Efficient risk-based collection of biospecimens in cohort studies: Designing a prospective study of diagnostic performance for multicancer detection tests.

In cohort studies, it can be infeasible to collect specimens on an entire cohort. For example, to estimate sensitivity of multiple Multi-Cancer Detection (MCD) assays, we desire an extra 80mL of cell-free DNA (cfDNA) blood, but this much extra blood is too expensive for us to collect on everyone. We propose a novel epidemiologic study design that efficiently oversamples those at highest baseline disease risk from whom to collect specimens, to increase the number of future cases with cfDNA blood collection. The variance reduction ratio from our risk-based subsample versus a simple random (sub)sample (SRS) depends primarily on the ratio of risk model sensitivity to the fraction of the cohort selected for specimen collection subject to constraining the risk model specificity. In a simulation where we chose 34% of Prostate, Lung, Colorectal, and Ovarian Screening Trial cohort at highest risk of lung cancer for cfDNA blood collection, we could enrich the number of lung cancers 2.42-fold and the standard deviation of lung-cancer MCD sensitivity was 31-33% reduced versus SRS. Risk-based collection of specimens on a subsample of the cohort could be a feasible and efficient approach to collecting extra specimens for molecular epidemiology.

Caregiver burden and risk of epithelial ovarian cancer in the Nurses' Health Studies.

Psychosocial stress may increase ovarian cancer risk and accelerate disease progression. We examined the association between caregiver burden, a common stressor, and risk of epithelial ovarian cancer. We prospectively followed 67,724 women in the Nurses' Health Study (NHS; 1992-2012) and 70,720 women in the NHSII (2001-2009) who answered questions on informal caregiving (i.e., caregiving outside of work). Women who reported no informal caregiving were considered non-caregivers while, among women who provided care outside of work, caregiver burden was categorized by time spent caregiving and perceived stress from caregiving. For the 34% of women who provided informal care for ≥15 hours per week, 42% described caregiving as moderately to extremely stressful. Pooled multivariate analyses indicated no difference in ovarian cancer risk for women providing ≥15 hours of care per week compared to non-caregivers (hazard ratio (HR)=0.96; 95% confidence interval (CI): 0.79-1.18), and no association was evident for women who reported moderate or extreme stress from caregiving compared to non-caregivers (HR=0.96; 95% CI: 0.75-1.22). Together with prior work evaluating job strain and ovarian cancer risk, our findings suggest that, when evaluating a stressor's role in cancer risk, it is critical to consider how the stressor contributes to the overall experience of distress.

Important Variations of Aortic Branches: Imaging Case Series.

Various anatomical variations are known to occur in branches of the aorta. Some of these variations are common while others are quite uncommon. However, these variations carry significant implications when the patient is diseased and some intervention or surgical procedure is to be done. Most of these variations are usually incidentally detected. This imaging case series illustrates some clinically important variations of aortic branches including branches of the aortic arch and abdominal aorta, with a review of the literature. All cases illustrated here were detected incidentally.

Cladistics of Rhipicephalus microplus and laboratory assessment of acaricidal efficacy of different Cassia fistula extracts against R. microplus larvae.

The present study aimed to analyze the cladistics and population structure analysis of Rhipicephalus microplus ticks infesting buffaloes in Haryana, India, as well as the assessment of the anti-tick efficacy of the ethanolic extracts of Cassia fistula (bark, pod pulp, and flowers) against R. microplus larvae. The molecular characterization and population structure analysis were performed by targeting the amplification of the partial mitochondrial cytochrome C oxidase subunit 1 (cox1) gene, whereas anti-tick efficacy was evaluated using a larval packet test. The sequences generated herein revealed a homology of 98.26-100% to the GenBank-archived R. microplus sequences. In population structure analysis, high haplotype (0.500 ± 0.265) and low nucleotide (0.002 ± 0.001) diversities were recorded for the sequences generated in this study. Significantly negative neutrality indices were recorded for the overall dataset. The extracts were found to significantly affect mortality rates in a dose-dependent manner, and the ethanolic extracts of the bark, pod pulp, and flowers of C. fistula exhibited median lethal concentration (LC50) values of 27.989, 40.457, and 49.43 mg/mL, respectively. The LC50 value recorded for the combination of the ethanolic extracts of the bark, flower, and pod pulp of C. fistula was 19.724 mg/mL, whereas the synthetic acaricide ivermectin had an LC50 value of 351.56 mg/mL. In conclusion, R. microplus populations infesting cattle and buffalo hosts in India exhibited negligible genetic differentiation and high gene flow between them. Additionally, the combination of all C. fistula extracts could serve as a potential substitute for the synthetic acaricide.

