How perception of time differs under different situations: Different behaviors of the central nervous system as a complex dynamic system

Abstract

rent results might be confounded by metbolic abnormalities. Consistent evidence suggests that the diameters of retinal arterioles are inversely proportional to high blood pressure and body mass index (BMI), while diameters of retinal venules are proportional to increase of BMI, serum glucose, triglyceride, and cholesterol levels. We aimed to assess retinal structures, including neural and vascular components, in patients with BD without metabolic problems (see Methods in Appendix S1). Moreover, as neurotrophins, such as vascular endothelial growth factor (VEGF), play important roles for vascular abnormalities in the retina (i.e., excessive levels of VEGF lead to proliferative retinopathy in diabetes mellitus), we also controlled the levels of growth factors. In order to avoid effects from age-related retinal degeneration, we limited the age range for participants to 18–45 years and 6 of myopia or hypermetropia and 3 of astigmatism were the upper limits for exclusion. History of any eye disease or surgery, brain surgery, any systemic disease, vascular or neurological diseases, hypertension, diabetes mellitus, nicotine consumption, anemia, and any infectious or inflammatory disease in the last 3 months were the other exclusion criteria. Accordingly, 31 HC and 41 patients with BD type I were enrolled (Table S1 in Appendix S1). Patients were in remission (n = 14), manic (n = 13), or depressed (n = 14) states. Moreover, patients were in the first 10 years of their disorder. Following psychiatric evaluations (see Methods in Appendix S1), participants had a comprehensive eye examination. Retinal assessments were performed with optical coherence tomography (OCT; Fig. S1A in Appendix S1; Spectralis OCT, Heidelberg, Germany) and a TOPCON-TRC.50IX retinal fundus camera (TOPCON Medical Systems Inc., Oakland, NJ, USA) (Fig. S1B–D in Appendix S1). Both eyes of each participant were photographed with a 50 digital camera with total magnification of 18.4× in a darkened room. All photographs were taken with the optic disk at the center of both eyes. The measured area of retinal vascular parameters was detected in the ring region where located between 0.5 and 1.0 disk diameter, 0.75 disk diameter, from the optic disk margin (see details in the Methods in Appendix S1). Adobe Photoshop CS6 and ImageJ (version 1.52n, Wayne Rasband, National Institute of Health, Bethesda, MD, USA) software were used for the image-analysis process. From a line selection five measurements (selection and two parallel shifts in both directions) were taken. According to the formula, central retinal arterial equivalent (CRAE) and central retinal venular equivalent (CRVE) were calculated. Comparison between groups in terms of biochemical and OCT measurements are reported in Tables S2 and S3 in Appendix S1, respectively. Calibers of retinal vessels (arterioles and venules) did not differ between the BD and HC groups (Table 1). Furthermore, there were no significant differences among manic, depressed, and euthymic BD states. Neurotrophin levels did not differ between the groups (Table S1) but VEGF levels were slightly decreased in the BD group in comparison to the HC group. However, there was no correlation between neurotrophin levels and the retinal measures of the vascular or neural structures (Tables S4 and S5 in Appendix S1). VEGF was the determinant of CRAE/CRVE ratio in patients with BD (Table S6 in Appendix S1). Disease progression, diabetes, hypertension, obesity and smoking may cause microvascular changes in the retina and most of the studies in the literature have not taken these risk factors into account. We could not detect retinal vascular abnormality in patients with BD. Obesity, increased insulin resistance, dyslipidemia, metabolic syndrome, and hypertension are risk factors for adverse vascular outcomes by severely disrupting endothelial functions as a result of local inflammation and oxidative damage. Moreover, it has been suggested that vascular pathologies cannot be fully explained by the above-mentioned risk factors in BD. Future studies controlling for the risk factors should further investigate vascular disturbances in BD.