Electroconvulsive therapy and cognitive performance from the Global ECT MRI Research Collaboration.

The Global ECT MRI Research Collaboration (GEMRIC) has collected clinical and neuroimaging data of patients treated with electroconvulsive therapy (ECT) from around the world. Results to date have focused on neuroimaging correlates of antidepressant response. GEMRIC sites have also collected longitudinal cognitive data. Here, we summarize the existing GEMRIC cognitive data and provide recommendations for prospective data collection for future ECT-imaging investigations. We describe the criteria for selection of cognitive measures for mega-analyses: Trail Making Test Parts A (TMT-A) and B (TMT-B), verbal fluency category (VFC), verbal fluency letter (VFL), and percent retention from verbal learning and memory tests. We performed longitudinal data analysis focused on the pre-/post-ECT assessments with healthy comparison (HC) subjects at similar timepoints and assessed associations between demographic and ECT parameters with cognitive changes. The study found an interaction between electrode placement and treatment number for VFC (F(1,107) = 4.14, p = 0.04). Higher treatment was associated with decreased VFC performance with right unilateral electrode placement. Percent retention showed a main effect for group, with post-hoc analysis indicating decreased cognitive performance among the HC group. However, there were no significant effects of group or group interactions observed for TMT-A, TMT-B, or VFL. We assessed the current GEMRIC cognitive data and acknowledge the limitations associated with this data set including the limited number of neuropsychological domains assessed. Aside from the VFC and treatment number relationship, we did not observe ECT-mediated neurocognitive effects in this investigation. We provide prospective cognitive recommendations for future ECT-imaging investigations focused on strong psychometrics and minimal burden to subjects.

Diffusion magnetic resonance spectroscopy captures microglial reactivity related to gut-derived systemic lipopolysaccharide: A preliminary study.

Neuroinflammation is a key component underlying multiple neurological disorders, yet non-invasive and cost-effective assessment of in vivo neuroinflammatory processes in the central nervous system remains challenging. Diffusion weighted magnetic resonance spectroscopy (dMRS) has shown promise in addressing these challenges by measuring diffusivity properties of different neurometabolites, which can reflect cell-specific morphologies. Prior work has demonstrated dMRS utility in capturing microglial reactivity in the context of lipopolysaccharide (LPS) challenges and serious neurological disorders, detected as changes of microglial metabolite diffusivity properties. However, the extent to which such dMRS metrics are capable of detecting subtler and more nuanced levels of neuroinflammation in populations without overt neuropathology is unknown. Here we examined the relationship between intrinsic, gut-derived levels of systemic LPS and dMRS-based apparent diffusion coefficients (ADC) of choline, creatine, and N-acetylaspartate (NAA) in two brain regions: the thalamus and the corona radiata. Higher plasma LPS concentrations were significantly associated with increased ADC of choline and NAA in the thalamic region, with no such relationships observed in the corona radiata for any of the metabolites examined. As such, dMRS may have the sensitivity to measure microglial reactivity across populations with highly variable levels of neuroinflammation, and holds promising potential for widespread applications in both research and clinical settings.

Alterations of cerebrovascular reactivity following pediatric mild traumatic brain injury are independent of neurodevelopmental changes.

Cerebrovascular dysfunction following mild traumatic brain injury (mTBI) is understudied relative to other microstructural injuries, especially during neurodevelopment. The blood-oxygen level dependent response was used to investigate cerebrovascular reactivity (CVR) in response to hypercapnia following pediatric mTBI (pmTBI; ages 8-18 years), as well as pseudocontinuous arterial spin labeling to measure cerebral blood flow (CBF). Data were collected ∼1-week (N = 107) and 4 months (N = 73) post-injury. Sex- and age-matched healthy controls (HC) underwent identical examinations at comparable time points (N = 110 and N = 91). Subtle clinical and cognitive deficits existed at ∼1 week that resolved for some, but not all domains at 4 months post-injury. At both visits, pmTBI showed an increased maximal fit between end-tidal CO2 regressor and the cerebrovascular response across multiple regions (primarily fronto-temporal), as well as increased latency to maximal fit in independent regions (primarily posterior). Hypoperfusion was also noted within the bilateral cerebellum. A biphasic relationship existed between CVR amplitude and age (i.e., positive until 14.5 years, negative thereafter) in both gray and white matter, but these neurodevelopment effects did not moderate injury effects. CVR metrics were not associated with post-concussive symptoms or cognitive deficits. In conclusion, cerebrovascular dysfunction may persist for up to four months following pmTBI.