A Prodrug Strategy to Reposition Atovaquone as a Long-Acting Injectable for Malaria Chemoprotection.

Recent malaria drug discovery approaches have been extensively focused on the development of oral, smallmolecule inhibitors for disease treatment whereas parenteral routes of administration have been avoided due to limitations in deploying a shelf-stable injectable even though it could be dosed less frequently. However, an updated target candidate profile from Medicines for Malaria Venture (MMV) and stakeholders have advocated for long-acting injectable chemopreventive agents as an important interventive tool to improve malaria prevention. Here, we present strategies for the development of a long-acting, intramuscular, injectable atovaquone prophylactic therapy. We have generated three prodrug approaches that are contrasted by their differential physiochemical properties and pharmacokinetic profiles: mCBK068, a docosahexaenoic acid ester of atovaquone formulated in sesame oil, mCKX352, a heptanoic acid ester of atovaquone formulated as a solution in sesame oil, and mCBE161, an acetic acid ester of atovaquone formulated as an aqueous suspension. As a result, from a single 20 mg/kg intramuscular injection, mCKX352 and mCBE161 maintain blood plasma exposure of atovaquone above the minimal efficacious concentration for >70 days and >30 days, respectively, in cynomolgus monkeys. The differences in plasma exposure are reflective of the prodrug strategy, which imparts altered chemical properties that ultimately influence aqueous solubility and depot release kinetics. On the strength of the pharmacokinetic and safety profiles, mCBE161 is being advanced as a first-in-class clinical candidate for first-in-human trials.

Effectiveness of Botulinum Toxin Injection With Casting in Children With Spastic Cerebral Palsy: A Randomized Controlled Trial.

BACKGROUND: The most common form of movement disorder presented in children with cerebral palsy is spasticity, and dynamic equinus is the most common spastic ankle deformity. Botulinum toxin (BT) injection is now an established first-line treatment for focal spasticity. AIM: To assess the effects of BT injection with casting in the treatment of dynamic equinus in children diagnosed with cerebral palsy with spastic diplegia. SETTING AND DESIGN: A prospective randomized controlled trial was conducted among patients aged 2-12 years with cerebral palsy and spastic diplegia, attending the general outpatient department and admitted to the indoor facility of the Department of Physical Medicine and Rehabilitation and the Department of Pediatric Orthopedics at King George's Medical University, Lucknow. MATERIAL AND METHODS: Two groups of 19 patients each were formed. Group A received BT injection with casting, whereas in group B, only a cast was applied. Outcome measures including spasticity by Modified Ashworth Scale (MAS), Modified Tardieu Scale (MTS), range of motion (ROM), passive ankle dorsiflexion, and Gross Motor Function Measure (GMFM-66) (dimensions D and E) were assessed before and after the intervention. RESULTS: The participants in groups A and B were age-matched. A statistically significant difference was seen within group A and group B for MAS, passive ROM-dorsiflexion (PROM-DF), and passive ROM-plantarflexion (PROM-PF) at various follow-ups. In the 3rd week, MAS in each group was statistically insignificant (p-value> 0.05). CONCLUSION: There was a significant improvement in tone and a significant increase in the passive range of motion in both groups.

