William P. Hetrick

P50 sensory gating ratios in schizophrenics and controls: A review and data analysis

Many studies have found that the P50 sensory gating ratio in a paired click task is smaller in normal control subjects than in patients with schizophrenia, indicating more effective sensory gating. However, a wide range of gating ratios has been reported in the literature for both groups. The purpose of this study was to compile these findings and to compare reported P50 gating ratios in controls and patients with schizophrenia. Current data collected from individual controls in eight studies from the University of California, Irvine (UCI), Indiana University (IU), and Yale University also are reported. The IU, UCI, and Yale data showed that approximately 40% of controls had P50 ratios within 1 S.D. below the mean of means for patients with schizophrenia. The meta-analysis rejected the null hypothesis that all studies showed no effect. The meta-analysis also showed that the differences were not the same across all studies. The mean ratios in 45 of the 46 group comparisons were smaller for controls than for patients, and the observed difference in means was significant for 35 of those studies. Reported gating ratios for controls from two laboratories whose findings were reported in the literature differed from all the other control groups. Variables affecting the gating ratio included band pass filter setting, rules regarding the inclusion of P30, sex, and age. Standards of P50 collection and measurement would help determine whether the gating ratio can be sufficiently reliable to be labeled an endophenotype, and suggestions are made toward this goal.

Haloperidol Impairs Learning and Error-related Negativity in Humans

Humans are able to monitor their actions for behavioral conflicts and performance errors. Growing evidence suggests that the error-related negativity (ERN) of the event-related cortical brain potential (ERP) may index the functioning of this response monitoring system and that the ERN may depend on dopaminergic mechanisms. We examined the role of dopamine in ERN and behavioral indices of learning by administering either 3 mg of the dopamine antagonist (DA) haloperidol (n = 17); 25 mg of diphenhydramine (n = 16), which has a similar CNS profile but without DA properties; or placebo (n = 18) in a randomized, double-blind manner to healthy volunteers. Three hours after drug administration, participants performed a go/no-go Continuous Performance Task, the Eriksen Flanker Task, and a learning-dependent Time Estimation Task. Haloperidol significantly attenuated ERN amplitudes recorded during the flanker task, impaired learning of time intervals, and tended to cause more errors of commission, compared to placebo, which did not significantly differ from diphenhydramine. Drugs had no significant effects on the stimulus-locked P1 and N2 ERPs or on behavioral response latencies, but tended to affect post-error reaction time (RT) latencies in opposite ways (haloperidol decreased and diphenhydramine increased RTs). These findings support the hypothesis that the DA system is involved in learning and the generation of the ERN.

Steady State Responses: Electrophysiological Assessment of Sensory Function in Schizophrenia

Persons with schizophrenia experience subjective sensory anomalies and objective deficits on assessment of sensory function. Such deficits could be produced by abnormal signaling in the sensory pathways and sensory cortex or later stage disturbances in cognitive processing of such inputs. Steady state responses (SSRs) provide a noninvasive method to test the integrity of sensory pathways and oscillatory responses in schizophrenia with minimal task demands. SSRs are electrophysiological responses entrained to the frequency and phase of a periodic stimulus. Patients with schizophrenia exhibit pronounced auditory SSR deficits within the gamma frequency range (35-50 Hz) in response to click trains and amplitude-modulated tones. Visual SSR deficits are also observed, most prominently in the alpha and beta frequency ranges (7-30 Hz) in response to high-contrast, high-luminance stimuli. Visual SSR studies that have used the psychophysical properties of a stimulus to target specific visual pathways predominantly report magnocellular-based deficits in those with schizophrenia. Disruption of both auditory and visual SSRs in schizophrenia are consistent with neuropathological and magnetic resonance imaging evidence of anatomic abnormalities affecting the auditory and visual cortices. Computational models suggest that auditory SSR abnormalities at gamma frequencies could be secondary to gamma-aminobutyric acid-mediated or N-methyl-D-aspartic acid dysregulation. The pathophysiological process in schizophrenia encompasses sensory processing that probably contributes to alterations in subsequent encoding and cognitive processing. The developmental evolution of these abnormalities remains to be characterized.

