Brain communications最新文献

Clearing amyloid-β pathology in Alzheimer's disease (AD) has been considered a prerequisite for restoring cognitive functions. Intriguingly, by application of a modality of scanning ultrasound (SUS) to mice that does not remove amyloid-β, we previously achieved significant cognitive improvements. This prompted us to explore SUS as a non-invasive brain stimulation strategy in an open-label safety trial in AD. We conducted a human pilot study in 12 participants with AD with the primary objective of determining feasibility, safety and tolerability. Exploratory secondary end-points were cognitive and behavioural measures, resting-state EEG and functional MRI. A portable device termed UltraThera^Pilot was built under medical device standard guidelines, integrating a Brainsight image-guided neuronavigation system. A single-element 286-kHz transducer was programmed to deliver non-derated ultrasound doses of 2.6, 1.95 or 1.3 MPa. With four treatment sessions spaced fortnightly, four participants received 30 sonications per session (precuneus, ∼30 cm³ brain tissue) and the remaining 8 received 100 sonications per session (bilateral precuneus and temporo-parietal association cortex, ∼100 cm³). Safety monitoring, EEG, MRI, cognitive and neuropsychiatric evaluations were performed. The treatment was fast, safe and well-tolerated at the 1.95 MPa dose. MRI showed no changes, whereas changes were observed in aperiodic EEG content. Cognitive performance did not change but statistically significant improvements in behavioural and psychological symptoms were found using the Neuropsychiatric Inventory test. In conclusion, this SUS safety trial met its primary and secondary end-points in biomarker-confirmed mild-to-moderate AD. It informs our future work in an upcoming efficacy trial in an AD population.

Brain atrophy is a natural consequence of ageing but can be accelerated by neurodegenerative diseases such as Alzheimer's disease. We apply an existing algorithm to identify new biomarkers that better track volumetric changes over time, i.e. atrophy. These new biomarkers are the volumetric ratio of two composite regions of interest, identified by an algorithm optimized to enhance the monitoring of Alzheimer's disease progression. The algorithm prioritizes biomarkers with less noisy trajectories (quantified by lower sample size estimates for clinical trials) and that capture disease signal by showing a greater rate of change in amyloid-positive versus amyloid-negative individuals, ensuring the biomarker effectively reflects Alzheimer's pathology. Data from 1381 individuals from the Alzheimer's Disease Neuroimaging Initiative database having multiple MRI scans were analysed. The new biomarkers outperformed traditional volumetric measures (whole brain, hippocampus and ventricles) across all metrics. This improvement was particularly pronounced in cognitively impaired individuals, where atrophy is more severe. Among the traditional measures, ventricular volume had the best performance. Results suggest that ratios of regional brain volumes could enhance disease progression tracking, as has been shown in other modalities like fluid biomarker ratios and standardized uptake value ratios from positron emission tomography.

Neuropathic pain is characterized by hyperalgesia, allodynia or spontaneous pain arising from lesions or pathology in the somatosensory nervous system. Multiple mechanisms contribute to this pain following peripheral nerve and spinal cord injuries. Evidence shows that injury-induced changes in dendritic spine morphology in the dorsal horn may contribute to neuropathic pain presentation. Dendritic spines, critical postsynaptic structures for synaptic transmission, undergo remodelling from filopodia-like structures to mature, mushroom-shaped spines in nociceptive spinal cord regions after injury. Recent evidence indicates that peripheral nerve and spinal cord injuries affect local tissues and also lead to pathology in supraspinal brain regions. Interestingly, different injuries appear to target specific brain regions, potentially causing corresponding remodelling of dendritic spines. To investigate this, we examined whether spared nerve injury, as a peripheral nerve injury model, and spinal cord injury induce morphological changes in dendritic spines in different brain regions and whether systemic administration of mesenchymal stem cells could alleviate neuropathic pain by altering dendritic spine morphology. Our results demonstrate that both injuries induce significant morphological changes in dendritic spines in the brain and spinal cord. Specifically, the peripheral nerve injury model increases the density of mushroom-shaped spines in superficial Lamina II of the dorsal horn, whereas spinal cord injury induces similar changes in deeper Lamina V. In the brain, the peripheral nerve injury model showed increased mushroom-shaped spines in the sensory cortex and ventral posterior complex of the thalamus. In contrast, the spinal cord injury model showed these changes primarily in the thalamic intralaminar nuclei. Infused mesenchymal stem cells partially alleviated neuropathic pain in both models and reduced the density of mushroom-shaped spines in the respective affected regions. Gene expression analysis of cytoskeletal genes related to actin associated with the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor (AKAP5, ACTR2, and SORBS2) revealed upregulation of these genes in the sensory cortex (in the peripheral nerve injury model) and the thalamus (in the spinal cord injury model). Mesenchymal stem cells suppressed these upregulations, which were associated with reduced neuropathic pain. These findings suggest that infused mesenchymal stem cells can protect against the abnormal remodelling of dendritic spines, thereby contributing to pain alleviation regardless of injury type or affected region. The systemic administration of mesenchymal stem cells thus offers a promising therapeutic approach for treating multiple neuropathic pain conditions through structural and molecular alterations in dendritic spines.

