Network Dysfunction Research Articles

Unraveling the mechanistic interplay of mediators orchestrating the neuroprotective potential of harmine.

Neurodegenerative diseases (NDDs) encompass a range of conditions characterized by the specific dysfunction and continual decline of neurons, glial cells, and neural networks within the brain and spinal cord. The majority of NDDs exhibit similar underlying causes, including oxidative stress, neuroinflammation, and malfunctioning of mitochondria. Elevated levels of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), alongside decreased expression of brain-derived neurotrophic factor (BDNF) and glutamate transporter subtype 1 (GLT-1), constitute significant factors contributing to the pathogenesis of NDDs. Additionally, the dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) gene has emerged as a significant target for the treatment of NDDs at the preclinical level. It significantly contributes to developmental brain defects, early onset neurodegeneration, neuronal loss, and dementia in Down syndrome. Moreover, an impaired ubiquitin-proteosome system (UPS) also plays a pathological role in NDDs. Malfunctioning of UPS leads to abnormal protein buildup or aggregation of α-synuclein. α-Synuclein is a highly soluble unfolded protein that accumulates in Lewy bodies and Lewy neurites in Parkinson's disease and other synucleinopathies. Recent research highlights the promising potential of natural products in combating NDDs relative to conventional therapies. Alkaloids have emerged as promising candidates in the fight against NDDs. Harmine is a tricyclic β-carboline alkaloid (harmala alkaloid) with one indole nucleus and a six-membered pyrrole ring. It is extracted from Banisteria caapi and Peganum harmala L. and exhibits diverse pharmacological properties, encompassing neuroprotective, antioxidant, anti-inflammatory, antidepressant, etc. Harmine has been reported to mediate its neuroprotective via reducing the level of inflammatory mediators, NADPH oxidase, AChE, BChE and reactive oxygen species (ROS). Whereas, it has been observed to increase the levels of BDNF, GLT-1 and anti-oxidant enzymes, along with protein kinase-A (PKA)-mediated UPS activation. This review aims to discuss the mechanistic interplay of various mediators involved in the neuroprotective effect of harmine.

Functional alterations in overweight/obesity: focusing on the reward and executive control network.

Overweight (OW) and obesity (OB) have become prevalent issues in the global public health arena. Serving as a prominent risk factor for various chronic diseases, overweight/obesity not only poses serious threats to people's physical and mental health but also imposes significant medical and economic burdens on society as a whole. In recent years, there has been a growing focus on basic scientific research dedicated to seeking the neural evidence underlying overweight/obesity, aiming to elucidate its causes and effects by revealing functional alterations in brain networks. Among them, dysfunction in the reward network (RN) and executive control network (ECN) during both resting state and task conditions is considered pivotal in neuroscience research on overweight/obesity. Their aberrations contribute to explaining why persons with overweight/obesity exhibit heightened sensitivity to food rewards and eating disinhibition. This review centers on the reward and executive control network by analyzing and organizing the resting-state and task-based fMRI studies of functional brain network alterations in overweight/obesity. Building upon this foundation, the authors further summarize a reward-inhibition dual-system model, with a view to establishing a theoretical framework for future exploration in this field.

Mendelian randomization analyses reveal causal relationships between brain functional networks and risk of psychiatric disorders.

Dysfunction of brain resting-state functional networks has been widely reported in psychiatric disorders. However, the causal relationships between brain resting-state functional networks and psychiatric disorders remain largely unclear. Here we perform bidirectional two-sample Mendelian randomization (MR) analyses to investigate the causalities between 191 resting-state functional magnetic resonance imaging (rsfMRI) phenotypes (n = 34,691 individuals) and 12 psychiatric disorders (n = 14,307 to 698,672 individuals). Forward MR identified 8 rsfMRI phenotypes causally associated with the risk of psychiatric disorders. For example, the increase in the connectivity of motor, subcortical-cerebellum and limbic network was associated with lower risk of autism spectrum disorder. In adddition, increased connectivity in the default mode and central executive network was associated with lower risk of post-traumatic stress disorder and depression. Reverse MR analysis revealed significant associations between 4 psychiatric disorders and 6 rsfMRI phenotypes. For instance, the risk of attention-deficit/hyperactivity disorder increases the connectivity of the attention, salience, motor and subcortical-cerebellum network. The risk of schizophrenia mainly increases the connectivity of the default mode and central executive network and decreases the connectivity of the attention network. In summary, our findings reveal causal relationships between brain functional networks and psychiatric disorders, providing important interventional and therapeutic targets for psychiatric disorders at the brain functional network level.

