As the most common neurodevelopmental and mental disorder around the world, attention-deficit/hyperactivity disorder (ADHD) affects primarily children and adolescents. Both genetic (polygenicity) and environmental variables interplay in the etiology of this disorder. The Wnt signaling pathway, which regulates proliferation and differentiation during neurodevelopment, has been implicated in ADHD. Clinically, individuals with ADHD may exhibit delays in structural and functional brain development. Available evidence suggests that methylphenidate (MPH) treatment can potentially improve these delays. However, the molecular and cellular mechanisms underlying ADHD and the therapeutic targets of MPH are not yet completely elucidated. In a pilot investigation, the proliferation of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) was significantly lowered in ADHD male patients. Yet, we did not observe any variations in proliferation rates during the iPSC stage. To extend the earlier results, we increased the sample size to include females, explored whether MPH may improve NSC proliferation in ADHD and clarified the role of the Wnt pathway. To do so, iPSC and NSC proliferation from five ADHD patients and five controls was assessed. The results corroborated our previous findings of decreased proliferation in ADHD NSCs. Conversely, ADHD NSC proliferation was modestly regulated by MPH treatment at 10 nM, which also showed modulatory effects on Wnt signaling in this group. Interestingly, no increase in proliferation was seen when DKK1 blocked Wnt signaling before MPH treatment. These findings suggest MPH regulates the canonical Wnt pathway and may partially explain ADHD-related neurodevelopmental abnormalities and MPH-specific benefits.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00702-025-02988-y.

Previous studies on the association between alcohol consumption and risk of Parkinson’s disease (PD) have produced controversial results. However, the relationship between alcohol consumption and mortality in PD has scarcely been investigated. Among the nationwide population data from Korea National Health Insurance Service, newly diagnosed PD (ICD-10 code: G20 and a rare intractable disease registration code: V124), between 2009 and 2017, were selected. Alcohol consumption habit was obtained from a self-reported questionnaire on the National Health Screening Program. 32,419 individuals with PD were followed-up longitudinally until December 31, 2017, and all-cause mortality was evaluated. During the follow-up period (mean 4.37 ± 2.67 years), 9,049 deaths occurred. When nondrinkers are used as a reference group, there were significant associations between alcohol consumption and all-cause mortality in mild (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.71–0.84) and moderate drinkers (HR 0.69, 95% CI 0.58–0.82), but not in heavy drinkers (HR 0.84, 95% CI 0.69–1.02). In the sensitivity analysis using never drinkers as the reference group, the results also showed an overall 20% reduced mortality risk among drinkers with PD. Regarding changes in alcohol consumption behavior before and after diagnosis, the mortality rate was higher in former drinkers (HR 1.20, 95% CI 1.02–1.41) and lower in constant drinkers (HR 0.74, 95% CI 0.65–0.83) than in never drinkers. Alcohol consumption appears to be associated with reduced all-cause mortality in PD, suggesting potential neuroprotective effects on disease progression. Although drinking does not appear to be detrimental to all-cause mortality in individuals with PD, alcohol consumption in PD requires attention considering individual motor and non-motor symptoms. Future studies in other ethnic groups are warranted to validate the association between alcohol consumption and disease progression, including mortality, in PD.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00702-025-02976-2.

Anhedonia is a core transnosographic symptom in several neuropsychiatric disorders. Recently, the Triple Network (TN) model has been proposed as a useful neurophysiological paradigm for conceptualizing anhedonia, providing new insights to clinicians and researchers. Despite this, the relationship between the functional dynamics of TN and the severity of anhedonia has been relatively understudied in non-clinical samples, especially in the resting state (RS) condition. Therefore, in the current study, we investigated this relationship using electroencephalography (EEG) functional connectivity. Eighty-two participants (36 males; mean age: 24.28 ± 7.35 years) underwent RS EEG recording with eyes-closed and completed the Beck Depression Inventory-derived 4-item anhedonia scale (BDI-Anh4) and the Brief Symptoms Inventory (BSI). EEG data on functional connectivity were analyzed using the exact low-resolution electromagnetic tomography (eLORETA). A significant positive correlation was observed between the BDI-Anh4 total score and salience-default mode network connectivity in the beta frequency band (r = 0.409; p = 0.010). The results of the hierarchical linear regression analysis also showed that this connectivity pattern was positively and independently associated (β = 0.358; p < 0.001) with the BDI-Anh4 total score and explained an additional 11% of the anhedonia variability. The association between anhedonia severity and increased salience-default mode network synchronization detected in the current study may reflect difficulty disengaging from internal/self-related mental contents, which consequently impairs the processing of other stimuli, including rewarding stimuli.

