The search for robust, reliable biomarkers of schizophrenia remains a high priority in psychiatry. Biomarkers are valuable because they can reveal the underlying mechanisms of symptoms and monitor treatment progress, and may predict future risk of developing schizophrenia. Despite the existence of various promising biomarkers that relate to symptoms across the schizophrenia-spectrum, and despite published recommendations encouraging multivariate metrics, they are rarely investigated simultaneously within the same individuals. In those with schizophrenia, the magnitude of purported biomarkers is complicated by comorbid diagnoses, medications, and other treatments. Here, we argue three points. First, we reiterate the importance of assessing multiple biomarkers simultaneously. Second, we argue that investigating biomarkers in those with schizophrenia-related traits (schizotypy) in the general population can accelerate progress in understanding the mechanisms of schizophrenia. We focus on biomarkers of sensory and working memory in schizophrenia and their smaller effects in individuals with nonclinical schizotypy. Third, we note irregularities across research domains leading to the current situation in which there is a preponderance of data on auditory sensory memory and visual working memory, but markedly less in visual (iconic) memory and auditory working memory, particularly when focusing on schizotypy where data are either scarce or inconsistent. Together, this review highlights opportunities for researchers without access to clinical populations to address gaps in knowledge. We conclude by highlighting the theory that early sensory memory deficits contribute negatively to working memory and vice versa. This presents a mechanistic perspective where biomarkers may interact with one another and impact schizophrenia-related symptoms.
Parkinson’s Disease (PD) and vitamin D share a unique link as Vitamin D deficiency (VDD) prevails in PD. Thus, an in-depth understanding of Vitamin D biology in PD might be crucial for therapeutic strategies emphasizing Vitamin D. Specifically, explicating the effect of VDD and genetic polymorphisms of vitamin D-associated genes in PD, like VDR (Vitamin D Receptor) or GC (Vitamin D Binding Protein), may aid the process along with polymorphisms of Vitamin D metabolizing genes (e.g., CYP2R1, CYP27A1) in PD. Literature review of single nucleotide polymorphisms (SNPs) related to Vitamin D levels [GC (GC1-rs7041, GC2-rs4588), CYP2R1, CYP24A1, CYP27B1] and Vitamin D function [VDR (FokI - rs2228570, ApaI - rs7976091, BsmI-rs1544410, TaqI-rs731236)] was conducted to explore their relationship with PD severity globally. Furthermore, the DisGeNET database was utilized to explore the gene-disease associations in PD, and STRING alongside Cytoscape was utilized to identify critical genes associated with PD. VDR-FokI polymorphism was reported to be significantly associated with PD in Hungarian, Chinese, and Japanese populations, whereas VDR-ApaI polymorphism was found to affect PD in the Iranian population. However, VDR-TaqI and BsmI polymorphisms had no significant association with PD severity. Conversely, GC1 polymorphisms reportedly affected Vitamin D levels without influencing the disease severity. CYP2R1 (excluding rs1993116) was also reportedly linked to clinical manifestations of PD. Genetic polymorphisms might cause VDD despite enough sunlight exposure and vitamin D-rich food intake, enhancing inflammation, and thereby influencing PD pathophysiology. Knowledge of the polymorphisms associated with vitamin D appears promising for developing new therapeutic strategies against PD.
The clinical assessment of patients with disorders of consciousness (DoC) relies on the observation of behavioral responses to standardized sensory stimulation. However, several medical comorbidities may directly impair the production of reproducible and appropriate responses, thus reducing the sensitivity of behavior-based diagnoses. One of these is Akinetic Mutism (AM), a rare neurological syndrome characterized by the inability to initiate volitional motor responses, sometimes associated with clinical presentations overlapping with those of DoC. Here we describe the case of a patient with large bilateral mesial frontal lesions showing a prolonged behavioral unresponsiveness and a severe disorganization of electroencephalographic (EEG) background, compatible with a vegetative state/unresponsive wakefulness syndrome (VS/UWS). By applying an unprecedented battery of multimodal longitudinal measurements encompassing spontaneous EEG, evoked potentials, event-related potentials, transcranial magnetic stimulation-evoked potentials, and structural and functional MRI, we provide (i) a demonstration of the preservation of consciousness despite unresponsiveness in the context of a complete AM, (ii) a plausible neurophysiological explanation of behavioral unresponsiveness and of its subsequent recovery during rehabilitation stay and (iii) novel insights into the relationships between DoC, AM and parkinsonism. The present case provides proof-of-principle evidence supporting the clinical utility of a multimodal hierarchical workflow combining conventional and advanced techniques to detect covert signs of consciousness in unresponsive patients.
