Patient-Specific Alterations in CO2 Cerebrovascular Responsiveness in Acute and Sub-Acute Sports-Related Concussion.

BACKGROUND: Preliminary studies suggest that sports-related concussion (SRC) is associated with alterations in cerebral blood flow (CBF) regulation. Here, we use advanced magnetic resonance imaging (MRI) techniques to measure CBF and cerebrovascular responsiveness (CVR) in individual SRC patients and healthy control subjects. METHODS: 15 SRC patients (mean age = 16.3, range 14-20 years) and 27 healthy control subjects (mean age = 17.6, range 13-21 years) underwent anatomical MRI, pseudo-continuous arterial spin labeling (pCASL) MRI and model-based prospective end-tidal targeting (MPET) of CO2 during blood oxygenation level-dependent (BOLD) MRI. Group differences in global mean resting CBF were examined. Voxel-by-voxel group and individual differences in regional CVR were examined using statistical parametric mapping (SPM). Leave-one-out receiver operating characteristic curve analysis was used to evaluate the utility of brain MRI CO2 stress testing biomarkers to correctly discriminate between SRC patients and healthy control subjects. RESULTS: All studies were tolerated with no complications. Traumatic structural findings were identified in one SRC patient. No significant group differences in global mean resting CBF were observed. There were no significant differences in the CO2 stimulus and O2 targeting during BOLD MRI. Significant group and patient-specific differences in CVR were observed with SRC patients demonstrating a predominant pattern of increased CVR. Leave-one-out ROC analysis for voxels demonstrating a significant increase in CVR was found to reliably discriminate between SRC patients and healthy control subjects (AUC of 0.879, p = 0.0001). The optimal cutoff for increased CVR declarative for SRC was 1,899 voxels resulting in a sensitivity of 0.867 and a specificity of 0.778 for this specific ROC analysis. There was no correlation between abnormal voxel counts and Postconcussion Symptom Scale scores among SRC patients. CONCLUSION: Acute and subacute SRCs are associated with alterations in CVR that can be reliably detected by brain MRI CO2 stress testing in individual patients.

Longitudinal Brain Magnetic Resonance Imaging CO2 Stress Testing in Individual Adolescent Sports-Related Concussion Patients: A Pilot Study.

BACKGROUND: Advanced neuroimaging studies in concussion have been limited to detecting group differences between concussion patients and healthy controls. In this small pilot study, we used brain magnetic resonance imaging (MRI) CO2 stress testing to longitudinally assess cerebrovascular responsiveness (CVR) in individual sports-related concussion (SRC) patients. METHODS: Six SRC patients (three males and three females; mean age = 15.7, range = 15-17 years) underwent longitudinal brain MRI CO2 stress testing using blood oxygen level-dependent (BOLD) MRI and model-based prospective end-tidal CO2 targeting under isoxic conditions. First-level and second-level comparisons were undertaken using statistical parametric mapping (SPM) to score the scans and compare them to an atlas of 24 healthy control subjects. RESULTS: All tests were well tolerated and without any serious adverse events. Anatomical MRI was normal in all study participants. The CO2 stimulus was consistent between the SRC patients and control subjects and within SRC patients across the longitudinal study. Individual SRC patients demonstrated both quantitative and qualitative patient-specific alterations in CVR (p < 0.005) that correlated strongly with clinical findings, and that persisted beyond clinical recovery. CONCLUSION: Standardized brain MRI CO2 stress testing is capable of providing a longitudinal assessment of CVR in individual SRC patients. Consequently, larger prospective studies are needed to examine the utility of brain MRI CO2 stress testing as a clinical tool to help guide the evaluation, classification, and longitudinal management of SRC patients.

Neuroimaging Assessment of Cerebrovascular Reactivity in Concussion: Current Concepts, Methodological Considerations, and Review of the Literature.

Concussion is a form of traumatic brain injury (TBI) that presents with a wide spectrum of subjective symptoms and few objective clinical findings. Emerging research suggests that one of the processes that may contribute to concussion pathophysiology is dysregulation of cerebral blood flow (CBF) leading to a mismatch between CBF delivery and the metabolic needs of the injured brain. Cerebrovascular reactivity (CVR) is defined as the change in CBF in response to a measured vasoactive stimulus. Several magnetic resonance imaging (MRI) techniques can be used as a surrogate measure of CBF in clinical and laboratory studies. In order to provide an accurate assessment of CVR, these sequences must be combined with a reliable, reproducible vasoactive stimulus that can manipulate CBF. Although CVR imaging currently plays a crucial role in the diagnosis and management of many cerebrovascular diseases, only recently have studies begun to apply this assessment tool in patients with concussion. In order to evaluate the quality, reliability, and relevance of CVR studies in concussion, it is important that clinicians and researchers have a strong foundational understanding of the role of CBF regulation in health, concussion, and more severe forms of TBI, and an awareness of the advantages and limitations of currently available CVR measurement techniques. Accordingly, in this review, we (1) discuss the role of CVR in TBI and concussion, (2) examine methodological considerations for MRI-based measurement of CVR, and (3) provide an overview of published CVR studies in concussion patients.

Brain magnetic resonance imaging CO2 stress testing in adolescent postconcussion syndrome.

