Cardiovascular regulation by skeletal muscle reflexes in health and disease

Heart rate and blood pressure are elevated at the onset and throughout the duration of dynamic or static exercise. These neurally mediated cardiovascular adjustments to physical activity are regulated, in part, by a peripheral reflex originating in contracting skeletal muscle termed the exercise pressor reflex. Mechanically sensitive and metabolically sensitive receptors activating the exercise pressor reflex are located on the unencapsulated nerve terminals of group III and group IV afferent sensory neurons, respectively. Mechanoreceptors are stimulated by the physical distortion of their receptive fields during muscle contraction and can be sensitized by the production of metabolites generated by working skeletal myocytes. The chemical by-products of muscle contraction also stimulate metaboreceptors. Once activated, group III and IV sensory impulses are transmitted to cardiovascular control centers within the brain stem where they are integrated and processed. Activation of the reflex results in an increase in efferent sympathetic nerve activity and a withdrawal of parasympathetic nerve activity. These actions result in the precise alterations in cardiovascular hemodynamics requisite to meet the metabolic demands of working skeletal muscle. Coordinated activity by this reflex is altered after the development of cardiovascular disease, generating exaggerated increases in sympathetic nerve activity, blood pressure, heart rate, and vascular resistance. The basic components and operational characteristics of the reflex, the techniques used in human and animals to study the reflex, and the emerging evidence describing the dysfunction of the reflex with the advent of cardiovascular disease are highlighted in this review.     

Melanopsin Bistability: A Fly's Eye Technology in the Human Retina

In addition to rods and cones, the human retina contains light-sensitive ganglion cells that express melanopsin, a photopigment with signal transduction mechanisms similar to that of invertebrate rhabdomeric photopigments (IRP). Like fly rhodopsins, melanopsin acts as a dual-state photosensitive flip-flop in which light drives both phototransduction responses and chromophore photoregeneration that bestows independence from the retinoid cycle required by rods and cones to regenerate photoresponsiveness following bleaching by light. To explore the hypothesis that melanopsin in humans expresses the properties of a bistable photopigment in vivo we used the pupillary light reflex (PLR) as a tool but with methods designed to study invertebrate photoreceptors. We show that the pupil only attains a fully stabilized state of constriction after several minutes of light exposure, a feature that is consistent with typical IRP photoequilibrium spectra. We further demonstrate that previous exposure to long wavelength light increases, while short wavelength light decreases the amplitude of pupil constriction, a fundamental property of IRP difference spectra. Modelling these responses to invertebrate photopigment templates yields two putative spectra for the underlying R and M photopigment states with peaks at 481 nm and 587 nm respectively. Furthermore, this bistable mechanism may confer a novel form of “photic memory” since information of prior light conditions is retained and shapes subsequent responses to light. These results suggest that the human retina exploits fly-like photoreceptive mechanisms that are potentially important for the modulation of non-visual responses to light and highlights the ubiquitous nature of photoswitchable photosensors across living organisms.     

Does pupil constriction under blue and green monochromatic light exposure change with age?

Many nonvisual functions are regulated by light through a photoreceptive system involving melanopsin-expressing retinal ganglion cells that are maximally sensitive to blue light. Several studies have suggested that the ability of light to modulate circadian entrainment and to induce acute effects on melatonin secretion, subjective alertness, and gene expression decreases during aging, particularly for blue light. This could contribute to the documented changes in sleep and circadian regulatory processes with aging. However, age-related modification in the impact of light on steady-state pupil constriction, which regulates the amount of light reaching the retina, is not demonstrated. We measured pupil size in 16 young (22.8±4 years) and 14 older (61±4.4 years) healthy subjects during 45-second exposures to blue (480 nm) and green (550 nm) monochromatic lights at low (7×10(12) photons/cm2/s), medium (3×10(13) photons/cm2/s), and high (10(14) photons/cm2/s) irradiance levels. Results showed that young subjects had consistently larger pupils than older subjects for dark adaptation and during all light exposures. Steady-state pupil constriction was greater under blue than green light exposure in both age groups and increased with increasing irradiance. Surprisingly, when expressed in relation to baseline pupil size, no significant age-related differences were observed in pupil constriction. The observed reduction in pupil size in older individuals, both in darkness and during light exposure, may reduce retinal illumination and consequently affect nonvisual responses to light. The absence of a significant difference between age groups for relative steady-state pupil constriction suggests that other factors such as tonic, sympathetic control of pupil dilation, rather than light sensitivity per se, account for the observed age difference in pupil size regulation. Compared to other nonvisual functions, the light sensitivity of steady-state pupil constriction appears to remain relatively intact and is not profoundly altered by age.     

