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Four sites collaborated with the NIMH to develop a resource for the genetic study of bipolar (BP) illness. Common methods of ascertainment and assessment were developed in 1989. A series of families with a bipolar I (BPI) proband and at least one BPI or schizoaffective, bipolar type (SA/BP) first-degree relative has been studied. We now report initial data from a genomic survey with an average intermarker interval of 10 cM on 540 subjects from 97 families. This is the largest commonly ascertained and assessed linkage sample for bipolar illness reported to date; it includes 232 subjects with BPI, 32 SA/BP, 72 bipolar II (BPII), and 88 unipolar, recurrent (UPR). Nonparametric methods of analysis were employed, with all sites using affected sib pair analysis. The strongest findings thus far appear to be on chromosomes 1, 6, 7, 10, 16, and 22. Support has also been found for some previously reported linkages, including 21q and possibly Xq26. All these areas (as well as others) will be followed up with additional markers and further analyses. No locus tested thus far meets stringent criteria for an initial finding of significant linkage. Am. J. Med. Genet. 74:227-237, 1997. © 1997 Wiley-Liss, Inc.KEY WORDS: bipolar affective disorder; genetics; linkage; genomic survey; nonparametric analysis INTRODUCTIONBipolar affective disorder (BP) is a disabling condition involving dysregulation of multiple physiologic functions, including mood, appetite, sleep, and activity [Goodwin and Jamison, 1990]. It occurs in about 1% of the population, with usual onset in young adulthood. With appropriate management the condition is substantially treatment-responsive, but episodes tend to recur throughout life. This condition has long been observed to aggregate within families [Nurnberger et al., 1994b]. Twin and adoption studies suggest significant heritable risk factors [Bertelsen et al., 1977;Mendlewicz and Rainer, 1977]. The genetics of BP illness is complex, with segregation analyses generally not consistent with single major locus inheritance [Nurnberger et al., 1994b]. No pathognomonic biochemical abnormality is currently known to be present, and diagnosis is based on clinical history and presentation.Following the successful identification of linkage of Huntington disease to markers on chromosome 4 [Gusella et al., 1983], the interest of investigators in psychiatric genetics moved toward the application of molecular methods to the major psychiatric disorders. The paradigm for Mendelian disorders at that time was the identification of single large pedigrees with multiple cases of illness over several generations, and analysis of restriction fragment length polymorphism (RFLP) variation within the pedigree using the LOD score method. Egeland et al. [1987] reported linkage between BP and markers on chromosome 11p15 in a large Amish family. Subsequent studies in other samples, however, did not confirm this finding [DeteraWadleigh et al., 1987;Hodgkinson et al., 1987], and a later analysis in the same family, with additional clinical i...

Background: Pharmacological magnetic resonance imaging has been used to investigate the neural effects of subanaesthetic ketamine in healthy volunteers. However, the effect of ketamine has been modelled with a single time course and without consideration of physiological noise. Aims: This study aimed to investigate ketamine-induced alterations in resting neural activity using conventional pharmacological magnetic resonance imaging analysis techniques with physiological noise correction, and a novel analysis utilising simultaneously recorded electroencephalography data. Methods: Simultaneous electroencephalography/functional magnetic resonance imaging and physiological data were collected from 30 healthy male participants before and during a subanaesthetic intravenous ketamine infusion. Results: Consistent with previous literature, we show widespread cortical blood-oxygen-level dependent signal increases and decreased blood-oxygenlevel dependent signals in the subgenual anterior cingulate cortex following ketamine. However, the latter effect was attenuated by the inclusion of motion regressors and physiological correction in the model. In a novel analysis, we modelled the pharmacological magnetic resonance imaging response with the power time series of seven electroencephalography frequency bands. This showed evidence for distinct temporal time courses of neural responses to ketamine. No electroencephalography power time series correlated with decreased blood-oxygen-level dependent signal in the subgenual anterior cingulate cortex. Conclusions: We suggest the decrease in blood-oxygen-level dependent signals in the subgenual anterior cingulate cortex typically seen in the literature is the result of physiological noise, in particular cardiac pulsatility. Furthermore, modelling the pharmacological magnetic resonance imaging response with a single temporal model does not completely capture the full spectrum of neuronal dynamics. The use of electroencephalography regressors to model the response can increase confidence that the pharmacological magnetic resonance imaging is directly related to underlying neural activity.

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