Cognitive impairment in people with multiple sclerosis (pwMS) is highly heterogeneous, highlighting the need to better understand the underlying pathophysiological processes of cognitive decline and the brain's mechanisms for adapting to MS damage. This longitudinal study explores functional connectivity (FC) changes and their relationship with cognitive trajectories over seven years in pwMS. We aimed to determine whether individuals with cognitive decline exhibited different FC patterns compared to those with stable cognitive performance. For this purpose, we analysed data from 58 pwMS, including cognitive assessments using the Rao's battery and functional MRI at two-time points with an interval of seven years. Cognitive worsening was defined as 25% decline in global cognitive scores. Graph-based networks metrics, including global and node-based strength, efficiency and clustering coefficient, alongside regional normalized grey matter (GM) volumes, were computed using MRI. We used mixed effect regression models with random subject-specific intercepts to explore FC and GM volume differences and the association between FC and cognition. The cohort was predominantly female (78%), with a mean age of 46.8 years and a median disease duration of 11.6 years. We found a significant group-by-time interaction, patients with cognitive decline showed reductions in node strength (21.1% of nodes), local efficiency (64.4%), and clustering coefficient (85.5%) particularly in the deep GM and parietal cortex at follow-up, and reduced global graph metrics. In contrast, the cognitively stable group exhibited increased node strength (15.8%) and local efficiency (5.3%), mainly in the temporal and prefrontal cortices. Both groups showed reduced GM volume in 84.2 and 79% of regions at follow-up, respectively. Several links were found between FC changes and cognitive performance. Findings confirm distinct FC trajectories in pwMS associated with their ability to cope with structural damage, impacting cognitive outcomes at mid-term. These findings indicate that patients with stable cognitive performance may engage compensatory network reorganization processes, which could mitigate the progression of cognitive decline.

ECHS1 deficiency (ECHS1D) is a rare and devastating neurometabolic disease that currently has no defined treatments. This disorder results from missense loss-of-function mutations in the ECHS1 gene that results in severe developmental delays, encephalopathy, hypotonia and early death. ECHS1 enzymatic activity is necessary for the beta-oxidation of fatty acids and the oxidation of branched-chain amino acids within the inner mitochondrial matrix. The pathogenesis of disease remains poorly understood. To expand our knowledge on disease mechanisms, we generated a novel mouse model of ECHS1D that possesses a disease-associated variant knocked-in (KI) the Echs1 allele and a knock-out (KO) of the other Echs1 allele. Neurological and metabolic abnormalities were assessed under basal conditions, and acute inflammation was tested as a potential disease driver. Mice containing KI/KI or KI/KO alleles were viable with normal development and survival, and the combined KI and KO alleles resulted in more than a 95% reduction of Echs1 protein levels. ECHS1D mice had significantly increased epileptiform EEG activity and were sensitive to seizure induction, which resulted in the death of 60% of ECHS1D mice. Power spectral analysis revealed ECHS1D mice had increased slow-wave EEG power that was associated with sleep dysfunction. Under basal conditions, energy status and mitochondrial function within the brain was unaffected, while aromatic amino acid content was increased. Markers of neuroinflammation were increased in ECHS1D mice in an age-dependent manner and acute inflammatory challenge resulted in failure to thrive and early lethality in ECHS1D mice. In conclusion, we developed a novel model of ECHS1D that can be used to study disease mechanisms and for therapeutic development.

