Convergent Neuroimaging and Molecular Signatures in Mild Cognitive Impairment and Alzheimer's Disease: A Data-Driven Meta-Analysis with N = 3,118.

The current study aimed to evaluate the susceptibility to regional brain atrophy and its biological mechanism in Alzheimer's disease (AD). We conducted data-driven meta-analyses to combine 3,118 structural magnetic resonance images from three datasets to obtain robust atrophy patterns. Then we introduced a set of radiogenomic analyses to investigate the biological basis of the atrophy patterns in AD. Our results showed that the hippocampus and amygdala exhibit the most severe atrophy, followed by the temporal, frontal, and occipital lobes in mild cognitive impairment (MCI) and AD. The extent of atrophy in MCI was less severe than that in AD. A series of biological processes related to the glutamate signaling pathway, cellular stress response, and synapse structure and function were investigated through gene set enrichment analysis. Our study contributes to understanding the manifestations of atrophy and a deeper understanding of the pathophysiological processes that contribute to atrophy, providing new insight for further clinical research on AD.

Risk factors for avascular necrosis of the femoral head after developmental hip dislocation reduction surgery and construction of Nomogram prediction model.

BACKGROUND: To analyze the risk factors for the development of avascular necrosis (AVN) of the femoral head after reduction surgery in children with developmental hip dysplasia (DDH), and to establish a prediction nomogram. METHODS: The clinical data of 134 children with DDH (169 hips) treated with closure reduction or open reduction from December 2016 to December 2019 were retrospectively analyzed. Independent risk factors for AVN after DDH reduction being combined with cast external immobilization were determined by univariate analysis and multivariate logistic regression and used to generate nomograms predicting the occurrence of AVN. RESULTS: A total of 169 hip joints in 134 children met the inclusion criteria, with a mean age at surgery of 10.7 ± 4.56 months (range: 4-22 months) and a mean follow-up duration of 38.32 ± 27.00 months (range: 12-94 months). AVN developed in 42 hip joints (24.9%); univariate analysis showed that the International Hip Dysplasia Institute (IHDI) grade, preoperative development of the femoral head ossification nucleus, cartilage acetabular index, femoral head to acetabular Y-shaped cartilage distance, residual acetabular dysplasia, acetabular abduction angle exceeding 60°, and the final follow-up acetabular index (AI) were associated with the development of AVN (P < 0.05). Multivariate logistic regression analysis showed that the preoperative IHDI grade, development of the femoral head ossification nucleus, acetabular abduction angle exceeding 60°, and the final follow-up AI were independent risk factors for AVN development (P < 0.05). Internal validation of the Nomogram prediction model showed a consistency index of 0.833. CONCLUSION: Preoperative IHDI grade, preoperative development of the femoral head ossification nucleus, final AI, and acetabular abduction angle exceeding 60° are risk factors for AVN development. This study successfully constructed a Nomogram prediction model for AVN after casting surgery for DDH that can predict the occurrence of AVN after casting surgery for DDH.

Profiling functional networks identify activation of corticostriatal connectivity in ET patients after MRgFUS thalamotomy.

BACKGROUND: MR-guided focused ultrasound (MRgFUS) thalamotomy is a novel and effective treatment for medication-refractory tremor in essential tremor (ET), but how the brain responds to this deliberate lesion is not clear. OBJECTIVE: The current study aimed to evaluate the immediate and longitudinal alterations of functional networks after MRgFUS thalamotomy. METHODS: We retrospectively obtained preoperative and postoperative 30-day, 90-day, and 180-day data of 31 ET patients subjected with MRgFUS thalamotomy from 2018 to 2020. Their archived resting-state functional MRI data were used for functional network comparison as well as graph-theory metrics analysis. Both partial least squares (PLS) regression and linear regression were conducted to associate functional features to tremor symptoms. RESULTS: MRgFUS thalamotomy dramatically abolished tremors, while global functional network only sustained immediate fluctuation within one week after the surgery. Network-based statistics have identified a long-term enhanced corticostriatal subnetwork by comparison between 180-day and preoperative data (P = 0.019). Within this subnetwork, network degree, global efficiency and transitivity were significantly recovered in ET patients right after MRgFUS thalamotomy compared to the pre-operative timepoint (P < 0.05), as well as hemisphere lateralization (P < 0.001). The PLS main component significantly accounted for 33.68 % and 34.16 % of the total variances of hand tremor score and clinical rating scale for tremor (CRST)-total score (P = 0.037 and 0.027). Network transitivity of this subnetwork could serve as a reliable biomarker for hand tremor score control prediction at 180-day after the surgery (ß = 2.94, P = 0.03). CONCLUSION: MRgFUS thalamotomy promoted corticostriatal connectivity activation correlated with tremor improvement in ET patient after MRgFUS thalamotomy.

