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Distressing and impairing separation anxiety symptoms with onset in adult life can be diagnosed as an anxiety disorder. Advances in understanding in epidemiology and possible neuropsychobiology make the condition worthy of further detailed consideration, but the absence of robustly evidence-based treatments limits the current utility of diagnosis in clinical practice.
Anhedonia and reward processing deficits are core features of Major Depressive Disorder (MDD). However, their persistence following remission remains unclear, hindering the differentiation between state versus trait characteristics. This study investigated clinically assessed anhedonia and reward-related learning in individuals with current MDD (MD), remitted MDD (RMD), and healthy controls (HC). We assessed 26 individuals with current MDD, 35 with RMD, and 37 HC. Anhedonia was measured using the Clinician-Administered Snaith-Hamilton Pleasure Scale (SHAPS-C-TR). Reward-related learning was evaluated using the Probabilistic Reward Task (PRT). Depressive and anxiety symptoms were also assessed. The MD group exhibited significantly higher anhedonia and greater depressive and anxiety symptoms compared to both RMD and HC groups. Crucially, anhedonia scores did not differ between the RMD and HC groups. While a significant learning effect on the PRT was observed across the entire sample, there were no significant differences in task performance among the three groups, even after controlling for covariates. Clinically assessed anhedonia appears to be a state-dependent symptom that normalizes with remission. In contrast, reward-related learning, assessed via the PRT, was not significantly impaired in either current or remitted depression. These findings suggest a potential dissociation between the experience of clinically assessed anhedonia and reward learning deficits in MDD.
Social withdrawal is a frequent marker of functional decline in schizophrenia, Alzheimer's disease (AD), and major depressive disorder (MDD), and is associated with deficits in facial-emotion recognition (FER). Magnetoencephalography (MEG) captures neuronal activity at millisecond resolution, enabling the assessment of fast oscillatory dynamics and functional connectivity during FER. This systematic review compares MEG responses during implicit and explicit FER tasks in adults with schizophrenia, AD, and MDD to identify possible transdiagnostic and disorder-specific alterations. However, no eligible studies were identified for AD. Following PRISMA guidelines, PubMed, Web of Science, and CINAHL were systematically searched from inception to February 2025 for MEG studies comparing adults with schizophrenia, AD, or MDD with healthy controls during implicit (i.e., passive viewing) or explicit (i.e., labeling) FER tasks. Eighteen studies met inclusion criteria (four schizophrenia, 14 MDD, none in AD). Schizophrenia and MDD showed transdiagnostic MEG patterns across disorder-specific studies, including early temporal-cortical hyperactivation (50-150 ms) during implicit FER and early amygdala hyper-reactivity (within 100 ms) followed by prefrontal hypo-recruitment (100-500 ms) during explicit FER, with disrupted cortico-limbic connectivity. Schizophrenia was associated with specific increases in theta-gamma coupling and unidirectional visual-limbic-prefrontal connectivity during explicit FER. MDD showed a shift from early gamma hyper-synchrony (50-150 ms) to late beta/gamma hypo-synchrony (250-500 ms), with reduced fronto-limbic and fusiform-amygdala coupling. MEG reveals a transdiagnostic signature of FER dysfunction that may be linked to social withdrawal and disorder-specific oscillatory patterns that may inform targeted neuromodulation.
