Association of Working Memory With Distributed Executive Control Networks in Schizophrenia.

OBJECTIVE: Working memory impairments represent a core cognitive deficit in schizophrenia, predictive of patients' daily functioning, and one that is unaffected by current treatments. To address this, working memory is included in the MATRICS Consensus Cognitive Battery (MCCB), a standardized cognitive battery designed to facilitate drug development targeting cognitive symptoms. However, the neurobiology underlying these deficits in MCCB working memory is currently unknown, mirroring the poor understanding in general of working memory deficits in schizophrenia. METHODS: Twenty-eight participants with schizophrenia were administered working memory tests from the MCCB and examined with resting-state functional MRI. Intrinsic connectivity networks were estimated with independent component analysis. Each voxel's time series was correlated with each network time series, creating a feature vector for voxel-level connectivity analysis. This feature vector was associated with working memory by using the distance covariance statistic. RESULTS: The neurobiology of MCCB working memory tests largely followed the multicomponent model of working memory but revealed unexpected differences. The dorsolateral prefrontal cortex was not associated with working memory. The central executive system was instead associated with delocalized right and left executive control networks. The phonologic loop within the multicomponent model, a subsystem involved in storing linguistic information, was associated with connectivity to the left temporoparietal junction and inferior frontal gyrus. However, connections to the language network did not predict working memory test performance. CONCLUSIONS: These results provide supporting evidence for the multicomponent model of working memory in terms of the biology underlying MCCB findings.

Pharmacokinetic Limitations on Effects of an Alpha7-Nicotinic Receptor Agonist in Schizophrenia: Randomized Trial with an Extended-Release Formulation.

The aim of the trial was to assess whether extending plasma levels of the alpha7-nicotinic acetylcholine receptor (nAChR) agonist 3-(2,4-dimethoxybenzylidene)-anabaseine (DMXB-A) over time enhances its cognitive effects in schizophrenia. Both smoking and non-smoking patients were studied, to determine whether effects differ between these two groups. Forty-three smokers and thirty-seven non-smokers who met DSM-IV criteria for schizophrenia were enrolled in a double-blind, randomized, placebo-controlled 1 month trial. DMXB-A 150 mg was formulated with hypromellose to produce extended release over 4 h and administered four times daily. The primary outcome (the Neurocognitive Composite of the MATRICS Consensus Cognitive Battery) and secondary outcomes (the MATRICS Attention-Vigilance Domain and P50 gating), showed no significant effect. Plasma levels were obtained 2.5 h post administration. In non-smokers, levels were similar to those reached transiently with 75-150 mg DMXB-A immediate-release formulations twice daily, which were earlier shown to be effective doses. However, the extended-release formulation produced no cognitive or clinical effect either in non-smokers or smokers. The 10-fold lower DMXB-A plasma levels in smokers suggest that chronic smoking enhances DMXB-A metabolism. Pro-cognitive effects of DMXB-A may result from transient increases in cell signaling that are limited by receptor tachyphylaxis. Future efforts to improve cognition in schizophrenia by enhancing alpha7 nAChR function may require consideration of these pharmacokinetic limitations.

Carl N. Zimet (1925-2015).

This article memorializes Carl N. Zimet (1925-2015). In 1963, Zimet was recruited to the University of Colorado School of Medicine as chief of the Division of Psychology. Throughout his career, he was engaged in the practice of psychotherapy. He served on numerous boards and committees of the American Psychological Association (APA), including APA's Board of Directors. Zimet was a founder of the National Register of Health Service Providers in Psychology and was its first president, a position he held for 11 years. The APA award for Distinguished Professional Contributions to Psychology was presented to Zimet in 1987. When Zimet retired at the age of 82 in 2007 as professor emeritus, he had led the Division of Psychology at the University of Colorado School of Medicine for 44 years. (PsycINFO Database Record

First in human trial of a type I positive allosteric modulator of alpha7-nicotinic acetylcholine receptors: Pharmacokinetics, safety, and evidence for neurocognitive effect of AVL-3288.

