Editor’s Choice Articles

Objective: The coronavirus belongs to the family of Coronaviridae, which are not branched single-stranded RNA viruses. COVID-19 creates respiratory problems and infections ranging from mild to severe. The virus features mechanisms that serve to delay the cellular immune response. The host’s response is responsible for the pathological process that leads to tissue destruction. Temporomandibular disorders are manifested by painful jaw musculature and jaw joint areas, clicks, or creaks when opening or closing the mouth. All these symptoms can be disabling and occur during chewing and when the patient yawns or even speaks. The pandemic situation has exacerbated anxieties and amplified the vulnerability of individuals. Therefore, from this mechanism, how the COVID-19 pandemic may have increased the incidence of temporomandibular disorders is perceived. The purpose of this review is to evaluate whether COVID-19-related anxiety has caused an increase in temporomandibular dysfunction symptoms in adults to children. Methods: PubMed, Web of Science, Lilacs, and Scopus were systematically searched, until 30 July 2022, to identify studies presenting: the connection between COVID-19 with temporomandibular disorders. Results: From 198 papers, 4 studies were included. Literature studies have shown that the state of uncertainty and anxiety has led to an increase in the incidence of this type of disorder, although not all studies agree. Seventy-three studies were identified after viewing all four search engines; at the end of the screening phase, only four were considered that met the PECO, the planned inclusion, and the exclusion criteria. All studies showed a statistically significant correlation between temporomandibular disorders and COVID-19 with a p < 0.05. Conclusions: All studies agreed that there is an association between COVID-19 and increased incidence of temporomandibular disorders. Full article

This article reviews the current status of research on the relationship between attachment and trauma in developmental psychopathology. Beginning with a review of the major issues and the state-of-the-art in relation to current thinking in the field of attachment about the impact of trauma and the inter-generational transmission of trauma, the review then considers recent neurobiological work on mentalizing and trauma and suggests areas of new development and implications for clinical practice. Full article

This study investigated how local gender stereotype information interacts with discourse context during Chinese discourse reading. Event-related potentials were recorded while participants read two-sentence discourses, in which the first sentence provided the discourse context that either introduced a gender stereotype-countering attitude towards roles, such as “One should strive for the target job, and getting a job should not be restricted by gender”., or was neutral. The second sentence contained the critical clause in which the stereotypical gender of the object noun (a role name) was either consistent or inconsistent with the gender specified by the head noun (a kinship term) of the subject noun phrase, as in “Li’s [daughter/son] became a nurse…”. The object nouns elicited a larger N400 and a larger late negativity (LN) for the inconsistent compared to the consistent conditions in the neutral contexts. Crucially, when the discourse context offered information countering gender stereotypes, both the N400 and LN effects were reversed, with the negativities being smaller for the inconsistent compared to the consistent conditions. The reversal of the N400 effects suggests that discourse contexts can immediately override the processing of gender stereotypes, and thus readers compute discourse context and local pragmatic information simultaneously during discourse reading. Full article

Subitizing is the ability to enumerate small quantities efficiently and automatically. Counting is a strategy adopted for larger numerosities resulting in a near linear increase in response time with each increase in quantity. Some developmental studies suggest that being able to subitize efficiently may be a predictor of later arithmetical ability. Being able to enumerate small quantities efficiently may be necessary for at least some aspects of arithmetical skill and understanding to develop. According to this view, arithmetic ability ultimately depends upon subitizing. If this were the case, when acquired brain injury results in impaired performance on subitizing tasks, mathematical performance may also be impaired. The following study tested eleven healthy control participants and nine chronic patients with acquired brain injury on tasks focused on visual enumeration, addition and multiplication to explore a potential relationship between subitizing ability and calculation performance. No overall correlations were found between subitizing and addition or multiplication speed. However, a very clear subitizing impairment was found in two patients who then demonstrated very different levels of preserved addition skills. The dissociations found and the large inter-individual variability supports a more componential view of arithmetical ability. Full article

Rapid eye movements (REMs), an expression of REM sleep phasic activity, occur against a stable background of cortical desynchronization and the absence of axial tone. The significance of REMs during the sleep period was initially attributed to the mental content of dreams, linking the REMs to the dream scenario. Although fascinating, the so-called “scanning hypothesis” has not been supported by consistent evidence, and thus an alternative hypothesis is necessary to understand REMs significance during sleep. Some data suggest that the frequency of REMs during the REM sleep period, known as REM density, might be related to sleep depth or arousal during sleep. REM density increases across the night concomitantly with the progressive reduction in sleep pressure, and consistently it is higher at the circadian time when arousal appears to be higher, and it is decreased in those conditions, such as after sleep deprivation, which produce increased sleep pressure. REM density is also increased in major affective disorders, and it has been suggested either as a risk factor to develop the illness or as a predictive index of response to drug treatment. Disfunction of the neurotransmitter systems involved in arousal mechanisms and wake/sleep control might underlie the altered REM density described in depression. Understanding of the REM density mechanisms could help to untangle functional significance and regulation of REM sleep. Following the seminal idea of Aserinsky that REM density is an index of sleep satiety, it may also provide a sensitive measure of sleep homeostasis in addition to, or even as an alternative to, the consolidated analysis of slow wave activity. REM density can also be utilized to explore those mechanisms which end sleep, and considered a physiological marker which indicate during sleep the “time to wake”. Full article

Prior to the COVID-19 pandemic, we demonstrated the efficacy of a novel Cognitive Behavioural Therapy programme for the treatment of Non-Rapid Eye Movement Parasomnias (CBT-NREMP) in reducing NREM parasomnia events, insomnia and associated mood severities. Given the increased prevalence and worsening of sleep and affective disorders during the pandemic, we examined the sustainability of CBT-NREMP following the U.K.’s longest COVID-19 lockdown (6 January 2021–19 July 2021) by repeating the investigations via a mail survey in the same 46 patient cohort, of which 12 responded. The survey included validated clinical questionnaires relating to NREM parasomnia (Paris Arousal Disorder Severity Scale), insomnia (Insomnia Severity Index) and anxiety and depression (Hospital Anxiety and Depression Scale). Patients also completed a targeted questionnaire (i.e., Impact of COVID-19 Lockdown Questionnaire, ICLQ) to assess the impact of COVID-19 lockdown on NREM parasomnia severity, mental health, general well-being and lifestyle. Clinical measures of NREM parasomnia, insomnia, anxiety and depression remained stable, with no significant changes demonstrated in questionnaire scores by comparison to the previous investigatory period prior to the COVID-19 pandemic: p (ISI) = 1.0; p (HADS) = 0.816; p (PADSS) = 0.194. These findings support the longitudinal effectiveness of CBT-NREMP for up to three years following the clinical intervention, and despite of the COVID-19 pandemic. Full article

