Medial Prefrontal Cortex Dysfunction Mediates Working Memory Deficits in Patients With Schizophrenia.

Background: Schizophrenia (SCZ) is marked by working memory (WM) deficits, which predict poor functional outcome. While most functional magnetic resonance imaging studies of WM in SCZ have focused on the dorsolateral prefrontal cortex (PFC), some recent work suggests that the medial PFC (mPFC) may play a role. We investigated whether task-evoked mPFC deactivation is associated with WM performance and whether it mediates deficits in SCZ. In addition, we investigated associations between mPFC deactivation and cortical dopamine release. Methods: Patients with SCZ (n = 41) and healthy control participants (HCs) (n = 40) performed a visual object n-back task during functional magnetic resonance imaging. Dopamine release capacity in mPFC was quantified with [11C]FLB457 in a subset of participants (9 SCZ, 14 HCs) using an amphetamine challenge. Correlations between task-evoked deactivation and performance were assessed in mPFC and dorsolateral PFC masks and were further examined for relationships with diagnosis and dopamine release. Results: mPFC deactivation was associated with WM task performance, but dorsolateral PFC activation was not. Deactivation in the mPFC was reduced in patients with SCZ relative to HCs and mediated the relationship between diagnosis and WM performance. In addition, mPFC deactivation was significantly and inversely associated with dopamine release capacity across groups and in HCs alone, but not in patients. Conclusions: Reduced WM task-evoked mPFC deactivation is a mediator of, and potential substrate for, WM impairment in SCZ, although our study design does not rule out the possibility that these findings could relate to cognition in general rather than WM specifically. We further present preliminary evidence of an inverse association between deactivation during WM tasks and dopamine release capacity in the mPFC.

Antipsychotic binding to the dopamine-3 receptor in humans: A PET study with [(11)C]-(+)-PHNO.

BACKGROUND: All currently available antipsychotic medications bind to both the dopamine-2 (D2) and dopamine-3 (D3) receptors in vitro. However, there is conflicting evidence from in vivo studies about whether or not antipsychotic medications bind to the D3 receptor (D3R). The purpose of this study was to determine whether acute doses of risperidone bind to the D3R in humans. METHODS: We performed PET scans on an mCT scanner with [(11)C]-(+)-PHNO injected as a bolus, before and after a 2mg oral dose of risperidone in five medication free subjects with schizophrenia. The subjects were scanned for 120min and underwent an MRI scan for region of interest delineation and coregistration. Cerebellum was used as a reference region. Simplified reference tissue modeling (SRTM) was used to calculate BPND. RESULTS: We observed binding to the D3R receptor by risperidone as evidenced by observable occupancy in regions in which the [(11)C]-(+)-PHNO signal is almost exclusively from the D3R (i.e., substantia nigra/ventral tegmental area). Using a regression model to estimate D2R:D3R selectivity, we observed a D2R:D3R selectivity of 2.1 for risperidone. CONCLUSION: Our preliminary results provide further support that acute doses of antipsychotic medications bind to the D3R and provide additional support for the further development of this receptor as a treatment target in schizophrenia.

Heterogeneity of auditory verbal working memory in schizophrenia.

The heterogeneity of schizophrenia remains an obstacle for understanding its pathophysiology. Studies using a tone discrimination screening test to classify patients have found evidence for 2 subgroups having either a specific deficit in verbal working memory (WM) or deficits in both verbal and nonverbal memory. This study aimed to (a) replicate in larger samples differences between these subgroups in auditory verbal WM; (b) evaluate their performance on tests of explicit memory and sustained attention; (c) determine the relation of verbal WM deficits to auditory hallucinations and other symptoms; and (d) examine medication effects. The verbal WM and tone discrimination performance did not differ between medicated (n = 45) and unmedicated (n = 38) patients. Patients with schizophrenia who passed the tone screening test (discriminators; n = 60) were compared with those who did not (nondiscriminators; n = 23) and healthy controls (n = 47). The discriminator subgroup showed poorer verbal WM than did controls and a deficit in verbal but not visual memory on the Wechsler Memory Scale-Revised (Wechsler, 1987), whereas the nondiscriminator subgroup showed overall poorer performance on both verbal and nonverbal tests and a marked deficit in sustained attention. Verbal WM deficits in discriminators were correlated with auditory hallucinations but not with negative symptoms. The results are consistent with a verbal memory deficit in a subgroup of schizophrenia having intact auditory perception, which may stem from dysfunction of language-related cortical regions, and a more generalized cognitive deficit in a subgroup having auditory perceptual and attentional dysfunction.

