Psychiatric and genetic studies of binocular rivalry: an endophenotype for bipolar disorder?

In the early twentieth century, it was reported that the rate of perceptual alternation of the Necker cube (shown in Fig. 1a) was slower in patients with manic depression than in patients with dementia praecox (1,2). Despite several subsequent studies of perceptual alternation rates in psychiatric groups [see (3)], these observations remained relatively obscure until, independently and serendipitously, Pettigrew and Miller (4) found similar slowing of alternation rate in bipolar disorder (BD) using binocular rivalry. Like the Necker cube, binocular rivalry involves perceptual alternations every few seconds (Fig. 1b), but occurs because of conflicting retinal input rather than conflicting depth perspectives. Pettigrew and Miller (4) examined binocular rivalry rate (BRR) in a sample of euthymic subjects with BD-I and controls. Their first study used high-strength stimuli, i.e. drifting gratings of high spatial frequency, and found BRR was indeed significantly slower in BD. These high-strength stimuli produced excellent group separation, as shown in Fig. 2a, though with some clear false positives and false negatives. On average, control subjects would experience perceptual switches every 1–2 s, whereas for BD subjects this occurred every 3–4 s with some perceptual periods as long as 7–10 s. In a subsequent study, Miller et al. (3) used lower-strength stimuli, i.e. stationary gratings of low spatial frequency, in a different sample and again found significantly slower BRR in BD-I compared with controls (Fig. 2a). However, group separation in this study was less than in their previous one, suggesting that high-strength stimuli better distinguish BD from control subjects. The second study also examined BRR in schizophrenia and major depression (3), and found no significant differences in these groups compared with controls (though again with some individuals in all non-BD groups clearly showing slow BRR; Fig. 2a). Furthermore, although unpublished, BRR has also been assessed in a small number of first-degree relatives of BD probands using lower-strength stimuli. These data show that some relatives of BD probands exhibit slow BRR while others do not (Fig. 2a). Since these BRR studies, there have been two independent replications reported. The first, by Krug et al. (5), used an ambiguous structure-from-motion stimulus, which is a very low-strength stimulus, inducing alternations more than an order of magnitude slower than binocular rivalry stimuli, i.e. on average, just over every 30 s in controls and 40 s in BD. Their study, nevertheless, did report significantly slower alternation rate in BD-I compared with controls, though to a lesser extent than the previous studies of Pettigrew and Miller (3,4). This disparity, in our view, was because of the use of such low-strength stimuli by Krug et al. The second replication study, by Nagamine et al. (6), used binocular rivalry stimuli of intermediate strength and again reported significantly slower BRR in BD-I compared with controls. They also found that BRR in BD-II, a less severe form of the disorder, was similar to that observed in controls (Fig. 2b). Slow BRR as an endophenotype for bipolar disorder?