Population structure and haplotype network analyses of Hyalomma anatolicum based on the large subunit ribosomal RNA (16S rRNA) gene.

Hyalomma anatolicum, an Anatolian hard tick is a well-recognized vector involved in the transmission of various pathogens to animals and humans. The present study elucidated the population structure and haplotype network of H. anatolicum based on the mitochondrial large subunit ribosomal RNA (16S rRNA) gene sequence. The population structure and haplotype network analysis of 75 sequences archived in the GenBank, including the 15 sequences generated herein, yielded 24 haplotypes. Haplotype 1 (Hap_1) was the predominant haplotype consisting of 45 sequences from India, China, Pakistan, Turkey, Egypt, Iraq, and Tajikistan. The complete haplotype network exhibited a stellate conformation, highlighting a recent population expansion. The overall dataset, together with the sequences corresponding to India, China, and Pakistan, showed a high haplotype (0.638 ± 0.065, 0.671 ± 0.103, 0.753 ± 0.099, and 0.854 ± 0.061, respectively) and low nucleotide (0.00407 ± 0.00090, 0.00525 ± 0.00196, 0.00680 ± 0.00233, and 0.00453 ± 0.00056, respectively) diversity, further emphasized a recent population expansion. The neutrality indices including Tajima's D, Fu and Li's D, and Fu and Li's F for the complete dataset (- 2.661, - 6.008, and - 5.649, respectively) as well as for the sequences from India (- 2.223, - 3.414, and - 3.567, respectively) were negative, suggesting deviation from neutrality and a recent population expansion. The present study provided novel insights into the population structure and haplotype networks of H. anatolicum based on the mitochondrial 16S rRNA gene, and the different tests inferred a low genetic differentiation and suggested a recent population expansion of this economically important tick species.

Case Report: Post-transplant lymphoproliferative disorder as a serious complication of vascularized composite allotransplantation.

Vascularized composite allotransplantation (VCA) is an emerging field in transplant surgery. Despite overall positive outcomes, VCA confers risk for multiple complications related to the procedure and subsequent immunosuppression. Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of lymphoproliferative disorders occurring after solid organ and hematopoietic stem cell transplant. A patient with PTLD after bilateral upper extremity transplantation is presented as well as a review of all known cases of PTLD after VCA, with a focus on the unique epidemiology, presentation, and treatment in this population.

Loss of Epitranscriptomic Modification N6-Methyladenosine (m6A) Reader YTHDF1 Exacerbates Ischemic Brain Injury in a Sexually Dimorphic Manner.

N6-Methyladenosine (m6A) is a neuronal-enriched, reversible post-transcriptional modification that regulates RNA metabolism. The m6A-modified RNAs recruit various m6A-binding proteins that act as readers. Differential m6A methylation patterns are implicated in ischemic brain damage, yet the precise role of m6A readers in propagating post-stroke m6A signaling remains unclear. We presently evaluated the functional significance of the brain-enriched m6A reader YTHDF1, in post-stroke pathophysiology. Focal cerebral ischemia significantly increased YTHDF1 mRNA and protein expression in adult mice of both sexes. YTHDF1-/- male, but not female, mice subjected to transient middle cerebral artery occlusion (MCAO) showed worsened motor function recovery and increased infarction compared to sex-matched YTHDF1+/+ mice. YTHDF1-/- male, but not female, mice subjected to transient MCAO also showed significantly perturbed expression of genes related to inflammation, and increased infiltration of peripheral immune cells into the peri-infarct cortex, compared with sex-matched YTHDF1+/+ mice. Thus, this study demonstrates a sexual dimorphism of YTHDF1 in regulating post-ischemic inflammation and pathophysiology. Hence, post-stroke epitranscriptomic regulation might be sex-dependent.

A blood-brain barrier-penetrant AAV gene therapy improves neurological function in symptomatic mucolipidosis IV mice.