Background: There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. Aim: The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Conclusions: Although the common belief that cannabinoids, including cannabis, its main studied components—tetrahydrocannabinol (THC) and cannabidiol (CBD)—or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement. Full article

The diagnosis of apathy, one of the most common behavioral changes after acquired brain injury (ABI), is important for improving clinical understanding and treatment of persons with ABI. The main aim of this study was to determine the possible role of apathy in conflict monitoring, by using choice reaction time tasks. Methods: We examined behavioral responses of conflict monitoring during three different flanker tasks in 10 severe ABI patients with or without diagnosis of apathy (3 M, mean age = 56.60; 3 M, mean age ± SD = 58.60, respectively), and 15 healthy controls (9 M, mean age = 54.46) Reaction times (RTs), accuracy, and global index of performance (GIP) were analyzed for each task. Results: Only apathetic ABI patients showed a significant difference from healthy subjects (p-value ≤ 0.001), while the performance of patients without apathy was not significantly different from that of healthy controls (p-value = 0.351). Healthy participants had higher accuracy in comparison to both ABI patients with (p < 0.001) and without (p-value = 0.038) apathy, whilst slower RTs were shown by ABI patients without apathy in comparison to both healthy subjects (p-value = 0.045) and apathetic ABI patients (p-value = 0.022). Only patients with apathy exhibited a significantly higher number of missing trials (p-value = 0.001). Conclusions: Our results may suggest a potential link between apathy following severe ABI and conflict monitoring processes, even though further investigations with larger sample size are needed. Full article

This study examined the associations between thought control strategies and subjective and objective sleep quality, across the adult lifespan. One hundred forty-nine individuals without insomnia (age range 18–86 years; M = 45.35, SD = 20.53) completed the Thought Control Questionnaire Insomnia–Revised for assessing sleep-related thought control strategies. Self-reported sleep quality was measured with the Pittsburgh Sleep Quality Index. Then, subjective and objective sleep parameters (i.e., total sleep time, sleep onset latency, sleep efficiency) were recorded through a sleep diary and an actigraph across 7 days. Results from linear mixed-effects models showed that a worry strategy was associated with longer subjective sleep latency and shorter subjective total sleeping time. An aggressive suppression strategy was associated with longer subjective total sleeping time. No such involvement of thought control strategies was detected for subjective sleep efficiency and all of the objective sleep parameters. Other individual differences (i.e., age, sex, circadian preference, self-reported sleep quality) also explained both subjective and objective sleep parameters, though to a different extent depending on the sleep parameter considered. The assessment of sleep-related thought control strategies, along with other individual characteristics, should be considered to account for individual differences in sleep quality and implement practices/interventions to support it in adulthood and older age. Full article

Recent findings indicate that Music Therapy (MT) and Music-Based Interventions (MBIs) may reduce craving symptoms in people with Substance Use Disorders (SUD). However, MT/MBIs can lead SUD clients to recall memories associated with their drug history and the corresponding strong emotions (addiction memories). Craving is a central component of SUD, possibly linked to relapse and triggered by several factors such as the recall of memories associated with the drug experience. Therefore, to address the topic of what elements can account for an improvement in craving symptoms after MT/MBIs, we conducted a narrative review that (1) describes the brain correlates of emotionally salient autobiographical memories evoked by music, (2) outlines neuroimaging and neurophysiological studies suggesting how the experience of craving may encompass the recall of emotionally filled moments, and (3) points out the role of perineuronal nets (PNNs) in addiction memory neuroplasticity. We highlight how autobiographical memory retrieval, music-evoked autobiographical memories, and craving share similar neural activations with PNNs which represent a causal element in the processing of addiction memory. We finally conclude by considering how the neuroplastic characteristics of addiction memory might represent the ground to update and/or recalibrate, within the therapy, the emotional content related to the recall. 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

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

Stroke is a major cause of disability because of its motor and cognitive sequelae even when the acute phase of stabilization of vital parameters is overcome. The most important improvements occur in the first 8–12 weeks after stroke, indicating that it is crucial to improve our understanding of the dynamics of phenomena occurring in this time window to prospectively target rehabilitation procedures from the earliest stages after the event. Here, we studied the intracortical excitability properties of delivering transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) of left and right hemispheres in 17 stroke patients who suffered a mono-lateral left hemispheric stroke, excluding pure cortical damage. All patients were studied within 10 days of symptom onset. TMS-evoked potentials (TEPs) were collected via a TMS-compatible electroencephalogram system (TMS–EEG) concurrently with motor-evoked responses (MEPs) induced in the contralateral first dorsal interosseous muscle. Comparison with age-matched healthy volunteers was made by collecting the same bilateral-stimulation data in nine healthy volunteers as controls. Excitability in the acute phase revealed relevant changes in the relationship between left lesioned and contralesionally right hemispheric homologous areas both for TEPs and MEPs. While the paretic hand displayed reduced MEPs compared to the non-paretic hand and to healthy volunteers, TEPs revealed an overexcitable lesioned hemisphere with respect to both healthy volunteers and the contra-lesion side. Our quantitative results advance the understanding of the impairment of intracortical inhibitory networks. The neuronal dysfunction most probably changes the excitatory/inhibitory on-center off-surround organization that supports already acquired learning and reorganization phenomena that support recovery from stroke sequelae. 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

