Mismatch negativity predicts initial auditory-based targeted cognitive training performance in a heterogeneous population across psychiatric disorders.

Auditory-based targeted cognitive training (ATCT) programs are emerging pro-cognitive therapeutic interventions which aim to improve auditory processing to attenuate cognitive impairment in a "bottom up" manner. Biomarkers of early auditory information processing (EAIP) like mismatch negativity (MMN) and P3a have been used successfully to predict gains from a full 40 h course of ATCT in schizophrenia (SZ). Here we investigated the ability of EAIP biomarkers to predict ATCT performance in a group of subjects (n = 26) across SZ, MDD, PTSD and GAD diagnoses. Cognition was assessed via the MATRICS Consensus Cognitive Battery (MCCB) and MMN/P3a were collected prior to completing 1 h of "Sound Sweeps," a representative ATCT exercise. Baseline and final performance over the first two levels of cognitive training served as the primary dependent variables. Groups had similar MMN, but the SZ group had attenuated P3a. MMN and MCCB cognitive domain t-scores, but not P3a, were strongly correlated with most ATCT performance measures, and explained up to 61% of variance in ATCT performance. Diagnosis was not a significant predictor for ATCT performance. These data suggest that MMN can predict ATCT performance in heterogeneous neuropsychiatric populations and should be considered in ATCT studies across diagnostically diverse cohorts.

Preliminary Evidence that Memantine Enhances Prepulse Effects on Startle Magnitude and Latency in Patients with Alzheimer's Disease.

BACKGROUND: The uncompetitive NMDA antagonist, memantine (MEM), enhances prepulse inhibition of startle (PPI) across species. MEM is used to treat Alzheimer's disease (AD); conceivably, its acute impact on PPI might be used to predict a patient's sensitivity to MEM's therapeutic effects. OBJECTIVE: To begin to test this possibility, we studied MEM effects on PPI and related measures in AD patients. METHODS: 18 carefully screened individuals with AD (mean age = 72.8 y; M:F=9 : 9) completed double-blind order-balanced testing with MEM (placebo versus 20 mg), assessing acoustic startle magnitude, habituation, PPI, and latency. RESULTS: Fifteen out of 18 participants exhibited reliable startle responses. MEM did not significantly impact startle magnitude or habituation. Compared to placebo responses, PPI was significantly increased after MEM (p < 0.04; d = 0.40); this comparison reached a large effect size for the 60 ms interval (d = 0.62), where maximal MEM effects on PPI were previously detected. Prepulses reduced peak startle latency ("latency facilitation") and this effect was amplified after MEM (p = 0.03; d = 0.41; for 60 ms intervals, d = 0.69). No effects of MEM were detected on cognition, nor were MEM effects on startle associated with cognitive or clinical measures. CONCLUSION: MEM enhances prepulse effects on startle magnitude and latency in AD; these changes in PPI and latency facilitation with MEM suggest that these measures can be used to detect an AD patient's neural sensitivity to acute MEM challenge. Studies in progress will determine whether such a "biomarker" measured at the outset on treatment can predict sensitivity to MEM's therapeutic effects.

The viability of the frequency following response characteristics for use as biomarkers of cognitive therapeutics in schizophrenia.

Deficits in early auditory information processing contribute to cognitive and psychosocial disability; this has prompted development of interventions that target low-level auditory processing, which may alleviate these disabilities. The frequency following response (FFR) is a constellation of event-related potential and frequency characteristics that reflect the processing of acoustic stimuli at the level of the brainstem and ascending portions of the auditory pathway. While FFR is a promising candidate biomarker of response to auditory-based cognitive training interventions, the psychometric properties of FFR in schizophrenia patients have not been studied. Here we assessed the psychometric reliability and magnitude of group differences across 18 different FFR parameters to determine which of these parameters demonstrate adequate internal consistency. Electroencephalography from 40 schizophrenia patients and 40 nonpsychiatric comparison subjects was recorded during rapid presentation of an auditory speech stimulus (6000 trials). Patients showed normal response amplitudes but longer latencies for most FFR peaks and lower signal-to-noise ratios (SNRs) than healthy subjects. Analysis of amplitude and latency estimates of peaks, however, indicated a need for a substantial increase in task length to obtain internal consistency estimates above 0.80. In contrast, excellent internal consistency (>0.95) was shown for FFR sustained responses. Only SNR scores reflecting the FFR sustained response yielded significant group differences and excellent internal consistency, suggesting that this measure is a viable candidate for use in clinical treatment studies. The present study highlights the use of internal consistency estimates to select FFR characteristics for use in future intervention studies interested in individual differences among patients.

