Basal Ganglia Research Articles

Spike-phase coupling of subthalamic neurons to posterior opercular cortex predicts speech sound accuracy.

Speech provides a rich context for understanding how cortical interactions with the basal ganglia contribute to unique human behaviors, but opportunities for direct intracranial recordings across cortical-basal ganglia networks are rare. We recorded electrocorticographic signals in the cortex synchronously with single units in the basal ganglia during awake neurosurgeries where subjects spoke syllable repetitions. We discovered that individual STN neurons have transient (200ms) spike-phase coupling (SPC) events with multiple cortical regions. The spike timing of STN neurons was coordinated with the phase of theta-alpha oscillations in the posterior supramarginal and superior temporal gyrus during speech planning and production. Speech sound errors occurred when this STN-cortical interaction was delayed. Our results suggest that the STN supports mechanisms of speech planning and auditory-sensorimotor integration during speech production that are required to achieve high fidelity of the phonological and articulatory representation of the target phoneme. These findings establish a framework for understanding cortical-basal ganglia interaction in other human behaviors, and additionally indicate that firing-rate based models are insufficient for explaining basal ganglia circuit behavior.

Post-infectious Moyamoya Syndrome: A Review of Existing Scientific Literature From 2000 to 2023.

Moyamoya disease (MMD) is considered a primary disorder of an unknown etiology. In contrast, Moyamoya syndrome (MMS) refers to MMD associated with other underlying diseases, such as meningitis in childhood, neurofibromatosis type II, Down syndrome, cranial irradiation, and different types of anemias, particularly hemoglobinopathies. We aimed to provide a comprehensive clinicopathological overview of MMS. All case reports and case series published from 2000 to 2023 pertaining to MMD were included in the study. Case studies, original articles, editorials, letters to editors, and clinical images were excluded. The search was conducted using the Boolean operators ("AND" and "OR") on PubMed and Google Scholar. A total of 13 case reports and one case series study were included. The study suggests infection might be a trigger in susceptible individuals. The autoimmune antibody findings (anti-double stranded DNA IgG) suggest a potential autoimmune component in some cases. There were diverse presentations and outcomes of post-infectious MMS, with a striking predominance of pediatric cases (66.66%) and a possible female predominance. Both computerized tomography (CT) and magnetic resonance imaging (MRI) showed evidence of restricted blood flow. CT showed that stenosis, occlusion, and collateral formation were frequent vascular findings, but often unspecified in severity. Infarction, hypodensities, and hematoma were the most common parenchymal findings (22.22% each). The findings on MRI were stenosis (50%) and collateral formation (44.44%). Infarction was the most common finding (66.66%) in parenchyma. Hydrocephalus, encephalomalacia, and atrophy were less frequent. Lesions were most frequent in the internal carotid artery (66.66%),middle cerebral artery (66.66%), and anterior cerebral artery (50%). Lesions were less frequent in the posterior cerebral, vertebral, and basilar arteries. The frontal lobe (38.89%) and basal ganglia (33.33%) were commonly affected parenchymal regions. The most common risk factor was human immunodeficiency virus (HIV) infection (50%), followed by trisomy 21, cryptococcal, and other types of meningitides. Aspirin (50%) and antiretroviral therapy (38.89%) were the cornerstones of treatment for MMS. This review accentuates the noteworthy obstacles presented by post-infectious MMS, especially its catastrophic effect on children and its correlation with HIV/AIDS. According to our elaborate literature search using PubMed and Google Scholar, this is the first narrative review in the existing scientific literature summarizing the literature on post-infectious MMS.

Alcohol Toxicity in the Developing Cerebellum.

