ORIGINAL ARTICLE Sensory Gating Endophenotype Based on Its Neural Oscillatory Pattern and Heritability Estimate L. Elliot Hong, MD; Ann Summerfelt, BS; Braxton D. Mitchell, PhD; Robert P. McMahon, PhD; Ikwunga Wonodi, MD; Robert W. Buchanan, MD; Gunvant K. Thaker, MD Context: The auditory sensory gating deficit has been con- first-degree relatives (n=74), and control participants from sidered a leading endophenotype in schizophrenia. How- the community (n=70). ever, the commonly used index of sensory gating, P50, has low heritability in families of people with schizophrenia, Main Outcome Measures: Gating of frequency- raising questions about its utility in genetic studies. We hy- specific oscillatory responses, gating of the P50 wave, and pothesized that the sensory gating deficit may occur in a their heritability estimates. specific neuronal oscillatory frequency that reflects the un- derlying biological process of sensory gating. Frequency- Results: Gating of the ␪-␣–band responses of the con- specific sensory gating may be less complex than the P50 trol participants were significantly different from those response, and therefore closer to the direct genetic effects, with schizophrenia (PϽ.001) and their first-degree and thus a more valid endophenotype. relatives (P=.04 to .009). The heritability of ␪-␣–band gating was estimated to be between 0.49 and 0.83 and Objectives: To compare the gating of frequency- was at least 4-fold higher than the P50 heritability esti- specific oscillatory responses with the gating of P50 and mate. to compare their heritabilities. Conclusions: Gatingofthe␪-␣–frequency oscillatory sig- Design: We explored single trial–based oscillatory gat- nal in the paired-click paradigm is more strongly asso- ing responses in people with schizophrenia, their rela- ciated with schizophrenia and has significantly higher tives, and control participants from the community. heritability compared with the traditional P50 gating. This measure may be better suited for genetic studies of the Setting: Outpatient clinics. gating deficit in schizophrenia. Participants: Persons with schizophrenia (n=102), their Arch Gen Psychiatry. 2008;65(9):1008-1016 BNORMAL SENSORY GATING Although it is often considered an en- may index the inability of dophenotype for schizophrenia, the tra- people with schizophrenia ditional P50 gating measure has low heri- to sufficiently filter un- tability, which has been estimated at 0.10 wanted sensory informa- in the families of people with schizophre- Ation and is considered a leading endophe- nia.12 Low heritabilities compromise the notype in schizophrenia.1,2 Sensory gating utility of this phenotype for genetic stud- is efficiently probed using a simple paired- ies and even call into question the valid- click auditory evoked potential paradigm; ity of the phenotype, given the high heri- the gating response is reflected by a dimi- tability of the schizophrenia phenotype.13 nution of evoked potential response elic- We sought to refine the sensory gat- Author Affiliations: Maryland ited by the second of a pair of identical au- ing paradigm by studying single-trial Psychiatric Research Center, ditory stimuli. Most previous sensory gating oscillatory responses to an auditory stimu- Department of Psychiatry studies have focused on the averaged P50 lus, independent of any averaged wave- (Drs Hong, McMahon, Wonodi, wave in response to the auditory stimuli.3,4 forms. Schizophrenia is a disease associ- Buchanan, and Thaker, and Such P50 gating impairments have been ob- ated with aberrant processing of sensory Ms Summerfelt) and Department of Medicine, served in people with schizophrenia and information. Sufficient data have shown 5-8 9-11 University of Maryland School their relatives in many, but not all stud- that neuronal assemblies have the intrin- of Medicine, Baltimore ies. More comprehensive review can be sic capacity to oscillate at different fre- (Dr Mitchell). found elsewhere.4 quencies in response to sensory input,14 (REPRINTED) ARCH GEN PSYCHIATRY/ VOL 65 (NO. 9), SEP 2008 WWW.ARCHGENPSYCHIATRY.COM 1008 ©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 representing different stages of sensory information pro- years above or below the age of the probands), sex, ethnicity, cessing.14-16 These oscillations constitute rhythmic modu- and neighborhood (same zip code); the list was generated using lations in neuronal excitability that affect the likelihood the State of Maryland Motor Vehicle Administration registra- of spike output in response to subsequent input.17,18 It is tion. Control participants had no family history of psychosis possible that a deficit in sensory gating can be more di- for 3 generations. Available first-degree relatives of