Extracellular free water elevations are associated with brain volume and maternal cytokine response in a longitudinal nonhuman primate maternal immune activation model.

Maternal infection has emerged as an important environmental risk factor for neurodevelopmental disorders, including schizophrenia and autism spectrum disorders. Animal model systems of maternal immune activation (MIA) suggest that the maternal immune response plays a significant role in the offspring's neurodevelopment and behavioral outcomes. Extracellular free water is a measure of freely diffusing water in the brain that may be associated with neuroinflammation and impacted by MIA. The present study evaluates the brain diffusion characteristics of male rhesus monkeys (Macaca mulatta) born to MIA-exposed dams (n = 14) treated with a modified form of the viral mimic polyinosinic:polycytidylic acid at the end of the first trimester. Control dams received saline injections at the end of the first trimester (n = 10) or were untreated (n = 4). Offspring underwent diffusion MRI scans at 6, 12, 24, 36, and 45 months. Offspring born to MIA-exposed dams showed significantly increased extracellular free water in cingulate cortex gray matter starting as early as 6 months of age and persisting through 45 months. In addition, offspring gray matter free water in this region was significantly correlated with the magnitude of the maternal IL-6 response in the MIA-exposed dams. Significant correlations between brain volume and extracellular free water in the MIA-exposed offspring also indicate converging, multimodal evidence of the impact of MIA on brain development. These findings provide strong evidence for the construct validity of the nonhuman primate MIA model as a system of relevance for investigating the pathophysiology of human neurodevelopmental psychiatric disorders. Elevated free water in individuals exposed to immune activation in utero could represent an early marker of a perturbed or vulnerable neurodevelopmental trajectory.

Multimodal neuroimaging in pediatric type 1 diabetes: a pilot multisite feasibility study of acquisition quality, motion, and variability.

Type 1 diabetes (T1D) affects over 200,000 children and is associated with an increased risk of cognitive dysfunction. Prior imaging studies suggest the neurological changes underlying this risk are multifactorial, including macrostructural, microstructural, and inflammatory changes. However, these studies have yet to be integrated, limiting investigation into how these phenomena interact. To better understand these complex mechanisms of brain injury, a well-powered, prospective, multisite, and multimodal neuroimaging study is needed. We take the first step in accomplishing this with a preliminary characterization of multisite, multimodal MRI quality, motion, and variability in pediatric T1D. We acquire structural T1 weighted (T1w) MRI, diffusion tensor MRI (DTI), functional MRI (fMRI), and magnetic resonance spectroscopy (MRS) of 5-7 participants from each of two sites. First, we assess the contrast-to-noise ratio of the T1w MRI and find no differences between sites. Second, we characterize intervolume motion in DTI and fMRI and find it to be on the subvoxel level. Third, we investigate variability in regional gray matter volumes and local gyrification indices, bundle-wise DTI microstructural measures, and N-acetylaspartate to creatine ratios. We find the T1-based measures to be comparable between sites before harmonization and the DTI and MRS-based measures to be comparable after. We find a 5-15% coefficient of variation for most measures, suggesting ~150-200 participants per group on average are needed to detect a 5% difference across these modalities at 0.9 power. We conclude that multisite, multimodal neuroimaging of pediatric T1D is feasible with low motion artifact after harmonization of DTI and MRS.

Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis.

Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, inflammatory processes may be associated with altered brain levels of metabolites, such as glutathione (GSH). Consequently, we sought to test the hypotheses that FW is increased and associated with decreased GSH in patients with first-episode schizophrenia (SZ) compared with healthy controls (HC). SZ (n = 36) and HC (n = 40) subjects underwent a multi-shell diffusion MRI scan on a Siemens 3T scanner. 1H-MR spectroscopy data were acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH/creatine ratios were calculated for DLPFC (SZ: n = 33, HC: n = 37) and visual cortex (SZ: n = 29, HC: n = 35) voxels. Symptoms and functioning were measured using the SANS, SAPS, BPRS, and GSF/GRF. SZ demonstrated significantly elevated FW in whole-brain gray (p = .001) but not white matter (p = .060). There was no significant difference between groups in GSH in either voxel. However, there was a significant negative correlation between DLPFC GSH and both whole-brain and DLPFC-specific gray matter FW in SZ (r = -.48 and -.47, respectively; both p < .05), while this relationship was nonsignificant in HC and in both groups in the visual cortex. These data illustrate an important relationship between a metabolite known to be important for immune function-GSH-and the diffusion extracellular FW measure, which provides additional support for these measures as neuroinflammatory biomarkers that could potentially provide tractable treatment targets to guide pharmacological intervention.

