Brain communications最新文献

5q-spinal muscular atrophy (SMA) is a fatal autosomal recessive disease characterized by the progressive muscle weakness and atrophy. In this retrospective study, we described the long-term clinical outcomes of novel disease-modifying therapies (DMTs) for 5q-spinal muscular atrophy, drawing on experience from southern China. This is a single-centre large cohort which enrolled 102 paediatric patients confirmed with 5q-spinal muscular atrophy at Guangzhou Women and Children's Medical Center from 2019 to 2024. One hundred and two patients were included, 24 were classified as SMA type 1, 56 with type 2 and 22 with type 3. One hundred per cent of the patients received nusinersen, with 31 (30.3%) patients starting risdiplam and 2 patients transitioning to zolgensma therapy. Over the 5-year treatment and follow-up period (2019-24), the survival rate reached 97.08%. One child with SMA type 1 and two with SMA type 2 died while receiving nusinersen monotherapy. Compared with baseline, the enrolled SMA patients exhibited statistically significant motor function gains. Nevertheless, type 1 patients experienced weight loss, while linear growth was compromised in both type 1 and type 2 patients after treatment. Serum insulin-like growth factor-1 levels rose modestly in types 1 and 2, but the increase did not reach statistical significance. Respiratory tract infections, malnutrition, scoliosis and fracture are the main complications and potential life-threatening risk factors during DMTs. Moreover, longer diagnostic to treatment intervals were significantly and inversely associated with motor function gains and directly associated with higher complication rates. This retrospective study confirms the effectiveness of nusinersen and risdiplam for 5q-spinal muscular atrophy and highlights the critical importance of early initiation of DMTs.

Sirolimus, an inhibitor of mammalian target of rapamycin complex (mTORC) 1, a regulatory protein involved in seizures and a modulator of inflammation, represents a potential new treatment strategy for pneumococcal meningitis. This study investigates the effects of mTORC1 inhibition using sirolimus in a mouse model of experimental pneumococcal meningitis. In a prospective, investigator-blinded and randomized trial, 96 mice were infected intracisternally with Streptococcus pneumoniae serotype 2. Mice were randomized for treatment with sirolimus and all mice received antibiotic treatment. In a clinical severity experiment, 48 mice were infected and scored every 4 h for disease severity until 72 h. In a time-point experiment, 48 mice were infected and terminated at 6 or 24 h after infection for evaluation. In the clinical severity experiment, sirolimus treatment did not improve survival, although seizures tended to occur less in treated mice [3 of 24 (13%) versus 5 of 24 (21%), P = 0.7]. In the time point experiment, clinical severity scores were increased in sirolimus-treated mice [maximum difference at 24 h after infection with a median of 10 (interquartile range 10-13) versus 7.5 (interquartile range 5-9) at 24 h after infection, P < 0.01]. While bacterial loads were similar across groups, sirolimus treatment increased inflammation. In the brain of treated mice, interleukin 6 was increased (median 8900 pg/ml versus 4804 pg/ml, P = 0.04), while interleukin 12 was elevated in both the brain (median 591 pg/ml versus 405 pg/ml, P = 0.03) and plasma (median 216 pg/ml versus 7 pg/ml, P < 0.01). Our findings illustrate the importance of mTORC1 signalling during pneumococcal meningitis in regulating inflammation. However, our results indicate that sirolimus is unlikely to be an effective treatment for this condition.