Photic sensitivity ranges of hamster pupillary and circadian phase responses do not overlap

Mammalian retinal photoreceptors form an irradiance detection system that drives many nonvisual responses to light such as pupil reflex and resetting of the circadian clock. To understand the role of pupil size in circadian light responses, pupil diameter was pharmacologically manipulated and the effect on behavioral phase shifts at different irradiance levels was studied in the Syrian hamster. Dose-response curves for steady-state pupil size and for behavioral phase shifts were constructed for 3 pupil conditions (dilated, constricted, and control). Retinal irradiance was calculated from corneal irradiance, pupil size, retinal surface area, and absorption of ocular media. The sensitivity of photic responses to retinal irradiance is approximately 1.5 log units higher than to corneal irradiance. When plotted against corneal irradiance, pharmacological pupil constriction reduces the light sensitivity of the circadian system, but pupil dilation has no effect. As expected, when plotted against retinal irradiance all dose-response curves superimposed, confirming that the circadian system responds to photon flux on the retina. Pupil dilation does not increase the circadian response to increasing irradiance, since the response of the circadian system attains saturation at irradiance levels lower than those required to induce pupil constriction. The main finding shows that due to the different response sensitivities, the effect of pupil constriction on the light sensitivity of the circadian system in the hamster under natural conditions is virtually negligible. We further suggest the existence of distinct modulating mechanisms for the differential retinal irradiance sensitivity of the pupil system and the circadian system, which enables the different responses to be tuned to their specific tasks while using similar photoreceptive input.     

A systematic review on the effect of low-dose radiation on hearing

Numerous studies have documented the adverse effects of high-dose radiation on hearing in patients. On the other hand, radiographers are exposed to a low dose of ionizing radiation, and the effect of a low dose of radiation on hearing is quite abstruse. Therefore, the present systematic review aimed to elucidate the effect of low-dose ionizing radiation on hearing. Two authors independently carried out a comprehensive data search in three electronic databases, including PUBMED/MEDLINE, CINAHL, and SCOPUS. Eligible articles were independently assessed for quality by two authors. Cochrane Risk of Bias tool was used assess quality of the included studies. Two articles met the low-dose radiation exposure criteria given by Atomic Energy Regulatory Board (AERB) and National Council on Radiation Protection (NCRP) guidelines. Both studies observed the behavioral symptoms, pure-tone hearing sensitivity at the standard, extended high frequencies, and the middle ear functioning in low-dose radiation-exposed individuals and compared with age and gender-matched controls. One study assessed the cochlear function using transient-evoked otoacoustic emissions (TEOAE). Both studies reported that behavioral symptoms of auditory dysfunction and hearing thresholds at extended high frequencies were higher in radiation-exposed individuals than in the controls. The current systematic review concludes that the low-dose ionizing radiation may affect the hearing adversely. Nevertheless, further studies with robust research design are required to explicate the cause and effect relationship between the occupational low-dose ionizing radiation exposure and hearing.

     

Hearing impairment in Stickler syndrome: a systematic review

Background

Stickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory defects. It is caused by mutations in different collagen genes, namely COL2A1, COL11A1 and COL11A2 (autosomal dominant inheritance), and COL9A1 and COL9A2 (autosomal recessive inheritance). The auditory phenotype in Stickler syndrome is inconsistently reported. Therefore we performed a systematic review of the literature to give an up-to-date overview of hearing loss in Stickler syndrome, and correlated it with the genotype.

