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Background Dysfunctional reward processing is implicated in multiple mental disorders. Novelty seeking (NS) assesses preference for seeking novel experiences, which is linked to sensitivity to reward environmental cues. Methods A subset of 14-year-old adolescents (IMAGEN) with the top 20% ranked high-NS scores was used to identify high-NS–associated multimodal components by supervised fusion. These features were then used to longitudinally predict five different risk scales for the same and unseen subjects (an independent dataset of subjects at 19 years of age that was not used in predictive modeling training at 14 years of age) (within IMAGEN, n ≈ 1100) and even for the corresponding symptom scores of five types of patient cohorts (non-IMAGEN), including drinking (n = 313), smoking (n = 104), attention-deficit/hyperactivity disorder (n = 320), major depressive disorder (n = 81), and schizophrenia (n = 147), as well as to classify different patient groups with diagnostic labels. Results Multimodal biomarkers, including the prefrontal cortex, striatum, amygdala, and hippocampus, associated with high NS in 14-year-old adolescents were identified. The prediction models built on these features are able to longitudinally predict five different risk scales, including alcohol drinking, smoking, hyperactivity, depression, and psychosis for the same and unseen 19-year-old adolescents and even predict the corresponding symptom scores of five types of patient cohorts. Furthermore, the identified reward-related multimodal features can classify among attention-deficit/hyperactivity disorder, major depressive disorder, and schizophrenia with an accuracy of 87.2%. Conclusions Adolescents with higher NS scores can be used to reveal brain alterations in the reward-related system, implicating potential higher risk for subsequent development of multiple disorders. The identified high-NS–associated multimodal reward-related signatures may serve as a transdiagnostic neuroimaging biomarker to predict disease risks or severity.

Recent theoretical models of schizophrenia posit that dysfunction of the neural mechanisms subserving predictive coding contributes to symptoms and cognitive deficits, and this dysfunction is further posited to result from N-methyl-D-aspartate glutamate receptor (NMDAR) hypofunction. Previously, by examining auditory cortical responses to self-generated speech sounds, we demonstrated that predictive coding during vocalization is disrupted in schizophrenia. To test the hypothesized contribution of NMDAR hypofunction to this disruption, we examined the effects of the NMDAR antagonist, ketamine, on predictive coding during vocalization in healthy volunteers and compared them with the effects of schizophrenia.In two separate studies, the N1 component of the event-related potential elicited by speech sounds during vocalization (talk) and passive playback (listen) were compared to assess the degree of N1 suppression during vocalization, a putative measure of auditory predictive coding. In the crossover study, 31 healthy volunteers completed two randomly ordered test days, a saline day and a ketamine day. Event-related potentials during the talk/listen task were obtained before infusion and during infusion on both days, and N1 amplitudes were compared across days. In the case-control study, N1 amplitudes from 34 schizophrenia patients and 33 healthy control volunteers were compared.N1 suppression to self-produced vocalizations was significantly and similarly diminished by ketamine (Cohen's d = 1.14) and schizophrenia (Cohen's d = .85).Disruption of NMDARs causes dysfunction in predictive coding during vocalization in a manner similar to the dysfunction observed in schizophrenia patients, consistent with the theorized contribution of NMDAR hypofunction to predictive coding deficits in schizophrenia.

Background Drugs that induce psychosis may do so by increasing the level of task-irrelevant random neural activity or neural noise. Increased levels of neural noise have been demonstrated in psychotic disorders. We tested the hypothesis that neural noise could also be involved in the psychotomimetic effects of delta-9-tetrahydrocannabinol (Δ 9 -THC), the principal active constituent of cannabis. Methods Neural noise was indexed by measuring the level of randomness in the electroencephalogram during the prestimulus baseline period of an oddball task using Lempel-Ziv complexity, a nonlinear measure of signal randomness. The acute, dose-related effects of Δ 9 -THC on Lempel-Ziv complexity and signal power were studied in humans ( n = 24) who completed 3 test days during which they received intravenous Δ 9 -THC (placebo, .015 and .03 mg/kg) in a double-blind, randomized, crossover, and counterbalanced design. Results Δ 9 -THC increased neural noise in a dose-related manner. Furthermore, there was a strong positive relationship between neural noise and the psychosis-like positive and disorganization symptoms induced by Δ 9 -THC, which was independent of total signal power. Instead, there was no relationship between noise and negative-like symptoms. In addition, Δ 9 -THC reduced total signal power during both active drug conditions compared with placebo, but no relationship was detected between signal power and psychosis-like symptoms. Conclusions At doses that produced psychosis-like effects, Δ 9 -THC increased neural noise in humans in a dose-dependent manner. Furthermore, increases in neural noise were related with increases in Δ 9 -THC-induced psychosis-like symptoms but not negative-like symptoms. These findings suggest that increases in neural noise may contribute to the psychotomimetic effects of Δ 9 -THC.