The role of neurodegeneration in essential tremor (ET) remains debated, particularly in patients with late disease onset. Neuropathological studies have identified structural changes in the Purkinje cells and its connections. Recent studies additionally suggested a role of cerebellar astrocytes. Increased levels of serum glial fibrillary acidic protein (sGFAP), an astrocytic intermediate filament, were found in various neuroinflammatory and neurodegenerative diseases. The objective of this case–control study was to investigate the role of sGFAP in ET focusing on early-stage late-onset patients. sGFAP was quantified by single molecule array at baseline and follow-up in 36 ET-patients (median follow-up period 5.3 years) and 36 age-matched healthy controls (4.9 years). ET-patients were assessed both at baseline and follow-up using the Fahn–Tolosa–Marin–Tremor-Rating-Scale. The ET group was stratified (1) by median age at onset and median disease duration in early-stage late-onset and early-onset/late-stage ET, and (2) by median sGFAP-level at baseline. Early-stage late-onset ET-patients had higher baseline-sGFAP than controls (p = 0.023) and higher follow-up-sGFAP and annual sGFAP-increase than both controls (p = 0.023; p = 0.007) and early-onset/late-stage ET-patients (p = 0.021; p = 0.024). Baseline sGFAP-level correlated with tremor severity at follow-up in the early-stage late-onset (rs = 0.704, p = 0.011) but not in the early-onset/late-stage group. Patients with high compared to low sGFAP-baseline levels had later disease onset (p < 0.001) and sGFAP-increase was associated to tremor progression only in high sGFAP-patients (p = 0.041). ET-plus and pure-ET-patients did not differ in any of the sGFAP-parameters. sGFAP is elevated in early stages of late-onset ET and associated to tremor progression, substantiating the role of a neurodegenerative process in ET in this subgroup.

Neurodegenerative diseases raise public health concerns. Recent evidence indicates that Alzheimer’s disease (AD) sufferers will triple by 2050. The rising incidence of dementia diagnoses raises concerns about the socio-economical and emotional impact of this uncurable illness, which reduces quality of life through cognitive decline. Although genetic and environmental factors may contribute to its aetiology, neuropathological mechanisms underlying these disorders are still under investigation. One is brain insulin resistance (BIR), which has been associated with clinical cognitive dysfunction and linked to mitochondrial dysfunction, neurogenesis deficits, and cell death. Not limited to neurodegeneration, these phenotypes have been associated with other neuropsychiatric disorders. Streptozotocin (STZ), a diabetes-causing drug that targets pancreatic β-cells, may imitate BIR in suitable models. From patients’ neuroimaging to in vitro approaches, scientists have been striving to understand the pathophysiology of such disorders at the behavioural, molecular, and cellular levels. Although animal models are useful for studying insulin resistance’s systemic effects, in vitro phenotypic research represents an alternative to study molecular and cellular aspects. STZ and hypoglycaemia-like scenarios have been successful for studying neurodegenerative disorders in primary cell culture (e.g., neuroblastoma cells) and patient-specific neural cell lines derived from pluripotent stem cells (iPSCs). Intriguingly, STZ treatment or hypoglycaemia-like conditions in a dish were able to induce AD pathological characteristics such Aβ plaque deposition and Tau protein hyperphosphorylation. Such approaches have shown potential in understanding molecular and cellular implications of metabolic changes in neuropsychiatric disorders, according to this review. Furthermore, these models may help identify novel treatment targets.

