Frank Gaston

Reproducibility of phase rotation STEAM at 3T: Focus on glutathione

The purpose of this study was to determine the reproducibility of a very short echo time (TE) phase rotation stimulated echo acquisition mode (STEAM) sequence at 3T with a focus on the detection of glutathione.

Assessment of whole brain white matter integrity in youths and young adults with a family history of substance-use disorders.

Individuals with a family history of substance use disorders (FH+) are at a greater risk of developing substance use disorders than their peers with no such family histories (FH−) and this vulnerability is proportional to the number of affected relatives (FH density). The risk for developing substance use disorders peaks during adolescence to early adulthood in the general population, and that is thought to be related to delayed maturation of frontocortical and frontostriatal functional circuits. We hypothesized that FH+ youth and young adults have impaired myelination of frontocortical and frontostriatal white matter tracts. We examined fractional anisotropy (FA) data in 80 FH+ and 34 FH− youths (12.9 ± 1.0 years) and in 25 FH+ and 30 FH− young adults (24.3 ± 3.4 years). FH+ youths had lower FA values in both frontocortical and frontostriatal tracts as well as parietocortical tracts including the anterior, superior and posterior corona radiata and the superior frontal‐occipital fasciculus. Moreover, FA values in these tracts were negatively correlated with FH density. FH+ adults had lower FA values in two frontocortical tracts: the genu of the corpus callosum and anterior corona radiata and also significant negative correlations between FA and FH density in these same tracts. In both groups, lower FA values corresponded to higher radial diffusivity suggesting reduced axonal myelination. We interpreted our findings as evidence for impaired myelination of frontal white matter that was proportional to FH density. Our data suggest that deficits may partially resolve with age, paralleling an age‐related decline in risk for developing substance use disorders. Hum Brain Mapp 35:5401–5413, 2014.

Combining diffusion tensor imaging and magnetic resonance spectroscopy to study reduced frontal white matter integrity in youths with family histories of substance use disorders

Individuals with a family history of substance use disorder (FH+) show impaired frontal white matter as indicated by diffusion tensor imaging (DTI). This impairment may be due to impaired or delayed development of myelin in frontal regions, potentially contributing to this populations increased risk for developing substance use disorders. In this study, we examined high angular resolution DTI and proton magnetic resonance spectroscopy data from the anterior corona radiata were collected in 80 FH+ and 34 FH− youths (12.9 ± 1.0 years old). White matter integrity indices included fractional anisotropy (FA), N‐acetylaspartate (NAA), and total choline (tCho). Lower FA suggests decreased myelination. Decreased NAA coupled with higher tCho suggests impaired build‐up and maintenance of cerebral myelin and consequently greater breakdown of cellular membranes. We found FH+ youths had lower FA (P < 0.0001) and NAA (P = 0.017) and higher tCho (P = 0.04). FH density (number of parents and grandparents with substance use disorders) was negatively correlated with FA (P < 0.0001) and NAA (P = 0.011) and positively correlated with tCho (P = 0.001). FA was independently predicted by both FH density (P =0.006) and NAA (P= 0.002), and NAA and tCho were both independent predictors of FH density (P < 0.001). Our finding of lower frontal FA in FH+ youths corresponding to lower NAA and increased tCho is consistent with delayed or impaired development of frontal white matter in FH+ youths. Longitudinal studies are needed to determine how these differences relate to substance use outcomes. Hum Brain Mapp 35:5877–5887, 2014.

Altered Glutamate and Regional Cerebral Blood Flow Levels in Schizophrenia: A (1)H-MRS and pCASL study.

The neurobiology of schizophrenia (SZ) may be altered in older versus younger adults with SZ, as less frequent episodes of symptom exacerbation and increased sensitivity to medications are observed in older age. The goal of this study was to examine the effect of age and diagnosis on glutamate and cerebral blood flow (rCBF) in adults with SZ and healthy controls. Young and older adults with SZ and healthy controls were recruited to participate in this study. Participants completed a neuropsychological battery and neuroimaging that included optimized magnetic resonance spectroscopy to measure anterior cingulate (AC) glutamate (Glu) and glutamine (Gln) and arterial spin labeling evaluation for rCBF. Regression analyses revealed significant effects of age with Glu, Gln, Gln/Glu, and AC white matter (WM) rCBF. Glu and WM rCBF decreased linearly with age while Gln and Gln/Glu increased linearly with age. Glu was lower in adults with SZ compared with healthy controls and in older adults versus younger adults but there was no interaction. Glu and WM rCBF were correlated with the UCSD Performance-Based Skills Assessment (UPSA) and processing speed, and the correlations were stronger in the SZ group. In the largest sample to date, lower Glu and elevated Gln/Glu levels were observed in adults with SZ and in older subjects. Contrary to expectation, these results do not show evidence of accelerated Glu aging in the anterior cingulate region in SZ compared with healthy controls.