Disrupted topological properties of structural brain networks present a glutamatergic neuropathophysiology in people with narcolepsy.

STUDY OBJECTIVES: Growing evidences have documented various abnormalities of the white matter bundles in people with narcolepsy. We sought to evaluate topological properties of brain structural networks, and their association with symptoms and neuropathophysiological features in people with narcolepsy. METHODS: Diffusion tensor imaging was conducted for people with narcolepsy (n = 30) and matched healthy controls as well as symptoms assessment. Structural connectivity for each participant was generated to analyze global and regional topological properties and their correlations with narcoleptic features. Further human brain transcriptome was extracted and spatially registered for connectivity vulnerability. Genetic functional enrichment analysis was performed and further clarified using in vivo emission computed tomography data. RESULTS: A wide and dramatic decrease in structural connectivities was observed in people with narcolepsy, with descending network degree and global efficiency. These metrics were not only correlated with sleep latency and awakening features, but also reflected alterations of sleep macrostructure in people with narcolepsy. Network-based statistics identified a small hyperenhanced subnetwork of cingulate gyrus that was closely related to rapid eye movement sleep behavior disorder (RBD) in narcolepsy. Further imaging genetics analysis suggested glutamatergic signatures were responsible for the preferential vulnerability of connectivity alterations in people with narcolepsy, while additional PET/SPECT data verified that structural alteration was significantly correlated with metabotropic glutamate receptor 5 (mGlutR5) and N-methyl-D-aspartate receptor (NMDA). CONCLUSIONS: People with narcolepsy endured a remarkable decrease in the structural architecture, which was not only closely related to narcolepsy symptoms but also glutamatergic signatures.

Robustly uncovering the heterogeneity of neurodegenerative disease by using data-driven subtyping in neuroimaging: A review.

Neurodegenerative diseases are associated with heterogeneity in genetics, pathology, and clinical manifestation. Understanding this heterogeneity is particularly relevant for clinical prognosis and stratifying patients for disease modifying treatments. Recently, data-driven methods based on neuroimaging have been applied to investigate the subtyping of neurodegenerative disease, helping to disentangle this heterogeneity. We reviewed brain-based subtyping studies in aging and representative neurodegenerative diseases, including Alzheimer's disease, mild cognitive impairment, frontotemporal dementia, and Lewy body dementia, from January 2000 to November 2022. We summarized clustering methods, validation, robustness, reproducibility, and clinical relevance of 71 eligible studies in the present study. We found vast variations in approaches between studies, including ten neuroimaging modalities, 24 cluster algorithms, and 41 methods of cluster number determination. The clinical relevance of subtyping studies was evaluated by summarizing the analysis method of clinical measurements, showing a relatively low clinical utility in the current studies. Finally, we conclude that future studies of heterogeneity in neurodegenerative disease should focus on validation, comparison between subtyping approaches, and prioritise clinical utility.

A neuroimaging biomarker for Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN): a cross-sectional study.