<p>Introduction: Emotion regulation (ER) is essential for psychological functioning and daily life. Deficits in ER are associated with various psychiatric disorders and are important targets for therapeutic interventions. Self-compassion, the practice of responding to one's own suffering with kindness, has been proposed to support adaptive ER. This study examined changes during a 6-week psychiatric inpatient rehabilitation program to evaluate the effects of a mindfulness- and self-compassion-based intervention on ER. In a randomized controlled trial, 168 psychiatric inpatients were allocated to either a Mindful Self-Compassion (MSC) intervention group (n = 95) or an active control group receiving Progressive Muscle Relaxation (PMR; n = 73). Participants completed assessments at baseline and post-treatment, including the Self-Compassion Scale (SCS), the Emotion Regulation Questionnaire (ERQ), and the Positive and Negative Affect Schedule (PANAS). At post-treatment, the Reappraisal Inventiveness Test (RIT) was additionally administered. Data were analyzed using mixed-design ANOVAs and independent t tests. Both MSC and PMR groups showed significant increases in self-compassion, positive affect, and self-reported cognitive reappraisal. No significant changes were observed in expressive suppression, and no between-group differences were found for reappraisal inventiveness as measured by the RIT. Participation in either intervention was associated with enhanced use of cognitive reappraisal, suggesting that both MSC and PMR may foster adaptive ER in psychiatric rehabilitation. Further research is warranted to clarify the specific mechanisms and potential long-term benefits of mindful self-compassion interventions in clinical populations. </p>.
<p>Introduction: In recent years, growing attention has been given to the role of sleep disturbances in mental health outcomes, assuming a potential link between sleep problems and suicidality. This study applies a network analysis to examine how sleep quality is interconnected with suicidal thoughts and behaviors, as well as with a range of psychopathological symptoms. A total sample of 1,674 participants (75.3% female, 24.7% male) from the general population were investigated and completed standardized assessments of sleep quality and psychopathological symptoms. A regularized cross-sectional partial correlation network between sleep quality (Pittsburgh Sleep Quality Index [PSQI]), suicidality (Scale for Suicidal Experience and Behavior [SSEV]), and psychopathological symptoms (Brief Symptom Inventory [BSI-18]) was estimated using the EBICglasso algorithm. Node centrality, predictability, and bridge centrality were evaluated, and bootstrap methods were employed to test the stability and significance of the network structure. The network was found to be stable, supporting reliable interpretations. Active suicide thoughts, anxiety, and subjective sleep quality were found to be the most influential nodes within the investigated psychopathological network. Depression and daytime impairment due to poor sleep quality were observed as nodes with the highest bridge centrality. These findings highlight that depression and, importantly, daytime functioning related to poor sleep quality play a central role in linking suicidality and sleep quality. This emphasizes the need to address not only nighttime sleep problems but also daytime impairments as key clinical targets. Prioritizing interventions that improve sleep and restore daytime functioning may therefore be crucial in suicide prevention and clinical care. </p>.
<p>Introduction: Severe depressive episodes with suicidal ideation present major therapeutic challenges and often require interventions beyond standard antidepressant therapy. Electroconvulsive therapy (ECT) remains a cornerstone treatment for refractory depression, while ketamine, an N-methyl-D-aspartate receptor antagonist, has emerged as a rapid-acting antidepressant with potential benefits in reducing suicidal ideation. This study compares the efficacy, onset of action, and tolerability of intravenous ketamine and ECT as adjunctive treatments in severe major depressive disorder with active suicidal ideation. A randomised controlled trial was conducted at a tertiary care psychiatry department in India, enrolling 64 patients aged 18-60 years with severe depression (HAM-D ≥19, SSI ≥4). Participants were randomly assigned to receive either intravenous ketamine (n = 31) or ECT (n = 33), alongside ongoing oral antidepressants. Both groups underwent six treatment sessions over 2 weeks. Outcomes were assessed at baseline, post-treatment, and 4 weeks after completion. Primary endpoints included changes in depression severity (HAM-D) and suicidal ideation (SSI), while secondary outcomes included response and remission rates, as well as safety and tolerability profiles. Both ECT and ketamine significantly reduced depressive symptoms and suicidal ideation (p < 0.001). HAM-D scores declined from 27 to 1 in the ECT group and from 26 to 2 in the ketamine group by the 4-week follow-up. SSI scores showed parallel improvement, from 12.1 to 1.2 with ECT and 12.6 to 2.0 with ketamine. Ketamine demonstrated a faster onset of clinical improvement, while ECT showed slightly greater durability of response. Side effects were mild in both groups, though ECT was associated with transient cognitive impairment, whereas ketamine produced minor dissociative and urinary symptoms. Ketamine offers a faster reduction in suicidal ideation than ECT, making it a promising acute intervention. Both are effective, safe adjunctive therapies, with treatment choice guided by patient profile and tolerability. </p>.
