Editor’s Choice Articles

Developmental dyslexia can be viewed as the result of the effects of single deficits or multiple deficits. This study presents a test of the applicability of a multifactor-interactive model (MFi-M) with a preliminary set of five variables corresponding to different neuropsychological functions involved in the reading process. The model has been tested on a sample of 55 school-age children with developmental dyslexia. The results show that the data fit a model in which each variable contributes to the reading ability in a non-additive but rather interactive way. These findings constitute a preliminary validation of the plausibility of the MFi-M, and encourage further research to add relevant factors and specify their relative weights. It is further discussed how subtype-based intervention approaches can be a suitable and advantageous framework for clinical intervention in a MFi-M perspective. Full article

This article assesses the cool–hot executive function (EF) framework during childhood. First, conceptual analyses suggest that cool EF (cEF) is generally distinguished from hot EF (hEF). Second, both EFs can be loaded into different factors using confirmatory factor analyses. Third, the cognitive complexity of EF is similar across cEF tasks, and the cognitive complexity of cEF is similar to hEF tasks. Finally, neuroimaging analysis suggests that children activate the lateral prefrontal regions during all EF tasks. Taken together, we propose that the cool–hot framework is a useful, though not definitive way of characterizing differences in EF. Full article

Depression and anxiety are highly prevalent in most neurological disorders and can have a major impact on the patient’s disability and quality of life. However, mostly due to the heterogeneity of symptoms and the complexity of the underlying comorbidities, depression can be difficult to diagnose, resulting in limited recognition and in undertreatment. The early detection and treatment of depression simultaneously with the neurological disorder is key to avoiding deterioration and further disability. Although the neurologist should be able to identify and treat depression initially, a neuropsychiatry team should be available for severe cases and those who are unresponsive to treatment. Neurologists should be also aware that in neurodegenerative diseases, such as Alzheimer’s or Parkinson’s, different depression symptoms could develop at different stages of the disease. The treatment options for depression in neurological diseases include drugs, cognitive-behavioral therapy, and somatic interventions, among others, but often, the evidence-based efficacy is limited and the results are highly variable. Here, we review recent research on the diagnosis and treatment of depression in the context of Alzheimer’s disease, Parkinson’s disease, and strokes, with the aim of identifying common approaches and solutions for its initial management by the neurologist. Full article

Deep learning has shown impressive diagnostic abilities in Alzheimer’s disease (AD) research in recent years. However, although neuropsychological tests play a crucial role in screening AD and mild cognitive impairment (MCI), there is still a lack of deep learning algorithms only using such basic diagnostic methods. This paper proposes a novel semi-supervised method using neuropsychological test scores and scarce labeled data, which introduces difference regularization and consistency regularization with pseudo-labeling. A total of 188 AD, 402 MCI, and 229 normal controls (NC) were enrolled in the study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. We first chose the 15 features most associated with the diagnostic outcome by feature selection among the seven neuropsychological tests. Next, we proposed a dual semi-supervised learning (DSSL) framework that uses two encoders to learn two different feature vectors. The diagnosed 60 and 120 subjects were randomly selected as training labels for the model. The experimental results show that DSSL achieves the best accuracy and stability in classifying AD, MCI, and NC (85.47% accuracy for 60 labels and 88.40% accuracy for 120 labels) compared to other semi-supervised methods. DSSL is an excellent semi-supervised method to provide clinical insight for physicians to diagnose AD and MCI. Full article

Background: Depression and cancer share common risk factors and mechanisms of disease. The current literature has not explored the effect of depression on cancer risk. We assessed the difference in cancer risk in patients with and without depression in a large cohort in Germany. Methods: We compared cancer risk and incidence in patients with and without depression aged 18 or above diagnosed between 2015 and 2018 documented in the Disease Analyzer Database. Patients from a comparator group were matched 1:1 to patients with depression based on propensity scores. Patients with previous bipolar disorder (F31), mania (F30) or schizophrenia (F20–29) and cancer diagnosis 3 years prior to index date were excluded. Analyses were stratified by cancer type, age group, and gender. Results: A total of 117,702 patients with depression were included and matched 1:1, resulting in a cohort overall of 235,404. 4.9% of patients with depression compared to 4.1% without depression received at least one cancer diagnosis over 3.9 years median follow-up. The depression group showed an 18% increase in risk for a cancer diagnosis overall, with largest increased risk in lung cancer (HR: 1.39 [1.21–1.60], p < 0.0001), cancers of the gastro-intestinal-tract (HR: 1.30 [1.15–1.46], p < 0.0001), breast (HR: 1.23 [1.12–1.35], p < 0.0001) and urinary (HR: 1.23 [1.06–1.43], p < 0.01). Similarly, the incidence of cancer diagnosis overall increased by 22% for depressed patients. IRs showed no difference across cancer types. Conclusions: Depression increased the risk for cancer diagnosis consistently independent of the comparison method used. The potential mediating factors or shared mechanisms of the disease require further investigation. Full article

The need to identify new potentially druggable biochemical mechanisms for Alzheimer’s disease (AD) is an ongoing priority. The therapeutic limitations of amyloid-based approaches are further motivating this search. Amino acid metabolism, particularly tryptophan metabolism, has the potential to emerge as a leading candidate and an alternative exploitable biomolecular target. Multiple avenues support this contention. Tryptophan (trp) and its associated metabolites are able to inhibit various enzymes participating in the biosynthesis of β-amyloid, and one metabolite, 3-hydroxyanthranilate, is able to directly inhibit neurotoxic β-amyloid oligomerization; however, whilst certain trp metabolites are neuroprotectant, other metabolites, such as quinolinic acid, are directly toxic to neurons and may themselves contribute to AD progression. Trp metabolites also have the ability to influence microglia and associated cytokines in order to modulate the neuroinflammatory and neuroimmune factors which trigger pro-inflammatory cytotoxicity in AD. Finally, trp and various metabolites, including melatonin, are regulators of sleep, with disorders of sleep being an important risk factor for the development of AD. Thus, the involvement of trp biochemistry in AD is multifactorial and offers a plethora of druggable targets in the continuing quest for AD therapeutics. Full article

Objective: To identify patterns of social dysfunction in adolescents with autism spectrum disorder (ASD), study the potential linkage between social brain networks and stereotyped behavior, and further explore potential targets of non-invasive nerve stimulation to improve social disorders. Methods: Voxel-wise and ROI-wise analysis methods were adopted to explore abnormalities in the functional activity of social-related regions of the brain. Then, we analyzed the relationships between clinical variables and the statistical indicators of social-related brain regions. Results: Compared with the typically developing group, the functional connectivity strength of social-related brain regions with the precentral gyrus, postcentral gyrus, supplementary motor area, paracentral lobule, median cingulum, and paracingulum gyri was significantly weakened in the ASD group (all p < 0. 01). The functional connectivity was negatively correlated with communication, social interaction, communication + social interaction, and the total score of the ADOS scale (r = −0.38, −0.39, −0.40, and −0.3, respectively; all p < 0.01), with social awareness, social cognition, social communication, social motivation, autistic mannerisms, and the total score of the SRS scale (r = −0.32, −0.32, −0.40, −0.30, −0.28, and −0.27, respectively; all p < 0.01), and with the total score of SCQ (r = −0.27, p < 0.01). In addition, significant intergroup differences in clustering coefficients and betweenness centrality were seen across multiple brain regions in the ASD group. Conclusions: The functional connectivity between social-related brain regions and many other brain regions was significantly weakened compared to the typically developing group, and it was negatively correlated with social disorders. Social network dysfunction seems to be related to stereotyped behavior. Therefore, these social-related brain regions may be taken as potential stimulation targets of non-invasive nerve stimulation to improve social dysfunction in children with ASD in the future. Full article