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

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

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

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

Modern computational solutions used in the reconstruction of the global neuronal network arrangement seem to be particularly valuable for research on neuronal disconnection in schizophrenia. However, the vast number of algorithms used in these analyses may be an uncontrolled source of result inconsistency. Our study aimed to verify to what extent the characteristics of the global network organization in schizophrenia depend on the inclusion of a given type of functional connectivity measure. Resting-state EEG recordings from schizophrenia patients and healthy controls were collected. Based on these data, two identical procedures of graph-theory-based network arrangements were computed twice using two different functional connectivity measures (phase lag index, PLI, and phase locking value, PLV). Two series of between-group comparisons regarding global network parameters calculated on the basis of PLI or PLV gave contradictory results. In many cases, the values of a given network index based on PLI were higher in the patients, and the results based on PLV were lower in the patients than in the controls. Additionally, selected network measures were significantly different within the patient group when calculated from PLI or PLV. Our analysis shows that the selection of FC measures significantly affects the parameters of graph-theory-based neuronal network organization and might be an important source of disagreement in network studies on schizophrenia. 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

Background: The clinical high risk for psychosis (CHR-P) phase represents an opportunity for prevention and early intervention in young adults, which also could focus on improving physical health trajectories. Methods: We conducted a RECORD-compliant clinical register-based cohort study. The primary outcome was to describe the physical health of assessed CHR-P individuals, obtained via Electronic Health Records at the South London and Maudsley (SLaM) NHS Foundation Trust, UK (January 2013–October 2020). Results: The final database included 194 CHR-P subjects (46% female). Mean age was 23.70 ± 5.12 years. Percentage of tobacco smokers was 41% (significantly higher than in the age-matched general population [24%]). We found that 49% of subjects who consumed alcohol had an AUDIT-C (Alcohol Use Disorder Identification Test) score above 5 (hazardous drinking), with an average score of 4.94 (significantly higher than in the general population [2.75]). Investigating diet revealed low fiber intake in most subjects and high saturated fat intake in 10% of the individuals. We found that 47% of CHR-P subjects met the UK recommended physical activity guidelines (significantly lower than in the general population [66%]). Physical parameters (e.g., weight, heart rate, blood pressure) were not significantly different from the general population. Conclusions: This evidence corroborates the need for monitoring physical health parameters in CHR-P subjects, to implement tailored interventions that target daily habits. Full article

The Obstructive Sleep Apnea Syndrome (OSAS) significantly impacts cognitive functioning. The prolonged use (more than 3 months) of ventilotherapy with continuous positive airway pressure (CPAP) seems to have positive effects in restoring cognitive difficulties. However, there is poor evidence about its possible short-term effect. We investigated whether the short use (less than 15 days at testing) of CPAP improved the cognitive functioning in fifty individuals with OSAS by collecting retrospective neuropsychological measures about verbal memory and learning, information processing speed, attention (i.e., alerting, orienting, and executive system), and executive functions (i.e., strategic reasoning, problem-solving, and mental planning). The predictive role of days of CPAP use on the neuropsychological scores was assessed by hierarchical multiple linear regression analyses, over and above the possible role of demographics, body mass index, level of OSAS severity, and the level of anxiety and depression. The average number of days since CPAP adaptation was 4.70 (SD = 3.90; range = 0–15). As the days of CPAP adaptation increased, verbal learning and long-term memory significantly improved, contrary to the other assessed domains. Our results show a significant improvement in some cognitive functions even after a short treatment with CPAP, pointing to the importance of the early use of ventilotherapy to rapidly improve cognitive functioning. Identifying which cognitive functions can or cannot be restored with CPAP use may enable the design of complementary neuropsychological interventions focused on those residual difficulties, possibly enhancing patients’ compliance to the treatment. Full article

Objective: To evaluate the potential of the first-trimester ultrasound (US) features for the detection of central nervous system (CNS) anomalies. Methods/Methodology: This is a prospective one-center three-year study. Unselected singleton pregnant women were examined using an extended first-trimester anomaly scan (FTAS) that included the CNS assessment: the calvaria shape, the septum (falx cerebri), the aspect of the lateral ventricles, the presence of the third ventricle and aqueduct of Sylvius (AS) and the posterior brain morphometry: the fourth ventricle, namely intracranial translucency (IT), brain stem/brain stem–occipital bone ratio (BS/BSOB) and cisterna magna (CM). The spine and underlying skin were also evaluated. The cases were also followed during the second and third trimesters of pregnancy and at delivery. FTAS efficiency to detect major CNS abnormalities was calculated. Results: We detected 17 cases with CNS major abnormalities in a population of 1943 first-trimester (FT) fetuses, including spina bifida with myelomeningocele, exencephaly-anencephaly, holoprosencephaly, hydrocephaly, cephalocele and Dandy-Walker malformation. The CNS features in the abnormal group are presented. In the second trimester (ST), we further diagnosed cases of corpus callosum agenesis, cerebellar hypoplasia, vein of Galen aneurysm and fetal infection features (ventriculomegaly, intraventricular bands, intraventricular cyst and hyperechoic foci), all declared normal at the FTAS. During the third trimester (TT) scan we identified a massive fetal cerebral haemorrhage absent at previous investigations. We report a detection rate of 72.7% of fetal brain anomalies in the FT using the proposed CNS parameters. The sensitivity of the examination protocol was 72.7%, and the specificity was 100%. Conclusion: A detailed FT CNS scan is feasible and efficient. The majority of cases of major CNS abnormalities can be detected early in pregnancy. The visualization rates of the CNS parameters in the FT are great with short, if any, additional investigation time. FT cerebral disorders such as haemorrhage or infections were missed in the FT even when an extended evaluation protocol was used. Full article