Evaluation of the frequency following response as a predictive biomarker of response to cognitive training in schizophrenia.

Neurophysiological biomarkers of auditory processing show promise predicting outcomes following auditory-based targeted cognitive training (TCT) in schizophrenia, but the viability of the frequency following response (FFR) as a biomarker has yet to be examined, despite its ecological and face validity for auditory-based interventions. FFR is an event-related potential (ERP) that reflects early auditory processing. We predicted that schizophrenia patients would show acute- and longer-term FFR malleability in the context of TCT. Patients were randomized to either TCT (n = 30) or treatment as usual (TAU; n = 22), and electroencephalography was recorded during rapid presentation of an auditory speech stimulus before treatment, after one hour of training, and after 30 h of training. Whereas patients in the TCT group did not show changes in FFR after training, amplitude reductions were observed in the TAU. FFR was positively associated with performance on a measure of single word-in-noise perception in the TCT group, and with a measure of sentence-in-noise perception in both groups. Psychometric reliability analyses of FFR scores indicated high internal consistency but low one-hour and 12-week test-rest reliability. These findings support the dissociation between measures of speech discriminability along the hierarchy of cortical and subcortical early auditory information processing in schizophrenia.

Unique contributions of sensory discrimination and gamma synchronization deficits to cognitive, clinical, and psychosocial functional impairments in schizophrenia.

BACKGROUND: Schizophrenia patients show widespread deficits in neurocognitive, clinical, and psychosocial functioning. Mismatch negativity (MMN) and gamma-band auditory steady-state response (ASSR) are robust translational biomarkers associated with schizophrenia and associated with cognitive dysfunction, negative symptom severity, and psychosocial disability. Although these biomarkers are conceptually linked as measures of early auditory information processing, it is unclear whether MMN and gamma-band ASSR account for shared vs. non-shared variance in cognitive, clinical, and psychosocial functioning. METHODS: Multiple regression analyses with MMN, gamma-band ASSR, and clinical measures were performed in large cohorts of schizophrenia outpatients (N = 428) and healthy comparison subjects (N = 283). RESULTS: Reduced MMN (d = 0.67), gamma-band ASSR (d = -0.40), and lower cognitive function were confirmed in schizophrenia patients. Regression analyses revealed that reduced MMN amplitude showed unique associations with lower verbal learning and negative symptoms, reduced gamma-band ASSR showed a unique association with working memory deficits, and both reduced MMN amplitude and reduced gamma-band ASSR showed an association with daily functioning impairment in schizophrenia patients. CONCLUSION: MMN and ASSR measures are non-redundant and complementary measures of early auditory information processing that are associated with important domains of functioning. Studies are needed to clarify the neural substrates of MMN and gamma-band ASSR to improve our understanding of the pathophysiology of schizophrenia and accelerate their use in the development of novel therapeutic interventions.

Heritability of acoustic startle magnitude and latency from the consortium on the genetics of schizophrenia.

BACKGROUND: Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort. METHODS: Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1. RESULTS: 980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p < 0.0001), with heritability of 34-41% for latency and 45-59% for magnitude. CONCLUSION: Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.

A distributed frontotemporal network underlies gamma-band synchronization impairments in schizophrenia patients.

Synaptic interactions between parvalbumin-positive γ-aminobutyric acid (GABA)-ergic interneurons and pyramidal neurons evoke cortical gamma oscillations, which are known to be abnormal in schizophrenia. These cortical gamma oscillations can be indexed by the gamma-band auditory steady-state response (ASSR), a robust electroencephalographic (EEG) biomarker that is increasingly used to advance the development of novel therapeutics for schizophrenia, and other related brain disorders. Despite promise of ASSR, the neural substrates of ASSR have not yet been characterized. This study investigated the sources underlying ASSR in healthy subjects and schizophrenia patients. In this study, a novel method for noninvasively characterizing source locations was developed and applied to EEG recordings obtained from 293 healthy subjects and 427 schizophrenia patients who underwent ASSR testing. Results revealed a distributed network of temporal and frontal sources in both healthy subjects and schizophrenia patients. In both groups, primary contributing ASSR sources were identified in the right superior temporal cortex and the orbitofrontal cortex. In conjunction with normal activity in these areas, schizophrenia patients showed significantly reduced source dipole density of gamma-band ASSR (ITC > 0.25) in the left superior temporal cortex, orbitofrontal cortex, and left superior frontal cortex. In conclusion, a distributed network of temporal and frontal brain regions supports gamma phase synchronization. We demonstrated that failure to mount a coherent physiologic response to simple 40-Hz stimulation reflects disorganized network function in schizophrenia patients. Future translational studies are needed to more fully understand the neural mechanisms underlying gamma-band ASSR network abnormalities in schizophrenia.