The role of chemokines in motor abnormalities (MAs) in first-episode psychosis (FEP) is underexplored. Investigating immune biomarker levels in FEP, their association with MAs, and their differences with individuals without FEP may reveal therapeutic targets. Thirty-eight patients and thirty-four controls were included. Primary outcomes assessed group differences in chemokines related immune whole blood biomarkers, including innate (CCL2, CCL3, and CCL11), compensatory (PPARα, CXCL1, and CB2), natural immune chemotaxis biomarkers (CXCL2 and CXCR4), and growth factors (LPAR2, brain-derived neurotrophic factor [BDNF], and vascular endothelial growth factor [VEGF]). Our secondary aim was to examine their association with the total score of five motor scales: the Neurological Evaluation Scale (NES), Simpson Angus Scale (SAS), catatonia symptom of the Comprehensive Assessment of Symptoms and History (CASH), Barnes Akathisia Rating Scale, and Unified Parkinson's Disease Rating Scale (UPDRS). We found significantly higher levels of protein markers (CCL2, VEGF, and CXCL12) and mRNA expression (CXCR4, PPARα, CB2, and LPAR2) in FEP patients compared to the control group. We only observed positive and significant results for CCL2-UPDRS total and CXCR4-SAS associations in post hoc multivariate analyses (β = 0.401, p = 0.036 and β = 0.58, p = 0.001, respectively). Elevated levels of potential neurotoxic (CCL2) and neuroprotective (PPARα and CB2) biomarkers were seen in FEP patients when compared to controls. Moreover, CCL2 levels seem to be directly associated with Parkinsonism in FEP patients, while CXCR4 may be protective against extrapyramidal symptoms. Further research should clarify immune differences between FEP and non-FEP groups, especially in chemotaxis and endocannabinoid pathways.
Orthopedic and musculoskeletal pain is a leading cause of disability worldwide, and many patients continue to experience suboptimal relief despite advances in pharmacological and physical therapies. Magnetic field-based interventions, including pulsed electromagnetic field therapy (PEMF) and repetitive peripheral magnetic stimulation (rPMS), have emerged as non-invasive approaches for pain modulation and functional improvement. This systematic review aimed to evaluate the efficacy and safety of low-intensity (PEMF) and high-intensity (rPMS) magnetic field therapies in adults with musculoskeletal conditions. Randomized controlled trials published between 2015 and 2025 were identified through searches in PubMed, Embase, Scopus, and Web of Science. Eligible studies compared PEMF or rPMS with sham, placebo, or standard care and reported outcomes related to pain intensity, functional performance, and safety. Eight RCTs met the inclusion criteria. Most included studies reported reductions in pain and improvements in functional outcomes, including the Oswestry Disability Index and WOMAC. No serious adverse events were reported. PEMF was primarily linked to sustained analgesic and anti-inflammatory effects, whereas rPMS showed faster pain reduction, likely related to neuromuscular activation and modulation of descending inhibitory pathways. Some studies reported greater benefits using higher stimulation intensities or combining therapy with exercise. Magnetic field therapies appear to be safe and well tolerated, with potential benefits for pain and function for the management of musculoskeletal pain. Their complementary mechanisms suggest potential clinical synergy; however, larger and more standardized trials are needed to establish optimal protocols and long-term effectiveness. https://www.crd.york.ac.uk/PROSPERO/view/CRD420251170876, PROSPERO CRD420251170876.