Prism adaptation (PA) is a useful method to investigate short-term sensorimotor plasticity. Following active exposure to prisms, individuals show consistent after-effects, probing that they have adapted to the perturbation. Whether after-effects are transferable to another task or remain specific to the task performed under exposure, represents a crucial interest to understand the adaptive processes at work. Motor imagery (MI, i.e., the mental representation of an action without any concomitant execution) offers an original opportunity to investigate the role of cognitive aspects of motor command preparation disregarding actual sensory and motor information related to its execution. The aim of the study was to test whether prism adaptation through MI led to transferable after-effects. Forty-four healthy volunteers were exposed to a rightward prismatic deviation while performing actual (Active group) versus imagined (MI group) pointing movements, or while being inactive (inactive group). Upon prisms removal, in the MI group, only participants with the highest MI abilities (MI+ group) showed consistent after-effects on pointing and, crucially, a significant transfer to throwing. This was not observed in participants with lower MI abilities and in the inactive group. However, a direct comparison of pointing after-effects and transfer to throwing between MI+ and the control inactive group did not show any significant difference. Although this interpretation requires caution, these findings suggest that exposure to intersensory conflict might be responsible for sensory realignment during prism adaptation which could be transferred to another task. This study paves the way for further investigations into MI’s potential to develop robust sensorimotor adaptation. 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

Both short- and long-term memories decline with healthy ageing. The aims of the current study were twofold: firstly, to build on previous studies and investigate the presence of a relationship between short- and long-term memories and, secondly, to examine cross-sectionally whether there are changes in this relationship with age. In two experiments, participants across the age range were tested on contextual-spatial memories after short and long memory durations. Experimental control in stimulus materials and task demands enabled the analogous encoding and probing for both memory durations, allowing us to examine the relationship between the two memory systems. Across two experiments, in line with previous studies, we found both short-term memory and long-term memory declined from early to late adulthood. Additionally, there was a significant relationship between short- and long-term memory performance, which, interestingly, persisted throughout the age range. Our findings suggest a significant degree of common vulnerability to healthy ageing for short- and long-term memories sharing the same spatial-contextual associations. Furthermore, our tasks provide a sensitive and promising framework for assessing and comparing memory function at different timescales in disorders with memory deficits at their core. 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

Trait-related impulsiveness is highly prevalent in patients with mood disorders, being associated with negative outcomes. The predictive role of affective temperaments on trait-related impulsivity is still understudied. The aim of the present study is to investigate the relationship between impulsivity and affective temperaments in a sample of euthymic patients with mood disorders. This is a real-world multicentric observational study, carried out at the outpatient units of seven university sites in Italy. All patients filled in the short version of Munster Temperament Evaluation of the Memphis, Pisa, Paris and San Diego and the Barratt Impulsiveness Scale. The study sample included 653 participants, mainly female (58.2%), with a mean age of 46.9 (±14.1). Regression analyses showed that higher levels of trait-related impulsivity were associated to suicide attempts (p < 0.000), the presence of psychotic symptoms during acute phases (p < 0.05), a seasonal pattern (p < 0.05), a lower age at onset of the disorder (p < 0.05), cyclothymic (p < 0.01) and irritable temperaments (p < 0.01). The results of our study highlight the importance to screen patients with mood disorders for impulsivity and affective temperaments in order to identify patients who are more likely to present a worse outcome and to develop personalized and integrated early pharmacological and psychosocial treatment plans. Novelties of the present paper include the recruitment of patients in a stable phase, which reduced possible bias in patients’ self-reports, and the multicentric nature of the study, resulting in the recruitment of a large sample of patients with mood disorders, geographically distributed across Italy, thus improving the generalizability of study results. Full article

The principal reason for measuring mental workload is to quantify the cognitive cost of performing tasks to predict human performance. Unfortunately, a method for assessing mental workload that has general applicability does not exist yet. This is due to the abundance of intuitions and several operational definitions from various fields that disagree about the sources or workload, its attributes, the mechanisms to aggregate these into a general model and their impact on human performance. This research built upon these issues and presents a novel method for mental workload modelling from EEG data employing deep learning. This method is self-supervised, employing a continuous brain rate, an index of cognitive activation, and does not require human declarative knowledge. The aim is to induce models automatically from data, supporting replicability, generalisability and applicability across fields and contexts. This specific method is a convolutional recurrent neural network trainable with spatially preserving spectral topographic head-maps from EEG data, aimed at fitting a novel brain rate variable. Findings demonstrate the capacity of the convolutional layers to learn meaningful high-level representations from EEG data since within-subject models had, on average, a test Mean Absolute Percentage Error of around 11%. The addition of a Long-Short Term Memory layer for handling sequences of high-level representations was not significant, although it did improve their accuracy. These findings point to the existence of quasi-stable blocks of automatically learnt high-level representations of cognitive activation because they can be induced through convolution and seem not to be dependent on each other over time, intuitively matching the non-stationary nature of brain responses. Additionally, across-subject models, induced with data from an increasing number of participants, thus trained with data containing more variability, obtained a similar accuracy to the within-subject models. This highlights the potential generalisability of the induced high-level representations across people, suggesting the existence of subject-independent cognitive activation patterns. This research contributes to the body of knowledge by providing scholars with a novel computational method for mental workload modelling that aims to be generally applicable and does not rely on ad hoc human crafted models. Full article

Alzheimer’s disease (AD) was used to describe pre-senile dementia to differentiate it from senile dementia, which develops in the adult age group of more than 65 years. AD is characterized by the deposition of amyloid beta (Aβ) plaque and tau-neurofibrillary tangles (TNTs) in the brain. The neuropathological changes in AD are related to the deposition of amyloid plaques, neurofibrillary tangles, and progression of neuroinflammation, neuronal mitochondrial dysfunction, autophagy dysfunction, and cholinergic synaptic dysfunction. Statins are one of the main cornerstone drugs for the management of cardiovascular disorders regardless of dyslipidemia status. Increasing the use of statins, mainly in the elderly groups for primary and secondary prevention of cardiovascular diseases, may affect their cognitive functions. Extensive and prolonged use of statins may affect cognitive functions in healthy subjects and dementia patients. Statins-induced cognitive impairments in both patients and health providers had been reported according to the post-marketing survey. This survey depends mainly on sporadic cases, and no cognitive measures were used. Evidence from prospective and observational studies gives no robust conclusion regarding the beneficial or detrimental effects of statins on cognitive functions in AD patients. Therefore, this study is a narrative review aimed with evidences to the beneficial, detrimental, and neutral effects of statins on AD. Full article

