Reduced slow wave density is associated with worse positive symptoms in clinical high risk: An objective readout of symptom severity for early treatment interventions?

Individuals at clinical high risk for psychosis (CHR) present subsyndromal psychotic symptoms that can escalate and lead to the transition to a diagnosable psychotic disorder. Identifying biological parameters that are sensitive to these symptoms can therefore help objectively assess their severity and guide early interventions in CHR. Reduced slow wave oscillations (∼1 Hz) during non-rapid eye movement sleep were recently observed in first-episode psychosis patients and were linked to the intensity of their positive symptoms. Here, we collected overnight high-density EEG recordings from 37 CHR and 32 healthy control (HC) subjects and compared slow wave (SW) activity and other SW parameters (i.e., density and negative peak amplitude) between groups. We also assessed the relationships between clinical symptoms and SW parameters in CHR. While comparisons between HC and the entire CHR group showed no SW differences, CHR individuals with higher positive symptom severity (N = 18) demonstrated a reduction in SW density in an EEG cluster involving bilateral prefrontal, parietal, and right occipital regions compared to matched HC individuals. Furthermore, we observed a negative correlation between SW density and positive symptoms across CHR individuals, suggesting a potential target for early treatment interventions.

Unhealthy white matter connectivity, cognition, and racialization in older adults.

INTRODUCTION: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non-Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology-affected regions and cognition. METHODS: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions. Individual regression models tested associations of UWMC in beta-amyloid (Aß) or tau pathology-affected regions with cognition overall, stratified by racialized group, and with a racialized group interaction. RESULTS: In 201 older adults ranging from cognitively unimpaired to AD, BA participants exhibited greater UWMC and worse cognition than nHW participants. UWMC was negatively associated with cognition in 17 and 5 Aß- and tau-affected regions, respectively. Racialization did not modify these relationships. DISCUSSION: Differential UWMC burden, not differential UWMC-and-cognition associations, may drive clinical AD disparities between racialized groups. HIGHLIGHTS: Unhealthy white matter connectivity (UWMC) in Alzheimer's disease (AD) pathology-affected brain regions is associated with cognition. Relationships between UWMC and cognition are similar between Black American (BA) and non-Hispanic White (nHW) individuals. More UWMC may partially drive higher clinical AD burden in BA versus nHW populations. UWMC risk factors, particularly social and environmental, should be identified.

MISPEL: A supervised deep learning harmonization method for multi-scanner neuroimaging data.

Large-scale data obtained from aggregation of already collected multi-site neuroimaging datasets has brought benefits such as higher statistical power, reliability, and robustness to the studies. Despite these promises from growth in sample size, substantial technical variability stemming from differences in scanner specifications exists in the aggregated data and could inadvertently bias any downstream analyses on it. Such a challenge calls for data normalization and/or harmonization frameworks, in addition to comprehensive criteria to estimate the scanner-related variability and evaluate the harmonization frameworks. In this study, we propose MISPEL (Multi-scanner Image harmonization via Structure Preserving Embedding Learning), a supervised multi-scanner harmonization method that is naturally extendable to more than two scanners. We also designed a set of criteria to investigate the scanner-related technical variability and evaluate the harmonization techniques. As an essential requirement of our criteria, we introduced a multi-scanner matched dataset of 3T T1 images across four scanners, which, to the best of our knowledge is one of the few datasets of this kind. We also investigated our evaluations using two popular segmentation frameworks: FSL and segmentation in statistical parametric mapping (SPM). Lastly, we compared MISPEL to popular methods of normalization and harmonization, namely White Stripe, RAVEL, and CALAMITI. MISPEL outperformed these methods and is promising for many other neuroimaging modalities.

Sex matters: acute functional connectivity changes as markers of remission in late-life depression differ by sex.