A multicenter study of ketamine effects on functional connectivity: Large scale network relationships, hubs and symptom mechanisms.

Ketamine is an uncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist. It induces effects in healthy individuals that mimic symptoms associated with schizophrenia. We sought to root these experiences in altered brain function, specifically aberrant resting state functional connectivity (rsfMRI). In the present study, we acquired rsfMRI data under ketamine and placebo in a between-subjects design and analyzed seed-based measures of rsfMRI using large-scale networks, dorsolateral prefrontal cortex (DLPFC) and sub-nuclei of the thalamus. We found ketamine-induced alterations in rsfMRI connectivity similar to those seen in patients with schizophrenia, some changes that may be more comparable to early stages of schizophrenia, and other connectivity signatures seen in patients that ketamine did not recreate. We do not find any circuits from our regions of interest that correlates with positive symptoms of schizophrenia in our sample, although we find that DLPFC connectivity with ACC does correlate with a mood measure. These results provide support for ketamine's use as a model of certain biomarkers of schizophrenia, particularly for early or at-risk patients.

Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders: A Randomized Clinical Trial.

Importance: Despite strong theoretical rationale and preclinical evidence, several glutamate-targeted treatments for schizophrenia have failed in recent pivotal trials, prompting questions as to target validity, compound inadequacy, or lack of target engagement. A key limitation for glutamate-based treatment development is the lack of functional target-engagement biomarkers for translation between preclinical and early-stage clinical studies. We evaluated the utility of 3 potential biomarkers-ketamine-evoked changes in the functional magnetic imaging (fMRI) blood oxygen level-dependent response (pharmacoBOLD), glutamate proton magnetic resonance spectroscopy (1H MRS), and task-based fMRI-for detecting ketamine-related alterations in brain glutamate. Objective: To identify measures with sufficient effect size and cross-site reliability to serve as glutamatergic target engagement biomarkers within early-phase clinical studies. Design, Setting, and Participants: This randomized clinical trial was conducted at an academic research institution between May 2014 and October 2015 as part of the National Institute of Mental Health-funded Fast-Fail Trial for Psychotic Spectrum Disorders project. All raters were blinded to study group. Healthy volunteers aged 18 to 55 years of either sex and free of significant medical or psychiatric history were recruited from 3 sites. Data were analyzed between November 2015 and December 2016. Interventions: Volunteers received either sequential ketamine (0.23 mg/kg infusion over 1 minute followed by 0.58 mg/kg/h infusion over 30 minutes and then 0.29 mg/kg/h infusion over 29 minutes) or placebo infusions. Main Outcomes and Measures: Ketamine-induced changes in pharmacoBOLD, 1H MRS, and task-based fMRI measures, along with symptom ratings. Measures were prespecified prior to data collection. Results: Of the 65 volunteers, 41 (63%) were male, and the mean (SD) age was 31.1 (9.6) years; 59 (91%) had at least 1 valid scan. A total of 53 volunteers (82%) completed both ketamine infusions. In pharmacoBOLD, a highly robust increase (Cohen d = 5.4; P < .001) in fMRI response was observed, with a consistent response across sites. A smaller but significant signal (Cohen d = 0.64; P = .04) was also observed in 1H MRS-determined levels of glutamate+glutamine immediately following ketamine infusion. By contrast, no significant differences in task-activated fMRI responses were found between groups. Conclusions and Relevance: These findings demonstrate robust effects of ketamine on pharmacoBOLD across sites, supporting its utility for definitive assessment of functional target engagement. Other measures, while sensitive to ketamine effects, were not sufficiently robust for use as cross-site target engagement measures. Trial Registration: clinicaltrials.gov Identifier: NCT02134951.

Methods for acquiring MRI data in children with autism spectrum disorder and intellectual impairment without the use of sedation.

