Kevin M. Spencer

Neurophysiological biomarkers for drug development in schizophrenia

Schizophrenia represents a pervasive deficit in brain function, leading to hallucinations and delusions, social withdrawal and a decline in cognitive performance. As the underlying genetic and neuronal abnormalities in schizophrenia are largely unknown, it is challenging to measure the severity of its symptoms objectively, or to design and evaluate psychotherapeutic interventions. Recent advances in neurophysiological techniques provide new opportunities to measure abnormal brain functions in patients with schizophrenia and to compare these with drug-induced alterations. Moreover, many of these neurophysiological processes are phylogenetically conserved and can be modelled in preclinical studies, offering unique opportunities for use as translational biomarkers in schizophrenia drug discovery.

Localization of the event-related potential novelty response as defined by principal components analysis

Recent research indicates that novel stimuli elicit at least two distinct components, the Novelty P3 and the P300. The P300 is thought to be elicited when a context updating mechanism is activated by a wide class of deviant events. The functional significance of the Novelty P3 is uncertain. Identification of the generator sources of the two components could provide additional information about their functional significance. Previous localization efforts have yielded conflicting results. The present report demonstrates that the use of principal components analysis (PCA) results in better convergence with knowledge about functional neuroanatomy than did previous localization efforts. The results are also more convincing than that obtained by two alternative methods, MUSIC-RAP and the Minimum Norm. Source modeling on 129-channel data with BESA and BrainVoyager suggests the P300 has sources in the temporal-parietal junction whereas the Novelty P3 has sources in the anterior cingulate.

γ-Band Auditory Steady-State Responses Are Impaired in First Episode Psychosis

BACKGROUND In chronic schizophrenia and chronic bipolar disorder, gamma band (30-100 Hz) auditory steady-state electroencephalogram responses (ASSRs) are reduced in power and phase locking, likely reflecting neural circuit dysfunction. Here we examined whether gamma ASSR deficits are also present at first hospitalization for psychosis. METHODS Subjects were 16 first episode schizophrenia patients (SZ), 16 first episode affective disorder patients (AFF) (13 with bipolar disorder), and 33 healthy control subjects (HC). Stimuli were 20-, 30-, and 40-Hz binaural click trains. The ASSR phase locking and evoked power were analyzed with the Morlet wavelet transform. RESULTS At 40-Hz stimulation, SZ and AFF had significantly reduced phase locking compared with HC. This deficit was more pronounced over the left hemisphere in SZ. Evoked power at 40 Hz was also reduced in the patients compared with HC. At 30-Hz stimulation phase locking and evoked power were reduced in both patient groups. The 20-Hz ASSR did not differ between groups, but phase locking and evoked power of the 40-Hz harmonic of the 20-Hz ASSR were reduced in both SZ and AFF. Phase locking of this 40-Hz harmonic was correlated with total positive symptoms in SZ. CONCLUSIONS The gamma ASSR deficit is present at first hospitalization for both schizophrenia and affective disorder but shows a left hemisphere bias in first hospitalized SZ. Some of the neural circuitry abnormalities underlying the gamma ASSR deficit might be common to psychoses in general, whereas others might be specific to particular disorders.

Left Auditory Cortex Gamma Synchronization and Auditory Hallucination Symptoms in Schizophrenia