Type I positive allosteric modulators (PAMs) of the alpha7-nicotinic receptor enhance its cholinergic activation while preserving the spatiotemporal features of synaptic transmission and the receptor's characteristic rapid desensitization kinetics. Alpha7-nicotinic receptor agonists have shown promise for improving cognition in schizophrenia, but longer-term trials have been disappointing. Therefore, the type I PAM AVL-3288 was evaluated for safety and preliminary evidence of neurocognitive effect in healthy human subjects. Single-dose oral administration in ascending doses was conducted in a double-blind, placebo-controlled Phase I trial in non-smokers. The trial found indication of positive but non-significant effects on neurocognition at 10 and 30 mg, two doses that produced overlapping peak levels. There was also some evidence for effects on inhibition of the P50 auditory evoked potential to repeated stimuli, a biomarker that responds to alpha7-nicotinic receptor activation. The pharmacokinetic characteristics were consistent between subjects, and there were no safety concerns. The effects and safety profile were also assessed at 3 mg in a cohort of smokers, in whom concurrent nicotine administration did not alter either effects or safety. The trial demonstrates that a type I PAM can be safely administered to humans and that it has potential positive neurocognitive effects in central nervous system (CNS) disorders.

Schizophrenia, smoking status, and performance on the matrics Cognitive Consensus Battery.

Cognitive deficits and high rates of nicotine dependence are consistently documented in the schizophrenia literature. However, there is currently no consensus about how regular smoking influences cognition in schizophrenia or which cognitive domains are most affected by chronic smoking. Previous studies have also failed to disambiguate the effects of chronic nicotine from those of acute exposure. The current study uses a novel approach to testing nicotine addicted patients at a time-point between acute enhancement and withdrawal and implements the MATRICS Cognitive Consensus Battery (MCCB) to compare the overall cognitive performance of regular smokers (n=40) and nonsmokers (n=36) with schizophrenia. Controlling for age, gender, and education, smokers with schizophrenia were significantly more impaired on a visual learning task, the Brief Visuospatial Memory Test-Revised (BVMT-R), than their nonsmoking peers. Among smokers, smoking behavior (i.e., exhaled carbon monoxide levels of smokers) predicted BVMT-R T score; greater smoking was associated with more impaired visual learning. Negative symptom severity was not predictive of greater visual learning deficits in smokers or nonsmokers. Future longitudinal research will be required to determine if there is a dose-response relationship between chronic nicotine and visual learning impairment in patients at various stages of psychotic illness.

Intrinsic hippocampal activity as a biomarker for cognition and symptoms in schizophrenia.

OBJECTIVE: Identification of biomarkers for cognitive dysfunction in schizophrenia is a priority for psychiatry research. Functional imaging studies suggest that intrinsic "resting state" hippocampal hyperactivity is a characteristic feature of schizophrenia. The relationships between this phenotype and symptoms of the illness, however, are largely unexplored. The authors examined resting hippocampal activity in schizophrenia patients and healthy comparison subjects and analyzed the relationship between intrinsic hippocampal activity and cognitive function in patients as measured by the MATRICS Consensus Cognitive Battery (MCCB). METHOD: Twenty-eight schizophrenia patients and 28 age-matched healthy comparison subjects underwent functional "resting state" 3-T MR scanning. Hippocampal activity was extracted by group independent component analysis. Correlation analyses were used to examine the relationship between hippocampal activity and MCCB composite and domain scores in patients, as well as between hippocampal activity and positive and negative symptoms. RESULTS: Greater activity of the right hippocampus at rest was observed in patients relative to comparison subjects. In patients, a significant negative correlation was observed between right hippocampal activity and composite MCCB T-score. The correlation was driven by the MCCB domains of attention/vigilance, working memory, and visual learning. Hippocampal activity was positively correlated with negative symptoms. MCCB scores were inversely correlated with negative symptoms. CONCLUSIONS: These findings suggest that greater intrinsic hippocampal activity is a characteristic feature of schizophrenia that is broadly associated with cognitive dysfunction, and they support hippocampal activity as a candidate biomarker for therapeutic development.

Initial phase 2 trial of a nicotinic agonist in schizophrenia.