Stimulus- and response-locked neuronal generator patterns of auditory and visual word recognition memory in schizophrenia.

Examining visual word recognition memory (WRM) with nose-referenced EEGs, we reported a preserved ERP 'old-new effect' (enhanced parietal positivity 300-800 ms to correctly-recognized repeated items) in schizophrenia ([Kayser, J., Bruder, G.E., Friedman, D., Tenke, C.E., Amador, X.F., Clark, S.C., Malaspina, D., Gorman, J.M., 1999. Brain event-related potentials (ERPs) in schizophrenia during a word recognition memory task. Int. J. Psychophysiol. 34(3), 249-265.]). However, patients showed reduced early negative potentials (N1, N2) and poorer WRM. Because group differences in neuronal generator patterns (i.e., sink-source orientation) may be masked by choice of EEG recording reference, the current study combined surface Laplacians and principal components analysis (PCA) to clarify ERP component topography and polarity and to disentangle stimulus- and response-related contributions. To investigate the impact of stimulus modality, 31-channel ERPs were recorded from 20 schizophrenic patients (15 male) and 20 age-, gender-, and handedness-matched healthy adults during parallel visual and auditory continuous WRM tasks. Stimulus- and response-locked reference-free current source densities (spherical splines) were submitted to unrestricted Varimax-PCA to identify and measure neuronal generator patterns underlying ERPs. Poorer (78.2+/-18.7% vs. 87.8+/-11.3% correct) and slower (958+/-226 vs. 773+/-206 ms) performance in patients was accompanied by reduced stimulus-related left-parietal P3 sources (150 ms pre-response) and vertex N2 sinks (both overall and old/new effects) but modality-specific N1 sinks were not significantly reduced. A distinct mid-frontal sink 50-ms post-response was markedly attenuated in patients. Reductions were more robust for auditory stimuli. However, patients showed increased lateral-frontotemporal sinks (T7 maximum) concurrent with auditory P3 sources. Electrophysiologic correlates of WRM deficits in schizophrenia suggest functional impairments of posterior cortex (stimulus representation) and anterior cingulate (stimulus categorization, response monitoring), primarily affecting memory for spoken words.

Enhanced sensitivity to the euphoric effects of alcohol in schizophrenia.

The purpose of this study was to determine whether schizophrenia was associated with alterations in alcohol response that might explain the elevated risk for AUDs in this population. In a randomized, double-blind, placebo-controlled, counter-balanced 3 test day laboratory study, the effects of alcohol were compared in 23 subjects with schizophrenia (without any previous alcohol use disorder (AUD) but with some alcohol exposure) and in 14 healthy subjects matched for age, gender, education, and lifetime exposure to alcohol. Standard alcohol drinks in a scheduled design were administered to produce blood alcohol levels of 0, 0.02-0.04 mg%, or 0.06-0.08 mg%. Schizophrenia symptoms, perceptual alterations, stimulant and depressant subjective effects of alcohol, and 'high' were measured before alcohol administration and at several post-drug time points. Verbal learning and recall, vigilance and distractibility, and motor function were assessed once per test day. Relative to healthy subjects, subjects with schizophrenia reported greater euphoria and stimulatory effects in response to alcohol. Alcohol produced small transient increases in positive psychotic symptoms and perceptual alterations without affecting negative symptoms. Alcohol also impaired several aspects of immediate and delayed recall, and vigilance, and distractibility. Schizophrenia patients showed increased euphoric and stimulatory responses to alcohol. These exaggerated positive responses to alcohol doses may contribute to the increased risk for AUDs associated with schizophrenia. The absence of 'beneficial' effects of alcohol does not support a self-medication hypothesis of alcohol use in schizophrenia.

