Search Results (984)

Autism spectrum disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders marked by deficits in communication and social interaction, often accompanied by anxiety, seizures, and intellectual disability. FXS, the most common monogenic cause of ASD, results from silencing of the FMR1 gene and consequent loss of FMRP, a regulator of synaptic protein synthesis. Disruptions in cyclic nucleotide (cAMP and cGMP) signaling underlie both ASD and FXS contributing to impaired neurodevelopment, synaptic plasticity, learning, and memory. Notably, reduced cAMP levels have been observed in platelets, lymphoblastoid cell lines and neural cells from FXS patients as well as Fmr1 KO and dfmr1 Drosophila models, linking FMRP deficiency to impaired cAMP regulation. Phosphodiesterase (PDE) inhibitors, which prevent the breakdown of cAMP and cGMP, have emerged as promising therapeutic candidates due to their ability to modulate neuronal signaling. Several PDE isoforms—including PDE2A, PDE4D, and PDE10A—have been implicated in ASD, and FXS, as they regulate pathways involved in synaptic plasticity, cognition, and social behavior. Preclinical and clinical studies show that PDE inhibition modulates neuroplasticity, neurogenesis, and neuroinflammation, thereby ameliorating autism-related behaviors. BPN14770 (a PDE4 inhibitor) has shown promising efficacy in FXS patients while cilostazol, pentoxifylline, resveratrol, and luteolin have showed improvements in children with ASD. However, challenges such as isoform-specific targeting, optimal therapeutic window, and timing of intervention remain. Collectively, these findings highlight PDE inhibition as a novel therapeutic avenue with the potential to restore cognitive and socio-behavioral functions in ASD and FXS, for which effective targeted treatments remain unavailable. Full article

Background/Objectives: This study evaluated a novel rehabilitation tool that combines prismatic adaptation (PA) and cognitive training through serious games (SGs) in patients with mild cognitive impairment (MCI) due to prodromal Alzheimer’s dementia or consequent to Parkinson’s disease. While non-pharmacological interventions have been shown to improve cognition or delay dementia onset, their underlying neurobiological mechanisms, such as brain plasticity, remain unclear. Leveraging studies suggesting neuromodulatory effects of PA, we investigated whether the combined PA+SGs treatment could influence plasticity-related mechanisms, assessed through brain-derived neurotrophic factor (BDNF) serum levels, compared to cognitive training with only SGs and standard cognitive rehabilitation (SCR). Methods: Twenty three MCI patients were randomized into three intervention groups: PA+SGs (experimental group), SG-only (control group), and SCR (control group), completing ten treatment sessions. Patients underwent neuropsychological assessments and blood sampling pre- and post-treatment. Results: At baseline, demographic, clinical, and biological characteristics were comparable across groups. Post-treatment, though differences from control groups were not statistically significant, the PA+SGs group showed significant within-group improvements in memory, with trend-level changes also in executive function and visuospatial abilities, which, however, did not reach the significance threshold. Notably, only the PA+SGs group exhibited increased BDNF levels, which positively correlated with memory and language performance. Conclusions: Our findings suggest that combining PA with cognitive training may enhance cognitive functioning in MCI patients, yielding results comparable to SCR. Furthermore, PA appears to enhance neuroplasticity mechanisms that may support the behavioral improvements observed in cognitive training. Future research should validate these findings and further explore the relationship between cognitive impairment and its rehabilitation, while also considering the underlying neurobiological mechanisms. Full article

Major depression (MD) is associated with chronic inflammation and impaired neuroplasticity; however, the cellular mechanisms underlying antidepressant action remain incompletely understood. We performed transcriptomic profiling and functional validation in human microglia treated with venlafaxine (VEN) and vortioxetine (VOR), or with stable ST3GAL5 overexpression (ST3GAL5OE). Differential expression analysis, enrichment studies, and functional assays using NF-κB-RE-NlucP and SIE-NlucP reporter lines were conducted to assess the impact on inflammatory signaling. Microarray analysis identified 41 genes consistently upregulated and 316 consistently downregulated across VEN, VOR, and ST3GAL5OE conditions. Upregulated genes were enriched for synaptic organization, whereas downregulated genes were associated with nitric oxide biosynthesis and pro-inflammatory pathways, including Rap1, MAPK, and PI3K-Akt signaling. Functional assays confirmed that VEN and VOR suppressed cytokine-induced NF-κB and STAT3 activation, effects that were recapitulated by exogenous GM3 treatment and ST3GAL5 overexpression. Chronic exposure to VEN or VOR produced more modest, pathway-specific suppression, supporting convergence on the ST3GAL5–GM3 axis. These findings extend the conventional monoaminergic model of antidepressant action by highlighting the ST3GAL5–GM3 lipid remodeling axis as a novel regulatory pathway that attenuates microglial inflammatory signaling. Although validation in primary microglia and in vivo models is required, our results suggest that this axis could serve as both a therapeutic target and a candidate biomarker for inflammation-associated MD. Full article

