Whole-brain, gray, and white matter time-locked functional signal changes with simple tasks and model-free analysis.

Recent studies have revealed the production of time-locked blood oxygenation level-dependent (BOLD) functional MRI (fMRI) signals throughout the entire brain in response to tasks, challenging the existence of sparse and localized brain functions and highlighting the pervasiveness of potential false negative fMRI findings. "Whole-brain" actually refers to gray matter, the only tissue traditionally studied with fMRI. However, several reports have demonstrated reliable detection of BOLD signals in white matter, which have previously been largely ignored. Using simple tasks and analyses, we demonstrate BOLD signal changes across the whole brain, in both white and gray matters, in similar manner to previous reports of whole brain studies. We investigated whether white matter displays time-locked BOLD signals across multiple structural pathways in response to a stimulus in a similar manner to the cortex. We find that both white and gray matter show time-locked activations across the whole brain, with a majority of both tissue types showing statistically significant signal changes for all task stimuli investigated. We observed a wide range of signal responses to tasks, with different regions showing different BOLD signal changes to the same task. Moreover, we find that each region may display different BOLD responses to different stimuli. Overall, we present compelling evidence that, just like all gray matter, essentially all white matter in the brain shows time-locked BOLD signal changes in response to multiple stimuli, challenging the idea of sparse functional localization and the prevailing wisdom of treating white matter BOLD signals as artifacts to be removed.

Unlocking the link: how hippocampal glutathione-glutamate coupling predicts cognitive impairment in multiple sclerosis patients.

Cognitive impairment is a common symptom of multiple sclerosis and profoundly impacts quality of life. Glutathione (GSH) and glutamate (Glu) are tightly linked in the brain, participating in cognitive function. However, GSH-Glu couplings in cognitive brain regions and their relationship with cognitive impairment in relapsing-remitting multiple sclerosis (RRMS) remains unclear. Forty-one RRMS patients and 43 healthy controls underwent magnetic resonance spectroscopy to measure GSH and Glu levels in the posterior cingulate cortex, medial prefrontal cortex and left hippocampus. Neuropsychological tests were used to evaluate the cognitive function. The Glu/GSH ratio was used to indicate the coupling between GSH and Glu and was tested as a predictor of cognitive performance. The results show that RRMS patients exhibited reduced hippocampal GSH and Glu levels, which were found to be significant predictors of worse verbal and visuospatial memory, respectively. Moreover, GSH levels were dissociated from Glu levels in the left hippocampus of RRMS patients. Hippocampal Glu/GSH ratio is significantly correlated with processing speed and has a greater predictive effect. Here we show the hippocampal Glu/GSH ratio could serve as a new potential marker for characterizing cognitive impairment in RRMS, providing a new direction for clinical detection of cognitive impairment.

Quantification of mediation effects of white matter functional characteristics on cognitive decline in aging.

Cognitive decline with aging involves multifactorial processes, including changes in brain structure and function. This study focuses on the role of white matter functional characteristics, as reflected in blood oxygenation level-dependent signals, in age-related cognitive deterioration. Building on previous research confirming the reproducibility and age-dependence of blood oxygenation level-dependent signals acquired via functional magnetic resonance imaging, we here employ mediation analysis to test if aging affects cognition through white matter blood oxygenation level-dependent signal changes, impacting various cognitive domains and specific white matter regions. We used independent component analysis of resting-state blood oxygenation level-dependent signals to segment white matter into coherent hubs, offering a data-driven view of white matter's functional architecture. Through correlation analysis, we constructed a graph network and derived metrics to quantitatively assess regional functional properties based on resting-state blood oxygenation level-dependent fluctuations. Our analysis identified significant mediators in the age-cognition relationship, indicating that aging differentially influences cognitive functions by altering the functional characteristics of distinct white matter regions. These findings enhance our understanding of the neurobiological basis of cognitive aging, highlighting the critical role of white matter in maintaining cognitive integrity and proposing new approaches to assess interventions targeting cognitive decline in older populations.

Abnormal white and gray matter functional connectivity is associated with cognitive dysfunction in presbycusis.