BackgroundOscillatory electroencephalogram (EEG) abnormalities may reflect neural circuit dysfunction in neuropsychiatric disorders. Previously we have found positive correlations between the phase synchronization of beta and gamma oscillations and hallucination symptoms in schizophrenia patients. These findings suggest that the propensity for hallucinations is associated with an increased tendency for neural circuits in sensory cortex to enter states of oscillatory synchrony. Here we tested this hypothesis by examining whether the 40 Hz auditory steady-state response (ASSR) generated in the left primary auditory cortex is positively correlated with auditory hallucination symptoms in schizophrenia. We also examined whether the 40 Hz ASSR deficit in schizophrenia was associated with cross-frequency interactions.Sixteen healthy control subjects (HC) and 18 chronic schizophrenia patients (SZ) listened to 40 Hz binaural click trains. The EEG was recorded from 60 electrodes and average-referenced offline. A 5-dipole model was fit from the HC grand average ASSR, with 2 pairs of superior temporal dipoles and a deep midline dipole. Time-frequency decomposition was performed on the scalp EEG and source data.ResultsPhase locking factor (PLF) and evoked power were reduced in SZ at fronto-central electrodes, replicating prior findings. PLF was reduced in SZ for non-homologous right and left hemisphere sources. Left hemisphere source PLF in SZ was positively correlated with auditory hallucination symptoms, and was modulated by delta phase. Furthermore, the correlations between source evoked power and PLF found in HC was reduced in SZ for the LH sources.ConclusionThese findings suggest that differential neural circuit abnormalities may be present in the left and right auditory cortices in schizophrenia. In addition, they provide further support for the hypothesis that hallucinations are related to cortical hyperexcitability, which is manifested by an increased propensity for high-frequency synchronization in modality-specific cortical areas.

The influence of stimulus deviance and novelty on the P300 and novelty P3.

This study examined the relationship between ERP components elicited by deviant stimuli by disentangling the P300 and Novelty P3 components, using spatiotemporal principal components analysis and a dense electrode array. The three-tone paradigm was used and the pitch attributes of the tones were systematically manipulated so as to map the amplitude of the ERP components on the stimulus context. A comparison was made between the components elicited by events in the three-stimulus, classical oddball, and novelty oddball paradigms. Responses to deviant stimuli consisted of independent and dissociable ERP components in the 400-600-ms time range: A parietal component (P300) that was larger for targets than rare nontargets and was affected by the difficulty of discrimination, a fronto-central component (Novelty P3) that was larger for novel tones and for rare nontargets in the difficult discrimination condition, and an additional anterior negative component responded similarly to all types of deviant stimuli.

Sensory-Evoked Gamma Oscillations in Chronic Schizophrenia

BACKGROUND The early visual-evoked gamma oscillation (VGO) elicited by Gestalt stimuli is reduced in schizophrenia patients compared with healthy individuals, but it is unknown whether this effect is specific to these particular stimuli and task. In contrast, the early auditory-evoked gamma oscillation (AGO) was reported to be unaffected in a sample of unmedicated, mostly first-episode schizophrenics, but it is unknown whether this oscillation is abnormal in chronic, medicated patients. We investigated these issues by examining the VGO and AGO in chronic schizophrenic (SZ) and matched healthy control (HC) subjects. METHODS Subjects (21 HC, 23 SZ) performed visual and auditory oddball tasks. Visual stimuli were letters, and auditory stimuli were simple tones. Event-related spectral measures (phase locking factor and evoked power) were computed on Morlet wavelet-transformed single epochs from the standard trials. RESULTS VGO phase locking at occipital electrodes was reduced in SZ compared with HC. In contrast, AGO phase locking and evoked power did not differ between groups. CONCLUSIONS The VGO deficit may be a general phenomenon in schizophrenia, whereas the AGO evoked by simple tone stimuli does not appear to be abnormal in chronic, medicated schizophrenia patients.

Syntactic parsing preferences and their on-line revisions: a spatio-temporal analysis of event-related brain potentials.

The present study investigates the processes involved in the recovery from temporarily ambiguous garden-path sentences. Event-related brain potentials (ERP) were recorded while subjects read German subject-object ambiguous relative and complement clauses. As both clause types are initially analyzed as subject-first structures, object-first structures require a revision which is more difficult for complement than for relative clauses. The hypothesis is tested that the revision process consists of two sub-processes, namely diagnosis and actual reanalysis. Applying a spatio-temporal principal component analysis to the ERP data, distinct positive sub-components presumably reflecting different sub-processes could be identified in the time range of the P300 and P600. It will be argued that the P600 is not a monolithic component, and that different sub-processes may be involved at varying time points depending on the type of garden-path sentence.