Advances in applied machine learning techniques for neuroimaging have encouraged scientists to implement models to diagnose brain disorders such as Alzheimer’s disease at early stages. Predicting the exact stage of Alzheimer’s disease is challenging; however, complex deep learning techniques can precisely manage this. While successful, these complex architectures are difficult to interrogate and computationally expensive. Therefore, using novel, simpler architectures with more efficient pattern extraction capabilities, such as transformers, is of interest to neuroscientists. This study introduced an optimized vision transformer architecture to predict the group membership by separating healthy adults, mild cognitive impairment, and Alzheimer’s brains within the same age group (>75 years) using resting-state functional (rs-fMRI) and structural magnetic resonance imaging (sMRI) data aggressively preprocessed by our pipeline. Our optimized architecture, known as OViTAD is currently the sole vision transformer-based end-to-end pipeline and outperformed the existing transformer models and most state-of-the-art solutions. Our model achieved F1-scores of $97\%\pm 0.0$ and $99.55\%\pm 0.39$ from the testing sets for the rs-fMRI and sMRI modalities in the triple-class prediction experiments. Furthermore, our model reached these performances using 30% fewer parameters than a vanilla transformer. Furthermore, the model was robust and repeatable, producing similar estimates across three runs with random data splits (we reported the averaged evaluation metrics). Finally, to challenge the model, we observed how it handled increasing noise levels by inserting varying numbers of healthy brains into the two dementia groups. Our findings suggest that optimized vision transformers are a promising and exciting new approach for neuroimaging applications, especially for Alzheimer’s disease prediction. Full article

Anxiety disorders are the most common group of mental disorders, but they are often underrecognized and undertreated in primary care. Dysfunctional breathing is a hallmark of anxiety disorders; however, mainstays of treatments do not tackle breathing in patients suffering anxiety. This scoping review aims to identify the nature and extent of the available research literature on the efficacy of breathwork interventions for adults with clinically diagnosed anxiety disorders using the DSM-5 classification system. Using the PRISMA extension for scoping reviews, a search of PubMed, Embase, and Scopus was conducted using terms related to anxiety disorders and breathwork interventions. Only clinical studies using breathwork (without the combination of other interventions) and performed on adult patients diagnosed with an anxiety disorder using the DSM-5 classification system were included. From 1081 articles identified across three databases, sixteen were included for the review. A range of breathwork interventions yielded significant improvements in anxiety symptoms in patients clinically diagnosed with anxiety disorders. The results around the role of hyperventilation in treatment of anxiety were contradictory in few of the examined studies. This evidence-based review supports the clinical utility of breathwork interventions and discusses effective treatment options and protocols that are feasible and accessible to patients suffering anxiety. Current gaps in knowledge for future research directions have also been identified. Full article

An inflammatory response after an aneurysmal subarachnoid hemorrhage (aSAH) has always been in the spotlight. However, few studies have compared the prognostic impact of inflammatory biomarkers. Moreover, why these inflammatory biomarkers contribute to a poor prognosis is also unclear. We retrospectively reviewed aSAH patients admitted to our institution between January 2015 and December 2020. The 90-day unfavorable functional outcome was defined as a modified Rankin scale (mRS) of ≥ 3. Independent inflammatory biomarker-related risk factors associated with 90-day unfavorable outcomes were derived from a forward stepwise multivariate analysis. Receiver operating characteristic curve analysis was conducted to identify the best cut-off value of inflammatory biomarkers. Then, patients were divided into two groups according to each biomarker’s cut-off value. To eliminate the imbalances in baseline characteristics, propensity score matching (PSM) was carried out to assess the impact of each biomarker on in-hospital complications. A total of 543 patients were enrolled in this study and 96 (17.7%) patients had unfavorable 90-day outcomes. A multivariate analysis showed that the white blood cell (WBC) count, the systemic inflammation response index, the neutrophil count, the neutrophil-to-albumin ratio, the monocyte count, and the monocyte-to-lymphocyte ratio were independently associated with 90-day unfavorable outcomes. The WBC count showed the best predictive ability (area under the curve (AUC) = 0.710, 95% CI = 0.652–0.769, p < 0.001). After PSM, almost all abnormal levels of inflammatory biomarkers were associated with a higher incidence of pneumonia during hospitalization. The WBC count had the strongest association with poor outcomes. Similar to nearly all other inflammatory biomarkers, the cause of poor prognosis may be the higher incidence of in-hospital pneumonia. Full article

In recent years, the rapid development of artificial intelligence has promoted the widespread application of convolutional neural networks (CNNs) in neuroimaging analysis. Although three-dimensional (3D) CNNs can utilize the spatial information in 3D volumes, there are still some challenges related to high-dimensional features and potential overfitting issues. To overcome these problems, patch-based CNNs have been used, which are beneficial for model generalization. However, it is unclear how the choice of a patchwise sampling strategy affects the performance of the Alzheimer’s Disease (AD) classification. To this end, the present work investigates the impact of a patchwise sampling strategy for 3D CNN based AD classification. A 3D framework cascaded by two-stage subnetworks was used for AD classification. The patch-level subnetworks learned feature representations from local image patches, and the subject-level subnetwork combined discriminative feature representations from all patch-level subnetworks to generate a classification score at the subject level. Experiments were conducted to determine the effect of patch partitioning methods, the effect of patch size, and interactions between patch size and training set size for AD classification. With the same data size and identical network structure, the 3D CNN model trained with 48 × 48 × 48 cubic image patches showed the best performance in AD classification (ACC = 89.6%). The model trained with hippocampus-centered, region of interest (ROI)-based image patches showed suboptimal performance. If the pathological features are concentrated only in some regions affected by the disease, the empirically predefined ROI patches might be the right choice. The better performance of cubic image patches compared with cuboidal image patches is likely related to the pathological distribution of AD. The image patch size and training sample size together have a complex influence on the performance of the classification. The size of the image patches should be determined based on the size of the training sample to compensate for noisy labels and the problem of the curse of dimensionality. The conclusions of the present study can serve as a reference for the researchers who wish to develop a superior 3D patch-based CNN model with an appropriate patch sampling strategy. Full article

Diabetic polyneuropathy (DPN) is the most frequent, although neglected, complication of long-term diabetes. Nearly 30% of hospitalized and 20% of community-dwelling patients with diabetes suffer from DPN; the incidence rate is approximately 2% annually. To date, there has been no curable therapy for DPN. Under these circumstances, cell therapy may be a vital candidate for the treatment of DPN. The epidemiology, classification, and treatment options for DPN are disclosed in the current review. Cell-based therapies using bone marrow-derived cells, embryonic stem cells, pluripotent stem cells, endothelial progenitor cells, mesenchymal stem cells, or dental pulp stem cells are our primary concern, which may be a useful treatment option to ease or to stop the progression of DPN. The importance of cryotherapies for treating DPN has been observed in several studies. These findings may help for the future researchers to establish more focused, accurate, effective, alternative, and safe therapy to reduce DPN. Cell-based therapy might be a permanent solution in the treatment and management of diabetes-induced neuropathy. Full article

