Cortical white matter microstructural alterations underlying the impaired gamma-band auditory steady-state response in schizophrenia.

The gamma-band auditory steady-state response (ASSR), primarily generated from the auditory cortex, has received substantial attention as a potential brain marker indicating the pathophysiology of schizophrenia. Previous studies have shown reduced gamma-band ASSR in patients with schizophrenia and demonstrated correlations with impaired neurocognition and psychosocial functioning. Recent studies in clinical and healthy populations have suggested that the neural substrates of reduced gamma-band ASSR may be distributed throughout the cortices surrounding the auditory cortex, especially in the right hemisphere. This study aimed to investigate associations between the gamma-band ASSR and white matter alterations in the bundles broadly connecting the right frontal, parietal and occipital cortices to clarify the networks underlying reduced gamma-band ASSR in patients with schizophrenia. We measured the 40 Hz ASSR using electroencephalography and diffusion tensor imaging in 42 patients with schizophrenia and 22 healthy comparison subjects. The results showed that the gamma-band ASSR was positively correlated with fractional anisotropy (an index of white matter integrity) in the regions connecting the right frontal, parietal and occipital cortices in healthy subjects (ß = 0.41, corrected p = 0.075, uncorrected p = 0.038) but not in patients with schizophrenia (ß = 0.17, corrected p = 0.46, uncorrected p = 0.23). These findings support our hypothesis that the generation of gamma-band ASSR is supported by white matter bundles that broadly connect the cortices and that these relationships may be disrupted in schizophrenia. Our study may help characterize and interpret reduced gamma-band ASSR as a useful brain marker of schizophrenia.

Longitudinal change in mismatch negativity (MMN) but not in gamma-band auditory steady-state response (ASSR) is associated with psychological difficulties in adolescence.

Adolescence is a critical period for psychological difficulties. Auditory mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are representative electrophysiological indices that mature during adolescence. However, the longitudinal association between MMN/ASSR and psychological difficulties among adolescents remains unclear. We measured MMN amplitude for duration and frequency changes and ASSR twice in a subsample (n = 67, mean age 13.4 and 16.1 years, respectively) from a large-scale population-based cohort. No significant longitudinal changes were observed in any of the electroencephalography indices. Changes in SDQ-TD were significantly associated with changes in duration MMN, but not frequency MMN and ASSR. Furthermore, the subgroup with higher SDQ-TD at follow-up showed a significant duration MMN decrease over time, whereas the subgroup with lower SDQ-TD did not. The results of our population neuroscience study suggest that insufficient changes in electroencephalography indices may have been because of the short follow-up period or non-monotonic change during adolescence, and indicated that the longitudinal association with psychological difficulties was specific to the duration MMN. These findings provide new insights that electrophysiological change may underlie the development of psychosocial difficulties emerging in adolescence.

Weight of evidence approach using a TK gene mutation assay with human TK6 cells for follow-up of positive results in Ames tests: a collaborative study by MMS/JEMS.

BACKGROUND: Conflicting results between bacterial mutagenicity tests (the Ames test) and mammalian carcinogenicity tests might be due to species differences in metabolism, genome structure, and DNA repair systems. Mutagenicity assays using human cells are thought to be an advantage as follow-up studies for positive results in Ames tests. In this collaborative study, a thymidine kinase gene mutation study (TK6 assay) using human lymphoblastoid TK6 cells, established in OECD TG490, was used to examine 10 chemicals that have conflicting results in mutagenicity studies (a positive Ames test and a negative result in rodent carcinogenicity studies). RESULTS: Two of 10 test substances were negative in the overall judgment (20% effective as a follow-up test). Three of these eight positive substances were negative after the short-term treatment and positive after the 24 h treatment, despite identical treatment conditions without S9. A toxicoproteomic analysis of TK6 cells treated with 4-nitroanthranilic acid was thus used to aid the interpretation of the test results. This analysis using differentially expressed proteins after the 24 h treatment indicated that in vitro specific oxidative stress is involved in false positive response in the TK6 assay. CONCLUSIONS: The usefulness of the TK6 assay, by current methods that have not been combined with new technologies such as proteomics, was found to be limited as a follow-up test, although it still may help to reduce some false positive results (20%) in Ames tests. Thus, the combination analysis with toxicoproteomics may be useful for interpreting false positive results raised by 24 h specific reactions in the assay, resulting in the more reduction (> 20%) of false positives in Ames test.

Early-life stress induces anxiety-like behaviors and activity imbalances in the medial prefrontal cortex and amygdala in adult rats.

Early-life stress increases the prevalence of psychiatric diseases associated with emotional dysregulation. Emotional regulation requires the inhibitory influence of the medial prefrontal cortex (mPFC) on amygdalar activity, and dysfunction of this system is believed to induce anxiety. Because mPFC and amygdala have dense reciprocal connections and projections between them continue to develop until adolescence, early-life stress may impair the function of this circuit and cause emotional dysregulation. We examined the effects of stress during circuit development on anxiety-like behaviors, neural activities in the mPFC and amygdala, and impulse transmission in the mPFC-amygdala circuit in adult rats. Early-life stress, unpredictable stress twice a day for 12 days following early weaning, increased anxiety-like behaviors in the open-field and elevated plus-maze tests. In the open-field test, stress altered Fos expression in the mPFC and amygdala. Compared to non-stressed rats, which were exposed to neither unpredictable stress nor early weaning, stressed rats exhibited decreased Fos expression in the right superficial layers of the infralimbic cortex and increased Fos expression in the right basolateral amygdala and both sides of the central amygdala. Electrophysiological analysis revealed that excitatory latencies of mPFC neurons to amygdalar stimulation in stressed rats were significantly longer than control rats in the right, but not left, hemisphere. Stress had no effect on excitatory latencies of amygdalar neurons to mPFC stimulation in the mPFC-amygdala circuits in the both hemisphere. These data suggest that early-life stress impairs the mPFC-amygdala circuit development, resulting in imbalanced mPFC and amygdala activities and anxiety-like behaviors.