Given the present data we are not

Given the present data, we are not able to explain why the left auditory trp channels was overactivated during 80-Hz ASSR stimulation. However, the left and right transverse temporal gyri and left planum temporale have some differential cytoarchitectonic features (Seldon, 1981; Hutsler and Gazzaniga, 1996) that may be implicated in lateralized activation. Previously, our group reported left-lateralized abnormally-evoked gamma oscillations to vowel sounds in patients with schizophrenia (Hirano et al., 2008). Additionally, Dierks et al. demonstrated increased fMRI activation in the left transverse temporal gyrus during auditory hallucinations in right-handed individuals with schizophrenia (Dierks et al., 1999). In the current study, increased severity of global auditory hallucinatory experiences was associated with larger BOLD percent signal changes in the left auditory cortex in the AESZ group. Thus, the present results may support the view that the left auditory cortex is the site of defective anatomical substrate associated with auditory hallucinations in acute schizophrenia. We found group differences in the time course of alterations in ASSR-BOLD. Specifically, we found that, unlike the NASZ and HC groups, the AESZ group exhibited a BOLD increase in high gamma-band ASSRs, especially during the period from 9 to 18s after the onset of 80-Hz stimuli. In the HC group, BOLD signals decreased from 6 to 9s for the same stimuli. This phenomenon may be associated with ASSR habituation, as demonstrated by an exponential electrophysiological decrease following repeated exposure to stimuli in rats (Prado-Gutierrez et al., 2015). Indeed, AESZ patients may show delayed habituation to 80-Hz stimuli; however, further studies will be needed to clarify this issue. In interpreting the current study, it is important to consider several possible limitations. First, ASSR-BOLD responses are involved not only in gamma band activities, but broadband activities as well. However, only gamma band oscillations have been highly correlated with hemodynamic responses (Niessing et al., 2005). The 80-Hz stimulation may be a resonant frequency with respect to the activation of ASSR-BOLD signals. Future studies should investigate this using simultaneous EEG-fMRI recordings. Second, our sample size was relatively small (24 HC, 14 NASZ, and 15 AESZ participants), partially due to the challenges of scanning schizophrenia patients in the acute phase. The association between 80-Hz ASSR-BOLD signals and auditory hallucinatory experiences should be confirmed in a larger sample.
Funding Sources This work was supported in part by a Grant-in-Aid for Scientific Research (B25293252 to S.K., C23591712 to T.O., B22791129 and 15K09836 to Y.H.), a Grant-in-Aid for Young Scientists (B) (15K19735 to N.O. and 25861044 to H.K.), and the Program for Advancing Strategic International Networks to Accelerate the Circulation of Talented Researchers from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (S2208 to S.K. and T.O.); a Research Grant from the Brain Science Foundation to Y.H.; the Research Group for Schizophrenia to N.O. and H.K.; the Health and Labor Sciences Research Grants for Comprehensive Research on Persons with Disabilities from Japan Agency for Medical Research and Development, AMED (16dk0307047h0002) to S.K.; and JSPS KAKENHI Grant numbers 25117011 and 25117001 to S.K. No additional external funding was received for this study. The funders had no role in study design, data collection, data analysis, interpretation, or writing of this report.
Conflicts of Interest
Author Contributions
Acknowledgements
Introduction Transmissible spongiform encephalopathies, also called ‘prion diseases,’ are caused by abnormally accumulated prion protein (PrP-res) in the central nervous system (CNS). The causative agent is thought to be solely composed of amyloid prion proteins and is not inactivated by standard and popular procedures. Iatrogenic Creutzfeldt-Jakob disease (CJD) can be caused by the reuse of neurosurgical instruments or contamination of biomaterials, such as dura mater graft material (Thadani et al., 1988; Bernoulli et al., 1977; Will & Matthews, 1982). However, extensive investigations have concluded that accidental prion transmission, as well as sporadic CJD (sCJD), which is the idiopathic form of CJD, is not likely the consequence of spontaneous somatic mutations. The proteinase K (PK)-resistant (PK-res) PrP in sCJD has been shown to be limited to cases with biological materials from the CNS or cornea. Additionally, in sCJD, prion infectivity has not been detected in extracerebral organs in studies using animal models, suggesting that infectious prions are restricted to the CNS. However, recent studies used Western blotting analysis to detect PrP-res in the spleen of a sCJD patient, although the PrPSc levels were lower by a factor of approximately 10 than in brain tissue (Glatzel et al., 2003). These studies highlight the need to elucidate prion distribution in humans to reduce the risk of accidental prion infection. Various studies have already detected PK-resistant PrP in peripheral tissues in natural and experimental sCJD cases. For instance, Glatzel M, et al. (Glatzel et al., 2003) used Western blotting to show the presence of PrPSc in the spleen, as well as in the muscle of some sCJD patients. Additionally, Rubenstains et al. detected PrPSc in tonsil and lymph node tissues of sCJD patients (Rubenstein & Chang, 2013). Experimentally, Herzog et al. infected nonhuman primates with the sCJD agent (among others) to investigate the involvement of peripheral organs (Herzog et al., 2005). They also confirmed the presence of PrPSc in lymphoreticular organs and muscles.