Joshua Chiappelli

Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia.

IMPORTANCE Auditory mismatch negativity (MMN) is a biomarker for schizophrenia thought to reflect glutamatergic N-methyl-d-aspartate receptor function and excitatory-inhibitory neurotransmission balance. However, the association of glutamate level with MMN has not been directly examined in patients with schizophrenia, to our knowledge. OBJECTIVE To investigate the contributions of glutamate and γ-aminobutyric acid (GABA) to MMN and digit sequencing task (DST) performance, an assessment of verbal working memory, in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS Fifty-three control participants from the community and 45 persons with schizophrenia from outpatient clinics completed an electroencephalographic session for MMN, magnetic resonance spectroscopy for glutamate and GABA, and a DST. The study dates were July 2011 to May 2014, and the dates of our analysis were May 2014 to August 2015. MAIN OUTCOMES AND MEASURES Glutamate, GABA, the ratio of glutamine to glutamate, MMN amplitude, and DST. Structural equation modeling was used to test the effects of neurochemistry and MMN amplitude on DST performance. RESULTS The 45 persons with schizophrenia were a mean (SD) of 37.7 (12.8) years and the control participants were 37.1 (13.1) years. The schizophrenia group had a mean (SD) of 14.7 (12.1) years of illness. Mismatch negativity amplitude (F = 4.39, P = .04) and glutamate (F = 9.69, P = .002) were reduced in the schizophrenia group. Smaller MMN amplitude was significantly associated with lower GABA level (P = .008), lower glutamate level (P = .05), and higher ratio of glutamine to glutamate (P = .003). Reduced MMN amplitude was linked to poor verbal working memory in schizophrenia (P = .002). Modeling revealed that a proxy of glutamatergic function, indexed by the ratio of glutamine to glutamate, influenced a path from the ratio of glutamine to glutamate to MMN to verbal working memory (P = .38 [root-mean-square error of approximation, P < .001] by χ2 test), supporting the contention that MMN serves as an intermediate biomarker linking glutamatergic function to DST performance in schizophrenia. CONCLUSIONS AND RELEVANCE The role of glutamate and GABA in MMN and verbal working memory deficits in schizophrenia has been frequently debated. These data provide in vivo evidence that support glutamatergic and GABAergic regulation of MMN and verbal working memory function in schizophrenia.

Individualized Brain Inhibition and Excitation Profile in Response to Paired-Pulse TMS

ABSTRACT Short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) are generated from paired-pulse transcranial magnetic stimulations (ppTMS) using certain interstimulus intervals (ISIs). ppTMS provides an accessible technique to evaluate inhibitory and facilitatory motor neural circuits. However, SICI and ICF are highly variable such that individual variability is not captured by any one static ISI. The authors hypothesized that individuals may have individualized and relatively stable pattern of SICI-ICF profiles. They tested SICI and ICF profiles using ISIs from 1 to 500 ms, on 2 occasions about 3 weeks apart, and the test-retest reliability, in 23 healthy controls. Moderate-to-good test-retest reliabilities were found at ppTMS with 1 and 3 ms ISIs (SICI) and with 12, 15, 18, and 21 ms ISIs (ICF), but not with other control ISIs. A similar pattern of results was obtained for men and women. Interestingly, the peak facilitation, peak inhibition, and maximum inhibition and facilitation ranges were individualized, such that they varied considerably across individuals but had high repeatability within individual (Cronbachs α = 0.76 to 0.85). Therefore, individuals appear to have unique inhibition-facilitation profiles that are relatively stable. Although the functional implications of individualized profiles are currently unknown, the relatively stable profiles may index underlying neural inhibition and excitation traits.

Multimodal white matter imaging to investigate reduced fractional anisotropy and its age-related decline in schizophrenia.

We hypothesized that reduced fractional anisotropy (FA) of water diffusion and its elevated aging-related decline in schizophrenia patients may be caused by elevated hyperintensive white matter (HWM) lesions, by reduced permeability-diffusivity index (PDI), or both. We tested this hypothesis in 40/30 control/patient participants. FA values for the corpus callosum were calculated from high angular resolution diffusion tensor imaging (DTI). Whole-brain volume of HWM lesions was quantified by 3D-T2w-fluid-attenuated inversion recovery (FLAIR) imaging. PDI for corpus callosum was ascertained using multi b-value diffusion imaging (15 b-shells with 30 directions per shell). Patients had significantly lower corpus callosum FA values, and there was a significant age-by-diagnosis interaction. Patients also had significantly reduced PDI but no difference in HWM volume. PDI and HWM volume were significant predictors of FA and captured the diagnosis-related variance. Separately, PDI robustly explained FA variance in schizophrenia patients, but not in controls. Conversely, HWM volume made equally significant contributions to variability in FA in both groups. The diagnosis-by-age effect of FA was explained by a PDI-by-diagnosis interaction. Post hoc testing showed a similar trend for PDI of gray mater. Our study demonstrated that reduced FA and its accelerated decline with age in schizophrenia were explained by pathophysiology indexed by PDI, rather than HWM volume.