The innate immune response plays an important role in the pathological process of ischemic stroke. Increasing evidence suggests that the inflammatory response triggered by the innate immune system hinders neurological and behavioral recovery after stroke. The perception of abnormal DNA and its downstream effects are an important part of the innate immune system. The abnormal DNA is the major inducing factor for innate immune response and is sensed by a series of DNA sensors. In this review, we discussed the multiple roles of DNA sensing in the pathological process of ischemic stroke, with a special focus on DNA sensors Toll-like receptor 9 (TLR9), absent in melanoma 2 (AIM2) and cyclic GMP-AMP synthase (cGAS).
Ageing is accompanied by numerous changes within the sensory and motor component of the muscle spindle pathway. To further document these age-related changes, this study compared the characteristics of the Hoffmann (H) reflex and M wave, evoked with several pulse durations, between young and old adults. The H-reflex and M-wave recruitment curves were analysed from recordings performed at rest in the flexor carpi radialis of 12 young (21-36 yrs) and 12 old adults (62-80 yrs). For each pulse duration (0.05-ms, 0.2-ms, and 1-ms), the maximal H-reflex amplitude (HMAX), the associated M wave (MHmax), and the H-reflex amplitude for a stimulus intensity evoking an M-wave of 5% MMAX (HM5%) were measured. The strength-duration time constant and response threshold were estimated from the charge/stimulus-duration relation for H reflex and M wave. The main results indicate that varying pulse duration mainly induces similar effect on H-reflex and M-wave recruitment curves between young and old adults. However, regardless of pulse duration, old adults had lesser HMAX (p = 0.029) but greater HM5% (p<0.001) and MHmax (p<0.001). The strength-duration time constant was lesser in old than young adults for the H reflex (p=0.048) but not the M wave (p=0.21). The H-reflex and M-wave response thresholds were greater in old than young adults (p=0.003). These results suggest greater age-related changes in the sensory than motor component of the H-reflex pathway, which may be indicative of a greater loss of sensory than motor axons or alterations of synapses between Ia afferents and motor neurones.
The pro-inflammatory cytokines IL-1α, IL-6 and TNF-α are associated with major depressive disorder, psychological distress, cardiovascular health, and obesity. However, there is limited research that has examined multiple associations between these variables, among individuals with major depressive disorder in comparison to a control cohort, including sex differences. In this study, data was analysed from 60 individuals with major depressive disorder and 60 controls, including plasma IL-1α, IL-6 and TNF-α, adiposity measures (body mass index; waist circumference), cardiovascular health indices (blood pressure; heart rate) and psychological symptoms (depressive severity; anxiety; hostility; stress). The cytokines were compared by group and sex, and correlated with measures of adiposity, cardiovascular health indices and psychological health. Plasma IL-1α and IL-6 were higher in major depressive disorder group versus control, but with a sex interaction for IL-6, with this group difference only among females. TNF-α did not differ between groups. IL-1α and IL-6 correlated with depressive severity, anxiety, hostility, and stress, while TNF-α correlated only with anxiety and hostility. Psychopathology was associated with IL-1α in males only, and with IL-6 and TNF-α in females only. None of the cytokines correlated with body mass index, waist circumference, blood pressure or heart rate. The result of group by sex interaction for IL-6, and sex specific associations between pro-inflammatory cytokines and psychometrics could be aetiologically important in depression interventions and treatments for females versus males, warranting further investigation.