Job satisfaction and burnout are components of job morale. In general, and among healthcare provider personnel, these are psychological factors of the job and under the influence of different conditions and the organizational management of the healthcare systems. Both job burnout and job satisfaction among healthcare service providers have received scant attention in the literature, particularly in the healthcare systems of the Kurdistan Region of Iraq (KRI) as one low- or middle-income country (LMIC). The burnout rate and job satisfaction in a daycare center for children with autism spectrum disorders were reviewed and measured using a sample consisting of 34 employees from three different sections. The Maslach Burnout Inventory-Third Edition (MBI-3) and the Job Descriptive Index (JDI) were used. The relationships between the two scales and their consisting factors were examined using Pearson Correlation and Chi-square test to understand the correlation and levels of significant difference between the expected and the observed frequencies. There was a significant negative correlation between job burnout and satisfaction with the job and some significant correlations between the factors of the scales. Lower levels of emotional exhaustion and depersonalization factors of the burnout scale were statistically correlated. It was shown that the personnel were mainly satisfied with their jobs through their choices in the four parts of the job satisfaction scale. Further investigations are needed to understand different contributing factors to job satisfaction and burnout among healthcare providers in KRI. The current study might highlight the importance of understanding the healthcare providers’ perspectives on their careers. Full article

Transcutaneous auricular vagus nerve stimulation was recently reported to have a therapeutic potential for functional dyspepsia (FD). This study aimed to explore the integrative effects and mechanisms of auricular vagus nerve stimulation (aVNS) in a rodent model of FD. Methods: We evaluated the effects of aVNS on visceral hypersensitivity, gastric motility and open field test (OFT) activity in iodoacetamide (IA)-treated rats. The autonomic function was assessed; blood samples and tissues were collected and analyzed by an enzyme-linked immunosorbent assay and western blot. Vagotomy was performed to investigate the role of vagal efferent nerve. Results: aVNS reduced the electromyography response to gastric distension, improved gastric emptying and increased the horizontal and vertical motion scores of the OFT in IA-treated rats. The sympathovagal ratio was increased in IA-treated rats but normalized with aVNS. The serum cytokines TNF-α, IL-6, IL-1β and NF-κBp65 were increased in IA-treated rats and decreased with aVNS. The hypothalamus–pituitary–adrenal axis was hyperactive in IA-treated rats but inhibited by aVNS. The expression of duodenal desmoglein 2 and occludin were all decreased in IA-treated rats and increased with aVNS but not sham-aVNS. Vagotomy abolished the ameliorating effects of aVNS on gastric emptying, horizontal motions, serum TNF-α and duodenal NF-κBp65. Conclusion: aVNS improves gastric motility and gastric hypersensitivity probably by anti-inflammatory mechanisms via the vago-vagal pathways. A better understanding on the mechanisms of action involved with aVNS would lead to the optimization of the taVNS methodology and promote taVNS as a non-pharmacological alternative therapy for FD. Full article

The extent of resection beyond the enhancing core (EC) in glioblastoma IDH-wild type (GBM, IDHwt) is one of the most debated topics in neuro-oncology. Indeed, it has been demonstrated that local disease recurrence often arises in peritumoral areas and that radiologically-defined FLAIR hyperintensity areas of GBM IDHwt are often visible beyond the conventional EC. Therefore, the need to extend the surgical resection also to the FLAIR hyperintensity areas is a matter of debate. Since little is known about the histological composition of FLAIR hyperintensity regions, in this study we aimed to provide a comprehensive description of the histological features of EC and FLAIR hyperintensity regions sampled intraoperatively using neuronavigation and 5-aminolevulinic acid (5-ALA) fluorescence, in 33 patients with GBM, IDHwt. Assessing a total 109 histological samples, we found that FLAIR areas consisted in: (i) fragments of white matter focally to diffusely infiltrated by tumor cells in 76% of cases; (ii) a mixture of white matter with reactive astrogliosis and grey matter with perineuronal satellitosis in 15% and (iii) tumor tissue in 9%. A deeper knowledge of the histology of FLAIR hyperintensity areas in GBM, IDH-wt may serve to better guide neurosurgeons on the choice of the most appropriate surgical approach in patients with this neoplasm. Full article

Intellectual disability (ID) has a prevalence of ~2–3% in the general population, having a large societal impact. The underlying cause of ID is largely of genetic origin; however, identifying this genetic cause has in the past often led to long diagnostic Odysseys. Over the past decades, improvements in genetic diagnostic technologies and strategies have led to these causes being more and more detectable: from cytogenetic analysis in 1959, we moved in the first decade of the 21st century from genomic microarrays with a diagnostic yield of ~20% to next-generation sequencing platforms with a yield of up to 60%. In this review, we discuss these various developments, as well as their associated challenges and implications for the field of ID, which highlight the revolutionizing shift in clinical practice from a phenotype-first into genotype-first approach. Full article

Caffeine substantially affects cardiovascular functioning, yet wide variability exists in caffeine control procedures in cardiovascular reactivity research. This study was conducted in order to identify a minimal abstention duration in habitual coffee consumers whereby cardiovascular reactivity is unconfounded by caffeine; Six hours (caffeine’s average half-life) was hypothesized. Thirty-nine subjects (mean age: 20.9; 20 women) completed a repeated measures study involving hand cold pressor (CP) and memory tasks. Caffeinated and decaffeinated coffee were administered. The following cardiovascular indices were acquired during pre-task, task, and post-task epochs prior to coffee intake, 30 min-, and six hours post-intake: Heart rate (HR), high-frequency heart rate variability (HF-HRV), root mean squared successive differences (RMSSD), systolic and diastolic blood pressures (SBP, DBP), mean arterial pressure (MAP), pre-ejection period (PEP), left ventricular ejection time (LVET), systemic vascular resistance (SVR), systemic vascular resistance index (SVRI). Results support the adequacy of a six-hour abstention in controlling for caffeine-elicited cardiovascular changes. The current study offers a suggested guideline for caffeine abstention duration in cardiovascular research in psychophysiology. Consistent practice in caffeine abstention protocols would promote validity and reliability across such studies. Full article

The impact of cognitive impairments on the health-related quality of life (HRQoL) in individuals with schizophrenia is unclear. The aim of this study was to examine the association between cognitive impairments and HRQoL in individuals with schizophrenia. A total of 609 individuals with schizophrenia were assessed on the Positive and Negative Syndrome Scale (PANSS) and a neurocognitive battery which comprised of the Wechsler Abbreviated Scale of Intelligence matrix reasoning, the Benton Judgment of Line Orientation Test, Continuous Performance Tests-Identical Pairs, and the Brief Assessment of Cognition in Schizophrenia. A cognitive factor g was derived from the neurocognitive battery. EuroQol five-dimensional (EQ-5D-5L) utility scores were derived from PANSS scores via a previously validated algorithm and used as a measure of HRQoL. Hierarchical multiple regression was conducted to examine the association between cognitive factor g and the EQ-5D-5L. Cognitive factor g (β = 0.189, t = 4.956, p < 0.001) was found to be significantly associated with EQ-5D-5L scores. Age (β = −0.258, t = −6.776, p < 0.001), sex (β = 0.081, t = 2.117, p = 0.035), and being employed (β = 0.091, t = 2.317, p = 0.021) were also significant predictors of EQ-5D-5L. Our results add to the extant literature on the burden cognitive impairments exact in individuals with schizophrenia. More research is needed to develop effective interventions for cognitive impairments in schizophrenia. Full article