Suicide is a major global public health problem, responsible for over 1 in 100 deaths worldwide, with South Asian countries bearing a particularly high burden. In Pakistan, the absence of a national suicide surveillance system obscures the true scale of the issue. This review aims to systematically map the existing literature on suicide in Pakistan, with a focus on identifying key contributing factors, commonly used methods, and the role of underlying mental health conditions associated with suicidal ideation, deliberate self-harm, and suicidal attempts. This scoping review followed methodological approach outlined by Arksey and O'Malley, integrating the evidence from both peer-reviewed sources and gray literature. We searched National library of medicine MEDLINE (PUBMED), Directory of open access Journals (DOAJ), Cochrane trial registers (CRG), Pakistan Medical Research Council (PMRC) Publications, <ext-link ext-link-type="uri" xlink:href="http://Pakmedinet.com" xmlns:xlink="http://www.w3.org/1999/xlink">Pakmedinet.com</ext-link>, Google scholar, PubMed Central (PMC) from year 2010 to 2025 using a combination of key terms. A total of 61 studies were included, including a thesis from the gray literature. Most of the included studies were cross-sectional and urban-based, with limited focus on rural areas, indicating a significant data gap. Females showed higher rates of deliberate self-harm and suicide. At-risk groups included young adults and transgender individuals. The key contributing factors were domestic violence, academic pressure, emotional strain, and low socioeconomic status. Self-poisoning was the most common method, with increasing cases involving paraphenylenediamine. Emerging trends also include suicide related to online gaming (e.g., PUBG). Hanging and firearm use remain prevalent methods. Although formal psychiatric diagnoses were rarely reported, depression and anxiety were frequently associated with suicide. Suicide remains a critical yet underreported issue in Pakistan, driven by easy access to lethal means, weak regulation, and evolving risk factors such as online gaming. Vulnerable groups include women, transgender individuals, and youth, often affected by violence, academic pressure, and untreated mental health conditions. Addressing this crisis requires improved surveillance, restricted access to means, early mental health intervention, and coordinated prevention efforts across sectors.
Women exhibit distinct stress-response patterns shaped by dynamic interactions between ovarian hormones, the autonomic nervous system (ANS), and cortical stress-processing circuits. Across the female lifespan, hormonal transitions, including the menstrual cycle, pregnancy, postpartum period, perimenopause, and menopause, are associated with heightened vulnerability to mood and anxiety disorders, underscoring the need for sex-specific physiological frameworks. This narrative review synthesizes current evidence on how hormonal fluctuations modulate stress physiology in women, with a particular focus on noninvasive biomarkers derived from heart rate variability (HRV), electrodermal activity (EDA), and electroencephalography (EEG). HRV emerges as a core biomarker of female stress reactivity, reflecting shifts in sympathetic-parasympathetic balance that vary across hormonal states and life stages. Estrogen is generally associated with enhanced vagal modulation and higher HRV, whereas progesterone and estrogen withdrawal are linked to sympathetic dominance and reduced HRV, patterns that are especially pronounced during the luteal phase, pregnancy progression, postpartum, and menopause. Complementary measures provide additional insight: EDA indexes sympathetic arousal and captures hormonally driven changes in emotional reactivity, while EEG reflects cortical dynamics underlying affective style, cognitive control, and stress sensitivity. Evidence indicates that multimodal HRV-EDA-EEG approaches improve detection of stress-related vulnerability by integrating autonomic and cortical signatures rather than relying on a single system. By consolidating findings across key female life stages, this review highlights how hormonal modulation of ANS-brain interactions contribute to sex-specific stress profiles and psychiatric risk. We conclude that multimodal physiological assessment holds substantial promise for advancing personalized prevention and intervention strategies in women's mental health, while emphasizing the need for standardized methodologies, longitudinal designs, and hormone-informed analytic frameworks in future research.