Presbycusis is characterized by high-frequency hearing loss and is closely associated with cognitive decline. Previous studies have observed functional reorganization of gray matter in presbycusis, but the information transmission between gray matter and white matter remains ill-defined. Using resting-state functional magnetic resonance imaging, we investigated differences in functional connectivity (GM-GM, WM-WM, and GM-WM) between 60 patients with presbycusis and 57 healthy controls. Subsequently, we examined the correlation between these connectivity differences with high-frequency hearing loss as well as cognitive impairment. Our results revealed significant alterations in functional connectivity involving the body of the corpus callosum, posterior limbs of the internal capsule, retrolenticular region of the internal capsule, and the gray matter regions in presbycusis. Notably, disrupted functional connectivity was observed between the body of the corpus callosum and ventral anterior cingulate cortex in presbycusis, which was associated with impaired attention. Additionally, enhanced functional connectivity was found in presbycusis between the internal capsule and the ventral auditory processing stream, which was related to impaired cognition in multiple domains. These two patterns of altered functional connectivity between gray matter and white matter may involve both bottom-up and top-down regulation of cognitive function. These findings provide novel insights into understanding cognitive compensation and resource redistribution mechanisms in presbycusis.

USF1 transcriptionally activates USP14 to drive atherosclerosis by promoting EndMT through NLRC5/Smad2/3 axis.

BACKGROUND: Endothelial-to-Mesenchymal Transformation (EndMT) plays key roles in endothelial dysfunction during the pathological progression of atherosclerosis; however, its detailed mechanism remains unclear. Herein, we explored the biological function and mechanisms of upstream stimulating factor 1 (USF1) in EndMT during atherosclerosis. METHODS: The in vivo and in vitro atherosclerotic models were established in high fat diet-fed ApoE-/- mice and ox-LDL-exposed human umbilical vein endothelial cells (HUVECs). The plaque formation, collagen and lipid deposition, and morphological changes in the aortic tissues were evaluated by hematoxylin and eosin (HE), Masson, Oil red O and Verhoeff-Van Gieson (EVG) staining, respectively. EndMT was determined by expression levels of EndMT-related proteins. Target molecule expression was detected by RT-qPCR and Western blotting. The release of pro-inflammatory cytokines was measured by ELISA. Migration of HUVECs was detected by transwell and scratch assays. Molecular mechanism was investigated by dual-luciferase reporter assay, ChIP, and Co-IP assays. RESULTS: USF1 was up-regulated in atherosclerosis patients. USF1 knockdown inhibited EndMT by up-regulating CD31 and VE-Cadherin, while down-regulating α-SMA and vimentin, thereby repressing inflammation, and migration in ox-LDL-exposed HUVECs. In addition, USF1 transcriptionally activated ubiquitin-specific protease 14 (USP14), which promoted de-ubiquitination and up-regulation of NLR Family CARD Domain Containing 5 (NLRC5) and subsequent Smad2/3 pathway activation. The inhibitory effect of sh-USF1 or sh-USP14 on EndMT was partly reversed by USP14 or NLRC5 overexpression. Finally, USF1 knockdown delayed atherosclerosis progression via inhibiting EndMT in mice. CONCLUSION: Our findings indicate the contribution of the USF1/USP14/NLRC5 axis to atherosclerosis development via promoting EndMT, which provide effective therapeutic targets.

DNMT3B activates FGFR3-mediated endoplasmic reticulum stress by regulating PTPN2 promoter methylation to promote the development of atherosclerosis.

Endoplasmic reticulum (ER) stress is closely associated with atherosclerosis (AS). Nevertheless, the regulatory mechanism of ER stress in endothelial cells during AS progression is unclear. Here, the role and regulatory mechanism of DNA (cytosine-5-)- methyltransferase 3 beta (DNMT3B) in ER stress during AS progression were investigated. ApoE-/- mice were fed with high fat diet to construct AS model in vivo. HE and Masson staining were performed to analyze histopathological changes and collagen deposition. HUVECs stimulated by ox-LDL were used as AS cellular model. Cell apoptosis was examined using flow cytometry. DCFH-DA staining was performed to examine ROS level. The levels of pro-inflammatory cytokines were assessed using ELISA. In addition, MSP was employed to detect PTPN2 promoter methylation level. Our results revealed that DNMT3B and FGFR3 were significantly upregulated in AS patient tissues, whereas PTPN2 was downregulated. PTPN2 overexpression attenuate ox-LDL-induced ER stress, inflammation and apoptosis in HUVECs and ameliorated AS symptoms in vivo. PTPN2 could suppress FGFR3 expression in ox-LDL-treated HUVECs, and FGFR3 knockdown inhibited ER stress to attenuate ox-LDL-induced endothelial cell apoptosis. DNMT3B could negatively regulate PTPN2 expression and positively FGFR2 expression in ox-LDL-treated HUVECs; DNMT3B activated FGFR2 expression by increasing PTPN2 promoter methylation level. DNMT3B downregulation repressed ox-LDL-induced ER stress, inflammation and cell apoptosis in endothelial cells, which was reversed by PTPN2 silencing. DNMT3B activated FGFR3-mediated ER stress by increasing PTPN2 promoter methylation level and suppressed its expression, thereby boosting ER stress to facilitate AS progression.

