic) response pattern. Here we observed that acute stress impairs homeostatic metaplasticity. The dysfunctional regulation of cortical plastic changes after stress could play a pivotal role in the pathogenesis of neurological and psychiatric diseases.

Off-Label Use of Second-Generation Antipsychotics in Borderline Personality Disorder: A Survey of Italian Psychiatrists.

The guidelines for borderline personality disorder (BPD) treatment suggest non-pharmacological treatment as the first option, but second-generation antipsychotics (SGAs) are among the overprescribed medications. This study aimed to explore Italian psychiatrists' attitudes toward off-label use of SGAs in BPD. A randomly selected sample of Italian psychiatrists completed a questionnaire regarding off-label prescription of SGAs. Most respondents reported the off-label use of SGAs. Among the reasons supporting the prescription of SGAs, the presence of strong published data was the most determining factor (51.5%). The SGA olanzapine is considered the most appropriate, followed by quetiapine and aripiprazole. Although off-label prescription of SGAs represents a common clinical practice in accordance with a worldwide trend, the use of long-acting injection formulations was considered inappropriate by 69% of psychiatrists in our sample. Our results reiterate the discrepancy between everyday clinical practice and international recommendations, and show how relevant the literature is in off-label drug prescription.

Vitamin D and Depressive Symptoms in Adults with Multiple Sclerosis: A Scoping Review.

BACKGROUND: Vitamin D deficiency has been correlated with Multiple Sclerosis (MS) risk and disease activity. There is some controversy as to whether vitamin D could have an impact on depressive symptoms in people with MS (pwMS). The aim of this scoping review was to evaluate the association between vitamin D status and depressive symptoms in pwMS. METHODS: We searched databases to include studies published up to March 2021 to provide an overview of the available evidence on the correlation between vitamin D status and depressive symptoms in pwMS. The eligibility criteria were as follows: studies evaluating the use of vitamin D measurement on depressive symptoms in patients suffering from MS, including randomized and non-randomized studies; studies written in English; and studies exploring an adult population over the age of 18. RESULTS: Eleven studies met our inclusion criteria: two of them were abstracts only; the majority were cross-sectional studies; two were prospective longitudinal studies; one was a retrospective cohort study; and one was a randomized placebo-controlled trial (RCT). Of the eleven studies selected, seven showed a potential correlation between low vitamin D levels and depressive symptoms. CONCLUSION: Future RCT studies should include patients with greater severity of depressive symptoms and should consider confounding factors such as sun exposure and seasonal variation of vitamin D.

Mood spectrum symptoms during a major depressive episode: Differences between 145 patients with bipolar disorder and 155 patients with major depressive disorder. Arguments for a dimensional approach.

BACKGROUND: Several studies have challenged the traditional unipolar-bipolar dichotomy in favor of a more dimensional approach. OBJECTIVE: To evaluate the differences in mood spectrum between patients with bipolar disorder (BD) and major depressive disorder (MDD) during a major depressive episode (MDE). METHOD: Study participants were 145 patients with BD and 155 patients with MDD recruited at three University Medical Centers in Italy. All study subjects met Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for MDE and completed the Mood Spectrum-Self-Report-Last Month questionnaire. RESULTS: Patients with BD endorsed more items in the mood manic/hypomanic and energy depressive subdomains of the MOODS-SR questionnaire. Significant differences were also found for specific depressive and manic items, which were more frequently endorsed by patients with BD. A large number of patients with BD, but also a considerable number of patients with MDD, endorsed manic items during a depressive episode. CONCLUSIONS: There are differences between BD and MDD in terms of the number and type of mood spectrum items that are endorsed during a MDE, which may help to identify patients with BD when a retrospective assessment of a history of mania or hypomania is not possible or not reliable. A high number of patients with BD and a considerable number of patients with MDD endorsed several items in the manic section of the mood, energy, and cognition domains, this confirming the centrality of mixed features in patients with mood disorders and the need for a unitary, dimensional, descriptive and dynamic approach to MDD and BD, such as the recently proposed ACE (Activity, Cognition, Energy) model.

Motor facilitation during observation of implied motion: Evidence for a role of the left dorsolateral prefrontal cortex.

The phenomenon of motor resonance (the increase in motor cortex excitability during observation of actions) has been previously described. Transcranial magnetic stimulation (TMS) studies have demonstrated a similar effect during perception of implied motion (IM). The left dorsolateral prefrontal cortex (DLPFC) seems to be activated during action observation. Furthermore, the role of this brain area in motor resonance to IM is yet to be investigated. Fourteen healthy volunteers were enrolled into the study. We used transcranial direct current stimulation (tDCS) to stimulate DLPFC aiming to investigate whether stimulation with different polarities would affect the amplitude of motor evoked potential collected during observation of images with and without IM. The results of our experiment indicated that Cathodal tDCS over the left DLPFC prevented motor resonance during observation of IM. On the contrary, anodal and sham tDCS did not significantly modulate motor resonance to IM. The current study expands the understanding of the neural circuits engaged during observation of IM. Our results are consistent with the hypothesis that action understanding requires the interaction of large networks and that the left DLPFC plays a crucial role in generating motor resonance to IM.

Asenapine in the management of impulsivity and aggressiveness in bipolar disorder and comorbid borderline personality disorder: an open-label uncontrolled study.