Brain functional network changes in patients with juvenile myoclonic epilepsy: a study based on graph theory and Granger causality analysis.

Many resting-state functional magnetic resonance imaging (rs-fMRI) studies have shown that the brain networks are disrupted in adolescent patients with juvenile myoclonic epilepsy (JME). However, previous studies have mainly focused on investigating brain connectivity disruptions from the perspective of static functional connections, overlooking the dynamic causal characteristics between brain network connections. In our study involving 37 JME patients and 35 Healthy Controls (HC), we utilized rs-fMRI to construct whole-brain functional connectivity network. By applying graph theory, we delved into the altered topological structures of the brain functional connectivity network in JME patients and identified abnormal regions as key regions of interest (ROIs). A novel aspect of our research was the application of a combined approach using the sliding window technique and Granger causality analysis (GCA). This method allowed us to delve into the dynamic causal relationships between these ROIs and uncover the intricate patterns of dynamic effective connectivity (DEC) that pervade various brain functional networks. Graph theory analysis revealed significant deviations in JME patients, characterized by abnormal increases or decreases in metrics such as nodal betweenness centrality, degree centrality, and efficiency. These findings underscore the presence of widespread disruptions in the topological features of the brain. Further, clustering analysis of the time series data from abnormal brain regions distinguished two distinct states indicative of DEC patterns: a state of strong connectivity at a lower frequency (State 1) and a state of weak connectivity at a higher frequency (State 2). Notably, both states were associated with connectivity abnormalities across different ROIs, suggesting the disruption of local properties within the brain functional connectivity network and the existence of widespread multi-functional brain functional networks damage in JME patients. Our findings elucidate significant disruptions in the local properties of whole-brain functional connectivity network in patients with JME, revealing causal impairments across multiple functional networks. These findings collectively suggest that JME is a generalized epilepsy with localized abnormalities. Such insights highlight the intricate network dysfunctions characteristic of JME, thereby enriching our understanding of its pathophysiological features.

Research status and global trends of late-life depression from 2004 to 2023: bibliometric analysis.

Global research hotspots and future research trends in the neurobiological mechanisms of late-life depression (LLD) as well as its diagnosis and treatment are not yet clear. This study profiled the current state of global research on LLD and predicted future research trends in the field. Literature with the subject term LLD was retrieved from the Web of Science Core Collection, and CiteSpace software was used to perform econometric and co-occurrence analyses. The results were visualized using CiteSpace, VOSviewer, and other software packages. In total, 10,570 publications were included in the analysis. Publications on LLD have shown an increasing trend since 2004. The United States and the University of California had the highest number of publications, followed consecutively by China and England, making these countries and institutions the most influential in the field. Reynolds, Charles F. was the author with the most publications. The International Journal of Geriatric Psychiatry was the journal with the most articles and citations. According to the co-occurrence analysis and keyword/citation burst analysis, cognitive impairment, brain network dysfunction, vascular disease, and treatment of LLD were research hotspots. Late-life depression has attracted increasing attention from researchers, with the number of publications increasing annually. However, many questions remain unaddressed in this field, such as the relationship between LLD and cognitive impairment and dementia, or the impact of vascular factors and brain network dysfunction on LLD. Additionally, the treatment of patients with LLD is currently a clinical challenge. The results of this study will help researchers find suitable research partners and journals, as well as predict future hotspots.

Long-term adaptation of prefrontal circuits in a mouse model of NMDAR hypofunction

Pharmacological approaches to induce N-methyl-d-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in male mice that underwent a 7-day subchronic phencyclidine (PCP 10 mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds.

Households’ willingness-to-pay for different strategies aimed at reducing water supply network dysfunctions. A French case-study

ABSTRACT Using an original contingent valuation, this study compares the Willingness-To-Pay (WTP) of households for three water pipes renewal programs focused respectively on water quality, reducing leaks in networks and preventing breaks. A survey was conducted in southwest France: respondents were asked to rank the different renewal programs and then state the maximum amount they would be willing to pay in order to benefit from each. Results of a Heckman model suggest that variables influencing the probability of refusing to pay for a non-economic reason and the WTP differ from one program to another, which validates this choice of model. WTP estimates are not of the same order of magnitude whatever the program, and remained relatively low when compared to the actual water bill. While asset management is often only seen as an activity calling for specialised technical knowledge, users are able to perceive the outcome of that management process.