Background miR-137 dysregulation has been implicated in the etiology of schizophrenia, but its functional role remains to be determined. Methods Functional magnetic resonance imaging scans were acquired on 48 schizophrenia patients and 63 healthy volunteers (total sample size N = 111 subjects), with similar mean age and sex distribution, while subjects performed a Sternberg Item Response Paradigm with memory loads of one, three, and five numbers. Dorsolateral prefrontal cortex (DLPFC) retrieval activation for the working memory load of three numbers, for which hyperactivation had been shown in schizophrenia patients compared with control subjects, was extracted. The genome-wide association study confirmed schizophrenia risk single nucleotide polymorphism rs1625579 (miR-137 locus) was genotyped (schizophrenia: GG n = 0, GT n = 9, TT n = 39; healthy volunteers: GG=2, GT n = 15, and TT n = 46). Fisher's exact test examined the effect of diagnosis on rs1625579 allele frequency distribution ( p = nonsignificant). Mixed model regression analyses examined the effects of diagnosis and genotype on working memory performance measures and DLPFC activation. Results Patients showed significantly higher left DLPFC retrieval activation on working memory load 3, lower working memory performance, and longer response times compared with controls. There was no effect of genotype on working memory performance or response times in either group. However, individuals with the rs1625579 TT genotype had significantly higher left DLPFC activation than those with the GG/GT genotypes. Conclusions Our study suggests that the rs1625579 TT (miR-137 locus) schizophrenia risk genotype is associated with the schizophrenia risk phenotype DLPFC hyperactivation commonly considered a measure of brain inefficiency.

Background Phase synchronization of neural activity preceding a motor act may reflect an efference copy of the motor plan and its expected sensory consequences (corollary discharge), which is sent to sensory cortex to herald the arrival of self-generated sensations and dampen the resulting sensory experience. We performed time-frequency decomposition of response-locked electroencephalogram (EEG) to examine phase synchronization of oscillations across trials (phase-locking factor [PLF]) to self-paced button presses. If prepress PLF reflects the activity in motor cortex, it should be contralateralized. If it reflects the action of the efference copy, it should be related to subsequent sensory suppression. If efference copy/corollary discharge mechanisms are abnormal in schizophrenia, it should be reduced in patients with schizophrenia. Methods Electroencephalogram was collected while 23 patients (20 schizophrenia; 3 schizoaffective) and 25 age-matched control subjects pressed a button, at will, every 1 to 2 sec. Phase-locking factor preceding and following button presses was calculated from single-trial EEG; averaging single trials yielded response-locked event-related potentials (ERPs) to the tactile response associated with button pressing. Results Consistent with its hypothesized reflection of efference copy/corollary discharge signals, prepress gamma band neural synchrony was 1) maximal over the contralateral sensory-motor cortex in healthy subjects, 2) correlated with the ipsilateralized somatosensory ERP amplitude evoked by the press, and 3) reduced in patients. Prepress neural synchrony in the beta band was also reduced in patients, especially those with avolition/apathy. Conclusions These data are consistent with dysfunction of forward model circuitry in schizophrenia and suggest that the specific motor-sensory system affected is selectively linked to symptoms involving that system.

