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.

Parkinson's disease cerebrovascular reactivity pattern: A feasibility study.

A mounting body of research points to cerebrovascular dysfunction as a fundamental element in the pathophysiology of Parkinson's disease (PD). In the current feasibility study, blood-oxygen-level-dependent (BOLD) MRI was used to measure cerebrovascular reactivity (CVR) in response to hypercapnia in 26 PD patients and 16 healthy controls (HC), and aimed to find a multivariate pattern specific to PD. Whole-brain maps of CVR amplitude (i.e., magnitude of response to CO2) and latency (i.e., time to reach maximum amplitude) were computed, which were further analyzed using scaled sub-profile model principal component analysis (SSM-PCA) with leave-one-out cross-validation. A meaningful pattern based on CVR latency was identified, which was named the PD CVR pattern (PD-CVRP). This pattern was characterized by relatively increased latency in basal ganglia, sensorimotor cortex, supplementary motor area, thalamus and visual cortex, as well as decreased latency in the cerebral white matter, relative to HC. There were no significant associations with clinical measures, though sample size may have limited our ability to detect significant associations. In summary, the PD-CVRP highlights the importance of cerebrovascular dysfunction in PD, and may be a potential biomarker for future clinical research and practice.

Amplitude-determined seizure-threshold, electric field modeling, and electroconvulsive therapy antidepressant and cognitive outcomes.

Electroconvulsive therapy (ECT) pulse amplitude, which dictates the induced electric field (E-field) magnitude in the brain, is presently fixed at 800 or 900 milliamperes (mA) without clinical or scientific rationale. We have previously demonstrated that increased E-field strength improves ECT's antidepressant effect but worsens cognitive outcomes. Amplitude-determined seizure titration may reduce the E-field variability relative to fixed amplitude ECT. In this investigation, we assessed the relationships among amplitude-determined seizure-threshold (STa), E-field magnitude, and clinical outcomes in older adults (age range 50 to 80 years) with depression. Subjects received brain imaging, depression assessment, and neuropsychological assessment pre-, mid-, and post-ECT. STa was determined during the first treatment with a Soterix Medical 4×1 High Definition ECT Multi-channel Stimulation Interface (Investigation Device Exemption: G200123). Subsequent treatments were completed with right unilateral electrode placement (RUL) and 800 mA. We calculated Ebrain defined as the 90th percentile of E-field magnitude in the whole brain for RUL electrode placement. Twenty-nine subjects were included in the final analyses. Ebrain per unit electrode current, Ebrain/I, was associated with STa. STa was associated with antidepressant outcomes at the mid-ECT assessment and bitemporal electrode placement switch. Ebrain/I was associated with changes in category fluency with a large effect size. The relationship between STa and Ebrain/I extends work from preclinical models and provides a validation step for ECT E-field modeling. ECT with individualized amplitude based on E-field modeling or STa has the potential to enhance neuroscience-based ECT parameter selection and improve clinical outcomes.

Comparison of automated and manual quantification methods for neuromelanin-sensitive MRI in Parkinson's disease.

Neuromelanin-sensitive magnetic resonance imaging quantitative analysis methods have provided promising biomarkers that can noninvasively quantify degeneration of the substantia nigra in patients with Parkinson's disease. However, there is a need to systematically evaluate the performance of manual and automated quantification approaches. We evaluate whether spatial, signal-intensity, or subject specific abnormality measures using either atlas based or manually traced identification of the substantia nigra better differentiate patients with Parkinson's disease from healthy controls using logistic regression models and receiver operating characteristics. Inference was performed using bootstrap analyses to calculate 95% confidence interval bounds. Pairwise comparisons were performed by generating 10,000 permutations, refitting the models, and calculating a paired difference between metrics. Thirty-one patients with Parkinson's disease and 22 healthy controls were included in the analyses. Signal intensity measures significantly outperformed spatial and subject specific abnormality measures, with the top performers exhibiting excellent ability to differentiate patients with Parkinson's disease and healthy controls (balanced accuracy = 0.89; area under the curve = 0.81; sensitivity =0.86; and specificity = 0.83). Atlas identified substantia nigra metrics performed significantly better than manual tracing metrics. These results provide clear support for the use of automated signal intensity metrics and additional recommendations. Future work is necessary to evaluate whether the same metrics can best differentiate atypical parkinsonism, perform similarly in de novo and mid-stage cohorts, and serve as longitudinal monitoring biomarkers.