Glioblastoma multiforme (GBM) represents the most common and aggressive central nervous system tumor associated with a poor prognosis. The aim of this study was to depict the role of intraoperative imaging techniques in GBM surgery and how they can ensure the maximal extent of resection (EOR) while preserving the functional outcome. The authors conducted a systematic review following PRISMA guidelines on the PubMed/Medline and Scopus databases. A total of 1747 articles were identified for screening. Studies focusing on GBM-affected patients, and evaluations of EOR and functional outcomes with the aid of advanced image-guided techniques were included. The resulting studies were assessed for methodological quality using the Risk of Bias in Systematic Review tool. Open Science Framework registration DOI 10.17605/OSF.IO/3FDP9. Eighteen studies were eligible for this systematic review. Among the selected studies, eight analyzed Sodium Fluorescein, three analyzed 5-aminolevulinic acid, two evaluated IoMRI imaging, two evaluated IoUS, and three evaluated multiple intraoperative imaging techniques. A total of 1312 patients were assessed. Gross Total Resection was achieved in the 78.6% of the cases. Follow-up time ranged from 1 to 52 months. All studies assessed the functional outcome based on the Karnofsky Performance Status scale, while one used the Neurologic Assessment in Neuro-Oncology score. In 77.7% of the cases, the functional outcome improved or was stable over the pre-operative assessment. Combining multiple intraoperative imaging techniques could provide better results in GBM surgery than a single technique. However, despite good surgical outcomes, patients often present a neurocognitive decline leading to a marked deterioration of the quality of life. Advanced intraoperative image-guided techniques can allow a better understanding of the anatomo-functional relationships between the tumor and the surrounding brain, thus maximizing the EOR while preserving functional outcomes. Full article

Despite proving its usefulness for over a century, the concept of developmental dyslexia (DD) is currently in severe disarray because of the recent introduction of the phonological theory of its causation. Since mastering the phonological principle is essential for all reading, failure to do so cannot be used to distinguish DD from the many other causes of such failure. To overcome this problem, many new psychological, signal detection, and neurological theories have been introduced recently. All these new theories converge on the idea that DD is fundamentally caused by impaired signalling of the timing of the visual and auditory cues that are essential for reading. These are provided by large ‘magnocellular’ neurones which respond rapidly to sensory transients. The evidence for this conclusion is overwhelming. Especially convincing are intervention studies that have shown that improving magnocellular function improves dyslexic children’s reading, together with cohort studies that have demonstrated that the magnocellular timing deficit is present in infants who later become dyslexic, long before they begin learning to read. The converse of the magnocellular deficit in dyslexics may be that they gain parvocellular abundance. This may often impart the exceptional ‘holistic’ talents that have been ascribed to them and that society needs to nurture. Full article

To date, the relationship between central hallmarks of multiple sclerosis (MS), such as white matter (WM)/cortical demyelinated lesions and cortical gray matter atrophy, remains unclear. We investigated the interplay between cortical atrophy and individual lesion-type patterns that have recently emerged as new radiological markers of MS disease progression. We employed a machine learning model to predict mean cortical thinning in whole-brain and single hemispheres in 150 cortical regions using demographic and lesion-related characteristics, evaluated via an ultrahigh field (7 Tesla) MRI. We found that (i) volume and rimless (i.e., without a “rim” of iron-laden immune cells) WM lesions, patient age, and volume of intracortical lesions have the most predictive power; (ii) WM lesions are more important for prediction when their load is small, while cortical lesion load becomes more important as it increases; (iii) WM lesions play a greater role in the progression of atrophy during the latest stages of the disease. Our results highlight the intricacy of MS pathology across the whole brain. In turn, this calls for multivariate statistical analyses and mechanistic modeling techniques to understand the etiopathogenesis of lesions. Full article

Sleep disturbances are the most prevalent non-motor symptoms in the preclinical stage of Parkinson’s disease (PD). Adenosine, glial-derived neurotrophic factor (GDNF), and associated neurotransmitters are crucial in the control of sleep arousal. This study aimed to detect the serum levels of adenosine, GDNF, and associated neurotransmitters and explored their correlations with PD with sleep disorders. Demographic characteristics and clinical information of PD patients and healthy participants were assessed. Serum concentrations of adenosine, GDNF, and related neurotransmitters were detected by ELISA and LC-MS. The correlation between serum levels of adenosine, GDNF, and associated neurotransmitters and sleep disorders was explored using logistic regression. PD patients with sleep disorders had higher scores of HAMA, HAMD, ESS, UPDRS-III, and H-Y stage. Lower levels of adenosine, GDNF, and γ-GABA were observed in PD patients who had sleep problems. Logistic regression analysis showed adenosine and GDNF were protective factors for preventing sleep disorders. Adenosine combined with GDNF had a higher diagnostic efficiency in predicting PD with sleep disorders by ROC analysis. This study revealed low adenosine and GDNF levels may be risk factors for sleep disorders in PD. The decrease of serum adenosine and GDNF levels may contribute to the diagnosis of PD with sleep disturbances. Full article

Adolescent behavior is closely related to academic and long-term personal development, and adolescents are vulnerable to the influences from people around them. This study aimed to analyze the factors and mechanisms that influence the behavior of adolescents. It examines the impact of family, teachers, and peers on adolescent prosocial behavior and misconduct. Data were obtained from the China Education Panel Survey (CEPS) follow-up data (2014–2015 school year) and 7835 middle school student participants were used for analysis. Structural equation modeling (SEM) was used to explore the influence and mechanisms of family, teachers, and peers on the development of adolescent social behavior. The findings showed that parental relationships, parental discipline, teacher supervision, and positive peer behavior were positively associated with adolescent prosocial behaviors and reduced the incidence of delinquent behaviors, while frequent home–school contact was associated with misconduct (all p < 0.01). These results remained significant after controlling for gender, residence, only-child status, family financial situation, and paternal education. Significant others in an adolescent’s life play multiple essential roles in forming and developing adolescent behavior and in directly influencing them. To guide the prosocial behaviors of middle school students and reduce delinquent behavior, we should build harmonious parent—child, peer, and teacher–student relationships, teach according to their aptitudes, pay attention to particular groups and strengthen psychological health education to develop their self-esteem and self-confidence. Full article

A central tenet of network science states that the structure of the network influences processing. In this study of a phonological network of English words we asked: how does damage alter the network structure (Study 1)? How does the damaged structure influence lexical processing (Study 2)? How does the structure of the intact network “protect” processing with a less efficient algorithm (Study 3)? In Study 1, connections in the network were randomly removed to increasingly damage the network. Various measures showed the network remained well-connected (i.e., it is resilient to damage) until ~90% of the connections were removed. In Study 2, computer simulations examined the retrieval of a set of words. The performance of the model was positively correlated with naming accuracy by people with aphasia (PWA) on the Philadelphia Naming Test (PNT) across four types of aphasia. In Study 3, we demonstrated another way to model developmental or acquired disorders by manipulating how efficiently activation spread through the network. We found that the structure of the network “protects” word retrieval despite decreases in processing efficiency; words that are relatively easy to retrieve with efficient transmission of priming remain relatively easy to retrieve with less efficient transmission of priming. Cognitive network science and computer simulations may provide insight to a wide range of speech, language, hearing, and cognitive disorders. Full article

Background: The thalamus has been reported to be associated with pain modulation and processing. However, the functional changes that occur in the thalamus of vestibular migraine (VM) patients remain unknown. Methods: In total, 28 VM patients and 28 healthy controls who were matched for age and sex underwent resting-state functional magnetic resonance imaging. They also responded to standardized questionnaires aimed at assessing the clinical features associated with migraine and vertigo. Differences in the amplitude of low-frequency fluctuation (ALFF) were analyzed and brain regions with altered ALFF in the two groups were used for further analysis of whole-brain functional connectivity (FC). The relationship between clusters and clinical features was investigated by correlation analyses. Results: The ALFF in the thalamus was significantly decreased in the VM group versus the control group. In the VM group, the ALFF in the left thalamus negatively correlated with VM episode frequency. Furthermore, the left thalamus showed significantly weaker FC than both regions of the medial prefrontal cortex, both regions of the anterior cingulum cortex, the left superior/middle temporal gyrus, and the left temporal pole in the VM group. Conclusions: The thalamus plays an important role in VM patients and it is suggested that connectivity abnormalities of the thalamocortical region contribute to abnormal pain information processing and modulation, transmission, and multisensory integration in patients with VM. Full article

