Lauren E. Ethridge

Identification of Distinct Psychosis Biotypes Using Brain-Based Biomarkers

OBJECTIVE Clinical phenomenology remains the primary means for classifying psychoses despite considerable evidence that this method incompletely captures biologically meaningful differentiations. Rather than relying on clinical diagnoses as the gold standard, this project drew on neurobiological heterogeneity among psychosis cases to delineate subgroups independent of their phenomenological manifestations. METHOD A large biomarker panel (neuropsychological, stop signal, saccadic control, and auditory stimulation paradigms) characterizing diverse aspects of brain function was collected on individuals with schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis (N=711), their first-degree relatives (N=883), and demographically comparable healthy subjects (N=278). Biomarker variance across paradigms was exploited to create nine integrated variables that were used to capture neurobiological variance among the psychosis cases. Data on external validating measures (social functioning, structural magnetic resonance imaging, family biomarkers, and clinical information) were collected. RESULTS Multivariate taxometric analyses identified three neurobiologically distinct psychosis biotypes that did not respect clinical diagnosis boundaries. The same analysis procedure using clinical DSM diagnoses as the criteria was best described by a single severity continuum (schizophrenia worse than schizoaffective disorder worse than bipolar psychosis); this was not the case for biotypes. The external validating measures supported the distinctiveness of these subgroups compared with clinical diagnosis, highlighting a possible advantage of neurobiological versus clinical categorization schemes for differentiating psychotic disorders. CONCLUSIONS These data illustrate how multiple pathways may lead to clinically similar psychosis manifestations, and they provide explanations for the marked heterogeneity observed across laboratories on the same biomarker variables when DSM diagnoses are used as the gold standard.

Resting state EEG abnormalities in autism spectrum disorders

Autism spectrum disorders (ASD) are a group of complex and heterogeneous developmental disorders involving multiple neural system dysfunctions. In an effort to understand neurophysiological substrates, identify etiopathophysiologically distinct subgroups of patients, and track outcomes of novel treatments with translational biomarkers, EEG (electroencephalography) studies offer a promising research strategy in ASD. Resting-state EEG studies of ASD suggest a U-shaped profile of electrophysiological power alterations, with excessive power in low-frequency and high-frequency bands, abnormal functional connectivity, and enhanced power in the left hemisphere of the brain. In this review, we provide a summary of recent findings, discuss limitations in available research that may contribute to inconsistencies in the literature, and offer suggestions for future research in this area for advancing the understanding of ASD.

Neural activations during auditory oddball processing discriminating schizophrenia and psychotic bipolar disorder.

BACKGROUND Reduced amplitude of the P300 event-related potential in auditory oddball tasks may characterize schizophrenia (SZ) but is also reported in bipolar disorder. Similarity of auditory processing abnormalities between these diagnoses is uncertain, given the frequent combination of both psychotic and nonpsychotic patients in bipolar samples; abnormalities may be restricted to psychosis. In addition, typically only latency and amplitude of brain responses at selected sensors and singular time points are used to characterize neural responses. Comprehensive quantification of brain activations involving both spatiotemporal and time-frequency analyses could better identify unique auditory oddball responses among patients with different psychotic disorders. METHODS Sixty SZ, 60 bipolar I with psychosis (BPP), and 60 healthy subjects (H) were compared on neural responses during an auditory oddball task using multisensor electroencephalography. Principal components analysis was used to reduce multisensor data before evaluating group differences on voltage and frequency of neural responses over time. RESULTS Linear discriminant analysis revealed five variables that best differentiated groups: 1) late beta activity to standard stimuli; 2) late beta/gamma activity to targets discriminated BPP from other groups; 3) midlatency theta/alpha activity to standards; 4) target-related voltage at the late N2 response discriminated both psychosis groups from H; and 5) target-related voltage during early N2 discriminated BPP from H. CONCLUSIONS Although the P300 significantly differentiated psychotic groups from H, it did not uniquely discriminate groups beyond the above variables. No variable uniquely discriminated SZ, perhaps indicating utility of this task for studying psychosis-associated neurophysiology generally and BPP specifically.