When performing bimanual tasks, hands are typically not controlled individually but rather as a coupled system to achieve high spatiotemporal coordination. On a brain level, intra- and interhemispheric connections networks that control the left and right hand are necessary to exchange information between hemispheres and to couple movements. Behaviorally, coupling is, however, highly task-specific requiring, for example, to maintain a specific relative phase in cyclic tasks (e.g., in- or antiphase) or to perform a role differentiated task where one hand is modulating and the other hands is stabilizing and needs to be kept as still as possible (e.g., holding a notepad and writing on it). In this study, we used electroencephalography to investigate functional brain network characteristics (task-related activation and connectivity) in bimanual force-control tasks with different coordination modes: inphase, antiphase and role-differentiated with the left- or right-hand stabilizing and the other hand manipulating. We aimed to examine i) how network characteristics differ with respect to the coordination mode and ii) how they are related to the performance. Results showed, task-related differences in the overall activation and connectivity, but no task-specific patterns (i.e., different regions being more active or integrated during some tasks than others). We did show, however, that the strength of bimanual coupling is modulated in a task-specific way through networks including C3, FC3 and F3 electrodes. Results suggest that interhemispheric crosstalk for bimanual coordination is modulated in a task-specific way through left frontocentral networks.
Semantic memory remains relatively stable with normal cognitive aging and declines in early stages of neurodegenerative disease. We measured electroencephalography (EEG) oscillatory correlates of semantic memory retrieval to examine the effects of normal and pathological aging. Twenty-nine cognitively healthy young adults (YA), 22 cognitively healthy aging adults (HA), and 20 patients with mild cognitive impairment (MCI) completed a semantic memory retrieval task with concurrent EEG recording in which they judged whether two words (features of objects) led to retrieval of an object (retrieval) or not (non-retrieval). Event-related power changes contrasting the two conditions (retrieval vs. non-retrieval) within theta, alpha, low-beta, and high-beta EEG frequency bands were analyzed across time to examine normal aging (YA versus HA) and pathological aging effects (HA versus MCI). Though no behavioral differences between the cognitively healthy groups were observed, we found later theta and alpha power differences between conditions only in YA, and a high-beta power difference between conditions only in HA. For pathological aging effects, we found reduced accuracy in MCI. While we found different EEG patterns of early beta power differences between conditions in MCI compared to HA, a low-beta power difference between conditions was found only in HA. We conclude that the aging brain relies on faster (beta) oscillations during the semantic memory task. With pathological aging, retrieval accuracy declines and patterns of beta oscillation changes. The findings improve understanding on age-related neural mechanisms underlying semantic memory and have implications for early detection of pathological aging.
Alzheimer’s disease (AD) is a neurological ailment that primarily affects the elderly and necessitates an efficient treatment regimen backed up by extensive care. At the moment, treatment for AD is still in its early stages and is often regarded as insufficient by the medical community, with synthetic medications commonly used that have several side-effects. Consequently, research groups are constantly attempting to improve its early detection, particularly through biomarkers, as well as to find effective complementary and alternative therapies for its management. Medicinal plants have long been used as a source of biomolecules as well as complementary medicines. Africa ranks second among biodiversity hotspots in the world due to geographical variances in distribution and vegetation zones. In comparison to nations like India and China, it is believed that much of its biodiversity remains unexplored, and that it may be home to many previously unknown medicinal plants. This calls for more research on African medicinal herbs and finding a key remedy to treat and manage AD. The major scientific biomedical literature databases viz. PubMed, Scifinder, The Lens, Google Scholar, etc. were accessed and the information available till September 2022 was reviewed, with a focus on documenting such herbs along with their active biomolecules that could lead to noble drugs against AD. Also, the review has looked up on the risk factors prevalent among African communities to have a perspective on how race may affect AD risk and expression.
Visual attention is mainly goal-directed and allocated based on the upcoming action to be performed. However, it is unclear how far this feature of gaze behavior generalizes in more naturalistic settings. The present study investigates active inference processes revealed by eye movements during interaction with familiar and novel tools with two levels of realism of the action affordance. In a between-subject design, a cohort of participants interacted with a VR controller in a low realism environment; another performed the task with an interaction setup that allowed differentiated hand and finger movements in a high-realism environment. We investigated the differences in odds of fixations and their eccentricity towards the tool parts before action initiation. The results show that participants fixate more on the tool’s effector part before action initiation when asked to use the tool and during interaction with unfamiliar tools. The spatial viewing bias on the tool reveals early fixations are influenced by the task and the familiarity of the tools. Our findings suggest that fixations are made in a task-oriented way to plan the intended action well before action initiation. With more realistic action affordances, more fixations were allocated toward the tool handle. We hypothesize that these fixations are made towards the proximal goal of planning the grasp even though the perceived action on the tools is identical for both experimental setups. Taken together, proximal and distal goal-oriented planning is contextualized to the realism of action/interaction afforded by an environment.