The association between different levels of depression and overactive bladder: A cross-sectional study of the 2005-2018 National Health and Nutrition Examination Survey.

BACKGROUND: There is growing evidence of a possible correlation between depression and overactive bladder (OAB). However, few studies have classified depression according to its severity. Whether there is an association between different levels of depression and OAB symptoms remains unclear. METHODS: Participants with complete information about depression, OAB, and covariates in the National Health and Nutrition Examination Survey (NHANES) 2005-2018 were included in this study. Depression symptoms were assessed by the Patient Health Questionnaire-9. OAB symptoms were evaluated by the Overactive Bladder Symptom Score. Weighted multivariate logistic regression models were applied to analyze the relationship between depression and OAB. RESULTS: A total of 30 359 participants were included in this study, consisting of 6245 OAB patients and 24 114 non-OAB participants. The multivariate logistic regression suggested depression independently correlated with OAB (odds ratio [OR] = 2.764, 95% confidence interval [CI] = 2.429-3.146, p < 0.001). Further, mild (OR = 2.355, 95% CI = 2.111-2.627, p < 0.001), moderate (OR = 3.262, 95% CI = 2.770-3.841, p < 0.001), and moderately severe to severe depression (OR = 3.927, 95% CI = 3.246-4.752, p < 0.001) were all associated with OAB. Additionally, depression was also correlated with urgency urinary incontinence (OR = 2.249, 95% CI = 1.986-2.548, p < 0.001) and nocturia (OR = 2.166, 95% CI = 1.919-2.446, p < 0.001). CONCLUSION: This study indicated different levels of depression, even mild depression, were independent risk factors for OAB. Given the frequent coexistence and potential interactions between depression and OAB, clinicians should be aware of the importance of assessing both physical and psychological symptoms in these patients. Early diagnosis and holistic treatment may improve the treatment outcomes, particularly for those suffering from both conditions.

Power spectra reveal distinct BOLD resting-state time courses in white matter.

Accurate characterization of the time courses of blood-oxygen-level-dependent (BOLD) signal changes is crucial for the analysis and interpretation of functional MRI data. While several studies have shown that white matter (WM) exhibits distinct BOLD responses evoked by tasks, there have been no comprehensive investigations into the time courses of spontaneous signal fluctuations in WM. We measured the power spectra of the resting-state time courses in a set of regions within WM identified as showing synchronous signals using independent components analysis. In each component, a clear separation between voxels into two categories was evident, based on their power spectra: one group exhibited a single peak, and the other had an additional peak at a higher frequency. Their groupings are location specific, and their distributions reflect unique neurovascular and anatomical configurations. Importantly, the two categories of voxels differed in their engagement in functional integration, revealed by differences in the number of interregional connections based on the two categories separately. Taken together, these findings suggest WM signals are heterogeneous in nature and depend on local structural-vascular-functional associations.

Neurochemical and functional reorganization of the cognitive-ear link underlies cognitive impairment in presbycusis.

Recent studies suggest that the interaction between presbycusis and cognitive impairment may be partially explained by the cognitive-ear link. However, the underlying neurophysiological mechanisms remain largely unknown. In this study, we combined magnetic resonance spectroscopy (MRS) and resting-state functional magnetic resonance imaging (fMRI) to investigate auditory gamma-aminobutyric acid (GABA) and glutamate (Glu) levels, intra- and inter-network functional connectivity, and their relationships with auditory and cognitive function in 51 presbycusis patients and 51 well-matched healthy controls. Our results confirmed reorganization of the cognitive-ear link in presbycusis, including decreased auditory GABA and Glu levels and aberrant functional connectivity involving auditory networks (AN) and cognitive-related networks, which were associated with reduced speech perception or cognitive impairment. Moreover, mediation analyses revealed that decreased auditory GABA levels and dysconnectivity between the AN and default mode network (DMN) mediated the association between hearing loss and impaired information processing speed in presbycusis. These findings highlight the importance of AN-DMN dysconnectivity in cognitive-ear link reorganization leading to cognitive impairment, and hearing loss may drive reorganization via decreased auditory GABA levels. Modulation of GABA neurotransmission may lead to new treatment strategies for cognitive impairment in presbycusis patients.