Borderline personality disorder (BPD) often co-occurres with bipolar disorder (BD). Impulsivity and aggressiveness represent core shared features and their pharmacological management is mainly based on mood stabilizers and antipsychotics, although scarce evidence is available for this context of comorbidity. The aim of the present study was to evaluate the role of Asenapine as an adjunctive drug for reducing aggressiveness and impulsivity in a sample of Italian BD type I outpatients with or without a comorbid BPD. This was an observational 12-week open-label uncontrolled clinical study carried out from April to October 2014 in two psychiatric clinics in Sicily. Each patient was treated with asenapine at two dose options, 5 mg (twice daily) or 10 mg (twice daily), and concomitant ongoing medications were not discontinued. We measured impulsivity using the Barratt Impulsiveness Scale (BIS) and aggressiveness using the Aggressive Questionnaire (AQ). For the analysis of our outcomes, patients were divided into two groups: with or without comorbid BPD. Adjunctive therapy was associated with a significant decrease of BIS and AQ overall scores in the entire bipolar sample. Yet, there was no significant difference in BIS and AQ reductions between subgroups. Using a regression model, we observed that concomitant BPD played a negative role on the Hostility subscale and overall AQ score variations; otherwise, borderline co-diagnosis was related positively to the reduction of physical aggression. According to our post-hoc analysis, global aggressiveness scores are less prone to decrease in patients with a dual diagnosis, whereas physical aggressiveness appears to be more responsive to the add-on therapy in patients with comorbidity.

Modulation of sensorimotor circuits during retrieval of negative Autobiographical Memories: Exploring the impact of personality dimensions.

Autobiographical Memory (AM) retrieval refers to recollection of experienced past events. Previous Transcranial Magnetic Stimulation (TMS) studies have shown that presentation of emotional negative stimuli affects human motor cortex excitability resulting in larger motor evoked potentials (MEPs). Up to date no TMS studies have been carried out in order to investigate the effect of personal memories with negative emotional value on corticospinal excitability. In this study we hypothesized that negative AM retrieval will modulate corticomotor excitability and sensorimotor integration as determined by TMS neurophysiological parameters. Furthermore, we investigated whether TMS responses during retrieval of negative AM are associated with specific personality traits. Twelve healthy subjects were asked to recall either a negative or a neutral AM across two different days in a randomized order. During this memory retrieval, the following TMS parameters were recorded: MEPs; Short- interval intracortical inhibition (SICI) and Intracortical facilitation (ICF); Short-latency afferent inhibition (SAI) and Long- latency afferent inhibition (LAI). Personality traits were assessed by using the Big Five scale. Statistical analysis was performed using factorial ANOVAs and multiple linear regression models. When compared to retrieval of neutral AM, recollection of negative AM induced a larger increase in MEP amplitude, an increase in ICF, and a decrease in SAI. The neuroticism personality trait was a significant predictor of the MEP amplitude increase during retrieval of negative AM. Altogether these results indicate that cortical excitability and sensorimotor integration are selectively modulated by the valence of AM. These results provide the first TMS evidence that the modulatory effect of the AM retrieval is associated with specific personality traits.

Valeriana officinalis Root Extract Modulates Cortical Excitatory Circuits in Humans.

BACKGROUND: Valeriana officinalis extract (VE) is a popular herbal medicine used for the treatment of anxiety and sleep disorders. Although the anxiolytic and sedative effects are mainly attributed to the modulation of GABA-ergic transmission, the mechanism of action has not been fully investigated in humans. Noninvasive brain stimulation protocols can be used to elucidate the mechanisms of action of psychoactive substances at the cortical level in humans. In this study, we investigated the effects of a single dose of VE on cortical excitability as assessed with transcranial magnetic stimulation (TMS). METHODS: Fifteen healthy volunteers participated in a double-blind, randomized, cross-over, placebo-controlled study. Subjects were required to take either 900 mg of VE (valerenic acid 0.8%) or placebo (an equal dose of vitamin E). Motor cortex excitability was studied by single and paired TMS before and at 1 h and 6 h after the oral administration. Cortical excitability was assessed using different TMS parameters: resting motor threshold, motor-evoked potential amplitude, cortical silent period, short-interval intracortical inhibition, and intracortical facilitation. Furthermore, we assessed sensorimotor integration by short-latency and long-latency afferent inhibition. RESULTS: We found a significant reduction in ICF, without any significant changes in other TMS measures of motor cortex excitability. The amount of ICF returned to baseline value 6 h after the intake of the VE. CONCLUSION: A single oral dose of VE modulates intracortical facilitatory circuits. Our results in healthy subjects could be predictive markers of treatment response in patients and further support the use of pharmaco-TMS to investigate the neuropsychiatric effects of herbal therapies in humans.

Observation of implied motion in a work of art modulates cortical connectivity and plasticity.

Following the discovery of mirror neurons, much attention has been de-voted to understanding the neural responses evoked by observation of implied motion in works of art. Neuroimaging studies have demonstrated that dorsal premotor cortex (PMd) is commonly involved during observation of movements but the role of the inhibitory and excitatory connections between PMd and primary motor cortex (M1) during observation of implied motion remains uncertain. In this study, using high and low frequency repetitive transcranial magnetic stimulation (rTMS), we examined PMd-M1 connectivity and plasticity during observation of Michelangelo's frescos with and without implied motion (Sistine Chapel, 1508-1512). We found that observation of implied motion in a painting specifically reduces the activity of inhibitory PMd-M1 connections. On the contrary PMd-M1 facilitatory connections, as examined by means of 5-Hz rTMS, were not modulated during observation of the painting. Our data suggest that observation of implied motion in a painting modulates PMd-M1 connectivity and plasticity. These results are consistent with the hypothesis that art with implied motion might be used as a plasticity-based intervention in rehabilitation.