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. METHODS: PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. RESULTS: ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DISCUSSION: Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

Mismatch negativity impairment is associated with deficits in identifying real-world environmental sounds in schizophrenia.

BACKGROUND: Patients with schizophrenia (SZ) have impairments in processing auditory information that have been linked to deficits in cognitive and psychosocial functioning. Dysfunction in auditory sensory processing in SZ has been indexed by mismatch negativity (MMN), an event-related potential evoked by a rare, deviant stimulus embedded within a sequence of identical standard stimuli. Although MMN deficits in SZ have been studied extensively, relatively little is known about how these deficits relate to accurately identifying real-world, ecologically-salient sounds. METHODS: MMN was assessed in SZ patients (n=21) and non-psychiatric comparison subjects (NCS; n=16). Participants were also assessed in their ability to identify common environmental sounds using a subset of 80 sound clips from the International Affective Digitized Sounds 2nd Ed collection. RESULTS: SZ patients made significantly more errors in environmental sound identification (p<0.001, d=0.86) and showed significantly reduced MMN amplitude deficits in MMN compared to NCS (p<0.01, d=0.97). In SZ patients, MMN deficits were associated with significantly greater environmental sound identification errors (r=0.61, p<0.01). CONCLUSIONS: Impairments in early auditory information processing in schizophrenia account for significant proportions of variance in the ability to identify real-world, functionally relevant environmental sounds. This study supports the view that interventions targeting deficits in low-level auditory sensory processing may also impact more complex cognitive brain processes relevant to psychosocial disability.

Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2.

Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n=824, SZ n=966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d=0.96) and P3a (d=0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.

Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS.

BACKGROUND: Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site "COGS-2" study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data. METHODS: Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60 ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures. RESULTS: 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis×test site interaction. HCS>schizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures. DISCUSSION: The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia "endophenotype" of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses.

Demand and modality of directed attention modulate "pre-attentive" sensory processes in schizophrenia patients and nonpsychiatric controls.

BACKGROUND: Mismatch negativity (MNN) and P3a are event related potential (ERP) measures of early sensory information processing. These components are usually conceptualized as being "pre-attentive" and therefore immune to changes with variations in attentional functioning. This study aimed to determine whether manipulations of attention influence the amplitudes and latencies of MMN and P3a and, if so, the extent to which these early sensory processes govern concurrent behavioral vigilance performance in schizophrenia patients and normal subjects. METHODS: Schizophrenia patients (SZ; n = 20) and Nonpsychiatric Control Subjects (NCS; n = 20) underwent auditory ERP testing to assess MMN and P3a across 4 EEG recording sessions in which attentional demand (low vs. high) and sensory modality of directed attention (visual vs. auditory) were experimentally varied. RESULTS: Across conditions, SZ patients exhibited deficits in MMN and P3a amplitudes. Significant amplitude and latency modulation were observed in both SZ and NCS but there were no group-by-condition interactions. The amount of MMN amplitude attenuation from low- to high-demand tasks was significantly associated with increased vigilance performance in both SZ and NCS groups (r = -0.67 and r = -0.60). Several other robust associations were also observed among neurophysiologic, clinical and cognitive variables. CONCLUSIONS: Attentional demand and modality of directed attention significantly influence the amplitude and latencies of "pre-attentive" ERP components in both SZ and NCS. Deficits in MMN and P3a were not "normalized" when attention was directed to the auditory stimuli in schizophrenia patients. The adaptive modulation of early sensory information processing appears to govern concurrent attentional task performance. The temporal window reflecting automatic sensory discrimination as indexed as MMN and P3a may serve as a gateway to some higher order cognitive operations necessary for psychosocial functioning.

Electroencephalography (EEG) and event-related potentials (ERPs) with human participants.