The efficacy of antidepressant treatment in late-life is modest, a problem magnified by an aging population and increased prevalence of depression. Understanding the neurobiological mechanisms of treatment response in late-life depression (LLD) is imperative. Despite established sex differences in depression and neural circuits, sex differences associated with fMRI markers of antidepressant treatment response are underexplored. In this analysis, we assess the role of sex on the relationship of acute functional connectivity changes with treatment response in LLD. Resting state fMRI scans were collected at baseline and day one of SSRI/SNRI treatment for 80 LLD participants. One-day changes in functional connectivity (differential connectivity) were related to remission status after 12 weeks. Sex differences in differential connectivity profiles that distinguished remitters from non-remitters were assessed. A random forest classifier was used to predict the remission status with models containing various combinations of demographic, clinical, symptomatological, and connectivity measures. Model performance was assessed with area under the curve, and variable importance was assessed with permutation importance. The differential connectivity profile associated with remission status differed significantly by sex. We observed evidence for a difference in one-day connectivity changes between remitters and non-remitters in males but not females. Additionally, prediction of remission was significantly improved in male-only and female-only models over pooled models. Predictions of treatment outcome based on early changes in functional connectivity show marked differences between sexes and should be considered in future MR-based treatment decision-making algorithms.

Efficacy of a Vibrating Crib Mattress to Reduce Pharmacologic Treatment in Opioid-Exposed Newborns: A Randomized Clinical Trial.

Importance: Pharmacologic agents are often used to treat newborns with prenatal opioid exposure (POE) despite known adverse effects on neurodevelopment. Alternative nonpharmacological interventions are needed. Objective: To examine efficacy of a vibrating crib mattress for treating newborns with POE. Design, Setting, and Participants: In this dual-site randomized clinical trial, 208 term newborns with POE, enrolled from March 9, 2017, to March 10, 2020, were studied at their bedside throughout hospitalization. Interventions: Half the cohort received treatment as usual (TAU) and half received standard care plus low-level stochastic (random) vibrotactile stimulation (SVS) using a uniquely constructed crib mattress with a 3-hour on-off cycle. Study initiated in the newborn unit where newborns were randomized to TAU or SVS within 48 hours of birth. All infants whose symptoms met clinical criteria for pharmacologic treatment received morphine in the neonatal intensive care unit per standard care. Main Outcomes and Measures: The a priori primary outcomes analyzed were pharmacotherapy (administration of morphine treatment [AMT], first-line medication at both study sites [number of infants treated], and cumulative morphine dose) and hospital length of stay. Intention-to-treat analysis was conducted. Results: Analyses were performed on 181 newborns who completed hospitalization at the study sites (mean [SD] gestational age, 39.0 [1.2] weeks; mean [SD] birth weight, 3076 (489) g; 100 [55.2%] were female). Of the 181 analyzed infants, 121 (66.9%) were discharged without medication and 60 (33.1%) were transferred to the NICU for morphine treatment (31 [51.7%] TAU and 29 [48.3%] SVS). Treatment rate was not significantly different in the 2 groups: 35.6% (31 of 87 infants who received TAU) and 30.9% (29 of 94 infants who received SVS) (P = .60). Adjusting for site, sex, birth weight, opioid exposure, and feed type, infant duration on the vibrating mattress in the newborn unit was associated with reduction in AMT (adjusted odds ratio, 0.88 hours per day; 95% CI, 0.81-0.93 hours per day). This translated to a 50% relative reduction in AMT for infants who received SVS on average 6 hours per day. Among 32 infants transferred to the neonatal intensive care unit for morphine treatment who completed treatment within 3 weeks, those assigned to SVS finished treatment nearly twice as fast (hazard ratio, 1.96; 95% CI, 1.01-3.81), resulting in 3.18 fewer treatment days (95% CI, -0.47 to -0.04 days) and receiving a mean 1.76 mg/kg less morphine (95% CI, -3.02 to -0.50 mg/kg) than the TAU cohort. No effects of condition were observed among infants treated for more than 3 weeks (n = 28). Conclusions and Relevance: The findings of this clinical trial suggest that SVS may serve as a complementary nonpharmacologic intervention for newborns with POE. Reducing pharmacotherapy with SVS has implications for reduced hospitalization stays and costs, and possibly improved infant outcomes given the known adverse effects of morphine on neurodevelopment. Trial Registration: ClinicalTrials.gov Identifier: NCT02801331.

Shared and distinct abnormalities in sleep-wake patterns and their relationship with the negative symptoms of Schizophrenia Spectrum Disorder patients.