(1) Background: Exercise exerts many neuroprotective effects in diabetes-induced brain disorders. In this study, we investigated the effect of high-intensity interval training (HIIT) on brain molecular changes and cognitive and anxiety-like behaviors in rats with type 2 diabetes. (2) Methods: Twenty-eight adult male rats were divided into four groups (n = 7): control (C), exercise + control (C+EX), diabetes (DM), and diabetes + exercise (DM+EX). Diabetes was induced using a two-month high-fat diet and a single dose of streptozotocin (35 mg/kg) in the DM and DM+EX groups. After, the C+EX and DM+EX groups performed HIIT for eight weeks (five sessions per week, running at 80–100% of V_Max, 4–10 intervals) on a motorized treadmill. Then, the elevated plus maze (EPM) and open field test (OFT) were performed to evaluate anxiety-like behaviors. The Morris water maze (MWM) and shuttle box were used to assess cognitive function. The hippocampal levels of beta-amyloid and tau protein were also assessed using Western blot. (3) Results: The hippocampal levels of beta-amyloid and tau protein were increased in the DM group, but HIIT restored these changes. While diabetes led to a significant decrease in open arm time percentage (%OAT) and open arm enters percentage (%OAE) in the EPM, indicating anxiety-like behavior, HIIT restored them. In the OFT, grooming was decreased in diabetic rats, which was restored by HIIT. No significant difference between groups was seen in the latency time in the shuttle box or for learning and memory in the MWM. (4) Conclusions: HIIT-induced hippocampal molecular changes were associated with anxiety-like behavior improvement but not cognitive function in rats with type 2 diabetes. Full article

Electroencephalography (EEG) records the electrical activity of the brain, which is an important tool for the automatic detection of epileptic seizures. It is certainly a very heavy burden to only recognize EEG epilepsy manually, so the method of computer-assisted treatment is of great importance. This paper presents a seizure detection algorithm based on variational modal decomposition (VMD) and a deep forest (DF) model. Variational modal decomposition is performed on EEG recordings, and the first three variational modal functions (VMFs) are selected to construct the time–frequency distribution of the EEG signals. Then, the log−Euclidean covariance matrix (LECM) is computed to represent the EEG properties and form EEG features. The deep forest model is applied to complete the EEG signal classification, which is a non-neural network deep model with a cascade structure that performs feature learning through the forest. In addition, to improve the classification accuracy, postprocessing techniques are performed to generate the discriminant results by moving average filtering and adaptive collar expansion. The algorithm was evaluated on the Bonn EEG dataset and the Freiburg long−term EEG dataset, and the former achieved a sensitivity and specificity of 99.32% and 99.31%, respectively. The mean sensitivity and specificity of this method for the 21 patients in the Freiburg dataset were 95.2% and 98.56%, respectively, with a false detection rate of 0.36/h. These results demonstrate the superior performance advantage of our algorithm and indicate its great research potential in epilepsy detection. Full article

A comparative single-evaluation cross-sectional study was performed to evaluate cognitive damage in post-COVID-19 patients. The psychophysics tests of Two-Alternative Forced Choice (2AFC) and Simple Reaction Time (SRT), under a designed virtual environment, were used to evaluate the cognitive processes of decision-making, visual attention, and information processing speed. The population under study consisted of 147 individuals, 38 controls, and 109 post-COVID patients. During the 2AFC test, an Emotiv EPOC+^® headset was used to obtain EEG signals to evaluate their Focus, Interest, and Engagement metrics. Results indicate that compared to healthy patients or recovered patients from mild-moderate COVID-19 infection, patients who recovered from a severe-critical COVID infection showed a poor performance in different cognitive tests: decision-making tasks required higher visual sensitivity (p = 0.002), Focus (p = 0.01) and information processing speed (p < 0.001). These results signal that the damage caused by the coronavirus on the central nervous and visual systems significantly reduces the cognitive processes capabilities, resulting in a prevalent deficit of 42.42% in information processing speed for mild-moderate cases, 46.15% for decision-making based on visual sensitivity, and 62.16% in information processing speed for severe-critical cases. A psychological follow-up for patients recovering from COVID-19 is recommended based on our findings. Full article

The heterogeneous and multi-factorial nature of dementia requires the consideration of all health aspects when predicting the risk of its development and planning strategies for its prevention. This systematic review of reviews provides a comprehensive synthesis of those factors associated with cognition in the context of dementia, identifying the role of social aspects and evidencing knowledge gaps in this area of research. Systematic reviews and meta-analyses from 2009–2021 were searched for within Medline, PsycINFO, CINAHL Complete, Cochrane, and Epistemonikos. Reviewers independently screened, reviewed, and assessed the records, following the PRISMA-2020 guidelines. From 314 included studies, 624 cognitive-related factors were identified, most of them risk factors (61.2%), mainly belonging to the group of ‘somatic comorbidities’ (cardiovascular disease and diabetes) and ‘genetic predispositions’. The protective factors (20%) were mainly related to lifestyle, pointing to the Mediterranean diet, regular physical activity, and cognitively stimulating activities. Social factors constituted 9.6% of all identified factors. Research on biological and medical factors dominates the reviewed literature. Greater social support and frequent contact may confer some protection against cognitive decline and dementia by delaying its onset or reducing the overall risk; however, overall, our findings are inconsistent. Further research is needed in the fields of lifestyle, psychology, social health, and the protective factors against cognitive decline and dementia. Full article

Tropomyosin 4 (TPM4) has been reported as an oncogenic gene across different malignancies. However, the role of TPM4 in glioma remains unclear. This study aimed to determine the clinical characterization and prognostic value of TPM4 in gliomas. Transcriptome expression and clinical information were collected from the CGGA and TCGA datasets, which included 998 glioma patients. ScRNA-seq data were obtained from CGGA. R software was utilized for statistical analyses. There was a positive correlation between TPM4 and WHO grades. IDH-wildtype and mesenchymal subtype gliomas were accompanied by TPM4 upregulation. GO and GSEA analysis suggested that TPM4 was profoundly associated with epithelial-to-mesenchymal transition (EMT). Subsequent GSVA revealed a robust correlation between TPM4 and three signaling pathways of EMT (hypoxia, TGF-β, PI3K/AKT). Furthermore, TPM4 showed a synergistic effect with mesenchymal biomarkers, particularly with N-cadherin, Slug, Snail, TWIST1, and vimentin. ScRNA-seq analysis suggested that higher TPM4 was mainly attributed to tumor cells and macrophages and associated with tumor cell progression and macrophage polarization. Finally, high TPM4 was significantly associated with unfavorable outcomes. In conclusion, our findings indicate that TPM4 is significantly correlated with more malignant characteristics of gliomas, potentially through involvement in EMT. TPM4 could predict worse survival for patients with glioma. Full article