Background: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that poses a worldwide public health challenge. A neuroimaging biomarker would significantly improve early diagnosis and intervention, ultimately enhancing the quality of life for affected individuals and reducing the burden on healthcare systems. Methods: Cross-sectional and longitudinal data (10,099 participants with 13,380 scans) from 12 independent datasets were used in the present study (this study was performed between September 1, 2021 and February 15, 2023). The Individual Brain-Related Abnormalities In Neurodegeneration (IBRAIN) score was developed via integrated regional- and network-based measures under an ensemble machine learning model based on structural MRI data. We systematically assessed whether IBRAIN could be a neuroimaging biomarker for AD. Findings: IBRAIN accurately differentiated individuals with AD from NCs (AUC = 0.92) and other neurodegenerative diseases, including Frontotemporal dementia (FTD), Parkinson's disease (PD), Vascular dementia (VaD) and Amyotrophic Lateral Sclerosis (ALS) (AUC = 0.92). IBRAIN was significantly correlated to clinical measures and gene expression, enriched in immune process and protein metabolism. The IBRAIN score exhibited a significant ability to reveal the distinct progression of prodromal AD (i.e., Mild cognitive impairment, MCI) (Hazard Ratio (HR) = 6.52 [95% CI: 4.42∼9.62], p < 1 × 10-16), which offers similar powerful performance with Cerebrospinal Fluid (CSF) Aß (HR = 3.78 [95% CI: 2.63∼5.43], p = 2.13 × 10-14) and CSF Tau (HR = 3.77 [95% CI: 2.64∼5.39], p = 9.53 × 10-15) based on the COX and Log-rank test. Notably, the IBRAIN shows comparable sensitivity (beta = -0.70, p < 1 × 10-16) in capturing longitudinal changes in individuals with conversion to AD than CSF Aß (beta = -0.26, p = 4.40 × 10-9) and CSF Tau (beta = 0.12, p = 1.02 × 10-5). Interpretation: Our findings suggested that IBRAIN is a biologically relevant, specific, and sensitive neuroimaging biomarker that can serve as a clinical measure to uncover prodromal AD progression. It has strong potential for application in future clinical practice and treatment trials. Funding: Science and Technology Innovation 2030 Major Projects, the National Natural Science Foundation of China, Beijing Natural Science Funds, the Fundamental Research Funds for the CentralUniversity, and the Startup Funds for Talents at Beijing Normal University.

Magnetic Resonance-Guided Focused Ultrasound Thalamotomy Rebalances Atypical Functional Hierarchy in Patients with Essential Tremor.

Magnetic resonance-guided focused ultrasound (MRgFUS) has brought thalamotomy back to the frontline for essential tremor (ET). As functional organization of human brain strictly follows hierarchical principles which are frequently deficient in neurological diseases, whether additional damage from MRgFUS thalamotomy induces further disruptions of ET functional scaffolds are still controversial. This study was to examine the alteration features of brain functional frameworks following MRgFUS thalamotomy in patients with ET. We retrospectively obtained preoperative (ETpre) and postoperative 6-month (ET6m) data of 30 ET patients underwent MRgFUS thalamotomy from 2018 to 2020. Their archived functional MR images were used to functional gradient comparison. Both supervised pattern learning and stepwise linear regression were conducted to associate gradient features to tremor symptoms with additional neuropathophysiological analysis. MRgFUS thalamotomy relieved 78.19% of hand tremor symptoms and induced vast global framework alteration (ET6m vs. ETpre: Cohen d = - 0.80, P < 0.001). Multiple robust alterations were identified especially in posterior cingulate cortex ([Formula: see text] ET6m vs. [Formula: see text] ETpre: Cohen d = 0.87, P = 0.048). Compared with matched health controls (HCs), its gradient distances to primary communities were significantly increased in [Formula: see text] ETpre patients with anomalous stepwise connectivity (P < 0.05 in ETpre vs. HCs), which were restored after MRgFUS thalamotomy. Both global and regional gradient features could be used for tremor symptom prediction and were linked to neuropathophysiological features of Parkinson disease and oxidative phosphorylation. MRgFUS thalamotomy not only suppress tremor symptoms but also rebalances atypical functional hierarchical architecture of ET patients.

Morphological connectivity differences in Alzheimer's disease correlate with gene transcription and cell-type.

