Stressful life events are major precipitants of depressive episodes, yet their effects vary across individuals. Childhood trauma is a well-established vulnerability factor that may increase sensitivity to subsequent stress. However, the neural correlates of this interaction in major depressive disorder (MDD) remain poorly characterized. This study investigated whether childhood trauma moderates the association between recent stress exposure and brain structure and functional connectivity in MDD. Structural magnetic resonance imaging (MRI) data were obtained from 130 inpatients with MDD; resting-state functional MRI data were available for a subsample (n = 97). Whole-brain cortical thickness and surface-based functional connectivity measures, including global correlation (GCOR) and local correlation (LCOR), were examined to test interaction effects between childhood trauma and recent stress exposure. A significant interaction between childhood trauma and recent stress was observed in medial prefrontal regions, including the anterior cingulate cortex, where greater stress exposure was associated with reduced cortical thickness at higher levels of early adversity. Convergent interaction effects were also observed at the functional level, with greater recent stress associated with lower LCOR in the left superior frontal gyrus and precuneus at higher levels of childhood trauma. No interaction effects were observed for GCOR. Analyses of specific trauma dimensions indicated partially distinct effects of abuse and neglect. Childhood trauma moderated the association between recent stress exposure and structural and functional brain measures in MDD, particularly within prefrontal regulatory regions. These multimodal findings are consistent with stress sensitization models and suggest that early adversity may contribute to heterogeneity in neural correlates of stress in depression.

In addition to response fluctuations caused by the pharmacokinetics of dopamine replacement medication, temporal variation in the expression and severity of motor and non-motor symptoms, which is not or only partially attributable to the effects of the medication, are also common in Parkinson's disease (PD). The spectrum of transient changes of motor symptom expression unrelated to the classical ON-OFF fluctuations ranges from brief episodes of gait freezing or tremor breakthroughs to severe akinetic crisis and non-motor phenomena include discontinuous changes in cognition and vigilance. Disease-related factors such as dementia or orthostatic dysregulation or disturbances of the circadian rhythm may also contribute to these non-pharmacological symptom fluctuations. Additionally, external factors including infections or surgery and general anaesthesia can lead to transient changes of PD symptom severity and drug responsiveness. Accurately classifying these symptom oscillations and distinguishing them from drug-induced ON-OFF fluctuations is essential for their appropriate management.

No baseline disability weights (DW) or disability-adjusted life years (DALY) have been established for X-linked dystonia-parkinsonism (XDP). This study aimed to calculate the DW and estimate the DALY for XDP using the Health Utility Index-3 (HUI-3). A cross-sectional study was conducted with 96 genetically confirmed male patients with XDP from movement disorder clinics in the Philippines. HUI-3 was used to measure 8 health attributes. DW were derived by subtracting utility scores from 1 and analyzed against variables using various statistical tests. DALY, years lived with disability, and years of life lost were estimated using a pragmatic framework based on the XDP census and Global Burden of Disease 2010 life expectancy. The mean age of patients was 45.57 ± 8.26 years. The mean DW was 0.48 ± 0.31, with a median of 0.40. Because DW is derived directly from HUI-3 attribute scores, multivariable regression was used to decompose HUI-3 attributes into the relative contributions of each attribute, with ambulation (β = 0.109), and emotion (β = 0.097) being the strongest contributors. Current or prior employment was a significant predictor of DW (β = 0.172, p = 0.021). Based on registry data, the estimated total disability-adjusted life years for XDP in the Philippines was 9718.84, representing a rate of 10.53 per 100,000 population. The disease burden was 40.2% years lived with disability, and 59.8% years of life lost. XDP imposes a substantial disease burden through both chronic disability and premature mortality. These findings provide a conservative baseline for quantifying the impact of XDP to inform public health policy in the Philippines.

