Jordan P. Hamm

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.

Abnormalities of Neuronal Oscillations and Temporal Integration to Low- and High-Frequency Auditory Stimulation in Schizophrenia

BACKGROUND Electroencephalography and magnetoencephalography studies indicate among schizophrenia patients (SZ) abnormal, often reduced, entrained steady-state (aSSR) and transient (N100/M100) neural responses to auditory stimuli. We complement this literature by focusing analyses on auditory cortices, assessing a wide range of stimulation frequencies with long driving periods and evaluating relationships between aSSR and M100 reductions in SZ. METHODS Seventeen SZ and 17 healthy subjects (H) participated. Stimuli were 1500 msec binaural broadband noise sequences modulated at 5, 20, 40, 80, or 160 Hz. Magnetoencephalography data were collected and co-registered with structural magnetic resonance images. The aSSRs and M100s projected into brain space were analyzed as a function of hemisphere, stimulus density, and time. RESULTS For aSSR, SZ displayed weaker entrainment bilaterally at low (5-Hz) and high (80-Hz) modulation frequencies. To 40-Hz stimuli, SZ showed weaker entrainment only in right auditory cortex. For M100, while responses for H increased linearly with stimulus density, this effect was weaker or absent in SZ. A principal components analysis of SZ deficits identified low (5-Hz entrainment and M100) and high (40- to 80-Hz entrainment) frequency components. Discriminant analysis indicated that the low-frequency component uniquely differentiated SZ from H. The high-frequency component correlated with negative symptoms among SZ. CONCLUSIONS The SZ auditory cortices were unable to 1) generate healthy levels of theta and high gamma band (80-Hz) entrainment (aSSR), and 2) augment transient responses (M100s) to rapidly presented auditory information (an index of temporal integration). Only the latter was most apparent in left hemisphere and may reflect a prominent neurophysiological deficit in schizophrenia.

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.

Augmented gamma band auditory steady-state responses: Support for NMDA hypofunction in schizophrenia

Individuals with schizophrenia (SZ) have deviations in auditory perception perhaps attributable to altered neural oscillatory response properties in thalamo-cortical and/or local cortico-cortical circuits. Previous EEG studies of auditory steady-state responses (aSSRs; a measure of sustained neuronal entrainment to repetitive stimulation) in SZ have indicated attenuated gamma range (≈40 Hz) neural entrainment. Stimuli in most such studies have been relatively brief (500-1000 ms) trains of 1 ms clicks or amplitude modulated pure tones (1000 Hz) with short, fixed interstimulus intervals (200-1000 ms). The current study used extended (1500 ms), more aurally dense broadband stimuli (500-4000 Hz noise; previously demonstrated to elicit larger aSSRs) with longer, variable interstimulus intervals (2700-3300 ms). Dense array EEG (256 sensor) was collected while 17 SZ and 16 healthy subjects passively listed to stimuli modulated at 15 different frequencies spanning beta and gamma ranges (16-44 Hz in 2 Hz steps). Results indicate that SZ have augmented aSSRs that were most extreme in the gamma range. Results also constructively replicate previous findings of attenuated low frequency auditory evoked responses (2-8 Hz) in SZ. These findings (i) highlight differential characteristics of low versus high frequency and induced versus entrained oscillatory auditory responses in both SZ and healthy stimulus processing, (ii) provide support for an NMDA-receptor hypofunction-based pharmacological model of SZ, and (iii) report a novel pattern of aSSR abnormalities suggesting that gamma band neural entrainment deviations among SZ may be more complex than previously supposed, including possibly being substantially influenced by physical stimulus properties.

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.

Smooth Pursuit Eye Movement, Prepulse Inhibition, and Auditory Paired Stimuli Processing Endophenotypes Across the Schizophrenia-Bipolar Disorder Psychosis Dimension