Long-range synchrony of gamma oscillations and auditory hallucination symptoms in schizophrenia

Phase locking in the gamma-band range has been shown to be diminished in patients with schizophrenia. Moreover, there have been reports of positive correlations between phase locking in the gamma-band range and positive symptoms, especially hallucinations. The aim of the present study was to use a new methodological approach in order to investigate gamma-band phase synchronization between the left and right auditory cortex in patients with schizophrenia and its relationship to auditory hallucinations. Subjects were 18 patients with chronic schizophrenia (SZ) and 16 healthy control (HC) subjects. Auditory hallucination symptom scores were obtained using the Scale for the Assessment of Positive Symptoms. Stimuli were 40-Hz binaural click trains. The generators of the 40Hz-ASSR were localized using eLORETA and based on the computed intracranial signals lagged interhemispheric phase locking between primary and secondary auditory cortices was analyzed. Current source density of the 40 ASSR response was significantly diminished in SZ in comparison to HC in the right superior and middle temporal gyrus (p<0.05). Interhemispheric phase locking was reduced in SZ in comparison to HC for the primary auditory cortices (p<0.05) but not in the secondary auditory cortices. A significant positive correlation was found between auditory hallucination symptom scores and phase synchronization between the primary auditory cortices (p<0.05, corrected for multiple testing) but not for the secondary auditory cortices. These results suggest that long-range synchrony of gamma oscillations is disturbed in schizophrenia and that this deficit is related to clinical symptoms such as auditory hallucinations.

A Roadmap for the Development and Validation of Event-Related Potential Biomarkers in Schizophrenia Research

New efforts to develop treatments for cognitive dysfunction in mental illnesses would benefit enormously from biomarkers that provide sensitive and reliable measures of the neural events underlying cognition. Here, we evaluate the promise of event-related potentials (ERPs) as biomarkers of cognitive dysfunction in schizophrenia. We conclude that ERPs have several desirable properties: (1) they provide a direct measure of electrical activity during neurotransmission; (2) their high temporal resolutions make it possible to measure neural synchrony and oscillations; (3) they are relatively inexpensive and convenient to record; (4) animal models are readily available for several ERP components; (5) decades of research has established the sensitivity and reliability of ERP measures in psychiatric illnesses; and 6) feasibility of large N (>500) multisite studies has been demonstrated for key measures. Consequently, ERPs may be useful for identifying endophenotypes and defining treatment targets, for evaluating new compounds in animals and in humans, and for identifying individuals who are good candidates for early interventions or for specific treatments. However, several challenges must be overcome before ERPs gain widespread use as biomarkers in schizophrenia research, and we make several recommendations for the research that is necessary to develop and validate ERP-based biomarkers that can have a real impact on treatment development.

Poststimulus EEG spectral analysis and P300: attention, task, and probability.

Event-related potentials (ERPs) were elicited with auditory stimuli, and spectral analysis was performed on the poststimulus electroencephalographic (EEG) activity to assess how variables that influence the P300 affect spectral parameters of the resultant ERP. In Experiment 1, a no-stimulus condition was compared with a single repeated tone that was either ignored or counted. In Experiment 2, an auditory oddball paradigm was used in which the subject ignored all stimuli, counted only the target, or counted both the target and the standard stimuli in different conditions. In Experiment 3, stimulus probability was manipulated in separate conditions (.20, .50, .80), with the subject required to count the target stimulus. Delta and theta band spectral power increased whenever P300 amplitude increased. However, as the attentional requirements increased across tasks, alpha-1 and alpha-2 power and mean frequency increased. The findings indicate that auditory stimulus processing modulates the EEG more than just by adding ERP components to the epoch.