Clinical Outcomes of Rural Patients with Diabetes Treated by ECHO-Trained Providers Versus an Academic Medical Center.

BACKGROUND: Despite clinical practice guidelines prioritizing cardiorenal risk reduction, national trends in diabetes outcomes, particularly in rural communities, do not mirror the benefits seen in clinical trials with emerging therapeutics and technologies. OBJECTIVE: Project ECHO supports implementation of guidelines in under-resourced areas through virtual communities of practice, sharing of best practices, and case-based learning. We hypothesized that diabetes outcomes of patients treated by ECHO-trained primary care providers (PCPs) would be similar to those of patients treated by specialists at an academic medical center. DESIGN: Specialists from the University of New Mexico (UNM) launched a weekly diabetes ECHO program to mentor dyads consisting of a PCP and community health worker at ten rural clinics. PARTICIPANTS: We compared cardiorenal risk factor changes in patients with diabetes treated by ECHO-trained dyads to patients treated by specialists at the UNM Diabetes Comprehensive Care Center (DCCC). Eligible participants included adults with type 1 diabetes, type 2 diabetes on insulin, or diabetes of either type with A1c > 9%. MAIN MEASURES: The primary outcome was change from baseline in A1c in the ECHO and DCCC cohorts. Secondary outcomes included changes in body mass index (BMI), blood pressure, cholesterol, and urine albumin to creatinine ratio (UACR). KEY RESULTS: Compared to the DCCC cohort (n = 151), patients in the ECHO cohort (n = 856) experienced greater A1c reduction (-1.2% vs -0.6%; p = 0.02 for difference in difference). BMI decreased in the Endo ECHO cohort and increased in the DCCC cohort (-0.2 vs. +1.3 kg/m2; p = 0.003 for difference in difference). Diastolic blood pressure declined in the Endo ECHO cohort only. Improvements of similar magnitude were observed in low-density lipoprotein cholesterol in both groups. UACR remained stable in both groups. CONCLUSIONS: ECHO may be a suitable intervention for improving diabetes outcomes in rural, under-resourced communities with limited access to a specialist.

A cautionary tale on the effects of different covariance structures in linear mixed effects modeling of fMRI data.

With the steadily increasing abundance of longitudinal neuroimaging studies with large sample sizes and multiple repeated measures, questions arise regarding the appropriate modeling of variance and covariance. The current study examined the influence of standard classes of variance-covariance structures in linear mixed effects (LME) modeling of fMRI data from patients with pediatric mild traumatic brain injury (pmTBI; N = 181) and healthy controls (N = 162). During two visits, participants performed a cognitive control fMRI paradigm that compared congruent and incongruent stimuli. The hemodynamic response function was parsed into peak and late peak phases. Data were analyzed with a 4-way (GROUP×VISIT×CONGRUENCY×PHASE) LME using AFNI's 3dLME and compound symmetry (CS), autoregressive process of order 1 (AR1), and unstructured (UN) variance-covariance matrices. Voxel-wise results dramatically varied both within the cognitive control network (UN>CS for CONGRUENCY effect) and broader brain regions (CS>UN for GROUP:VISIT) depending on the variance-covariance matrix that was selected. Additional testing indicated that both model fit and estimated standard error were superior for the UN matrix, likely as a result of the modeling of individual terms. In summary, current findings suggest that the interpretation of results from complex designs is highly dependent on the selection of the variance-covariance structure using LME modeling.

Role of non-chromosomal birth defects on the risk of developing childhood Hodgkin lymphoma: A Children's Oncology Group study.