Functional alterations in bipartite network of white and grey matters during aging.

The effects of normal aging on functional connectivity (FC) within various brain networks of gray matter (GM) have been well-documented. However, the age effects on the networks of FC between white matter (WM) and GM, namely WM-GM FC, remains unclear. Evaluating crucial properties, such as global efficiency (GE), for a WM-GM FC network poses a challenge due to the absence of closed triangle paths which are essential for assessing network properties in traditional graph models. In this study, we propose a bipartite graph model to characterize the WM-GM FC network and quantify these challenging network properties. Leveraging this model, we assessed the WM-GM FC network properties at multiple scales across 1,462 cognitively normal subjects aged 22-96 years from three repositories (ADNI, BLSA and OASIS-3) and investigated the age effects on these properties throughout adulthood and during late adulthood (age ≥70 years). Our findings reveal that (1) heterogeneous alterations occurred in region-specific WM-GM FC over the adulthood and decline predominated during late adulthood; (2) the FC density of WM bundles engaged in memory, executive function and processing speed declined with age over adulthood, particularly in later years; and (3) the GE of attention, default, somatomotor, frontoparietal and limbic networks reduced with age over adulthood, and GE of visual network declined during late adulthood. These findings provide unpresented insights into multi-scale alterations in networks of WM-GM functional synchronizations during normal aging. Furthermore, our bipartite graph model offers an extendable framework for quantifying WM-engaged networks, which may contribute to a wide range of neuroscience research.

Chronic remote ischemic conditioning treatment in patients with chronic stable angina (EARLY-MYO-CSA): a randomized, controlled proof-of-concept trial.

BACKGROUND: Chronic remote ischemic conditioning (CRIC) has been shown to improve myocardial ischemia in experimental animal studies; however, its effectiveness in patients with chronic stable angina (CSA) has not been investigated. We conducted a proof-of-concept study to investigate the efficacy and safety of a six-month CRIC treatment in patients with CSA. METHODS: The EARLY-MYO-CSA trial was a prospective, randomized, controlled trial evaluating the CRIC treatment in patients with CSA with persistent angina pectoris despite receiving ≥ 3-month guideline-recommended optimal medical therapy. The CRIC and control groups received CRIC (at 200 mmHg) or sham CRIC (at 60 mmHg) intervention for 6 months, respectively. The primary endpoint was the 6-month change of myocardial flow reserve (MFR) on single-photon emission computed tomography. The secondary endpoints were changes in rest and stress myocardial blood flow (MBF), angina severity according to the Canadian Cardiovascular Society (CCS) classification, the Seattle Angina Questionnaire (SAQ), and a 6-min walk test (6-MWT). RESULTS: Among 220 randomized CSA patients, 208 (105 in the CRIC group, and 103 in the control group) completed the treatment and endpoint assessments. The mean change in MFR was significantly greater in the CRIC group than in the control group (0.27 ± 0.38 vs. - 0.04 ± 0.25; P < 0.001). MFR increased from 1.33 ± 0.48 at baseline to 1.61 ± 0.53 (P < 0.001) in the CRIC group; however, a similar increase was not seen in the control group (1.35 ± 0.45 at baseline and 1.31 ± 0.44 at follow-up, P = 0.757). CRIC treatment, when compared with controls, demonstrated improvements in angina symptoms assessed by CCS classification (60.0% vs. 14.6%, P < 0.001), all SAQ dimensions scores (P < 0.001), and 6-MWT distances (440 [400-523] vs. 420 [330-475] m, P = 0.016). The incidence of major adverse cardiovascular events was similar between the groups. CONCLUSIONS: CSA patients benefit from 6-month CRIC treatment with improvements in MFR, angina symptoms, and exercise performance. This treatment is well-tolerated and can be recommended for symptom relief in this clinical population. TRIAL REGISTRATION: [chictr.org.cn], identifier [ChiCTR2000038649].

Bioinformatics analysis of potential common pathogenic mechanisms for systemic lupus erythematosus and acute myocardial infarction.