Understanding the basic neural processes that underlie complex higher-order cognitive operations and functional domains is a fundamental goal of cognitive neuroscience. Electroencephalography (EEG) is a non-invasive and relatively inexpensive method for assessing neurophysiological function that can be used to achieve this goal. EEG measures the electrical activity of large, synchronously firing populations of neurons in the brain with electrodes placed on the scalp. This unit outlines the basics of setting up an EEG experiment with human participants, including equipment, and a step-by-step guide to applying and preparing an electrode cap. Also included are support protocols for two event-related potential (ERP) paradigms, P50 suppression, and mismatch negativity (MMN), which are measures of early sensory processing. These paradigms can be used to assess the integrity of early sensory processing in normal individuals and clinical populations, such as individuals with schizophrenia.

Effects of olanzapine, risperidone and haloperidol on prepulse inhibition in schizophrenia patients: a double-blind, randomized controlled trial.

Prepulse inhibition (PPI), whereby the startle eyeblink response is inhibited by a relatively weak non-startling stimulus preceding the powerful startle eliciting stimulus, is a measure of sensorimotor gating and has been shown to be deficient in schizophrenia patients. There is considerable interest in whether conventional and/or atypical antipsychotic medications can "normalize" PPI deficits in schizophrenia patients. 51 schizophrenia patients participated in a randomized, double-blind controlled trial on the effects of three commonly-prescribed antipsychotic medications (risperidone, olanzapine, or haloperidol) on PPI, startle habituation, and startle reactivity. Patients were tested at baseline, Week 4 and Week 8. Mixed model regression analyses revealed that olanzapine significantly improved PPI from Week 4 to Week 8, and that at Week 8 patients receiving olanzapine produced significantly greater PPI than those receiving risperidone, but not haloperidol. There were no effects of medication on startle habituation or startle reactivity. These results support the conclusion that olanzapine effectively increased PPI in schizophrenia patients, but that risperidone and haloperidol had no such effects. The results are discussed in terms of animal models, neural substrates, and treatment implications.

Multi-site studies of acoustic startle and prepulse inhibition in humans: initial experience and methodological considerations based on studies by the Consortium on the Genetics of Schizophrenia.

BACKGROUND: Startle and its inhibition by weak lead stimuli ("prepulse inhibition": PPI) are studied to understand the neurobiology of information processing in patients and community comparison subjects (CCS). PPI has a strong genetic basis in infrahumans, and there is evidence for its heritability, stability and reliability in humans. PPI has gained increasing use as an endophenotype to identify vulnerability genes for brain disorders, including schizophrenia. Genetic studies now often employ multiple, geographically dispersed test sites to accommodate the need for large and complex study samples. Here, we assessed the feasibility of using PPI in multi-site studies. METHODS: Within a 7-site investigation with multiple measures, the Consortium on the Genetics of Schizophrenia conducted a methodological study of acoustic startle and PPI in CCS. Methods were manualized, videotaped and standardized across sites with intensive in-person training sessions. Equipment was acquired and programmed at the "PPI site" (UCSD), and stringent quality assurance (QA) procedures were used. Testing was completed on 196 CCS over 2.5 years, with 5 primary startle dependent measures: eyeblink startle magnitude, habituation, peak latency, latency facilitation and PPI. RESULTS: Analyses identified significant variability across sites in some but not all primary measures, and determined factors both within the testing process and subject characteristics that influenced a number of test measures. QA procedures also identified non-standardized practices with respect to testing methods and procedural "drift", which may be particularly relevant to multi-site studies using these measures. CONCLUSION: With thorough oversight and QA procedures, measures of acoustic startle PPI can be acquired reliably across multiple testing sites. Nonetheless, even among sites with substantial expertise in utilizing psychophysiological measures, multi-site studies using startle and PPI as dependent measures require careful attention to methodological procedures.

Startle gating deficits in a large cohort of patients with schizophrenia: relationship to medications, symptoms, neurocognition, and level of function.