BACKGROUND: Non-chromosomal birth defects are an important risk factor for several childhood cancers. However, these associations are less clear for Hodgkin lymphoma (HL). Therefore, we sought to more fully elucidate the association between non-chromosomal birth defects and HL risk. PROCEDURE: Information on cases (n = 517) diagnosed with HL (ages of 0-14) at Children's Oncology Group Institutions for the period of 1989-2003 was obtained. Control children without a history of cancer (n = 784) were identified using random digit dialing and individually matched to cases on sex, race/ethnicity, age, and geographic location. Parents completed comprehensive interviews and answered questions including whether their child had been born with a non-chromosomal birth defect. To test the association between birth defects and HL risk, conditional logistic regression was applied to generate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: Children born with any non-chromosomal birth defect were not more likely to be diagnosed with HL at 0-14 years of age (aOR: 0.91; 95% CI: 0.69-1.21). No associations were detected between major or minor birth defects and HL (aOR: 1.34; 95% CI: 0.67-2.67 and aOR: 0.88; 95% CI: 0.57-1.34, respectively). Similarly, no association was observed for children born with any birth defect and EBV-positive HL (aOR: 0.57; 95% CI: 0.25-1.26). CONCLUSIONS: Previous assessments of HL in children with non-chromosomal birth defects have been limited. Using data from the largest case-control study of HL in those <15 years of age, we did not observe strong associations between being born with a birth defect and HL risk.

Neural correlates of cognitive control deficits in pediatric mild traumatic brain injury.

There is a growing body of research showing that cerebral pathophysiological processes triggered by pediatric mild traumatic brain injury (pmTBI) may extend beyond the usual clinical recovery timeline. It is paramount to further unravel these processes, because the possible long-term cognitive effects resulting from ongoing secondary injury in the developing brain are not known. In the current fMRI study, neural processes related to cognitive control were studied in 181 patients with pmTBI at sub-acute (SA; ~1 week) and early chronic (EC; ~4 months) stages post-injury. Additionally, a group of 162 age- and sex-matched healthy controls (HC) were recruited at equivalent time points. Proactive (post-cue) and reactive (post-probe) cognitive control were examined using a multimodal attention fMRI paradigm for either congruent or incongruent stimuli. To study brain network function, the triple-network model was used, consisting of the executive and salience networks (collectively known as the cognitive control network), and the default mode network. Additionally, whole-brain voxel-wise analyses were performed. Decreased deactivation was found within the default mode network at the EC stage following pmTBI during both proactive and reactive control. Voxel-wise analyses revealed sub-acute hypoactivation of a frontal area of the cognitive control network (left pre-supplementary motor area) during proactive control, with a reversed effect at the EC stage after pmTBI. Similar effects were observed in areas outside of the triple-network during reactive control. Group differences in activation during proactive control were limited to the visual domain, whereas for reactive control findings were more pronounced during the attendance of auditory stimuli. No significant correlations were present between task-related activations and (persistent) post-concussive symptoms. In aggregate, current results show alterations in neural functioning during cognitive control in pmTBI up to 4 months post-injury, regardless of clinical recovery. We propose that subacute decreases in activity reflect a general state of hypo-excitability due to the injury, while early chronic hyperactivation represents a compensatory mechanism to prevent default mode interference and to retain cognitive control.

Prospective Study of Gray Matter Atrophy Following Pediatric Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: The clinical and physiologic time course for recovery following pediatric mild traumatic brain injury (pmTBI) remains actively debated. The primary objective of the current study was to prospectively examine structural brain changes (cortical thickness and subcortical volumes) and age-at-injury effects. A priori study hypotheses predicted reduced cortical thickness and hippocampal volumes up to 4 months postinjury, which would be inversely associated with age at injury. METHODS: Prospective cohort study design with consecutive recruitment. Study inclusion adapted from American Congress of Rehabilitation Medicine (upper threshold) and Zurich Concussion in Sport Group (minimal threshold) and diagnosed by Emergency Department and Urgent Care clinicians. Major neurologic, psychiatric, or developmental disorders were exclusionary. Clinical (Common Data Element) and structural (3 T MRI) evaluations within 11 days (subacute visit [SA]) and at 4 months (early chronic visit [EC]) postinjury. Age- and sex-matched healthy controls (HC) to control for repeat testing/neurodevelopment. Clinical outcomes based on self-report and cognitive testing. Structural images quantified with FreeSurfer (version 7.1.1). RESULTS: A total of 208 patients with pmTBI (age = 14.4 ± 2.9; 40.4% female) and 176 HC (age = 14.2 ± 2.9; 42.0% female) were included in the final analyses (>80% retention). Reduced cortical thickness (right rostral middle frontal gyrus; d = -0.49) and hippocampal volumes (d = -0.24) observed for pmTBI, but not associated with age at injury. Hippocampal volume recovery was mediated by loss of consciousness/posttraumatic amnesia. Significantly greater postconcussive symptoms and cognitive deficits were observed at SA and EC visits, but were not associated with the structural abnormalities. Structural abnormalities slightly improved balanced classification accuracy above and beyond clinical gold standards (∆+3.9%), with a greater increase in specificity (∆+7.5%) relative to sensitivity (∆+0.3%). DISCUSSION: Current findings indicate that structural brain abnormalities may persist up to 4 months post-pmTBI and are partially mediated by initial markers of injury severity. These results contribute to a growing body of evidence suggesting prolonged physiologic recovery post-pmTBI. In contrast, there was no evidence for age-at-injury effects or physiologic correlates of persistent symptoms in our sample.