Methods

English-language literature was reviewed through searches of PubMed and Web of Science, in order to find relevant articles describing auditory features in Stickler patients, along with genotype. Prevalences of hearing loss are calculated and correlated with the different affected genes and type of mutation.

Results

313 patients (102 families) individually described in 46 articles were included. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Hearing impairment was predominantly sensorineural (67.8%). Conductive (14.1%) and mixed (18.1%) hearing loss was primarily found in young patients or patients with a palatal defect. Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).

Conclusions

Hearing impairment in patients with Stickler syndrome is common. Sensorineural hearing loss predominates, but also conductive hearing loss, especially in children and patients with a palatal defect, may occur. The distinct disease-causing collagen genes are associated with a different prevalence of hearing impairment, but still large phenotypic variation exists. Regular auditory follow-up is strongly advised, particularly because many Stickler patients are visually impaired.

     

Effect of retinal ischemia on the non-image forming visual system

Retinal ischemic injury is an important cause of visual impairment. The loss of retinal ganglion cells (RGCs) is a key sign of retinal ischemic damage. A subset of RGCs expressing the photopigment melanopsin (mRGCs) regulates non-image-forming visual functions such as the pupillary light reflex (PLR), and circadian rhythms. We studied the effect of retinal ischemia on mRGCs and the non-image-forming visual system function. For this purpose, transient ischemia was induced by raising intraocular pressure to 120?mm Hg for 40?min followed by retinal reperfusion by restoring normal pressure. At 4 weeks post-treatment, animals were subjected to electroretinography and histological analysis. Ischemia induced a significant retinal dysfunction and histological alterations. At this time point, a significant decrease in the number of Brn3a(+) RGCs and in the anterograde transport from the retina to the superior colliculus and lateral geniculate nucleus was observed, whereas no differences in the number of mRGCs, melanopsin levels, and retinal projections to the suprachiasmatic nuclei and the olivary pretectal nucleus were detected. At low light intensity, a decrease in pupil constriction was observed in intact eyes contralateral to ischemic eyes, whereas at high light intensity, retinal ischemia did not affect the consensual PLR. Animals with ischemia in both eyes showed a conserved locomotor activity rhythm and a photoentrainment rate which did not differ from control animals. These results suggest that the non-image forming visual system was protected against retinal ischemic damage.     

Molecular imaging for mitochondrial metabolism and oxidative stress in mitochondrial diseases and neurodegenerative disorders

BackgroundIncreasing evidence from pathological and biochemical investigations suggests that mitochondrial metabolic impairment and oxidative stress play a crucial role in the pathogenesis of mitochondrial diseases, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, and various neurodegenerative disorders. Recent advances in molecular imaging technology with positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have accomplished a direct and non-invasive evaluation of the pathophysiological changes in living patients.Scope of reviewIn this review, we focus on the latest achievements of molecular imaging for mitochondrial metabolism and oxidative stress in mitochondrial diseases and neurodegenerative disorders.Major conclusionsMolecular imaging with PET and MRI exhibited mitochondrial metabolic changes, such as enhanced glucose utilization with lactic acid fermentation, suppressed fatty acid metabolism, decreased TCA-cycle metabolism, impaired respiratory chain activity, and increased oxidative stress, in patients with MELAS syndrome. In addition, PET imaging clearly demonstrated enhanced cerebral oxidative stress in patients with Parkinson's disease or amyotrophic lateral sclerosis. The magnitude of oxidative stress correlated well with clinical severity in patients, indicating that oxidative stress based on mitochondrial dysfunction is associated with the neurodegenerative changes in these diseases.General significanceMolecular imaging is a promising tool to improve our knowledge regarding the pathogenesis of diseases associated with mitochondrial dysfunction and oxidative stress, and this would facilitate the development of potential antioxidants and mitochondrial therapies.     