Eye Gaze and Individual Differences Consistent with Learned Attention in Associative Blocking and Highlighting.

The associative learning effects called blocking and highlighting have previously been explained by covert learned attention, but evidence for learned attention has been indirect, via models of response choice. The present research reports results from eye tracking consistent with the attentional hypothesis: Gaze duration is diminished for blocked cues and augmented for highlighted cues. If degree of attentional learning varies across individuals but is relatively stable within individuals, then the magnitude of blocking and highlighting should covary across individuals. This predicted correlation is obtained for both choice and eye gaze. A connectionist model that implements attentional learning is shown to fit the data and account for individual differences by variation in its attentional parameters.

Effects of P50 temporal variability on sensory gating in schizophrenia

The conditioning-testing (S1-S2) P50 auditory evoked potential (EP) has been well-documented and accepted as an important tool for measuring sensory gating in schizophrenia research. However, the physiological mechanism of the phenomenon is not known. In this study a single-trial analysis was used to determine the influence of the latency variability of the responses in the formation of the averaged P50. Ten schizophrenic patients and 10 normal controls were tested in the dual-click EP paradigm. Using ensemble averaging analysis, we replicated the previous finding of a lower S1 P50 amplitude and higher S2/S1 ratio in schizophrenics compared with normal controls. The single-trial analysis revealed that patients had significantly higher trial-to-trial latency variability in S1 responses than normal subjects, while the S2 showed the same variability as in controls. Measured by the single-trial procedure, the arithmetic mean amplitudes of P50 responses to S1 and S2 were similar between normal and schizophrenic subjects. The same measure also eliminated the difference in averaged P50 amplitude between S1 and S2 for both groups. Temporal variability appears to be an important factor in the assessment of averaged EPs and thus contribute to the change of P50 amplitude observed in schizophrenia.

Temporal processing dysfunction in schizophrenia

Schizophrenia may be associated with a fundamental disturbance in the temporal coordination of information processing in the brain, leading to classic symptoms of schizophrenia such as thought disorder and disorganized and contextually inappropriate behavior. Despite the growing interest and centrality of time-dependent conceptualizations of the pathophysiology of schizophrenia, there remains a paucity of research directly examining overt timing performance in the disorder. Accordingly, the present study investigated timing in schizophrenia using a well-established task of time perception. Twenty-three individuals with schizophrenia and 22 non-psychiatric control participants completed a temporal bisection task, which required participants to make temporal judgments about auditory and visually presented durations ranging from 300 to 600 ms. Both schizophrenia and control groups displayed greater visual compared to auditory timing variability, with no difference between groups in the visual modality. However, individuals with schizophrenia exhibited less temporal precision than controls in the perception of auditory durations. These findings correlated with parameter estimates obtained from a quantitative model of time estimation, and provide evidence of a fundamental deficit in temporal auditory precision in schizophrenia.

Steady state and induced auditory gamma deficits in schizophrenia.

Steady state auditory evoked potentials (SSAEPs) in the electroencephalogram (EEG) and magnetoencephalogram (MEG) have been reported to be reduced in schizophrenia, most consistently to frequencies in the gamma range (40 Hz and greater). The current study evaluated the specificity of this deficit over a broad range of stimulus frequencies and harmonics, the relationship between phase locking and signal power, and whether induced 40 Hz activity was also affected. SSAEPs to amplitude modulated tones from 5 to 50 Hz were obtained from subjects with schizophrenia (SZ) and healthy control subjects in 5 Hz steps. Time-frequency spectral analysis was used to differentiate EEG activity synchronized in phase across trials using Phase Locking Factor (PLF) and Mean Power (MP) change from baseline activity. In the SSAEP frequency response condition, patients with SZ showed broad band reductions in both PLF and MP. In addition, the control subjects showed a more pronounced increase in PLF with increases in power compared to SZ subjects. A noise pulse embedded in 40 Hz stimuli resulted in a transient reduction of PLF and MP at 40 Hz in control subjects, while SZ showed diminished overall PLF. Finally, induced gamma (around 40 Hz) response to unmodulated tone stimuli was also reduced in SZ, indicating that disturbances in this oscillatory activity are not confined to SSAEPs. In summary, SZ subjects show impaired oscillatory responses in the gamma range across a wide variety of experimental conditions. Reduction of PLF along with reduced MP may reflect abnormalities in the auditory cortical circuits, such as a reduction in pyramidal cell volume, spine density and alterations in GABAergic neurons.