Blood-brain barrier disruption measured by albumin index correlates with inflammatory fluid biomarkers.

Blood-brain barrier (BBB) permeability can be measured by the ratio of albumin in cerebrospinal fluid (CSF) and blood and by dynamic contrast-enhanced MRI (DCEMRI). Albumin is a large molecule measured in CSF and blood to form the albumin index (Qalb), which is a global measure of BBB permeability, while the smaller Gadolinium molecule measures regional transfer (Ktrans); few studies have directly compared them in the same patients. We used both methods as part of a study of mechanisms of white matter injury in patients with different forms of dementia. In addition, we also measured biomarkers for inflammation, including proteases, angiogenic growth factors, and cytokines, and correlated them with the BBB results. We found that there was no correlation between Qalb and Ktrans. The Qalb was associated with the matrix metalloproteinases (MMP-2, MMP-3, and MMP-10), the angiogenic factors (VEGF-C and PlGF), and the cytokines (IL-6, IL-8 and TNF-α). On the other hand, Ktrans was associated with the diffusion measures, mean free water and PSMD, which indicate white matter injury. Our results show that the Qalb and Ktrans measure different aspects of BBB permeability, with albumin being a measure of inflammatory BBB opening and Ktrans indicating white matter injury.

MARKOV SPATIAL FLOWS IN BOLD FMRI: A NOVEL LENS ON THE BOLD SIGNAL REVEALS ATTRACTING PATTERNS OF SIGNAL INTENSITY.

While the analysis of temporal signal fluctuations and co-fluctuations has long been a fixture of blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) research, the role and implications of spatial propagation within the 4D neurovascular BOLD signal has been almost entirely neglected. As part of a larger research program aimed at capturing and analyzing spatially propagative dynamics in BOLD fMRI, we report here a method that exposes large-scale functional attractors of spatial flows formulated as Markov processes defined at the voxel level. The brainwide stationary distributions of these voxel-level Markov processes represent patterns of signal accumulation toward which we find evidence that the brain exerts a probabilistic propagative undertow. These probabilistic propagative attractors are spatially structured and organized interpretably over functional regions. They also differ significantly between schizophrenia patients and controls.

Multicompartmental models and diffusion abnormalities in paediatric mild traumatic brain injury.

The underlying pathophysiology of paediatric mild traumatic brain injury and the time-course for biological recovery remains widely debated, with clinical care principally informed by subjective self-report. Similarly, clinical evidence indicates that adolescence is a risk factor for prolonged recovery, but the impact of age-at-injury on biomarkers has not been determined in large, homogeneous samples. The current study collected diffusion MRI data in consecutively recruited patients (n = 203; 8-18 years old) and age and sex-matched healthy controls (n = 170) in a prospective cohort design. Patients were evaluated subacutely (1-11 days post-injury) as well as at 4 months post-injury (early chronic phase). Healthy participants were evaluated at similar times to control for neurodevelopment and practice effects. Clinical findings indicated persistent symptoms at 4 months for a significant minority of patients (22%), along with residual executive dysfunction and verbal memory deficits. Results indicated increased fractional anisotropy and reduced mean diffusivity for patients, with abnormalities persisting up to 4 months post-injury. Multicompartmental geometric models indicated that estimates of intracellular volume fractions were increased in patients, whereas estimates of free water fractions were decreased. Critically, unique areas of white matter pathology (increased free water fractions or increased neurite dispersion) were observed when standard assumptions regarding parallel diffusivity were altered in multicompartmental models to be more biologically plausible. Cross-validation analyses indicated that some diffusion findings were more reproducible when ∼70% of the total sample (142 patients, 119 controls) were used in analyses, highlighting the need for large-sample sizes to detect abnormalities. Supervised machine learning approaches (random forests) indicated that diffusion abnormalities increased overall diagnostic accuracy (patients versus controls) by ∼10% after controlling for current clinical gold standards, with each diffusion metric accounting for only a few unique percentage points. In summary, current results suggest that novel multicompartmental models are more sensitive to paediatric mild traumatic brain injury pathology, and that this sensitivity is increased when using parameters that more accurately reflect diffusion in healthy tissue. Results also indicate that diffusion data may be insufficient to achieve a high degree of objective diagnostic accuracy in patients when used in isolation, which is to be expected given known heterogeneities in pathophysiology, mechanism of injury and even criteria for diagnoses. Finally, current results indicate ongoing clinical and physiological recovery at 4 months post-injury.