Background: Parkinson’s disease (PD) is a neurodegenerative disorder affecting men more frequently than women, a difference that might be due to many factors, including sexual hormones. Estrogens seem to confer a protective effect on the nigrostriatal pathway in experimental studies but their effects on cognition in patients with PD are unknown. Aim: To investigate the impact of the exogenous and endogenous estrogens on cognitive impairment in women with PD. Methods and materials: We recruited and consecutively interviewed outpatient women affected by PD. Each patient underwent a cognitive assessment via the Montreal Cognitive Assessment scale (MoCA), an anamnestic collection of the reproductive lifespan variables and clinical features. We investigated if some of the reproductive lifespan variables investigated could predict cognition outcomes in post-menopausal women with PD. Results: A total of 90 women with PD were recruited. Women with MoCA ≥ 26 (n = 27) had a lower median age at menarche (11 [11,12] vs. 13 [12–14], p < 0.0001), lower disease duration in years (8.3 [6.1–12.7] vs. 9.4 [6–12.7], p = 0.6), and less advanced disease (1 [1,2] vs. 2 [1–3], p = 0.02). Among all the reproductive life-span variables, only earlier age at menarche significantly predicted higher scores on MoCA (aOR = 0.5 [0.3–0.8], p = 0.005). No other clinical and reproductive factors have been shown to have an influence on cognitive scores. Conclusions: Age at menarche correlated with cognitive outcomes. Our study suggests that earlier exposure to endogenous estrogens during a phase of development and plasticity of the brain might preserve women with PD from cognitive decline. Full article

Personalized psychiatry represents an innovative therapeutic approach that integrates biological, genetic, and clinical data to optimize the treatment of mental disorders. Laboratory diagnostics play a fundamental role in this process by providing precise biomarkers that characterize pathophysiological mechanisms such as neuroinflammatory processes, oxidative stress, dysfunction of the Hypothalamic–Pituitary–Adrenal (HPA) axis, as well as disturbances in neuroplasticity and neurodegeneration. This article discusses the use of advanced analytical techniques, such as immunoenzymatic assays for pro-inflammatory cytokines (Interleukin-1β- IL-1β; Interleukin-6-IL-6; Interleukin-18-IL-18; and Tumor Necrosis Factor- α - TNF-α). It also emphasizes the role of pharmacogenomic diagnostics in the individualization of psychotropic therapy. Interdisciplinary collaboration between laboratory diagnosticians and clinicians supports the potential for multidimensional analysis of biomarker data in a clinical context, which supports precise patient profiling and monitoring of treatment responses. Despite progress, there are limitations, such as the lack of standardization in measurement methods, insufficient biomarker validation, and limited availability of tests in clinical practice. Development prospects include the integration of multi-marker panels, the use of point-of-care diagnostics, and the implementation of artificial intelligence tools for the analysis of multidimensional data. As a result, laboratory diagnostics are becoming an integral element of personalized psychiatry, enabling a better understanding of the neurobiology of mental disorders and the implementation of more effective therapeutic strategies. Full article