Preparatory Activations across a Distributed Cortical Network Determine Production of Express Saccades in Humans

Reaction time variability across trials to identical stimuli may arise from both ongoing and transient neural processes occurring before trial onset. These processes were examined with dense-array EEG as humans completed saccades in a “gap” paradigm known to elicit bimodal variability in response times, including separate populations of “express” and regular reaction time saccades. Results indicated that express reaction time trials could be differentiated from regular reaction time trials by (1) pretrial phase synchrony of occipital cortex oscillations in the 8–9 Hz (low alpha) frequency range (lower phase synchrony preceding express trials), (2) subsequent mid- and late-gap period cortical activities across a distributed occipital-parietal network (stronger activations preceding express trials), and (3) posttarget parietal activations locked to response generation (weaker preceding express trials). A post hoc path analysis suggested that the observed cortical activations leading to express saccades are best understood as an interdependent chain of events that affect express saccade production. These results highlight the importance of a distributed posterior cortical network, particularly in right hemisphere, that prepares the saccade system for rapid responding.

Spatiotemporal and frequency domain analysis of auditory paired stimuli processing in schizophrenia and bipolar disorder with psychosis

Individuals with schizophrenia (SZ) or bipolar disorder with psychosis (BPP) may share neurophysiological abnormalities as measured in auditory paired-stimuli paradigms with electroencephalography (EEG). Such investigations have been limited, however, by quantifying only event-related potential peaks and/or broad frequency bands at limited scalp locations without considering possible mediating factors (e.g., baseline differences). Results from 64-sensor EEG collected in 180 age- and gender-matched participants reveal (i) accentuated prestimulus gamma oscillations and (ii) reduced P2 amplitudes and theta/alpha oscillations to S1 among participants with both SZ and BPP. Conversely, (iii) N1s in those with SZ to S1 were reduced compared to healthy volunteers and those with BPP, whereas (iv) beta range oscillations 200-300 ms following S2 were accentuated in those with BPP but not those with SZ. Results reveal a pattern of both unique and shared neurophysiological phenotypes occurring within major psychotic diagnoses.

Event-Related Potential and Time-Frequency Endophenotypes for Schizophrenia and Psychotic Bipolar Disorder

BACKGROUND The investigators compared event-related potential (ERP) amplitudes and event-related oscillations across a broad frequency range during an auditory oddball task using a comprehensive analysis approach to describe shared and unique neural auditory processing characteristics among healthy subjects (HP), schizophrenia probands (SZ) and their first-degree relatives, and bipolar disorder I with psychosis probands (BDP) and their first-degree relatives. METHODS This Bipolar-Schizophrenia Network on Intermediate Phenotypes sample consisted of clinically stable SZ (n = 229) and BDP (n = 188), HP (n = 284), first-degree relatives of schizophrenia probands (n = 264), and first-degree relatives of bipolar disorder I with psychosis probands (n = 239). They were administered an auditory oddball task in the electroencephalography environment. Principal components analysis derived data-driven frequency bands evoked power. Spatial principal components analysis reduced ERP and frequency data to component waveforms for each subject. Clusters of time bins with significant group differences on response magnitude were assessed for proband/relative differences from HP and familiality. RESULTS Nine variables survived a linear discriminant analysis between HP, SZ, and BDP. Of those, two showed evidence (deficit in relatives and familiality) as genetic risk markers more specific to SZ (N1, P3b), one was specific to BDP (P2) and one for psychosis in general (N2). CONCLUSIONS This study supports for both shared and unique deficits in early sensory and late cognitive processing across psychotic diagnostic groups. Additional ERP and time-frequency component alterations (frontal N2/P2, late high, early, mid, and low frequency) may provide insight into deficits in underlying neural architecture and potential protective/compensatory mechanisms in unaffected relatives.

Behavioral response inhibition in psychotic disorders: Diagnostic specificity, familiality and relation to generalized cognitive deficit