Sensory processing sensitivity (SPS) describes innate temperament, which consists of three characteristics: ease of excitation (EOE), low sensory threshold (LST), and aesthetic sensitivity (AES). There has been no research on SPS in bipolar disorder (BD), nor the effect of treatment on these traits. Relations between temperament, personality, and the course of BD are complex and modify the effect of treatment. Long-term lithium treatment modifies course of the illness and excellent lithium responders are known from their unique clinical characteristic. The aim of the study was to examine the relation between pharmacological treatment and SPS in BD patients. The study group comprised 35 patients (F/M = 26/9) with BD, where 20 patients were diagnosed with BD type I and 15 patients with BD type II. Twenty patients were treated with lithium (16 ± 13 years) and fifteen with other mood stabilizers (14 ± 4 years). The comparison between groups included parameters: BD type, clinical characteristics (family history, suicidal attempts, duration of illness, duration of treatment), type of treatment and gender in relation to sensory sensitivity traits. The highly sensitive person scale (HSPS) including 27 items and distinguishing three parameters: EOE, LST, and AES were used. To assess quality of lithium treatment, the Alda scale was implemented. Lithium-treated patients obtained significantly lower scores on HSPS total score (4.27 vs. 4.98, p = 0.009) and EOE (4.05 vs. 5.23, p = 0.002), compared to patients treated with other mood stabilizers. AES and LST remained on similar level in both groups (however, the results are limited by insufficient statistical power). Also, the negative correlation between LST score and Alda scale score was obtained (r = -0.484; p = 0.031). There was no difference according to clinical characteristics between BD I and BD II, as well as between males and females. Longitudinal treatment with lithium could reduce overall SPS traits, particularly "EOE". However, it is possible that low intensity of these traits is a factor in good response to lithium. Also, lithium treatment may not reduce aesthetic sensitivity, parameter related to creativity. "Low sensory threshold" can be considered as negative predictor of lithium treatment outcome.
<p>Introduction: Nutrition is an important determinant of health among people with mental disorders; however, barriers to dietary counselling exist. The Eating and Supplementation for Generalized Anxiety Disorder study ("EASe-GAD") was the first trial to assess the impact of these interventions on anxiety symptoms. The primary objective of the present companion qualitative study was to gather and analyze qualitative data about the acceptability, participant experience, impact, barriers and facilitators, strengths, and weaknesses of the EASe-GAD program while also identifying opportunities for improvement. Participants were eligible for this study if they participated in the EASe-GAD trial. Data were collected using focus groups which followed a semi-structured interview approach with a set of predetermined questions. The sessions were recorded and transcribed for data analysis. Data were analyzed by thematic analysis. Three focus groups were completed, involving a total of 12 women. They reported a range of components that they found helpful, such as increased self-efficacy, as well as positive outcomes that they attributed to the intervention, such as improved mental and physical health. They reported components of the program that were less enjoyable, such as having their body weight measured, and also suggested opportunities for improvement. Many participants reported that cost implications of a diet intervention were an important consideration. This project provided valuable insight into the participant experience and impact of the pilot dietary counselling program. Participants reported benefits and opportunities for improvement for subsequent studies aimed at improving nutrition among people with anxiety disorders. </p>.