Exploring Advanced Therapies for Primary Biliary Cholangitis: Insights from the Gut Microbiota-Bile Acid-Immunity Network.

Primary biliary cholangitis (PBC) is a cholestatic liver disease characterized by immune-mediated injury to small bile ducts. Although PBC is an autoimmune disease, the effectiveness of conventional immunosuppressive therapy is disappointing. Nearly 40% of PBC patients do not respond to the first-line drug UDCA. Without appropriate intervention, PBC patients eventually progress to liver cirrhosis and even death. There is an urgent need to develop new therapies. The gut-liver axis emphasizes the interconnection between the gut and the liver, and evidence is increasing that gut microbiota and bile acids play an important role in the pathogenesis of cholestatic diseases. Dysbiosis of gut microbiota, imbalance of bile acids, and immune-mediated bile duct injury constitute the triad of pathophysiology in PBC. Autoimmune cholangitis has the potential to be improved through immune system modulation. Considering the failure of conventional immunotherapies and the involvement of gut microbiota and bile acids in the pathogenesis, targeting immune factors associated with them, such as bile acid receptors, microbial-derived molecules, and related specific immune cells, may offer breakthroughs. Understanding the gut microbiota-bile acid network and related immune dysfunctions in PBC provides a new perspective on therapeutic strategies. Therefore, we summarize the latest advances in research of gut microbiota and bile acids in PBC and, for the first time, explore the possibility of related immune factors as novel immunotherapy targets. This article discusses potential therapeutic approaches focusing on regulating gut microbiota, maintaining bile acid homeostasis, their interactions, and related immune factors.

Altered long-range functional connectivity in PTSD: Role of the infraslow oscillations of cortical activity amplitude envelopes

ObjectiveCoupling between the amplitude envelopes (AEs) of regional cortical activity reflects mechanisms that coordinate the excitability of large-scale cortical networks. We used resting-state MEG recordings to investigate the association between alterations in the coupling of cortical AEs and symptoms of post-traumatic stress disorder (PTSD). MethodsParticipants (n = 96) were service members with combat exposure and various levels of post-traumatic stress severity (PTSS). We assessed the correlation between PTSS and (1) coupling of broadband cortical AEs of beta band activity, (2) coupling of the low- (<0.5 Hz) and high-frequency (>0.5 Hz) components of the AEs, and (3) their time-varying patterns. ResultsPTSS was associated with widespread hypoconnectivity assessed from the broadband AE fluctuations, which correlated with subscores for the negative thoughts and feelings/emotional numbing (NTF/EN) and hyperarousal clusters of symptoms. Higher NTF/EN scores were also associated with smaller increases in resting-state functional connectivity (rsFC) with time during the recordings. The distinct patterns of rsFC in PTSD were primarily due to differences in the coupling of low-frequency (infraslow) fluctuations of the AEs of beta band activity. ConclusionsOur findings implicate the mechanisms underlying the regulation/coupling of infraslow oscillations in the alterations of rsFC assessed from broadband AEs and in PTSD symptomatology. SignificanceAltered coordination of infraslow amplitude fluctuations across large-scale cortical networks can contribute to network dysfunction and may provide a target for treatment in PTSD.

Monoaminergic Network Dysfunction and Development of Depression in Multiple Sclerosis: A Longitudinal Investigation (P3-6.012)

Monoaminergic Network Dysfunction and Development of Depression in Multiple Sclerosis: A Longitudinal Investigation (P3-6.012)

Low Functional network integrity in cognitively unimpaired and MCI subjects with depressive symptoms: results from a multi-center fMRI study

Evidence suggests that depressive symptomatology is a consequence of network dysfunction rather than lesion pathology. We studied whole-brain functional connectivity using a Minimum Spanning Tree as a graph-theoretical approach. Furthermore, we examined functional connectivity in the Default Mode Network, the Frontolimbic Network (FLN), the Salience Network, and the Cognitive Control Network. All 183 elderly subjects underwent a comprehensive neuropsychological evaluation and a 3 Tesla brain MRI scan. To assess the potential presence of depressive symptoms, the 13-item version of the Beck Depression Inventory (BDI) or the Geriatric Depression Scale (GDS) was utilized. Participants were assigned into three groups based on their cognitive status: amnestic mild cognitive impairment (MCI), non-amnestic MCI, and healthy controls. Regarding affective symptoms, subjects were categorized into depressed and non-depressed groups. An increased mean eccentricity and network diameter were found in patients with depressive symptoms relative to non-depressed ones, and both measures showed correlations with depressive symptom severity. In patients with depressive symptoms, a functional hypoconnectivity was detected between the Anterior Cingulate Cortex (ACC) and the right amygdala in the FLN, which impairment correlated with depressive symptom severity. While no structural difference was found in subjects with depressive symptoms, the volume of the hippocampus and the thickness of the precuneus and the entorhinal cortex were decreased in subjects with MCI, especially in amnestic MCI. The increase in eccentricity and diameter indicates a more path-like functional network configuration that may lead to an impaired functional integration in depression, a possible cause of depressive symptomatology in the elderly.