The impact of ethanol on the fetus is a significant concern as an estimated 2-5% of live births may be affected by prenatal alcohol exposure. This exposure can lead to various functional and structural abnormalities in the cerebral cortex, basal ganglia, diencephalon, and cerebellum, resulting in region-specific symptoms. The deficits relate to the motor and cognitive domains, affecting, in particular, general intelligence, attention, executive functions, language, memory, visual perception, and social skills-collectively called the fetal alcohol spectrum disorder (FASD). Recent studies suggest that damage to the developing cerebellum (in form of alcohol exposure) can impair the cortical targets of the cerebello-thalamo-cortical tract. This malfunction in the cerebello-cerebral loop optimization may be due to disruptions in the formation of the foundational elements of the internal model within the developing cerebellum. Alcohol exposure targets multiple nodes in the reciprocal loops between the cerebellum and cerebral cortex. Here, we examine the possibility that prenatal alcohol exposure damages the developing cerebellum and disrupts the connectivity within the cerebello-cerebral neuronal circuits, exacerbating FASD-related cortical dysfunctions. We propose that malfunctions between cerebellar internal model (critically involved in predictions) and cerebral regions contribute to the deficits observed in FASD. Given the major role of the cerebellum in motor, cognitive, and affective functions, we suggest that therapies should target these malfunctions to mitigate the burden of FASD. We discuss the concept of therapies oriented towards malfunctioning cerebello-cerebral loops (TOMCCLs), emphasizing anti-inflammatory strategies and treatments aimed at modulating cerebellar myelination to restore optimal and predictive cerebello-cerebral functions.

Associations of 10-year atherosclerotic cardiovascular disease risk scores with cerebral small vessel disease: the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study.

10-year atherosclerotic cardiovascular disease (ASCVD) risk scores were useful for predicting large vessel disease, but the relationships between them and cerebral small vessel disease (CSVD) were unclear. Our study aimed to evaluate associations of 10-year ASCVD risk scores with CSVD and its magnetic resonance imaging (MRI) markers. Community-dwelling residents from the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events study were included in this cross-sectional study. At baseline, we collected data related to the Framingham Risk Score (FRS), pooled cohort equation (PCE), prediction for ASCVD risk in China (China-PAR) and Systematic COronary Risk Evaluation model 2 (SCORE2), and classified participants into low, moderate and high groups. Participants underwent brain MRI scans. We evaluated white matter hyperintensity (WMH), lacunes, cerebral microbleeds (CMBs) and enlarged perivascular spaces in basal ganglia (BG-EPVS) according to criteria of Wardlaw and Rothwell, and calculated total CSVD score and modified total CSVD score. A total of 3063 participants were included, and 53.5% of them were female. A higher FRS was associated with higher total CSVD score (moderate vs. low: cOR 1.89, 95% CI 1.53-2.34; high vs. low: cOR 3.23, 95%CI 2.62-3.97), and the PCE, China-PAR or SCORE2 score was positively related to total CSVD score (P < 0.05). Moreover, higher 10-year ASCVD scores were associated with higher odds of WMH (P < 0.05), lacunes (P < 0.05), CMBs (P < 0.05) and BG-EPVS (P < 0.05). The 10-year ASCVD scores were positively associated with CSVD and its MRI markers. These scores provided a method of risk stratification in the population with CSVD.

Quantifying dilated perivascular spaces in children with sickle cell disease.

Sickle cell disease (SCD)-related neurological effects are particularly devastating. Dilated perivascular spaces (dPVS) are a well-described component of cerebral small vessel disease in older adults without SCD. However, the burden and association of dPVS with neurological complications in children with SCD have not been described. In this study, we used the international consensus criteria to quantify dPVS in the centrum semiovale and basal ganglia in T2-weighted magnetic resonance images (MRI) of children with SCD who were randomized as part of the Silent Cerebral Infarct Transfusion (SIT) trial. We examined the relationship between global and/or regional dPVS burden and presence or area of silent cerebral infarctions, hematological measures, demographic variables, and full-scale intelligence quotient (FSIQ) scores. The study included 156 SIT trial participants who had pre-randomization and study exit MRI. Their median age was 9.6 (5-15) years, 39% were female, and 94 (60%) participants had a high dPVS burden. Participants randomized to the blood transfusion arm and who had a high dPVS burden at baseline had a moderate decline in dPVS score over 36months compared to no change in the observation group. On multivariable logistic regression, intelligence quotient was not associated with dPVS burden. Children with SCD included in the SIT trial have a high burden of dPVS compared to children without SCD. However, dPVS do not appear to have the same pathophysiology of silent cerebral infarcts. Further study is needed to determine both their etiology and clinical relevance.