Alzheimer's Disease (AD) is neurodegenerative disorder characterized by deposition of Aβ plaques, tau-positive neurofibrillary tangles, neuroinflammation and clinical dementia. Epidemiological and experimental evidence suggest that peripheral immune inflammation is a risk factor for age-related neurodegeneration but whether its sustained activation is sufficient to drive behavioural, molecular and cellular changes consistent with AD-associated neurodegenerative vulnerability remains unclear. Here we investigated whether prenatal immune stimulation followed by an adult systemic re-challenge with Polyinosinic-polycytidylic acid (Poly(I:C)) induces persistent cognitive/motivational/social deficits and hippocampal neurodegeneration in wild-type mice, consistent with long-lasting neuroimmune priming mechanism(s). Pregnant C57Bl/6J dams received intravenously Poly(I:C) at gestational day 17 and male offspring received intraperitoneal Poly(I:C) at 9 months (single- or double-hit design) and were analyzed at 12 months. Recognition memory, working memory, reward-related learning, and social interaction were assessed followed by hippocampal Western blotting and immunofluorescence. Poly(I:C)-exposed mice exhibited impaired recognition and working memory, reduced palatable food-induced conditioned place preference, and blunted social investigation. These behavioral abnormalities were accompanied by increased amyloidogenic APP processing (BACE1/PSEN1 upregulation and β-CTF accumulation), tau dysregulation (AT8 hyperphosphorylation), microglial activation (Iba1/CD68 upregulation and process retraction), synaptic alterations (α-synuclein reduction), and bioenergetic impairment (reduced mitochondrial and glycolytic markers) in the hippocampus. Overall, these findings indicate that repeated prenatal and postnatal peripheral activation of innate immunity may act as a contributing factor to neurodegenerative phenotype with features relevant to AD-related susceptibility, paving the way for the development of next-generation therapeutical interventions affecting systemic-to-brain inflammatory signaling.
Autism spectrum disorder (ASD) lacks disease-modifying therapies. Gene therapy offers a promising avenue to target the underlying molecular causes of ASD, particularly in monogenic or syndromic forms where single-gene mutations play a central role. A scoping review was conducted following the PRISMA-ScR framework. We searched PubMed, Scopus, Web of Science, PsycINFO, and the Cochrane Library (2000-July 2025), with the last search completed in July 2025. Eligible studies included preclinical or translational investigations involving gene-therapy modalities (e.g., AAV vectors, ASOs, CRISPR-based editing) targeting high-confidence ASD-linked genes; non-gene-therapy studies, unrelated conditions, reviews, and non-English papers were excluded. Data were charted using a standardized extraction form and synthesized descriptively across two evidence streams. Stream 1 evaluated preclinical studies of gene therapy, while Stream 2 examined translational advances and ethical considerations. Twenty-one preclinical studies were identified in Stream 1, focusing on genes such as UBE3A, MECP2, FMR1, SHANK3/2, SCN2A, and SYNGAP1. Most demonstrated molecular correction and improvements in synaptic, electrophysiological, and behavioral outcomes, with therapeutic effects observed from early developmental to adult timepoints. Stream 2 synthesized 12 studies highlighting translational challenges, including delivery innovations (e.g., engineered viral capsids, nanoparticles), safety concerns (immune responses, dose-dependent toxicities), and ethical considerations (pediatric consent, neurodiversity perspectives, equity in access). Limitations include heterogeneity across models, reliance on rodent studies, and absence of completed human clinical trials. Gene therapy for ASD shows considerable promise but faces significant translational and ethical hurdles. Standardized study designs, comprehensive safety evaluation, and transparent stakeholder engagement will be critical for developing responsible and effective clinical applications.
Adolescent-onset major depressive disorder (MDD) is associated with high morbidity, recurrence, and suicide risk. However, few studies have prospectively examined its long-term course into emerging adulthood. Ninety-four female adolescents (aged 15-17 years) diagnosed with MDD between January and August 2012 were enrolled. After 10 years, 54 participants were reassessed. Psychiatric diagnoses were established using the Kiddie Schedule for Affective Disorders and Schizophrenia (K-SADS) at baseline and the Structured Clinical Interview for DSM-5 Disorders (SCID-5) at follow-up. Global functioning was rated using the Global Assessment of Functioning (GAF). At both time points, participants completed the Beck Depression Inventory (BDI), Emotional Autonomy Scale (EAS), Parent Adolescent Relationship Questionnaire (PARQ), and Identity Development Assessment Tool (IDAT). Nearly, all participants (94.4%) experienced recurrent depressive episodes, and 79.6% met criteria for at least one current psychiatric disorder at the follow-up assessment. The most common current diagnoses were MDD and attention-deficit/hyperactivity disorder (each 35.2%). The mean GAF score at follow-up was 64.2 ± 8.1, indicating moderate functional impairment. Lifetime suicide attempts were reported by 32 participants (59.3%). Runaway behaviour was a significant risk factor for suicidal behaviour (odds ratio [OR] = 5.91, 95% confidence interval [CI]: [1.27-27.54], p = 0.024), while earlier psychiatric contact (OR = 0.40, 95% CI: [0.18-0.88], p = 0.027) served as a protective factor. Despite the ongoing need, one-fifth of individuals (n = 11) was receiving psychiatric care in emerging adulthood. Adolescent-onset major depressive disorder is highly recurrent and carries a significant long-term risk for further psychiatric issues and suicide. However, the rigid transition from child to adult services at age 18 appears to disrupt care continuity. Runaway behaviour should be considered a marker of suicide risk, whereas earlier psychiatric contact may be protective. Youth psychiatry programs are needed to bridge the child-adult service gap for adolescents with depression.