Frailty is increasingly defined as a multidimensional clinical condition whose prevalence rises with advancing age, extending across multiple medical specialties and exhibiting significant sex- and gender-related differences. Chronic diseases, including neurological conditions such as Parkinson's disease (PD), are key contributors to frailty, possibly through shared mechanisms. Conversely, frailty adversely influences clinical outcomes and disease trajectories, increases mortality risk and alters the risk-benefit profile of therapeutic interventions. This review summarizes current evidence on the aetiologies, clinical and instrumental assessment, emerging fluid biomarkers, and therapeutic implications of frailty in PD. Conventional frailty tools, including the Frailty Index and Fried phenotype, are useful but lack specificity in this specific population, notably because PD-related symptoms overlap with frailty criteria. A multimodal approach integrating gait and balance analysis, cognitive testing, dysautonomia assessment, sarcopenia screening, dysphagia evaluation, and nutritional markers may improve risk stratification. Emerging biomarkers, including inflammatory cytokines, albumin, C-reactive protein/albumin ratio, vitamin D, sarcopenia-related markers, neurofilament light chain, and glial fibrillary acidic protein (GFAP), may further capture biological vulnerability, although validation remains limited. Frailty substantially modulates PD treatment decisions by increasing susceptibility to adverse effects, polypharmacy, falls, cognitive complications, and procedural risk. Frailty should therefore be systematically integrated into pharmacological prescribing, deprescribing, rehabilitation, neuropalliative approaches, and selection (as well as timing) of device-aided therapies. Routine frailty assessment, independent of chronological age, may support more individualized, patient-centred PD care, prioritizing functional independence, safety, quality of life, and minimisation of treatment burden alongside conventional motor management.

Social jetlag (SJL), defined as a mismatch in midsleep timing between school or workdays and free days, has been associated with adverse mental health, cognitive, and brain outcomes in adults. However, its effects in youth remain insufficiently studied. We investigated the effects of SJL on these factors and on tryptophan metabolites implicated in sleep, fatigue, and social function. Based on SJL assessed using the Munich ChronoType Questionnaire, 89 healthy youths aged 6-17 years were classified into high-SJL (≥ 1 h; n = 25) or low-SJL (< 1 h; n = 64) groups. Fatigue, chronotype, Trail Making Test (TMT) performance, urinary tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) levels, gray matter volume (GMV), and resting-state functional connectivity (FC) were evaluated. Compared with the low-SJL group, the high-SJL group exhibited greater fatigue (p-FDR = 0.034), a later chronotype (p-FDR = 0.00003), and higher urinary tryptophan levels (p-FDR = 0.014). Moreover, the high-SJL group showed smaller GMV in the left inferior occipital/fusiform region (p-FWE = 0.002), right inferior temporal region (p-FWE = 0.006), right angular gyrus (p-FWE = 0.012), left temporal pole (p-FWE = 0.013), and left superior parietal lobule (p-FWE = 0.024). However, TMT performance, urinary 5-HIAA levels, and FC did not differ between groups. An SJL of ≥ 1 h was associated with elevated tryptophan levels and structural vulnerability in temporal pole, ventral occipitotemporal regions, and parietal regions. These findings suggest that higher SJL may contribute to molecular and region-specific structural disadvantages relevant to socioemotional and higher-order cognitive processes in youth.

Late-stage Parkinson's disease (LSPD) presents with disabling motor and non-motor symptoms, the latter becoming dominant in the late stage. There is limited information on LSPD. This study aimed to identify common symptoms and common drug treatments of LSPD. We conducted an online survey of physicians treating patients with Parkinson's disease in specialized palliative care across Austria, Germany and Switzerland, followed by a two-round Delphi survey involving movement disorder specialists. Consensus was defined as ≥ 75% agreement. 118 participants of 1252 contacted institutions completed the survey. In the Delphi process, eight experts out of 19 participated. Most frequently reported symptoms were dysphagia (94%), rigidity (78%), speech disorder (70%), bradykinesia (61%), dementia (74%) and constipation (64%). Most frequently used medications for motor symptom control at admission to palliative care were levodopa (96%) and rotigotine (48%). Similarly, levodopa (64%) and rotigotine (49%) were most frequently reported to be prescribed until the end of palliative care. Delphi experts agreed on the importance of oral and intestinal levodopa as well as rotigotine for the palliative care phase. Levodopa therapy should be maintained until end of life. Regarding non-motor symptom control, Delphi panelists concluded that laxatives, antipsychotics and medications for hypersalivation should be administered until end of life. Macrogol (70%) and sodium picosulfate (71%) were the most favored laxatives. Among antipsychotics quetiapine was most recommended for psychosis (76%) and delirium (59%) management. However, Delphi panelists agreed on clozapine for psychosis management and quetiapine for delirium management. For hypersalivation, consensus was reached on botulinum toxin injection. harmacological treatment of LSPD should be based on a symptom-oriented and stage-based approach. Therapy encompasses levodopa and non-dopaminergic treatments for non-motor symptom control.