Determinants and Biomarkers of Progression Independent of Relapses in Multiple Sclerosis.

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1-20.

Brain correlates of recall of negative autobiographical memories in patients with schizophrenia

Introduction Autobiographical memory is known to be disturbed in schizophrenia. In addition, a leading theory of auditory hallucinations (AVH) is that they are intrusive – typically negative – autobiographical memories that are misinterpreted as perceptions.ObjectivesThe aim of this study was to examine the brain functional correlates of recall of negatively emotionally valanced autobiographical memories in patients with schizophrenia, with a longer term aim of comparing patients with and without AVH.Methods11 patients meeting DSM-5 criteria for schizophrenia or schizoaffective disorder and 10 age, sex and estimated premorbid IQ-matched healthy controls have so far taken part.Participants underwent functional MRI in a 3T scanner while performing a task requiring them to recall autobiographical memories in response to individually tailored pairs of cue words. The cue words were based on autobiographical memories previously elicited in an interview with each patient and were designed to evoke the same memory. The cue words were presented in 10 20-second blocks interspersed with blocks where the subjects viewed cue words that did not evoke autobiographical memories. Brain activations were examined in three contrasts of interest: memory evoking words vs baseline, neutral words vs baseline and memory evoking vs neutral words.Pre-processing and analysis were carried out with the FEAT module included in the FSL software. Statistical analysis was performed by means of a General Linear Model (GLM) approach.ResultsIn the memory evoking vs baseline contrast the patients showed hypoactivation in the medial frontal cortex compared to the healthy controls (Figure 1). There were no differences in activation between the patients and the controls comparing the memory evoking and neutral cues.Image:Conclusions The finding of hypoactivation in the medial frontal cortex compared to low level baseline in patients with schizophrenia suggests dysfunction in the default mode network, which is known to activate during recall of autobiographical memories.These preliminary results suggest that recall of negative autobiographical memories in patients with schizophrenia is associated with reduced activity in the default mode network. A planned larger sample of patients and controls will be used to examine activations in patients with and without AVH.Disclosure of InterestNone Declared

A Long-Acting Lyotropic Liquid Crystalline Implant Promotes the Drainage of Macromolecules by Brain-Related Lymphatic System in Treating Aged Alzheimer's Disease.

Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aβ accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.

Large-scale network abnormality in behavioral addiction

BackgroundResearchers have endeavored to ascertain the network dysfunction associated with behavioral addiction (BA) through the utilization of resting-state functional connectivity (rsFC). Nevertheless, the identification of aberrant patterns within large-scale networks pertaining to BA has proven to be challenging. MethodsWhole-brain seed-based rsFC studies comparing subjects with BA and healthy controls (HC) were collected from multiple databases. Multilevel kernel density analysis was employed to ascertain brain networks in which BA was linked to hyper-connectivity or hypo-connectivity with each prior network. ResultsFifty-six seed-based rsFC publications (1755 individuals with BA and 1828 HC) were included in the meta-analysis. The present study indicate that individuals with BAs exhibit (1) hypo-connectivity within the fronto-parietal network (FN) and hypo- and hyper-connectivity within the ventral attention network (VAN); (2) hypo-connectivity between the FN and regions of the VAN, hypo-connectivity between the VAN and regions of the FN and default mode network (DMN), hyper-connectivity between the DMN and regions of the FN; (3) hypo-connectivity between the reward system and regions of the sensorimotor network (SS), DMN and VAN; (4) hypo-connectivity between the FN and regions of the SS, hyper-connectivity between the VAN and regions of the SS. ConclusionsThese findings provide impetus for a conceptual framework positing a model of BA characterized by disconnected functional coordination among large-scale networks.