Aripiprazole is approved for various severe mental disorders in adults and adolescents. However, off-label prescribing is common, especially in children and adolescents (youth) in whom aripiprazole therapeutic serum level reference ranges are lacking for any disorders. The aim of the study was to evaluate the relationship between aripiprazole dose and serum concentrations and provide further knowledge on the use of aripiprazole in order to improve drug safety and effectiveness in the treatment of minors. The clinical course of youth treated with aripiprazole in the multicentre pharmacovigilance study TDM-VIGIL was systematically followed and serum concentrations measured. Sex, age, weight and comedications were analysed to identify possible effect modifiers. A preliminary therapeutic reference range was estimated for youth with schizophrenia-spectrum disorders, affective disorders and behavioural/emotional/tic disorders coded as treatment responders based on a Clinical-Global Impressions-Improvement (CGI-I) score of much or very much improved. In 93 youth (mean age = 15.2 ± 2.6, range = 7.4–18.2 years, females = 53%, CGI-Severity = 4.4 ± 1.1, responders = 64%), a positive, moderate correlation between the weight-normalized daily dose (WNDD) and aripiprazole serum concentration (=0.791, p < 0.0001) was found. The WNDD and co-medications that interact with CYP2D6 and CYP3A4 affected aripiprazole serum levels, explaining 64% of the variance. In patients within the preliminary therapeutic ranges determined by interquartile ranges (IQRs), slightly better outcomes and fewer adverse drug reactions were found versus patients within preliminary therapeutic ranges determined by the mean ± SD. The preliminary reference range for paediatric patients with schizophrenia-spectrum disorders calculated by the IQR showed an identical lower threshold (100–230 ng/ml) compared to adult schizophrenia-spectrum disorders patients (100–350 ng/ml). The preliminary therapeutic ranges for patients with affective disorders was: 60–160 ng/ml and for patients with behavioural/tic disorders 60–140 ng/ml. The therapeutic reference ranges for aripiprazole in youth estimated via the 25th and 75th IQRs may result in more clinically relevant therapeutic windows. Further studies need to confirm these results, especially in patients with affective and behavioural/tic disorder diagnoses.

Quantitative susceptibility mapping (QSM) and transcranial sonography (TCS) offer proximal evaluations of iron load in the substantia nigra. Our prospective study aimed to investigate the relationship between QSM and TCS measurements of nigral iron content in patients with Parkinson’s disease (PD). In secondary analyses, we wanted to explore the correlation of substantia nigra imaging data with clinical and laboratory findings. Eighteen magnetic resonance imaging and TCS examinations were performed in 15 PD patients at various disease stages. Susceptibility measures of substantia nigra were calculated from referenced QSM maps. Echogenicity of substantia nigra on TCS was measured planimetrically (echogenic area) and by digitized analysis (echo-intensity). Iron-related blood serum parameters were measured. Clinical assessments included the Unified PD Rating Scale and non-motor symptom scales. Substantia nigra susceptibility correlated with echogenic area (Pearson correlation, r = 0.53, p = 0.001) and echo-intensity (r = 0.78, p < 0.001). Individual asymmetry indices correlated between susceptibility and echogenic area measurements (r = 0.50, p = 0.042) and, more clearly, between susceptibility and echo-intensity measurements (r = 0.85, p < 0.001). Substantia nigra susceptibility (individual mean of bilateral measurements) correlated with serum transferrin saturation (Spearman test, r = 0.78, p < 0.001) and, by trend, with serum iron (r = 0.69, p = 0.004). Nigral echogenicity was not clearly related to serum values associated with iron metabolism. Susceptibility and echogenicity measurements were unrelated to PD duration, motor subtype, and severity of motor and non-motor symptoms. The present results support the assumption that iron accumulation is involved in the increase of nigral echogenicity in PD. Nigral echo-intensity probably reflects ferritin-bound iron, e.g. stored in microglia.

