William Hetrick

NMDA receptor antagonists can induce a schizophrenia-like psychosis, but the role of NMDA receptors in the pathophysiology of schizophrenia remains unclear. Expression patterns of mRNAs for five NMDA receptor subunits (NR1/NR2A-D) were determined by in situ hybridization in prefrontal, parieto-temporal, and cerebellar cortex of brains from schizophrenics and from neuroleptic-treated and nonmedicated controls. In the cerebral cortex of both schizophrenics and controls, mRNAs for NR1, NR2A, NR2B, and NR2D subunits were preferentially expressed in layers II/III, Va, and VIa, with much higher levels in the prefrontal than in the parieto-temporal cortex. Levels of mRNA for the NR2C subunit were very low overall. By contrast, the cerebellar cortex of both schizophrenics and controls contained very high levels of NR2C subunit mRNA, whereas levels for the other subunit mRNAs were very low, except NR1, for …

<h3 class="gsh_h3">Background:</h3>The cortical subplate is a transitory structure involved in the formation of connections in developing cerebral cortex. Interstitial neurons, normally present in subcortical white matter (WM) of the adult brain, have escaped the programmed cell death that eliminates most subplate neurons. Previous investigations indicated a maldistribution of one population of interstitial neurons in the WM of brains of schizophrenic patients, suggesting a defect of the subplate during brain development.<h3 class="gsh_h3">Methods:</h3>Three histochemically or immunocytochemically defined neuronal populations were studied in WM beneath the middle frontal gyrus of 20 schizophrenic patients and 20 matched control subjects.<h3 class="gsh_h3">Results:</h3>Brains of schizophrenic patients showed significant changes in the distribution of the three neuronal populations: microtubule-associated protein 2 and nonphosphorylated neurofilament-immunoreactive neurons …

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 …

Studies of task switching demonstrate that task switches are associated with response costs and that these costs are reduced when a cue is presented in advance of a switch. The present study examined cortical event‐related potential correlates of task switching and switch costs in 39 participants during a cued match/mismatch discrimination task. Compared with non‐switch trials, switch trials were associated with a larger cue‐related, anticipatory P3b‐like waveform. Switch trials were also associated with smaller target‐related, stimulus‐dependent P2 and P3‐like components. Moreover, the switch‐related amplitude variability in the P3b to the cue and the P2 to the target were associated with unique components of the residual switch costs. The results support an integrated model of task switching with complementary yet distinct roles for anticipatory and stimulus‐dependent processes in task switching and switch …

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.(PsycINFO Database Record (c) 2016 APA, all rights reserved)

Auditory P300 latency prolongation or amplitude reduction has been reported in patients affected by bipolar disorder and in schizophrenia. The purpose of this study was to test whether the auditory P300 and earlier event-related potential (ERP) components elicited during an auditory discrimination task could differentiate between these two disorders. Thirteen patients with manic or mixed bipolar disorder, 12 patients with schizophrenia, and 24 control subjects were evaluated. None of the subjects had a history of alcohol or substance abuse or dependence. ERPs were elicited during an auditory discrimination task in which a subject pressed a key to infrequent 1500 Hz tones interspersed amid a series of 1000 Hz tones. The amplitude and latency of N100 and P200 were measured from ERPs to non-target tones, and N200 and P300 were measured from ERPs to target tones. N100, P200 and N200 amplitudes were …

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 …

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 …

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 showed S2 the same variability as in controls. Measured by the single-trial procedure, the …

<h3 class="gsh_h3">Objective</h3>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 (4 Hz) to gamma (40 Hz) range.<h3 class="gsh_h3">Methods</h3>The SSVEPs to seven different frequencies of stimulation (4, 8, 17, 20, 23, 30 and 40 Hz) 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.<h3 class="gsh_h3">Results</h3>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 …

Background: Abnormal P50 response has been hypothesized to reflect the sensory gating deficit in schizophrenia. Despite the extensive literature concerning the sensory filtering or gating deficit in schizophrenia, no evidence has been provided to test the relationship of the P50 phenomenon with patients’ experiences of perceptual anomalies.Methods: Sixteen drug-free DSM-IV diagnosed schizophrenic patients who reported moderate to severe perceptual anomalies in the auditory or visual modality were examined as compared to 16 schizophrenic patients who did not report perceptual anomalies, and 16 normal subjects. Both control groups were age- and gender-matched with the study group.Results: Patients reporting perceptual anomalies exhibited P50 patterns that did not differ from normal subjects. In contrast, patients who did not report perceptual anomalies showed the abnormal P50 ratios previously …

<h3 class="gsh_h3">Background</h3>Deficits in attention and cognition are common in schizophrenia. Using an auditory dual-click paradigm, a number of studies have found that, compared with normal controls, patients with schizophrenia show impaired inhibition, or gating, of repeated stimulation as measured by the average P50 evoked response to the second click. Since responses to many trials are collected to study the average response, fluctuations in the timing of the P50 response from trial to trial may influence the differences observed. We present a computerized, objective procedure that evaluates temporal variability in brain responses of patients with schizophrenia.<h3 class="gsh_h3">Methods</h3>Ten normal controls and 10 patients diagnosed with schizophrenia were studied using the dual-click procedure. For each single trial, the temporal shift in P50 that yielded the best alignment with the average P50 response was used to derive a measure of P50 …

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 …

Clinical descriptions of perceptual and attentional anomalies in schizophrenia emphasize phenomena such as flooding, or inundation, by sensory stimuli. A failure of sensory “gating” mechanisms in the brain is hypothesized to account for these symptoms, and this hypothesis has led to a marked interest in their putative psychophysiological substrates. However, there are no systematic analyses of the phenomenology of these perceptual experiences, nor has the hypothesized connection between the clinical phenomena and their reported psychophysiological substrates been tested. In this investigation, a structured interview instrument was developed to measure perceptual anomalies as distinct from hallucinations and to determine their prevalence across sensory modalities in schizophrenia in 67 schizophrenia subjects and 98 normal controls. The instrument includes Likert ratings of hypersensitivity …

Central nervous system (CNS) inhibitory mechanisms hypothesized to “gate” repetitive sensory inputs have been implicated in the pathology of schizophrenia. The present study investigated gender differences in inhibitory gating of evoked brain responses to repeated stimuli in normal subjects (30 women and 30 men) using an auditory conditioning—testing paradigm. Pairs of click stimuli (S1 and S2) were presented with a 0.5 s intrapair and a 10 s interpair interval. The amplitudes and latencies of the P50, N100, P180 components of the auditory evoked response to the conditioning (S1) and test response (S2) were measured, and the gating ratios were computed (T/C ratio = S2/S1 * 100). The amplitudes to S1 were not significantly different between men and women at P50, N100, or P180. However, women had significantly higher amplitudes to S2 at P50 (p = 0.03) and N100 (p = 0.04). The T/C ratios for women …