CONTEXT: Patients with schizophrenia exhibit deficits in automatic, preattentive sensorimotor gating (prepulse inhibition [PPI]) of the startle reflex. OBJECTIVE: To assess the relationships between PPI deficits and demographic, clinical, neurocognitive, and functional status in a large cohort of patients with schizophrenia. DESIGN: Cross-sectional comparison of patients with schizophrenia and normal comparison subjects. SETTING: University-based psychophysiology laboratory. PARTICIPANTS: Carefully screened patients with schizophrenia (n = 103) and normal comparison subjects (n = 66). MAIN OUTCOME MEASURES: Participants were assessed in structured clinical interviews and tested in measures of acoustic startle PPI and neurocognition. The level of functioning was assessed in patients using validated scales. Analyses first compared all of the patients vs normal comparison subjects. Patients were then divided based on sex, medications, smoking status, and levels of PPI. The associations of PPI to clinical, neurocognitive, and functional variables were assessed using both continuous and categorical analyses. RESULTS: Compared with normal comparison subjects, patients exhibited PPI deficits at 60-millisecond intervals but not at 30- or 120-millisecond intervals. In addition, patients exhibited deficits in neurocognition. Among patients, PPI levels were associated with sex (higher in men than in women), medication status (highest in patients treated with atypical antipsychotics), and smoking (higher in smokers than in nonsmokers). Compared with patients in the highest quartile of PPI, those in the lowest quartile of PPI were significantly more impaired on specific functional measures but did not differ in neurocognitive measures or symptom severity. The relationship between low PPI and functional impairment was most pronounced and orderly in male patients. CONCLUSIONS: These findings highlight several important factors (sex, medications, and smoking status) that strongly impact the study and interpretation of PPI deficits in patient populations. These results also support the concept that deficient PPI is associated with impaired functional status in schizophrenia.

Gamma band oscillations reveal neural network cortical coherence dysfunction in schizophrenia patients.

BACKGROUND: Gamma band activity has been associated with many sensory and cognitive functions, and is important for cortico-cortical transmission and the integration of information across neural networks. The aims of the present study were to determine if schizophrenia patients have deficits in the generation and maintenance of coherent, synchronized oscillations in response to steady-state stimulation, and to examine the clinical and cognitive correlates of the electroencephalography (EEG) oscillatory dynamics. METHODS: Schizophrenia patients (n = 100) and nonpsychiatric subjects (n = 80) underwent auditory steady-state event-related potential testing. Click trains varying in rate of stimulation (20, 30, and 40 Hz) were presented; EEG-evoked power and intertrial phase synchronization were obtained in response to each stimulation frequency. Subjects also underwent clinical and neurocognitive assessments. RESULTS: Patients had reductions in both evoked power and phase synchronization in response to 30- and 40-Hz stimulation but normal responsivity to 20-Hz stimulation. Maximal deficits were detected in response to 40-Hz stimulation. A modest association of reduced working memory performance and 40-Hz intertrial phase synchronization was present in schizophrenia patients (r = .32, p <.01). CONCLUSIONS: Schizophrenia patients have frequency-specific deficits in the generation and maintenance of coherent gamma-range oscillations, reflecting a fundamental degradation of basic integrated neural network activity.

Prepulse-elicited motor reactions do not differ between schizophrenia patients and control subjects.

Electromyographic (EMG) measures were made of the eyeblink response to stimuli 2-16 dB over a 70-dBA noise background as well as the eyeblink response to startling 115-dBA pulses in 15 schizophrenia patients and 10 control subjects. In patients and in control subjects, weak stimuli did not elicit EMG activation. Startling stimuli elicited robust EMG activation in both groups. Compared with control subjects, schizophrenia patients are not more sensitive to motor-activating effects of weak acoustic stimuli that served as prepulses in published reports of prepulse inhibition deficits in schizophrenia. Thus, differential sensitivity to the motor-activating effects of prepulses should not contribute to reduced prepulse inhibition in schizophrenia patients versus control subjects.

Female schizophrenia patients have prepulse inhibition deficits.

BACKGROUND: Prepulse inhibition (PPI) of startle shows sexual dimorphism: women have lower levels of PPI than do men, and have menstrual cycle shifts in PPI. Many studies report PPI deficits in male schizophrenia patients; one recent report identified PPI deficits in male but not female patients. This study was designed to determine whether female schizophrenia patients have lower levels of PPI than normal females. METHODS: Twenty-five female schizophrenia patients, and 26 normal females were tested in a startle paradigm using 115 dB startle pulses and prepulses of 8 and 16 dB above a 70 dB background, with 30 and 120 msec prepulse intervals. RESULTS: Female patients had significantly less PPI compared with normal females, particularly when 16 dB prepulses were utilized. Patients also exhibited a nonsignificant trend towards lower levels of habituation compared to normal subjects. CONCLUSIONS: Under the present paradigmatic and subject acquisition conditions, female schizophrenia patients had PPI deficits compared to normal females.