Parathyroid Hormone,Cognitive Function and Dementia: A Systematic Review

BackgroundMetabolic factors are increasingly recognized to play an important role in the pathogenesis of Alzheimer’s disease and dementia. Abnormal parathyroid hormone (PTH) levels play a role in neuronal calcium dysregulation, hypoperfusion and disrupted neuronal signaling. Some studies support a significant link between PTH levels and dementia whereas others do not.MethodsWe conducted a systematic review through January 2014 to evaluate the association between PTH and parathyroid conditions, cognitive function and dementia. Eleven electronic databases and citation indexes were searched including Medline, Embase and the Cochrane Library. Hand searches of selected journals, reference lists of primary studies and reviews were also conducted along with websites of key organizations. Two reviewers independently screened titles and abstracts of identified studies. Data extraction and study quality were performed by one and checked by a second reviewer using predefined criteria. A narrative synthesis was performed due to the heterogeneity of included studies.ResultsThe twenty-seven studies identified were of low and moderate quality, and challenging to synthesize due to inadequate reporting. Findings from six observational studies were mixed but suggest a link between higher serum PTH levels and increased odds of poor cognition or dementia. Two case-control studies of hypoparathyroidism provide limited evidence for a link with poorer cognitive function. Thirteen pre-post surgery studies for primary hyperparathyroidism show mixed evidence for improvements in memory though limited agreement in other cognitive domains. There was some degree of cognitive impairment and improvement postoperatively in observational studies of secondary hyperparathyroidism but no evident pattern of associations with specific cognitive domains.ConclusionsMixed evidence offers weak support for a link between PTH, cognition and dementia due to the paucity of high quality research in this area.     

Monoterpenes as a perspective for the treatment of seizures: A Systematic Review

BackgroundEpilepsy affects more than 65 million people worldwide. Treatment for epileptic seizures is ineffective and has many adverse effects. For this reason, the search for new therapeutic options capable of filling these limitations is necessary.Hypothesis/PurposeIn this sense, natural products, such as monoterpenes, have been indicated as a new option to control neurological disorders such as epilepsy.Study DesignTherefore, the objective of this study was to review the monoterpenes that have anticonvulsive activity in animal models.MethodsThe searches were performed in the PubMed, Web of Science and Scopus databases in September, 2020 and compiled studies using monoterpenes as an alternative to seizure. Two independent reviewers performed the study selection, data extraction and methodological quality assessment using the Syrcle tool.Results51 articles that described the anticonvulsant activity of 35 monoterpenes were selected with action on the main pharmacological target, including GABAA receptors, glutamate, calcium channels, sodium and potassium. In addition, these compounds are capable of reducing neuronal inflammation and oxidative stress caused by seizure.ConclusionThese compounds stand out as a promising alternative for acting through different pharmacological mechanisms, which may not only reduce seizure, but also promote neuroprotective effect by reducing toxicity in brain regions. However, further studies are needed to determine the mechanism of action and safety assessment of these compounds.     

The English national risk-reduction programme for preservation of sight in diabetes

This paper discusses the new national guidelines for a systematic screening programme to detect sight-threatening diabetic retinopathy in the population of people with diabetes in England. A review of the literature examines the evidence base to support screening interventions and effective management and treatments in diabetic retinopathy. The current evidence supports the establishment of a digital retinal photography system using pupil dilation. A Policy Advisory Group has been formulated by the National Screening Committee to guide the meeting of this target in England. A conclusion is made that with increased effort and organisation, health care professionals can ensure that the screening programme is successfully implemented and rates of visual impairment and blindness caused by diabetic retinopathy can be reduced significantly. (Mol Cell Biochem 261: 183–185, 2004)     

A Biofeedback System of Baroreceptor Cardiac Reflex Sensitivity

The evidence presently available suggests that the parasympathetic nervous system and sympathetic-parasympathetic interactions could play a role in the pathophysiology of cardiovascular disorders and, specifically, in hypertension. A loss of sensitivity of the baroreceptor reflex is one of the fundamental mechanisms underlying the deficits found in parasympathetic cardiac control. The baroreceptor reflex is a basic mechanism for the regulation of blood pressure, a powerful source of vagal afferent input to the central nervous system, and one of the most important physiological mechanisms affecting efferent cardiac vagal activity. This paper describes a computerized system for the on-line analysis of the baroreceptor cardiac reflex function using the noninvasive spontaneous sequence method in the time domain. The system provides feedback of the baroreceptor reflex sensitivity (the change in heart period per unit change in systolic blood pressure) differentially both when the systolic blood pressure is increasing and when it is decreasing. The accuracy of the described system has been tested against the conventional off-line procedure. None of the parameters supplied by the analysis show a significant difference between the on-line and off-line methods. These results confirm the accuracy of the on-line system to analyze baroreceptor cardiac reflex function.     