OBJECTIVE: Nicotinic acetylcholine receptors are possible therapeutic targets for schizophrenia, as shown by neurobiological and molecular evidence for deficiencies in expression of alpha(7)-nicotinic receptors. Patients' heavy smoking suggests attempted self-medication through this mechanism. The agent 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) is a partial alpha(7)-nicotinic agonist and can be taken orally. A phase 1 trial showed evidence for cognitive enhancement in schizophrenia. METHOD: Thirty-one subjects with schizophrenia received DMXB-A at two different doses and placebo for periods of 4 weeks in a three-arm, two-site, double-blind, crossover phase 2 trial. The MATRICS Consensus Cognitive Battery assessed cognitive effects, and the Scale for the Assessment of Negative Symptoms (SANS) and Brief Psychiatric Rating Scale (BPRS) assessed clinical effects. Subjects continued their current antipsychotic drug during the trial and were nonsmokers. RESULTS: There were no significant differences in the MATRICS cognitive measures between DMXB-A and placebo over the three treatment arms, but the patients experienced significant improvement at the higher DMXB-A dose on the SANS total score and nearly significant improvement on the BPRS total score. Improvement was most notable on the SANS anhedonia and alogia subscales. Examination of the first treatment arm showed effects of DMXB-A on the attention/vigilance and working memory MATRICS domains, compared to baseline. Five subjects developed mild tremor, and nearly half had mild nausea while taking DMXB-A. CONCLUSION: DMXB-A, a nicotinic agonist that activates alpha(7)-nicotinic receptors, improved clinical ratings of negative symptoms that are generally resistant to treatment with dopamine antagonist antipsychotic drugs. The clinical utility of this treatment is not yet determined.

Symbol vs. digit substitution task performance in diverse cultural and linguistic groups.

In spite of limited empirical data to guide their use, nonverbal neuropsychological measures are frequently utilized in the assessment of non-native English speakers in an effort to minimize cultural and linguistic factors that may influence performance. In this study, three groups of participants from different cultural and linguistic backgrounds were compared on two brief, nonverbal substitution tasks sensitive to cerebral dysfunction: WAIS-R Digit Symbol and the Symbol Digit Modalities Test. Within each group, participants exhibited a similar pattern of performance, earning higher scores on Digit Symbol. However, when dominant Spanish speakers were further subdivided into higher and lower education groups, less educated Spanish speakers achieved lower scores compared to all other groups on both tasks, and failed to show the performance advantage for Digit Symbol. In spite of differences in the respective countries of educational experience, the more highly educated dominant Spanish speakers performed as well as monolingual nonHispanic and Hispanic bilingual participants on both tasks. Years of formal education appears to be the most relevant variable in explaining performance differences across cultural and linguistic groups on these tasks.

Stability of attention deficits in schizophrenia.

Deficits in attention and concentration are consistently identified as an enduring feature of schizophrenia and interfere significantly with successful social and occupational functioning in individuals with this illness. The short-term effects of hospitalization (2 weeks) on attention dysfunction in individuals with schizophrenia were studied in comparison to nonpsychiatric, healthy individuals. In addition, patients who remained stable on medications throughout hospitalization were compared to patients initiating an antipsychotic regimen upon admission. Attention and concentration were significantly enhanced after two weeks in the previously unmedicated group. However, improvement failed to reach the level of performance of comparison subjects.

Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia.

CONTEXT: The alpha7 nicotinic acetylcholine receptor gene, CHRNA7, is associated with genetic transmission of schizophrenia and related cognitive and neurophysiological sensory gating deficits. Cognitive dysfunction is responsible for significant psychosocial disability in schizophrenia. Nicotine, a low-potency agonist at the alpha7 receptor, has some positive effects on neurophysiological and neurocognitive deficits associated with schizophrenia, which suggests that more effective receptor activation might meaningfully enhance cognition in schizophrenia. OBJECTIVES: To determine if 3-[(2,4-dimethoxy)benzylidene]anabaseine (DMXB-A), a natural alkaloid derivative and a partial alpha7 nicotinic cholinergic agonist, significantly improves neurocognition, and to assess, by effects on P50 auditory evoked potential inhibition, whether its neurobiological actions are consistent with activation of alpha7 nicotinic receptors. DESIGN: Randomized, double-blind crossover trial of 2 drug doses and 1 placebo. SETTING: General clinical research center. PATIENTS: Twelve persons with schizophrenia who did not smoke and were concurrently treated with antipsychotic drugs. One person was withdrawn because of a transient decrease in white blood cell count. INTERVENTION: Administration of DMXB-A. MAIN OUTCOME MEASURES: Total scale score of the Repeatable Battery for the Assessment of Neuropsychological Status and P50 inhibitory gating. RESULTS: Significant neurocognitive improvement was found on the Repeatable Battery for the Assessment of Neuropsychological Status total scale score, particularly for the lower DMXB-A dose compared with placebo. Effects were greater than those of nicotine in a similar study. Significant improvement in P50 inhibition also occurred. Patients generally tolerated the drug well. CONCLUSIONS: An alpha7 nicotinic agonist appears to have positive effects on neurocognition in persons with schizophrenia. Longer trials are needed to determine the clinical utility of this novel treatment strategy.