Alzheimer's disease (AD) is one of the most prevalent forms of dementia in older individuals. Convergent evidence suggests structural connectome abnormalities in specific brain regions are linked to AD progression. The biological basis underpinnings of these connectome changes, however, have remained elusive. We utilized an individual regional mean connectivity strength (RMCS) derived from a regional radiomics similarity network to capture altered morphological connectivity in 1654 participants (605 normal controls, 766 mild cognitive impairment [MCI], and 283 AD). Then, we also explored the biological basis behind these morphological changes through gene enrichment analysis and cell-specific analysis. We found that RMCS probes of the hippocampus and medial temporal lobe were significantly altered in AD and MCI, with these differences being spatially related to the expression of AD-risk genes. In addition, gene enrichment analysis revealed that the modulation of chemical synaptic transmission is the most relevant biological process associated with the altered RMCS in AD. Notably, neuronal cells were found to be the most pertinent cells in the altered RMCS. Our findings shed light on understanding the biological basis of structural connectome changes in AD, which may ultimately lead to more effective diagnostic and therapeutic strategies for this devastating disease.

Reproducible Abnormalities and Diagnostic Generalizability of White Matter in Alzheimer's Disease.

Alzheimer's disease (AD) is associated with the impairment of white matter (WM) tracts. The current study aimed to verify the utility of WM as the neuroimaging marker of AD with multisite diffusion tensor imaging datasets [321 patients with AD, 265 patients with mild cognitive impairment (MCI), 279 normal controls (NC)], a unified pipeline, and independent site cross-validation. Automated fiber quantification was used to extract diffusion profiles along tracts. Random-effects meta-analyses showed a reproducible degeneration pattern in which fractional anisotropy significantly decreased in the AD and MCI groups compared with NC. Machine learning models using tract-based features showed good generalizability among independent site cross-validation. The diffusion metrics of the altered regions and the AD probability predicted by the models were highly correlated with cognitive ability in the AD and MCI groups. We highlighted the reproducibility and generalizability of the degeneration pattern of WM tracts in AD.

Altered large-scale dynamic connectivity patterns in Alzheimer's disease and mild cognitive impairment patients: A machine learning study.

Alzheimer's disease (AD) is a common neurodegeneration disease associated with substantial disruptions in the brain network. However, most studies investigated static resting-state functional connections, while the alteration of dynamic functional connectivity in AD remains largely unknown. This study used group independent component analysis and the sliding-window method to estimate the subject-specific dynamic connectivity states in 1704 individuals from three data sets. Informative inherent states were identified by the multivariate pattern classification method, and classifiers were built to distinguish ADs from normal controls (NCs) and to classify mild cognitive impairment (MCI) patients with informative inherent states similar to ADs or not. In addition, MCI subgroups with heterogeneous functional states were examined in the context of different cognition decline trajectories. Five informative states were identified by feature selection, mainly involving functional connectivity belonging to the default mode network and working memory network. The classifiers discriminating AD and NC achieved the mean area under the receiver operating characteristic curve of 0.87 with leave-one-site-out cross-validation. Alterations in connectivity strength, fluctuation, and inter-synchronization were found in AD and MCIs. Moreover, individuals with MCI were clustered into two subgroups, which had different degrees of atrophy and different trajectories of cognition decline progression. The present study uncovered the alteration of dynamic functional connectivity in AD and highlighted that the dynamic states could be powerful features to discriminate patients from NCs. Furthermore, it demonstrated that these states help to identify MCIs with faster cognition decline and might contribute to the early prevention of AD.

Closed reduction and plaster immobilization: an alternative solution for patients with developmental dysplasia of the hip who failed Pavlik harness treatment.