Mucolipidosis IV (MLIV) is a rare, autosomal recessive, lysosomal disease characterized by intellectual disability, motor deficits, and progressive vision loss. Using adeno-associated vector 9 (AAV9) and AAV-PHP.B as delivery vectors, we previously demonstrated the feasibility of modifying disease course in a mouse model of MLIV by the human MCOLN1 gene transfer. Here, using a primate-enabling capsid AAV.CPP.16 (CPP16), we constructed a new, clinic-oriented MCOLN1 gene expression vector and demonstrated its efficacy in the preclinical model of MLIV. Systemic administration of CPP16-MCOLN1 in adult symptomatic Mcoln1 -/- mice at a dose of 1e12 vg per mouse resulted in MCOLN1 expression in the brain and peripheral tissues, alleviated brain pathology, rescued neuromotor function, and completely prevented paralysis. Notable expression of MCOLN1 transcripts was also detected in the retina of the mouse, which had exhibited significant degeneration at the time of the treatment. However, no increase in retinal thickness was observed after gene therapy treatment. Our results suggest a new AAV-based systemic gene replacement therapy for the treatment of MLIV that could be translated into clinical studies.

The risk and benefit profiles of US eligible lung cancer screening attendees vs. non-attendees.

BACKGROUND: The United States Preventive Services Task Force (USPSTF) recommend lung-cancer screening for individuals aged 50-80 with ≥20 pack-years and ≤15 quit-years, but uptake is low. The risk and benefit profiles of screening attendees are unknown; consequently, the impact and lost opportunity of ongoing lung-cancer screening in the US remains unclear. METHODS: We estimated lung-cancer death risk (using the Lung Cancer Death Risk Assessment Tool) and life gained from screening (using the LYFS-CT model) for individuals 50-79 who ever-smoked in the US-representative 2022 Behavioral Risk Factor Surveillance System. We compared lung-cancer death risk and life-gained among USPSTF-eligible individuals by screening status (self-reported screened vs not screened in past year), and estimated the number of lung-cancer deaths averted and life-years gained under current screening levels and if everyone eligible was screened. RESULTS: USPSTF-eligibility was 33.7% (95%CI:33.1-34.4%), of whom 17.9% (95%CI : 17.0-18.8%) self-reported screening. Screening uptake increased with increasing lung-cancer death risk quintile (Q1 = 5.2% (95%CI : 3.0%-8.8%); Q5 = 21.8% (95%CI : 20.3%-23.3%)) and life-gain from screening quintile (Q1 = 6.2% (95%CI : 3.8%-9.9%); Q5 = 20.8% (95%CI : 19.5%-22.2%)). Screened individuals had higher lung-cancer death risk (Risk Ratio [RR]=1.35, 95%CI : 1.26-1.46) and life-years gained (RR = 1.19, 95%CI : 1.12-1.25) than unscreened individuals. Currently screening averts 19,306 lung-cancer deaths and gains 237,564 life-years; screening everyone eligible would additionally avert 56,956 lung-cancer deaths and gain 751,850 life-years. Two-thirds of USPSTF-lung-eligible women were up-to-date with breast-cancer screening, but only 17.3% attended lung screening in the past year. CONCLUSIONS: Eligible screening attendees had higher lung-cancer death risk and benefit from screening. Higher rates of screening could substantially increase the number of lung-cancer deaths prevented.

Exploring Inner Ear and Brain Connectivity through Perilymph Sampling for Early Detection of Neurological Diseases: A Provocative Proposal.

