Retinal phosphenes and discrete dark noises in rods: a new biophysical
framework JPHOTOBIOL-D-09-00103R1
Journal of Photochemistry and Photobiology B: Biology In press 2009
István Bókkon1 and Ram Lakhan Pandey Vimal2
1
Doctoral School of Pharmaceutical and Pharmacological Sciences,
Semmelweis University, H-1085 Üllői út 26, Budapest, Hungary;
2
Vision Research Institute, 428 Great Road, Suite 11, Acton, MA 01720 USA
Corresponding author: bokkoni@yahoo.com (I Bókkon)
Emails: rlpvimal@yahoo.co.in (RLP Vimal)
Abstract
Spontaneous rhodopsin activation produces discrete noises indistinguishable from singlephoton responses. However, there is a serious discrepancy between the apparent energy barrier of
thermal events compared with that of the photon-driven process. Current estimates of the
activation energies of discrete dark noises in vertebrate rod and cone pigments are 40-50
kcal/mol for activation by photon and 20-25 kcal/mol for activation by heat. To reconcile this
discrepancy, it was assumed that thermal activation and photon activation of rhodopsin follow
different molecular mechanisms. The most convincing hypothesis for a separate low-energy
thermal pathway is that the discrete dark noises of rods arise in a small subpopulation of
rhodopsins, where the Schiff base linking the chromophore to the protein part has been
deprotonated.
According to Narici et al.’ experiments (2009, Radiation Measurements), phosphene
perception in space travel is due to the ionizing-radiation-induced free radicals that generate
chemiluminescent photons from lipid peroxidation. These photons are absorbed by the
photoreceptors chromophores, which modify the rhodopsin molecules (bleaching) and start the
photo-transduction cascade resulting in the perception of phosphenes.
Here, we point out that not only retinal phosphenes but also the discrete dark noise of rods
can be due to the natural redox related (free radical) bioluminescent photons in the retina. In
other words, under regulated conditions, lipid oxidation is a natural process in cells and also in
retinal membranes. Since the natural lipid oxidation is one of the main sources of bioluminescent
photons and the photoreceptors have the highest oxygen demand and polyunsaturated fatty acid
(PUFA) concentration, there is a continuous, low level bioluminescent photon emission in the
retina without any external photonic stimulation. During photopic or scotopic vision, evanescent
bioluminescent photon emission is negligible. In contrast, in dark-adapted retinal cells this
evanescent bioluminescent photon emission is not negligible. Therefore, our hypothesis is that
the discrete dark noise of rods can be due to these bioluminescent photons.
Keywords: Radicals as signals Redox molecular mechanism, Natural bioluminescent processes
Lipid peroxidation Retinal phosphenes Discrete dark noise of rods
1. Introduction
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are traditionally
viewed as dangerous byproducts of cellular metabolism. However, recent findings have provided
evidence of fundamental roles of ROS and RNS in intracellular signaling and intercellular
communication processes. ROS and RNS can regulate redox homeostasis, gene expression,
apoptosis, cell growth, cell adhesion, chemotaxis, protein-protein interactions and enzymatic
functions, Ca2+ homeostasis, and numerous other processes in cells [1-4]. ROS and RNS are also
essential for normal brain functions and synaptic processes. Free radicals and their derivatives act
as signaling molecules in cerebral circulation and are necessary in molecular signal processes
such as synaptic plasticity, neurotransmitters release, hippocampal long-term potentiation,
memory formation, etc. under physiological circumstances in the brain [5-9].
Previously, we proposed [10] a new biophysical (redox molecular/free radical)
explanation of phosphene phenomenon. Namely, phosphene lights due to the transient
overproduction of free radicals and excited species that can elicit an excess bioluminescent
photon emission in various parts of the visual system. If this excess bioluminescent photon
emission exceeds a distinct threshold, it can appear as phosphene lights.
Recently, our prediction [10] about retinal phosphenes was experimentally verified by
Narici et al. [11] during space travel. According to Narici et al. [11], phosphene perception in
space travel possible due to the ionizing radiation induced free radical processes. That is, these
ionizing radiation (cosmic particles) induced free radicals generate chemiluminescent photons
from lipid peroxidation, which are absorbed by the photoreceptor chromophores, modify the
rhodopsin molecules (bleaching) and start the photo-transduction cascade resulting in the
perception of phosphene lights. Besides, it was shown that radicals from lipid peroxidation of the
photoreceptors (rods) outer segments of the retina can generate (bio)chemiluminescent photons
(bioluminescence is a type of chemiluminescence, which naturally occurs in living organisms) in
the visual spectrum [12]. This paper points out that not only retinal phosphenes but also the
discrete dark noise of rods can be due to the natural redox related (free radical) bioluminescent
photons in the retina.