BACKGROUND: The current study aims to investigate the clinical efficacy of closed reduction and cast immobilization for patients with developmental dysplasia of the hip (DDH) who failed Pavlik harness treatment. METHODS: Patients with DDH who underwent cast immobilization under general anaesthesia after the failure of the Pavlik harness or Tübingen brace treatment between January 2015 and December 2020 were retrospectively recruited. General information, including Graf classification of initial diagnosis, initial treatment, age of cast immobilization, IHDI classification, AI index, avascular necrosis (AVN), and residual dysplasia, was collected. The incidence of AVN and late acetabular dysplasia (LACD) was also estimated. Moreover, factors related to AVN and LACD were investigated by multiple logistic regression analysis. RESULTS: Thirty-four patients (47 hips) were finally included in the current study. Of these patients, 31 hips (66.0%) were successfully treated with closed reduction and cast immobilization. Open reduction was successfully performed in 16 hips (34.0%). Till the latest follow-up, LACD and AVN were found in 13 (27.7%) and 10 (21.3%) hips, respectively. In the open reduction group, type III and IV of the IHDI classification and type IV of the Ultrasound Graf classification were significantly higher when compared with the closed reduction group. Multiple logistic regression showed that failure of closed reduction was related to the initial types of the Ultrasound Graf and IHDI classifications. CONCLUSIONS: Although the success rate of closed reduction after early harness failure in DDH is only 66%, we still advocate closed reduction as a first-line treatment for children who have failed sling treatment. Even if closed reduction fails, open reduction can still achieve acceptable results.

Altered global signal topography in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease associated with widespread disruptions in intrinsic local specialization and global integration in the functional system of the brain. These changes in integration may further disrupt the global signal (GS) distribution, which might represent the local relative contribution to global activity in functional magnetic resonance imaging (fMRI). METHODS: fMRI scans from a discovery dataset (n = 809) and a validated dataset (n = 542) were used in the analysis. We investigated the alteration of GS topography using the GS correlation (GSCORR) in patients with mild cognitive impairment (MCI) and AD. The association between GS alterations and functional network properties was also investigated based on network theory. The underlying mechanism of GSCORR alterations was elucidated using imaging-transcriptomics. FINDINGS: Significantly increased GS topography in the frontal lobe and decreased GS topography in the hippocampus, cingulate gyrus, caudate, and middle temporal gyrus were observed in patients with AD (Padj < 0.05). Notably, topographical GS changes in these regions correlated with cognitive ability (P < 0.05). The changes in GS topography also correlated with the changes in functional network segregation (ρ = 0.5). Moreover, the genes identified based on GS topographical changes were enriched in pathways associated with AD and neurodegenerative diseases. INTERPRETATION: Our findings revealed significant changes in GS topography and its molecular basis, confirming the informative role of GS in AD and further contributing to the understanding of the relationship between global and local neuronal activities in patients with AD. FUNDING: Beijing Natural Science Funds for Distinguished Young Scholars, China; Fundamental Research Funds for the Central Universities, China; National Natural Science Foundation, China.

Four Distinct Subtypes of Alzheimer's Disease Based on Resting-State Connectivity Biomarkers.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder with significant heterogeneity. Different AD phenotypes may be associated with specific brain network changes. Uncovering disease heterogeneity by using functional networks could provide insights into precise diagnoses. METHODS: We investigated the subtypes of AD using nonnegative matrix factorization clustering on the previously identified 216 resting-state functional connectivities that differed between AD and normal control subjects. We conducted the analysis using a discovery dataset (n = 809) and a validated dataset (n = 291). Next, we grouped individuals with mild cognitive impairment according to the model obtained in the AD groups. Finally, the clinical measures and brain structural characteristics were compared among the subtypes to assess their relationship with differences in the functional network. RESULTS: Individuals with AD were clustered into 4 subtypes reproducibly, which included those with 1) diffuse and mild functional connectivity disruption (subtype 1), 2) predominantly decreased connectivity in the default mode network accompanied by an increase in the prefrontal circuit (subtype 2), 3) predominantly decreased connectivity in the anterior cingulate cortex accompanied by an increase in prefrontal cortex connectivity (subtype 3), and 4) predominantly decreased connectivity in the basal ganglia accompanied by an increase in prefrontal cortex connectivity (subtype 4). In addition to these differences in functional connectivity, differences between the AD subtypes were found in cognition, structural measures, and cognitive decline patterns. CONCLUSIONS: These comprehensive results offer new insights that may advance precision medicine for AD and facilitate strategies for future clinical trials.

Impaired time-distance reconfiguration patterns in Alzheimer's disease: a dynamic functional connectivity study with 809 individuals from 7 sites.