17α-Ethinyl estradiol-3-sulfate increases survival and hemodynamic functioning in a large animal model of combined traumatic brain injury and hemorrhagic shock: a randomized control trial.

BACKGROUND: Traumatic brain injury (TBI) and severe blood loss resulting in hemorrhagic shock (HS) represent leading causes of trauma-induced mortality, especially when co-occurring in pre-hospital settings where standard therapies are not readily available. The primary objective of this study was to determine if 17α-ethinyl estradiol-3-sulfate (EE-3-SO4) increases survival, promotes more rapid cardiovascular recovery, or confers neuroprotection relative to Placebo following TBI + HS. METHODS: All methods were approved by required regulatory agencies prior to study initiation. In this fully randomized, blinded preclinical study, eighty (50% females) sexually mature (190.64 ± 21.04 days old; 28.18 ± 2.72 kg) Yucatan swine were used. Sixty-eight animals received a closed-head, accelerative TBI followed by removal of approximately 40% of circulating blood volume. Animals were then intravenously administered EE-3-SO4 formulated in the vehicle at 5.0 mg/mL (dosed at 0.2 mL/kg) or Placebo (0.45% sodium chloride solution) via a continuous pump (0.2 mL/kg over 5 min). Twelve swine were included as uninjured Shams to further characterize model pathology and replicate previous findings. All animals were monitored for up to 5 h in the absence of any other life-saving measures (e.g., mechanical ventilation, fluid resuscitation). RESULTS: A comparison of Placebo-treated relative to Sham animals indicated evidence of acidosis, decreased arterial pressure, increased heart rate, diffuse axonal injury and blood-brain barrier breach. The percentage of animals surviving to 295 min post-injury was significantly higher for the EE-3-SO4 (28/31; 90.3%) relative to Placebo (24/33; 72.7%) cohort. EE-3-SO4 also restored pulse pressure more rapidly post-drug administration, but did not confer any benefits in terms of shock index. Primary blood-based measurements of neuroinflammation and blood brain breach were also null, whereas secondary measurements of diffuse axonal injury suggested a more rapid return to baseline for the EE-3-SO4 group. Survival status was associated with biological sex (female > male), as well as evidence of increased acidosis and neurotrauma independent of EE-3-SO4 or Placebo administration. CONCLUSIONS: EE-3-SO4 is efficacious in promoting survival and more rapidly restoring cardiovascular homeostasis following polytraumatic injuries in pre-hospital environments (rural and military) in the absence of standard therapies. Poly-therapeutic approaches targeting additional mechanisms (increased hemostasis, oxygen-carrying capacity, etc.) should be considered in future studies.

Inflammatory Biomarkers Aid in Diagnosis of Dementia.

Dual pathology of Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) commonly are found together at autopsy, but mixed dementia (MX) is difficult to diagnose during life. Biological criteria to diagnose AD have been defined, but are not available for vascular disease. We used the biological criteria for AD and white matter injury based on MRI to diagnose MX. Then we measured multiple biomarkers in CSF and blood with multiplex biomarker kits for proteases, angiogenic factors, and cytokines to explore pathophysiology in each group. Finally, we used machine learning with the Random forest algorithm to select the biomarkers of maximal importance; that analysis identified three proteases, matrix metalloproteinase-10 (MMP-10), MMP-3 and MMP-1; three angiogenic factors, VEGF-C, Tie-2 and PLGF, and three cytokines interleukin-2 (IL-2), IL-6, IL-13. To confirm the clinical importance of the variables, we showed that they correlated with results of neuropsychological testing.

Hypoxia promotes tau hyperphosphorylation with associated neuropathology in vascular dysfunction.