Major depressive disorder (MDD) is a prevalent and disabling condition. Transcranial direct current stimulation (tDCS) may improve symptoms by modulating neuroplastic and inflammatory mechanisms. This randomized, double-blind, placebo-controlled trial will recruit adult outpatients with MDD showing residual symptoms despite at least four weeks of stable SSRI treatment. Participants will be randomized to active or sham add-on tDCS while continuing their antidepressant regimen. The intervention will consist of 15 sessions over 3 weeks, targeting the left dorsolateral prefrontal cortex (anode F3, cathode F4) at 2 mA for 30 min per session. The primary outcome is the reduction of depressive symptoms measured by the Hamilton Depression Rating Scale-17 (HDRS), with remission defined as HDRS-17 ≤ 7. Secondary outcomes include cognitive performance (attention, executive functioning, memory), serum biomarkers (BDNF, VEGF, NGF, NRG1, angiogenin, IGF1, IL-6, TNF-α), cortical excitability assessed by transcranial magnetic stimulation (motor threshold, silent period, intracortical inhibition/facilitation), and cerebral hemodynamics by transcranial Doppler sonography (blood flow velocity, pulsatility, resistivity). Assessments will occur at baseline, post-treatment, and 3- and 6-month follow-ups. This trial aims to evaluate the efficacy of adjunctive tDCS in MDD with residual symptoms and its biological correlates, bridging clinical improvement with electrophysiological and neurovascular mechanisms. Full article

Erythema ab igne (EAI), also known as “hot water bottle rash” or “toasted skin syndrome”, is a benign cutaneous condition caused by chronic exposure to low-level infrared heat. It typically begins as transient erythema and evolves into a reticulated brown pigmentation with telangiectasias. A skin biopsy, ideally taken from the central area of the hyperpigmented lesion, is recommended to exclude differential diagnoses. Although usually benign, EAI has been associated with rare malignant transformations, supported only by low-level evidence. Elimination of the heat source is essential, and topical treatments such as hydroquinone or retinoids may be considered, while agents like 5-fluorouracil or imiquimod are reserved for dysplastic lesions. Women with endometriosis frequently use heating devices to alleviate dysmenorrhea and chronic pelvic pain. However, prolonged or inappropriate heat application can lead to chronic thermal injury, including EAI, and may delay medical consultation. While controlled trials confirm short-term analgesic efficacy of heat therapy, extrapolating these findings to unrestricted home use without standardized safety recommendations can be misleading. EAI illustrates the broader impact of chronic pain in endometriosis, linking cutaneous manifestations with neuroplastic alterations and psychiatric comorbidities. A nuanced approach combining patient education on safe use of heat, close dermatologic monitoring, and multidisciplinary pain management is warranted. Full article

Psychedelic compounds are gaining renewed attention across disciplines for their profound psychological and neurobiological effects. Emerging research highlights their efficacy in treating mood disorders, PTSD, and addiction by enhancing neuroplasticity and disrupting maladaptive cognitive patterns. From a psychological standpoint, psychedelics facilitate introspection, emotional processing, and therapeutic breakthroughs. Neuroscientific findings reveal altered brain network dynamics, while anthropological and philosophical perspectives contextualize their cultural and existential significance. In medicine, they offer novel interventions for chronic pain and palliative care. The present review article underscores the need for rigorous, ethically grounded research to explore psychedelics’ potential in reshaping mental health paradigms and cognitive science from a multidisciplinary perspective. Full article

Chronic stress induces mood disturbances, disrupts gut barrier function, and promotes low-grade systemic inflammation. This study assessed the therapeutic effects of atomoxetine (ATX), escitalopram (ESC), cannabidiol (CBD), and CBD-loaded lipid nanoparticles (CBD/LNP) in male rats exposed to repeated restraint stress. Stressed rats exhibited a 2.03-fold increase in interleukin-6 and a 1.89-fold increase in TNF-α, a 1.20-fold decrease in brain-derived neurotrophic factor, a 1.36-fold decrease in osteocalcin, accompanied by alterations in gut metabolites, particularly short-chain fatty acids (SCFAs; from 155.3 to 94.83 μmol/L), polyamines (from 273.6 to 192.4 μmol/L), and bile acids (BAs; from 21.19 to 14.53 μmol/L), compared with the control group. Protein analysis revealed gut barrier disruption and microglial/macrophage activation, accompanied by reduced synaptic plasticity. ATX improved gut permeability and reduced glial activation but did not restore osteocalcin. ESC provided neuroimmune benefits with limited and BA gut restoration and modulated the gut–brain axis and improved anxiety-like behaviors, partly by altering gut microbiota and metabolites. CBD and CBD/LNP treatment restored intestinal barrier function, as indicated by intestinal permeability in the range of 1.15–1.61-fold. These treatments also normalized bile acids (1.0–1.38-fold) and osteocalcin (1.0–1.28-fold) and significantly reduced glial activation (0.63–1.12-fold) as opposed to the non-treated stressed group. All treatments were found to be effective in correcting SCFA and polyamine levels. Histological analysis confirmed that CBD/LNP, ATX, and ESC ameliorated tissue alterations. These findings highlight CBD/LNP as a promising intervention for stress-induced gut–brain–bone axis disruption, supporting its potential as a therapeutic alternative through modulation of microbiota-driven gut–brain communication in stress-associated disorders. Full article