2. Bioluminescent (bio)photons produced from free radical reactions
Biophotons are spontaneously and continuously emitted by all living cells without any
excitation, and this autoluminescence can be stimulated in response to many stresses [13-20].
Ultraweak photon emission is termed by various names as low-intensity chemiluminescence,
dark luminescence, ultraweak electromagnetic light, ultraweak bioluminescence, ultraweak
photons, biophotons, etc. This phenomenon is attributable to the endogenous production of
excited states during natural oxidative processes. The source of bioluminescent photons is due to
the various biochemical reactions, especially bioluminescent free radical and nonradical reactions
of ROS and RNS, and the simple cessation of excited states. For examples: non-enzymatic and
enzymatic lipid peroxidation, mitochondrial respiration chain and peroxisomal reactions,
oxidation of catecholamines, oxidation of tyrosine and tryptophan residues in proteins, etc. [2123]. The main source of biophotons derives from oxidative metabolism of mitochondria and lipid
peroxidation that generate light-emitting molecules such as excited triplet carbonyls RO and
singlet oxygen 1O2 [23,24].
Singlet oxygen is essentially ubiquitously and even quantitatively formed in so many
peroxide reactions. For example, during dimol emission of singlet oxygen, a red photon (635
nm) is released that is equivalent to 45 kcal/mol [25].
Dimol emission of singlet oxygen: 1O2 + 1O2  2 3O2 + h (635 nm)
Neural cells also emit continuously bioluminescent (bio)photons during their natural
metabolism. In vivo intensity of biophoton emission from a rat's brain correlates with cerebral
energy metabolism, EEG activity, cerebral blood flow, and oxidative stress [26]. Spontaneous
biophoton emission of neural tissue depends on the neuronal membrane depolarization and Ca2+
entry into the cells [27]. Indeed, the neural activity-dependent ultraweak biophoton emission has
been measured from hippocampal slices of rat brain [18,26,27].
Since generation of ROS and RNS is not a haphazard process rather a well-behaved
organized mechanism that can contribute to signaling pathways under various physiological
conditions, bioluminescent biophoton emission may not be just a byproduct of biochemical
processes but it could also be linked to precise signaling pathways of ROS and RNS. Namely,
during natural oxidative metabolism, regulated generation of ROS and RNS can also produce
regulated bioluminescent biophoton emission in cells and the brain.
We should consider that the real biophoton intensity within cells and neurons can be
considerably higher than one would expect from the measurements on ultraweak
bioluminescence, which are generally measured macroscopically several centimeters in distance
from the tissue or cell cultures. Namely, the most significant fraction of natural biophoton
emission cannot be measurable because it is absorbed during cellular processes.
3. Retinal noise
The retina contains two types of photoreceptors, rods and cones. The pigment protein in
rods is called rhodopsin, while the pigment protein in cones is called iodopsin. In each retina,
about 6 million cones provide the human eye's color sensitivity and they are more concentrated in
the central yellow spot known as the macula [28]. The rods are more numerous (about some 120
million in each retina) and are more sensitive than the cones. In the vertebrate retina, rods
mediate twilight vision and cones mediate daylight vision. A rod cell in the eye can perceive and
transform a single photon (the smallest unit of energy) of light into a neural signal [29]. Still, in
complete darkness, cones require the coincident absorption of several photons (some four to
seven) to generate a detectable signal [30-33]. The light-sensitivity of cones is 102 times lower
than that of rods, and the photoresponse kinetics are much faster in cones.
The amplitude of the spontaneous photoreceptor membrane current and voltage
fluctuations in the dark is referred as the dark noise. According to the electrical recordings, rods
have two components of the dark noise: a continuously present low amplitude component
(amplitude about 0.2 pA) and a discrete component (amplitude about 1pA) [34,35]. Dark noise
characteristics, in tiger salamander retina, differ among cones depending on their visual pigment,
and in all cone subtypes, noise lacks discrete, single photon transitions [36]. Cones are noisier
than rods, and cone photocurrents are smaller in peak amplitude and faster in time to peak than
those in rods.