Stress-Induced Increase in Kynurenic Acid as a Potential Biomarker for Patients With Schizophrenia and Distress Intolerance

IMPORTANCE Several lines of evidence have linked the endogenous neuromodulator kynurenic acid (KYNA) to schizophrenia. The pathophysiology of schizophrenia is commonly associated with stress, and stress plays a key regulatory role in the first, rate-limiting step of the kynurenine pathway, which produces KYNA. OBJECTIVE To determine whether the level of KYNA changes following psychological stress and whether this change is associated with stress-related behavior. DESIGN, SETTING, AND PARTICIPANTS The KYNA level was measured in saliva samples taken at baseline and at 2 times following a laboratory-based psychological stress challenge in 128 participants (64 patients with schizophrenia from outpatient clinics and 64 healthy controls from the community). EXPOSURE Laboratory-based psychological stress challenge. MAIN OUTCOMES AND MEASURES Quitting the stressful task early was used as a behavioral marker of distress intolerance. RESULTS Patients with schizophrenia showed a significantly higher rate of distress intolerance compared with healthy controls (P = .003). Salivary KYNA levels increased significantly between baseline and 20 minutes following the stress task in both patients and controls (mean [SEM], 6.72nM [0.65nM] vs 8.43nM [1.05nM], respectively; P = .007). Patients who were unable to tolerate the stressful tasks and quit early showed significantly higher levels of KYNA than patients who tolerated the psychological stressor (P = .02) or healthy controls (P = .02). In patients with distress intolerance, KYNA elevation significantly correlated with the severity of clinical symptoms (ρ = 0.64; P = .008). CONCLUSIONS AND RELEVANCE Distress intolerance is more common in patients with schizophrenia. Patients with this behavioral phenotype have elevated salivary KYNA levels. This stress response behavior-linked biomarker may aid heterogeneity reduction in schizophrenia and other stress-related psychiatric conditions.

Accelerated white matter aging in schizophrenia: role of white matter blood perfusion

Elevated rate of age-related decline in white matter integrity, indexed by fractional anisotropy (FA) from diffusion tensor imaging, was reported in patients with schizophrenia. Its etiology is unknown. We hypothesized that a decline of blood perfusion to the white matter may underlie the accelerated age-related reduction in FA in schizophrenia. Resting white matter perfusion and FA were collected using pseudo-continuous arterial spin labeling and high-angular-resolution diffusion tensor imaging, respectively, in 50 schizophrenia patients and 70 controls (age = 18-63 years). Main outcome measures were the diagnosis-by-age interaction on whole-brain white matter perfusion, and FA. Significant age-related decline in brain white matter perfusion and FA were present in both groups. Age-by-diagnosis interaction was significant for FA (p < 0.001) but not white matter perfusion. Age-by-diagnosis interaction for FA values remained significant even after accounting for age-related decline in perfusion. Therefore, we replicated the finding of an increased rate of age-related white matter FA decline in schizophrenia and observed a significant age-related decline in white matter blood perfusion, although the latter did not contribute to the accelerated age-related decline in FA. The results suggest that factors other than reduced perfusion account for the accelerated age-related decline in white matter integrity in schizophrenia.

Perfusion shift from white to gray matter may account for processing speed deficits in schizophrenia

Reduced speed of cerebral information processing is a cognitive deficit associated with schizophrenia. Normal information processing speed (PS) requires intact white matter (WM) physiology to support information transfer. In a cohort of 107 subjects (47/60 patients/controls), we demonstrate that PS deficits in schizophrenia patients are explained by reduced WM integrity, which is measured using diffusion tensor imaging, mediated by the mismatch in WM/gray matter blood perfusion, and measured using arterial spin labeling. Our findings are specific to PS, and testing this hypothesis for patient‐control differences in working memory produces no explanation. We demonstrate that PS deficits in schizophrenia can be explained by neurophysiological alterations in cerebral WM. Whether the disproportionately low WM integrity in schizophrenia is due to illness or secondary due to this disorder deserves further examination. Hum Brain Mapp 36:3793–3804, 2015.