the con- trols were also recruited. Controls and relatives of patients with rectly evaluated by examining the rhythmic modulatory schizophrenia who did not have schizophrenia were screened process of sensory input rather than an averaged wave- using the Structured Clinical Interview for DSM-IV and iden- form, which may diminish the ability to examine the un- tical inclusion/exclusion criteria. They had no DSM-IV psy- derlying oscillatory mechanism. We hypothesized that chotic or bipolar disorders. Controls and relatives with other the sensory gating deficit in schizophrenia would be in- Axis I disorders were accepted so that the group differences re- dexed by neural oscillations in a specific time frequency flected differences in family history of schizophrenia alone and measurable on single trials. This may represent a more not in other psychiatric conditions. None of the subjects had elementary physiological process and thus be more sen- participated in our previous study.19 All subjects gave written sitive to the direct genetic effect underlying sensory gat- informed consent in accordance with the University of Mary- ing, yielding higher heritability estimates compared with land institutional review board guidelines. the averaged P50 wave. Using a discrete wavelet trans- form technique to identify single-trial oscillatory com- SAMPLE SIZE FOR GROUP COMPARISONS ponents contributing to sensory gating, we previously found that auditory responses are represented by a range The analysis included 246 subjects: 102 with schizophrenia (93 of time frequency–specific oscillatory components, and probands and 9 of their relatives with schizophrenia), 74 first- that ␤- and, to a lesser extent, ␣-frequency oscillations degree relatives without schizophrenia, and 70 control partici- pants from the community. Not included in the sample were 9 indexed the strength of P50 suppression in healthy con- 19 subjects who completed event-related potential recording but trols. In this study, we sought to identify single-trial scalp had excessive artifacts or had equipment problems during re- electrical oscillatory signals that are suppressed by re- cording. peated stimuli. Once such a signal was found, we tested whether it is a better endophenotype compared with P50, based on the following a priori endophenotype SAMPLE SIZE FOR HERITABILITY ESTIMATES testing criteria: (1) its association with the schizophre- This sample included 48 family units of subjects with schizo- nia phenotype; (2) its presence in family members phrenia, consisting of 48 probands and 75 first-degree rela- without schizophrenia who are not taking antipsy- tives (with or without schizophrenia). The 48 families in- chotic medications; (3) whether it has significant heri- cluded 30 of size 2 (2 subjects per family), 11 of size 3, 6 of tability; and (4) if it is superior to the P50 gating mea- size 4, and 1 of size 6. In total, this set included 134 sibling- sure, ie, provides better differentiation between control sibling or parent-offspring pairs used for the heritability esti- participants and persons with schizophrenia, between mate. The community control samples included 20 small fami- controls and family members of persons with schizo- lies (20 probands and 23 first-degree relatives) but formed only phrenia, and higher heritability when compared with 23 informative relative pairs. P50 gating. LABORATORY PROCEDURE METHODS Evoked Potential for P50 PARTICIPANTS Evoked potentials were recorded and processed using the same procedures previously reported.22 Smokers refrained from smok- All participants were between the ages of 16 and 58 years, with ing for 1 hour prior to recording. Subjects sat in a semireclin- no neurological conditions or current substance abuse or de- ing chair in a sound chamber with their eyes open and lis- pendence. Patients with schizophrenia were diagnosed using tened to 150 paired-click stimuli (1-millisecond duration; the Structured Clinical Interview for DSM-IV.20 Patients were 72 dB; 500-millisecond interclick interval; 10-second inter- recruited through our outpatient research programs and Bal- trial interval). The electroencephalogram reading was sampled timore-area mental health clinics. Four were taking a first- at 1 kHz (200-Hz low pass; 0.1-Hz high pass; 60-Hz notch fil- generation antipsychotic, 4 were not taking an antipsychotic, ter applied during recording) to yield 500-millisecond ep- and the rest were taking second-generation antipsychotic agents. ochs, including a 100-millisecond prestimulus window. Arti- In addition, 18.6% were also taking a selective serotonin re- facts were removed from single trials, with a rejection criterion uptake inhibitor and 9.8% were taking benzodiazepine. Pa- above or