Recent evidence shows that it is possible to identify the elements responsible for sensorineural hearing loss, such as pro-inflammatory cytokines and macrophages, by performing perilymph sampling. However, current studies have only focused on the diagnosis of such as otologic conditions. Hearing loss is a feature of certain neuroinflammatory disorders such as multiple sclerosis, and sensorineural hearing loss (SNHL) is widely detected in Alzheimer's disease. Although the environment of the inner ear is highly regulated, there are several communication pathways between the perilymph of the inner ear and cerebrospinal fluid (CSF). Thus, examination of the perilymph may help understand the mechanism behind the hearing loss observed in certain neuroinflammatory and neurodegenerative diseases. Herein, we review the constituents of CSF and perilymph, the anatomy of the inner ear and its connection with the brain. Then, we discuss the relevance of perilymph sampling in neurology. Currently, perilymph sampling is only performed during surgical procedures, but we hypothesize a simplified and low-invasive technique that could allow sampling in a clinical setting with the same ease as performing an intratympanic injection under direct visual check. The use of this modified technique could allow for perilymph sampling in people with hearing loss and neuroinflammatory/neurodegenerative disorders and clarify the relationship between these conditions; in fact, by measuring the concentration of neuroinflammatory and/or neurodegenerative biomarkers and those typically expressed in the inner ear in aging SNHL, it could be possible to understand if SNHL is caused by aging or neuroinflammation.

An unexpected role for the ketogenic diet in triggering tumor metastasis by modulating BACH1-mediated transcription.

We have found that the ketogenic (Keto) diet is able to, unexpectedly, promote the metastatic potential of cancer cells in complementary mouse models. Notably, the Keto diet-induced tumor metastasis is dependent on BTB domain and CNC homolog 1 (BACH1) and its up-regulation of pro-metastatic targets, including cell migration-inducing hyaluronidase 1, in response to the Keto diet. By contrast, upon genetic knockout or pharmacological inhibition of endogenous BACH1, the Keto diet-mediated activation of those targets is largely diminished, and the effects on tumor metastasis are completely abolished. Mechanistically, upon administration of the Keto diet, the levels of activating transcription factor 4 (ATF4) are markedly induced. Through direct interaction with BACH1, ATF4 is recruited to those pro-metastatic target promoters and enhances BACH1-mediated transcriptional activation. Together, these data implicate a distinct transcription regulatory program of BACH1 for tumor metastasis induced by the Keto diet. Our study also raises a potential health risk of the Keto diet in human patients with cancer.

Beyond the Norm: Navigating a Unique Papillary Carcinoma Journey in Breast Cancer.

The presence of papillary structures inside the tumor is a unique and uncommon characteristic of breast cancer, and it is known as papillary carcinoma. In contrast to other forms of breast cancer, this variant usually manifests as a well-defined mass in imaging investigations and is frequently linked to a good prognosis. We present a case of a 72-year-old female with papillary carcinoma of the breast identified after presenting with a palpable breast lump. Following a left simple mastectomy and adjuvant treatment, the presence of papillary structures inside the tumor was verified by a histopathological study. Understanding the clinical and pathological characteristics of breast papillary carcinoma is crucial for precise diagnosis and suitable therapy strategizing. More research is required to further understand the molecular traits and best practices for treating this uncommon subtype of breast cancer.

Effectiveness of Mannheim's Peritonitis Index in Patients With Peritonitis Secondary to Hollow Viscus Perforation in a Tertiary Care Hospital in Jharkhand, India.

