Episodic memory deficits are a core feature of neurodegenerative disorders. Muscarinic M sub(1) receptors play a critical role in modulating learning and memory and are highly expressed in the ...hippocampus. We examined the effect of GSK1034702, a potent M sub(1) receptor allosteric agonist, on cognitive function, and in particular episodic memory, in healthy smokers using the nicotine abstinence model of cognitive dysfunction. The study utilized a randomized, double-blind, placebo-controlled, cross-over design in which 20 male nicotine abstained smokers were tested following single doses of placebo, 4 and 8 mg GSK1034702. Compared to the baseline (nicotine on-state), nicotine abstinence showed statistical significance in reducing immediate (p=0.019) and delayed (p=0.02) recall. GSK1034702 (8 mg) significantly attenuated (i.e. improved) immediate recall (p=0.014) but not delayed recall. None of the other cognitive domains was modulated by either nicotine abstinence or GSK1034702. These findings suggest that stimulating M sub(1) receptor mediated neurotransmission in humans with GSK1034702 improves memory encoding potentially by modulating hippocampal function. Hence, selective M sub(1) receptor allosteric agonists may have therapeutic benefits in disorders of impaired learning including Alzheimer's disease.
Evidence is reviewed that dysplastic brain development in the second half of pregnancy predisposes to schizophrenia. We suggest that an important corollary of aberrant development at this stage of ...ontogenesis is abnormal afferentation of the cortical plate, and that this may be macroscopically measurable in terms of abnormal correlational structure in adult brain imaging data. This prediction is tested by analysis of multiple cortical volume measures on magnetic resonance imaging data acquired from 35 male right-handed schizophrenics and 35 matched controls. There are no significant differences between groups in global, intra-hemispheric or inter-hemispheric correlational structure; but schizophrenics are shown to have significantly reduced dependencies between frontal and temporal lobe volumes, and frontal and hippocampal volumes, in the left hemisphere. We conclude that anatomical dysconnectivity (between frontal and temporal cortex) in schizophrenia may be caused by dysplasia.
Establishing a neurobiological account of delusion formation that links cognitive processes, brain activity, and symptoms is important to furthering our understanding of psychosis.
To explore a ...theoretical model of delusion formation that implicates prediction error-dependent associative learning processes in a pharmacological functional magnetic resonance imaging study using the psychotomimetic drug ketamine.
Within-subject, randomized, placebo-controlled study.
Hospital-based clinical research facility, Addenbrooke's Hospital, Cambridge, England. The work was completed within the Wellcome Trust and Medical Research Council Behavioral and Clinical Neuroscience Institute, Cambridge.
Fifteen healthy, right-handed volunteers (8 of whom were male) with a mean +/- SD age of 29 +/- 7 years and a mean +/- SD predicted full-scale IQ of 113 +/- 4 were recruited from within the local community by advertisement.
Subjects were given low-dose ketamine (100 ng/mL of plasma) or placebo while performing a causal associative learning task during functional magnetic resonance imaging. In a separate session outside the scanner, the dose was increased (to 200 ng/mL of plasma) and subjects underwent a structured clinical interview.
Brain activation, blood plasma levels of ketamine, and scores from psychiatric ratings scales (Brief Psychiatric Ratings Scale, Present State Examination, and Clinician-Administered Dissociative States Scale).
Low-dose ketamine perturbs error-dependent learning activity in the right frontal cortex (P = .03). High-dose ketamine produces perceptual aberrations (P = .01) and delusion-like beliefs (P = .007). Critically, subjects showing the highest degree of frontal activation with placebo show the greatest occurrence of drug-induced perceptual aberrations (P = .03) and ideas or delusions of reference (P = .04).
These findings relate aberrant prediction error-dependent associative learning to referential ideas and delusions via a perturbation of frontal cortical function. They are consistent with a model of delusion formation positing disruptions in error-dependent learning.
When considering the cognitive abilities of people with autism, the majority of studies have explored domains in which there are deficits. However, on tests of local processing and visual search, ...exemplified by the Embedded Figures Task (EFT), people with autism have been reported to demonstrate superiority over normal controls. This study employed functional MRI of subjects during the performance of the EFT to test the hypothesis that normal subjects and a group with autism would activate different brain regions and that differences in the patterns of these regional activations would support distinct models of cerebral processing underlying EFT performance in the two groups. It was found that several cerebral regions were similarly activated in the two groups. However, normal controls, as well as demonstrating generally more extensive task-related activations, additionally activated prefrontal cortical areas that were not recruited in the group with autism. Conversely, subjects with autism demonstrated greater activation of ventral occipitotemporal regions. These differences in functional anatomy suggest that the cognitive strategies adopted by the two groups are different: the normal strategy invokes a greater contribution from working memory systems while the autistic group strategy depends to an abnormally large extent on visual systems for object feature analysis. This interpretation is discussed in relation to a model of autism which proposes a predisposition towards local rather than global modes of information processing.
Background Binge drinking is a serious public health issue associated with cognitive, physiological, and anatomical differences from healthy individuals. No studies, however, have reported ...subcortical grey matter differences in this population. To address this, we compared the grey matter volumes of college-age binge drinkers and healthy controls, focusing on the ventral striatum, hippocampus and amygdala. Method T1-weighted images of 19 binge drinkers and 19 healthy volunteers were analyzed using voxel-based morphometry. Structural data were also covaried with Alcohol Use Disorders Identification Test (AUDIT) scores. Cluster-extent threshold and small volume corrections were both used to analyze imaging data. Results Binge drinkers had significantly larger ventral striatal grey matter volumes compared to controls. There were no between group differences in hippocampal or amygdalar volume. Ventral striatal, amygdalar, and hippocampal volumes were also negatively related to AUDIT scores across groups. Conclusions Our findings stand in contrast to the lower ventral striatal volume previously observed in more severe forms of alcohol use disorders, suggesting that college-age binge drinkers may represent a distinct population from those groups. These findings may instead represent early sequelae, compensatory effects of repeated binge and withdrawal, or an endophenotypic risk factor.
Impairments in the neural circuitry of verbal working memory are evident in depression. Factors of task demand and depressive state might have significant effects on its functional neuroanatomy. ...Methods Two groups underwent functional magnetic resonance imaging while performing a verbal working memory task of varying cognitive load (n-back). The patient group comprised 20 medication-free individuals in an acute episode of unipolar major depression and the control group comprised 20 healthy individuals. Scans were acquired at weeks 0 (baseline), 2, and 8. Patients received treatment with fluoxetine after the baseline scan. Cerebral activations were measured for mean overall activation as well as the linear and quadratic load-response activity with increasing task demand (1-, 2-, 3-back). Results There were no significant differences in performance accuracy between groups. However, a main effect of group was observed in the load-response activity in frontal and posterior cortical regions within the verbal working memory network in which patients showed a greater load-response relative to control subjects. Group by time effects were revealed in the load-response activity in the caudate and thalamus. As a marker of treatment response, a lower linear load-response at baseline in the dorsal anterior cingulate, left middle frontal, and lateral temporal cortices was associated with an improved clinical outcome. Conclusions Maintenance of performance accuracy in patients was accompanied by a significant increase in the load-response activity in frontal and posterior cortical regions within the verbal working memory network. These data also provide further support for resilience of activity in the anterior cingulate as a predictor of treatment response in depression.
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