Improved p50 auditory gating with ondansetron in medicated schizophrenia patients.

OBJECTIVE: Most schizophrenia patients have a deficit in auditory sensory gating, which appears to be mediated by the alpha-7 nicotinic receptor, that is not improved with conventional antipsychotic treatment. This study examined the effects of ondansetron, a highly selective 5-HT3 antagonist, on the P50 auditory evoked potential. METHOD: Eight medicated outpatients with schizophrenia were given either ondansetron (16 mg) or placebo in a double-blind, placebo-controlled design. Evoked potentials were recorded at baseline and 1 hour, 2 hours, and 3 hours after receipt of drug. RESULTS: There was a highly significant improvement in P50 gating after ondansetron treatment. The maximal treatment difference was at 2 hours posttreatment (ondansetron: mean=41.4%, SD=39.7%; placebo: mean=80.2%, SD=21.3%). CONCLUSIONS: Ondansetron significantly enhanced P50 auditory gating in schizophrenia patients treated with typical antipsychotics.

Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients.

OBJECTIVE: Sensory gating deficits found in schizophrenia can be assessed by using a paired auditory stimulus paradigm to measure auditory evoked response. The ratio of the P50 response amplitude of the second or test stimulus to that of the first or conditioning stimulus is expressed as a percentage. Normal subjects generally suppress the second response and typically have ratios of less than 40%. Subjects with schizophrenia and half their first-degree relatives have deficits in sensory gating, with P50 ratios that are generally greater than 50%. Treatment with typical neuroleptics does not reverse this deficit. However, previous studies have shown that treatment with clozapine, an atypical neuroleptic, ameliorates this deficit in clinically responsive patients. This study sought to determine whether other atypical neuroleptics improve P50 ratios. METHOD: P50 evoked potential recordings were obtained from 132 patients with schizophrenia and 177 healthy comparison subjects. Eighty-eight patients were being treated with atypical neuroleptics (clozapine [N=26], olanzapine [N=31], risperidone [N=22], and quetiapine [N=9]). Thirty-four patients were taking typical neuroleptics, and 10 were unmedicated. RESULTS: Healthy subjects exhibited P50 suppression that was significantly better than the schizophrenia patients receiving typical neuroleptics (mean=19.8% [SD=21.0%] versus 110.1% [SD=87.9%]). Patients receiving atypical neuroleptics had a mean P50 ratio that fell between these two means (mean=70.4%, SD=53.7%). When patients treated with different atypical neuroleptics were compared, only the clozapine group had mean P50 ratios that were in the normal range. All other groups exhibited auditory P50 response inhibition that was significantly poorer than that of the healthy subjects. CONCLUSIONS: Improvement in P50 gating appears to be greatest in patients treated with clozapine.

Effects of nicotine on cognitive deficits in schizophrenia.

Several lines of evidence suggest a pathophysiological role for nicotinic receptors in schizophrenia. Activation by nicotine alters physiological dysfunctions, such as eye movement and sensory gating abnormalities, but effects on neuropsychological performance are just beginning to be investigated. Nicotine-induced desensitization and the well-known tachyphylaxis of nicotinic receptors may confound such efforts. In all, 20 schizophrenics, 10 smokers, and 10 nonsmokers were assessed following the administration of nicotine gum and placebo gum. The Repeatable Battery for the Assessment of Neuropsychological Status was administered. Nicotine affected only the Attention Index; there were no effects on learning and memory, language, or visuospatial/constructional abilities. Attentional function was increased in nonsmokers, but decreased in nicotine-abstinent smokers after nicotine administration. The effects of nicotine in schizophrenia do not extend to all areas of cognition. Effects on attention may be severely limited by tachyphylaxis, such that decremented performance occurs in smokers, while modest effects may be achieved in nonsmokers.

