Keywords
cigarette smoking, visual system, color discrimination, color vision, Cambridge Colour Test, Trivector, nicotinic receptors
This article is included in the Eye Health gateway.
cigarette smoking, visual system, color discrimination, color vision, Cambridge Colour Test, Trivector, nicotinic receptors
In order to meet the specifications and reviewers recommendations, substantial changes were made.
Introduction: We've added some information about smoking impairments/damages in visual processing. In addition, we bring the importance of our study and the use of visual psychophysics, more precisely of the Trivector test, to evaluate congenital or acquired impairments of conditions that affect the central nervous system (such as chronic heavy smoking).
Methods: We chose to include a subsection in the Methods where we detailed the cutoff points of the Trivector test (based on the average results of Trivector test in Brazilian studies and in a longitudinal study by Paramei et al.66). Thus, we provided the reader with information about what value is considered normal and what value we can already consider as possible impairment in color discrimination.
Results: We changed the description of the results, facilitating the reading and avoiding dubious explanations. In this way, we inform that the lower the threshold, the better the discrimination. Therefore, when the group presents a higher threshold, being statistically significant, we can infer a possible impairment in color discrimination. Figure 1 was replaced with one at a higher resolution in order to improve reader viewing and interpretation of the data
Discussion: We corrected a few words in the discussion section and added a paragraph informing that our results for the control group are in agreement with most of the studies that use the Trivector, and that the differences found can be classified as losses in color discrimination, since they crossed the threshold of the normative data.
Natalia Leandro de Almeida was added as a co-author to the paper due to her substantial contributions, such as re-analysis, interpretation and correction of the manuscript.
See the authors' detailed response to the review by Marine Raquel Diniz da Rosa
See the authors' detailed response to the review by Goro Maehara
Cigarette smoking is still a major source of exposure to chemicals that are toxic for humans. The compounds in cigarettes and cigarette smoke, such as nicotine, oxygen dioxide and formaldehyde, are highly harmful to health1. Data from the World Health Organization (WHO) hypothesize that by 2030, cigarettes could kill nearly 9 million people a year around the world2,3.
Cigarette nicotine deprivation in chronic users may impair cognitive and attentional abilities even after long time of cessation4,5. The neurotoxic effects of chronic use and smoking abstinence on the nervous system have not been extensively studied6–8. However, chronic cigarette smoking increases cardiovascular response9, which, in turn, affects retinal responses through altered blood flow10. In addition, tobacco compounds may increase free radical that would cause macular degeneration along with the action of ischemia11. Whereas smoking effects on color vision are understudied, the existing data are controversial and highlights the importance of a rigorous testing procedure that measures color discrimination12,13. Thus, to identify the mechanisms underlying neurotoxic smoking effects on multisensory integration, we need to understand how smoking may alter early visual processing.
A visual percept may consist of stimuli that vary over the space (spatial contrast), time (temporal contrast) or direction of motion, and vary in luminance (achromatic) and chromaticity (saturation and hue color)12,14,15. Thus, chromatic contrast involves chromaticity differences, which can be expressed by the distance in the CIE 1976 uniform chromaticity scale diagram and assessed by thresholds of vectors on the Cambridge Color Test (CCT), for example16,17. It has the advantage of being used to evaluate in detail whether these anomalies are due to congenital factors or acquired conditions16,17.
We base our rationale on the premise that chronic exposure to nicotine will led to receptor desensitization and not suffer influence of arousal and increase in attentional resources in smokers18. The purpose of the present study was to assess the influence of chronic heavy smoking on color discrimination (CD).
In this study, 15 non-smokers (mean age = 32.5 years; SD = 9.1; 7 male), 15 cigarette smokers (mean age = 32.1 years; SD = 5.7; 7 male) and 15 deprived smokers (mean age = 31.9 years; SD = 6.3; 7 male) between the ages of 20 and 45 years, who were working as staff or were students at Federal University of Paraiba, were recruited through printed advertisements. Participants were excluded if they had any one of the following criteria: younger than 20 and older than 45 years (since the effects of the human visual system immaturation or aging could superestimate the results19,20); current history of neurologic disorder; a history of head trauma, color blindness, current or previous drug abuse; drinking more than 10 alcoholic drinks per week or current use of medications that may affect visual processing and cognition. In addition, subjects were required to have a good ocular health: no abnormalities were detected in the fundoscopic examination and in the optical coherence tomography exam. All participants had normal or corrected-to-normal vision as determined by a visual acuity of at least 20/20.