It is well documented that synapse loss correlates with cognitive decline in Alzheimer's disease. However, the mechanisms that contribute to synapse loss remain poorly understood. Studies have shown that amyloid-β directly signals to neurons to trigger changes in synaptic function leading to the subsequent loss of synapses. Other studies have demonstrated that glial cells directly target synapses in Alzheimer's disease. In this study, we determine the temporal relationship between changes in synapses and glial cells (microglia and astrocytes) in the NL-G-F knock-in mouse model of Alzheimer's disease. We evaluated synapse number and histological changes in glial cells in the hippocampus of NL-G-F mice using confocal microscopy across three timepoints, 2, 5, and 9 months, compared to their wild-type littermates. Using real-time quantitative PCR, we also evaluated molecular changes in glial cells. At 2 months of age, when very few amyloid-β plaques are present, inhibitory synapse number was transiently increased by more than 50% in NL-G-F mice, accompanied by a small increase in the microglial marker, Cx3cr1, and considerable changes in astrocyte markers, including a decreased level of Thbs1/2. At 5 months, when amyloid-β plaque load is notable, excitatory synapse number was decreased immediately proximal to plaques, whereas inhibitory synapse number was no different between NL-G-F and wild-type mice. At the cellular level, changes in microglia and astrocytes were also observed in NL-G-F mice in regions closely surrounding plaques. From 5 months, PCR analyses indicated marked and progressive changes in microglia and astrocyte markers, including increased Trem2 and Gfap expression. By 9 months, changes in excitatory synapse number and microglia at the cellular level were exacerbated, with evident synapse loss extending up to 30 µm away from plaques. Together, our data show that inhibitory synapses are the earliest change in NL-G-F mice occurring concomitantly with molecular changes in glial cells and preceding substantial plaque deposition, excitatory synapse loss, and glial cellular alterations.

Although functional neurological disorder (FND) is common, increasingly recognized, potentially disabling, and treatable, it remains stigmatized, and concerns about feigning persist among clinicians. We examined the prevalence of malingering and factitious disorder diagnoses in individuals with FND, their associated demographic and clinical characteristics, and evidence of clinician bias in the diagnosis of feigning. In this retrospective cohort and case-control study using the international TriNetX electronic health record network, we analysed diagnostic codes (International Classification of Diseases, Tenth Revision) for FND, malingering and factitious disorder to assess their prevalence and overlap. We then compared rates of malingering and factitious disorder following a diagnosis of FND with those in cohorts of patients with multiple sclerosis and with depression, used as comparison conditions. We also examined demographic characteristics and comorbidities of FND cases with and without records of feigning, as well as temporal trends in the proportion diagnosed with malingering. Between 2015 and 2024, 143 471 individuals were diagnosed with FND, 54 685 with malingering and 5215 with factitious disorder. 2.2% of individuals with FND also received a record of malingering or, less commonly, factitious disorder, or both. Following diagnosis, FND was associated with higher rates of malingering (1.36%) and factitious disorder (0.62%) compared to multiple sclerosis (0.17%, odds ratio 7.97, 95% confidence interval 7.17-8.87; and 0.03%, odds ratio 20.47, 95% confidence interval 16.15-25.94, respectively) and depression (0.42%, odds ratio 3.23, 95% confidence interval 3.08-3.39; and 0.05%, odds ratio 12.17, 95% confidence interval 11.18-13.31, respectively). Among FND cases, factitious disorder was more prevalent in White individuals, whereas malingering was more frequent in males, Black individuals and seizure presentations. Compared to other FND cases, those with diagnoses of malingering or factitious disorder had more psychiatric, neurological, and medical comorbidities, greater socio-economic adversity and increased mortality. Records of malingering were more likely in FND cases with histories of other stigmatized disorders, such as sexually transmitted diseases, viral hepatitis and HIV. Their proportion declined from 2018 to 2023. Malingering and factitious disorder are more frequently diagnosed in FND than in comparable disorders, although both remain uncommon. Their presence is associated with greater clinical complexity and poorer outcomes. Associations with ethnicity, socio-economic adversity and certain comorbidities suggest possible clinician bias, while declining malingering diagnoses in FND may reflect growing awareness among clinicians.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by the premutation (55-200 CGG repeats) in the fragile X messenger ribonucleoprotein-1 (FMR1) gene. An open question is: In what sequential order do FXTAS symptoms typically appear, and how does that sequence vary among patients and between males and females? We applied the ordinal-outcomes version of the Subtype and Stage Inference algorithm ('Ordinal SuStaIn') to identify the sequential events of clinical and brain MRI changes in cross-sectional data collected during baseline visits from a longitudinal cohort of FXTAS patients at Stages 0-5. We included 28 neurodegenerative symptoms collected from 253 premutation carriers (101 females and 152 males) and 44 controls (7 females and 37 males), aged 40-86 years old at entry, who participated in two longitudinal studies, with entry dates between 2008 and 2023. We found substantial differences in order of events depending on sex, and possibly in combination of sex and CGG repeats. The main finding is the predominance of the psychiatric co-morbidities that occur early in females (often before the onset of tremor and ataxia) compared to males. These findings suggest that the sequence of neuropsychiatric symptoms for FXTAS is different in females compared to males, particularly for early symptoms in disease development and progression. This could lead to sex-specific modifications of the FXTAS diagnostic stages.