Sensory processing as a neurological construct is the perception and interpretation of sensory information from both the body and the environment. Disruptions to sensory processing adversely impact daily functioning. One type of disruption that is particularly interesting is altered sensory modulation, leading to hypersensitivity or hyposensitivity, which are common in many neurodevelopmental and psychiatric conditions such as autism spectrum disorder, attention-deficit/hyperactivity disorder, Alzheimer's, and schizophrenia. Here we aim to identify modality-specific and cross-modality brain networks involved in altered auditory and somatosensory processing. A systematic review identified 61 patients with new-onset sensory alterations following focal brain injury. Lesions were traced and combined with resting-state data from 1000 healthy controls to generate normative lesion connectivity maps. The specificity of our cohort's lesion-connectivity compared to lesions associated with 22 other neuropsychiatric symptoms was assessed with voxel-wise two-sample t-tests performed with the FSL Permutation Analysis of Linear Models tool (family-wise error P < 0.05). A conjunction analysis against lesions associated with hallucination was conducted by binarizing and multiplying one-sample T-test maps to identify common lesion-connections between the conditions. Modality-specific networks were connected to their unimodal cortices and the cerebellum. Overall, lesions associated with cross-modality sensitivity changes had convergent connections to the substantia nigra, medial orbitofrontal cortex, and cerebellum (Lobule V, medial Lobule VIIIa). Subgroup analysis by direction revealed that lesions causing decreased sensitivity were connected to lobule X, in addition to the aforementioned cerebellar regions, while those causing increased sensitivity were only connected to medial V and bilateral V. Regardless of directionality, 90% of lesions exhibited connections to bilateral Lobule V. Conjunction analysis with hallucinations revealed common lesion-connections to cerebellar vermis and frontal pole. Our analysis identified significant lesion-connections to the substantia nigra, medial orbitofrontal cortex, and cerebellum-highlighting these key regions in cross-modality sensory processing. These findings emphasize the role of higher cognitive functions in sensory integration and suggest potential targets for neuromodulation to improve sensory processing.

Patients with sustained shoulder elevation postures were observed over time in our movement disorders clinic and occasionally reported in literature as variants of dystonia or post-traumatic movement disorders. We retrospectively assessed the clinical records of patients in our movement disorders registry with sustained or fixed shoulder elevation. Their clinical phenomenology, response to treatment and precipitants were investigated. The patients underwent neurophysiologic, genetic and neuropsychologic tests. A PubMed search of cases with similar presentation was performed. Six patients fulfilled the inclusion criteria. Their phenomenology showed a sustained postural abnormality with elevation of one shoulder that often involves neighbouring regions; pain was a common accompanying feature; there were no alleviating manoeuvres, mirror or overflow phenomena. A recent preceding local trauma was reported by two patients; the onset was acute or gradual, progression was stable after initial worsening. There was poor benefit from oral medications; botulinum neurotoxin treatment improved pain and had little influence on postural abnormalities. Deep brain stimulation was ineffective in one patient; motor cortex stimulation caused partial or temporary improvement in two. All the patients received a diagnosis of functional movement disorder and met diagnostic criteria for functional neurological symptom (conversion) disorder with abnormal movements. The search strategies identified 19 publications reporting 75 similar cases, 75% of which were preceded by a minor traumatic injury. The motor abnormality responded poorly to oral medications, botulinum neurotoxin or physical therapy. We expand here on a peculiar phenomenology of sustained or fixed shoulder elevation that represents a recognizable syndrome with diagnostic and prognostic implications.

Identifying wilful brain activity in patients with disorders of consciousness is critical, as some patients fail to exhibit behavioural signs of consciousness at the bedside but respond to active tasks via neuroimaging or electrophysiological measures. Standardized terminology for this subgroup is absent while it is essential for advancing research and clinical care. The objective of this study was to determine the level of consensus among a large group of international experts on terminology and definitions for this clinical entity, as described by terms such as covert awareness, cognitive motor dissociation, functional locked-in syndrome, and non-behavioural minimally conscious state. A Delphi study was conducted using REDCap to evaluate expert agreement on terminology and definitions. The study was conducted among international experts, primarily from Europe/UK, the USA and other regions. Ninety-six experts participated. Among these, 75 (78%) completed both rounds. Participants were predominantly clinical scientists (71%) working in rehabilitation settings (63%). A Delphi method was followed. Consensus on terminology and related definitions was defined as a median score of 5, an interquartile range ≤1 and ≥75% agreement (scores of 4 or 5). Within two rounds, consensus was achieved for over two-thirds of the statements. The term 'Covert Awareness' and its associated definition were identified as the preferred terminology by an international expert panel. We recommend the use of 'Covert Awareness' since our large group of international experts consistently agreed on such preferred term for this subgroup of patients with disorders of consciousness. This consensus (>75% agreement) establishes a foundation both for future research and clinical standardization. The findings have implications for improving diagnostic accuracy and advancing understanding of covert awareness, although further study is needed to refine and apply the agreed-upon definition in clinical practice.