Gastrointestinal Disorders in people with Parkinson's disease (PwP) are able to cause widespread clinical symptoms which can be challenging to classify in day-to-day clinical practice. In the upper gastrointestinal tract (GIT) oropharyngeal dysphagia, esophageal motility disorders as well as delayed gastric emptying may cause nutrition problems and reduce the efficacy of oral pharmacotherapy. In the lower GIT, bacterial overgrowth and prolonged colorectal transit times induce different stages of constipation leading to reduced quality of life and GIT comorbidities as well. Most of these symptoms reflect alpha-synuclein pathology in both the enteric nervous system and at various sites of the peripheral and central nervous systems. Besides, the growing use of various device aided therapies may additionally raise specific clinical questions about the interference with the GIT motility. This standard operating procedure (SOP) is intended to provide specific recommendations for diagnostic steps as well as therapeutic options, especially for interprofessional neurological outpatient care teams.

Behavioral disinhibition is a core feature of behavioral variant frontotemporal dementia (bvFTD) and occurs across related FTD-spectrum presentations. Serotonergic dysfunction may contribute to behavioral dysregulation; therefore, we primarily examined dorsal raphe (DR)-centered midbrain [123]I-FP-CIT uptake as an indirect extrastriatal signal that may partly reflect serotonin transporter-related binding. Because striatal dopaminergic circuits support reward learning, behavioral inhibition, and context-dependent behavioral updating, striatal uptake was examined exploratorily. This retrospective exploratory study included 21 patients within the FTD spectrum who underwent Neuropsychiatric Inventory (NPI) assessment, magnetic resonance imaging, and [123]I-FP-CIT single-photon emission computed tomography within a 3-month window. The primary outcome was the NPI disinhibition score. DR-centered midbrain and striatal specific uptake ratios (SURs) were calculated using the cerebellum as the reference region. Age- and sex-adjusted quasi-Poisson models with a log link were fitted. DR-centered midbrain SUR was not significantly associated with disinhibition in the primary model (β = -1.027, p = 0.353). In the exploratory model, higher striatal SUR was nominally associated with lower disinhibition scores (β = -0.438, p = 0.022). The negative direction of the striatal association was generally preserved across sensitivity analyses, although nominal significance was not retained in all models. DR-centered midbrain SUR was not significantly associated with behavioral disinhibition in this small FTD-spectrum cohort. Lower striatal SUR showed a directionally consistent but sensitivity-dependent nominal association with greater disinhibition. This hypothesis-generating finding may reflect broader frontostriatal disease burden, striatal neurodegeneration, parkinsonian-spectrum overlap, or partial-volume effects and does not establish a disinhibition-specific dopaminergic mechanism.

Advances in psychiatric genetics have substantially reshaped current models of schizophrenia-spectrum disorders, shifting the focus from single risk factors to polygenic liability and its interaction with environmental adversity. Polygenic risk scores (PRS) provide a quantitative index of genetic vulnerability; however, how this liability interfaces with early-life stress-particularly childhood trauma-across neurodevelopment remains insufficiently conceptualized. Accumulating evidence indicates that the interplay between polygenic risk and childhood trauma influences not only the likelihood of psychosis onset but also the emergence of specific symptom dimensions during clinical high-risk states and early stages of illness. Yet, existing theoretical frameworks tend to consider genetic predisposition and environmental exposure as parallel or additive processes, offering limited insight into their developmental convergence. In this Perspective, we examine current neurodevelopmental models of schizophrenia and integrate them within a unified framework, proposing that polygenic liability, environmental exposures (including early trauma), and psychological processes interact dynamically and bidirectionally across sensitive developmental windows, shaping distinct neuropsychodevelopmental trajectories. Integrating polygenic, environmental, and developmental domains within a unified neuropsychodevelopmental framework may help explain clinical heterogeneity, with important implications for early identification, risk stratification, and personalized preventive strategies.