Gastrodin is the active ingredient in Gastrodia elata. Our previous studies demonstrated that gastrodin ameliorated cerebral ischemia–reperfusion and hypoperfusion injury and improved cognitive deficit in Alzheimer’s disease. This study aims to examine the effects of gastrodin on REM sleep deprivation in rats. Gastrodin (100 and 150 mg/kg) was orally administered for 7 consecutive days before REM sleep deprivation. Seventy-two hours later, pentobarbital-induced sleep tests and a Morris water maze were performed to measure REM sleep quality and learning and memory ability. Histopathology was observed with hematoxylin–eosin staining, and the expression of the NF-κB and Wnt/β-catenin signaling pathways was examined using Western blot. After REM sleep deprivation, sleep latency increased and sleep duration decreased, and the ability of learning and memory was impaired. Neurons in the hippocampal CA1 region and the cortex were damaged. Gastrodin treatment significantly improved REM sleep-deprivation-induced sleep disturbance, cognitive deficits and neuron damage in the hippocampus CA1 region and cerebral cortex. A mechanism analysis revealed that the NF-κB pathway was activated and the Wnt/β-catenin pathway was inhibited after REM sleep deprivation, and gastrodin ameliorated these aberrant changes. Gastrodin improves REM sleep-deprivation-induced sleep disturbance and cognitive dysfunction by regulating the TLR4/NF-κB and Wnt/β-catenin signaling pathways and can be considered a potential candidate for the treatment of REM sleep deprivation. Full article

Schizophrenia is a chronic, invalidating, and polymorphic disease, characterized by relapses and remission periods. The main treatment option in schizophrenia are antipsychotics, administered as an oral or as a long-acting injectable (LAI) formulation. Although international guidelines rarely recommend it, mood stabilizers (MS) and/or benzodiazepines (BZD) are frequently prescribed as adjunctive therapy in schizophrenia patients for various reasons. This is an observational, cross-sectional study including stabilized schizophrenia patients. A total of 315 patients were enrolled. Of these, 77 patients (24.44%) were stabilized on LAIs and 238 (75.56%) patients on oral antipsychotics (OAP). Eighty-four patients (26.66%) had concomitant treatment with MS and 119 patients (37.77%) had concomitant benzodiazepine treatment. No statistical significance was observed in MS or BZD use between LAIs and OAPs. In total, 136 patients (43.17%) were stabilized on antipsychotic monotherapy. Our study shows that the long-term use of benzodiazepines and mood stabilizers remains elevated among stabilized schizophrenia patients, regardless of the antipsychotic formulation (oral or LAI). Patients receiving second-generation LAI antipsychotics (SGA-LAI) seem to be more likely to be stabilized on monotherapy compared to those receiving oral antipsychotics. Further randomized controlled trials are necessary in order to clarify the benefits of the current drug polypharmacy trends. Full article

Parkinson’s disease (PD) is a common progressive neurodegenerative disorder. Various evidence has revealed the possible penetration of peripheral immune cells in the substantia nigra, which may be essential for PD. Our study uses machine learning (ML) to screen for potential PD genetic biomarkers. Gene expression profiles were screened from the Gene Expression Omnibus (GEO). Differential expression genes (DEGs) were selected for the enrichment analysis. A protein–protein interaction (PPI) network was built with the STRING database (Search Tool for the Retrieval of Interacting Genes), and two ML approaches, namely least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE), were employed to identify candidate genes. The external validation dataset further tested the expression degree and diagnostic value of candidate biomarkers. To assess the validity of the diagnosis, we determined the receiver operating characteristic (ROC) curve. A convolution tool was employed to evaluate the composition of immune cells by CIBERSORT, and we performed correlation analyses on the basis of the training dataset. Twenty-seven DEGs were screened in the PD and control samples. Our results from the enrichment analysis showed a close association with inflammatory and immune-associated diseases. Both the LASSO and SVM algorithms screened eight and six characteristic genes. AGTR1, GBE1, TPBG, and HSPA6 are overlapping hub genes strongly related to PD. Our results of the area under the ROC (AUC), including AGTR1 (AUC = 0.933), GBE1 (AUC = 0.967), TPBG (AUC = 0.767), and HSPA6 (AUC = 0.633), suggested that these genes have good diagnostic value, and these genes were significantly associated with the degree of immune cell infiltration. AGTR1, GBE1, TPBG, and HSPA6 were identified as potential biomarkers in the diagnosis of PD and provide a novel viewpoint for further study on PD immune mechanism and therapy. Full article

Short sleep is a common issue nowadays. The purpose of this study was to investigate prefrontal cortical hemodynamics by evaluating changes in concentrations of oxygenated hemoglobin (HbO) in cognitive tests among short-sleep young adults and to explore the relationship between sleep duration, physical activity level, and cognitive function in this specific population. A total of 46 participants (25 males and 21 females) were included in our study, and among them, the average sleep duration was 358 min/day. Stroop performance in the short sleep population was linked to higher levels cortical activation in distinct parts of the left middle frontal gyrus. This study found that moderate-to-vigorous physical activity (MVPA) was significantly associated with lower accuracy of incongruent Stroop test. The dose-response relationship between sleep duration and Stroop performance under different levels of light-intensity physical activity (LPA) and MVPA was further explored, and increasing sleep time for different PA level was associated with better Stroop performance. In summary, this present study provided neurobehavioral evidence between cortical hemodynamics and cognitive function in the short sleep population. Furthermore, our findings indicated that, in younger adults with short sleep, more MVPA was associated with worse cognitive performance. Short sleep young adults should increase sleep time, rather than more MVPA, to achieve better cognitive function. Full article

Background: Antibodies against acetylcholine receptors (AChRs) can also target nicotinic AChRs that are present throughout the central nervous system, thus leading to cognitive dysfunctions in patients with myasthenia gravis (MG). However, the presence of cognitive impairment in MG is controversial, and the factors that may influence this risk are almost completely unknown. In this study, the frequency of mild cognitive impairment (MCI) in MG, as well as the clinical, immunological, and behavioral correlates of MCI in MG were evaluated. Methods: A total of 52 patients with MG underwent a comprehensive assessment including motor and functional scales, serological testing, and neuropsychological and behavioral evaluation. Results: The frequency of MCI was 53.8%, and the most impaired cognitive domains were, in order, visuoconstructive/visuospatial skills, memory, and attention. After multivariate analysis, only pyridostigmine use was inversely associated with the presence of MCI, while a trend toward a positive association between MCI and disease severity and arms/legs hyposthenia was found. Correlation analyses showed that daily doses of prednisone and azathioprine significantly correlated with depressive symptomatology, while disease severity significantly correlated with depressive symptomatology and sleep disturbance. Conclusions: The presence of MCI is rather frequent in MG and is characterized by multidomain amnestic impairment. Such preliminary data need further confirmation on larger case series. Full article

Brain-derived neurotrophic factor (BDNF) belongs to the family of neurotrophins, which are growth factors with trophic effects on neurons. BDNF is the most widely distributed neurotrophin in the central nervous system (CNS) and is highly expressed in the prefrontal cortex (PFC) and hippocampus. Its distribution outside the CNS has also been demonstrated, but most studies have focused on its effects in neuropsychiatric disorders. Despite the advances in medicine in recent decades, neurological and psychiatric diseases are still characterized by high drug resistance. This review focuses on the use of BDNF in the developmental assessment, treatment monitoring, and pharmacotherapy of selected diseases, with a particular emphasis on epilepsy, depression, anorexia, obesity, schizophrenia, and Alzheimer’s disease. The limitations of using a molecule with such a wide distribution range and inconsistent method of determination are also highlighted. Full article