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.

Longitudinal hippocampal subfields, CSF biomarkers, and cognition in patients with Parkinson disease.

Objective: Hippocampal atrophy is an indicator of emerging dementia in PD, though it is unclear whether cerebral spinal fluid (CSF) Abeta-42, t-tau, or alpha-syn predict hippocampal subfield atrophy in a de novo cohort of PD patients. To examine whether levels of CSF alpha-synuclein (alpha-syn), beta-amyloid 1-42 (Abeta-42), or total-tau (t-tau) are associated with hippocampal subfield volumes over time. Methods: We identified a subset of Parkinson's Progression Markers Initiative (PPMI) de novo PD patients with longitudinal T1-weighted imaging (baseline plus at least two additional visits across 12, 24, and 48 months) and CSF biomarkers available at baseline. We performed cross-sectional, regression, and linear mixed model analyses to evaluate the baseline and longitudinal CSF biomarkers, hippocampal subfields, and cognition. A false discovery rate (FDR) was used to correct for multiple comparisons. Results: 88 PD-CN and 21 PD-MCI had high quality longitudinal data. PD-MCI patients exhibited reduced bilateral CA1 volumes relative to PD-CN, though there were no significant differences in CSF biomarkers between these groups. Relationships between CSF biomarkers and hippocampal subfields changed over time, with a general pattern that lower CSF Abeta-42, higher t-tau and higher alpha-syn were associated with smaller hippocampal subfields, primarily in the right hemisphere. Conclusion: We replicated prior reports that demonstrated reduced CA1 volumes in PD-MCI in a de novo PD cohort. CSF biomarkers were associated with individual subfields, with evidence that the increased CSF t-tau was associated with smaller subiculum volumes at baseline and over time, though there was no clear indication that the subfields associated with cognition (CA1 and HATA) were associated with CSF biomarkers.

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.

A trichotomy method for defining homogeneous subgroups in a dementia population.

INTRODUCTION: Diagnosis of dementia in the aging brain is confounded by the presence of multiple pathologies. Mixed dementia (MX), a combination of Alzheimer's disease (AD) proteins with vascular disease (VD), is frequently found at autopsy, and has been difficult to diagnose during life. This report develops a method for separating the MX group and defining preclinical AD (presence of AD factors with normal cognition) and preclinical VD subgroups (presence of white matter damage with normal cognition). METHODS: Clustering was based on three diagnostic axes: (1) AD factor (ADF) derived from cerebrospinal fluid proteins (Aß42 and pTau), (2) VD factor (VDF) calculated from mean free water and peak width of skeletonized mean diffusivity in the white matter, and (3) Cognition (Cog) based on memory and executive function. The trichotomy method was applied to an Alzheimer's Disease Neuroimaging Initiative cohort (N = 538). RESULTS: Eight biologically defined subgroups were identified which included the MX group with both high ADF and VDF (9.3%) and a preclinical VD group (3.9%), and a preclinical AD group (13.6%). Cog is significantly associated with both ADF and VDF, and the partial-correlation remains significant even when the effect of the other variable is removed (r(Cog, ADF/VDF removed) = 0.46, p < 10-28 and r(Cog, VDF/ADF removed) = 0.24, p < 10-7 ). DISCUSSION: The trichotomy method creates eight biologically characterized patient groups, which includes MX, preclinical AD, and preclinical VD subgroups. Further longitudinal studies are needed to determine the utility of the 3-way clustering method with multimodal biological biomarkers.