Tracking longitudinal thalamic volume changes during early stages of SCA1 and SCA2.

Spinocerebellar ataxia SCA1 and SCA2 are adult-onset hereditary disorders, due to triplet CAG expansion in their respective causative genes. The pathophysiology of SCA1 and SCA2 suggests alterations of cerebello-thalamo-cortical pathway and its connections to the basal ganglia. In this framework, thalamic integrity is crucial for shaping efficient whole-brain dynamics and functions. The aims of the study are to identify structural changes in thalamic nuclei in presymptomatic and symptomatic SCA1 and SCA2 patients and to assess disease progression within a 1-year interval. A prospective 1-year clinical and MRI assessment was conducted in 27 presymptomatic and 23 clinically manifest mutation carriers for SCA1 and SCA2 expansions. Cross-sectional and longitudinal changes of thalamic nuclei volume were investigated in SCA1 and SCA2 individuals and in healthy participants (n = 20). Both SCA1 and SCA2 patients had significant atrophy in the majority of thalamic nuclei, except for the posterior and partly medial nuclei. The 1-year longitudinal evaluation showed a specific pattern of atrophy in ventral and posterior thalamus, detectable even at the presymptomatic stage of the disease. For the first time in vivo, our exploratory study has shown that different thalamic nuclei are involved at different stages of the degenerative process in both SCA1 and SCA2. It is therefore possible that thalamic alterations might significantly contribute to the progression of the disease years before overt clinical manifestations occur.

Pathways from the Superior Colliculus to the Basal Ganglia.

The present work aims to review the structural organization of the mammalian superior colliculus (SC), the putative pathways connecting the SC and the basal ganglia, and their role in organizing complex behavioral output. First, we review how the complex intrinsic connections between the SC's laminae projections allow for the construction of spatially aligned, visual-multisensory maps of the surrounding environment. Moreover, we present a summary of the sensory-motor inputs of the SC, including a description of the integration of multi-sensory inputs relevant to behavioral control. We further examine the major descending outputs toward the brainstem and spinal cord. As the central piece of this review, we provide a thorough analysis covering the putative interactions between the SC and the basal ganglia. To this end, we explore the diverse thalamic routes by which information from the SC may reach the striatum, including the pathways through the lateral posterior, parafascicular, and rostral intralaminar thalamic nuclei. We also examine the interactions between the SC and subthalamic nucleus, representing an additional pathway for the tectal modulation of the basal ganglia. Moreover, we discuss how information from the SC might also be relayed to the basal ganglia through midbrain tectonigral and tectotegmental projections directed at the substantia nigra compacta and ventrotegmental area, respectively, influencing the dopaminergic outflow to the dorsal and ventral striatum. We highlight the vast interplay between the SC and the basal ganglia and raise several missing points that warrant being addressed in future studies.

Interconnections between the dorsal thalamus and the basal nuclei in a reptile

Reciprocal connections between the thalamus and the cortex are one of the most characteristic features of forebrain organization in mammals. To date, this circuit has been documented only in turtles. However, reptiles, including turtles, have an additional path from the dorsal thalamus to the telencephalon. This terminates in a pallial structure known as the dorsal ventricular ridge. Yet, no reciprocal connection from the dorsal ventricular ridge to thalamic nuclei has been uncovered. Since axons from the thalamus pass through the basal nuclei on route to the dorsal ventricular ridge, the basal nuclei might be a source of reciprocal connections. Accordingly, the location and distribution of neurons after retrograde tracer placement into the dorsal thalamus were examined. Retrogradely labeled neurons in the basal nuclei were indeed found. One possibility to explain this observation is that connections with the dorsal ventricular ridge are present during development but later pruned during embryogenesis.

The Basal Ganglia and Mesencephalic Locomotor Region Connectivity Matrix.