Background: Existing studies indicate that some computed tomography perfusion (CTP) parameters may predict hemorrhagic transformation (HT) after acute ischemic stroke (AIS), but there is an inconsistency in the conclusions alongside a lack of comprehensive comparison. Objective: To comprehensively evaluate the predictive value of CTP parameters in HT after AIS. Data sources: A systematical literature review of existing studies was conducted up to 1st October 2022 in six mainstream databases that included original data on the CTP parameters of HT and non-HT groups or on the diagnostic performance of relative cerebral blood flow (rCBF), relative permeability-surface area product (rPS), or relative cerebral blood volume (rCBV) in patients with AIS that completed CTP within 24 h of onset. Data Synthesis: Eighteen observational studies were included. HT and non-HT groups had statistically significant differences in CBF, CBV, PS, rCBF, rCBV, and rPS (p < 0.05 for all). The hierarchical summary receiver operating characteristic (HSROC) revealed that rCBF (area under the curve (AUC) = 0.9), rPS (AUC = 0.89), and rCBV (AUC = 0.85) had moderate diagnostic performances in predicting HT. The pooled sensitivity and specificity of rCBF were 0.85 (95% CI, 0.75–0.91) and 0.83 (95% CI, 0.63–0.94), respectively. Conclusions: rCBF, rPS, and rCBV had moderate diagnostic performances in predicting HT, and rCBF had the best pooled sensitivity and specificity. Full article

Chronic pain burdens patients and healthcare systems worldwide. Pain control remains urgently required. IL-17 (interleukin-17)-mediated neuroinflammation is of unique importance in spinal nociceptive transduction in pathological pain development. Recently, resolvin D2 (RvD2), as a bioactive, specialized pro-resolving mediator derived from docosahexaenoic acid, exhibits potent resolution of inflammation in several neurological disorders. This preclinical study evaluates the therapeutic potential and underlying targets of RvD2 in two mouse models of chronic pain, including sciatic nerve ligation-caused neuropathic pain and sarcoma-caused bone cancer pain. Herein, we report that repetitive injections of RvD2 (intrathecal, 500 ng) reduce the initiation of mechanical allodynia and heat hyperalgesia following sciatic nerve damage and bone cancer. Single exposure to RvD2 (intrathecal, 500 ng) attenuates the established neuropathic pain and bone cancer pain. Furthermore, systemic RvD2 (intravenous, 5 μg) therapy is effective in attenuating chronic pain behaviors. Strikingly, RvD2 treatment suppresses spinal IL-17 overexpression, chemokine CXCL1 release and astrocyte activation in mice undergoing sciatic nerve trauma and bone cancer. Pharmacological neutralization of IL-17 ameliorates chronic neuropathic pain and persistent bone cancer pain, as well as reducing spinal CXCL1 release. Recombinant IL-17-evoked acute pain behaviors and spinal CXCL1 release are mitigated after RvD2 administration. In addition, RvD2 treatment dampens exogenous CXCL1-caused transient pain phenotypes. Overall, these current findings identify that RvD2 therapy is effective against the initiation and persistence of long-lasting neuropathic pain and bone cancer pain, which may be through spinal down-modulation of IL-17 secretion, CXCL1 release and astrocyte activation. Full article

Synucleinopathies are a group of neurodegenerative diseases with common pathological lesions associated with the excessive accumulation and abnormal intracellular deposition of toxic species of α-synuclein. The shared clinical features are chronic progressive decline of motor, cognitive, and behavioral functions. These disorders include Parkinson’s disease, dementia with Lewy body, and multiple system atrophy. Vigorous research in the mechanisms of pathology of these illnesses is currently under way to find disease-modifying treatment and molecular markers for early diagnosis. α-Synuclein is a prone-to-aggregate, small amyloidogenic protein with multiple roles in synaptic vesicle trafficking, neurotransmitter release, and intracellular signaling events. Its expression is controlled by several mechanisms, one of which is epigenetic regulation. When transmitted to the nucleus, α-synuclein binds to DNA and histones and participates in epigenetic regulatory functions controlling specific gene transcription. Here, we discuss the various aspects of α-synuclein involvement in epigenetic regulation in health and diseases. Full article

Neurodegenerative diseases (ND) include a wide range of conditions that result from progressive damage to the neurons. Alzheimer’s disease (AD) is one of the most common NDs, and neuroinflammation and oxidative stress (OS) are the major factors in the development and progression of the disease. Many naturally occurring phytochemical compounds exhibit antioxidant and anti-inflammatory activities with potential neuroprotective effects. Several plant species, including Alpinia katsumadai and Alpinia conchigera, contain cardamonin (CD). CD (2′,4′-dihydroxy-6′methoxychalcone) has many therapeutic properties, including anticancer, anti-inflammatory, antioxidant, antiviral, and antibiotic activities. CD is a potent compound that can reduce OS and modulate the inflammatory processes that play a significant part in developing neurodegenerative diseases. CD has been shown to modulate a variety of signaling molecules involved in the development and progression of ND, including transcription factors (NF-kB and STAT3), cytokines (TNF-α, IL-1, and IL-6), enzymes (COX-2, MMP-9, and ALDH1), and other proteins and genes (Bcl-2, XIAP, and cyclin D1). Additionally, CD effectively modulates miRNA levels and autophagy-related CD-protective mechanisms against neurodegeneration. In summary, this review provides mechanistic insights into CD’s ability to modify multiple oxidative stress–antioxidant system pathways, Nrf2, and neuroinflammation. Additionally, it points to the possible therapeutic potential and preventive utilization of CD in neurodegenerative diseases, most specifically AD. Full article

Psychotic treatment-resistant depression is a complex and challenging manifestation of mood disorders in the clinical setting. Psychotic depression is a subtype of major depressive disorder characterized by mood-consistent hallucinations and/or delusions. Psychotic depression is often underdiagnosed and undertreated. Ketamine appears to have rapid and potent antidepressant effects in clinical studies, and the Federal Drug Agency approved the use of ketamine enantiomer esketamine-nasal spray for treatment-resistant depression pharmacotherapy in 2019. This study aimed to assess the usage of ketamine for major depressive disorder with psychotic features as an add-on treatment to the standard of care. Here we present four inpatients suffering from treatment-resistant depression with psychotic features, including one with severe suicidal crisis, all treated with 0.5 mg/kg intravenous infusion of ketamine. Subsequent monitoring revealed no exacerbation of psychotic symptoms in short and long-term observation, while stable remission was observed in all cases with imminent antisuicidal effect. Results suggest ketamine may benefit individuals with treatment-resistant depression with psychotic features. Full article

Stroke is a massive public health problem. The rupture of vulnerable carotid atherosclerotic plaques is the most common cause of acute ischemic stroke (AIS) across the world. Currently, vessel wall high-resolution magnetic resonance imaging (VW-HRMRI) is the most appropriate and cost-effective imaging technique to characterize carotid plaque vulnerability and plays an important role in promoting early diagnosis and guiding aggressive clinical therapy to reduce the risk of plaque rupture and AIS. In recent years, great progress has been made in imaging research on vulnerable carotid plaques. This review summarizes developments in the imaging and hemodynamic characteristics of vulnerable carotid plaques on the basis of VW-HRMRI and four-dimensional (4D) flow MRI, and it discusses the relationship between these characteristics and ischemic stroke. In addition, the applications of artificial intelligence in plaque classification and segmentation are reviewed. Full article