Sleep and rest-activity-rhythm (RAR) abnormalities are commonly reported in schizophrenia spectrum disorder (SSD) patients. However, an in-depth characterization of sleep/RAR alterations in SSD, including patients in different treatment settings, and the relationship between these alterations and SSD clinical features (e.g., negative symptoms) is lacking. SSD (N = 137 altogether, N = 79 residential and N = 58 outpatients) and healthy control (HC) subjects (N = 113) were recruited for the DiAPAson project. Participants wore an ActiGraph for seven consecutive days to monitor habitual sleep-RAR patterns. Sleep/rest duration, activity (i.e., M10, calculated on the 10 most active hours), rhythm fragmentation within days (i.e., intra-daily variability, IV; beta, steepness of rest-active changes), and rhythm regularity across days (i.e., inter-daily stability, IS) were computed in each study participant. Negative symptoms were assessed in SSD patients with the Brief Negative Symptom Scale (BNSS). Both SSD groups showed lower M10 and longer sleep/rest duration vs. HC, while only residential patients had more fragmented and irregular rhythms than HC. Compared to outpatients, residential patients had lower M10 and higher beta, IV and IS. Furthermore, residential patients had worse BNSS scores relative to outpatients, and higher IS contributed to between-group differences in BNSS score severity. Altogether, residentials and outpatients SSD had both shared and unique abnormalities in Sleep/RAR measures vs. HC and relative to one another, which also contributed to the patients' negative symptom severity. Future work will help establish whether improving some of these measures may ameliorate the quality of life and clinical symptoms of SSD patients.

Laminar-Specific Alterations in Calbindin-Positive Boutons in the Prefrontal Cortex of Subjects With Schizophrenia.

BACKGROUND: Cognitive deficits in schizophrenia are associated with altered GABA (gamma-aminobutyric acid) neurotransmission in the prefrontal cortex (PFC). GABA neurotransmission requires GABA synthesis by 2 isoforms of glutamic acid decarboxylase (GAD65 and GAD67) and packaging by the vesicular GABA transporter (vGAT). Current postmortem findings suggest that GAD67 messenger RNA is lower in a subset of the calbindin-expressing (CB+) class of GABA neurons in schizophrenia. Hence, we assessed if CB+ GABA neuron boutons are affected in schizophrenia. METHODS: For 20 matched pairs of subjects with schizophrenia and unaffected comparison subjects, PFC tissue sections were immunolabeled for vGAT, CB, GAD67, and GAD65. The density of CB+ GABA boutons and levels of the 4 proteins per bouton were quantified. RESULTS: Some CB+ GABA boutons contained both GAD65 and GAD67 (GAD65+/GAD67+), whereas others contained only GAD65 (GAD65+) or GAD67 (GAD67+). In schizophrenia, vGAT+/CB+/GAD65+/GAD67+ bouton density was not altered, vGAT+/CB+/GAD65+ bouton density was 86% higher in layers 2/superficial 3 (L2/3s), and vGAT+/CB+/GAD67+ bouton density was 36% lower in L5-6. Bouton GAD levels were differentially altered across bouton types and layers. In schizophrenia, the sum of GAD65 and GAD67 levels in vGAT+/CB+/GAD65+/GAD67+ boutons was 36% lower in L6, GAD65 levels were 51% higher in vGAT+/CB+/GAD65+ boutons in L2, and GAD67 levels in vGAT+/CB+/GAD67+ boutons were 30% to 46% lower in L2/3s-6. CONCLUSIONS: These findings indicate that schizophrenia-associated alterations in the strength of inhibition from CB+ GABA neurons in the PFC differ across cortical layers and bouton classes, suggesting complex contributions to PFC dysfunction and cognitive impairments in schizophrenia.

Sleep Abnormalities in Different Clinical Stages of Psychosis: A Systematic Review and Meta-analysis.