Background: The scalp-recorded N1 and P300 components of the event-related brain potential (ERP) are commonly reduced in patients with schizophrenia but not in patients with epilepsy. Epilepsy patients with interictal chronic schizophrenialike features (EPI-SZ) provide a comparison group for determining whether the ERP amplitude abnormalities seen in schizophrenic patients are associated with shared clinical features of EPI-SZ and schizophrenic patients or overlapping pathophysiologies, or are specific to a distinct schizophrenia etiology. Methods: Patients with schizophrenia ( n = 24) were compared with normal control subjects ( n = 32) and patients with epilepsy syndromes on visual and auditory oddball ERP paradigms. Epilepsy patients included those with chronic interictal schizophrenialike features ( n = 6) and those without ( n = 16). Results: Auditory P300 amplitude was reduced in both schizophrenic and EPI-SZ patients, whose positive or negative symptoms did not differ. In contrast, N1 amplitude was reduced only in schizophrenic patients. Delays in both N1 and P300 were associated with epilepsy patients and EPI-SZ but not schizophrenic patients. Conclusions: The schizophrenialike symptoms in epilepsy probably represent a phenocopy of schizophrenia with common clinical features and some common pathophysiologies but distinct etiologies. P300 amplitude appears to be sensitive to schizophrenialike features, regardless of whether they occur in the context of schizophrenia or epilepsy. N1 amplitude reduction appears to be specific to schizophrenia, suggesting its sensitivity to the distinct etiology of schizophrenia.

Background: The P300 component of the auditory event-related potential (ERP) is both reduced in amplitude and delayed in schizophrenia. P300 is prolonged and, less consistently, reduced with normal aging. Additional latency delays are observed in neurodegenerative disorders. We asked whether P300 is reduced and delayed with longer illness duration in schizophrenia, consistent with a neurodegenerative process. Methods: P300 amplitude and latency were recorded to infrequent auditory target stimuli from 35 men with schizophrenia (DSM-III-R) and 26 control men. Effects of current age, age of onset, and duration of illness on P300 were assessed using regression analysis. Results: P300 amplitude showed no age-related decrease in either group; however, among schizophrenic participants, P300 amplitude correlated positively with onset age and negatively with illness duration. P300 latency correlated positively with age in schizophrenic participants and also tended to increase with age in controls. Slopes of the latency–age relationships were significantly greater in schizophrenic participants than in control participants. Latency also correlated positively with illness duration but showed no relationship to onset age. Conclusions: P300 amplitude and latency are reduced and delayed with longer illness duration in schizophrenia, consistent with a progressive pathophysiological process. Reduced P300 amplitude may also be a marker of an early onset variant of schizophrenia.

Background: Relationships between illness severity and neurobiologic abnormalities in schizophrenia were studied in subpopulations varying in clinical severity. Methods: Auditory ERPs were collected from 28 severely ill, chronically hospitalized schizophrenic men from a state hospital; 29 moderately ill inpatient and outpatient schizophrenic men from a veterans hospital; and 30 healthy male subjects from the community as controls. Clinical symptoms were evaluated in patients using the Brief Psychiatric Rating Scale (BPRS). Results: Both schizophrenic patient groups had smaller P300 amplitude than the control subjects. Severely ill patients had smaller P300s than moderately ill patients and scored higher on three BPRS factor scores as well as BPRS Total. Among severely ill patients, P300 amplitude was unrelated to clinical symptoms. Among moderately ill patients, P300 was related to Withdrawal/Retardation, Anxiety/Depression, and BPRS Total. After combining patients, Thinking Disturbance emerged as an additional correlate of P300. Group differences in P300 could not be accounted for by group differences in symptom severity using analysis of covariance. Conclusions: Reduced P300 amplitude marks the diagnosis of schizophrenia, but also reflects individual differences in severity, including positive symptoms. Previous failures to find relationships between positive symptoms and P300 may have been due to a restricted range of clinical severity.

Thirty unmedicated schizophrenics were compared to 29 age-matched controls on auditory and visual event-related brain potential (ERP) paradigms. Twenty-one of these patients were tested again after 1 week on placebo and after 4 weeks on antipsychotic medication. Before treatment, N1, N2, and P3 components of the auditory ERP were smaller in the schizophrenics than in the controls. Although visual N2 was smaller in schizophrenics, visual P3 was not. In spite of significant clinical improvement with antipsychotic treatment, amplitudes of auditory and visual N1, N2, and P3 were not significantly changed. Higher blood levels of antipsychotic medication were related to reductions in auditory P3 latency, however. In addition, higher levels of cerebrospinal fluid (CSF) MHPG (methoxyhydroxyphenylglycol) were associated with larger auditory N1s and larger auditory and visual P3s, suggesting an influence of arousal on these components in schizophrenics. In spite of this influence, reduction of the auditory P3 in schizophrenia is an enduring trait of the disease, which is not affected by antipsychotic medication or clinical improvement.