Although classically considered a relay station for basal ganglia (BG) output, the anatomy, connectivity, and function of the mesencephalic locomotor region (MLR) were redefined during the last two decades. In striking opposition to what was initially thought, MLR and BG are actually recip- rocally and intimately interconnected. New viral-based, optogenetic, and mapping technologies re- vealed that cholinergic, glutamatergic, and GABAergic neurons coexist in this structure, which, in ad- dition to extending descending projections, send long-range ascending fibers to the BG. These MLR projections to the BG convey motor and non-motor information to specific synaptic targets throughout different nuclei. Moreover, MLR efferent fibers originate from precise neuronal subpopulations locat- ed in particular MLR subregions, defining independent anatomo-functional subcircuits involved in particular aspects of animal behavior such as fast locomotion, explorative locomotion, posture, fore- limb-related movements, speed, reinforcement, among others. In this review, we revised the literature produced during the last decade linking MLR and BG. We conclude that the classic framework con- sidering the MLR as a homogeneous output structure passively receiving input from the BG needs to be revisited. We propose instead that the multiple subcircuits embedded in this region should be taken as independent entities that convey relevant and specific ascending information to the BG and, thus, actively participate in the execution and tuning of behavior.

High baseline perivascular space volume in basal ganglia is associated with attention and executive function decline in Parkinson's disease.

Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinson's disease (PD). However, whether this impacts specific cognitive domains has not been investigated. This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals. A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains.

Separation of Channels Subserving Approach and Avoidance/Escape at the Level of the Basal Ganglia and Related Brainstem Structures.

The basal ganglia have the key function of directing our behavior in the context of events from our environment and/or our internal state. This function relies on afferents targeting the main input structures of the basal ganglia, entering bids for action selection at the level of the striatum or sig- nals for behavioral interruption at the level of the subthalamic nucleus, with behavioral reselection facilitated by dopamine signaling. Numerous experiments have studied action selection in relation to inputs from the cerebral cortex. However, less is known about the anatomical and functional link between the basal ganglia and the brainstem. In this review, we describe how brainstem structures also project to the main input structures of the basal ganglia, namely the striatum, the subthalamic nucleus and midbrain dopaminergic neurons, in the context of approach and avoidance (including escape from threat), two fundamental, mutually exclusive behavioral choices in an animal's repertoire in which the brainstem is strongly involved. We focus on three particularly well-described loci involved in approach and avoidance, namely the superior colliculus, the parabrachial nucleus and the periaqueductal grey nucleus. We consider what is known about how these structures are related to the basal ganglia, focusing on their projections toward the striatum, dopaminergic neurons and subthalamic nucleus, and explore the functional consequences of those interactions.

Quantitative susceptibility mapping based basal ganglia segmentation via AGSeg: leveraging active gradient guiding mechanism in deep learning.

With better visual contrast and the ability for magnetic susceptibility quantification analysis, quantitative susceptibility mapping (QSM) has emerged as an important magnetic resonance imaging (MRI) method for basal ganglia studies. Precise segmentation of basal ganglia is a prerequisite for quantification analysis of tissue magnetic susceptibility, which is crucial for subsequent disease diagnosis and surgical planning. The conventional method of localizing and segmenting basal ganglia heavily relies on layer-by-layer manual annotation by experts, resulting in a tedious amount of workload. Although several morphology registration and deep learning based methods have been developed to automate segmentation, the voxels around the nuclei boundary remain a challenge to distinguish due to insufficient tissue contrast. This paper proposes AGSeg, an active gradient guidance-based susceptibility and magnitude information complete (MIC) network for real-time and accurate basal ganglia segmentation. Various datasets, including clinical scans and data from healthy volunteers, were collected across multiple centers with different magnetic field strengths (3T/5T/7T), with a total of 210 three-dimensional (3D) susceptibility measurements. Manual segmentations following fixed rules for anatomical borders annotated by experts were used as ground truth labels. The proposed network took QSM maps and Magnitude images as two individual inputs, of which the features are selectively enhanced in the proposed magnitude information complete (MIC) module. AGSeg utilized a dual-branch architecture, with Seg-branch aiming to generate a proper segmentation map and Grad-branch to reconstruct the gradient map of regions of interest (ROIs). With the support of the newly designed active gradient module (AGM) and gradient guiding module (GGM), the Grad-branch provided attention guidance for the Seg-branch, facilitating it to focus on the boundary of target nuclei. Ablation studies were conducted to assess the functionality of the proposed modules. Significant performance decrement was observed after ablating relative modules. AGSeg was evaluated against several existing methods on both healthy and clinical data, achieving an average Dice similarity coefficient (DSC) =0.874 and average 95% Hausdorff distance (HD95) =2.009. Comparison experiments indicated that our model had superior performance on basal ganglia segmentation and better generalization ability over existing methods. The AGSeg outperformed all implemented comparison deep learning algorithms with average DSC enhancement ranging from 0.036 to 0.074. The current work integrates a deep learning-based method into automated basal ganglia segmentation. The high processing speed and segmentation robustness of AGSeg contribute to the feasibility of future surgery planning and intraoperative navigation. Experiments show that leveraging active gradient guidance mechanisms and magnitude information completion can facilitate the segmentation process. Moreover, this approach also offers a portable solution for other multi-modality medical image segmentation tasks.