Reduced and Delayed Cerebrovascular Reactivity in Patients with Parkinson's Disease.

BACKGROUND: Cerebrovascular dysfunction in Parkinson's disease (PD) is heterogeneous and may contribute to disease pathophysiology or progression. There is a need to understand the mechanisms by which cerebrovascular dysfunction is altered in participants with PD. OBJECTIVES: The objective of this study is to test the hypothesis that participants with PD exhibit a significant reduction in the ability of the cerebral vessels to dilate in response to vasoactive challenges relative to healthy controls (HC). METHODS: The current study uses a vasodilatory challenge while participants undergo functional magnetic resonance imaging to quantify the amplitude and delay of cerebrovascular reactivity in participants with PD relative to age and sex-matched HC. An analysis of covariance was used to evaluate differences in cerebrovascular reactivity amplitude and latency between PD participants and HC. RESULTS: A significant main effect of group was observed for whole-brain cerebrovascular reactivity amplitude (F(1, 28) = 4.38, p = 0.046, Hedge's g = 0.73) and latency (F(1, 28) = 16.35, p < 0.001, Hedge's g = 1.42). Participants with PD exhibited reduced whole-brain amplitude and increased latencies in cerebrovascular reactivity relative to HC. The evaluation of regional effects indicates that the largest effects were observed in the cuneus, precuneus, and parietal regions. CONCLUSIONS: PD participants exhibited reduced and delayed cerebrovascular reactivity. This dysfunction may play an important role in chronic hypoxia, neuroinflammation, and protein aggregation, mechanisms that could lead to disease progression. Cerebrovascular reactivity may serve as an important biomarker and target for future interventions. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Electric Field, Ictal Theta Power, and Clinical Outcomes in Electroconvulsive Therapy.

BACKGROUND: Electroconvulsive therapy (ECT) is efficacious for treatment-resistant depression. Treatment-induced cognitive impairment can adversely impact functional outcomes. Our pilot study linked the electric field to ictal theta power from a single suprathreshold treatment and linked ictal theta power to changes in phonemic fluency. In this study, we set out to replicate our findings and expand upon the utility of ictal theta power as a potential cognitive biomarker. METHODS: Twenty-seven participants (18 female and 9 male) received right unilateral ECT for treatment-resistant depression. Pre-ECT magnetic resonance imaging and finite element modeling determined the 90th percentile maximum electric field in the brain. Two-lead electroencephalographs were digitally captured across the ECT course, with the earliest suprathreshold treatment used to determine power spectral density. Clinical and cognitive outcomes were assessed pre-, mid-, and post-ECT. We assessed the relationship between the electric field in the brain, ictal theta power, clinical outcome (Inventory of Depressive Symptomatology), and cognitive outcomes (phonemic and semantic fluency) with linear models. RESULTS: Ictal theta power in the Fp1 and Fp2 channels was associated with the electric field, antidepressant outcome, and phonemic and semantic fluency. The relationship between ictal theta power and phonemic fluency was strengthened in the longitudinal analysis. The electric field in the brain was directly associated with phonemic and semantic fluency but not with antidepressant outcome. CONCLUSIONS: Ictal theta power is a potential cognitive biomarker early on in the ECT course to help guide parameter changes. Larger studies are needed to further assess ictal theta power's role in predicting mood outcome and changes with ECT parameters.

A patient-centered comparative effectiveness research study of culturally appropriate options for diabetes self-management.