One-third of patients with major depressive disorder (MDD) exhibit low-grade inflammation as reflected by C-reactive protein (CRP) concentrations >3 mg/L. We explored whether CRP changes from baseline to week one of antidepressant treatment (ΔCRP) can serve as a marker of treatment response. CRP serum levels were measured at baseline and after the first week of treatment in 33 MDD patients and correlated with patients' Hamilton Depression Rating Scale (HAM-D), while adjusting for age, gender, and body mass index. We assessed antidepressant responses at weeks one and four of treatment as a >25% and >50% HAM-D score reduction (ΔHAM-D) compared to baseline, respectively. We compared baseline and week-one CRP levels with the paired t test within responders and nonresponders separately and ΔCRP between the groups with the ANCOVA. Higher ΔCRP correlated with lower week-four ΔHAM-D scores (r = -0.5, p = 0.006). Nonresponders showed higher ΔCRP - but not baseline and week-one CRP - than responders (p = 0.018, Cohen's d = 1.1). A ΔCRP increase was observed in 13/16 (81%) nonresponders and 7/17 (41%) responders (Fisher's exact test's p = 0.03). A ΔCRP increase combined with a week-one nonresponse was observed in 13/16 (81%) nonresponders and 1/17 (6%) responders (p < 0.0001). Rather ΔCRP at week one than baseline CRP might be indicative of treatment response at week four, especially if combined with week-one ΔHAM-D. In the future, ΔCRP could be introduced into psychiatric practice to guide treatment plans.
Monoamine neurotransmitters, including catecholamines (i.e., norepinephrine, epinephrine, and dopamine), and the indolamine serotonin play important roles in signaling in the central and peripheral nervous systems. Alterations in neurotransmission may be suggestive of neuroendocrine or psychiatric disorders, may reflect therapeutic responses, and are often considered relevant to mental health. Monoamine modulators and their metabolites are detectable in saliva, suggesting that saliva could represent an attractive, non-invasive, and cost-effective matrix for identifying and monitoring conditions in both healthy and diseased individuals. Accordingly, measuring salivary monoamine neurotransmitters may have scientific and possible clinical relevance. In this review, we summarize and critically evaluate current evidence on salivary dopamine, norepinephrine, epinephrine, serotonin and their respective metabolites. Although further research is required to clarify their biological significance and clinical applicability, existing findings suggest that salivary monoamine measurement may hold potential, albeit with important limitations.