BACKGROUND: Systemic lupus erythematosus (SLE) patients have a higher risk of acute myocardial infarction (AMI) compared to the general population. However, the underlying common mechanism of this association is not fully understood. This study aims to investigate the molecular mechanism of this complication. METHODS: Gene expression profiles of SLE (GSE50772) and AMI (GSE66360) were obtained from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (DEGs) in SLE and AMI were identified, and functional annotation, protein-protein interaction (PPI) network analysis, module construction, and hub gene identification were performed. Additionally, transcription factor (TF)-gene regulatory network and TF-miRNA regulatory network were constructed for the hub genes. RESULTS: 70 common DEGs (7 downregulated genes and 63 upregulated genes) were identified and were mostly enriched in signaling pathways such as the IL-17 signaling pathway, TNF signaling pathway, lipid metabolism, and atherosclerosis. Using cytoHubba, 12 significant hub genes were identified, including IL1B, TNF, FOS, CXCL8, JUN, PTGS2, FN1, EGR1, CXCL1, DUSP1, MMP9, and ZFP36. CONCLUSIONS: This study reveals a common pathogenesis of SLE and AMI and provides new perspectives for further mechanism research. The identified common pathways and hub genes may have important clinical implications for the prevention and treatment of AMI in SLE patients.

The "L-Sandwich" Strategy for True Coronary Bifurcation Lesions: A Randomized Clinical Trial.

Background: This study explored the efficacy of the "L-sandwich" strategy, which involves the implantation of stents in the main vessel (MV) and shaft of the side branch (SB) with a drug-coated balloon (DCB) applied to the SB ostium, for coronary true bifurcation lesions. Methods and Results: Of 99 patients with true bifurcation lesions, 38 patients underwent the "L-sandwich" strategy (group A), 32 patients underwent a two-stent strategy (group B), and 29 patients underwent a single-stent + DCB strategy (group C). Angiography outcomes (late lumen loss [LLL], minimum lumen diameter [MLD]), and clinical outcomes (major adverse cardiac events [MACEs]) were analyzed. At 6 months, the MLD of the SB ostium in groups A and B were similar (P > 0.05) and group A larger than group C (P < 0.05). The LLL of group B was the largest among the three groups (P < 0.05). The MLD of the SB shaft in groups A and B were larger than in group C (P < 0.05). The LLL of the SB shaft in group C was the lowest (P < 0.05). Two patients in group B received target vessel revascularization at the 6-month followup (P > 0.05), and patients in the other groups had no MACEs. Conclusions: The "L-sandwich" strategy was feasible for the treatment of true coronary bifurcation lesions. It is a simpler procedure with similar acute lumen gain than the two-stent strategy, results in a larger SB lumen than the single-stent + DCB strategy, and it can also be used as a remedy for dissection following the single-stent + DCB strategy.

SPECT myocardial blood flow quantitation for the detection of angiographic stenoses with cardiac-dedicated CZT SPECT.

PURPOSE: CZT SPECT with the enhanced imaging characteristic facilitates SPECT myocardial blood flow (MBF) quantitation moving toward a clinical utility to uncover myocardial ischemia. The purpose of this study was to investigate the diagnostic performance of stress MBF, myocardial flow reserve (MFR) and myocardial flow capacity (MFC) derived from CZT SPECT in the detection of coronary artery disease (CAD). METHODS: One-hundred and eighty patients underwent two-day rest/adenosine-stress scans for SPECT MBF quantitation. All dynamic SPECT images were reconstructed and corrected with necessary corrections. The one-tissue two-compartment kinetic model was utilized to fit kinetic parameters (K1, k2 and FBV) by numeric optimization and converted to MBF from K1. Rest MBF, stress MBF and MFR in left ventricle and coronary territories were calculated from flow polar maps. MFC was assessed by extents of moderately and severely abnormal flow statuses using an integrated flow diagram. Per-patient and per-vessel analyses were performed to determine cutoff values for the detection of angiographically obstructive and flow-limited CAD. RESULTS: Using the threshold of ≥ 50% stenosis, 149 patients (82.78%) were classified to have obstructive lesions in 355 vessels (65.74%). Using the threshold of ≥ 70% stenosis, 113 patients (62.78%) were classified to have flow-limited lesions in 282 vessels (52.22%). On per-patient analysis, the optimal cutoff values of stress MBF and MFR to detect ≥ 50% stenosis were (1.44 ml/min/g, 1.96) and (1.34 ml/min/g and 1.75) to detect ≥ 70% stenosis. The optimal cutoff values for severely and combined moderately severely abnormal MFC extents were (2.3-2.5%, 23.1%) and (7.5%, 29.4%), respectively. The overall sensitivity of MFC (0.84-0.86, 0.86-0.90) to detect ≥ 50% and ≥ 70% lesions surpassed those of stress MBF (0.78. 0.78) and MFR (0.80, 0.75) (all p < 0.05) with similar specificity (MFC = 0.84-0.90, 0.87-0.91; stress MBF = 0.87, 0.91; MFR = 0.84, 0.89) (all p≥ 0.05). CONCLUSION: The non-invasive SPECT MBF quantitation using CZT SPECT is a reliable method to detect angiographically obstructive and flow-limited CAD. Myocardial flow capacity can outperform with higher diagnostic sensitivity than stress MBF or MFR alone.

