Robert Freedman

..It is certain that there are many genetic factors in schizophrenia and bipolar disorder; what is needed is a complete and precise description of the contribution of each individual factor to the pathophysiology of these illnesses...

..Examples are given from work on the role of the alpha(T)nicotinic receptor and its gene CHRNA7 on chromosome 15 in the neurobiology and genetic transmission of schizophrenia...

..Further sequencing in these two groups may yield more definitive identification of the molecular pathology...

..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...

..Thus, as predicted by Venables, the substrates of schizotypy and schizophrenia may arise from variants in normal brain function...

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..The alpha7-receptor is a ligand-gated ion channel that admits calcium ions into cells, and it has been proposed to have various developmental roles. Its malfunction may be part of the developmental pathogenesis of schizophrenia...

..Polymorphisms in the core promoter of the gene are associated with schizophrenia and also with diminished inhibition of the P50 response. These genetic data may identify a new pathophysiologic target for drug discovery...

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..This study examined the effects of DMXB-A on default network activity as a biomarker for drug effects on pathologic brain function associated with schizophrenia...

..This improvement was blocked by pre-administration of alpha-bungarotoxin but not di-hydro-beta-erythroidine. Like clozapine, olanzapine acts via alpha7 nicotinic receptors to elicit improved inhibitory processing of auditory stimuli...

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..A second aim was to determine whether subjects with schizoaffective disorder, bipolar type, were neurophysiologically more similar to subjects with schizophrenia or subjects with bipolar disorder...

..We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes...

..Imaging of drug response is useful in planning future clinical tests of this compound and other nicotinic agonists for schizophrenia...

..The purpose of this study was to determine if CHRNA7 promoter allelic variants are also associated with abnormal P50 ratios in persons with schizoaffective disorder, bipolar type...

..Exploration of the genetic architecture of specific endophenotypes may be a powerful strategy for understanding the genetic basis of schizophrenia...

..This study fine-mapped genes at 15q13-q14 to determine whether the association is unique to CHRNA7...

..005, allele p=0.015), and in Caucasians (genotype p=0.015, allele p=0.009). We conclude that the presence of the 2 bp polymorphism at the CHRFAM7A locus may have a functional significance in schizophrenia...

..Genetic studies now often employ multiple, geographically dispersed test sites to accommodate the need for large and complex study samples. Here, we assessed the feasibility of using PPI in multi-site studies...

..Twenty-one variants were found in the exons, but non-synonymous changes were rare. Although the expression of CHRNA7 is decreased in schizophrenia, the general structure of the remaining receptors is likely to be normal...

..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...

..The lack of a main effect on withdrawal, but correlation of thalamic blood flow with withdrawal symptoms suggests that more complex mechanisms mediate the subjective features of the withdrawal state...

..Therapeutic implications, including perinatal dietary choline supplementation, are discussed...

..This study used functional magnetic resonance imaging (fMRI) to examine changes in brain hemodynamic response associated with nicotine administration during a smooth pursuit eye movement task in subjects with schizophrenia...

..This inhibitory process, which involves the alpha(7) nicotinic receptor mediated release of gamma-aminobutyric acid (GABA) by hippocampal interneurons, represents a potential new target for therapeutic intervention in schizophrenia...

..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...

..The results are consistent with the hypothesis that genetic liability in HR offspring increases risk for prodromal symptoms, and prodromal symptoms, in turn, increase risk for impaired sensory gating...

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..Effects on attention may be severely limited by tachyphylaxis, such that decremented performance occurs in smokers, while modest effects may be achieved in nonsmokers...

..In addition, session-dependent changes in activation were greater in some regions than others and may indicate areas of brain, such as the supplementary eye fields, that are sensitive to attentional modulation of eye movements...

..The purpose of this work was to determine if nicotine differentially affects brain activity in schizophrenic and control subjects during pursuit eye tracking...

..The investigators used functional magnetic resonance imaging (fMRI) to compare brain hemodynamic response during a smooth pursuit eye movement task in patients with schizophrenia and healthy comparison subjects...

..This study presents DNA sequence analysis of the core promoter region for CHRNA7 in schizophrenic and control subjects...

..This study used functional magnetic resonance imaging (fMRI) to investigate the functional neuroanatomy of sensory gating deficits in schizophrenia...

..alpha7 Nicotinic acetylcholine receptor agonists appear to be viable candidates for the treatment of cognitive disturbances in schizophrenia...

..The endophenotype strategy offers powerful and exciting opportunities to understand the genetically conferred neurobiological vulnerabilities and possible new strong inference and molecularly based treatments for schizophrenia...

..The atypical antipsychotic clozapine also normalizes this deficit in schizophrenia patients, but by an unknown mechanism...

..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...

..These results suggest that REM sleep is an appropriate state during which to assess P50 gating in order to disentangle the effects of state and trait on sensory gating impairment in other clinical populations...

..The authors investigated the effects of perinatal choline supplementation on the development of cerebral inhibition in human infants...

..The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment...

..The authors used P50 auditory sensory gating, a putative marker of early attentional processes measurable in young infants, to assess the impact of maternal anxiety and antidepressant use...

..The early appearance and complex, prolonged pattern of development of the alpha7 receptor suggest that it may influence processes as diverse as cell migration, dendritic elaboration and apoptosis during hippocampal maturation...

..Nevertheless, these results demonstrate that the neural circuits underlying sensory gating are functional very early in postnatal development...

..Evidence from multiple studies supports a broad region of genetic linkage around the marker D15S1360...

..We demonstrate that local eye movements will influence whole-head motion correction procedures, resulting in inaccurate movement parameters and potentially lowering the sensitivity to detect activations...

..However, auto-detrending (selecting the best algorithm or none, if detrending is not useful) appears to be the most judicious choice, particularly for analyzing fMRI data with weak activations in the presence of baseline drift...

..These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia...

..Event-related potentials (ERPs) have been suggested as possible endophenotypes of schizophrenia. We investigated the test-retest reliabilities and heritabilities of three ERP components in healthy monozygotic and dizygotic twin pairs...

..These results suggest that behavioral measures of time processing may reflect different processes than those captured by preattentive physiological measures in this population...

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..Similar to schizophrenic patients, DBA/2 mice spontaneously exhibit a deficit in inhibitory processing of the P20-N40 auditory evoked potential, which is thought to be a rodent analog of the human P50 auditory evoked potential...

..These results confirm previous findings of antisaccade deficits in schizophrenia subjects and support the use of the antisaccade task as a potential schizophrenia endophenotype in multi-site genetic studies...

..This article reviews the rationale for these 3 approaches and provides an update on the development of therapeutic agents, which act through one of these 3 mechanisms...

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..3-p15.2, 5p15.2-q13.3, 10p15.3-p14, 10q25.3-q26.3, and 11p13-q23.3. The highest increase in Z(lr) scores was observed for 5p14.1-q12.1, where the maximum Z(lr) increased from 2.77 initially to 3.80 after fine mapping in the EA families...

..Given the heritability of BP disorder, the lack of agreement between studies emphasizes that susceptibility alleles are likely to be modest in effect size and require even larger samples for detection...