Importance: Abnormal sleep is frequent in psychosis; however, sleep abnormalities in different stages (ie, clinical high risk for psychosis [CHR-P], early psychosis [EP], and chronic psychosis [CP]) have not been characterized. Objective: To identify sleep abnormalities across psychosis stages. Data Sources: Web of Science and PubMed were searched between inception and June 15, 2022. Studies written in English were included. Study Selection: Sleep disturbance prevalence studies and case-control studies reporting sleep quality, sleep architecture, or sleep electroencephalography oscillations in CHR-P, EP, or CP. Data Extraction and Synthesis: This systematic review and meta-analysis followed Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Stage-specific and pooled random-effects meta-analyses were conducted, along with the assessment of heterogeneity, study quality, and meta-regressions (clinical stage, sex, age, medication status, and psychotic symptoms). Main Outcomes and Measures: Sleep disturbance prevalence, self-reported sleep quality, sleep architecture (total sleep time, sleep latency, sleep efficiency, nonrapid eye movement, rapid eye movement stages, and number of arousals), and sleep electroencephalography oscillations (spindle density, amplitude, and duration, and slow wave density). Results: Fifty-nine studies with up to 6710 patients (n = 5135 for prevalence) and 977 controls were included. Sleep disturbance prevalence in pooled cases was 50% (95% CI, 40%-61%) and it was similar in each psychosis stage. Sleep quality was worse in pooled cases vs controls (standardized mean difference [SMD], 1.00 [95% CI, 0.70-1.30]). Sleep architecture alterations included higher sleep onset latency (SMD [95% CI]: pooled cases, 0.96 [0.62-1.30]; EP, 0.72 [0.52-0.92]; CP, 1.36 [0.66-2.05]), higher wake after sleep onset (SMD [95% CI]: pooled cases, 0.5 [0.29-0.71]; EP, 0.62 [0.34-0.89]; CP, 0.51 [0.09-0.93]), higher number of arousals (SMD [95% CI]: pooled cases, 0.45 [0.07-0.83]; CP, 0.81 [0.30-1.32]), higher stage 1 sleep (SMD [95% CI]: pooled cases, 0.23 [0.06-0.40]; EP, 0.34 [0.15-0.53]), lower sleep efficiency (SMD [95% CI]: pooled cases, -0.75 [-0.98 to -0.52]; EP, -0.90 [-1.20 to -0.60]; CP, -0.73 [-1.14 to -0.33]), and lower rapid eye movement density (SMD [95% CI]: pooled cases, 0.37 [0.14-0.60]; CP, 0.4 [0.19-0.77]). Spindle parameter deficits included density (SMD [95% CI]: pooled cases, -1.06 [-1.50 to -0.63]; EP, -0.80 [-1.22 to -0.39]; CP, -1.39 [-2.05 to -0.74]; amplitude: pooled cases, -1.08 [-1.33 to -0.82]; EP, -0.86 [-1.24 to -0.47]; CP, -1.25 [-1.58 to -0.91]; and duration: pooled cases: -1.2 [-1.69 to -0.73]; EP, -0.71 [-1.08 to -0.34]; CP, -1.74 [-2.10 to -1.38]). Individuals with CP had more frequent arousals vs CHR-P (z = 2.24, P = .02) and reduced spindle duration vs EP (z = -3.91, P < .001). Conclusions and Relevance: In this systematic review and meta-analysis, sleep disturbances were found to be prevalent throughout the course of psychosis, and different psychosis stages showed both shared and distinct abnormalities in sleep quality, architecture, and spindles. These findings suggest that sleep should become a core clinical target and research domain from at-risk to early and chronic stages of psychosis.

Dorsolateral Prefrontal Cortex Glutamate/Gamma-Aminobutyric Acid (GABA) Alterations in Clinical High Risk and First-Episode Schizophrenia: A Preliminary 7-T Magnetic Resonance Spectroscopy Imaging Study.

Converging lines of evidence suggest that an imbalance between excitation and inhibition is present in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia (SCZ). Gamma-aminobutyric-acid (GABA) and, to a lesser extent, glutamate (Glu) abnormalities were reported in the DLPFC of SCZ patients, especially on the right hemisphere, by post-mortem studies. However, in vivo evidence of GABA, Glu, and Glu/GABA DLPFC abnormalities, particularly on the right side and the early stages of illness, is limited. In this preliminary study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to investigate bilateral Glu/Creatine (Cre), GABA/Cre, and Glu/GABA in the DLPFC of sixteen first episode schizophrenia (FES), seventeen clinical high risk (CHR), and twenty-six healthy comparison (HC) subjects. FES and CHR had abnormal GABA/Cre and Glu/GABA in the right DLPFC (rDLPFC) compared with HC participants, while no differences were observed in the left DLPFC (lDLPFC) among the three groups. Furthermore, HC had higher Glu/GABA in rDLPFC compared to lDLPFC (R > L), whereas the opposite relationship (R < L) was observed in the DLPFC Glu/GABA of FES patients. Altogether, these findings indicate that GABA/Cre and Glu/GABA DLPFC alterations are present before illness manifestation and worsen in FES patients, thus representing a putative early pathophysiological biomarker for SCZ and related psychotic disorders.

