Duration and Frequency Mismatch Negativity in Schizophrenia, Unaffected first-degree relatives, and Healthy controls

Background: Mismatch negativity (MMN) is elicited upon detecting background irregularities in the sensory environment and subsequent updating of the sensory context. Auditory MMN amplitude is reliably attenuated in schizophrenia patients. However, due to diversity in MMN deviant types (duration, frequency, intensity, gap, etc.), considerable variability exists in MMN findings reported from the early course and chronic samples. MMN is sometimes reported to be impaired or associated with schizotypy, but MMN and schizotypy are yet to be well examined in unaffected first-degree relatives of schizophrenia patients. Methods: Fifty-two schizophrenia patients (SZ) were compared with thirty-six unaffected first-degree relatives (FDR) of schizophrenia patients and thirty-two age and sex-matched healthy controls (HC) on MMN indices using a two-tone passive auditory oddball paradigm with two conditions - duration deviant (MMNd) and frequency deviant (MMNf) event-related potential experiment. SZ sample was further split into two sub-groups 1) early-course/drug-naive or drug-free (dSZ), and 2) chronic/medicated (cSZ) to examine the effect of illness chronicity and medication on MMN indices. We also checked whether schizotypy scores associated with MMNd and MMNf amplitudes in the FDR group. Results: At baseline, SZ group had significantly diminished MMNd amplitude compared to both HC and FDR groups (p<0.001). The SZ group also had significantly lower MMNd latency than the FDR group (p<0.014). The cSZ and dSZ groups did not differ from each other on MMN amplitude or latency, though cSZ group had lower MMN amplitude. Only cSZ patients showed negative correlation of MMNd amplitude with hallucinations scores and total duration of illness. In FDRs, MMNd and MMNf amplitudes showed negative correlation with the cognitive-perceptual factor of schizotypy. Discussion: Deficient MMNd in SZ patients adds further support to the prediction error estimation abnormalities in schizophrenia. MMNd is a more robust measure than MMNf in differentiating SZ from FDR and HC. MMNd amplitude could be more impaired in hallucinating SZ patients and associate with illness chronicity. Though unaffected FDRs have MMN comparable to healthy controls, higher schizotypy in FDR is associated with lower MMN amplitude. MMN and schizotypy are potentially linked and deserve a nuanced examination. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study is supported by the Department of Biotechnology (DBT) - Wellcome Trust India Alliance grants (500236/Z/11/Z and IA/CRC/19/1/610005) to Ganesan Venkatasubramanian. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institute Ethics Committee at National Institute of Mental Health And Neuro Sciences gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data from this study are not publicly available due to ethical and privacy restrictions. However, data will be made available upon reasonable request from the corresponding authors.