In the last decades, it has been proposed that executive functions may be particularly vulnerable to weight-related issues. However, evidence on the matter is mixed, especially when the effects of sociodemographic variables are weighted. Thus, the current study aimed at further examining the relationship between executive functions and obesity. To this aim, we compared treatment-seeking overweight, obese, and morbidly obese patients with normal-weight control participants. We examined general executive functioning (Frontal Assessment Battery–15) and different executive subdomains (e.g., inhibitory control, verbal fluency, and psychomotor speed) in a clinical sample including 208 outpatients with different degrees of BMI (52 overweight, BMI 25–30, M age = 34.38; 76 obese, BMI 30–40, M age = 38.00; 80 morbidly obese, BMI > 40, M age = 36.20). Ninety-six normal-weight subjects served as controls. No difference on executive scores was detected when obese patients were compared with over- or normal-weight subjects. Morbidly obese patients reported lower performance on executive scores than obese, overweight, and normal-weight subjects. Between-group difference emerged also when relevant covariates were taken into account. Our results support the view that morbid obesity is associated with lower executive performance, also considering the critical role exerted by sociodemographic (i.e., sex, age, and education) variables. Our results support the view that executive functioning should be accounted into the management of the obese patient because of non-negligible clinical relevance in diagnostic, therapeutic, and prognostic terms. Full article

The incidence of stroke and the burden on health care and society are expected to increase significantly in the coming years, due to the increasing aging of the population. Various sensory, motor, cognitive and psychological disorders may remain in the patient after survival from a stroke. In hemiplegic patients with movement disorders, the impairment of upper limb function, especially hand function, dramatically limits the ability of patients to perform activities of daily living (ADL). Therefore, one of the essential goals of post-stroke rehabilitation is to restore hand function. The recovery of motor function is achieved chiefly through compensatory strategies, such as hand rehabilitation robots, which have been available since the end of the last century. This paper reviews the current research status of hand function rehabilitation devices based on various types of hand motion recognition technologies and analyzes their advantages and disadvantages, reviews the application of artificial intelligence in hand rehabilitation robots, and summarizes the current research limitations and discusses future research directions. Full article

In recent years, there has been debate about the optimal conceptualisation of psychopathology. Structural models of psychopathology have been developed to counter issues, including comorbidity and poor diagnostic stability prevalent within the traditional nosological approach. Regardless of the conceptualisation of psychological dysfunction, deficits in neurocognitive abilities have been claimed to be an aetiological feature of psychopathology. Explorations of the association between neurocognition and psychopathology have typically taken a linear approach, overlooking the potential interactive dynamics of neurocognitive abilities. Previously, we proposed a multidimensional hypothesis, where within-person interactions between neurocognitive domains are fundamental to understanding the role of neurocognition within psychopathology. In this study, we used previously collected psychopathology data for 400 participants on psychopathological symptoms, substance use, and performance on eight neurocognitive tasks and compared the predictive accuracy of linear models to artificial neural network models. The artificial neural network models were significantly more accurate than the traditional linear models at predicting actual (a) lower-level and (b) high-level dimensional psychopathology. These results provide support for the multidimensional hypothesis: that the study of non-linear interactions and compensatory neurocognitive profiles are integral to understanding the functional associations between neurocognition and of psychopathology. Full article

Bone fracture following traumatic injury or due to osteoporosis is characterized by severe pain and motor impairment and is a major cause of global mortality and disability. Fracture pain often originates from mechanical distortion of somatosensory nerve terminals innervating bones and muscles and is maintained by central sensitization. Chronic fracture pain (CFP) after orthopedic repairs is considered one of the most critical contributors to interference with the physical rehabilitation and musculoskeletal functional recovery. Analgesics available for CFP in clinics not only have poor curative potency but also have considerable side effects; therefore, it is important to further explore the pathogenesis of CFP and identify safe and effective therapies. The typical physiopathological characteristics of CFP are a neuroinflammatory response and excitatory synaptic plasticity, but the specific molecular mechanisms involved remain poorly elucidated. Recent progress has deepened our understanding of the emerging properties of chemokine production, proinflammatory mediator secretion, caspase activation, neurotransmitter release, and neuron-glia interaction in initiating and sustaining synaptogenesis, synaptic strength, and signal transduction in central pain sensitization, indicating the possibility of targeting neuroinflammation to prevent and treat CFP. This review summarizes current literature on the excitatory synaptic plasticity, microgliosis, and microglial activation-associated signaling molecules and discusses the unconventional modulation of caspases and stimulator of interferon genes (STING) in the pathophysiology of CFP. We also review the mechanisms of action of analgesics in the clinic and their side effects as well as promising therapeutic candidates (e.g., specialized pro-resolving mediators, a caspase-6 inhibitor, and a STING agonist) for pain relief by the attenuation of neuroinflammation with the aim of better managing patients undergoing CFP in the clinical setting. Full article