BACKGROUND: The dynamic functional connectivity (dFC) has been used successfully to investigate the dysfunction of Alzheimer's disease (AD) patients. The reconfiguration intensity of nodal dFC, which means the degree of alteration between FCs at different time scales, could provide additional information for understanding the reconfiguration of brain connectivity. RESULTS: In this paper, we introduced a feature named time distance nodal connectivity diversity (tdNCD), and then evaluated the network reconfiguration intensity in every specific brain region in AD using a large multicenter dataset (N = 809 from 7 independent sites). Our results showed that the dysfunction involved in three subnetworks in AD, including the default mode network (DMN), the subcortical network (SCN), and the cerebellum network (CBN). The nodal tdNCD inside the DMN increased in AD compared to normal controls, and the nodal dynamic FC of the SCN and the CBN decreased in AD. Additionally, the classification analysis showed that the classification performance was better when combined tdNCD and FC to classify AD from normal control (ACC = 81%, SEN = 83.4%, SPE = 80.6%, and F1-score = 79.4%) than that only using FC (ACC = 78.2%, SEN = 76.2%, SPE = 76.5%, and F1-score = 77.5%) with a leave-one-site-out cross-validation. Besides, the performance of the three classes classification was improved from 50% (only using FC) to 53.3% (combined FC and tdNCD) (macro F1-score accuracy from 46.8 to 48.9%). More importantly, the classification model showed significant clinically predictive correlations (two classes classification: R = -0.38, P < 0.001; three classes classification: R = -0.404, P < 0.001). More importantly, several commonly used machine learning models confirmed that the tdNCD would provide additional information for classifying AD from normal controls. CONCLUSIONS: The present study demonstrated dynamic reconfiguration of nodal FC abnormities in AD. The tdNCD highlights the potential for further understanding core mechanisms of brain dysfunction in AD. Evaluating the tdNCD FC provides a promising way to understand AD processes better and investigate novel diagnostic brain imaging biomarkers for AD.

Regional Radiomics Similarity Networks Reveal Distinct Subtypes and Abnormality Patterns in Mild Cognitive Impairment.

Individuals with mild cognitive impairment (MCI) of different subtypes show distinct alterations in network patterns. The first aim of this study is to identify the subtypes of MCI by employing a regional radiomics similarity network (R2SN). The second aim is to characterize the abnormality patterns associated with the clinical manifestations of each subtype. An individual-level R2SN is constructed for N = 605 normal controls (NCs), N = 766 MCI patients, and N = 283 Alzheimer's disease (AD) patients. MCI patients' R2SN profiles are clustered into two subtypes using nonnegative matrix factorization. The patterns of brain alterations, gene expression, and the risk of cognitive decline in each subtype are evaluated. MCI patients are clustered into "similar to the pattern of NCs" (N-CI, N = 252) and "similar to the pattern of AD" (A-CI, N = 514) subgroups. Significant differences are observed between the subtypes with respect to the following: 1) clinical measures; 2) multimodal neuroimaging; 3) the proportion of progression to dementia (61.54% for A-CI and 21.77% for N-CI) within three years; 4) enriched genes for potassium-ion transport and synaptic transmission. Stratification into the two subtypes provides new insight for risk assessment and precise early intervention for MCI patients.

Altered Connection and Diagnosis Utility of White Matter in Alzheimer's Disease: A Multi-site Automated Fiber Quantification Study.

Alzheimer's disease (AD) is a typical neurodegenerative disease that is associated with cognitive decline, memory loss, and functional disconnection. Diffusion tensor imaging (DTI) has been widely used to investigate the integrity and degeneration of white matter in AD. In this study, with one of the world's largest DTI biobanks (865 individuals), we aim to explore the diagnosis utility and stability of tractbased features (extracted by automated fiber quantification (AFQ) pipeline) in AD. First, we studied the clinical association of tract-based features by detecting AD-associated alterations of diffusion properties along fiber bundles. Then, a binary classification experiment between AD and normal controls was performed using tract-based diffusion properties as features and support vector machine (SVM) as a classifier with an independent site cross-validation strategy. The average accuracy of 77.90% (the highest was 88.89%) showed that white matter properties as biomarkers had a relatively stable role in the clinical diagnosis of AD.Clinical Relevance- White matter characteristics are valid and robust biomarkers of AD, which have high accuracy and generalizability in the AD diagnosis in a large multi-site dataset.