BACKGROUND: Hypertension-induced microvascular brain injury is a major vascular contributor to cognitive impairment and dementia. We hypothesized that chronic hypoxia promotes the hyperphosphorylation of tau and cell death in an accelerated spontaneously hypertensive stroke prone rat model of vascular cognitive impairment. METHODS: Hypertensive male rats (n = 13) were fed a high salt, low protein Japanese permissive diet and were compared to Wistar Kyoto control rats (n = 5). RESULTS: Using electron paramagnetic resonance oximetry to measure in vivo tissue oxygen levels and magnetic resonance imaging to assess structural brain damage, we found compromised gray (dorsolateral cortex: p = .018) and white matter (corpus callosum: p = .016; external capsule: p = .049) structural integrity, reduced cerebral blood flow (dorsolateral cortex: p = .005; hippocampus: p < .001; corpus callosum: p = .001; external capsule: p < .001) and a significant drop in cortical oxygen levels (p < .05). Consistently, we found reduced oxygen carrying neuronal neuroglobin (p = .008), suggestive of chronic cerebral hypoperfusion in high salt-fed rats. We also observed a corresponding increase in free radicals (NADPH oxidase: p = .013), p-Tau (pThr231) in dorsolateral cortex (p = .011) and hippocampus (p = .003), active interleukin-1ß (p < .001) and neurodegeneration (dorsolateral cortex: p = .043, hippocampus: p = .044). Human patients with subcortical ischemic vascular disease, a type of vascular dementia (n = 38; mean age = 68; male/female ratio = 23/15) showed reduced hippocampal volumes and cortical shrinking (p < .05) consistent with the neuronal cell death observed in our hypertensive rat model as compared to healthy controls (n = 47; mean age = 63; male/female ratio = 18/29). CONCLUSIONS: Our data support an association between hypertension-induced vascular dysfunction and the sporadic occurrence of phosphorylated tau and cell death in the rat model, correlating with patient brain atrophy, which is relevant to vascular disease.

Connectivity dynamics in typical development and its relationship to autistic traits and autism spectrum disorder.

Recent advances in neuroimaging techniques have provided significant insights into developmental trajectories of human brain function. Characterizations of typical neurodevelopment provide a framework for understanding altered neurodevelopment, including differences in brain function related to developmental disorders and psychopathology. Historically, most functional connectivity studies of typical and atypical development operate under the assumption that connectivity remains static over time. We hypothesized that relaxing stationarity assumptions would reveal novel features of both typical brain development related to children on the autism spectrum. We employed a "chronnectomic" (recurring, time-varying patterns of connectivity) approach to evaluate transient states of connectivity using resting-state functional MRI in a population-based sample of 774 6- to 10-year-old children. Dynamic connectivity was evaluated using a sliding-window approach, and revealed four transient states. Internetwork connectivity increased with age in modularized dynamic states, illustrating an important pattern of connectivity in the developing brain. Furthermore, we demonstrated that higher levels of autistic traits and ASD diagnosis were associated with longer dwell times in a globally disconnected state. These results provide a roadmap to the chronnectomic organization of the developing brain and suggest that characteristics of functional brain connectivity are related to children on the autism spectrum.

Evidence of cryptic incidence in childhood diseases.

Persistence and extinction are key processes in infectious disease dynamics that, owing to incomplete reporting, are seldom directly observable. For fully immunizing diseases, reporting probabilities can be readily estimated from demographic records and case reports. Yet reporting probabilities are not sufficient to unambiguously reconstruct disease incidence from case reports. Here, we focus on disease presence (i.e. marginal probability of non-zero incidence), which provides an upper bound on the marginal probability of disease extinction. We examine measles and pertussis in pre-vaccine era United States (US) cities, and describe a conserved scaling relationship between population size, reporting probability and observed presence (i.e. non-zero case reports). We use this relationship to estimate disease presence given perfect reporting, and define cryptic presence as the difference between estimated and observed presence. We estimate that, in early twentieth century US cities, pertussis presence was higher than measles presence across a range of population sizes, and that cryptic presence was common in small cities with imperfect reporting. While the methods employed here are specific to fully immunizing diseases, our results suggest that cryptic incidence deserves careful attention, particularly in diseases with low case counts, poor reporting and longer infectious periods.

Building an EEG-fMRI Multi-Modal Brain Graph: A Concurrent EEG-fMRI Study.