BACKGROUND: Magnetic resonance imaging (MRI) has been widely used in studies evaluating the neuropathology of autism spectrum disorder (ASD). Studies are often limited, however, to higher functioning individuals with ASD. MRI studies of individuals with ASD and comorbid intellectual disability (ID) are lacking, due in part to the challenges of acquiring images without the use of sedation. METHODS: Utilizing principles of applied behavior analysis (ABA), we developed a protocol for acquiring structural MRI scans in school-aged children with ASD and intellectual impairment. Board certified behavior analysts worked closely with each child and their parent(s), utilizing behavior change techniques such as pairing, shaping, desensitization, and positive reinforcement, through a series of mock scanner visits to prepare the child for the MRI scan. An objective, quantitative assessment of motion artifact in T1- and diffusion-weighted scans was implemented to ensure that high-quality images were acquired. RESULTS: The sample consisted of 17 children with ASD who are participants in the UC Davis Autism Phenome Project, a longitudinal MRI study aimed at evaluating brain developmental trajectories from early to middle childhood. At the time of their initial scan (2-3.5 years), all 17 children had a diagnosis of ASD and development quotient (DQ) <70. At the time of the current scan (9-13 years), 13 participants continued to have IQs in the range of ID (mean IQ = 54.1, sd = 12.1), and four participants had IQs in the normal range (mean = 102.2, sd = 7.5). The success rate in acquiring T1-weighted images that met quality assurance for acceptable motion artifact was 100 %. The success rate for acquiring high-quality diffusion-weighted images was 94 %. CONCLUSIONS: By using principles of ABA in a research MRI setting, it is feasible to acquire high-quality images in school-aged children with ASD and intellectual impairment without the use of sedation. This is especially critical to ensure that ongoing longitudinal studies of brain development can extend from infancy and early childhood into middle childhood in children with ASD at all levels of functioning, including those with comorbid ID.

A multimodal analysis of antipsychotic effects on brain structure and function in first-episode schizophrenia.

IMPORTANCE: Recent data suggest that treatment with antipsychotics is associated with reductions in cortical gray matter in patients with schizophrenia. These findings have led to concerns about the effect of antipsychotic treatment on brain structure and function; however, no studies to date have measured cortical function directly in individuals with schizophrenia and shown antipsychotic-related reductions of gray matter. OBJECTIVE: To examine the effects of antipsychotics on brain structure and function in patients with first-episode schizophrenia, using cortical thickness measurements and administration of the AX version of the Continuous Performance Task (AX-CPT) during event-related functional magnetic resonance imaging. DESIGN, SETTING, AND PARTICIPANTS: This case-control cross-sectional study was conducted at the Imaging Research Center of the University of California, Davis, from November 2004 through July 2012. Participants were recruited on admission into the Early Diagnosis and Preventive Treatment Clinic, an outpatient clinic specializing in first-episode psychosis. Patients with first-episode schizophrenia who received atypical antipsychotics (medicated patient group) (n = 23) and those who received no antipsychotics (unmedicated patient group) (n = 22) and healthy control participants (n = 37) underwent functional magnetic resonance imaging using a 1.5-T scanner. MAIN OUTCOMES AND MEASURES: Behavioral performance was measured by trial accuracy, reaction time, and d'-context score. Voxelwise statistical parametric maps tested differences in functional activity during the AX-CPT, and vertexwise maps of cortical thickness tested differences in cortical thickness across the whole brain. RESULTS: Significant cortical thinning was identified in the medicated patient group relative to the control group in prefrontal (mean reduction [MR], 0.27 mm; P < .001), temporal (MR, 0.34 mm; P = .02), parietal (MR, 0.21 mm; P = .001), and occipital (MR, 0.24 mm; P = .001) cortices. The unmedicated patient group showed no significant cortical thickness differences from the control group after clusterwise correction. The medicated patient group showed thinner cortex compared with the unmedicated patient group in the dorsolateral prefrontal cortex (DLPFC) (MR, 0.26 mm; P = .001) and temporal cortex (MR, 0.33 mm; P = .047). During the AX-CPT, both patient groups showed reduced DLPFC activity compared with the control group (P = .02 compared with the medicated group and P < .001 compared with the unmedicated group). However, the medicated patient group demonstrated higher DLPFC activation (P = .02) and better behavioral performance (P = .02) than the unmedicated patient group. CONCLUSIONS AND RELEVANCE: These findings highlight the complex relationship between antipsychotic treatment and the structural, functional, and behavioral deficits repeatedly identified in schizophrenia. Although short-term treatment with antipsychotics was associated with prefrontal cortical thinning, treatment was also associated with better cognitive control and increased prefrontal functional activity. This study adds important context to the growing literature on the effects of antipsychotics on the brain and suggests caution in interpreting neuroanatomical changes as being related to a potentially adverse effect on brain function.