This project compared the effectiveness of two evidence-based models of culturally competent diabetes health promotion: The Diabetes Self-Management Support Empowerment Model (DSMS), and The Chronic Care Model (CCM). Our primary outcome was improvement in patient capacity for diabetes self-management as measured by the Diabetes Knowledge Questionnaire (DKQ) and the Patient Activation Measure (PAM). Our secondary outcome was patient success at diabetes self-management as measured by improvement in A1c, depression sores using the PHQ-9, and Body Mass Index (BMI). We also gathered data on the cultural competence of the program using the Consumer Assessment of Healthcare Providers and Systems Cultural Competence Set (CAHPS-CC). We compared patient outcomes in two existing sites in Albuquerque, New Mexico that serve a large population of Latino diabetes patients from low-income households. Participants were enrolled as dyads-a patient participant (n=226) and a social support participant (n=226). Outcomes over time and by program were analyzed using longitudinal linear mixed modeling, adjusted for patient participant demographic characteristics and other potential confounding covariates. Secondary outcomes were also adjusted for potential confounders. Interactions with both time and program helped to assess outcomes. This study did not find a difference between the two sites with respect to the primary outcome measures and only one of the three secondary outcomes showed differential results. The main difference between programs was that depression decreased more for CCM than for DSMS. An exploratory, subgroup analysis revealed that at CCM, patient participants with a very high A1c (>10) demonstrated a clinically meaningful decrease. However, given the higher cultural competence rating for the CCM, statistically significant improvement in depression, and the importance of social support to the patients, results suggest that a culturally and contextually situated diabetes self-management and education program design may deliver benefit for patients, especially for patients with higher A1c levels.

Associations between depression and diabetes among Latinx patients from low-income households in New Mexico.

Depression and diabetes are co-occurring epidemics. This article explores the association between depression and diabetes in a cohort of Latinx patients with diabetes from low-income households. Data were gathered in Albuquerque, New Mexico (U.S.) between 2016 and 2020 as part of a patient-engaged comparative effectiveness trial comparing two culturally appropriate diabetes self-management programs-the Chronic Care Model (CCM) and the standard of care, Diabetes Self-Management Support Empowerment Model (DSMS). We proposed that the program most culturally and contextually situated in the life of the patient would have the greatest impact on diabetes self-management. Participants were enrolled as dyads-226 Latinx diabetes patient participants (PPs) from low-income households and 226 social support participants (SSPs). Data gathered at baseline, 3, 6, and 12 months included a measure of depression and A1c testing. Outcomes between programs were analyzed using longitudinal linear mixed modeling, adjusted for patient demographic characteristics and other potential confounding covariates. Patient A1c had an initial slight decrease at 3 months in both programs. At CCM, patients with a very high A1c (greater than 10%) demonstrated a clinically meaningful decrease in A1c over time. Patients at CCM experienced a large initial decrease in depression and continued to decrease throughout the study, while patients at DSMS showed a slight initial decrease through 6 months, but depression increased again by 12 months, nearly rebounding to baseline levels. A subgroup analysis revealed that a higher baseline A1c was associated with higher depression, and patients with higher A1c achieved greater reductions in depression at CCM than at DSMS. CCM scored higher on Consumer Assessment of Healthcare Providers and Systems cultural competence (CAHPS-CC). Interpretation of results suggests that the more culturally, contextually situated program, CCM, had better outcomes. This study demonstrates that culturally and contextually situating a diabetes intervention can deliver improved benefits for Latinx patients.

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.

We Need You Here! Predictors of Job Placement and Practice among New Mexico Family Medicine Residents.

OBJECTIVES: Primary health care (PHC) is essential for a well-functioning health system. Although PHC has been shown to have adverse effects on health outcomes, many barriers prevent adequate access, including a shortage of primary care physicians. In New Mexico, 32 of 33 counties are designed as primary care health professional shortage areas, and the state has a lower-than-average primary care provider density compared with other states. This study explored the predictors of job placement among New Mexican Family Medicine residents. METHODS: A retrospective cohort study design was used, which included a subset of data from The University of New Mexico (UNM) Family Medicine Residency Alumni Database and hard copy personnel files. The study's population consisted of the 260 graduates from the UNM Family Medicine Residency Program between 1998 and 2019. Analysis included simple and multiple logistic regression. RESULTS: Results indicated that, consistently, approximately two-thirds of first practices are in New Mexico, whereas the percentage with a current practice in New Mexico decreases over time. Those born in New Mexico or who attended the UNM School of Medicine were more likely to have their first and current practice in New Mexico. CONCLUSIONS: The results of this study provide further evidence that the relationship between place of birth and place of medical training are determining factors for both place of first and current practice. These results can inform practice, policy, and future research to address the pressing need for PHC in underserved and rural communities.