The topological architecture of brain connectivity has been well-characterized by graph theory based analysis. However, previous studies have primarily built brain graphs based on a single modality of brain imaging data. Here we develop a framework to construct multi-modal brain graphs using concurrent EEG-fMRI data which are simultaneously collected during eyes open (EO) and eyes closed (EC) resting states. FMRI data are decomposed into independent components with associated time courses by group independent component analysis (ICA). EEG time series are segmented, and then spectral power time courses are computed and averaged within 5 frequency bands (delta; theta; alpha; beta; low gamma). EEG-fMRI brain graphs, with EEG electrodes and fMRI brain components serving as nodes, are built by computing correlations within and between fMRI ICA time courses and EEG spectral power time courses. Dynamic EEG-fMRI graphs are built using a sliding window method, versus static ones treating the entire time course as stationary. In global level, static graph measures and properties of dynamic graph measures are different across frequency bands and are mainly showing higher values in eyes closed than eyes open. Nodal level graph measures of a few brain components are also showing higher values during eyes closed in specific frequency bands. Overall, these findings incorporate fMRI spatial localization and EEG frequency information which could not be obtained by examining only one modality. This work provides a new approach to examine EEG-fMRI associations within a graph theoretic framework with potential application to many topics.

The Role of Childhood Infections and Immunizations on Childhood Rhabdomyosarcoma: A Report From the Children's Oncology Group.

BACKGROUND: Rhabdomyosarcoma (RMS) is a rare, highly malignant tumor arising from primitive mesenchymal cells that differentiate into skeletal muscle. Relatively little is known about RMS susceptibility. Based on growing evidence regarding the role of early immunologic challenges on RMS development, we evaluated the role of infections and immunizations on this clinically significant pediatric malignancy. PROCEDURE: RMS cases (n = 322) were enrolled from the third trial coordinated by the Intergroup Rhabdomyosarcoma Study Group. Population-based controls (n = 322) were pair matched to cases on race, sex, and age. The following immunizations were assessed: diphtheria, pertussis, and tetanus (DPT); measles, mumps, and rubella; and oral polio vaccine. We also evaluated if immunizations were complete versus incomplete. We examined selected infections including chickenpox, mumps, pneumonia, scarlet fever, rubella, rubeola, pertussis, mononucleosis, and lung infections. Conditional logistic regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for maternal education and total annual income. RESULTS: Incomplete immunization schedules (OR = 5.30, 95% CI: 2.47-11.33) and incomplete DPT immunization (OR = 1.56, 95% CI: 1.06-2.29) were positively associated with childhood RMS. However, infections did not appear to be associated with childhood RMS. CONCLUSIONS: This is the largest study of RMS to date demonstrating a possible protective effect of immunizations against the development of childhood RMS. Further studies are needed to validate our findings. Our findings add to the growing body of literature, suggesting a protective role of routine vaccinations in childhood cancer and specifically in childhood RMS.

Multidimensional frequency domain analysis of full-volume fMRI reveals significant effects of age, gender, and mental illness on the spatiotemporal organization of resting-state brain activity.

Clinical research employing functional magnetic resonance imaging (fMRI) is often conducted within the connectionist paradigm, focusing on patterns of connectivity between voxels, regions of interest (ROIs) or spatially distributed functional networks. Connectivity-based analyses are concerned with pairwise correlations of the temporal activation associated with restrictions of the whole-brain hemodynamic signal to locations of a priori interest. There is a more abstract question however that such spatially granular correlation-based approaches do not elucidate: Are the broad spatiotemporal organizing principles of brains in certain populations distinguishable from those of others? Global patterns (in space and time) of hemodynamic activation are rarely scrutinized for features that might characterize complex psychiatric conditions, aging effects or gender-among other variables of potential interest to researchers. We introduce a canonical, transparent technique for characterizing the role in overall brain activation of spatially scaled periodic patterns with given temporal recurrence rates. A core feature of our technique is the spatiotemporal spectral profile (STSP), a readily interpretable 2D reduction of the native four-dimensional brain × time frequency domain that is still "big enough" to capture important group differences in globally patterned brain activation. Its power to distinguish populations of interest is demonstrated on a large balanced multi-site resting fMRI dataset with nearly equal numbers of schizophrenia patients and healthy controls. Our analysis reveals striking differences in the spatiotemporal organization of brain activity that correlate with the presence of diagnosed schizophrenia, as well as with gender and age. To the best of our knowledge, this is the first demonstration that a 4D frequency domain analysis of full volume fMRI data exposes clinically or demographically relevant differences in resting-state brain function.