Patients with chronic pain often complain of cognitive difficulties, such as 'poor memory'. Both acute and chronic pain are thought to impair cognitive performance by demanding attentional and cognitive resources to the detriment of cognitive functioning. However, systematic experimental investigations in patients, as well as deeper understanding of factors that modulate these effects remain lacking. This study investigated whether patients with chronic migraine or patients with chronic low back pain are more susceptible to the disruptive effects of pain on memory as compared to pain-free healthy controls. Two groups of individuals with chronic pain (n = 55 patients with chronic migraine, n = 59 patients with chronic back pain) and n = 59 age-matched healthy controls, underwent experimental pain stimulation at either the back or head while performing a visual categorization and a subsequent recognition task. Pain-related cognitions and clinical parameters were assessed to explore their influence on pain-cognition interference. This large-scale experimental study revealed encouraging results regarding the impact of experimental pain on memory for the pain disorders studied here. Contrary to our hypothesis, patients with chronic migraine or chronic back pain showed no greater effects of experimental pain on recognition memory than healthy participants. Furthermore, the study showed no effect of stimulation site (i.e. head or lower back) or interaction with type of chronic pain. Pain-related cognitions, psychological variables and clinical parameters only had a marginal effect on pain-induced impairment of recognition memory in pain patients. Future research should focus on identifying cognitive and neural predictors associated with susceptibility or resilience to the disruptive effects of pain. Furthermore, larger and more diverse samples could enable person-centred methods to investigate how cognitive, clinical, and situational factors interact in shaping cognitive performance under pain. Such insights are crucial for the development of targeted, individualized therapeutic approaches in the management of chronic pain syndromes.

Attention is a critical cognitive ability that impacts everyday functioning and is subserved by multispectral neural oscillatory dynamics spanning extended frontoparietal brain networks. Throughout childhood and adolescence, attention networks are highly plastic as they undergo rapid and dynamic maturation. Concurrently, this period is marked by heightened vulnerability to the consequences of low-grade inflammation, which is known to impact attention networks in adults but has been seldom explored in youth. The current cross-sectional study sought to characterize the links between low-grade inflammation and neural dynamics serving attention processing in childhood and adolescence. A total of 100 youth ages 8-15 years (M = 12.21 years, SD = 2.27; 50 males, 50 females) completed a visuospatial attention task during magnetoencephalography and also provided a saliva sample from which we quantified biomarkers of inflammation. We found significant inflammation-related increases in beta (18-24 Hz) responses during the task in classical top-down attention control regions (βs = -0.36 to -0.32, Ps < 0.001 to 0.002). Additionally, we found inflammation-related decreases in gamma (70-88 and 66-82 Hz) responses in regions commonly implicated in bottom-up attention processes (βs = -0.34 and -0.33, Ps < 0.001 and 0.002). Taken together, our findings suggest decreased neural efficiency in top-down attention control systems, and atypical disengagement of bottom-up resources as a function of increasing low-grade inflammation in typically developing youth. These effects may be reflective of excitotoxicity that is commonly cited as a result of neuroinflammatory processes, though future work is needed to more clearly elucidate the nature of these aberrant oscillatory responses.