Genetic and behavioral characterization of a Kmt2d mouse mutant,a new model for Kabuki Syndrome

The recessive mutant mice bate palmas (bapa) ‐ claps in Portuguese arose from N‐ethyl‐N‐nitrosourea mutagenesis. A single nucleotide, T > C, change in exon 13, leading to a Thr₁₂₈₉Ala substitution, was identified in the lysine (K)‐specific methyltransferase 2D gene (Kmt2d) located on chromosome 15. Mutations with a loss‐of‐function in the KMT2D gene on chromosome 12 in humans are responsible for Kabuki syndrome (KS). Phenotypic characterization of the bapa mutant was performed using a behavioral test battery to evaluate the parameters related to general activity, the sensory nervous system, the psychomotor system, and the autonomous nervous system, as well as to measure motor function and spatial memory. Relative to BALB/cJ mice, the bapa mutant showed sensory and psychomotor impairments, such as hypotonia denoted by a surface righting reflex impairment and hindquarter fall, and a reduction in the auricular reflex, suggesting hearing impairment. Additionally, the enhanced general activity showed by the increased rearing and grooming frequency, distance traveled and average speed possibly presupposes the presence of hyperactivity of bapa mice compared with the control group. A slight motor coordination dysfunction was showed in bapa mice, which had a longer crossing time on the balance beam compared with BALB/cJ controls. Male bapa mice also showed spatial gait pattern changes, such as a shorter stride length and shorter step length. In conclusion, the bapa mouse may be a valuable animal model to study the mechanisms involved in psychomotor and behavior impairments, such as hypotonia, fine motor coordination and hyperactivity linked to the Kmt2d mutation.     

The circadian response of intrinsically photosensitive retinal ganglion cells

Intrinsically photosensitive retinal ganglion cells (ipRGC) signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central) or intrinsic (retinal) network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18-30 years) with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC) and outer retina (cone photoreceptors) was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux). Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO) was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin) retinal ganglion cells mediate this circadian variation.     

Melanopsin Gene Polymorphism I394T Is Associated with Pupillary Light Responses in a Dose-Dependent Manner

Background

Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) play an important role in non-image forming responses to light, such as circadian photoentrainment, light-induced melatonin suppression, and pupillary light response. Although it is known that there are some single nucleotide polymorphisms (SNPs) in the melanopsin (OPN4) gene in humans, the associations of the SNPs with non-image forming responses to light remains unclear. In the present study, we examined the associations of melanopsin gene polymorphisms with pupillary light response.

Methods

Japanese university students (mean age: 21.0±1.7 years) with the genotypes of TT (n = 38), TC (n = 28) and CC (n = 7) at rs1079610 (I394T) located in the coding region participated in the present study. They were matched by age and sex ratio. Dark-adapted pupil size (<1 lx) was first measured. Then steady-state pupil size was measured during exposure to five lighting conditions (10 lx, 100 lx, 1000 lx, 3000 lx, 6000 lx in the vertical direction at eye level).

Results

Significant interaction between the genotype of I394T (TT versus TC+CC) and luminance levels was found in pupil size. Under high illuminance levels (1000 lx, 3000 lx and 6000 lx), pupil sizes in subjects with the C allele were significantly smaller than those in subjects with the TT genotype. On the other hand, pupil size in subjects with the C allele under low illuminance (<1 lx) was significantly larger than that in subjects with the TT genotype. Percentages of pupil constriction under high illuminance levels were significantly greater in subjects with the C allele than in subjects with the TT genotype.

Conclusions

Human melanopsin gene polymorphism I394T interacted with irradiance in association with pupil size. This is the first evidence suggesting a functional connection between melanopsin gene polymorphism and pupillary light response as an index of non-image forming response to light.     