BACKGROUND This study examined smooth pursuit eye movement (SPEM), prepulse inhibition (PPI), and auditory event-related potentials (ERP) to paired stimuli as putative endophenotypes of psychosis across the schizophrenia-bipolar disorder dimension. METHODS Sixty-four schizophrenia probands (SZP), 40 psychotic bipolar I disorder probands (BDP), 31 relatives of SZP (SZR), 26 relatives of BDP (BDR), and 53 healthy controls (HC) were tested. Standard clinical characterization, SPEM, PPI, and ERP measures were administered. RESULTS There were no differences between either SZP and BDP or SZR and BDR on any of the SPEM, PPI, or ERP measure. Compared with HC, SZP and BDP had lower SPEM maintenance and predictive pursuit gain and ERP theta/alpha and beta magnitudes to the initial stimulus. PPI did not differ between the psychosis probands and HC. Compared with HC, SZR and BDR had lower predictive pursuit gain and ERP theta/alpha and beta magnitudes to the first stimulus with differences ranging from a significant to a trend level. Neither active symptoms severity nor concomitant medications were associated with neurophysiological outcomes. SPEM, PPI, and ERP scores had low intercorrelations. CONCLUSION These findings support SPEM predictive pursuit and lower frequency auditory ERP activity in a paired stimuli paradigm as putative endophenotypes of psychosis common to SZ and BD probands and relatives. PPI did not differ between the psychosis probands and HC. Future studies in larger scale psychosis family samples targeting putative psychosis endophenotypes and underlying molecular and genetic mediators may aid in the development of biology-based diagnostic definitions.

Pre-Cue Fronto-Occipital Alpha Phase and Distributed Cortical Oscillations Predict Failures of Cognitive Control

Cognitive control is required for correct performance on antisaccade tasks, including the ability to inhibit an externally driven ocular motor response (a saccade to a peripheral stimulus) in favor of an internally driven ocular motor goal (a saccade directed away from a peripheral stimulus). Healthy humans occasionally produce errors during antisaccade tasks, but the mechanisms associated with such failures of cognitive control are uncertain. Most research on cognitive control failures focuses on poststimulus processing, although a growing body of literature highlights a role of intrinsic brain activity in perceptual and cognitive performance. The current investigation used dense array electroencephalography and distributed source analyses to examine brain oscillations across a wide frequency bandwidth in the period before antisaccade cue onset. Results highlight four important aspects of ongoing and preparatory brain activations that differentiate error from correct antisaccade trials: (1) ongoing oscillatory beta (20–30 Hz) power in anterior cingulate before trial initiation (lower for error trials); (2) instantaneous phase of ongoing alpha/theta (7 Hz) in frontal and occipital cortices immediately before trial initiation (opposite between trial types); (3) gamma power (35–60 Hz) in posterior parietal cortex 100 ms before cue onset (greater for error trials); and (4) phase locking of alpha (5–12 Hz) in parietal and occipital cortices immediately before cue onset (lower for error trials). These findings extend recently reported effects of pre-trial alpha phase on perception to cognitive control processes and help identify the cortical generators of such phase effects.

Stimulus train duration but not attention moderates γ-band entrainment abnormalities in schizophrenia.

Electroencephalographic (EEG) studies of auditory steady-state responses (aSSRs) non-invasively probe gamma-band (40-Hz) oscillatory capacity in sensory cortex with high signal-to-noise ratio. Consistent reports of reduced 40-Hz aSSRs in persons with schizophrenia (SZ) indicate its potential as an efficient biomarker for the disease, but studies have been limited to passive or indirect listening contexts with stereotypically short (500ms) stimulus trains. An inability to modulate sensorineural processing in accord with behavioral goals or within the sensory environmental context may represent a fundamental deficit in SZ, but whether and how this deficit relates to reduced aSSRs is unknown. We systematically varied stimulus duration and attentional contexts to further mature the 40-Hz aSSR as biomarker for future translational or mechanistic studies. Eighteen SZ and 18 healthy subjects (H) were presented binaural pure-tones with or without sinusoidal amplitude modulation at 40-Hz. Stimulus duration (500-ms or 1500-ms) and attention (via a button press task) were varied across 4 separate blocks. Evoked potentials recorded with dense-array EEGs were analyzed in the time-frequency domain. SZ displayed reduced 40-Hz aSSRs to typical stimulation parameters, replicating previous findings. In H, aSSRs were reduced when stimuli were presented in longer trains and were slightly enhanced by attention. Only the former modulation was impaired in SZ and correlated with sensory discrimination performance. Thus, gamma-band aSSRs are modulated by both attentional and stimulus duration contexts, but only modulations related to physical stimulus properties are abnormal in SZ, supporting its status as a biomarker of psychotic perceptual disturbance involving non-attentional sensori-cortical circuits.