Psychedelic drugs show promise in treating a wide range of mental health conditions. These drugs are beneficial in part because they disrupt prior ideas and patterns of behavior and because they increase neurogenesis and neuroplasticity. It is important therefore to consider the causal impact of the social context not just during but also following psychedelic experiences. Modern cultural or social contexts might thwart or discourage spiritual integration, but local integration support groups are shown to be helpful, especially for those seeking to reflect the meaning of spiritual or religious themes. These groups might be offered within Christianity, which can provide (1) a connection to a community or a social context at the local level together with (2) a set of theological beliefs as an interpretive context that supports spiritual growth in general and psychedelic spiritual integration in particular. Full article

Background: This prospective pilot study included four participants with chronic visual impairment and assessed functional and electrophysiological recovery following visual evoked potential (VEP)-guided auditory biofeedback across diverse etiologies. Low vision affects more than two billion people worldwide and imposes a sustained personal and socioeconomic burden. Conventional rehabilitation emphasizes optical aids and environmental modification without directly stimulating the visual pathway. Emerging evidence indicates that auditory biofeedback based on real-time cortical activity can leverage adult neuroplasticity. Methods: Four men (mean age 58 ± 12 years) with chronic visual impairment attributable to occipital stroke, stage IV macular hole, end-stage open-angle glaucoma, or diabetic maculopathy completed ten 10-min monocular sessions with the Retimax Vision Trainer over three weeks (15 Hz pattern reversal, 90% contrast). Primary end points were best corrected visual acuity (BCVA, ETDRS letters) and P100 amplitude/latency. Fixation stability was recorded with MAIA microperimetry when feasible. A focused PubMed review (2010–2025) mapped current evidence and research gaps. Results: Median BCVA improved by seven letters (IQR 0–15); three of eight eyes gained ≥ 10 letters and none lost vision. Mean P100 amplitude increased from 1.0 ± 1.2 µV to 3.0 ± 1.1 µV, while latency shortened by 3.9 ms. Electrophysiological improvement paralleled behavioural gain irrespective of lesion site. No adverse events occurred. Conclusions: A concise course of VEP-guided auditory biofeedback produced concordant functional and neurophysiological gains across retinal, optic nerve, and cortical pathologies. These pilot data support integration of closed-loop biofeedback into routine low vision care and justify larger sham-controlled trials. Full article

Reactive sulfur species (RSS)—hydrogen sulfide (H₂S), low-molecular-weight persulfides/polysulfides and protein persulfidation—constitute a third redox axis alongside ROS and RNS. Nanomolar H₂S, produced by trans-sulfuration (CBS/CSE) and 3-MST, is oxidized by sulfide–quinone reductase to persulfides that fuel the respiratory chain while curbing superoxide. Reversible persulfidation reprograms cysteine sensors in metabolism (GAPDH), inflammation (NLRP3, p47^phox) and transcription (Keap1/NRF2), linking RSS to energy balance, vasodilation, innate immunity and neuroplasticity. Disrupted sulfur signaling—deficit or overload—contributes to heart failure, sarcopenia, neurodegeneration, cancer and post-COVID syndromes. Therapeutically, slow-release donors (SG1002, GYY4137), mitochondria-targeted vectors (AP39), photo- or thiol-activated “smart” scaffolds, diet-derived polysulfides/isothiocyanates and microbiota engineering aim to restore the protective RSS window. Key challenges are a narrow therapeutic margin and real-time quantification of persulfide fluxes. Harnessing RSS therefore offers a route to rebalance redox homeostasis across diverse chronic diseases. Full article