Introduction Peritonitis refers to the inflammation of the peritoneum and peritoneal cavity. Causes of peritonitis can be bacterial (gastrointestinal or non-gastrointestinal), chemical, traumatic, or ischemic. Peritonitis can be localized or diffuse, acute or chronic. Peritonitis can be primary, secondary, or tertiary, according to the pathogenesis. Peritonitis developed secondary to hollow viscus perforation is a life-threatening condition and a common cause of emergency surgery in India. The Mannheim peritonitis index (MPI) is a simple scoring system that can accurately predict the outcome of peritonitis. This study aimed to evaluate the effectiveness of MPI in predicting mortality risk or prognosis in patients with peritonitis due to hollow viscus perforation. Materials and methods This observational cross-sectional study at the Department of General Surgery, Rajendra Institute of Medical Sciences, Ranchi, involved 111 patients with peritonitis due to hollow viscus perforation from December 2021 to March 2022. Detailed history, clinical examination, relevant blood tests, and radiological investigations established a diagnosis of perforation peritonitis, followed by a score assessment. Data were analyzed using SPSS software (IBM Corp., Armonk, NY, USA). Results Patients >50 years had higher mortality (i.e., 18/43) than patients <50 years (i.e., 13/68). Overall mortality was 31, which included one in low risk, 12 in intermediate risk, and 18 in the high-risk group. Mortality was lowest in the low-risk group (i.e., 1/30), highest in the high-risk group (i.e., 18/40), and 12/41 in the intermediate-risk group; the p-value was <0.05, which was highly significant. Mortality was higher in patients presenting after 24 hours, having organ failure, and non-colonic sepsis. Conclusion The MPI scoring system is simple, easy to calculate, cost-effective, precise, and effective in assessing mortality and morbidity risk in patients with peritonitis due to hollow viscus perforation. It can also guide further management strategies.

Circadian-Dependent Intermittent Fasting Influences Ischemic Tolerance and Dendritic Spine Remodeling.

BACKGROUND: Preconditioning by intermittent fasting is linked to improved cognition and motor function, and enhanced recovery after stroke. Although the duration of fasting was shown to elicit different levels of neuroprotection after ischemic stroke, the impact of time of fasting with respect to the circadian cycles remains unexplored. METHODS: Cohorts of mice were subjected to a daily 16-hour fast, either during the dark phase (active-phase intermittent fasting) or the light phase (inactive-phase intermittent fasting) or were fed ad libitum. Following a 6-week dietary regimen, mice were subjected to transient focal cerebral ischemia and underwent behavioral functional assessment. Brain samples were collected for RNA sequencing and histopathologic analyses. RESULTS: Active-phase intermittent fasting cohort exhibited better poststroke motor and cognitive recovery as well as reduced infarction, in contrast to inactive-phase intermittent fasting cohort, when compared with ad libitum cohort. In addition, protection of dendritic spine density/morphology and increased expression of postsynaptic density protein-95 were observed in the active-phase intermittent fasting. CONCLUSIONS: These findings indicate that the time of daily fasting is an important factor in inducing ischemic tolerance by intermittent fasting.

Multi-location evaluation of field pea in Indian climates: eco-phenological dynamics, crop-environment relationships, and identification of mega-environments.

Characterization of crop-growing environments in relation to crop's genotypic performance is crucial to harness positive genotype-by-environment interactions (GEI) in systematic breeding programs. Given that, the study aimed to delineate the impact of diverse environments on crop phenology and yield traits of dwarf-statured field pea, pinpointing location(s) favoring higher yield and distinctiveness within breeding lines. We tested twelve field pea breeding lines across twenty locations in India, covering Central Zone (CZ), North Western Plain Zone (NWPZ), North Eastern Plain Zone (NEPZ), and Northern Hill Zone (NHZ). Across these locations, maximum and minimum temperatures during flowering (TMAXF, TMINF) and reproductive period (TMAXRP, TMINRP) ranged 18.9-28.3, 3.3-18.0, 15.0-30.8, and 7.9-22.1oC, respectively. Meanwhile, notable variations in phenological and agronomic traits (coefficient of variation) were observed: flowering (31%), days to maturity (21%), reproductive period (18%), grain yield (48%), and 100-seed weight (18%). Combined ANOVA demonstrated an oversized impact of environment (81%) on yield, while genotype and GEI effects were 2% and 14%, respectively. The variables TMINF, TMINRP, and cumulative growing degree-day showed positive correlations with yield, while extended vegetative and maturity durations negatively influenced yield (p < 0.05). Additionally, linear mixed-models and PCA results explained that instability in crop phenology had significant influence on field pea yield. Seed weight was markedly varied within the locations (9.9-20.8 g) and both higher and lower seed weights were associated with lower yields (Optimal = 17.1 g). HA-GGE biplot-based on environment focus-scaling demonstrated three mega-environments and specific locations viz. Kota (CZ), SK Nagar (CZ), Raipur (CZ), Sehore (CZ), and Pantnagar (NWPZ) as the ideal testing-environments with high efficiency in selecting new genotypes with wider adaptability. The study findings highlight distinct impact of environments on crop phenology and agronomic traits of field pea (dwarf-type), hold substantial value in designing efficient field pea (dwarf-type) breeding program at mega-environment scale.