A major challenge in neuroscience is to pinpoint neurobiological correlates of specific cognitive and neuropsychiatric traits. At the mesoscopic level, promising candidates for establishing such connections are brain oscillations that can be robustly recorded as local field potentials with varying frequencies in the hippocampus in vivo and in vitro. Inbred mouse strains show natural variation in hippocampal synaptic plasticity (e.g., long-term potentiation), a cellular correlate of learning and memory. However, their diversity in expression of different types of hippocampal network oscillations has not been fully explored. Here, we investigated hippocampal network oscillations in three widely used inbred mouse strains: C57BL/6J (B6J), C57BL/6NCrl (B6N) and 129S2/SvPasCrl (129) with the particular aim to identify common oscillatory characteristics in inbred mouse strains that show aberrant emotional/cognitive behaviour (B6N and 129) and compare them to “control” B6J strain. First, we detected higher gamma oscillation power in the hippocampal CA3 of both B6N and 129 strains. Second, an increased incidence of hippocampal sharp wave-ripple (SW-R) transients was evident in these strains. Third, we observed prominent differences in the densities of distinct interneuron types and CA3 associative network activity which are indispensable for sustainment of mesoscopic network oscillations. Together, these results supports the notion that in vitro hippocampal network oscillations, similar to classical plasticity read-outs measured in hippocampal slices, can be used as robust reductionist models to study electrophysiological correlates of emotional and cognitive phenotypes. Importantly, we add further evidence to profound physiological differences among inbred mouse strains commonly used in neuroscience research.
Environmental factors interact with biological and genetic factors influencing the development and well-being of an organism. The interest to better understand the role of environment on behavior and physiology led to the development of animal models of environmental manipulations. Environmental Enrichment (EE), an environmental condition that allows cognitive and sensory stimulation as well as social interaction, improves cognitive function, reduces anxiety and depressive-like behavior, and promotes neuroplasticity. In addition, it exerts protection against neurodegenerative disorders, cognitive aging and deficits aggravated by stressful experiences. Given the beneficial effects of EE on brain and behavior, preclinical studies focus on its protective role as an alternative, non-invasive manipulation, to help an organism to cope better with stress. A valid, reliable and effective animal model of chronic stress that enhances anxiety and depression-like behavior is the Chronic Unpredictable Mild Stress (CUMS). The variety of stressors and the unpredictability in the time and sequence of exposure to prevent habituation, render CUMS an ethologically relevant model. CUMS has been associated with dysregulation of the Hypothalamic-Pituitary-Adrenal axis, elevation in the basal levels of stress hormones, reduction in brain volume, dendritic atrophy and alterations in markers of synaptic plasticity. Although numerous studies have underlined the compensatory role of EE against the negative effects of various chronic stress regimens (e.g., restraint, social isolation), research concerning the interaction between EE and CUMS is sparse. The purpose of the current systematic review is to present up-to-date research findings regarding the protective role of EE against the negative effects of CUMS.
Sensorimotor atypicalities are common in Autism Spectrum Disorder (ASD) and are often evident prior to classical ASD symptoms. Despite evidence of differences in neural processing during imitation in ASD, research on integrity of basic sensorimotor processing is surprisingly sparce. To address this gap in the literature, here we examined basic sensorimotor processing in autism by analyzing EEG data recorded from a large sample of children and adolescents while they performed an audio-visual speeded reaction time task. Using response-locked signal averaging, we investigated the neural processes associated with execution of a cued movement in a large sample of children and adolescents with ASD (n=84) and without ASD (n=84). Analyses focused on motor related brain responses that are well-characterized in adults: the late berichtsheft potential, the motor potential, and the reafferent potential. Group differences were examined in data parsed by age (6-9 years, 9-12 years, 12-15 years), sensory cue preceding the response (auditory, visual, bi-sensory audio-visual), and reaction time quartile. Overall, the data revealed robust sensorimotor neural responses in ASD. Nevertheless, subtle sensorimotor atypicalities were present in autistic children across all parcellations, and these differences were most prominent in the youngest group of children (age 6-9). Future studies focused on younger children are needed to understand if differences in basic sensorimotor processing are more prominent earlier in development in autism.