Convergent structural network and gene signatures for MRgFUS thalamotomy in patients with Parkinson's disease.

MRgFUS has just been made available for the 1.7 million Parkinson's disease patients in China. Despite its non-invasive and rapid therapeutic advantages for involuntary tremor, some concerns have emerged about outcomes variability, non-specificity, and side-effects, as little is known about its impact on the long-term plasticity of brain structure. We sought to dissect the characteristics of long-term changes in brain structure caused by MRgFUS lesion and explored potential biological mechanisms. One-year multimodal imaging follow-ups were conducted for nine tremor-dominant Parkinson's disease patients undergoing unilateral MRgFUS thalamotomy. A structural connectivity map was generated for each patient to analyze dynamic changes in brain structure. The human brain transcriptome was extracted and spatially registered for connectivity vulnerability. Genetic functional enrichment analysis was performed and further clarified using in vivo emission computed tomography data. MRgFUS not only abolished tremors but also significantly disrupted the brain network topology. Network-based statistics identified a U-shape MRgFUS-sensitive subnetwork reflective of hand tremor recovery and surgical process, accompanied by relevant cerebral blood flow and gray matter alteration. Using human brain gene expression data, we observed that dopaminergic signatures were responsible for the preferential vulnerability associated with these architectural alterations. Additional PET/SPECT data not only validated these gene signatures, but also suggested that structural alteration was significantly correlated with D1 and D2 receptors, DAT, and F-DOPA measures. There was a long-term dynamic loop between structural alteration and dopaminergic signature for MRgFUS thalamotomy, which may be closely related to the long-term improvements in clinical tremor.

Association Between TPM1 Gene Polymorphisms and Idiopathic Congenital Talipes Equinovarus Risk in a Chinese Population.

Background: Idiopathic congenital talipes equinovarus (ICTEV) is one of the most common congenital deformities of children, and dysplasia of the striated muscle may be one of the causes of ICTEV. Previous studies have shown that polymorphisms of the rs4075583 SNP in the tropomyosin gene 1 (TPM1) were associated with ICTEV in Caucasian children. However, there are no studies investigating the correlations of TPM gene polymorphisms with the risk of ICTEV in Chinese children. Methods: We conducted a case-control study, including 430 children with ICTEV and 891 ICTEV-free children. We explored the potential correlations of three TPM gene polymorphisms (TPM1/rs4075583 G>A, tropomyosin gene 2 (TPM2)/rs2145925 C>T, and TPM2/rs2025126 G>A) with ICTEV risk. The three single nucleotide polymorphisms (SNPs) were genotyped using a TaqMan method. We calculated the odds ratios (ORs) and adjusted ORs and their 95% confidence intervals (CIs) to explore the associations between these selected SNP polymorphisms and ICTEV. Results: TPM1 rs4075583 A was found to be associated with an increased ICTEV risk (AA vs. GG: adjusted OR = 1.70, 95% CI = 1.15-2.49, p = 0.007; and GG/GA vs. AA: adjusted OR = 1.62, 95% CI = 1.14-2.31, p = 0.0071) after adjusting for age and sex. In addition, a risk effect of rs4075583 GA/AA with ICETV was observed for patients with affected right feet (adjusted OR = 1.62, 95% CI = 1.10-2.39, p = 0.014) in the stratified analysis. However, there were no significant differences in the risk for ICTEV associated with the rs2145925 and rs2025126 polymorphisms. Conclusion: These results indicate that the TPM1 rs4075583 G > A polymorphism is associated with ICTEV risk in a southern Chinese population; however, this finding needs to be confirmed in larger studies and through mechanistic studies.

Tübingen hip flexion splints for developmental dysplasia of the hip in infants aged 0-6 months.