The continuous component of rod noise results from the spontaneous activation of cGMP
phosphodiesterase molecules [37]. The discrete components of rod noise are indistinguishable in
shape and duration from those elicited by real photon induced photoisomerisations. So, they have
to originate at the very beginning of the transduction cascade. Current estimates of the activation
energies of discrete dark noises in vertebrate rod and cone pigments are about 40-50 kcal/mol for
activation by photon and 20-25 kcal/mol for activation by heat [38].
It has been suggested that the discrete events result from thermal activation of rhodopsin
[34], and the rate at which they occur sets a lower limit on visual sensitivity [39]. Barlow et al.
[40] proposed that the discrete retinal dark events arise in a small subpopulation of rhodopsins,
where the Schiff base linking the chromophore to the protein part has been deprotonated.
According to molecular computations, the unprotonated form has a much lower energy barrier for
chromophore isomerization, giving for the whole deprotonation-isomerization reaction an
apparent activation energy consistent with those found for the dark events [40,41]. However,
under this hypothesis, the dark event rate ought to be strongly pH dependent, but there is
contradiction about this hypothesis that thermal pigment activation depends on prior
deprotonation of the Schiff base [42]. However, we still lack a molecular theory that could
provide a more adequate explanation for the discrete retinal dark events of vertebrate rhodopsin.
4. Photoreceptor cells and polyunsaturated fatty acids
The photoreceptors have one of the highest demands for oxygen per square millimeter of
any tissue in the body and are very rich in mitochondria. The retina (photoreceptor outer
segments contain rhodopsin) and the brain (neuronal membranes, synapses) have the highest
concentration of polyunsaturated fatty acids (PUFA) particularly arachidonic acid (AA, omega-6,
20:4) and docosahexaenoic acid (DHA, omega-3, 22:6) [43,44]. The level of DHA is strictly
controlled, because any deviation from the physiological level results in disturbance of visual,
attentional cognitive functions, and neurodevelopment [45]. Photoreceptor cells (rods and cones)
are specialized neurons. Within the retina, DHA is concentrated in highly specialized membranes
that make up photoreceptor outer segments, and is found in phospholipids that are tightly
associated with the visual chromophore rhodopsin. Namely, the photopigments are surrounded by
the DHA-rich phospholipids in photoreceptor disk membranes [46]. Polyunsaturated fatty acids
can act directly on the light-sensitive channels or their lipid environment. Wiedmann et al. [47]
suggested that retinal disk membrane phospholipids are implicated in control of visual
transduction at the molecular level.
It is well known that a central part of fatty acid molecules contains a low ratio of
hydrogen atoms per carbon atoms, whereas at the polar heads of phospholipid and at the methyl
ends of fatty acids there are two saturated areas. Thus, when the phospholipids are arranged in the
membrane monolayer they form three distinct zones: a central unsaturated area and two saturated
areas located near the phospholipid heads and the methyl ends of fatty acids. According to
Zabelinskii et al. [48], in the unsaturated area, in contrast to the saturated ones, formation of
chemical bonds analogous to conjugated bonds can occur. As a result, the unsaturated area of the
membrane monolayer can have the ability to accept free electrons formed during various
chemical reactions. Namely, the unsaturated regions of phospholipid fatty acids in the membrane
monolayer can be involved in electron transfer. Moreover, conjugated-like bonds (pi-electrons of
phospholipid molecules) of the membrane may be able to absorb ultraviolet photons [49]. It
means that polyunsaturated fatty acids may take part in the retinal electron transfer processes and
the absorption of ultraviolet photons during natural visual actions.
5. Discrete dark noise of rods by bioluminescent photons
We could see that ROS and RNS play fundamental roles in intracellular signaling and
intercellular communication processes, and the main source of bioluminescent photons derives
from mitochondrial oxidative metabolism and lipid peroxidation processes. Mitochondrial
oxidative metabolism and lipid peroxidation processes can generate light-emitting molecules
such as triplet carbonyls and singlet oxygen. Since the photoreceptors have one of the highest
demands for oxygen, and the photoreceptor outer segments have the highest concentration of
polyunsaturated fatty acids [43,44], lipid peroxidation can be the most important sources of
bioluminescent photons in the retina. Moreover, phospholipids are tightly associated with the
visual chromophore rhodopsin, i.e., the photopigments are surrounded by the polyunsaturated
fatty acids in photoreceptor disk membranes [50], and only membrane-associated cGMP
phosphodiesterase is readily light activated [51].