Background Auditory mismatch negativity (MMN) and P300 event-related potentials (ERPs) are reduced in schizophrenia patients and healthy volunteers administered the N- methyl-D-aspartate glutamate receptor antagonist, ketamine. In rodents, N- acetylcysteine (NAC), a stimulator of the cystine-glutamate exchanger, attenuates the cognitive and behavioral effects of N- methyl-D-aspartate receptor antagonists. On the basis of these findings, we tested whether NAC would reduce ketamine effects on behavior, MMN, and P300 in healthy humans. Methods This randomized, double-blind, placebo-controlled study consisted of 2 test days during which subjects ( n = 16) were administered oral NAC (3000 mg in divided doses) or matching placebo 165 min before the infusion of saline and then ketamine (as a bolus of .23 mg/kg over 1 min followed by .58 mg/kg for 30 min, and then .29 mg/kg for 40 min) in a fixed order. Behavioral and ERP data including auditory MMN and P300 were collected during each test day. Results Ketamine produced psychotic-like positive symptoms, reductions in working memory and sustained attention performance, and amplitude reductions for the frequency- and intensity-deviant MMNs and P300. NAC pretreatment did not reduce the behavioral or ERP effects of ketamine. In addition, NAC reduced frequency-deviant MMN amplitude and increased target and novelty P3 amplitudes. The decrements in frequency-deviant MMN amplitude produced by ketamine and NAC were not additive. Conclusions NAC did not attenuate the effects of ketamine in humans, in contrast to previous studies in animals. NAC merits further investigation as a cognitive enhancing agent due to its ability to increase the P300 amplitude.

Background Impaired cortical plasticity may be part of the core pathophysiology of schizophrenia (SZ). Long-term potentiation is a form of neuroplasticity that has been recently demonstrated in humans by showing that repetitive visual stimulation produces lasting enhancement of visual evoked potentials (VEP). Using this paradigm, we examined whether visual cortical plasticity is impaired in SZ. Methods Electroencephalographic data were recorded from 19 SZ and 22 healthy control (HC) subjects during a visual long-term potentiation paradigm. Visual evoked potentials were elicited by standard visual stimuli (∼.83 Hz, 2-minute blocks) at baseline and at 2, 4, and 20 minutes following exposure to visual high-frequency stimulation (HFS) (∼8.8 Hz, 2 minutes) designed to induce VEP potentiation. To ensure attentiveness during VEP assessments, subjects responded with a button press to infrequent (10%) target stimuli. Visual evoked potentials were subjected to principal components analysis. Two negative-voltage components prominent over occipital-parietal electrode sites were evident at 92 msec (C1) and at 146 msec (N1b). Changes in C1 and N1b component scores from baseline to the post-HFS assessments were compared between groups. Results High-frequency stimulation produced sustained potentiation of visual C1 and N1b in HCs but not in SZs. The HCs and SZs had comparable HFS-driven electroencephalographic visual steady state responses. However, greater visual steady state responses to the HFS predicted greater N1b potentiation in HCs but not in SZs. Schizophrenia patients with greater N1b potentiation decreased their reaction times to target stimuli. Conclusions Visual cortical plasticity is impaired in schizophrenia, consistent with hypothesized deficits in N -methyl-D-aspartate receptor function.

Background: Communication between the frontal lobes, where speech and verbal thoughts are generated, and the temporal lobes, where they are perceived, may occur through the action of a corollary discharge. Its dysfunction may underlie failure to recognize inner speech as self-generated and account for auditory hallucinations in schizophrenia. Methods: Electroencephalogram was recorded from 10 healthy adults and 12 patients with schizophrenia (DSM-IV) in two conditions: talking aloud and listening to their own played-back speech. Event-related electroencephalogram coherence to acoustic stimuli presented during both conditions was calculated between frontal and temporal pairs, for delta, theta, alpha, beta, and gamma frequency bands. Results: Talking produced greater coherence than listening between frontal-temporal regions in all frequency bands; however, in the lower frequencies (delta and theta), there were significant interactions of group and condition. This finding revealed that patients failed to show an increase in coherence during talking, especially over the speech production and speech reception areas of the left hemisphere, and especially in patients prone to hallucinate. Conclusions: Reduced fronto-temporal functional connectivity may contribute to the misattribution of inner thoughts to external voices in schizophrenia.