Menopause is a natural phase in a woman’s life marked by the cessation of menstruation, typically accompanied by hormonal fluctuations that have significant impacts on physical and mental health. While much attention has been given to the physical symptoms of menopause, such as hot flashes and osteoporosis, the neurocognitive consequences of hormonal fluctuations during the menopausal transition and the subsequent sustained estrogen loss after menopause have received less focus. Estrogen receptors (ERs), specifically ERα and ERβ, play a critical role in maintaining brain health, influencing mood, memory, and cognition. This review explores the connection between estrogen receptor signaling and mental health during menopause, focusing on mood disorders such as depression and anxiety, as well as cognitive decline and dementia. We discuss the molecular mechanisms by which ERs modulate brain function, including their effects on neuroplasticity, neurotransmitter systems, and gene expression. The review also examines current clinical approaches to managing menopausal cognitive and mental health issues, including hormone replacement therapy and selective ER modulators, while emphasizing the need for further research into alternative therapies and individualized treatments. The importance of estrogen receptors in the menopausal brain and their potential as therapeutic targets is critically evaluated, aiming to shed light on this often-overlooked aspect of menopause and aging. Full article

Maternal behavior encompasses a range of biologically driven responses whose expression and duration vary across species. Maternal responses rely on robust adaptive changes in the female brain, enabling mothers to engage in caregiving, nourishing, and offspring protection. Morphological and functional changes in the maternal brain enhance sensitivity to offspring cues, eliciting maternal behaviors, rewarding responses, and social processing stimuli essential for parenting. Maternal behavior comprises a range of biological responses that extend beyond basic actions, reflecting a complex, evolutionarily shaped neurobiological adaptation. These behaviors can be broadly categorized into direct behaviors, which are explicitly aimed at the care of the offspring, and indirect behaviors that, overall, ensure the protection, nourishment, and survival of the newborn. The secretion of main neuropeptide hormones, such as oxytocin (OT), prolactin (PRL), and placental lactogens (PLs), during the peripartum period, is relevant for inducing and regulating maternal responses to offspring cues, including suckling behavior. Although PRL is primarily associated with reproductive and parental functions in vertebrates, it also modulates distinct neural functions during pregnancy that extend from lactogenesis to adult neurogenesis, neuroprotection, and neuroplasticity, all of which contribute to preparing the maternal brain for motherhood and parenting interactions. Parvocellular OT-containing neurons in the paraventricular nucleus (PVN) and in the anterior hypothalamic nucleus (AHN) project axon collaterals to the medial preoptic area, which, in turn, projects to the nucleus accumbens (NACC) and lateral habenula (lHb) via the retrorubral field (RRF) and the ventral tegmental area (VTA), which mediate the motivational aspects of maternal responses to offspring cues. The reshaping process of the brain and neural networks implicated in motherhood depends on several factors, such as up- and downregulation of neuronal gene expression of bioactive peptide hormones (i.e., OT, PRL, TIP-39, galanin, spexin, pituitary adenylate cyclase-activating polypeptide (PACAP), corticotropin-releasing hormone (CRH), peptide receptors, and transcription factors (i.e., c-fos and pSTAT)) in target neurons in hypothalamic nuclei, mesolimbic areas, the hippocampus, and the brainstem, which, overall, regulate the expression of maternal behavior to offspring cues, as shown in postpartum female rodents. In this review, we describe the modulatory neuropeptides, the neural networks underlying peptide transmission systems, and cell signaling involved in parenthood. We highlight the dysregulation of neuropeptide hormones and their receptors in the central nervous system in relation to psychiatric disorders. Full article

Orexin is a neuropeptide produced in the hypothalamus that plays a key role in regulating slee—wake cycles, energy metabolism, feeding behavior, and physical activity. It exists in two forms, orexin-A and orexin-B, which bind to G protein-coupled receptors OX₁R and OX₂R with differing affinities. Orexin signaling is widespread in the brain and extends to peripheral tissues, including adipose tissue. Its involvement in hypothalamic and extrahypothalamic circuits suggests a broad role in homeostatic regulation. Dysfunctions in the orexinergic system are implicated in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and multiple sclerosis, particularly through mechanisms involving sleep disturbances and neuroinflammation. This study examines how orexin influences neural circuits related to arousal, motivation, and motor control. It also explores how physical activity stimulates orexin release, enhancing neuroplasticity and cognitive resilience. In addition, orexin’s role in reward-related feeding, genetic susceptibility to obesity, and brown adipose tissue thermogenesis is discussed. Overall, the orexinergic system represents a vital neurochemical link between physical activity, metabolism, and cognitive health. Although many of its mechanisms remain to be clarified, its central role in integrating energy balance and behavioral responses makes it a promising target for future therapeutic strategies. Full article