Gliomatosis cerebri: neurobehavioral and neuropathological observations.

BACKGROUND: Gliomatosis cerebri is a rare neoplasm in which individual neoplastic cells diffusely permeate the brain; a cohesive tumor mass may appear late in the disease course, or not at all. The diagnosis can be made either at autopsy or premortem by combining biopsy and neuroimaging findings to demonstrate involvement of more than two lobes of the brain. Extensive hemispheric white matter and corpus callosum infiltration is characteristic, with lesser spread to subcortical and cortical gray matter. Whereas this pattern of localization can be predicted to cause significant disturbances of higher function, the neurobehavioral profile of gliomatosis cerebri patients has not been well described. METHOD: Three patients with gliomatosis cerebri had detailed neurobehavioral assessment, and one had neuropsychological testing early in the disease. Neuropathological investigation focused on the localization of the neoplasm, the correlation between extent of myelin and axon damage with tumor cell density, and the histogenesis of the tumor. RESULTS: The patient with neuropsychological testing had impaired executive function and verbal memory retrieval that reflected bifrontal and left temporal white matter tumor involvement seen on neuroimaging. In the other cases, apathy and fatigue progressed to severe dementia in association with bihemispheric white matter infiltration. Myelin and axon stains and myelin stains showed relative preservation of white matter architecture with severity of damage paralleling increased tumor cell density. Immunostaining for TP53 was found in a high percentage of tumor nuclei in two of three cases, suggesting overlapping features between gliomatosis cerebri and diffuse astrocytomas. CONCLUSIONS: Subtle cognitive and emotional alterations antedate the florid dementia that develops later in the course of gliomatosis cerebri. Clinical, neuroimaging, and neuropathological data suggest that white matter is damaged directly by the tumor and its associated mild edema, although infiltration of subcortical and cortical gray matter also occurs to a variable extent. Strong TP53 immunostaining in gliomatosis cerebri suggests a commonality with diffuse fibrillary astrocytomas that also often show TP53 staining. Gliomatosis cerebri can be considered a cause of white matter dementia resulting from preferential neoplastic disruption of white matter tracts.

Admixture analysis of smooth pursuit eye movements in probands with schizophrenia and their relatives suggests gain and leading saccades are potential endophenotypes.

Abnormalities during a smooth pursuit eye movement task (SPEM) are common in schizophrenic patients and their relatives. This study assessed various components of SPEM performance in first-degree unaffected relatives of schizophrenic patients. One hundred individuals with schizophrenia, 137 unaffected first-degree relatives, and 69 normal controls completed a 16.7 degrees/s SPEM task. Smooth pursuit gain, catch-up saccades (CUS), large anticipatory saccades, and leading saccades (LS) were identified. Groups were compared with parametric and admixture analyses. Schizophrenic patients performed more poorly than unaffected relatives and normals on gain, CUS, and LS. Unaffected relatives were more frequently impaired than normals only on gain and LS. Relatives of childhood-onset and adult-onset probands had similar impairments. Gain and frequency of leading saccades may be genetic endophenotypes in childhood-onset and adult-onset schizophrenia.

Increased hippocampal volume in schizophrenics' parents with ancestral history of schizophrenia.

OBJECTIVE: Decreased hippocampal volume is one of the hypothesized pathological features of schizophrenia, but it is not known if this abnormality is familially transmitted. The aim of this study was to measure the hippocampal volume of the parents of schizophrenic probands, in relationship to the apparent transmission of genetic risk. METHOD: Eighteen subjects from families consisting of a schizophrenic proband and two clinically unaffected parents were studied. Probands were compared to six control subjects, matched for age, sex, and educational level. The six families were selected so that only one parent had an ancestral family history of schizophrenia. The volumes of both hippocampi were measured by magnetic resonance imaging and adjusted for age and whole brain volume. RESULTS: The total hippocampal volumes of the parents with ancestral family history of schizophrenia were significantly larger than those of their schizophrenic offspring. CONCLUSIONS: This study suggests that decreased hippocampal volume in schizophrenia is not a familially transmitted abnormality. Rather, it appears that clinically unaffected parents who transmit apparent genetic risk for schizophrenia may have increased hippocampal volume, which may be a protective factor against the illness.