Contributions of Basal Ganglia Circuits to Perception, Attention, and Consciousness.

Research into ascending sensory pathways and cortical networks has generated detailed models of perception. These same cortical regions are strongly connected to subcortical structures, such as the basal ganglia (BG), which have been conceptualized as playing key roles in reinforcement learning and action selection. However, because the BG amasses experiential evidence from higher and lower levels of cortical hierarchies, as well as higher-order thalamus, it is well positioned to dynamically influence perception. Here, we review anatomical, functional, and clinical evidence to demonstrate how the BG can influence perceptual processing and conscious states. This depends on the integrative relationship between cortex, BG, and thalamus, which allows contributions to sensory gating, predictive processing, selective attention, and representation of the temporal structure of events.

Augmentation of perivascular space visualization in basal ganglia and white matter hyperintensity lesion is a meaningful finding for subsequent cognitive decline.

Cerebral small vessel disease (CSVD) causes cognitive decline and perivascular space enlargement is one of the image markers for CSVD. To search for clinical significance in the time-course augmentation of perivascular space in basal ganglia (BG-PVS) for cognitive decline. This study population included 179 participants from a community-based cohort, aged 70 years at baseline. They had undergone magnetic resonance imaging (MRI) studies two or three times between 2000 and 2008. Based on the severity of BG-PVS or white matter hyperintensity lesions (WMHL) in 2000, the participants were divided into low-grade or high-grade groups, respectively. In addition, their time-course augmentation was evaluated, and we created a categorical BG-PVS WMHL change score based on their augmentation (1 = neither, 2 = BG-PVS augmentation only, 3 = WMHL augmentation only, 4 = both). Cognitive function was assessed based on the Mini-Mental State Examination (MMSE); the change was defined as the difference between scores in 2000 and 2008. We used simple or multiple regression analysis for MMSE score change according to MRI findings and clinical characteristics that were probably related to cognitive decline. In univariate analysis, MMSE score change was negatively associated with BG-PVS high grade at baseline and BG-PVS WMHL change score 4; this remained significant in multivariate analysis. In the final model based on the Akaike Information Criterion, BG-PVS WMHL change score 4 was associated with a 3.3-point decline in subsequent MMSE score. This study suggested that augmentation in both BG-PVS and WMHL was associated with subsequent cognitive decline.

The Basal Ganglia Downstream Control of Action - An Evolutionarily Conserved Strategy.

The motor areas of the cortex and the basal ganglia both contribute to determining which motor actions will be recruited at any moment in time, and their functions are intertwined. Here, we review the basal ganglia mechanisms underlying the selection of behavior of the downstream control of motor centers in the midbrain and brainstem and show that the basic organization of the forebrain motor system is evolutionarily conserved throughout vertebrate phylogeny. The output level of the basal ganglia (e.g. substantia nigra pars reticulata) has GABAergic neurons that are spontaneously active at rest and inhibit a number of specific motor centers, each of which can be relieved from inhibition if the inhibitory output neurons themselves become inhibited. The motor areas of the cortex act partially via the dorsolateral striatum (putamen), which has specific modules for the forelimb, hindlimb, trunk, etc. Each module operates in turn through the two types of striatal projection neurons that control the output modules of the basal ganglia and thereby the downstream motor centers. The mechanisms for lateral inhibition in the striatum are reviewed as well as other striatal mechanisms contributing to action selection. The motor cortex also exerts a direct excitatory action on specific motor centers. An overview is given of the basal ganglia control exerted on the different midbrain/brainstem motor centers, and the efference copy information fed back via the thalamus to the striatum and cortex, which is of importance for the planning of future movements.