Difficulty inhibiting context-inappropriate behavior is a common deficit in psychotic disorders. The diagnostic specificity of this impairment, its familiality, and its degree of independence from the generalized cognitive deficit associated with psychotic disorders remain to be clarified. Schizophrenia, schizoaffective and bipolar patients with history of psychosis (n=523), their available first-degree biological relatives (n=656), and healthy participants (n=223) from the multi-site B-SNIP study completed a manual Stop Signal task. A nonlinear mixed model was used to fit logistic curves to success rates on Stop trials as a function of parametrically varied Stop Signal Delay. While schizophrenia patients had greater generalized cognitive deficit than bipolar patients, their deficits were similar on the Stop Signal task. Further, only bipolar patients showed impaired inhibitory control relative to healthy individuals after controlling for generalized cognitive deficit. Deficits accounted for by the generalized deficit were seen in relatives of schizophrenia and schizoaffective patients, but not in relatives of bipolar patients. In clinically stable patients with psychotic bipolar disorder, impaired inhibitory behavioral control was a specific cognitive impairment, distinct from the generalized neuropsychological impairment associated with psychotic disorders. Thus, in bipolar disorder with psychosis, a deficit in inhibitory control may contribute to risk for impulsive behavior. Because the deficit was not familial in bipolar families and showed a lack of independence from the generalized cognitive deficit in schizophrenia spectrum disorders, it appears to be a trait related to illness processes rather than one tracking familial risk factors.

Neural correlates of attentional and mnemonic processing in event-based prospective memory.

Prospective memory (PM), or memory for realizing delayed intentions, was examined with an event-based paradigm while simultaneously measuring neural activity with high-density EEG recordings. Specifically, the neural substrates of monitoring for an event-based cue were examined, as well as those perhaps associated with the cognitive processes supporting detection of cues and fulfillment of intentions. Participants engaged in a baseline lexical decision task (LDT), followed by a LDT with an embedded PM component. Event-based cues were constituted by color and lexicality (red words). Behavioral data provided evidence that monitoring, or preparatory attentional processes, were used to detect cues. Analysis of the event-related potentials (ERP) revealed visual attentional modulations at 140 and 220 ms post-stimulus associated with preparatory attentional processes. In addition, ERP components at 220, 350, and 400 ms post-stimulus were enhanced for intention-related items. Our results suggest preparatory attention may operate by selectively modulating processing of features related to a previously formed event-based intention, as well as provide further evidence for the proposal that dissociable component processes support the fulfillment of delayed intentions.

Reduced habituation of auditory evoked potentials indicate cortical hyper-excitability in Fragile X Syndrome

Sensory hypersensitivities are common, clinically distressing features of Fragile X Syndrome (FXS). Preclinical evidence suggests this abnormality may result from synaptic hyper-excitability in sensory systems. This model predicts reduced sensory habituation to repeated stimulus presentation. Fourteen adolescents and adults with FXS and 15 age-matched controls participated in a modified auditory gating task using trains of 4 identical tones during dense array electroencephalography (EEG). Event-related potential and single trial time–frequency analyses revealed decreased habituation of the N1 event-related potential response in FXS, and increased gamma power coupled with decreases in gamma phase-locking during the early-stimulus registration period. EEG abnormalities in FXS were associated with parent reports of heightened sensory sensitivities and social communication deficits. Reduced habituation and altered gamma power and phase-locking to auditory cues demonstrated here in FXS patients parallels preclinical findings with Fmr1 KO mice. Thus, the EEG abnormalities seen in FXS patients support the model of neocortical hyper-excitability in FXS, and may provide useful translational biomarkers for evaluating novel treatment strategies targeting its neural substrate.

A resting EEG study of neocortical hyperexcitability and altered functional connectivity in fragile X syndrome

BackgroundCortical hyperexcitability due to abnormal fast-spiking inhibitory interneuron function has been documented in fmr1 KO mice, a mouse model of the fragile X syndrome which is the most common single gene cause of autism and intellectual disability.MethodsWe collected resting state dense-array electroencephalography data from 21 fragile X syndrome (FXS) patients and 21 age-matched healthy participants.ResultsFXS patients exhibited greater gamma frequency band power, which was correlated with social and sensory processing difficulties. Second, FXS patients showed increased spatial spreading of phase-synchronized high frequency neural activity in the gamma band. Third, we observed increased negative theta-to-gamma but decreased alpha-to-gamma band amplitude coupling, and the level of increased theta power was inversely related to the level of resting gamma power in FXS.ConclusionsIncreased theta band power and coupling from frontal sources may represent a mechanism providing compensatory inhibition of high-frequency gamma band activity, potentially contributing to the widely varying level of neurophysiological and behavioral abnormalities and treatment response seen in full-mutation FXS patients. These findings extend preclinical observations and provide new mechanistic insights into brain alterations and their variability across FXS patients. Electrophysiological measures may provide useful translational biomarkers for advancing drug development and individualizing treatments for neurodevelopmental disorders with associated neuronal hyperexcitability.