OBJECT A neuroimaging assessment tool to visualize global and regional impairments in cerebral blood flow (CBF) and cerebrovascular responsiveness in individual patients with concussion remains elusive. Here the authors summarize the safety, feasibility, and results of brain CO2 stress testing in adolescents with postconcussion syndrome (PCS) and healthy controls. METHODS This study was approved by the Biomedical Research Ethics Board at the University of Manitoba. Fifteen adolescents with PCS and 17 healthy control subjects underwent anatomical MRI, pseudo-continuous arterial spin labeling MRI, and brain stress testing using controlled CO2 challenge and blood oxygen level-dependent (BOLD) MRI. Post hoc processing was performed using statistical parametric mapping to determine voxel-by-voxel regional resting CBF and cerebrovascular responsiveness of the brain to the CO2 stimulus (increase in BOLD signal) or the inverse (decrease in BOLD signal). Receiver operating characteristic (ROC) curves were generated to compare voxel counts categorized by control (0) or PCS (1). RESULTS Studies were well tolerated without any serious adverse events. Anatomical MRI was normal in all study participants. No differences in CO2 stimuli were seen between the 2 participant groups. No group differences in global mean CBF were detected between PCS patients and healthy controls. Patient-specific differences in mean regional CBF and CO2 BOLD responsiveness were observed in all PCS patients. The ROC curve analysis for brain regions manifesting a voxel response greater than and less than the control atlas (that is, abnormal voxel counts) produced an area under the curve of 0.87 (p < 0.0001) and 0.80 (p = 0.0003), respectively, consistent with a clinically useful predictive model. CONCLUSIONS Adolescent PCS is associated with patient-specific abnormalities in regional mean CBF and BOLD cerebrovascular responsiveness that occur in the setting of normal global resting CBF. Future prospective studies are warranted to examine the utility of brain MRI CO2 stress testing in the longitudinal assessment of acute sports-related concussion and PCS.

Pancreatic lipid content is not associated with beta cell dysfunction in youth-onset type 2 diabetes.

OBJECTIVE: To determine whether pancreatic lipid content is associated with type 2 diabetes and beta cell function in Indigenous and Caucasian adolescents. METHODS: This was a cross-sectional study comparing (1)H-magnetic resonance spectroscopy-derived pancreatic triglyceride content in adolescents 13 to 18 years of age with type 2 diabetes (n=20) and body mass index-matched normoglycemic controls (n=34). Beta cell function was measured by the acute insulin response and disposition index derived from intravenous glucose tolerance tests. RESULTS: Pancreatic lipid content was not significantly different in youth with type 2 diabetes and their normoglycemic body mass index-matched peers (2.41 [95% CI: 0.63, 5.60] vs. 1.22 [0.08, 5.93]; p=0.27). Pancreatic triglyceride levels were not associated with measures of beta cell function in the cohort. In subgroup analyses, pancreatic lipid content was ∼4-fold higher in youth with type 2 diabetes who were carriers of the G319S mutation in the HNF-1alpha gene (7.45 [2.85, 26.8] vs. 2.20 [0.350, 3.30] % Fat to Water Ratio F/W; p=0.032). CONCLUSIONS: Pancreatic lipid content is not elevated in Indigenous or Caucasian youth with type 2 diabetes compared to normoglycemic youth, nor is it associated with beta cell function. The presence of the G319S mutation in the HNF-1alpha gene in Indigenous youth with type 2 diabetes is associated with higher pancreatic lipid content. Further research is needed to understand the mechanisms that explain beta cell failure in overweight youth with type 2 diabetes.

Hepatic steatosis and low cardiorespiratory fitness in youth with type 2 diabetes.

The purpose of this study was to examine the association between cardiorespiratory fitness, ectopic triglyceride accumulation, and insulin sensitivity among youth with and without type 2 diabetes. Subjects included 137 youth ages 13-18 years including 27 with type 2 diabetes, 97 overweight normoglycemic controls, and 13 healthy weight normoglycemic controls. The primary outcome measure was cardiorespiratory fitness defined as peak oxygen uptake indexed to fat free mass. Secondary outcomes included liver and muscle triglyceride content determined by (1)H-magnetic resonance spectroscopy and insulin sensitivity determined by frequently sampled intravenous glucose tolerance test. Despite similar measures of adiposity, peak oxygen uptake was 11% lower (38.9 ± 7.9 vs. 43.9 ± 6.1 ml/kgFFM/min, P = 0.002) and hepatic triglyceride content was nearly threefold higher (14.4 vs. 5.7%, P = 0.001) in youth with type 2 diabetes relative to overweight controls. In all 137 youth, cardiorespiratory fitness was negatively associated with hepatic triglyceride content (r = -0.22, P = 0.02) and positively associated with insulin sensitivity (r = 0.29, P = 0.002) independent of total body and visceral fat mass. Hepatic triglyceride content was also negatively associated with insulin sensitivity (r = -0.35, P < 0.001), independent of adiposity, sex, age, and peak oxygen uptake. This study demonstrated that low cardiorespiratory fitness and elevated hepatic triglyceride content are features of type 2 diabetes in youth. Furthermore, cardiorespiratory fitness and hepatic triglyceride are associated with insulin sensitivity in youth. Taken together, these data suggest that cardiorespiratory fitness and hepatic steatosis are potential clinical biomarkers for type 2 diabetes among youth.

Deficit in schizophrenia to recruit the striatum in implicit learning: a functional magnetic resonance imaging investigation.

In schizophrenia, explicit learning deficits have been well established although it is less clear whether these patients have deficits in implicit learning (IL). IL is thought to depend on intact striatal functioning. This study examined the hypothesis that schizophrenia patients show deficient recruitment of striatal activation during an IL paradigm, relative to performance-matched healthy comparison subjects. Ten subjects with schizophrenia on atypical antipsychotic medication and 10 age, gender, education, and performance matched healthy comparison subjects underwent fMRI while performing an IL task. On the basis of whole-brain and striatal region-of-interest analyses, we found a relative lack of striatal activation in schizophrenia patients. This result is consistent with convergent evidence of striatal dysfunction in schizophrenia.