Since retinal metabolism continuously functional, the naturally lipid peroxidation also
constantly occurs during scotopic vision (night vision or rod vision) and photopic vision (daylight
vision or cone vision). Under regulated circumstances, the lipid oxidation is a natural process of
membrane phospholipid turnover. Since natural lipid oxidation is one of the main sources of
bioluminescent photons, there is a continuously, low level bioluminescent photon emission
within retina without any external photonic stimulation. During photopic or scotopic vision, low
level bioluminescent photon emission is negligible compared to the daylight or night external
photonic stimulation. In contrast, in dark-adapted retinal cells, the discrete dark noise of rods can
be due to the bioluminescent photons generated continuously by lipid peroxidation and retinal
oxidative metabolism.
Since, for example, during dimol emission of singlet oxygen, a red photon (635 nm) is
released that is equivalent to 45 kcal/mol [25], this presents a reasonable argument as to why
spontaneous rhodopsin activations are indistinguishable from single-photon responses. However,
rods can absorb the released bioluminescent photons, which are originated from the lipid
peroxidation of PUFA of adjacent rods. It is also possible that a given rod emits a bioluminescent
biophoton which changes it direction and a little later it might absorb its own biophoton.
We should mention further two facts. First, the increased frequency of dark events in
photoreceptors exposed to higher temperatures is evidence for the thermal contribution to the
generation of dark noise [34]. However, lipid peroxidation, free radical formation and
bioluminescent processes are also temperature dependent processes [52-57]. So, the
bioluminescent photon emission is also temperature dependent [57]. Second, dark event is the
result of Poisson fluctuations in photon absorption [29]. However, bioluminescent biophoton
emission also bears non-linear Poisson-like distributions [58-60].
6. Retinal phosphenes
Ionizing radiation consists of electromagnetic radiation as X-rays and gamma rays, and
particulate radiation, such as electrons, protons, and neutrons. It is well known, that ionizing
radiation changes the chemistry of matter along its passage and produces ions and free radicals in
the body [61]. Exposure to ionizing radiation produces oxygen-derived free radicals in the tissue
environment as hydroxyl radicals, superoxide anion radicals and hydrogen peroxide [62-64]. This
transient overproduction of locally induced free radicals by ionizing radiation produces an excess
biophoton emission in the visual system during space travel [10,11]. In other words, during space
travel, phosphene perception can be due to the transient increase of biophoton emission generated
by ionizing particle induced free radicals [10,11,65]. Since cerebral cortex has a much higher
threshold for detecting phosphenes induced by ionizing particles (as accelerated particles are)
than retina [66], the main source of ionizing particle induced phosphenes appears in the retina.
However, Narici et al. [11] first experimentally verified our prediction [10] about retinal
phosphenes during space travel. According to Narici et al., ionizing radiation (cosmic particles)
induced free radicals can create chemiluminescent photons from lipid peroxidation, which are
absorbed by the photoreceptor chromophores, modify the rhodopsin molecules (bleaching) and
start the photo-transduction cascade resulting in the perception of phosphene lights.
In contrast to discrete dark noise of rods, which can be due to the natural and evanescent
bioluminescent photons of lipid peroxidation (as we suggested in previously section of this
paper), the ionizing radiation can induce significant retinal lipid peroxidation and overproduction
of free radicals and bioluminescent photons, which can appear as phosphene flashes in our
conscious mind. In other words, if we consider that a rod cell in the eye can perceive and
transform a single photon of light into a neural signal [29], and that in complete darkness cones
require the coincident absorption of several photons (some four to seven) to generate a detectable
signal [30-33], these indicate that temporarily increased bioluminescent photons from ionizing
radiation induced retinal lipid peroxidation can be a real biophysical basis of phosphene flashes
during space travel.
According to Narici et al [11], “The time windows of rhodopsine ion-induced
bleaching/physiological regeneration and of the conscious perception of phosphenes in space
experiments are not comparable, yet the activation of the visual system in mammals follows a
cascade of sequential effects not inferable from early retinal events.” However, the perception of
color-related phosphenes, similar to the experiences related to color due to external light stimuli,
must involve V4/V8/VO-neural-network [67]. This implies that estimation of time must involve
from retina to the processing of phoshpene-information in this neural-net. This type of estimation
may be similar to that to the estimation using external photonic stimuli because more or less same
or similar processing is involved and may be up to 500 msec [68].
