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Functional magnetic resonance imaging of effects of a nicotinic agonist in schizophrenia.

ABSTRACT: 3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at alpha7-nicotinic acetylcholine receptors and is now in early clinical development for treatment of deficits in neurocognition and sensory gating in schizophrenia. During its initial phase 2 test, functional magnetic resonance imaging (fMRI) studies were conducted to determine whether the drug had its intended effect on hippocampal inhibitory interneurons. Increased hemodynamic activity in the hippocampus in schizophrenia is found during many tasks, including smooth pursuit eye movements, and may reflect inhibitory dysfunction. Placebo and two doses of drug were administered in a random, double-blind crossover design. After the morning drug/placebo ingestion, subjects underwent fMRI while performing a smooth pursuit eye movement task. Data were analyzed from 16 nonsmoking patients, including 7 women and 9 men. The 150-mg dose of DMXB-A, compared with placebo, diminished the activity of the hippocampus during pursuit eye movements, but the 75-mg dose was ineffective. The effect at the 150-mg dose was negatively correlated with plasma drug levels. The findings are consistent with the previously established function of alpha7-nicotinic receptors on inhibitory interneurons in the hippocampus and with genetic evidence for deficits in these receptors in schizophrenia. Imaging of drug response is useful in planning future clinical tests of this compound and other nicotinic agonists for schizophrenia.

SUBMITTER: Tregellas JR

PROVIDER: S-EPMC2834253 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Functional magnetic resonance imaging of effects of a nicotinic agonist in schizophrenia.

Tregellas Jason R JR Olincy Ann A Johnson Lynn L Tanabe Jody J Shatti Shireen S Martin Laura F LF Singel Debra D Du Yiping P YP Soti Ferenc F Kem William R WR Freedman Robert R

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20091202 4

3-(2,4-Dimethoxybenzylidene)-anabaseine (DMXB-A) is a partial agonist at alpha7-nicotinic acetylcholine receptors and is now in early clinical development for treatment of deficits in neurocognition and sensory gating in schizophrenia. During its initial phase 2 test, functional magnetic resonance imaging (fMRI) studies were conducted to determine whether the drug had its intended effect on hippocampal inhibitory interneurons. Increased hemodynamic activity in the hippocampus in schizophrenia is ...[more]

PMID: 19956085

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Project description:Schizophrenia symptoms can be conceptualized in terms of a breakdown of a balance between 1) activating, retrieving, and matching stored representations to incoming information (semantic memory-based processing) and 2) fully integrating activated semantic representations with one another and with other types of representations to form a gestalt representation of meaning (semantic integration). Semantic memory-based processes are relatively more dependent on inferior frontal and temporal cortices, whereas particularly demanding integrative processes additionally recruit the dorsolateral prefrontal cortex (DLPFC) and sometimes parietal cortices. We used functional magnetic resonance imaging (fMRI) to determine whether the modulation of temporal/inferior frontal cortices and the DLPFC can be neuroanatomically dissociated in schizophrenia, as semantic integration demands increase. Integration demands were manipulated by varying the nature (concrete vs. abstract) and the congruity (incongruous vs. congruous) of words within sentences.Sixteen right-handed schizophrenia patients and 16 healthy volunteers, matched on age and parental socioeconomic status, underwent event-related fMRI scanning while they read sentences. Blood oxygen level dependent (BOLD) effects were contrasted to words within sentences that were 1) concrete versus abstract and 2) semantically incongruous versus congruous with their preceding contexts.In both contrasts, large networks mediating the activation and retrieval of verbal and imagistic representations were normally modulated in patients. However, unlike control subjects, patients failed to recruit the DLPFC, medial frontal and parietal cortices to incongruous (relative to congruous) sentences, and failed to recruit the DLPFC to concrete (relative to abstract) sentences.As meaning is built from language, schizophrenia patients demonstrate a neuroanatomical dissociation in the modulation of temporal/inferior frontal cortices and the DLPFC.

Project description:Schizophrenia is a devastating illness with an indeterminate pathophysiology. Several lines of evidence implicate dysfunction in the thalamus, a key node in the distributed neural networks underlying perception, emotion, and cognition. Existing evidence of aberrant thalamic function is based on indirect measures of thalamic activity, but dysfunction has not yet been demonstrated with a causal method.To test the hypothesis that direct physiological stimulation of the cortex will produce an abnormal thalamic response in individuals with schizophrenia.We stimulated the precentral gyrus with single-pulse transcranial magnetic stimulation (spTMS) and measured the response to this pulse in synaptically connected regions (thalamus, medial superior frontal cortex, insula) using concurrent functional magnetic resonance imaging. The mean hemodynamic response from these regions was fit with the sum of 2 gamma functions, and response parameters were compared across groups.Academic research laboratory.Patients with schizophrenia and sex- and age-matched psychiatrically healthy subjects were recruited from the community.Peak amplitude of the thalamic hemodynamic response to spTMS of the precentral gyrus.The spTMS-evoked responses did not differ between groups at the cortical stimulation site. Compared with healthy subjects, patients with schizophrenia showed a reduced response to spTMS in the thalamus (P=1.86 × 10(-9)) and medial superior frontal cortex (P=.02). Similar results were observed in the insula. Sham TMS indicated that these results could not be attributed to indirect effects of TMS coil discharge. Functional connectivity analyses revealed weaker thalamus-medial superior frontal cortex and thalamus-insula connectivity in patients with schizophrenia compared with control subjects.Individuals with schizophrenia showed reduced thalamic activation in response to direct perturbation delivered to the cortex. These results extend prior work implicating the thalamus in the pathophysiology of schizophrenia and suggest that the thalamus contributes to the patterns of aberrant connectivity characteristic of this disease.

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Functional magnetic resonance imaging of effects of a nicotinic agonist in schizophrenia.

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Functional magnetic resonance imaging of effects of a nicotinic agonist in schizophrenia.

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