Effects of remote ischemic preconditioning on coronary blood flow and microcirculation.

This study aimed to determine the effect of short-term remote ischemic preconditioning (RIPC) on coronary blood flow and microcirculation function using the quantitative flow ratio (QFR) and index of microcirculatory resistance (IMR). We randomly divided 129 patients undergoing coronary angiography (CAG) into RIPC and control groups. Following the first CAG, we randomly divided the patients further into the unilateral upper limb and lower limb groups for four cycles of ischemia/reperfusion circulation; subsequently, we performed the second CAG. During each CAG, contrast-flow QFR (cQFR), fixed-flow QFR (fQFR), and IMR (in patients with cardiac syndrome X) were calculated and compared. We measured 253 coronary arteries in 129 patients. Compared to the control group, the average cQFR of the RIPC group increased significantly after RIPC. Additionally, 23 patients with cardiac syndrome X (IMR > 30) were included in this study. Compared to the control group, IMR and the difference between cQFR and fQFR (cQFR-fQFR) both decreased significantly after receiving RIPC. The application of RIPC can increase coronary blood flow and improve coronary microcirculation function.

Is Prolonged Use of Antibiotic Prophylaxis and Postoperative Antithrombotic and Antispasmodic Treatments Necessary After Digit Replantation or Revascularization?