Unilateral basal ganglia infarction presenting as sudden onset daytime sleepiness

Basal ganglia (BG) are involved in motor coordination. BG strokes usually present with problems controlling speech, movements, mood and posture leading to abulia which is a prominent feature. BG stroke presenting with daytime sleepiness is not well reported. We report a 63-year- old Asian woman with hypertension presenting with sudden onset daytime sleepiness due to basal ganglia infarction. This case highlights the importance of considering BG infarction as a differential diagnosis for sudden onset daytime sleepiness.

Gray matter morphometric biomarkers for distinguishing manganese-exposed welders from healthy adults revealed by source-based morphometry

BackgroundChronic overexposure to manganese (Mn) may result in neurotoxicity, which is characterized by motor and cognitive dysfunctions. This study aimed to utilize multivariate source-based morphometry (SBM) to explore the biomarkers for distinguishing Mn-exposed welders from healthy controls (HCs). MethodsHigh-quality 3D T1-weighted MRI scans were obtained from 45 Mn-exposed full-time welders and 33 age-matched HCs in this study. After extracting gray matter structural covariation networks by SBM, multiple classic interaction linear models were applied to investigate distinct patterns in welders compared to HCs, and Z-transformed loading coefficients were compared between the two groups. A receiver operating characteristic (ROC) curve was used to identify potential biomarkers for distinguishing Mn-exposed welders from HCs. Additionally, we assessed the relationships between clinical features and gray matter volumes in the welders group. ResultsA total of 78 subjects (45 welders, mean age 46.23±4.93 years; 33 HCs, mean age 45.55±3.40 years) were evaluated. SBM identified five components that differed between the groups. These components displayed lower loading weights in the basal ganglia, thalamus, default mode network (including the lingual gyrus and precuneus), and temporal lobe network (including the temporal pole and parahippocampus), as well as higher loading weights in the sensorimotor network (including the supplementary motor cortex). ROC analysis identified the highest classification power in the thalamic network. ConclusionsAltered brain structures might be implicated in Mn overexposure-related disturbances in motivative modulation, cognitive control and information integration. These results encourage further studies that focus on the interaction mechanisms, including the basal ganglia network, thalamic network and default mode network. Our study identified potential neurobiological markers in Mn-exposed welders and illustrated the utility of a multivariate method of gray matter analysis.

Inhibitory Pedunculopontine Neurons Gate Dopamine-Mediated Motor Actions of Unsigned Valence.

The pedunculopontine nucleus (PPN) maintains a bidirectional connectivity with the basal ganglia that supports their shared roles in the selection and execution of motor actions. Previous studies identified a role for PPN neurons in goal-directed behavior, but the cellular substrates underlying this function have not been elucidated. We recently revealed the existence of a monosynaptic GABAergic input from the PPN that inhibits dopamine neurons of the substantia nigra. Activation of this pathway interferes with the execution of learned motor sequences when the actions are rewarded, even though the inhibition of dopamine neurons did not shift the value of the action, hence suggesting executive control over the gating of behavior. To test the attributes of the inhibition of dopamine neurons by the PPN in the context of goal-directed behavior regardless of whether the outcome is positive or negative. We delivered optogenetic stimulation to PPN GABAergic axon terminals in the substantia nigra during a battery of behavioral tasks with positive and negative valence. Inhibition of dopamine neurons by PPN optogenetic activation during an appetitive task impaired the initiation and overall execution of the behavioral sequence without affecting the consumption of reward. During an active avoidance task, the same activation impaired the ability of mice to avoid a foot shock, but their escape response was unaffected. In addition, responses to potential threats were significantly attenuated. Our results show that PPN GABAergic neurons modulate learned, goal-directed behavior of unsigned valence without affecting overall motor behavior.

The effect of rifaximin and lactulose treatments to chronic hepatic encephalopathy rats: An [18F]PBR146 in-vivo neuroinflammation imaging study.