Brain-computer interface (BCI) can be used as a real-time bidirectional information gateway between the brain and machines. In particular, rapid progress in invasive BCI, propelled by recent developments in electrode materials, miniature and power-efficient electronics, and neural signal decoding technologies has attracted wide attention. In this review, we first introduce the concepts of neuronal signal decoding and encoding that are fundamental for information exchanges in BCI. Then, we review the history and recent advances in invasive BCI, particularly through studies using neural signals for controlling external devices on one hand, and modulating brain activity on the other hand. Specifically, regarding modulating brain activity, we focus on two types of techniques, applying electrical stimulation to cortical and deep brain tissues, respectively. Finally, we discuss the related ethical issues concerning the clinical application of this emerging technology. Full article

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder that interferes with normal brain development. Brain connectivity may serve as a biomarker for ASD in this respect. This study enrolled a total of 179 children aged 3−10 years (90 typically developed (TD) and 89 with ASD). We used a weighted phase lag index and a directed transfer function to investigate the functional and effective connectivity in children with ASD and TD. Our findings indicated that patients with ASD had local hyper-connectivity of brain regions in functional connectivity and simultaneous significant decrease in effective connectivity across hemispheres. These connectivity abnormalities may help to find biomarkers of ASD. Full article

One of the most visible effects of aging, even in healthy, normal aging, is a decline in motor performance. The range of strategies applicable to counteract this deterioration has increased. Transcranial direct current stimulation (tDCS), a non-invasive brain stimulation technique that can promote neuroplasticity, has recently gained attention. However, knowledge about optimized tDCS parameters in the elderly is limited. Therefore, in this study, we investigated the effect of different anodal tDCS intensities on motor sequence learning in the elderly. Over the course of four sessions, 25 healthy older adults (over 65 years old) completed the Serial Reaction Time Task (SRTT) while receiving 1, 2, or 3 mA of anodal or sham stimulation over the primary motor cortex (M1). Additionally, 24 h after stimulation, motor memory consolidation was assessed. The results confirmed that motor sequence learning in all tDCS conditions was maintained the following day. While increased anodal stimulation intensity over M1 showed longer lasting excitability enhancement in the elderly in a prior study, the combination of higher intensity stimulation with an implicit motor learning task showed no significant effect. Future research should focus on the reason behind this lack of effect and probe alternative stimulation protocols. Full article

Lithium has been a cornerstone treatment for bipolar disorder (BD). Despite descriptions in the literature regarding associations between long-term lithium therapy (LTLT) and development of a thyroid disorder (overt/subclinical hypo/hyperthyroidism, thyroid nodule, and goiter) in BD, factors such as time to onset of thyroid abnormalities and impact on clinical outcomes in the course of illness have not been fully characterized. In this study we aimed to compare clinical characteristics of adult BD patients with and without thyroid disorders who were on LTLT. We aimed to identify the incidence of thyroid disorders in patients with BD on LTLT and response to lithium between patients with and without thyroid disorders in BD. The Cox proportional model was used to find the median time to the development of a thyroid disorder. Our results showed that up to 32% of patients with BD on LTLT developed a thyroid disorder, of which 79% developed hypothyroidism, which was corrected with thyroid hormone replacement. We did not find significant differences in lithium response between patients with or without thyroid disorders in BD. Findings from this study suggest that patients with BD and comorbid thyroid disorders when adequately treated have a response to lithium similar to patients with BD and no thyroid disorders. Full article

Background: The neuroinflammation of the central nervous system (CNS) is a prevalent syndrome of brain dysfunction secondary to severe sepsis and is regulated by microglia. Triggering the receptor expressed on myeloid cells 2 (TREM2) is known to have protective functions that modulate the microglial polarization of M2 type to reduce inflammatory responses, thereby improving cognition. Methods: We examined the effect of TREM2 on the polarization state of microglia during the progression of neuroinflammation. After consecutive intraperitoneal injections of lipopolysaccharide for 7 days, we evaluated the inflammation of a septic mice model by hematoxylin–eosin (H&E) and electron microscopy, and we used immunofluorescence (IF) assays and Western blotting to visualize hippocampal sections in C57BL/6 mice to assess TREM2 expression. In addition, we analyzed the state of microglia polarization with quantitative RT-PCR. Result: The consecutive injection of LPS for 4 days elevated systemic inflammation and caused behavioral cognitive dysfunction in the septic model. However, on Day 7, the neuroinflammation was considerably attenuated. Meanwhile, TREM2 decreased on Day 4 and increased on Day 7 in vivo. Consistently, LPS could reduce the expression of TREM2 while IFN-β enhanced TREM2 expression in vitro. TREM2 regulated the microglial M1 phenotype’s conversion to the M2 phenotype. Conclusion: Our aim in this study was to investigate the interconnection between microglia polarization and TREM2 in neuroinflammation. Our results suggested that IFN-β could modulate TREM2 expression to alter the polarization state of microglia, thereby reducing LPS-induced neuroinflammation. Therefore, TREM2 is a novel potential therapeutic target for neuroinflammation. Full article

Resting state networks comprise several brain regions that exhibit complex patterns of interaction. Switching from eyes closed (EC) to eyes open (EO) during the resting state modifies these patterns of connectivity, but precisely how these change remains unclear. Here we use functional magnetic resonance imaging to scan healthy participants in two resting conditions (viz., EC and EO). Seven resting state networks were chosen for this study: salience network (SN), default mode network (DMN), central executive network (CEN), dorsal attention network (DAN), visual network (VN), motor network (MN) and auditory network (AN). We performed functional connectivity (FC) analysis for each network, comparing the FC maps for both EC and EO. Our results show increased connectivity between most networks during EC relative to EO, thereby suggesting enhanced integration during EC and greater modularity or specialization during EO. Among these networks, SN is distinctive: during the transition from EO to EC it evinces increased connectivity with DMN and decreased connectivity with VN. This change might imply that SN functions in a manner analogous to a circuit switch, modulating resting state relations with DMN and VN, when transitioning between EO and EC. Full article

(1) Background: Children can develop cognitive and social skills during play. Most research has focused on mothers, but the paternal features in interaction with children with autism spectrum disorder (ASD) are mainly unexplored. This study aimed to compare fathers’ and mothers’ interactive behaviors with their children with ASD to identify similarities and differences during playful exchanges. (2) Methods: A total of 72 mothers and 72 fathers of paired children with ASD (chronological age: M = 44.61 months; SD = 13.37) took part in this study. Data were collected during 10 min of video-recorded semi-structured interactions with mothers and fathers separately in interaction with their children. (3) Results: Mothers showed more symbolic play (W = 3537; p < 0.001) than fathers, who displayed higher levels of exploratory play (t(139.44) = −2.52; p = 0.013) compared to mothers. However, child cognitive functioning impacts maternal play but not the father’s play characteristics. (4) Conclusions: Highlighting mother–child and father–child features may have important service delivery implications for implementing personalized parental-based interventions based on the strengths and weaknesses of both caregivers in a complementary system. Full article