BACKGROUND: Ensuring the patency of repaired vessels is pivotal in improving the success rate of digit replantation. There is no consensus on how to best approach postoperative treatment for digit replantation. The influence of postoperative treatment on the risk of failure of revascularization or replantation remains unclear. QUESTIONS/PURPOSES: (1) Is there an increased risk of postoperative infection with early discontinuation of antibiotic prophylaxis? (2) How are anxiety and depression affected by a treatment protocol consisting of prolonged antibiotic prophylaxis and administration of antithrombotic and antispasmodic drugs and by the failure of a revascularization or replantation procedure? (3) Are there differences in the risk of revascularization or replantation failure based on the number of anastomosed arteries and veins? (4) What factors are associated with failure of revascularization or replantation? METHODS: This retrospective study was conducted between July 1, 2018, and March 31, 2022. Initially, 1045 patients were identified. One hundred two patients chose revision of amputation. In all, 556 were excluded because of contraindications. We included all patients in whom the anatomic structures of the amputated part of the digit were well preserved, and those with an ischemia time for the amputated part that did not exceed 6 hours. Patients in good health without any other serious associated injuries or systemic diseases and those without a history of smoking were eligible for inclusion. The patients underwent procedures that were performed or supervised by one of four study surgeons. Patients were treated with antibiotic prophylaxis (1 week); patients treated with antithrombotic and antispasmodic drugs were categorized into the prolonged antibiotic prophylaxis group. The remaining patients treated with antibiotic prophylaxis for less than 48 hours and no antithrombotic and no antispasmodic drugs were categorized into the nonprolonged antibiotic prophylaxis group. Postoperative follow-up was for a minimum of 1 month. Based on the inclusion criteria, 387 participants with 465 digits were selected for an analysis of postoperative infection. Twenty-five participants with a postoperative infection (six digits) and other complications (19 digits) were excluded from the next stage of the study, in which we assessed factors associated with the risk of failure of revascularization or replantation. A total of 362 participants with 440 digits were examined, including the postoperative survival rate, variation in Hospital Anxiety and Depression Scale scores, the association between the survival rate and Hospital Anxiety and Depression Scale scores, and the survival rate based on the number of anastomosed vessels. Postoperative infection was defined as swelling, erythema, pain, purulent discharge, or a positive bacterial culture result. Patients were followed for 1 month. The differences in anxiety and depression scores between the two treatment groups and the differences in anxiety and depression scores based on failure of revascularization or replantation were determined. The difference in the risk of revascularization or replantation failure based on the number of anastomosed arteries and veins was assessed. Except for statistically significant variables (injury type and procedure), we thought that the number of arteries, number of veins, Tamai level, treatment protocol, and surgeons would be important. A multivariable logistic regression analysis was used to perform an adjusted analysis of risk factors such as postoperative protocol, injury type, procedure, number of arteries, number of veins, Tamai level, and surgeon. RESULTS: Postoperative infection did not appear to increase without prolonged use of antibiotic prophylaxis beyond 48 hours (1% [3 of 327] versus 2% [3 of 138]; OR 2.4 [95% confidence interval (CI) 0.5 to 12.0]; p = 0.37). Intervention with antithrombotic and antispasmodic therapy increased the Hospital Anxiety and Depression Scale scores for anxiety (11.2 ± 3.0 versus 6.7 ± 2.9, mean difference 4.5 [95% CI 4.0 to 5.2]; p < 0.01) and depression (7.9 ± 3.2 versus 5.2 ± 2.7, mean difference 2.7 [95% CI 2.1 to 3.4]; p < 0.01). In the analysis based on the failure of revascularization or replantation, the Hospital Anxiety and Depression Scale scores for anxiety (11.4 ± 4.4 versus 9.7 ± 3.5, mean difference 1.7 [95% CI 0.6 to 2.8]; p < 0.01) and depression (8.5 ± 4.6 versus 7.0 ± 3.1, mean difference 1.5 [95% CI 0.5 to 2.5]; p < 0.01) were higher in the failed revascularization or replantation group than in the successful revascularization or replantation group. There was no increase in the artery-related risk of failure (one versus two anastomosed arteries: 91% versus 89%, OR 1.3 [95% CI 0.6 to 2.6]; p = 0.53). For patients with anastomosed veins, a similar outcome was observed for the two vein-related risk of failure (two versus one anastomosed vein: 90% versus 89%, OR 1.0 [95% CI 0.2 to 3.8]; p = 0.95) and three vein-related risk of failure (three versus one vein anastomosed: 96% versus 89%, OR 0.4 [95% CI 0.1 to 2.4]; p = 0.29). Factors associated with failure of revascularization or replantation included the mechanism of injury (crush: OR 4.2 [95% CI 1.6 to 11.2]; p < 0.01, avulsion: OR 10.2 [95% CI 3.4 to 30.7]; p < 0.01). Revascularization had a lower risk of failure than replantation (OR 0.4 [95% CI 0.2 to 1.0]; p = 0.04). Treatment with a protocol of prolonged antibiotics, antithrombotics, and antispasmodics was not associated with a lower risk of failure (OR 1.2 [95% CI 0.6 to 2.3]; p = 0.63). CONCLUSION: With proper wound debridement and patency of repaired vessels, prolonged use of antibiotic prophylaxis and regular antithrombotic and antispasmodic treatment may not be necessary for successful digit replantation. However, it may be associated with higher Hospital Anxiety and Depression Scale scores. Postoperative mental status is associated with digit survival. Well-repaired vessels, instead of the number of anastomosed vessels, could be critical to survival and decrease the influence of risk factors. Further research on consensus guidelines that compare postoperative treatment and the surgeon's level of expertise after digit replantation should be conducted at multiple institutions. LEVEL OF EVIDENCE: Level III, therapeutic study.

Dynamic variations of resting-state BOLD signal spectra in white matter.

Recent studies have demonstrated that the mathematical model used for analyzing and interpreting fMRI data in gray matter (GM) is inappropriate for detecting or describing blood-oxygenation-level-dependent (BOLD) signals in white matter (WM). In particular the hemodynamic response function (HRF) which serves as the regressor in general linear models is different in WM compared to GM. We recently reported measurements of the frequency contents of resting-state signal time courses in WM that showed distinct power spectra which depended on local structural-vascular-functional associations. In addition, multiple studies of GM have revealed how functional connectivity between regions, as measured by the correlation between BOLD time series, varies dynamically over time. We therefore investigated whether and how BOLD signals from WM in a resting state varied over time. We measured voxel-wise spectrograms, which reflect the time-varying spectral patterns of WM time courses. The results suggest that the spectral patterns are non-stationary but could be categorized into five modes that recurred over time. These modes showed distinct spatial distributions of their occurrences and durations, and the distributions were highly consistent across individuals. In addition, one of the modes exhibited a strong coupling of its occurrence between GM and WM across individuals, and two communities of WM voxels were identified according to the hierarchical structures of transitions among modes. Moreover, these modes are coupled to the shape of instantaneous HRFs. Our findings extend previous studies and reveal the non-stationary nature of spectral patterns of BOLD signals over time, providing a spatial-temporal-frequency characterization of resting-state signals in WM.

Detection of functional activity in brain white matter using fiber architecture informed synchrony mapping.