Glutamate and GABA contributions to medial prefrontal cortical activity to emotion: implications for mood disorders.

The dorsomedial prefrontal cortex (MdPFC) and anterior cingulate cortices (ACC) play a critical role in implicit emotion regulation; however the understanding of the specific neurotransmitters that mediate such role is lacking. In this study, we examined relationships between MdPFC concentrations of two neurotransmitters, glutamate and γ-amino butyric acid (GABA), and BOLD activity in ACC during performance of an implicit facial emotion-processing task. Twenty healthy volunteers, aged 20-35 years, were scanned while performing an implicit facial emotion-processing task, whereby presented facial expressions changed from neutral to one of the four emotions: happy, anger, fear, or sad. Glutamate concentrations were measured before and after the emotion-processing task in right MdPFC using magnetic resonance spectroscopy (MRS). GABA concentrations were measured in bilateral MdPFC after the emotion-processing task. Multiple regression models were run to determine the relative contribution of glutamate and GABA concentration, age, and gender to BOLD signal in ACC to each of the four emotions. Multiple regression analyses revealed a significant negative correlation between MdPFC GABA concentration and BOLD signal in subgenual ACC (p<0.05, corrected) to sad versus shape contrast. For the anger versus shape contrast, there was a significant negative correlation between age and BOLD signal in pregenual ACC (p<0.05, corrected) and a positive correlation between MdPFC glutamate concentration (pre-task) and BOLD signal in pregenual ACC (p<0.05, corrected). Our findings are the first to provide insight into relationships between MdPFC neurotransmitter concentrations and ACC BOLD signal, and could further understanding of molecular mechanisms underlying emotion processing in healthy and mood-disordered individuals.

Vigorous exercise increases brain lactate and Glx (glutamate+glutamine): a dynamic 1H-MRS study.

Vigorous exercise increases lactate and glucose uptake by the brain in excess of the increase in brain oxygen uptake. The metabolic fate of this non-oxidized carbohydrate entering the brain is poorly understood, but accumulation of lactate in the brain and/or increased net synthesis of amino acid neurotransmitters are possible explanations. Previous proton magnetic resonance spectroscopy (1H-MRS) studies using conventional pulse sequences have not detected changes in brain lactate following exercise. This contrasts with 1H-MRS studies showing increased brain lactate when blood lactate levels are raised by an intravenous infusion of sodium lactate. Using a J-editing 1H-MRS technique for measuring lactate, we demonstrated a significant 19% increase in lactate in the visual cortex following graded exercise to approximately 85% of predicted maximum heart rate. However, the magnitude of the increase was insufficient to account for more than a small fraction of the non-oxidized carbohydrate entering the brain with exercise. We also report a significant 18% increase in Glx (combined signal from glutamate and glutamine) in visual cortex following exercise, which may represent an activity-dependent increase in glutamate. Future studies will be necessary to test the hypothesis that non-oxidized carbohydrate entering the brain during vigorous exercise is directed, in part, toward increased net synthesis of amino acid neurotransmitters. The possible relevance of these findings to panic disorder and major depression is discussed.

Altered cerebral blood flow patterns associated with pathologic worry in the elderly.

BACKGROUND: Generalized anxiety disorder (GAD) is the most prevalent anxiety disorder among the elderly and has high functional and cognitive morbidity. However, late-life GAD is relatively understudied and its functional neuroanatomy is uncharted. Several imaging studies have suggested abnormalities in the cognitive control systems of emotion regulation in anxiety disorders in young adults. The aim of this study was to examine the neural correlates of emotion regulation in late-life GAD. METHOD: We compared 7 elderly GAD subjects and 10 elderly nonanxious comparison subjects using functional MRI. Regional cerebral blood flow (rCBF) was measured using pulsed arterial spin labeling perfusion MRI at rest and during an emotion regulation paradigm. RESULTS: Relative to the rest condition, elderly nonanxious comparison subjects had increased rCBF during worry induction (WI) in the right insula, bilateral amygdala, and associative temporooccipital areas. Elderly GAD subjects had increased rCBF during WI in the associative temporooccipital areas, but not in the insula or the amygdala. During worry suppression (WS), elderly nonanxious comparison subjects had increased rCBF in the prefrontal cortex (PFC) and dorsal ACC. Elderly GAD subjects had no changes in rCBF during WS in the PFC. CONCLUSIONS: When attempting to regulate their emotional responses, elderly anxious subjects failed to activate prefrontal regions involved in the downregulation of negative emotions. These results, showing that elderly anxious subjects are not effectively engaging the PFC in suppressing worry, may be clinically relevant for developing personalized therapeutic strategies for the treatment of late-life GAD.