Smokers reported a smoking history of at least 8 years, currently smoked more than 20 cigarettes/day and had a score of >5 on the Fagerstrom Test for Nicotine Dependence (FTND)21. Smokers and deprived smokers began smoking at an average of 16.5 years of age (SD = 3.25) and had been smoking for an average 15 years (SD = 6.45). Smokers were allowed to smoke until the beginning of experiment. Deprived smokers were not allowed to smoke 6 hours prior to testing and until the end of the experiment. Non-smokers had never smoked a cigarette. This research followed the ethical principles from the Declaration of Helsinki and was approved by the Committee of Ethics in Research of the Health Sciences Center of Federal University da Paraiba (CAAE: 60944816.3.0000.5188). Written informed consent was obtained from all participants.
Stimuli were presented on a 19 inch LG CRT monitor with 1024 × 786 resolution and a rate of 100 Hz. Stimuli were generated using a VSG 2/5 video card (Cambridge Research Systems), which was run on a microcomputer Precision T3500 with W3530 graphics card. All procedures were performed in a room at 26±1°C, with the walls covered in grey for better control of luminance during the experiments. All measurements were performed with binocular vision. Monitor luminance and chromatic calibrations were performed with a ColorCAL MKII photometer (Cambridge Research Systems).
The color vision test was performed using CCT, version 2.0, with Trivector subtest (Cambridge Research Systems; http://www.crsltd.com/tools-for-vision-science/measuring-visual-functions/cambridge-colour-test/). The CTT was performed in a darkened room with illumination provided only by the monitor used to present visual stimuli. Trivector provides a clinical assessment of color vision deficiencies as a rapid means screening of the existence of congenital or acquired deficits16. CCT uses pseudoisochromatic stimuli (Landolt C) defined by the test colors that are to be discriminated, on an achromatic background. The figure and the background are composed of grouped circles randomly varying in diameter and having no spatial structure (variation of 5.7° arcmin of external diameter and 2.8° arcmin of internal diameter). The luminance variation in each response avoids the existence of learning effect or use of tricks to respond correctly.
The four-alternative forced-choice16,22 (4-AFC) method was used, and the subjects’ task was to identify, using a remote control response box, whether the Landolt ‘C’ stimulus was presented at the left, right, up or down side of the monitor screen. The participant was instructed to answer even if could not identify the stimulus gap16. After each correct answer, the chromaticity of the target proceeded closer to that of background, while each wrong answer or omission was followed by the presentation of the target at a greater chromatic distance from the background. The step on the staircase was doubled or divided by two after each incorrect or correct answer, respectively. This process took place throughout the experiment. The experiment ended after 11 reversals for each axis and the threshold was estimated from the six final reversals23.
The trivector testing protocol estimates sensitivity for the short, medium and long wavelengths through the protanopic, deuteranopic, and tritanopic confusion axes, respectively23,24. Trivector protocol uses vectors as central measurement. The advantage of this brief test is that it can be performed in about 5 minutes and provides a reliable result16. The three confusion axes converge at a point called ‘point of intersection’, and the xy coordinates used were: protan (0.6579, 0.5013), deutan (-1.2174, 0.7826) and tritan (0.2573, 0.0000) (for more details, see 17).
In general, we used a default setting where the Landolt ‘C’ had an opening at 1° of visual angle, minimum luminance of 8 cd/m², maximum luminance of 18 cd/m², 6 s of response time for each trial and distance of 269 cm between participant and monitor screen.
Most of these procedures were performed late in the morning or mid-afternoon.