BACKGROUND: Developmental dysplasia of the hip (DDH) is a common disorder in infants. The present study aimed to evaluate the efficacy and safety of the Tübingen hip flexion splints in treating DDH in infants aged 0-6 months. METHODS: This is a retrospective study analyzing 259 hips in 195 infants with DDH of Graf type IIc or worse classifications treated between January 2015 and December 2017. Patients were followed up for at least 6 months. Avascular necrosis of the femoral head was diagnosed using plain radiographs at the last follow-up visit according to the Bucholz-Ogden classification. Successful treatment was defined as an improvement of the Graft classification to type I, or an improvement of the International Hip Dysplasia Institute classification to type I in patients aged > 6 months. RESULTS: Treatment was deemed successful in 128 patients (83.7%). Avascular necrosis occurred in 3 patients (3 hips). Univariate analysis showed that late treatment initiation, family history of DDH, Graf type IV and bilateral involvement were independent risk factors for treatment failure (p < 0.05). The receiver operating characteristic curve showed a cut-off value of 12 weeks for age at treatment initiation regarding successful treatment. Logistic regression analysis showed that gender, breech presentation, firstborn, swaddling, birth weight > 3.5 kg, oligohydramnios, foot deformity and torticollis did not affect the success rate of treatment (p > 0.05). CONCLUSIONS: The Tübingen splint showed good efficacy and safety in treating DDH in infants aged 0-6 months. Family history of DDH, Graf classification of type IV, bilateral involvement and treatment initiation after 12 weeks of age are risk factors of treatment failure. TRIAL REGISTRATION: N/A.

A polyaxial fixation brace for the treatment of idiopathic congenital talipes equinovarus in newborns.

BACKGROUND: Treatment of idiopathic congenital talipes equinovarus (CTEV) is challenging for pediatric orthopedic surgeons. The Ponseti method is an effective protocol for treatment due to its technique of manipulation, casting, and limited surgery. Plaster casting is an essential component of the Ponseti method. In this report, we describe a new brace that was developed for use in the treatment of clubfoot in newborns instead of a plaster cast. METHODS: This retrospective study was performed in two orthopedic medical centers. Between January 2011 and October 2013, 89 newborns with CTEV (131 ft) underwent corrective treatment using fixation braces in the experiment group (E-group) in our hospital, and 107 newborns with CTEV (141 ft) underwent plaster casting in the control group (C-group) in another medical center. All patients were treated according to the Ponseti method after the application of the inclusion and exclusion criteria. Plaster casts were applied to patients in the C-group. The patients in the E-group received the custom-made polyaxial fixation braces instead of plaster casts. Prospective follow-up was performed for a mean duration of 36 months. The efficacy of the treatment was assessed using Pirani's scoring system. Chi-squared and independent t tests were used for statistical analyses. RESULTS: In the E-group, 85 patients (125 ft) achieved good appearance within 3 months of treatment initiation (average, 1.7 months). Four patients (6 ft) required percutaneous Achilles tenotomy. Seven patients developed sores during treatment because of improper brace application, but all sores healed without scarring with timely treatment. In the C-group, 96 patients (123 ft) achieved good appearance within 3 months of treatment initiation (average, 1.6 months). Eleven patients (18 ft) required percutaneous Achilles tenotomy. Twenty-one feet developed sores during treatment because of plaster cast pressure on the dorsum of the feet. Sixteen sores healed without scarring with timely treatment, and 5 ft had obvious scars. The overall mean Pirani scores 1 year after treatment were 0.26 ± 0.06 in the E-group and 0.25 ± 0.03 in the C-group, and the Pirani scores 3 years after treatment were 0.23 ± 0.05 in the E-group and 0.22 ± 0.03 in the C-group. There were significant differences in the percutaneous Achilles tenotomy and skin sores but no significant difference in the Pirani scores between these two groups. CONCLUSIONS: Our results showed that the new polyaxial fixation brace used in this study was an effective tool for the corrective treatment of CTEV in newborns. We propose the use of this brace as an alternative treatment for newborns.