Joyce Sprock

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.

Positive symptoms of psychosis in posttraumatic stress disorder

The possible presence of hallucinations and delusional thoughts in posttraumatic stress disorder (PTSD) was investigated. Other symptom clusters were also assessed in order to further clarify the nature of PTSD. Twenty combat veterans with PTSD were compared to 18 combat veterans without PTSD on symptom rating scales. The subjects with PTSD exhibited a greater degree of depression, anxiety, agitation, anhedonia, and positive symptoms of psychosis than the comparison group. Specifically, the PTSD group manifested increased hallucinations, delusions, and bizarre behavior. Some of these positive symptoms did not appear to be due to reexperiencing of the trauma. The groups were not significantly different on indices of mania, thought disorder, or inertia. The clinical and diagnostic implications of the results are discussed. A diagnosis of PTSD should be considered with patients who have positive symptoms in the absence of thought disorder.

Characterization of neurophysiologic and neurocognitive biomarkers for use in genomic and clinical outcome studies of schizophrenia

Background Endophenotypes are quantitative, laboratory-based measures representing intermediate links in the pathways between genetic variation and the clinical expression of a disorder. Ideal endophenotypes exhibit deficits in patients, are stable over time and across shifts in psychopathology, and are suitable for repeat testing. Unfortunately, many leading candidate endophenotypes in schizophrenia have not been fully characterized simultaneously in large cohorts of patients and controls across these properties. The objectives of this study were to characterize the extent to which widely-used neurophysiological and neurocognitive endophenotypes are: 1) associated with schizophrenia, 2) stable over time, independent of state-related changes, and 3) free of potential practice/maturation or differential attrition effects in schizophrenia patients (SZ) and nonpsychiatric comparison subjects (NCS). Stability of clinical and functional measures was also assessed. Methods Participants (SZ n = 341; NCS n = 205) completed a battery of neurophysiological (MMN, P3a, P50 and N100 indices, PPI, startle habituation, antisaccade), neurocognitive (WRAT-3 Reading, LNS-forward, LNS-reorder, WCST-64, CVLT-II). In addition, patients were rated on clinical symptom severity as well as functional capacity and status measures (GAF, UPSA, SOF). 223 subjects (SZ n = 163; NCS n = 58) returned for retesting after 1 year. Results Most neurophysiological and neurocognitive measures exhibited medium-to-large deficits in schizophrenia, moderate-to-substantial stability across the retest interval, and were independent of fluctuations in clinical status. Clinical symptoms and functional measures also exhibited substantial stability. A Longitudinal Endophenotype Ranking System (LERS) was created to rank neurophysiological and neurocognitive biomarkers according to their effect sizes across endophenotype criteria. Conclusions The majority of neurophysiological and neurocognitive measures exhibited deficits in patients, stability over a 1-year interval and did not demonstrate practice or time effects supporting their use as endophenotypes in neural substrate and genomic studies. These measures hold promise for informing the “gene-to-phene gap” in schizophrenia research.

Information processing deficits of schizophrenia patients: relationship to clinical ratings, gender and medication status

Information processing deficits were explored in a large cohort of schizophrenia patients (N = 125) and non-psychiatric subjects (N = 52). Gender, medication status and symptom factors were assessed relative to measures of performance in critical stimulus duration (CSD), visual backward masking (VBM) and auditory reaction time (RT) paradigms. Schizophrenia patients exhibited significant impairments in measures of CSD, VBM and both RT speed and RT set. Females in both groups had inflated CSDs relative to males. Female schizophrenia patients showed slower RTs and elevated RT set scores, but comparable VBM performance, when compared to males. This gender difference was not observed in the non-psychiatric subjects. To test the hypothesis that impaired performance in the VBM and RT paradigms would be related to negative symptoms and thought disorder, regression analyses were performed using factor scores derived from a factor analysis of SANS and SAPS items that generated three symptom factors: negative, disorganized, and reality distortion. Significant variance in performance on VBM and RT measures was accounted for only by the negative symptom factor. We conclude that VBM and RT assess information processing deficits in schizophrenia patients that are more related to the negative versus positive or disorganized symptoms of schizophrenia. It is possible that VBM and RT share overlapping or interacting neural substrates.

Sex differences in sensorimotor gating of the human startle reflex: all smoke?