It was suggested that processing subject relative clauses (SRCs) are universally easier than processing object relative clauses (ORCs) based on the studies carried out in head-initial languages such as English, and German. However, studies carried out in head-final languages such as Chinese and Basque refuted this claim. Turkish is also a head-final language. Existing relative clause processing literature in Turkish is based solely on behavioural metrics. Even though an ORC processing disadvantage was suggested for Turkish, the results were not conclusive. Therefore, we aimed to investigate the neural dynamics of relative clause processing in Turkish. We asked 14 native Turkish speakers to answer Yes/No questions about 24 sentences each containing either SRC or ORC while their prefrontal hemodynamic activity was recorded with fNIRS. Our findings revealed hemodynamic activity in the lateral portions of the left prefrontal cortex in both conditions. However, hemodynamic activity was more widespread in prefrontal regions for ORC than SRC. Even though the behavioural metrics failed to produce a significant difference between SRC and ORC conditions, direct ORC>SRC contrast revealed significant activity in left and right DLPFC, which are known to be involved in language processing and conflict monitoring related processes, respectively. Our findings indicate that processing ORCs are more difficult and require further prefrontal resources than processing SRCs in Turkish, thus refuting the head-directionality based explanations of relative clause processing asymmetries.
Individuals diagnosed with schizophrenia spectrum disorders (SSD) exhibit a constellation of sensory and perceptual impairments, including hyporeactivity to external input. However, individuals with SSD also report subjective experiences of sensory flooding, suggesting sensory hyperexcitability. To identify the extent to which behavioral indices of hyperexcitability are related to non-psychotic symptoms of schizophrenia, we tested a non-clinical population measured for schizophrenia-like traits (schizotypy), and a behavioral measure of sensory hyperexcitability, specifically the number of illusions seen in the Pattern Glare Test. Two samples totaling 913 individuals completed an online version of the Schizotypal Personality Questionnaire – Brief Revised (SPQ-BR) and the Pattern Glare Test. Individuals with higher schizotypy traits reported more illusions in the Pattern Glare Test. Additionally, one of the three SPQ-BR factors, the disorganized factor, significantly predicted the number of illusions reported. These data illustrate the potential for research in non-clinical samples to inform clinically relevant research.
Visual perceptual learning (VPL) has great potential implications for clinical populations, but adequate improvement often takes weeks to months to obtain; therefore, practical applications of VPL are limited. Strategies that enhance visual performance acquisition make great practical sense. Transcranial direct current stimulation (tDCS) could be beneficial to VPL, but thus far, the results are inconsistent. The current study had two objectives: (1) investigate the effect of anodal tDCS on VPL and (2) determine whether the timing sequence of anodal tDCS and training influences VPL. Anodal tDCS was applied on the left human middle temporal (hMT+) during training on a coherent motion discrimination task (online), anodal tDCS was also applied before training (offline), and sham tDCS was applied during training (sham). The coherent thresholds were measured without stimulation before, 2 days after and one month after training. All participants trained for 5 consecutive days. Anodal tDCS resulted in more performance improvement when applied during daily training but not when applied before training. Additionally, neither within-session improvement nor between-session improvement differed among the online, offline and sham tDCS conditions. These findings contribute to the development of efficient stimulation protocols and a deep understanding of the mechanisms underlying the effect of tDCS on VPL.
Neuronal sensitivity to light stimulation can be a significant confounding factor for assays that use light to study neuronal processes, such as optogenetics and fluorescent imaging. While continuous light stimulation has been shown to be responsible for a decrease in firing activity in several neuronal subtypes, discontinuous light stimulation commonly used in optogenetic experiments is supposed to have a negligible action. In the present report, we experimentally test this theoretical prediction by evaluating the effect produced by ten of the most commonly used patterns of discontinuous light stimulation under several electrophysiological parameters.