This study aimed to determine how transcutaneous vagus nerve stimulation (tVNS) alters autonomic nervous activity by comparing the effects of different tVNS frequencies and current intensities. We also investigated the sex-dependent autonomic response to tVNS. Thirty-five healthy adult participants were stimulated using a tVNS stimulator at the left cymba conchae while sitting on a reclining chair; tVNS-induced waveform changes were then recorded for different stimulus frequencies (Experiment 1: 3.0 mA at 100 Hz, 25 Hz, 10 Hz, 1 Hz, and 0 Hz (no stimulation)) and current intensities (Experiment 2: 100 Hz at 3.0 mA, 1.0 mA, 0.2 mA (below sensory threshold), and 0 mA (no stimulation)) using an electrocardiogram. Pulse widths were set at 250 µs in both experiment 1 and 2. Changes in heart rate (HR), root-mean-square of the difference between two successive R waves (RMSSD), and the ratio between low-frequency (LF) (0.04–0.15 Hz) and high-frequency (HF) (0.15–0.40 Hz) bands (LF/HF) in spectral analysis, which indicates sympathetic and parasympathetic activity, respectively, in heart rate variability (HRV), were recorded for analysis. Although stimulation at all frequencies significantly reduced HR (p = 0.001), stimulation at 100 Hz had the most pronounced effect (p = 0.001) in Experiment 1 and was revealed to be required to deliver at 3.0 mA in Experiment 2 (p = 0.003). Additionally, participants with higher baseline sympathetic activity experienced higher parasympathetic response during stimulation, and sex differences may exist in the autonomic responses by the application of tVNS. Therefore, our findings suggest that optimal autonomic changes induced by tVNS to the left cymba conchae vary depending on stimulating parameters and sex. Full article

Background/Problem. Given the treatment-resistant gait deficits after stroke and known elevated energy cost of gait after stroke, it is important to study the patterns of mechanical energies of the lower limb segments. There is a dearth of information regarding mechanical energies specifically for the thigh and shank across the gait cycle. Therefore, the purpose of the current work was to characterize the following: (1) relative patterns of oscillation kinetic energy (KE) and potential energy (PE) within lower limb segments and across lower limb segments in healthy adults during the swing phase at chosen and slow gait speeds; (2) KE and PE swing phase patterns and values for stroke survivors versus healthy adults walking at slow speed; and (3) KE and PE patterns during the swing phase for two different compensatory gait strategies after stroke,. Methods. This was a gait characterization study, a two-group, parallel-cohort study of fourteen stroke survivors with gait deficits, walking at <0.4 m/s and eight adults with no gait deficits. For testing, the eight healthy adults walked at their chosen speed, and then at the imposed slow speed of <0.04 m/s. We used a standard motion capture system and calculation methods to acquire, calculate, and characterize oscillation patterns of KE and PE of the limb segments (thigh and shank) across the gait cycle. Results. In healthy adults, we identified key energy conservation mechanisms inherent in the interactions of KE and PE, both within the thigh and shank segments and across those limb segments, partially explaining the low cost of energy of the normal adult chosen speed gait pattern, and the underlying mechanism affording the known minimal set of activated muscles during walking, especially during the early swing phase. In contrast, KE was effectively absent for both healthy adults at imposed slow walking speed and stroke survivors at their very slow chosen speed, eliminating the normal conservation of energy between KE and PE within the thigh and across the thigh and shank. Moreover, and in comparison to healthy adult slow speed, stroke survivors exhibited greater abnormalities in mechanical energies patterns, reflected in either a compensatory stepping strategy (over-flexing the hip) or circumducting strategy (stiff-legged gait, with knee extended throughout the swing phase). Conclusions and contribution to the field. Taken together, these findings support targeted training to restore normal balance control and normal activation and de-activation coordination of hip, knee, and ankle muscles, respectively (agonist/antagonist at each joint), so as to eliminate the known post-stroke abnormal co-contractions; this motor training is critical in order to release the limb to swing normally in response to mechanical energies and afford the use of conservation of KE and PE energies within the thigh and across thigh and shank. Full article

Background: High-dose ionizing radiation (IR) (>0.5 Gy) is an established risk factor for cognitive impairments, but this cannot be concluded for low-to-moderate IR exposure (<0.5 Gy) in adulthood as study results are inconsistent. The objectives are to summarize relevant epidemiological studies of low-to-moderate IR exposure in adulthood and to assess the risk of non-cancerous CNS diseases. Methods: A systematic literature search of four electronic databases was performed to retrieve relevant epidemiological studies published from 2000 to 2022. Pooled standardized mortality ratios, relative risks, and excess relative risks (ERR) were estimated with a random effect model. Results: Forty-five publications were included in the systematic review, including thirty-three in the quantitative meta-analysis. The following sources of IR-exposure were considered: atomic bomb, occupational, environmental, and medical exposure. Increased dose-risk relationships were found for cerebrovascular diseases incidence and mortality (ERR_pooled per 100 mGy = 0.04; 95% CI: 0.03–0.05; ERR_pooled at 100 mGy = 0.01; 95% CI: −0.00–0.02, respectively) and for Parkinson’s disease (ERR_pooled at 100 mGy = 0.11; 95% CI: 0.06–0.16); Conclusions: Our findings suggest that adult low-to-moderate IR exposure may have effects on non-cancerous CNS diseases. Further research addressing inherent variation issues is encouraged. Full article

Post-stroke depression (PSD) is a kind of prevalent emotional disorder following stroke that usually results in slow functional recovery and even increased mortality. We had reported that the cysteinyl leukotriene receptor 2 (CysLT₂R) antagonist HAMI3379 (HM3379) contributes to the improvement of neurological injury. The present study was designed to investigate the role of HM3379 in PSD-induced chronic neuroinflammation and related mechanisms in gerbils. The gerbils were subjected to transient global cerebral ischemia (tGCI) and spatial restraint stress to induce the PSD model. They were randomized to receive the vehicle or HM3379 (0.1 mg/kg, i.p.) for a consecutive 14 days. In the PSD-treated gerbils, HM3379 had noteworthy efficacy in improving the modified neurological severity score (mNSS) and depression-like behaviors, including the sucrose preference test and the forced swim test. HM3379 administration significantly mitigated neuron loss, lessened TUNEL-positive neurons, and reduced the activation of microglia in the cerebral cortex. Importantly, HM3379 downregulated protein expressions of the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome and pyroptosis including NLRP3, cleaved caspase-1, interleukin-1β (IL-1β), IL-18, cleaved gasdermin-N domain (GSDMD-N), and apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC). Mechanistically, HM3379 could repress pyroptosis via inhibiting NLRP3 inflammasome activation under oxygen-glucose deprivation (OGD) stimulation. Knockdown of CysLT₂R by short hairpin RNA (shRNA) or overexpression of CysLT₂R by lentivirus (LV)-CysLT₂R could abolish or restore the anti-depression effect of HM3379. Our results demonstrated that the selective CysLT₂R antagonist HM3379 has beneficial effects on PSD, partially by suppressing the NLRP3 inflammasome/pyroptosis pathway. Full article