Rosette spectroscopic imaging: optimal parameters for alias-free, high sensitivity spectroscopic imaging.

PURPOSE: To optimize the Rosette trajectories for fast, high sensitivity spectroscopic imaging experiments and to compare this acquisition technique with other chemical shift imaging (CSI) methods. MATERIALS AND METHODS: A framework for comparing the sensitivity of the Rosette Spectroscopic Imaging (RSI) acquisition to other spectroscopic imaging experiments is outlined. Accounting for hardware constraints, trajectory parameters that provide for optimal sampling and minimal artifact production are found. Along with an analytical expression for the number of excitations to be used in an RSI experiment that is provided, the theoretical precompensation weights used for optimal image reconstruction are derived. RESULTS: The spectral response function for RSI is shown to be approximately the same as the point spread function of standard Fourier reconstructions. While the signal-to-noise ratio (SNR) for an RSI experiment is reduced by the inherent nonuniform sampling of these trajectories, their circular k-space support and speed of spatial encoding leads to greater SNR efficiency and improvements in the total data acquisition time relative to the gold standard CSI approach with square k-space support and to similar efficiency to spiral CSI acquisitions. Numerical simulations and in vivo experimental data are presented to demonstrate the properties of this data acquisition technique. CONCLUSION: This work demonstrates the use of Rosette trajectories and how to achieve improved efficiency for these trajectories in a two-dimensional spectroscopic imaging experiment.

Loss of cell ion homeostasis and cell viability in the brain: what sodium MRI can tell us.

This chapter demonstrates the use of sodium magnetic resonance imaging (MRI) as a noninvasive, in vivo means to assess metabolic changes that ensue from loss of cell ion homeostasis due to cell death in the brain. The chapter is organized in two sections. In the first section, the constraints imposed on the imaging methods by the nuclear magnetic resonance (NMR) properties of the sodium ion are discussed and strategies for avoiding their potential limitations are addressed. The second section illustrates the use of sodium MRI for monitoring focal brain ischemia in permanent and temporary primate models of endovascular middle cerebral artery occlusion.

Triple-quantum-filtered imaging of sodium in presence of B(0) inhomogeneities.

Triple quantum filtered sodium MRI techniques have been recently demonstrated in vivo. These techniques have been previously advocated as a means to separate the sodium NMR signal from different physiological compartments based on the differences between their relaxation rates. Among the different triple quantum coherence transfer filters, the three-pulse coherence transfer filter has been demonstrated to be better suited for human imaging than the traditional four-pulse implementation. While the three-pulse structure has distinct advantages in terms of RF efficiency, the lack of a refocusing pulse in the filter introduces an increased dependence on the main magnetic field inhomogeneities, which can sometimes lead to significant signal loss. In this paper, we characterize these dependencies and introduce a method for their compensation through the acquisition of a B(0) map and the use of a modified phase cycling scheme.

Algebraic description of spin 3/2 dynamics in NMR experiments.

The dynamics of spin 3/2 systems is analyzed using the density matrix theory of relaxation. By using the superoperator formalism, an algebraic formulation of the density matrix's evolution is obtained, in which the contributions from free relaxation and RF application are easily factored out. As an intermediate step, an exact form for the propagator of the density matrix for a spin 3/2 system, in the presence of static quadrupolar coupling, inhomogeneous static magnetic field, and relaxation is demonstrated. Using this algebraic formulation, exact expressions for the behavior of the density matrix in the classical one-, two-, and three-pulse experiments are derived. These theoretical formulas are then used to illustrate the bias introduced on the measured relaxation parameters by the presence of large spatial variations in the B0 and B1 fields. The theoretical predictions are easily evaluated through simple matrix algebra and the results agree very well with the experimental observations. This approach could prove useful for the characterization of the spatial variations of the signal intensity in multiple quantum-filtered sodium MRI experiments.