Suicide ideation and behaviors are major health issues in the field of mental health. Several psychological and psychosocial factors have been taken into account as possible predictors of suicidality. Only recently affective temperaments have been considered as possible factors linked to suicide. This study aims to investigate the relationship between affective temperaments and suicidality, including the lifetime onset of suicide ideation, lifetime presence of suicide attempts and the total number of lifetime suicide attempts. This is a naturalistic multicentric observational study, involving outpatient units of seven University sites in Italy. Patients were administered with the short version of TEMPS-M and the Columbia Suicide Severity Rating Scale. A total of 653 participants were recruited, with a diagnosis of bipolar (55.7%), unipolar (35.8%) and cyclothymic disorder (8.4%). Regression models showed that the presence of lifetime suicide behaviors was increased in patients presenting trait related impulsivity (p < 0.0001), poor free-interval functioning (p < 0.05), higher number of affective episodes (p < 0.01), higher number of hospitalizations (p < 0.0001), cyclothymic and irritable affective temperaments (p < 0.05 and p < 0.05, respectively). Conversely, the presence of hyperthymic affective disposition reduced the likelihood of having suicidal behaviors (p < 0.01). Lifetime suicidal ideation was associated with trait-related impulsivity (p < 0.001), poor free-interval functioning (p < 0.05), higher number of affective episodes (p < 0.001) and of hospitalizations (p < 0.001). Depressive temperaments increased the likelihood of presenting suicidal ideation (p < 0.05), along with irritable temperaments (p < 0.01), contrary to hyperthymic affective (p < 0.05). Results of the present study confirm that affective disposition has a significant impact on the onset of suicidal ideation and behaviors, and that affective dispositions should be assessed in clinical settings to identify people at risk of suicide. Moreover, a wider clinical evaluation, including different clinical psychopathological dimensions, should be taken into consideration to develop effective preventive interventions. Full article

Nonspeech (or paraspeech) parameters are widely used in clinical assessment of speech impairment in persons with dysarthria (PWD). Virtually every standard clinical instrument used in dysarthria diagnostics includes nonspeech parameters, often in considerable numbers. While theoretical considerations have challenged the validity of these measures as markers of speech impairment, only a few studies have directly examined their relationship to speech parameters on a broader scale. This study was designed to investigate how nonspeech parameters commonly used in clinical dysarthria assessment relate to speech characteristics of dysarthria in individuals with movement disorders. Maximum syllable repetition rates, accuracies, and rates of isolated and repetitive nonspeech oral–facial movements and maximum phonation times were compared with auditory–perceptual and acoustic speech parameters. Overall, 23 diagnostic parameters were assessed in a sample of 130 patients with movement disorders of six etiologies. Each variable was standardized for its distribution and for age and sex effects in 130 neurotypical speakers. Exploratory Graph Analysis (EGA) and Confirmatory Factor Analysis (CFA) were used to examine the factor structure underlying the diagnostic parameters. In the first analysis, we tested the hypothesis that nonspeech parameters combine with speech parameters within diagnostic dimensions representing domain–general motor control principles. In a second analysis, we tested the more specific hypotheses that diagnostic parameters split along effector (lip vs. tongue) or functional (speed vs. accuracy) rather than task boundaries. Our findings contradict the view that nonspeech parameters currently used in dysarthria diagnostics are congruent with diagnostic measures of speech characteristics in PWD. Full article

Background: Balance impairment is a common disability in post-stroke survivors, leading to reduced mobility and increased fall risk. Robotic gait training (RAGT) is largely used, along with traditional training. There is, however, no strong evidence about RAGT superiority, especially on balance. This study aims to determine RAGT efficacy on balance of post-stroke survivors. Methods: PubMed, Cochrane Library, and PeDRO databases were investigated. Randomized clinical trials evaluating RAGT efficacy on post-stroke survivor balance with Berg Balance Scale (BBS) or Timed Up and Go test (TUG) were searched. Meta-regression analyses were performed, considering weekly sessions, single-session duration, and robotic device used. Results: A total of 18 trials have been included. BBS pre-post treatment mean difference is higher in RAGT-treated patients, with a pMD of 2.17 (95% CI 0.79; 3.55). TUG pre-post mean difference is in favor of RAGT, but not statistically, with a pMD of −0.62 (95%CI − 3.66; 2.43). Meta-regression analyses showed no relevant association, except for TUG and treatment duration (β = −1.019, 95% CI − 1.827; −0.210, p-value = 0.0135). Conclusions: RAGT efficacy is equal to traditional therapy, while the combination of the two seems to lead to better outcomes than each individually performed. Robot-assisted balance training should be the focus of experimentation in the following years, given the great results in the first available trials. Given the massive heterogeneity of included patients, trials with more strict inclusion criteria (especially time from stroke) must be performed to finally define if and when RAGT is superior to traditional therapy. Full article

These are the preliminary results of a 12-week non-randomized, open-label, non-inferiority study comparing the effectiveness of trazodone in an extended-release formulation (XR) versus SSRIs in the treatment of major depressive disorder (MDD). Participants (n = 76) were recruited, and 42 were assigned to the trazodone XR group and 34 to the SSRIs group. The choice of drug was based on clinical presentation and relied upon the attending physician. Assessments were made at five observation time points, at the following weeks: 0, and after 2, 4, 8, and 12 weeks. The evaluations included: symptoms of depression (MADRS, QIDS-clinician, and self-rated versions-primary study endpoints), anhedonia (SHAPS), anxiety (HAM-A), insomnia (AIS), psychosocial functioning (SDS), and therapeutic efficacy (CGI). At baseline, the trazodone group had significantly more severe depressive, anxiety, and insomnia symptoms and worse psychosocial functioning compared to the SSRIs group. After 12 weeks, trazodone XR was more effective than SSRIs in reducing the severity of insomnia and depression. There were no differences between the groups in the frequencies of therapeutic response and remission, which indicated the non-inferiority of the trazodone XR treatment. In conclusion, our results showed that in a “real world” setting, trazodone XR is effective in the treatment of patients with MDD. Full article

There is currently no simple, widely available screening method for Alzheimer’s disease (AD), partly because the diagnosis of AD is complex and typically involves expensive and sometimes invasive tests not commonly available outside highly specialized clinical settings. Here, we developed an artificial intelligence (AI)-powered end-to-end system to detect AD and predict its severity directly from voice recordings. At the core of our system is the pre-trained data2vec model, the first high-performance self-supervised algorithm that works for speech, vision, and text. Our model was internally evaluated on the ADReSSo (Alzheimer’s Dementia Recognition through Spontaneous Speech only) dataset containing voice recordings of subjects describing the Cookie Theft picture, and externally validated on a test dataset from DementiaBank. The AI model can detect AD with average area under the curve (AUC) of 0.846 and 0.835 on held-out and external test set, respectively. The model was well-calibrated (Hosmer-Lemeshow goodness-of-fit p-value = 0.9616). Moreover, the model can reliably predict the subject’s cognitive testing score solely based on raw voice recordings. Our study demonstrates the feasibility of using the AI-powered end-to-end model for early AD diagnosis and severity prediction directly based on voice, showing its potential for screening Alzheimer’s disease in a community setting. Full article

Sepsis-Associated Encephalopathy (SAE) is common in sepsis patients, with high mortality rates. It is believed that neuroinflammation is an important mechanism involved in SAE. High mobility group box 1 protein (HMGB1), as a late pro-inflammatory factor, is significantly increased during sepsis in different brain regions, including the hippocampus. HMGB1 causes neuroinflammation and cognitive impairment through direct binding to advanced glycation end products (RAGE) and Toll-like receptor 4 (TLR4). Electroacupuncture (EA) at Baihui (GV20) and Zusanli (ST36) is beneficial for neurological diseases and experimental sepsis. Our study used EA to treat SAE induced by lipopolysaccharide (LPS) in male Sprague–Dawley rats. The Y maze test was performed to assess working memory. Immunofluorescence (IF) and Western blotting (WB) were used to determine neuroinflammation and the HMGB1 signaling pathway. Results showed that EA could improve working memory impairment in rats with SAE. EA alleviated neuroinflammation by downregulating the hippocampus’s HMGB1/TLR4 and HMGB1/RAGE signaling, reducing the levels of pro-inflammatory factors, and relieving microglial and astrocyte activation. However, EA did not affect the tight junctions’ expression of the blood–brain barrier (BBB) in the hippocampus. Full article