BackgroundRecently, a network model of cervical dystonia (CD) has been adopted that implicates nodes and pathways involving cerebellar, basal-ganglia and cortico-cortical connections. Although functional changes in the cerebello-thalamo-cortical network in dystonia have been reported in several studies, structural information of this network remain sparse.ObjectiveTo characterize the structural properties of the cerebellar motor network in isolated CD patients. This includes cerebellar lobules involved in motor processing, the dentate nucleus (DN), the thalamus, and the primary motor cortex (M1).MethodsMagnetic resonance imaging data of 18 CD patients and 18 healthy control subjects were acquired. In CD patients, the motor part of the Toronto Western Spasmodic Torticollis Rating Scale was assessed to evaluate motor symptom severity. The volume of cerebellar lobules I-VI and VIII, the DN and thalamus, and the cortical thickness (CT) of M1 were determined for a region of interest (ROI)-based quantitative analysis. Volumes/CT of these ROIs were compared between groups and associated with motor symptom severity in patients.ResultsThe volume of lobule VI and the CT of M1 were reduced in CD patients. The volumes of the other ROIs were not different between groups. No association was identified between the structural properties of lobule VI or M1 and the severity of CD motor symptoms.ConclusionAtrophy within the cerebellum and M1 contributes to CD’s complex motor network pathology. Further investigations are needed to ascertain the mechanisms underlying the local volume loss.

ObjectiveVagally-mediated heart rate variability (vmHRV) is regarded as transdiagnostic marker of emotion regulation and cognitive control capacity. We analysed vmHRV of children with attention deficit/hyperactivity disorder (ADHD). Based on previous research, we expected to find comorbid symptom dimensions (i.e. internalizing symptoms, conduct problems (CP), and callous unemotional (CU) traits) to relate to vmHRV measures.MethodsThe sample comprised 100 (70 boys) medication naïve children with ADHD. Children were 6 to 11 years old. High frequency HRV (HF-HRV) was measured at rest and during a delay of gratification task. Additionally, sympathetic reactivity was assessed via skin conductance responses (SCR). Comorbid symptoms were assessed by parent-report questionnaires and clinical interviews.ResultsThe multiple correlation between CU traits and the HF-HRV scores proved statistically significant. Higher CU traits were associated with higher HRV resting-state and response scores. CP were positively associated with the SCR score.ConclusionIn children with ADHD, increased CU traits might point to a comparatively less impaired self-regulation capacity in the reward-related context. The result corresponds to findings from previous studies. In the future, CU traits should be considered in analyses of autonomic regulation in ADHD.

In Parkinson’s disease (PD), impaired gait and cognition affect daily activities, particularly in the more advanced stages of the disease. This study investigated the relationship between gait parameters, cognitive performance, and brain morphology in patients with early untreated PD. 64 drug-naive PD patients and 47 healthy controls (HC) participated in the study. Single- and dual-task gait (counting task) were examined using an expanded Timed Up & Go Test measured on a GaitRite walkway. Measurements included gait speed, stride length, and cadence. A brain morphometry analysis was performed on T1-weighted magnetic resonance (MR) images. In PD patients compared to HC, gait analysis revealed reduced speed (p < 0.001) and stride length (p < 0.001) in single-task gait, as well as greater dual-task cost (DTC) for speed (p = 0.007), stride length (p = 0.014) and cadence (p = 0.029). Based on the DTC measures in HC, PD patients were further divided into two subgroups with normal DTC (PD-nDTC) and abnormally increased DTC (PD-iDTC). For PD-nDTC, voxel-based morphometric correlation analysis revealed a positive correlation between a cluster in the left primary motor cortex and stride-length DTC (r = 0.57, p = 0.027). For PD-iDTC, a negative correlation was found between a cluster in the right lingual gyrus and the DTC for gait cadence (r=-0.35, pFWE = 0.018). No significant correlations were found in HC. The associations found between brain morphometry and gait performance with a concurrent cognitive task may represent the substrate for gait and cognitive impairment occurring since the early stages of PD.