Background: Failures to recognize inner speech as self-generated may underlie positive symptoms of schizophrenia-like auditory hallucinations. This could result from a faulty comparison in auditory cortex between speech-related corollary discharge and reafferent discharges from thinking or speaking, with misattribution of internal thoughts to external sources. Although compelling, failures to monitor covert speech (thoughts) are not as amenable to investigation as failures to monitor overt speech (talking). Methods: Effects of talking on auditory cortex responsiveness were assessed in 10 healthy adults and 12 patients with schizophrenia (DSM-IV) using N1 event-related potentials (ERPs) to acoustic and visual probes during talking aloud, listening to one’s speech played back, and silent baseline. Trials contaminated by muscle artifact while talking were excluded. Results: Talking and listening affected N1 to acoustic but not to visual probes, reflecting modality specificity of effects. Patterns of responses to acoustic probes differed between control subjects and patients. N1 to acoustic probes was reduced during talking compared with baseline in control subjects, but not in patients. Listening reduced N1 equivalently in both groups. Conclusions: Although the failure of N1 to be reduced during talking was not related to current hallucinations in patients, it may be related to the potential to hallucinate.

Background: The P300 component of the auditory event-related brain potential (ERP) is consistently reduced in schizophrenia. Longitudinal data are examined to determine whether P300 amplitude is a trait marker of schizophrenia or a state marker tracking clinical fluctuations over time. Methods: Schizophrenic men (DSM-III-R) ( n = 36) received ERP and the Brief Psychiatric Rating Scale (BPRS) assessments on multiple occasions, at varying intervals, under varying medication states. Automatically elicited auditory P3a and effortfully elicited auditory and visual P3b amplitudes were assessed. Brief Psychiatric Rating Scale scores were regressed on P300 amplitude within patients using both multiple regression models and nonparametric analyses of individual patient slopes. Event related brain potentials in patients were compared to ERPs from 34 age-matched control men, and stability of P300 over time was estimated with intraclass correlations. Results: P300 amplitude, regardless of elicitation method or sensory modality, tracked BPRS Total and positive symptom scores over time, decreasing with symptom exacerbations and increasing with improvements. In addition, effortful auditory and visual P3b amplitudes tracked negative symptoms, and automatic auditory P3a tracked depression-anxiety symptoms. When analyses were limited to unmedicated occasions, auditory P3a and P3b persisted in tracking BPRS Total scores, with additional tracking of positive symptoms by P3b and mood symptoms by P3a. Mean auditory and visual P3bs, averaged over all measurement occasions for each individual, were inversely related to mean negative symptoms. Auditory P3a and P3b, but not visual P3b, amplitudes were smaller in patients than control subjects, even when patients were least symptomatic. P300 amplitudes showed high test–retest reliability in control subjects and patients and moderate stability over time in patients. Conclusions: Auditory, and possibly visual, P300 amplitudes track fluctuations in clinical state, but only auditory P300 amplitude is a trait marker of schizophrenia.

Because P300 is typically measured from an average of single trials, variations among individual trials may account for P300 amplitude reduction so often seen in patients with schizophrenia. We tested three hypotheses regarding single-trial contribution to small average P300s in schizophrenics: normal P300s are elicited on some trials and no P300s on others, all trials have consistently small P300s, or P300 latency varies over trials. Nineteen schizophrenics and 35 controls were tested on a two-tone auditory oddball event-related potential (ERP) paradigm. ERPs recorded from the parietal electrod (Pz) were subjected to a P300-screening procedure in which a 2 Hz half-sine wave template was moved across the electroencephalogram (EEG) to find the point of best fit. If, for the point of best fit, the EEG: Template covariance was greater in the signal epoch (280–600 msec) than in the noise epoch (610–930 msec), and if the EEG: Template correlation was statistically significant, the trial passed the P300-screen and was deemed to have a P300. Three types of average ERPs were constructed: Traditional Average from all good (artifact-free, correct response) trials, P300-Screen Average from all good trials that also passed the P300-screen, and Latency Adjusted Average by aligning the P300-screen trials at the latency of maximum covariance. Traditional average ERPs were significantly smaller in schizophrenics than in controls. The results of the P300-screen confirmed all three hypotheses: schizophrenics had fewer trials passing the P300-screen, smaller P300s on each trial, and P300s that were more variable in latency across trials. Even when trials without a P300 are excluded and trials with a P300 are latency adjusted, the average P300 is still reduced in schizophrenics. P300 amplitude reduction in schizophrenia is robust and not an artifact of trial selectionor averaging.