Steady state visual evoked potential abnormalities in schizophrenia

OBJECTIVE The steady state visual evoked potential (SSVEP) can be used to test the frequency response function of neural circuits. Previous studies have shown reduced SSVEPs to alpha and lower frequencies of stimulation in schizophrenia. We investigated SSVEPs in schizophrenia at frequencies spanning the theta (4Hz) to gamma (40Hz) range. METHODS The SSVEPs to seven different frequencies of stimulation (4, 8, 17, 20, 23, 30 and 40Hz) were obtained from 18 schizophrenia subjects and 33 healthy control subjects. Power at stimulating frequency (signal power) and power at frequencies above and below the stimulating frequency (noise power) were used to quantify the SSVEP responses. RESULTS Both groups showed an inverse relationship between power and frequency of stimulation. Schizophrenia subjects showed reduced signal power compared to healthy control subjects at higher frequencies (above 17Hz), but not at 4 and 8Hz at occipital region. Noise power was higher in schizophrenia subjects at frequencies between 4 and 20Hz over occipital region and at 4, 17 and 20Hz over frontal region. CONCLUSIONS SSVEP signal power at beta and gamma frequencies of stimulation were reduced in schizophrenia. Schizophrenia subjects showed higher levels of EEG noise during photic stimulation at beta and lower frequencies. SIGNIFICANCE Inability to generate or maintain oscillations in neural networks may contribute to deficits in visual processing in schizophrenia.

Temporal Discounting of Rewards in Patients With Bipolar Disorder and Schizophrenia

Patients with bipolar disorder (BD) and schizophrenia (SZ) often show decision-making deficits in everyday circumstances. A failure to appropriately weigh immediate versus future consequences of choices may contribute to these deficits. We used the delay discounting task in individuals with BD or SZ to investigate their temporal decision making. Twenty-two individuals with BD, 21 individuals with SZ, and 30 healthy individuals completed the delay discounting task along with neuropsychological measures of working memory and cognitive function. Both BD and SZ groups discounted delayed rewards more steeply than did the healthy group even after controlling for current substance use, age, gender, and employment. Hierarchical multiple regression analyses showed that discounting rate was associated with both diagnostic group and working memory or intelligence scores. In each group, working memory or intelligence scores negatively correlated with discounting rate. The results suggest that (a) both BD and SZ groups value smaller, immediate rewards more than larger, delayed rewards compared with the healthy group and (b) working memory or intelligence is related to temporal decision making in individuals with BD or SZ as well as in healthy individuals.

Timing dysfunctions in schizophrenia span from millisecond to several-second durations

Schizophrenia may be associated with a fundamental disturbance in the temporal coordination of information processing in the brain, leading to classic symptoms of schizophrenia such as thought disorder and disorganized and contextually inappropriate behavior. However, the majority of studies that have examined timing behavior in schizophrenia have employed temporal durations in the range of several seconds, which requires higher cognitive processes beyond initial sensory registration for temporal encoding. Accordingly, the present study assessed both millisecond and several-second duration estimates in schizophrenia using a well-established task of time perception. Twenty-eight individuals with schizophrenia and 31 non-psychiatric control participants completed two temporal bisection tasks, which required participants to make temporal judgments about auditory durations ranging from either 300 to 600 ms or 3000 to 6000 ms. Participants with schizophrenia displayed significantly greater timing variability under both millisecond and several-second timing conditions than the non-psychiatric group. These findings were consistent with parameter estimates obtained from a quantitative model of time estimation, and provide evidence for a fundamental timing deficit in schizophrenia that may be independent of the length of the to-be-timed duration.