Co-registration of stereotactic and preoperative magnetic resonance imaging (MRI) images can serve as an alternative for trajectory planning. However, the role of this strategy has not yet been proven by any control studies, and the trajectories of commonly used targets have not been systematically studied. The purpose of this study was to analyze the trajectories for various targets, and to assess the role of trajectories realized on fused images in preventing intracranial hemorrhage (ICH). Data from 1019 patients who underwent electrode placement for deep brain stimulation were acquired. Electrode trajectories were not planned for 396 patients, whereas trajectories were planned for 623 patients. Preoperative various MRI sequences and frame-placed MRI images were fused for trajectory planning. The patients’ clinical characteristics, the stereotactic systems, intracranial hemorrhage cases, and trajectory angles were recorded and analyzed. No statistically significant differences in the proportions of male patients, patients receiving local anesthesia, and diseases or target distributions (p > 0.05) were found between the trajectory planning group and the non-trajectory planning group, but statistically significant differences were observed in the numbers of both patients and leads associated with symptomatic ICH (p < 0.05). Regarding the ring and arc angle values, statistically significant differences were found among various target groups (p < 0.05). The anatomic structures through which leads passed were found to be diverse. Trajectory planning based on MRI fusion is a safe technique for lead placement. The electrode for each given target has its own relatively constant trajectory. Full article

(1) Background: Previous evidence demonstrates that tight glycemic control and good physical function could reduce the risk of delirium. This study aimed to investigate whether the occurrence of postoperative delirium (POD) in older hip fracture surgery patients is associated with preoperative glycemic control factors or pre-injury physical performance. (2) Methods: Three-hundred and nine individuals aged over 65 years and scheduled for hip fracture surgery were included at a single center. Glycemic control factors and pre-injury physical performance were assessed preoperatively. The presence of delirium was assessed using the Confusion Assessment Method on postoperative hospitalization days. Univariate and multivariable logistic regression models and a risk prediction model of POD were established. (3) Results: Among the 309 patients, 52 (16.83%) experienced POD during the hospital stay. The numbers of pre-injury physical performance and type 2 diabetes mellitus (T2DM) patients were significantly different in the POD and non-POD groups. The multivariable model showed that development of delirium was significantly explained by preoperative fasting blood glucose (FBG) (OR 0.804, p = 0.004), stair climbing (OR 0.709, p = 0.003), T2DM (odds ratio (OR) 3.654, p = 0.001), and age-adjusted Charlson comorbidity index (ACCI) (OR 1.270, p = 0.038). The area under the receiver operating characteristic curve (AUROC) of the risk prediction model including those covariates was 0.770. (4) Conclusions: More older T2DM patients develop POD after hip fracture surgery than patients without T2DM. A simple assessment of preoperative FBG and pre-injury stair climbing capacity may identify those at high risk for the development of POD. Higher preoperative FBG and good pre-injury stair climbing capacity are protective factors for POD. Full article

Polystyrene nanoparticles (PS-NPs) are organic pollutants that are widely detected in the environment and organisms, posing potential threats to both ecosystems and human health. PS-NPs have been proven to penetrate the blood–brain barrier and increase the incidence of neurodegenerative diseases. However, information relating to the pathogenic molecular mechanism is still unclear. This study investigated the neurotoxicity and regulatory mechanisms of PS-NPs in human neuroblastoma SHSY-5Y cells. The results show that PS-NPs caused obvious mitochondrial damages, as evidenced by inhibited cell proliferation, increased lactate dehydrogenase release, stimulated oxidative stress responses, elevated Ca²⁺ level and apoptosis, and reduced mitochondrial membrane potential and adenosine triphosphate levels. The increased release of cytochrome c and the overexpression of apoptosis-related proteins apoptotic protease activating factor-1 (Apaf-1), cysteinyl aspartate specific proteinase-3 (caspase-3), and caspase-9 indicate the activation of the mitochondrial apoptosis pathway. In addition, the upregulation of autophagy markers light chain 3-II (LC3-II), Beclin-1, and autophagy-related protein (Atg) 5/12/16L suggests that PS-NPs could promote autophagy in SHSY-5Y cells. The RNA interference of Beclin-1 confirms the regulatory role of autophagy in PS-NP-induced neurotoxicity. The administration of antioxidant N-acetylcysteine (NAC) significantly attenuated the cytotoxicity and autophagy activation induced by PS-NP exposure. Generally, PS-NPs could induce neurotoxicity in SHSY-5Y cells via autophagy activation and mitochondria dysfunction, which was modulated by mitochondrial oxidative stress. Mitochondrial damages caused by oxidative stress could potentially be involved in the pathological mechanisms for PS-NP-induced neurodegenerative diseases. Full article

Major depressive disorder is a leading cause of disability worldwide and a major contributor to the overall global burden of disease. While there are several options for antidepressant treatment, only about 40–60% of patients respond to initial monotherapy, while 30–40% of patients may even show resistance to treatment. This article offers a narrative review of those studies evaluating the predictive properties of various blood-based baseline biomarkers regarding treatment responses to the pharmacological, stimulation, or behavioral treatment of patients with treatment-resistant depression (TRD). Our results show that overall, there is only a very limited number of studies assessing baseline peripheral biomarkers regarding treatment response in TRD. Although there is some evidence for the predictive significance of particular biomarkers (e.g., IL-6, CRP, BDNF), the majority of the results are either single-study reports or studies with conflicting results. This may contribute to the wide variety of treatment protocols and different TRD definition criteria, the small number of patients included, and the existence of different biological phenotypes of the disorder used within the various studies. Taken together, there does not yet appear to be any specific baseline peripheral biomarker with sufficient discriminative predictive validity that can be used in the routine clinical practice of TRD. The discovery of new biomarkers and the better clinical characterization of known biomarkers could support the better classification and staging of TRD, the development of personalized treatment algorithms with higher rates of remission and fewer side effects, and the development of new precision drugs for specific subgroups of patients. Full article