Intersegmental neural modulation refers to the influence of voluntary activation of one limb on the excitability and inhibitory balance of remote motor representations. Recent evidence suggests that high-intensity upper-limb isometric contractions can transiently enhance corticospinal excitability and modulate intracortical or interhemispheric inhibition of lower-limb motor areas, yet the consistency of these findings remains unclear. This systematic review synthesized evidence on the effects of upper-limb isometric contractions on corticospinal excitability and inhibitory mechanisms of lower-limb motor representations in healthy adults. Following PRISMA 2020 guidelines, searches were conducted in PubMed/MEDLINE, Scopus, Web of Science, Embase, and Cochrane CENTRAL. Eligible studies included healthy adults (18-65 years) performing upper-limb isometric contractions quantified as percentage maximal voluntary contraction (%MVC), with outcomes assessing lower-limb corticospinal excitability or intracortical/interhemispheric inhibition. Two independent reviewers screened studies, extracted data, and assessed risk of bias. Seventeen studies (n = 351) met inclusion criteria. Most reported increases in lower-limb motor evoked potential amplitude during upper-limb contractions, particularly at intensities ≥ 70% MVC. Reductions in short-interval intracortical inhibition were common, indicating transient disinhibition of lower-limb primary motor cortex representations. Findings for interhemispheric inhibition were inconsistent, likely attributable to variability in contraction tasks and transcranial magnetic stimulation parameters. Upper-limb isometric contractions consistently facilitate lower-limb corticospinal excitability and reduce intracortical inhibition in healthy adults. Although mechanistic patterns converge, methodological heterogeneity limits confidence in the magnitude of effects. Future studies require standardized experimental protocols and adequate sample sizes to clarify intensity-response relationships and underlying neurophysiological mechanisms.
The study aimed to investigate whether alterations in tryptophan (TRP) metabolites reflect dysregulation of the kynurenine (KYN) pathway, which has been implicated in bipolar disorder (BD), and to examine their relationship with cognitive functioning by assessing TRP metabolite levels alongside executive performance in non-affected offspring of individuals diagnosed with BD. The study included 32 healthy offspring of parents with BD type I as the case group and 31 healthy offspring of parents without any psychiatric disorders as controls. Psychiatric screening was conducted using the Turkish adaptation of the Schedule for Affective Disorders and Schizophrenia for School Age Children - Present and Lifetime Version (K-SADS-PL-DSM-5). Executive functioning was examined using a neuropsychological battery that included the Stroop, Serial Digit Learning (SDLT), and Cancellation (CT) tests. Serum levels of TRP, KYN, kynurenic acid (KYNA), 3-hydroxy kynurenine (3-HK), and 3-hydroxyanthranilic acid, as well as metabolite ratios (KYN/TRP, KYNA/KYN, 3-HK/KYN, and KYNA/3-HK), were measured. Logistic regression analysis was applied as part of the statistical approach to evaluate whether these metabolites and ratios could distinguish the offspring of individuals with BD from healthy controls. Neurocognitive performance was significantly poorer in the case group than in the control group. Serum levels of TRP (t = 3.568, p = 0.001), KYN (t = 3.772, p = 0.001), KYNA (t = 2.797, p = 0.007), and the ratios of KYN/TRP (t = 2.550, p = 0.014) and KYNA/3-HK (z = -2.557, p = 0.011) were significantly decreased in cases, whereas KYNA/KYN (t = -2.562, p = 0.013) and 3-HK/KYN (z = -3.368, p = 0.001) ratios were significantly elevated. Correlation analyses showed significant associations between executive function deficits and TRP (r = 0.367, p = 0.039), KYN (r = 0.380, p = 0.032), KYNA (r = 0.488, p = 0.005), 3-HK (r = 0.492, p = 0.004), and the 3-HK/KYN ratio (r = 0.408, p = 0.020). Logistic regression analysis indicated that lower KYN levels distinguished cases from controls (OR = 0.986, 95% CI = 0.978-0.995, p = 0.002). The findings indicate that metabolism within the KYN pathway in the offspring of individuals with BD shows a shift toward its neurotoxic branch, reflected by increased 3-HK/KYN ratios and decreased KYNA-related indices, and this was associated with deficits in executive functioning. These findings indicate that alterations in TRP metabolism may play a role in altered cognitive processing among individuals with a familial predisposition to BD. Further research employing larger cohorts and dimensional analyses is needed to elucidate these relationships more precisely.
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