People with Tourette syndrome exhibit excessive motor actions known as tics. An aversive sensation called the premonitory urge often precedes these tics, leading to the conceptualization of Tourette syndrome as a sensorimotor disorder. In typical individuals, motor actions adapt flexibly to changes in the predictability of sensory cues. However, it remains unclear whether such sensorimotor predictions are altered in Tourette syndrome and, if so, which neural processes might underlie these changes. This study examined 30 individuals with Tourette syndrome and 30 control participants while recording EEG. Participants performed a motor cueing version of the Posner task, requiring behavioural adjustments to varying levels of cue predictability. Notably, while control participants exhibited the expected interaction between validity and cue predictability on motor responses, this effect was absent in individuals with Tourette syndrome. Neural signatures of flexible predictability-dependent processing were characterized by applying a Bayesian observer model to estimate trial-wise subjective beliefs about cue predictability from response speed and using these model-derived cue predictability estimates in single-trial regression analyses with EEG data. Our findings revealed that model-derived cue predictability modulated P3a amplitude, P3b onset and P3b amplitude differentially. Importantly, P3b amplitude modulations reflected beliefs about cue predictability, which were diminished in participants with Tourette syndrome. Overall, our results indicate that individuals with Tourette syndrome exhibit abnormal behavioural adaptation to the changing predictability of motor cues, suggesting an impaired processing of sensorimotor predictions. At the neural level, this is reflected by impaired activity associated with updating stimulus-response associations.

Resting-state functional connectivity has been linked to intelligence, and twin studies suggest that these associations may be influenced by genetic factors. To investigate this relationship, we analysed behavioural and resting-state functional magnetic resonance imaging data from young adult twins in the Human Connectome Project. General intelligence was assessed based on ten cognitive task performances. The results showed a positive correlation in both identical and fraternal twins, indicating a similarity of general intelligence among twin pairs. For the resting-state functional connectivity analysis, we conducted two approaches. In the first approach, twins were randomly assigned to two separate groups, ensuring that each pair was split between the groups. We then applied a connectome-based predictive method separately for identical and fraternal twins to predict general intelligence. Specifically, a predictive model was trained using one group's functional connectivity and then applied to its co-twin group to predict their general intelligence. Significant prediction was recorded in identical twins but not in fraternal twins, suggesting a high level of similarity of intelligence-related functional connectivity among identical twins. In the second approach, we aimed to quantify the intelligence similarity using the resting-state functional connectivity. To implement this, we generated models to predict the difference in general intelligence in twin pairs, where a smaller difference indicates a greater degree of similarity. The results showed that only the intelligence difference in identical twins was successfully predicted, where the default mode network showed a significant contribution, suggesting a higher neural basis for intelligence similarity in identical twins. Together, these findings demonstrate that functional connectivity patterns associated with intelligence extend across genetically identical twins. More broadly, they highlight the default mode network role in intelligence similarity and illustrate the utility of predictive modelling as a complementary framework to classical twin analyses.

Structural brain reserve capacity has recently gained an increasing interest in stroke recovery research. Focal and global measures of brain reserve have been linked with recovery trajectories. Whether the reserve localized within large-scale brain networks might also carry information to better understand outcome variability after stroke is an open question. This work analysed 31 patients with severe, first-ever unilateral, supratentorial stroke. Patients underwent MRI brain imaging and clinical testing within the first 2 weeks after the event and a longitudinal clinical follow-up after 3-6 months. Individual tractography in the contralesional hemisphere was performed to reconstruct structural connectomes to approximate the state of the ipsilesional brain networks before the stroke. Graph theory was applied to describe network integration and segregation topologies. Linear and ordinal logistic regression analyses were conducted to associate network topologies at baseline with neurological symptom burden, global and activity-related disability and motor impairment at follow-up. The main finding was that less segregated and more integrated networks, characterized by lower network modularity and higher efficiency, were linked with a more favourable outcome on follow-up. Modularity exerted a remarkably consistent influence across various outcome measures. This association was independent of the initial deficit, lesion volume or age. This study sheds novel light on brain reserve, localizing within the topology of pre-stroke structural brain networks, as a critical determinant of recovery after stroke.