Sleep spindle alterations relate to working memory deficits in individuals at clinical high-risk for psychosis.

STUDY OBJECTIVES: Sleep spindles are waxing and waning EEG waves exemplifying the main fast oscillatory activity occurring during NREM sleep. Several recent studies have established that sleep spindle abnormalities are present in schizophrenia spectrum disorders, including in early-course and first-episode patients, and those spindle deficits are associated with some of the cognitive impairments commonly observed in these patients. Cognitive deficits are often observed before the onset of psychosis and seem to predict poor functional outcomes in individuals at clinical high-risk for psychosis (CHR). Yet, the presence of spindle abnormalities and their relationship with cognitive dysfunction has not been investigated in CHR. METHODS: In this study, overnight high-density (hd)-EEG recordings were collected in 24 CHR and 24 healthy control (HC) subjects. Spindle density, duration, amplitude, and frequency were computed and compared between CHR and HC. Furthermore, WM was assessed for both HC and CHR, and its relationship with spindle parameters was examined. RESULTS: CHR had reduced spindle duration in centro-parietal and prefrontal regions, with the largest decrease in the right prefrontal area. Moderation analysis showed that the relation between spindle duration and spindle frequency was altered in CHR relative to HC. Furthermore, CHR had reduced WM performance compared to HC, which was predicted by spindle frequency, whereas in HC spindle frequency, duration, and density all predicted working memory performance. CONCLUSION: Altogether, these findings indicate that sleep spindles are altered in CHR individuals, and spindle alterations are associated with their cognitive deficits, thus representing a sleep-specific putative neurophysiological biomarker of cognitive dysfunction in psychosis risk.

Functional connectivity signatures of political ideology.

Emerging research has begun investigating the neural underpinnings of the biological and psychological differences that drive political ideology, attitudes, and actions. Here, we explore the neurological roots of politics through conducting a large sample, whole-brain analysis of functional connectivity (FC) across common fMRI tasks. Using convolutional neural networks, we develop predictive models of ideology using FC from fMRI scans for nine standard task-based settings in a novel cohort of healthy adults (n = 174, age range: 18 to 40, mean = 21.43) from the Ohio State University Wellbeing Project. Our analyses suggest that liberals and conservatives have noticeable and discriminative differences in FC that can be identified with high accuracy using contemporary artificial intelligence methods and that such analyses complement contemporary models relying on socio-economic and survey-based responses. FC signatures from retrieval, empathy, and monetary reward tasks are identified as important and powerful predictors of conservatism, and activations of the amygdala, inferior frontal gyrus, and hippocampus are most strongly associated with political affiliation. Although the direction of causality is unclear, this study suggests that the biological and neurological roots of political behavior run much deeper than previously thought.

Relationship between plasma clozapine/N-desmethylclozapine and changes in basal forebrain-dorsolateral prefrontal cortex coupling in treatment-resistant schizophrenia.

Clozapine (CLZ) demonstrates a unique clinical efficacy relative to other antipsychotic drugs. Previous work has linked the plasma ratio of CLZ and its major metabolite, N-desmethylclozapine (NDMC), to an inverse relationship with cognition via putative action on the cholinergic system. However, neuroimaging correlates of CLZ/NDMC remain unknown. Here, we examined changes in basal forebrain functional connectivity with the dorsolateral prefrontal cortex, and secondly, cognition in relation to the CLZ/NDMC ratio. A cohort of nineteen chronically ill participants with treatment-resistant schizophrenia (TRS) undergoing 12 weeks of CLZ treatment were included. Measures of cognition and plasma CLZ/NDMC ratios were obtained in addition to resting-state functional neuroimaging scans, captured at baseline and after 12 weeks of CLZ treatment. We observed a significant correlation between basal forebrain-DLPFC connectivity and CLZ/NDMC ratios across CLZ treatment (p = 0.02). Consistent with previous findings, we also demonstrate a positive relationship between CLZ/NDMC ratio and working memory (p = 0.03). These findings may reflect the action of CLZ and NDMC on the muscarinic cholinergic system, highlighting a possible neural correlate of cognition across treatment.

A multicenter randomized controlled trial comparing gamification with remote monitoring against standard rehabilitation for patients after arthroscopic shoulder surgery.