Using dynamic pupillometry as a simple screening tool to detect autonomic neuropathy in patients with diabetes: a pilot study

Background  

Autonomic neuropathy is a common and serious complication of diabetes. Early detection is essential to enable appropriate interventional therapy and management. Dynamic pupillometry has been proposed as a simpler and more sensitive tool to detect subclinical autonomic dysfunction. The aim of this study was to investigate pupil responsiveness in diabetic subjects with and without cardiovascular autonomic neuropathy (CAN) using dynamic pupillometry in two sets of experiments.     

Dysregulation of the Autonomous Nervous System in Patients with Temporomandibular Disorder: A Pupillometric Study

The role of the autonomic nervous system (ANS) was recently investigated in Temporomandibular disorders (TMD). Several authors argue that in subjects with TMD there is a dysregulation of ANS. Recent literature support that Pupillometry is a simple non-invasive tool to study ANS. The aim of this study was to investigate the relationship between TMD and ANS activity using pupillometry recording in Infrared light at rest Mandible Position (RP); Infrared light at Forced Habitual Occlusion (FHO); Yellow-green light at RP; Yellow-green light at FHO. Forty female subjects were enrolled: 20 case patients showed TMD based on the Research Diagnostic Criteria for TMD, and 20 control patients, aged matched, had no signs or symptoms of TMD. Statistical analysis was performed on average pupil size. Ratio between pupil size in FHO and RP (FHO/RP ratio) and yellow-green and infrared (light/darkness ratio) lighting were carried out. Within group differences of pupil size and of “ratio” were analyzed using a paired t test, while differences of pupil size between groups were tested using an unpaired t test. Statistical comparisons between groups showed no significant differences of absolute values of pupil dimension in RP and FHO, both in yellow-green and in infrared lighting. In addition, there were no significant differences within groups comparing RP and FHO in yellow-green light. In within group comparison of pupil size, differences between RP and FHO were significant in infrared conditions. Control subjects increased, whereas TMD patients decreased pupil size at FHO in infrared lightening. FHO/RP ratio in darkness and light/darkness ratio in RP were significantly different between groups. Taken together, these data suggest that TMD subjects have an impairment of the sympathetic-adrenergic component of the ANS to be activated under stress. The present study provides preliminary pupillometric data confirming that adrenergic function is dysregulated in patients with TMD.     

Association between melanopsin gene polymorphism (I394T) and pupillary light reflex is dependent on light wavelength

Background

Our aim was to determine the association between melanopsin gene polymorphism and pupillary light reflex under diverse photic conditions, including different intensities and wavelengths.

Methods

A total of 195 visually corrected subjects volunteered for investigation of the melanopsin gene of single nucleotide polymorphism (SNP) of rs1079610 (I394T). The genotype groups were TT (n = 126), TC (n = 55), and CC (n = 8), and 75 of the subjects, including subjects with TT (n = 34), TC (n = 33), and CC (n = 8) participated in our experiment. Three monochromatic lights with peak wavelengths of 465 nm (blue), 536 nm (green), and 632 nm (red) were prepared, and each light was projected to the subjects with five intensities, 12, 13, 14, 14.5 and 15 log photons/(cm² s), for one minute. The pupil size of the left eye was measured under each light condition after a 1-minute adaptation.

Results

The pupils of the TC + CC genotypes (n = 38) were significantly smaller than those of the TT genotype (n = 31) under a blue (463 nm) light condition with 15 log photons/(cm² s) (P < 0.05). In contrast, there were no significant differences under green (536 nm) and red (632 nm) light conditions. Conversely, relative pupil constrictions of the TC + CC genotypes were greater than those of the TT genotype under both blue and green conditions with high intensities (14.5 and 15 log photons/(cm² s)). In contrast, there were no significant differences between genotype groups in pupil size and relative pupilloconstriction under the red light conditions.

Conclusions

Our findings suggest that the melanopsin gene polymorphism (I394T) functionally interacts with pupillary light reflex, depending on light intensity and, particularly, wavelength, and that under a light condition fulfilling both high intensity and short wavelength, the pupillary light response of subjects with the C allele (TC + CC) is more sensitive to light than that of subjects with the TT genotype.