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.

Electroconvulsive therapy, electric field, neuroplasticity, and clinical outcomes.

Electroconvulsive therapy (ECT) remains the gold-standard treatment for patients with depressive episodes, but the underlying mechanisms for antidepressant response and procedure-induced cognitive side effects have yet to be elucidated. Such mechanisms may be complex and involve certain ECT parameters and brain regions. Regarding parameters, the electrode placement (right unilateral or bitemporal) determines the geometric shape of the electric field (E-field), and amplitude determines the E-field magnitude in select brain regions (e.g., hippocampus). Here, we aim to determine the relationships between hippocampal E-field strength, hippocampal neuroplasticity, and antidepressant and cognitive outcomes. We used hippocampal E-fields and volumes generated from a randomized clinical trial that compared right unilateral electrode placement with different pulse amplitudes (600, 700, and 800 mA). Hippocampal E-field strength was variable but increased with each amplitude arm. We demonstrated a linear relationship between right hippocampal E-field and right hippocampal neuroplasticity. Right hippocampal neuroplasticity mediated right hippocampal E-field and antidepressant outcomes. In contrast, right hippocampal E-field was directly related to cognitive outcomes as measured by phonemic fluency. We used receiver operating characteristic curves to determine that the maximal right hippocampal E-field associated with cognitive safety was 112.5 V/m. Right hippocampal E-field strength was related to the whole-brain ratio of E-field strength per unit of stimulation current, but this whole-brain ratio was unrelated to antidepressant or cognitive outcomes. We discuss the implications of optimal hippocampal E-field dosing to maximize antidepressant outcomes and cognitive safety with individualized amplitudes.

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.

A double-dichotomy clustering of dual pathology dementia patients.

INTRODUCTION: Subcortical ischemic vascular disease (SIVD) and Alzheimer's disease (AD) related dementia can coexist in older subjects, leading to mixed dementia (MX). Identification of dementia sub-groups is important for designing proper treatment plans and clinical trials. METHOD: An Alzheimer's disease severity (ADS) score and a vascular disease severity (VDS) score are calculated from CSF and MRI biomarkers, respectively. These scores, being sensitive to different Alzheimer's and vascular disease processes are combined orthogonally in a double-dichotomy plot. This formed an objective basis for clustering the subjects into four groups, consisting of AD, SIVD, MX and leukoaraiosis (LA). The relationship of these four groups is examined with respect to cognitive assessments and clinical diagnosis. RESULTS: Cluster analysis had at least 83% agreement with the clinical diagnosis for groups based either on Alzheimer's or on vascular sensitive biomarkers, and a combined agreement of 68.8% for clustering the four groups. The VDS score was correlated to executive function (r = -0.28, p < 0.01) and the ADS score to memory function (r = -0.35, p < 0.002) after adjusting for age, sex, and education. In the subset of patients for which the cluster scores and clinical diagnoses agreed, the correlations were stronger (VDS score-executive function: r = -0.37, p < 0.006 and ADS score-memory function: r = -0.58, p < 0.0001). CONCLUSIONS: The double-dichotomy clustering based on imaging and fluid biomarkers offers an unbiased method for identifying mixed dementia patients and selecting better defined sub-groups. Differential correlations with neuropsychological tests support the hypothesis that the categories of dementia represent different etiologies.