Hepatic encephalopathy (HE) is a severe neuropsychiatric complication of liver diseases characterized by neuroinflammation. The efficacies of nonabsorbable rifaximin (RIF) and lactulose (LAC) have been well documented in the treatment of HE. [18F]PBR146 is a translocator protein (TSPO) radiotracer used for in vivo neuroinflammation imaging. This study investigated anti-neuroinflammation effect of RIF or/and LAC in chronic HE rats by [18F]PBR146 micro-PET/CT. Bile duct ligation (BDL) operation induced chronic HE models, and this study included Sham+normal saline (NS), BDL+NS, BDL+RIF, BDL+LAC, and BDL+RIF+LAC groups. Behavioral assessment was performed to analyze the motor function, and fecal samples were collected after successfully established the chronic HE model (more than 28 days post-surgery). In addition, fecal samples collection and micro-PET/CT scans were performed sequentially. And we also collected the blood plasma, liver, intestinal, and brain samples after sacrificing the rats for further biochemical and pathological analyses. The RIF- and/or LAC-treated BDL rats showed similar behavioral results with Sham+NS group, while the treatment could not reverse the biliary obstruction resulting in sustained liver injury. The RIF or/and LAC treatments can inhibit IFN-γ and IL-10 productions. The global brain uptake values of [18F]PBR146 in BDL+NS group was significantly higher than other groups (p<.0001). The brain regions analysis showed that the basal ganglia, hippocampus, and cingulate cortex had radiotracer uptake differences among groups (all p<.05), which were consistent with the brain immunohistochemistry results. Sham+NS group was mainly enriched in Christensenella, Coprobacillus, and Pseudoflavonifractor. BDL+NS group was mainly enriched in Barnesiella, Alloprevotella, Enterococcus, and Enterorhabdus. BDL+RIF+LAC group was enriched in Parabacteroides, Bacteroides, Allobaculum, Bifidobacterium, and Parasutterella. RIF or/and LAC had anti-neuroinflammation in BDL-induced chronic HE rats with gut microbiota alterations. The [18F]PBR146 could be used for monitoring RIF or/and LAC treatment efficacy of chronic HE rats.

Clinical, imaging, and pathological characteristics of 35 cases of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome

Objective: To summarize the clinical, imaging, and pathological characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome (MELAS) to improve the diagnosis of this rare disease. Methods: A retrospective case series was conducted to collect the clinical data and results of genetic testing, muscle biopsy, and imaging studies including computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance spectroscopy (MRS) of 35 patients with MELAS admitted to the Nanjing Drum Tower Hospital from 2012 to 2021. Descriptive statistical analysis including mean, standard deviation, and frequency percentage were carried out. Results: The average age of onset of the patients was 30.2±2.3 years; the prevalence of family history was 20%. The two main initial symptoms were limb weakness and convulsions. The clinical manifestations of the neuromuscular system were proximal muscle weakness and exercise intolerance. The endocrine system is the most affected outside the neuromuscular system, with diabetes being the most common condition. Among the five patients who underwent brain CT, four showed hypodense lesions and two had calcified lesions. Brain MRI in 26 patients showed that the lesions more often affected the parietal lobe, basal ganglia, temporal lobe, occipital lobe, and frontal lobe than the infratentorial areas. Twelve of these individuals exhibited different levels of brain atrophy. Among the 10 patients who underwent 1H-MRS, nine showed a decrease in N-acetylaspartate (NAA) levels, eight exhibited abnormal lactate elevation (Lac peaks), whereas six had both reduced NAA levels and the presence of Lac peaks. Thirty-one patients underwent genetic testing; among them, 25 were found to have the mt.3243A>G mutation, while the remaining six exhibited rare gene alterations. Muscle biopsies were performed in 21 patients, and 15 showed abnormal mitochondrial proliferation manifested by ragged red fibers and defective oxidative phosphorylation manifested by cytochrome C oxidase (COX) enzyme-deficient muscle fibers. Conclusion: The clinical manifestations of MELAS syndrome are variable and complex, and early atypical symptoms could be missed or misdiagnosed. A detailed clinical history, imaging MRS analysis, muscle biopsy, and genetic testing are necessary to confirm the accurate diagnosis of MELAS.