Functional phenotypes in schizophrenia spectrum disorders: defining the constructs and identifying biopsychosocial correlates using data-driven methods.

Functional impairments contribute to poor quality of life in schizophrenia spectrum disorders (SSD). We sought to (Objective I) define the main functional phenotypes in SSD, then (Objective II) identify key biopsychosocial correlates, emphasizing interpretable data-driven methods. Objective I was tested on independent samples: Dataset I (N = 282) and Dataset II (N = 317), with SSD participants who underwent assessment of multiple functioning areas. Participants were clustered based on functioning. Objective II was evaluated in Dataset I by identifying key features for classifying functional phenotype clusters from among 65 sociodemographic, psychological, clinical, cognitive, and brain volume measures. Findings were replicated across latent discriminant analyses (LDA) and one-vs.-rest binomial regularized regressions to identify key predictors. We identified three clusters of participants in each dataset, demonstrating replicable functional phenotypes: Cluster 1-poor functioning across domains; Cluster 2-impaired Role Functioning, but partially preserved Independent and Social Functioning; Cluster 3-good functioning across domains. Key correlates were Avolition, anhedonia, left hippocampal volume, and measures of emotional intelligence and subjective social experience. Avolition appeared more closely tied to role functioning, and anhedonia to independent and social functioning. Thus, we found three replicable functional phenotypes with evidence that recovery may not be uniform across domains. Avolition and anhedonia were both critical but played different roles for different functional domains. It may be important to identify critical functional areas for individual patients and target interventions accordingly.

Primary Cytoreduction and Survival for Patients With Less-Common Epithelial Ovarian Cancer.

This cohort study examines the association between primary cytoreduction status and survival for patients with less-common, advanced-stage epithelial ovarian carcinoma.

Estimation of static and dynamic functional connectivity in resting-state fMRI using zero-frequency resonator.

Resting-state functional magnetic resonance imaging (rs-fMRI) is increasingly being used to infer the functional organization of the brain. Blood oxygen level-dependent (BOLD) features related to spontaneous neuronal activity, are yet to be clearly understood. Prior studies have hypothesized that rs-fMRI is spontaneous event-related and these events convey crucial information about the neuronal activity in estimating resting state functional connectivity (FC). Attempts have been made to extract these temporal events using a predetermined threshold. However, the thresholding methods in addition to being very sensitive to noise, may consider redundant events or exclude the low-valued inflection points. Here, we extract the event-related temporal onsets from the rs-fMRI time courses using a zero-frequency resonator (ZFR). The ZFR reflects the transient behavior of the BOLD events at its output. The conditional rate (CR) of the BOLD events occurring in a time course with respect to a seed time course is used to derive static FC. The temporal activity around the estimated events called high signal-to-noise ratio (SNR) segments are also obtained in the rs-fMRI time course and are then used to compute static and dynamic FCs during rest. Coactivation pattern (CAP) is the dynamic FC obtained using the high SNR segments driven by the ZFR. The static FC demonstrates that the ZFR-based CR distinguishes the coactivation and non-coactivation scores well in the distribution. CAP analysis demonstrated the stable and longer dwell time dominant resting state functional networks with high SNR segments driven by the ZFR. Static and dynamic FC analysis underpins that the ZFR-driven temporal onsets of BOLD events derive reliable and consistent FCs in the resting brain using a subset of the time points.