Abstract Rationale: A recent report described sex differences in the effects of nicotine use and withdrawal on prepulse inhibition of acoustic startle (PPI), but no sex differences in PPI in non-smokers. Objective: To determine whether previously reported male>female acoustic PPI reflect sex differences in smoking effects on PPI, rather than simple sex differences in the regulation of PPI. A retrospective analyses of >600 carefully screened normals tested over the past 12 years was completed. Results: Male>female acoustic PPI was detected in analyses that included: 1) all subjects; or 2) self-declared non-smokers. Conclusions: Sex differences in PPI cannot be accounted for by smoking history, because they are present across a large sample of non-smoking normal controls.

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.

Neural substrates of normal and impaired preattentive sensory discrimination in large cohorts of nonpsychiatric subjects and schizophrenia patients as indexed by MMN and P3a change detection responses

OBJECTIVE Schizophrenia (SZ) patients have information processing deficits, spanning from low level sensory processing to higher-order cognitive functions. Mismatch negativity (MMN) and P3a are event-related potential (ERP) components that are automatically elicited in response to unattended changes in ongoing, repetitive stimuli that provide a window into abnormal information processing in SZ. MMN and P3a are among the most robust and consistently identified deficits in SZ, yet the neural substrates of these responses and their associated deficits in SZ are not fully understood. This study examined the neural sources of MMN and P3a components in a large cohort of SZ and nonpsychiatric control subjects (NCS) using Exact Low Resolution Electromagnetic Tomography Analyses (eLORETA) in order to identify the neural sources of MMN and P3a as well as the brain regions associated with deficits commonly observed among SZ patients. METHODS 410 SZ and 247 NCS underwent EEG testing using a duration-deviant auditory oddball paradigm (1-kHz tones, 500ms SOA; standard p=0.90, 50-ms duration; deviant tones P=0.10, 100-ms duration) while passively watching a silent video. Voxel-by-voxel within- (MMN vs. P3a) and between-group (SZ vs. NCS) comparisons were performed using eLORETA. RESULTS SZ had robust deficits in MMN and P3a responses measured at scalp electrodes consistent with other studies. These components mapped onto neural sources broadly distributed across temporal, frontal, and parietal regions. MMN deficits in SZ were associated with reduced activations in discrete medial frontal brain regions, including the anterior-posterior cingulate and medial frontal gyri. These early sensory discriminatory MMN impairments were followed by P3a deficits associated with widespread reductions in the activation of attentional networks (frontal, temporal, parietal regions), reflecting impaired orienting or shifts of attention to the infrequent stimuli. CONCLUSIONS MMN and P3a are dissociable responses associated with broadly distributed patterns of neural activation. MMN deficits among SZ patients appear to be primarily accounted for by reductions in medial prefrontal brain regions that are followed by widespread dysfunction across cortical networks associated with P3a in a manner that is consistent with hierarchical information processing models of cognitive deficits in SZ patients. Impairments in automatic stimulus discrimination may contribute to higher-order cognitive and psychosocial deficits in SZ.

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.

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. Curr. Protoc. Neurosci. 52:6.25.1‐6.25.24.

Disentangling Early Sensory Information Processing Deficits in Schizophrenia

OBJECTIVE The disentangling of early sensory information processing deficits and examination of their relationships to demographic and clinical factors are important steps for the validation of potential biomarkers and/or endophenotypes of schizophrenia. The aims of the present study were to characterize commonly used sensory event-related potential deficits, to determine whether they are (1) distinct from one another and (2) independently associated with important clinical characteristics. METHODS MMN, P3a and RON event-related potentials (ERP) were recorded from schizophrenia patients (SZ; n=429) and nonpsychiatric comparison subjects (NCS; n=286). Subgroup analyses on demographic and clinical variables were performed. RESULTS Schizophrenia patients exhibited robust ERP deficits at frontocentral electrodes (MMN: d=1.10; P3a: d=0.87; RON: d=0.77), consistent with previous studies. Each ERP component uniquely accounted for variance in amplitude and schizophrenia deficits. Amplitude reductions occurred with increasing age in both NCS and SZ patients. A small subset of patients prescribed combinations of 1st and 2nd generation antipsychotics exhibited significantly reduced MMN amplitude relative to other medication-defined subgroups. CONCLUSIONS MMN, P3a, and RON are dissociable deficits with distinct relationships to age and medication status in schizophrenia patients, potentially reflecting divergent pathophysiological processes. Reduced MMN in patients taking multiple antipsychotic medications appear to be attributable to greater severity of symptoms and functional impairments, rather than a medication effect. SIGNIFICANCE Independent information processing deficits in schizophrenia patients may differentially contribute to the commonly observed deficits in neurocognitive and psychosocial functioning.