Anxiety symptoms without depression are associated with cognitive control network (CNN) dysfunction: An fNIRS study.

Anxiety is a common psychological disorder associated with other mental disorders, with depression being the most common comorbidity. Few studies have examined the neural mechanisms underlying anxiety after controlling for depression. This study aimed to explore whether there are differences in cortical activation in anxiety patients with different severities whose depression are normal. In the current study, depression levels were normal for 366 subjects-139 healthy subjects, 117 with mild anxiety, and 110 with major anxiety. Using the Hospital Anxiety and Depression Scale (HADS) and a verbal fluency task (VFT) to test subjects' anxiety and depression and cognitive function, respectively. A 53-channel guided near-infrared spectroscopic imaging technology (fNIRS) detected the concentration of oxyhemoglobin (oxy-Hb). Correlation analysis between anxiety severity and oxy-Hb concentration in the brain cortex was performed, as well as ANOVA analysis of oxy-Hb concentration among the three anxiety severity groups. The results showed that anxiety severity was significantly and negatively correlated with oxy-Hb concentrations in the left frontal eye field (lFEF) and in the right dorsolateral prefrontal area (rDLPFC). The oxy-Hb concentration in the lFEF and the rDLPFC were significantly lower in the major anxiety disorder group than that in the control group. This suggests that decreased cortical activity of the lFEF and rDLPFC may be neural markers of anxiety symptoms after controlling for depression. Anxiety symptoms without depression may be result from the dysfunction of the cognitive control network (CCN) which includes the lFEF and rDLPFC.

Transition and Propagation of Epilepsy in an Improved Epileptor Model Coupled with Astrocyte

In this paper, a tripartite synapse network is constructed to examine external and internal triggering factors of epilepsy transition and propagation in neurons with the Epileptor-2 model. We first explore the external stimuli in the environment that induce epileptic activities and transition behaviors among Ictal Discharges (IDs) and Interictal Discharges (IIDs) states. The higher the strength and abruptness of the stimuli, the more severe is the occurrence of epilepsy within a reasonable range of parameters. Then for the internal triggering factors, the results of the tripartite synapse network, which is improved by combining the Epileptor-2 model with astrocyte by means of ion exchange and new connections, show that astrocytes can transmit normal physiological activity information and filter out abnormal discharge information of neurons. One of the causes for epileptic seizures is the abnormal release of glial neurotransmitters in astrocytes. The excessive release of glutamate causes the discharge state of neurons to transit from nonepileptic to IIDs, IDs and tonic, while adenosine triphosphate can alleviate epilepsy. Meanwhile, the synapse dysfunction of an astrocyte-free network can also lead to seizures, and the epilepsy propagation ability of a tripartite synapse network becomes weaker than that of an astrocyte-free network. Our research is expected to provide some theoretical basis for the therapeutic approach to curing epilepsy in the intracellular and extracellular contexts.

Association of abnormal explicit sense of agency with cerebellar impairment in myoclonus-dystonia.

Non-motor aspects in dystonia are now well recognized. The sense of agency, which refers to the experience of controlling one's own actions, has been scarcely studied in dystonia, even though its disturbances can contribute to movement disorders. Among various brain structures, the cerebral cortex, the cerebellum, and the basal ganglia are involved in shaping the sense of agency. In myoclonus dystonia, resulting from a dysfunction of the motor network, an altered sense of agency may contribute to the clinical phenotype of the condition. In this study, we compared the explicit and implicit sense of agency in patients with myoclonus dystonia caused by a pathogenic variant of SGCE (DYT-SGCE) and control participants. We utilized behavioural tasks to assess the sense of agency and performed neuroimaging analyses, including structural, resting-state functional connectivity, and dynamic causal modelling, to explore the relevant brain regions involved in the sense of agency. Additionally, we examined the relationship between behavioural performance, symptom severity, and neuroimaging findings. We compared 19 patients with DYT-SGCE and 24 healthy volunteers. Our findings revealed that patients with myoclonus-dystonia exhibited a specific impairment in explicit sense of agency, particularly when implicit motor learning was involved. However, their implicit sense of agency remained intact. These patients also displayed grey-matter abnormalities in the motor cerebellum, as well as increased functional connectivity between the cerebellum and pre-supplementary motor area. Dynamic causal modelling analysis further identified reduced inhibitory effects of the cerebellum on the pre-supplementary motor area, decreased excitatory effects of the pre-supplementary motor area on the cerebellum, and increased self-inhibition within the pre-supplementary motor area. Importantly, both cerebellar grey-matter alterations and functional connectivity abnormalities between the cerebellum and pre-supplementary motor area were found to correlate with explicit sense of agency impairment. Increased self-inhibition within the pre-supplementary motor area was associated with less severe myoclonus symptoms. These findings highlight the disruption of higher-level cognitive processes in patients with myoclonus-dystonia, further expanding the spectrum of neurological and psychiatric dysfunction already identified in this disorder.