A general linear model is widely used for analyzing fMRI data, in which the blood oxygenation-level dependent (BOLD) signals in gray matter (GM) evoked in response to neural stimulation are modeled by convolving the time course of the expected neural activity with a canonical hemodynamic response function (HRF) obtained a priori. The maps of brain activity produced reflect the magnitude of local BOLD responses. However, detecting BOLD signals in white matter (WM) is more challenging as the BOLD signals are weaker and the HRF is different, and may vary more across the brain. Here we propose a model-free approach to detect changes in BOLD signals in WM by measuring task-evoked increases of BOLD signal synchrony in WM fibers. The proposed approach relies on a simple assumption that, in response to a functional task, BOLD signals in relevant fibers are modulated by stimulus-evoked neural activity and thereby show greater synchrony than when measured in a resting state, even if their magnitudes do not change substantially. This approach is implemented in two technical stages. First, for each voxel a fiber-architecture-informed spatial window is created with orientation distribution functions constructed from diffusion imaging data. This provides the basis for defining neighborhoods in WM that share similar local fiber architectures. Second, a modified principal component analysis (PCA) is used to estimate the synchrony of BOLD signals in each spatial window. The proposed approach is validated using a 3T fMRI dataset from the Human Connectome Project (HCP) at a group level. The results demonstrate that neural activity can be reliably detected as increases in fMRI signal synchrony within WM fibers that are engaged in a task with high sensitivities and reproducibility.

Correlated functional connectivity and glucose metabolism in brain white matter revealed by simultaneous MRI/positron emission tomography.

PURPOSE: There has been converging evidence of reliable detections of blood oxygenation level dependent (BOLD) signals evoked by neural stimulation and in a resting state in white matter (WM), within which few studies examined the relationship between BOLD functional signals and tissue metabolism. The purpose of the present study was to explore whether such relationship exists using combined functional MRI and positron emission tomography (PET) measurements of glucose uptake. METHODS: Functional and metabolic imaging data from 25 right-handed healthy human adults (aged 18-23 years, 18 females) were analyzed. Measures, including average resting state functional connectivity (FC) with respect to 82 Brodmann areas, fractional amplitude of low-frequency fluctuations (FALFF), and average fluorodeoxyglucose (FDG) uptake by PET, were computed for 48 predefined WM bundles. Pearson correlations across the bundles and 25 subjects studied were calculated among these measures. Linear mixed effects models were used to estimate the variance explainable by a predictor variable in the absence of inter-subject variations. RESULTS: Analysis of six separate imaging intervals found that average FC the bundles was significantly correlated with local FDG uptake (r = 0.25, p < 0.001), and the FC also covaried significantly with FALFF (r = 0.41, p < 0.001). When random effects from inter-subject variations were controlled, these correlations appeared to be medium to strong (r = 0.41 for FC vs. FDG uptake, and r = 0.65 for FALFF vs. FC). CONCLUSION: This study indicates that BOLD signals in WM are directly related to variations in metabolic demand and engagement with cortical processing and suggests they should be incorporated into more complete models of brain function.

Functional networks in non-human primate spinal cord and the effects of injury.

Spontaneous fluctuations of Blood Oxygenation-Level Dependent (BOLD) MRI signal in a resting state have previously been detected and analyzed to describe intrinsic functional networks in the spinal cord of rodents, non-human primates and human subjects. In this study we combined high resolution imaging at high field with data-driven Independent Component Analysis (ICA) to i) delineate fine-scale functional networks within and between segments of the cervical spinal cord of monkeys, and also to ii) characterize the longitudinal effects of a unilateral dorsal column injury on these networks. Seven distinct functional hubs were revealed within each spinal segment, with new hubs detected at bilateral intermediate and gray commissure regions in addition to the bilateral dorsal and ventral horns previously reported. Pair-wise correlations revealed significantly stronger connections between hubs on the dominant hand side. Unilateral dorsal-column injuries disrupted predominantly inter-segmental rather than intra-segmental functional connectivities as revealed by correlation strengths and graph-theory based community structures. The effects of injury on inter-segmental connectivity were evident along the length of the cord both below and above the lesion region. Connectivity strengths recovered over time and there was revival of inter-segmental communities as animals recovered function. BOLD signals of frequency 0.01-0.033 Hz were found to be most affected by injury. The results in this study provide new insights into the intrinsic functional architecture of spinal cord and underscore the potential of functional connectivity measures to characterize changes in networks after an injury and during recovery.