BACKGROUND: Gamification has become increasingly popular in rehabilitation and is viewed as a tool to improve patient activation, motivation, and engagement. The aim of this study was to compare the efficacy of validated exergames played through a system using "depth sensor" and bespoke software against standard physiotherapy in patients treated with arthroscopic shoulder surgery. This included the following common conditions: subacromial impingement syndrome, calcific tendinopathy, and rotator cuff tear. METHODS: Following arthroscopic shoulder surgery, patients were randomized into 1 of 2 groups: In the standard rehabilitation group, patients were followed up for 12 weeks after surgery with standard postoperative physiotherapy and underwent electronic measurements of their active range of movement (ROM). In the exergame group, patients followed a postoperative regimen of exergames using the principles of gamification with physiotherapy support. Patients were given an exergame schedule prescribed by their therapist on Medical Interactive Recovery Assistant (MIRA) software (MIRA Rehab, London, UK) paired with a Microsoft Kinect sensor (Microsoft, Redmond, WA, USA). The primary outcome was active ROM objectively measured by MIRA and Kinect. Secondary outcome measures included the Oxford Shoulder Score, the Disabilities of the Arm, Shoulder and Hand score, and the EQ-VAS score at 12 weeks after surgery. RESULTS: A total of 71 patients were recruited to the study. We excluded 7 patients based on intraoperative findings. Thirty-three patients were treated with exergames, and 31 patients underwent conventional physiotherapy. There was no significant difference between the 2 groups in baseline ROM. Postoperatively, there was no significant difference in any of the cardinal planes of movement (forward flexion, P = .64; abduction, P = .33; and external rotation, P = .75). The mean Oxford Shoulder Score improved from 29.25 to 38.2 in the control group (P = .001) and from 27.1 to 35.1 in the trial group (P = .01); there was no significant difference between the groups at 12 weeks (P = .246). The mean Disabilities of the Arm, Shoulder and Hand score improved from 38.13 to 16.98 in the control group (P = .001) and from 42.3 to 22.54 in the trial group (P = .007); there was no significant difference between the 2 groups (P = .328). There was no significant difference in the EQ-VAS score in either group at any time point (P = .5866). CONCLUSION: This randomized controlled trial demonstrates that exergames can be used effectively in the rehabilitation of patients following arthroscopic shoulder surgery. Outcomes, judged by ROM and patient-reported outcome measures, are equivalent to conventional physiotherapy rehabilitation protocols. This health care innovation has the potential to relieve some of the heavy burden placed on physiotherapy departments for "routine" postoperative care in shoulder surgery.

Verification of fetal evoked response by magnetic dipole fitting.

BACKGROUND: Investigation of fetal evoked response to auditory or visual stimuli is an important means of understanding the developmental stages and potential problems in prenatal life. It is, however, not without certain imperfections. The biggest challenge with fetal evoked response is its low signal to noise ratio. Under noisy conditions, the detected fetal evoked response should, therefore, be further investigated to confirm that the source of the signal is from fetal brain and is not related to random noise. Existing methods for verification are: (1) visual inspection of magnetic field maps, which requires user intervention and expert knowledge which can be highly subjective; (2) simultaneous ultrasound measurement, which is expensive and technically difficult to manage; and (3) equivalent current dipole fitting, which requires knowledge of the orientation of fetal head and its dimensions that may not be available at all times. OBJECTIVE: To verify that the detected fetal evoked response signal is originating from the fetal head by using an objective and feasible method that employs magnetic dipole fitting to fetal evoked response. STUDY DESIGN: From raw fetal magnetoencephalography data, the cardiac interference was removed by frequency dependent subtraction. After averaging over stimulus triggers, the resulting signal was taken as the candidate fetal evoked response. The fetal evoked response was investigated for the highest peak in between 0.2-0.5 s, which is the expected latency of the response to the stimulus. The magnetic field at this highest peak was used for magnetic dipole fitting. The validation of peak was based on the closeness of the magnetic dipole fit to vicinity of fetal head location determined by ultrasound and the anatomically reasonable distance from the fetal heart. The methodology was first tested on a sample neonatal data before application to fetal data. RESULTS: The results of neonatal application confirmed that the source localization by magnetic dipole fitting for the brain produced meaningful results. When applied to fetal data, auditory and visual evoked response was detected in 27 of the 38 recordings. This implied that with our verification method, fetal evoked responses were detected in 71% of fetuses. CONCLUSION: Detection rate of the evoked responses were similar to earlier reports where subjective visual inspection or simultaneous ultrasound measurement were used. Our method using magnetic dipole fitting for verification is more feasible and objective compared to the earlier methods.