Lower the threshold, the better the discrimination. Based on previous studies, cutoff points (median + IQR/2) for the trivector test were established to designate color vision impairment. Thus, values above the cut-off points are considered to be out of the normal range and, therefore, may represent visual losses. Baseline values for the confusion axes are as follows: Protan - 40.6 (7.8) / Deutan - 45.6 (9.3) / Tritan - 65.5 (10.5).
The normative values for the trivector can be found in Parameit et al.17 (mean + median + IQR + upper and lower limits)
The distributions for each group were compared with Shapiro-Wilk. Both groups showed non-normal distribution, thus non-parametric statistical methods were used to analyze the data. For group comparisons, the non-parametric univariate analysis was used, with pairwise comparisons by Mann-Whitney U test. Spearman’s rank correlation coefficients (rho) were conducted to assess the relationship between outcomes of color discrimination data and biosociodemographic variables, such as age, gender and education level. All the calculations were made using SPSS®, version 21.0.
The effect size (r) estimation was used from the conversion of z-score25,26:
Results are presented as medians. Center lines show the medians; box limits indicate the 25th and 75th percentiles as determined by SPSS software; whiskers extend 1.5 times the interquartile range from the 25th and 75th percentiles (ends of the whiskers are the maximum and minimum values). When presented, errors bars represent standard deviations (SD) of the median based on 1000 bootstrap resamplings. Bonferroni correction was the method of adjusting the P-value that we used. P < 0.016 was accepted as statistically significant for multiple comparisons and P < 0.025 for pairwise comparisons.
Color discrimination thresholds were obtained in u'v' units of the CIE 1976 color diagram, for protan, deutan, and tritan axes, respectively. Nonparametric analysis were carried out showing that there were significant differences in discrimination thresholds between groups along the protan (χ²(2) = 26.53, P < 0.001), deutan (χ²(2) = 22.40, P < 0.001) and tritan (χ²(2) = 14.93, P < 0.001) confusion axes. Thresholds for the smokers and deprived smokers were higher than the normative values observed in other studies. Therefore, there was a reduction in color discrimination in both groups. The results of the trivector measurements are shown in Figure 1.
Along protan vectors (Figure 1A), pairwise comparisons showed that discrimination thresholds were higher in the group of smokers compared to non-smokers (U = 132, P = 0.002, r = -.61). In addition, deprived smokers had the highest thresholds compared to the group of non-smokers (U = 105, P < 0.001, r = -.85) and smokers (U = 136, P = 0.002, r = -.58).
Along deutan vectors (Figure 1B), when compared with the control group, smokers (U = 136, P = 0.001, r = -.58) and deprived smokers (U = 108, P < 0.001, r = -.83) presented higher discrimination thresholds, with high effect size. There was statistically significant differences between smokers and deprived smokers (U = 154, P = 0.024, r = -.43).
Along tritan vectors (Figure 1C), when compared with the control group, smokers (U = 140, P = 0.003, r = -.55) and deprived smokers (U = 126, P < 0.001, r = -.67) presented higher discrimination thresholds. There was no statistically significant differences among smokers vs. deprived smokers (P = 0.250).
There is no relationship between color discrimination and gender (chi-square = 72, df = 39, P > 0.05). A spearman correlation showed no correlation between FTND and trivector data (P > 0.050), color discrimination and education years [rho = .078, P = 0.515], and color discrimination and age [rho = .096, P = 0.347].
The data indicated that smokers groups, as a whole, had higher discrimination thresholds when compared to non-smokers (P < 0.05), indicating the existence of a diffuse impairment in visual processing. Results showed good agreement between the normative data of control groups, being the protan and deutan thresholds lower than tritan thresholds, a pattern repeatedly observed in adults tested with the CCT17. Moreover, the higher thresholds observed in the group of smokers and deprived smokers are in agreement with the differences observed in other studies using CCT. The effect sizes reached medium to high values.
Small differences in blue-yellow color processing suggest that sensor neurons responsive to the short wavelength may differently operate from those responding to medium and long wavelengths27. Indeed, the koniocelular pathway may not suffer from the influences of tobacco components.