Evaluation of Myo-Inositol as a Potential Biomarker for Depression in Schizophrenia

Depression is highly prevalent in patients with schizophrenia and is associated with significant clinical consequences, but there is no known biomarker for depression in schizophrenia. One of the putative neurochemical biomarkers for depression in major depressive disorder (MDD) is reduced cerebral concentration of myo-Inositol. We examined whether myo-Inositol levels provide a potential marker for depressive symptoms in schizophrenia similar to that in MDD and are informative regarding causal biological pathways underlying both depression and schizophrenia. We used proton magnetic resonance spectroscopy to examine myo-Inositol levels in the anterior cingulate cortex (ACC) in 59 schizophrenia spectrum disorder (SSD) patients and 69 matched community comparison participants. Participants completed the Maryland Trait and State Depression (MTSD) scale to measure symptoms of depression experienced around time of assessment (‘State’ subscale) and longitudinally (‘Trait’ subscale). Myo-Inositol in the ACC was negatively correlated with MTSD-Trait scores in both patients (ρ=−0.336, p=0.009) and community comparison samples (ρ=−0.328, p=0.006). Furthermore, patients with a diagnosis of schizoaffective disorder or a history of at least one major depressive episode had lower levels of myo-Inositol compared with schizophrenia patients without a current or past affective diagnosis (p=0.012). Since reduced brain myo-Inositol is associated with MDD, myo-Inositol may be a biochemical marker of depressive mood symptoms across diagnostic boundaries. If confirmed, this finding may aid investigation of the pathophysiology and therapeutics of depression common between depression, schizophrenia and other psychiatric diagnoses.

Antigliadin Antibodies (AGA IgG) Are Related to Neurochemistry in Schizophrenia

Inflammation may play a role in schizophrenia; however, subgroups with immune regulation dysfunction may serve as distinct illness phenotypes with potential different treatment and prevention strategies. Emerging data show that about 30% of people with schizophrenia have elevated antigliadin antibodies of the IgG type, representing a possible subgroup of schizophrenia patients with immune involvement. Also, recent data have shown a high correlation of IgG-mediated antibodies between the periphery and cerebral spinal fluid in schizophrenia but not healthy controls, particularly AGA IgG suggesting that these antibodies may be crossing the blood–brain barrier with resulting neuroinflammation. Proton magnetic resonance spectroscopy (MRS) is a non-invasive technique that allows the quantification of certain neurochemicals in vivo that may proxy inflammation in the brain such as myoinositol and choline-containing compounds (glycerophosphorylcholine and phosphorylcholine). The objective of this exploratory study was to examine the relationship between serum AGA IgG levels and MRS neurochemical levels. We hypothesized that higher AGA IgG levels would be associated with higher levels of myoinositol and choline-containing compounds (glycerophosphorylcholine plus phosphorylcholine; GPC + PC) in the anterior cingulate cortex. Thirty-three participants with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder had blood drawn and underwent neuroimaging using MRS within 9 months. We found that 10/33 (30%) had positive AGA IgG (≥20 U) similar to previous findings. While there were no significant differences in myoinositol and GPC + PC levels between patients with and without AGA IgG positivity, there were significant relationships between both myoinositol (r = 0.475, p = 0.007) and GPC + PC (r = 0.36, p = 0.045) with AGA IgG levels. This study shows a possible connection of AGA IgG antibodies to putative brain inflammation as measured by MRS in schizophrenia.

Glutamatergic Response to Heat Pain Stress in Schizophrenia

Regulation of stress response involves top-down mechanisms of the frontal-limbic glutamatergic system. As schizophrenia is associated with glutamatergic abnormalities, we hypothesized that schizophrenia patients may have abnormal glutamatergic reactivity within the dorsal anterior cingulate cortex (dACC), a key region involved in perception of and reaction to stress. To test this, we developed a somatic stress paradigm involving pseudorandom application of safe but painfully hot stimuli to the forearm of participants while they were undergoing serial proton magnetic resonance spectroscopy to measure changes in glutamate and glutamine levels in the dACC. This paradigm was tested in a sample of 21 healthy controls and 23 patients with schizophrenia. Across groups, glutamate levels significantly decreased following exposure to thermal pain, while ratio of glutamine to glutamate significantly increased. However, schizophrenia patients exhibited an initial increase in glutamate levels during challenge that was significantly different from controls, after controlling for heat pain tolerance. Furthermore, in patients, the acute glutamate response was positively correlated with childhood trauma (r = .41, P = .050) and inversely correlated with working memory (r = -.49, P = .023). These results provide preliminary evidence for abnormal glutamatergic response to stress in schizophrenia patients, which may point toward novel approaches to understanding how stress contributes to the illness.

Glutamatergic metabolites are associated with visual plasticity in humans

Long-term potentiation (LTP) is a basic cellular mechanism underlying learning and memory. LTP-like plasticity in the visual cortex can be induced by high frequency visual stimulation in rodents and humans. Since glutamate plays a fundamental role in LTP, this study investigated if visual cortical glutamate and glutamine levels, measured by proton magnetic resonance spectroscopy (MRS), relate to visual plasticity in humans. Since plasticity requires a delicate excitation and inhibition balance, GABA was also explored. Eighteen healthy participants completed MRS and a visual fMRI paradigm. Results revealed enhanced fMRI activations after high frequency visual stimulation, suggesting visual plasticity occurred. Higher activations were associated with higher resting glutamine levels after family wise error-correction. Exploratory analyses revealed that higher resting glutamate and GABA levels were associated with visual plasticity, suggesting there may be a critical excitation-inhibition balance necessary for experience dependent plasticity. This is the first empirical evidence that resting glutamine levels and potentially glutamate and GABA levels are associated with visual plasticity in humans.

Comparing the reproducibility of commonly used magnetic resonance spectroscopy techniques to quantify cerebral glutathione: Reproducibility of MRS GSH Levels at 3T

Cerebral glutathione (GSH), a marker of oxidative stress, has been quantified in neurodegenerative diseases and psychiatric disorders using proton magnetic resonance spectroscopy (MRS). Using a reproducible MRS technique is important, as it minimizes the impact of measurement technique variability on the study results and ensures that other studies can replicate the results.