A systematic review of salivary biomarkers in Parkinson's disease.

The search for reliable and easily accessible biomarkers in Parkinson's disease is receiving a growing emphasis, to detect neurodegeneration from the prodromal phase and to enforce disease-modifying therapies. Despite the need for non-invasively accessible biomarkers, the majority of the studies have pointed to cerebrospinal fluid or peripheral biopsies biomarkers, which require invasive collection procedures. Saliva represents an easily accessible biofluid and an incredibly wide source of molecular biomarkers. In the present study, after presenting the morphological and biological bases for looking at saliva in the search of biomarkers for Parkinson's disease, we systematically reviewed the results achieved so far in the saliva of different cohorts of Parkinson's disease patients. A comprehensive literature search on PubMed and SCOPUS led to the discovery of 289 articles. After screening and exclusion, 34 relevant articles were derived for systematic review. Alpha-synuclein, the histopathological hallmark of Parkinson's disease, has been the most investigated Parkinson's disease biomarker in saliva, with oligomeric alpha-synuclein consistently found increased in Parkinson's disease patients in comparison to healthy controls, while conflicting results have been reported regarding the levels of total alpha-synuclein and phosphorylated alpha-synuclein, and few studies described an increased oligomeric alpha-synuclein/total alpha-synuclein ratio in Parkinson's disease. Beyond alpha-synuclein, other biomarkers targeting different molecular pathways have been explored in the saliva of Parkinson's disease patients: total tau, phosphorylated tau, amyloid-β1-42 (pathological protein aggregation biomarkers); DJ-1, heme-oxygenase-1, metabolites (altered energy homeostasis biomarkers); MAPLC-3beta (aberrant proteostasis biomarker); cortisol, tumor necrosis factor-alpha (inflammation biomarkers); DNA methylation, miRNA (DNA/RNA defects biomarkers); acetylcholinesterase activity (synaptic and neuronal network dysfunction biomarkers); Raman spectra, proteome, and caffeine. Despite a few studies investigating biomarkers targeting molecular pathways different from alpha-synuclein in Parkinson's disease, these results should be replicated and observed in studies on larger cohorts, considering the potential role of these biomarkers in determining the molecular variance among Parkinson's disease subtypes. Although the need for standardization in sample collection and processing, salivary-based biomarkers studies have reported encouraging results, calling for large-scale longitudinal studies and multicentric assessments, given the great molecular potentials and the non-invasive accessibility of saliva.

Moving across disorders: A cross-sectional study of cognition in early onset ataxia and dystonia

BackgroundEarly onset ataxia (EOA) and Early Onset Dystonia (EOD) are movement disorders developing in young people (age <25 per definition). These disorders result from dysfunctional networks involving the cerebellum and basal ganglia. As these structures are also important for cognition, cognitive deficits can be expected in EOA and EOD. EOA and EOD sometimes co-occur, but in those cases the predominant phenotype is determining. A pending question is whether predominantly EOA and EOD have different profiles of cognitive impairment. ObjectivesWe investigated whether cognitive functions were impaired in patients with either predominant EOA or predominant EOD and whether cognitive profiles differed between both patient groups. MethodsThe sample consisted of 26 EOA and 26 EOD patients with varying etiology but similar duration and severity of the disorder. Patient samples were compared to a group of 26 healthy controls, all matched on age and gender. All participants underwent neuropsychological testing for verbal intelligence, memory, working memory, attention/cognitive speed, executive functions, emotion recognition and language. ResultsEOA and EOD patients both performed significantly worse than healthy controls on tests of verbal intelligence, working memory and executive functions. Additionally, attention/cognitive speed and emotion recognition were impaired in the EOA group. Compared to EOD, EOA patients performed worse on attention/cognitive speed and verbal intelligence. ConclusionsOur results show overall similar profiles of cognitive deficits in both patient groups, but deficits were more pronounced in the patients with EOA. This suggests that more severe cognitive impairment is related to more severe cerebellar network dysfunction.