Electrophysiological Intermediate Biomarkers for Oxidative Stress in Schizophrenia

OBJECTIVE Diverse electrophysiological abnormalities have been associated with schizophrenia, but the underlying causes remain elusive. We tested whether the altered oxidative stress in schizophrenia contributes to the electrophysiological abnormalities. METHODS We used an auditory oddball task to measure mismatch negativity (MMN) and gamma band response on 29 schizophrenia patients and 25 normal controls. Oxidative stress was assessed by monomeric glutathione (GSH, reduced form) and glutathione disulfide (GSSG, oxidized form). RESULTS Patients had reduced MMN (p=0.015) and reduced power of gamma band responses at 21-40 Hz and 41-85 Hz (all p<0.001). GSH was significantly lower (p<0.001) while %GSSG was higher (p=0.023) in patients compared with controls. MMN was correlated with GSH in controls; while 21-40 Hz responses were correlated with GSH in patients. Lower GSH and higher GSSG levels were associated with low community functioning (p=0.018). Multivariate mediation modeling showed that gamma band at 21-40 Hz was a significant mediator for GSH effect on community functions. CONCLUSIONS High beta/low gamma range (21-40 Hz) responses may be an intermediate biomarker indexing oxidative stress and its effect on clinical functions. SIGNIFICANCE Electrophysiological abnormalities and associated clinical functional changes may in part be associated with heightened oxidative stress in schizophrenia.

Permeability-diffusivity modeling vs. fractional anisotropy on white matter integrity assessment and application in schizophrenia.

Introduction Diffusion tensor imaging (DTI) assumes a single pool of anisotropically diffusing water to calculate fractional anisotropy (FA) and is commonly used to ascertain white matter (WM) deficits in schizophrenia. At higher b-values, diffusion-signal decay becomes bi-exponential, suggesting the presence of two, unrestricted and restricted, water pools. Theoretical work suggests that semi-permeable cellular membrane rather than the presence of two physical compartments is the cause. The permeability–diffusivity (PD) parameters measured from bi-exponential modeling may offer advantages, over traditional DTI-FA, in identifying WM deficits in schizophrenia. Methods Imaging was performed in N = 26/26 patients/controls (age = 20–61 years, average age = 40.5 ± 12.6). Imaging consisted of fifteen b-shells: b = 250–3800 s/mm2 with 30 directions/shell, covering seven slices of mid-sagittal corpus callosum (CC) at 1.7 × 1.7 × 4.6 mm. 64-direction DTI was also collected. Permeability–diffusivity-index (PDI), the ratio of restricted to unrestricted apparent diffusion coefficients, and the fraction of unrestricted compartment (Mu) were calculated for CC and cingulate gray matter (GM). FA values for CC were calculated using tract-based-spatial-statistics. Results Patients had significantly reduced PDI in CC (p ≅ 10− 4) and cingulate GM (p = 0.002), while differences in CC FA were modest (p ≅ .03). There was no group-related difference in Mu. Additional theoretical-modeling analysis suggested that reduced PDI in patients may be caused by reduced cross-membrane water molecule exchanges. Conclusion PDI measurements for cerebral WM and GM yielded more robust patient–control differences than DTI-FA. Theoretical work offers an explanation that patient–control PDI differences should implicate abnormal active membrane permeability. This would implicate abnormal activities in ion-channels that use water as substrate for ion exchange, in cerebral tissues of schizophrenia patients.

Alterations in frontal white matter neurochemistry and microstructure in schizophrenia: implications for neuroinflammation

We investigated in vivo neurochemical markers reflective of neuronal health and glial activation to determine if these could yield clues regarding the reduced fractional anisotropy (FA) of white matter and accelerated decline of FA with age in schizophrenia. Participants with schizophrenia and healthy controls completed diffusion tensor imaging to assess FA and proton magnetic resonance spectroscopy to assess neurochemical metabolites in the same frontal region. Frontal FA was significantly lower in the schizophrenia and declined more rapidly with age compared with the healthy control group. In both groups, N-acetylaspartate (NAA), a putative marker of neuronal integrity, and glutamate declined with age, and this decline was stronger in patients. Myo-inositol, a marker of glial cells, was negatively related to FA in both groups. The relationship between FA and age remained significant in schizophrenia even when controlling for all metabolites. The relationships of FA, NAA and myo-inositol to age appear to be independent of one another. The relationship between FA and myo-inositol was independently present in both patients and controls, even after controlling for age, indicating a potential general effect of neuroinflammation on white matter microstructure. Further studies are warranted to determine the underlying mechanism driving the accelerated FA decline with age in schizophrenia.

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.