Xiaoming Du

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.

Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia.

Altered brain connectivity is implicated in the development and clinical burden of schizophrenia. Relative to matched controls, schizophrenia patients show (1) a global and regional reduction in the integrity of the brains white matter (WM), assessed using diffusion tensor imaging (DTI) fractional anisotropy (FA), and (2) accelerated age‐related decline in FA values. In the largest mega‐analysis to date, we tested if differences in the trajectories of WM tract development influenced patient–control differences in FA. We also assessed if specific tracts showed exacerbated decline with aging.

Acute nicotine administration effects on fractional anisotropy of cerebral white matter and associated attention performance

Introduction: Nicotinic acetylcholine receptors are present in the cerebral white matter (WM). We hypothesized that WM response to nicotine can be detected by diffusion tensor imaging (DTI); and that such responses may be associated with nicotine-led cognitive enhancement in sustained attention. Methods: A randomized, nicotine-placebo patch, crossover, double-blind clinical trial in two non-overlapping cohorts of smokers was used to test the hypothesis. The discovery cohort consisted of 39 subjects (N = 20/19 controls/schizophrenic patients, age = 36.8 ± 10.1 years) and the replication cohorts consisted of 38 healthy smokers (31.7 ± 10.5 years). WM integrity was measured by fractional anisotropy (FA) values for the whole brain and nine preselected WM tracts using tract-based-spatial-statistics. Results: Nicotine significantly enhanced FA values for the genu of corpus callosum compared with placebo (ΔFAgenu) (p = 0.01) in smokers with low recent smoking exposure as measured by low average cotinine level. This finding was replicated in the second cohort (p = 0.02). ΔFAgenu values explained 22% of variance in performance of a sustained attention task during the nicotine session (p = 0.006). However, this effect was limited to schizophrenia patients (r = 0.62 and 0.09; p = 0.003 and 0.7 for patients and controls, respectively). Conclusion: Acute pharmacological influence of nicotine patch on WM integrity appeared present, but was dependent on nicotine intake from recent smoking. Change in the WM integrity in the genu of corpus callosum was associated with a significant proportion of variability of nicotine-led changes in sustained attention/working memory of the smokers. Further studies will be necessary to understand biophysical underpinning of the nicotine-related changes in FA.

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.

The common genetic influence over processing speed and white matter microstructure: Evidence from the Old Order Amish and Human Connectome Projects.

Speed with which brain performs information processing influences overall cognition and is dependent on the white matter fibers. To understand genetic influences on processing speed and white matter FA, we assessed processing speed and diffusion imaging fractional anisotropy (FA) in related individuals from two populations. Discovery analyses were performed in 146 individuals from large Old Order Amish (OOA) families and findings were replicated in 485 twins and siblings of the Human Connectome Project (HCP). The heritability of processing speed was h(2)=43% and 49% (both p<0.005), while the heritability of whole brain FA was h(2)=87% and 88% (both p<0.001), in the OOA and HCP, respectively. Whole brain FA was significantly correlated with processing speed in the two cohorts. Quantitative genetic analysis demonstrated a significant degree to which common genes influenced joint variation in FA and brain processing speed. These estimates suggested common sets of genes influencing variation in both phenotypes, consistent with the idea that common genetic variations contributing to white matter may also support their associated cognitive behavior.

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.

The role of the left posterior parietal lobule in top-down modulation on space-based attention: A transcranial magnetic stimulation study

Converging evidence from neuroimaging as well as lesion and transcranial magnetic stimulation (TMS) studies has been obtained for the involvement of right ventral posterior parietal cortex (PPC) in exogenous orienting. However, the contribution of dorsal PPC to attentional orienting, particularly endogenous orienting, is still under debate. In an informative peripheral cueing paradigm, in which the exogenous and endogenous orienting can be studied in relative isolation within a single task, we applied TMS over sub‐regions of dorsal PPC to explore their possible distinct involvement in exogenous and endogenous processes. We found that disruption of the left posterior intraparietal sulcus (pIPS) weakened the attentional effects of endogenous orienting, but did not affect exogenous processes. In addition, TMS applied over the right superior parietal lobule (SPL) resulted in an overall increase in reaction times. The present study provides the causal evidence that the left pIPS plays a crucial role in voluntary orienting of visual attention, while right SPL is involved in the processing of arousal and/or vigilance. Hum Brain Mapp 33:2477–2486, 2012.

Association of White Matter With Core Cognitive Deficits in Patients With Schizophrenia

Importance Efforts to remediate the multiple cognitive function impairments in schizophrenia should consider white matter as one of the underlying neural mechanisms. Objective To determine whether altered structural brain connectivity is responsible for 2 of the core cognitive deficits in schizophrenia— reduced information processing speed and impaired working memory. Design, Setting, and Participants This cross-sectional study design took place in outpatient clinics from August 1, 2004, to August 31, 2015. Participants included 166 patients with schizophrenia and 213 healthy control individuals. These participants were from 3 independent cohorts, each of which had its own healthy control group. No participant had current or past neurological conditions or major medical conditions. Patients were diagnosed with either schizophrenia or schizoaffective disorder as defined by the DSM-IV. Controls had no Axis I psychiatric disorder. Main Outcomes and Measures Mediation analyses and structural equation modeling were used to analyze the associations among processing speed, working memory, and white matter microstructures. Whole-brain and regional diffusion tensor imaging fractional anisotropy were used to measure white matter microstructures. Results Of the study participants, the 166 patients with schizophrenia had a mean (SD) age of 38.2 (13.3) years and the 213 healthy controls had a mean (SD) age of 39.2 (14.0) years. There were significantly more male patients than controls in each of the 3 cohorts (117 [70%] vs 91 [43%]), but there were no significant differences in sex composition among the 3 cohorts. Patients had significantly reduced processing speed (Cohen d = 1.24; P = 6.91 × 10−30) and working memory deficits (Cohen d = 0.83; P = 1.10 × 10−14) as well as a significant whole-brain fractional anisotropy deficit (Cohen d = 0.63; P = 2.20 × 10−9). In schizophrenia, working memory deficit was mostly accounted for by processing speed deficit, but this deficit remained when accounting for working memory (Cohen d = 0.89; P = 2.21 × 10−17). Mediation analyses showed a significant association pathway from fractional anisotropy to processing speed to working memory (P = 5.01 × 10−7). The strength of this brain-to-cognition pathway in different white matter tracts was strongly associated with the severity of schizophrenia-associated fractional anisotropy deficits in the corresponding white matter tracts as determined by a meta-analysis (r = 0.85-0.94; all P < .001). The same pattern was observed in patients and controls either jointly or independently. Conclusions and Relevance Study findings suggest that (1) processing speed contributes to the association between white matter microstructure and working memory in schizophrenia and (2) white matter impairment in schizophrenia is regional tract–specific, particularly in tracts normally supporting processing speed performance.