An enhanced frequency dependent subtraction algorithm for removal of cardiac interference from fMEG by using minimum norm projection operator.

BACKGROUND: A frequency dependent subtraction method, SUBTR, is developed to remove maternal and fetal magnetocardiography (mMCG and fMCG) interference from fetal magnetoencephalography (fMEG). But channels close to fetal head cannot be used as references for SUBTR in order to protect fMEG from subtraction and this results in cardiac residual when these channels have important fMCG frequency components. Cardiac residual creates noise in evoked response (ER) which results in poor ER detection. NEW METHOD: We developed an enhanced SUBTR algorithm, which we call SUBTR with minimum norm projection operator (SUBTRwMNPO), by employing covariance based minimum norm projection operators (MNPO). mMCG and fMCG signals are extracted from the raw data using MNPO and they are subtracted in the frequency domain from raw data to extract fetal Evoked Response (fER). RESULTS: When tested on 87 datasets, SUBTRwMNPO is shown to attenuate cardiac interference almost totally resulting in a clean fER signal. COMPARISON WITH EXISTING METHODS: Cardiac attenuation with SUBTRwMNPO is either as good as or better than SUBTR. SUBTRwMNPO has higher attenuation rate for the datasets where SUBTR leaves cardiac residual. CONCLUSIONS: SUBTRwMNPO is successful in removing cardiac interference regardless of the orientation of fMCG and fMEG signal spaces. It can also be used to remove cardiac interference when there is no prior knowledge of fetal head location.

Electro-Mechanical Ionic Channel Modeling for Uterine Contractions and Oxytocin Effect during Pregnancy.

Uterine contractions during normal pregnancy and preterm birth are an important physiological activity. Although the cause of preterm labor is usually unknown, preterm birth creates very serious health concerns in many cases. Therefore, understanding normal birth and predicting preterm birth can help both newborn babies and their families. In our previous work, we developed a multiscale dynamic electrophysiology model of uterine contractions. In this paper, we mainly focus on the cellular level and use electromyography (EMG) and cell force generation methods to construct a new ionic channel model and a corresponding mechanical force model. Specifically, the ionic channel model takes into consideration the knowledge of individual ionic channels, which include the electrochemical and bioelectrical characteristics of individual myocytes. We develop a new sodium channel and a new potassium channel based on the experimental data from the human myometrium and the average correlations are 0.9946 and 0.9945, respectively. The model is able to generate the single spike, plateau type and bursting type of action potentials. Moreover, we incorporate the effect of oxytocin on changing the properties of the L-type and T-type calcium channels and further influencing the output action potentials. In addition, we develop a mechanical force model based on the new ionic channel model that describes the detailed ionic dynamics. Our model produces cellular mechanical force that propagates to the tissue level. We illustrate the relationship between the cellular mechanical force and the intracellular ionic dynamics and discuss the relationship between the application of oxytocin and the output mechanical force. We also propose a simplified version of the model to enable large scale simulations using sensitivity analysis method. Our results show that the model is able to reproduce the bioelectrical and electromechanical characteristics of uterine contractions during pregnancy.

A consistent organizational structure across multiple functional subnetworks of the human brain.

A recurrent theme of both cognitive and network neuroscience is that the brain has a consistent subnetwork structure that maps onto functional specialization for different cognitive tasks, such as vision, motor skills, and attention. Understanding how regions in these subnetworks relate is thus crucial to understanding the emergence of cognitive processes. However, the organizing principles that guide how regions within subnetworks communicate, and whether there is a common set of principles across subnetworks, remains unclear. This is partly due to available tools not being suited to precisely quantify the role that different organizational principles play in the organization of a subnetwork. Here, we apply a joint modeling technique - the correlation generalized exponential random graph model (cGERGM) - to more completely quantify subnetwork structure. The cGERGM models a correlation network, such as those given in functional connectivity, as a function of activation motifs - consistent patterns of coactivation (i.e., connectivity) between collections of nodes that describe how the regions within a network are organized (e.g., clustering) - and anatomical properties - relationships between the regions that are dictated by anatomy (e.g., Euclidean distance). By jointly modeling all features simultaneously, the cGERGM models the unique variance accounted for by each feature, as well as a point estimate and standard error for each, allowing for significance tests against a random graph and between graphs. Across eight functional subnetworks, we find remarkably consistent organizational properties guiding subnetwork architecture, suggesting a fundamental organizational basis for subnetwork communication. Specifically, all subnetworks displayed greater clustering than would be expected by chance, but lower preferential attachment (i.e., hub use). These findings suggest that human functional subnetworks follow a segregated highway structure, in which tightly clustered subcommunities develop their own channels of communication rather than relying on hubs.