Characterizing the onset and progression of Alzheimer's disease pathologies relative to one another is important for biological staging and clinical trial design. Recent advances in blood plasma assays of Alzheimer's disease amyloid and tau pathology have enabled detection of Alzheimer's disease pathophysiology during life, but it remains unclear when plasma biomarker abnormalities are detectable relative to established amyloid and tau PET imaging biomarkers, and the extent to which plasma biomarkers can be used for biological disease staging. This work applies a novel temporal modelling approach to amyloid PET and plasma p-tau217 data from two different assay platforms to characterize when plasma p-tau217 become abnormal relative to amyloid PET, tau PET, and cognitive decline in a predominantly cognitively unimpaired cohort. This study included a subset of 172 Wisconsin Registry for Alzheimer's Prevention participants (mean (standard deviation (SD)) age at baseline plasma = 63.2 (6.3) years; 149 cognitively unimpaired at last cognitive assessment) with available amyloid PET imaging and plasma p-tau217 data assayed on the Lilly Meso Scale Delivery and Quanterix Alzpath platforms. We estimated the within-person onsets of detectable amyloid PET and plasma p-tau217 using sampled iterative local approximation and investigated the impact of this timing on downstream tau PET accumulation and cognitive decline using linear mixed-effects models. Longitudinal modelling revealed that on average, amyloid PET positivity preceded p-tau217 positivity, and both amyloid and p-tau217 preceded detectable changes in brain tau accumulation. Comparisons of 'time from biomarker onset' indicated that time from p-tau217 onset explained more variability in tau PET accumulation and cognitive decline than time from amyloid PET onset for the Lilly assay but did not differ for the Alzpath assay. Overall, the timing between amyloid PET and p-tau217 onset (in a subset positive for both) ranged from -5.5-24.6 years. These results suggest that plasma p-tau217 follows a predictable path once above thresholds thereby enabling estimation of p-tau217 + age and suggesting these assays may be useful for disease staging. Information regarding the timing of abnormal detection of amyloid PET, plasma p-tau217, and tau PET in relation to preclinical cognitive decline suggests that an optimal window for secondary prevention of Alzheimer's disease may be within ten years of amyloid PET positivity and within five years of plasma p-tau217 positivity. Future work is needed to identify sources of observed interindividual heterogeneity in the timing of biomarker abnormalities and cognitive decline and impairment following biomarker positivity.

Two recent studies suggested that the APOE ε4 haplotype was associated with increased α-synuclein pathology in cell and mouse models. Genetic variants in the SNCA region have strong association with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and idiopathic REM sleep behaviour disorder (iRBD), while APOE is a genetic risk determinant for only DLB. To determine if genetic-level interactions between SNCA and APOE exists that can explain the protein-level association, we investigated the genotypic interaction of APOE and SNCA in cohorts of PD, DLB and iRBD. We analysed genome-wide association study (GWAS) data from 5229 PD patients and 5480 controls, 2610 DLB patients and 1920 controls, and 1055 iRBD patients and 3667 controls. We used logistic regression interaction models across all three cohorts independently between the (i) top GWAS signals of SNCA single nucleotide polymorphisms (SNPs) and APOE haplotypes and (ii) SNP×SNP and three-way SNP interaction across the entire coding region plus 200 kb flanking each gene. No significant interactions were found to be associated with any of the synucleinopathies after correction for multiple testing. Our results do not support a role for genetic interactions between APOE and SNCA across PD, DLB and iRBD. Since the tested genetic variants affect the expression and function of these proteins, it is likely that any interactions between them do not affect the risk of PD, DLB and iRBD.