Along the trivector protocol, smokers had more errors in protan and deutan confusion axes (Figure 1). An effect size analysis confirmed that smokers had the largest discrimination errors for protan (r = -85) and deutan (r = -82) confusion axes when comparing against non-smokers. As stated, this result does not support the idea of channel selectivity. However, we base our rational on the existence of diffuse processing impairment, which may include magno- and parvocellular pathways28.
Nicotine enhances dopamine (DA) release through a balance of activation and desensitization of nicotinic acetylcholine receptors (nAChRs) located mainly in the ventral tegmental area and in the striatum18,29. There are also nAChRs and DA receptors on the retina, so it is not hard to understand that the use of nicotine would enhance attentional resources30–32. However, we did not observe improvements in color discrimination. So, is there any relationship between smoking and color discrimination? The answer may lie in desensitization, which is one of many brain changes caused by addiction33. In addition, chronic nicotine exposure leads to nAChRs desensitization through brain upregulation34,35. Another property of cigarettes is that the more exposure, the greater the need for it activate the receptors, which changes affinity and response properties of the nAChRs36,37. Whereas nicotine enhancing effects decay and remain unchanged after chronic exposure, this may explain the lower discrimination, but the small similarity, between smokers and non-smokers in some of our data (Figure 1).
Then, why did the deprived smokers group have less discrimination? This can be explained by the withdrawal effect, which induces a hypofunctional effect of DA release38,39, reflecting both visual processing40–42 and brain reward function43. Visual attention plays a role for detection of environmental stimuli44.
As stated, impairments observed at color discrimination can occur due to cones saturation, amplification of the signals that reach visual cortex or by the action of nicotine in parvocelular pathway45. In agreement with studies, color vision impairments may be related to ventral stream, which processes color46. However, our tests used pseudoisochromatic stimuli. Thus, color discrimination may have occurred through dorsal and ventral stream28. Maybe it is too soon to conclude anything, but there may be nAChRs in both dorsal and ventral stream47. In addition, both streams may suffer from the action of DA hypofunction, affecting directly visual processing39–41,43.
Knowing the existence of the expression of nAChRs in bipolar, amacrine and ganglionar cells29,47,48, we suggest that smoking affects visual processing, regardless of deprivation. Although the differences between smokers and non-smokers were small, we could not ignore the existence of many harmful compounds to vision in cigarettes. As noted in others studies, exposure to cigarette smoking49–55 and solvents56,57 affects vision. Thus, smoking can be harmful even for passive smokers.
Our limitations need to be considered. We evaluated cigarette smoking as a whole, not the nicotine-only effects51,52. Which brings us to the idea of further studies, using nicotine gum and the same paradigm used here. Clearly, further work is needed, but this study highlights the relationship between smoking and color discrimination, involving short, medium and long wavelengths27. We conclude that cigarette compounds affect vision54,55 more than nicotine separately58–61.
Dataset 1: Patient demographics and Trivector results. Raw data of the subjects biosociodemographic and trivector (protan, deutan and tritan) results. doi, 10.5256/f1000research.10714.d15005962
TM: design of the work, data collection and interpretation, and drafting the article. NL: data reanalysis and interpretation and revision of the updated manuscript.
NA: design of the work, data analysis and interpretation, and critical revision of the article. All authors approved the final version to be published
National Counsel of Technological and Scientific Development (CNPq), Brazil (grant no., 303822/2010-4), CAPES and Federal University of Paraiba funded this paper.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Competing Interests: I am affiliated with The Federal University of Paraiba, where all 3 of the authors, Thiago Monteiro de Paiva Fernandes, Natalia Leandro Almeida and Natanael Antonio dos Santos are also affiliated.
Competing Interests: No competing interests were disclosed.
References
1. Mollon JD, Regan BC: Cambridge Colour Test Handbook. Cambridge Research Systems Ltd.2000.Competing Interests: I am affiliated with The Federal University of Paraiba, where all 3 of the authors, Thiago Monteiro de Paiva Fernandes, Natalia Leandro Almeida and Natanael Antonio dos Santos are also affiliated.
References
1. Mollon JD, Regan BC: Cambridge Colour Test Handbook (version 1.1). Cambridge Research Systems Ltd.2000. Reference SourceCompeting Interests: No competing interests were disclosed.
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