Effect of EKG Sampling Rate on Heart Rate Variability Analysis.

We studied the effect of EKG sampling rate on heart rate variability (HRV) analysis. We acquired EKG from four term hypoxic-ischemic encephalopathic infants undergoing therapeutic hypothermia. The EKG signal was acquired continuously for 4 days from the cardiorespiratory monitor through the analog port. The following HRV metrics were calculated: normalized low-frequency (nLF), normalized high-frequency (nHF), low-frequency (LF), high-frequency (HF), short-term detrended fluctuation analysis (DFA) exponent (αs), long-term DFA exponent (αL), root mean square (RMS) short (RMSS), and RMS long (RMSL). In addition, heart rate was used. These metrics were calculated for EKG acquired at 1 KHz (served as reference, EKGref) as well as from EKGs downsampled at 500 Hz (EKG500), 250 Hz (EKG250), and 125 Hz (EKG125). The bedside monitors were simultaneously sending the EKG to a data warehouse, storing the EKG (EKGDWH) at 250 Hz. All HRV metrics were also calculated for the EKGDWH. The comparison between HRV metrics calculated from EKGref and downsampled EKG (EKG500, EKG250, EKG125) was made with intraclass correlation coefficient (r). The comparisons of HRV metrics between EKG250 and EKGDWH were also made with ICC. Our results show that HRV calculated with EKGref and from downsampled EKG were highly correlated (r>0.8 for all comparisons, P<; 0.001). HRV metrics from EKG250 and EKGDWH were also significantly correlated (r=0.7, P<; 0.001) for all metrics except for HF (r=0.276). These data show that HF power is compromised in the EKGDWH signal and caution must be exercised in interpreting the HF power calculated from this EKG.

Does Hyperglycemia Affect Risk of Peripherally Inserted Central Catheter-Related Upper Extremity Venous Thrombosis?

It is not clear whether blood glucose (BG) affects the risk of peripherally inserted central catheter (PICC)-related upper extremity venous thrombosis (PRUEVT). A case-control study was conducted comparing patients with PRUEVT versus patients with PICCs who did not develop PRUEVT. BG on admission was significantly higher among cases with PRUEVT than controls. No significant differences were found between the groups in hemoglobin A1c or BG on the third day of hospitalization. PRUEVT cases were more likely to be diabetic, but this did not reach statistical significance. The time that a PICC was in place before PRUEVT was diagnosed was longer for diabetic patients, but the authors believe this result must be viewed with caution.

Tracking Fetal Movement Through Source Localization From Multisensor Magnetocardiographic Recordings.

Due to its high spatial and temporal resolution, fetal magnetocardiography (fMCG) measurements have been used for fetal movement (FM) detection in several studies, which considered the changes in the amplitude and/or morphology of measured fMCG signals. Using source localization for fMCG measurements, we propose a novel method to fit a magnetic dipole moment to fetal heart signals and investigate the positional changes of magnetic dipole in order to detect FMs. We first split each fMCG recording into 6-s time windows. Then, the magnetic dipole location and orientation for each time window are estimated using our inverse solution model. Finally, the distance between magnetic dipole positions in adjacent time windows is computed. Also, we calculate the dot products of the normalized magnetic dipoles to monitor the orientational changes. We analyzed 28 fMCG measurements from 23 subjects to investigate accuracy of the dipole fitting results. For each dipole fit, our model described the measured data with a goodness-of-fit value over 97% and with a fitting error of less than 2%. We observed that magnetic dipole positions significantly moved for some time windows. The time points at which the significant movement was observed were correlated with the heart rate acceleration as well. In addition to identifying the time points of the movement, our method is capable of observing rotational movement checking orientation of the dipoles.