ERP/CSD indices of impaired verbal working memory subprocesses in schizophrenia.

To disentangle subprocesses of verbal working memory deficits in schizophrenia, long EEG epochs (>10 s) were recorded from 13 patients and 17 healthy adults during a visual word serial position test. ERP generator patterns were summarized by temporal PCA from reference-free current source density (CSD) waveforms to sharpen 31-channel topographies. Patients showed poorer performance and reduced left inferior parietotemporal P3 source. Build-up of mid-frontal negative slow wave (SW) in controls during item encoding, integration, and active maintenance was absent in patients, whereas a sustained mid-frontal SW sink during the retention interval was comparable across groups. Mid-frontal SW sinks (encoding and retention periods) and posterior SW sinks and sources (encoding only) were related to performance in controls only. Data suggest disturbed processes in a frontal-parietotemporal network in schizophrenia, affecting encoding and early item storage.

gamma-Aminobutyric acid-serotonin interactions in healthy men: implications for network models of psychosis and dissociation.

BACKGROUND: This study tested the hypothesis that deficits in gamma-aminobutyric acid type A (GABA(A)) receptor function might create a vulnerability to the psychotogenic and perceptual altering effects of serotonergic (5-HT(2A/2C)) receptor stimulation. The interactive effects of iomazenil, an antagonist and partial inverse agonist of the benzodiazepine site of the GABA(A) receptor complex, and m-chlorophenylpiperazine (m-CPP), a partial agonist of 5-HT(2A/2C) receptors, were studied in 23 healthy male subjects. METHODS: Subjects underwent 4 days of testing, during which they received intravenous infusions of iomazenil/placebo followed by m-CPP/placebo in a double-blind, randomized crossover design. Behavioral, cognitive, and hormonal data were collected before drug infusions and periodically for 200 min after. RESULTS: Iomazenil and m-CPP interacted in a synergistic manner to produce mild psychotic symptoms and perceptual disturbances without impairing cognition. Iomazenil and m-CPP increased anxiety in an additive fashion. Iomazenil and m-CPP interacted in a synergistic manner to increase serum cortisol. CONCLUSIONS: Gamma-aminobutyric acid-ergic deficits might increase the vulnerability to the psychotomimetic and perceptual altering effects of serotonergic agents. These data suggest that interactions between GABA(A) and 5-HT systems might contribute to the pathophysiology of psychosis and dissociative-like perceptual states.

Verbal memory in schizophrenia: additional evidence of subtypes having different cognitive deficits.

A prior study found a selective deficit in verbal working memory in a subgroup of patients with schizophrenia who performed as well as healthy controls on a screening test of attention and auditory perception [Arch. Gen. Psychiatry 55 (1998) 1093]. Given the importance of defining pathophysiologically distinct subtypes of schizophrenia, the present study aimed to replicate and extend this finding. Patients with schizophrenia who passed the screening test (discriminators or Dsz patients) were compared to those who did not (nondiscriminators, NDsz patients), and healthy controls on a word serial position test (WSPT) and on other tests of verbal and nonverbal cognitive function. Dsz patients performed more poorly than controls on the WSPT and showed serial position effects consistent with a verbal memory deficit. They also showed a deficit in verbal memory but not visual memory on the Wechsler Memory Scale-Revised. In contrast, the NDsz patients showed overall poor performance on both verbal and nonverbal tests, consistent with a generalized deficit. Verbal working memory deficits were not related to education, gender, severity of symptoms, medication status, or hemispheric dominance for perceiving dichotic words. The findings add to growing evidence for the existence of a subgroup of schizophrenia having a specific verbal memory deficit that is not limited to working memory, but extends to learning and recall of verbal material.