Hyperexcitability of lateral (La) and basolateral (BL) amygdalar nuclei (BLA) is a hallmark of anxiety-related disorders in humans. Excitation of BLA projection neurons (PN) is fine-tuned by inhibitory interneurons (INs), and monoaminergic afferents to the BLA modulate PN and IN activity. In the present study, BLA-neurons immunoreactive(ir) for parvalbumin (PV) or neuropeptide Y (NPY) and their interrelations with serotonergic and catecholaminergic afferents were analyzed in wildtype (WT) and in serotonin (5-HT) transporter knockout (5-HTT KO) mice, a mouse model for anxiety- and stress-related disorders. In both genotypes, PV- and NPY-ir neurons possess perisomatic appositions by serotonergic and tyrosine hydroxylase-ir afferents. Dual immunolabeling shows no colocalization of PV and NPY. Qualitative analysis of NPY/somatostatin(SOM) dual labeling in WT and 5-HTT KO mice documents colocalization of the peptides in neurons with predominantly fusiform somata, and single labeling for NPY in neurons with predominantly round somata. Quantification of PV- and NPY-ir neurons documents a reduction in numbers and densities of NPY-ir neurons of the BLA in 5-HTT KO mice while PV-ir neuron numbers and densities remain unchanged. Quantitative PCR shows increased expression of Npy receptor 2, Som receptor 4, and corticotropin releasing factor receptor 1 in the BLA of 5-HTT KO mice. mRNA for the peptides is unchanged, indicating that it may be NPY propeptide translation which is reduced in 5-HTT KO mice. Taken together, the results document an effect of life-long serotonin imbalance on the BLA NPY-system, which may contribute to increased anxiety-like behavior in 5-HTT KO mice.

Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal postures or repetitive movements. Isolated lingual dystonia (ILD) is a rare form of oromandibular dystonia, which affects only the tongue and accounts for about 4% of all dystonia cases. This report describes two Filipino males, aged 43 and 48, who developed ILD. The first patient is a 43-year-old male from Cebu, with no significant family history or roots from Panay Island, who was found to carry the X-linked dystonia parkinsonism (XDP)-causing variant highlighting a novel presentation of ILD linked to XDP. The second patient is a 48-year-old male from Roxas City, with a family history suggesting XDP, who presented with ILD initially and later developed tremor, limb dystonia, and bradykinesia. His diagnosis of XDP was confirmed by genetic testing. These cases highlight the importance of considering XDP in the differential diagnosis of ILD among Filipinos, regardless of geographic or familial predispositions. Genetic testing and follow-up examinations are crucial for managing ILD, as it may precede more generalized dystonic and parkinsonian symptoms associated with XDP. This study contributes to the limited literature on ILD and suggests new insights into the clinical variability of XDP.

Posttraumatic stress disorder (PTSD) is associated with symptoms of intrusive memories, avoidance, and hyperarousal. Accumulated evidence shows that these symptoms are related to changes in brain areas involved in memory and emotion. The purpose of this paper was to review functional brain imaging studies in PTSD. Pubmed, midline, and psych info were queried for keywords related to PTSD and brain imaging from 1990-2024. The review focused on functional brain imaging using Positron Emission Tomography (PET), single photon emission tomography (SPECT) and functional magnetic resonance imaging (fMRI) and did not include structural or spectroscopic imaging. Studies implicated a network of brain regions involved in memory and emotion including the amygdala, insula, prefrontal cortex, cingulate gyrus and hippocampus. PTSD is associated with alterations in function in brain areas mediating memory and emotion.

Although quetiapine is increasingly used off-label in children and adolescents with various psychiatric disorders, there is little evidence on the relationship between quetiapine dose and serum concentration, and therapeutic reference ranges (TRR) have not yet been established for this age group. The aim of this study was to evaluate whether the TRR described for adults is applicable to minors. In addition, the study aimed to investigate the relationship between the daily dose, serum concentration and clinical outcome. The clinical course of 77 patients (females = 78%) aged between 12 and 17 years treated with quetiapine in the multicentre pharmacovigilance study TDM-VIGIL was systematically followed, and serum concentrations were measured. A positive mean correlation was observed between the weight-adjusted daily dose and serum concentration (rs = 0.580, p < 0.001). Most patients (84.7%) experienced no ADRs or ADRs not significantly interfering with the patients' functioning. A positive linear relationship between the therapeutic response and serum concentration was found (rs = 0.238, p = 0.006). Only 38.5% of all quetiapine serum concentrations were within the recommended TRR described for adults. Using two different calculation methods, mean ± SD and IQR, our data hinted at considerably lower TRR for minors of about 14-291 ng/ml and 53-234 ng/ml respectively, compared to the suggested TRR for adults. This study has the potential to contribute to the definition of a TRR for quetiapine in minors. However, further controlled studies with larger sample sizes are needed to verify the preliminary results.