7. Testing our biophysical interpretation
Testing our new interpretation about discrete dark noise of rods will require a converging
methods approach. It is well known that all living cells emit continuously biophotons without any
excitation. However, up to day, nobody has performed any bioluminescent photon measurements
on humans’ or animals’ retinal tissues or cell cultures. Therefore, a methodology needs to be
established to measure in vitro bioluminescent photon emission in humans’ and animals’ retinal
slices under dark-adapted conditions. A series of other tests and computational modeling should
be performed to compare the bioluminescent biophoton emission with the discrete dark noise
under various circumstances such as: temperature variation, administration of various
(hallucinogenic) drugs, etc. Moreover, a possible correlation between discrete dark noise and
retinal phosphene perception should be investigated. Lastly, although our prediction about retinal
phosphenes during space travel was first experimentally verified, several further experiments are
needed to study the ionizing radiation and other forms of stimuli that can induce retinal
phosphenes, and is also needed to find correlation between bioluminescent biophoton and
induced retinal phosphenes.
8. Summary
Spontaneous rhodopsin activation produces discrete noise events indistinguishable from
single-photon responses. So, they have to originate at the very beginning of the transduction
cascade. Current estimates of the activation energies of discrete dark noises in vertebrate rod and
cone pigments are about 40-50 kcal/mol for activation by photon and 20-25 kcal/mol for
activation by heat. However, there is an inevitable conclusion is faced with a serious discrepancy
in the apparent energy barrier of thermal events compared with the photon-driven process.
To reconcile this discrepancy, it was supposed that thermal activation and light activation
of rhodopsin follow different molecular paths. The most convincing hypothesis for a separate
low-energy thermal pathway is that the discrete dark noises of rods arise in a small subpopulation
of rhodopsins, where the Schiff base linking the chromophore to the protein part has been
deprotonated.
However, here, we suggested a new biophysical interpretation about discrete dark noise of
rods. Under regulated circumstances, lipid oxidation is a natural process in various cells and also
in retinal membrane. During retinal metabolism, natural lipid peroxidation also constantly occurs
during scotopic and photopic vision. Since natural lipid oxidation is one of the main sources of
bioluminescent photons, and the photoreceptors have the highest oxygen demand and PUFA
concentration, there is a continuously, low level bioluminescent photon emission in the retina
without any external photonic stimulation. During photopic or scotopic vision, evanescent
bioluminescent photon emission is negligible. In contrast, in dark-adapted retinal cells this
evanescent bioluminescent photon emission is not negligible, but the discrete dark noise of rods
can be due to these bioluminescent photons (generated constantly by retinal lipid peroxidation
and oxidative metabolism). Namely, the discrete dark noise of rods can emerge, because rods are
able to absorb bioluminescent photons that are originated from the lipid peroxidation of adjacent
rods. It is also possible that a given rod emits a biophoton, which changes it direction and a little
later it might absorb its own biophoton during bioluminescent processes.
This suggested biophysical interpretation about discrete dark noise of rods may be more
possible than the thermal activation hypothesis. Current calculations of the activation energies of
discrete dark noises in vertebrate rod and cone pigments are about 40-50 kcal/mol for activation
by photon. However, for example, dimol emission of singlet oxygen (that is originated from
retinal lipid peroxidation) can release a red photon that is equivalent to 45 kcal/mol.
Consequently, our biophysical explanation does not need any complex and theoretical
temperature calculations that whether the discrete noise due to the temperature fluctuations but
can present a reasonable argument as to why spontaneous rhodopsin activations are
indistinguishable from single-photon responses. In addition, this biophysical interpretation can be
experimentally confirmed by very sensitive photomultiplier devices. We should also mention that
our interpretation is supported by further arguments. First, both dark events in photoreceptors and
the bioluminescent photon emission (lipid peroxidation, free radical and bioluminescent
processes) are temperature dependent. Second, dark event is the result of Poisson fluctuations in
photon absorption. However, bioluminescent biophoton emission also bears non-linear Poissonlike distributions.
Lastly, this paper also pointed out that conjugated-like bond (pi-electrons of
polyunsaturated fatty acids in the membrane) of the membrane may take part in retinal electron
transfer processes and the absorption of ultraviolet photons during natural visual actions.
Acknowledgments
The authors (i) Bókkon I. gratefully acknowledges support of this work by the System
International Foundation (Hungary) and (ii) RLP Vimal would like to thank VP-Research
Foundation Trust and Vision Research Institute research Fund for the support. RLP Vimal is also
affiliated with Dristi Anusandhana Sansthana, A-60 Umed Park, Sola Road, Ahmedabad-61,
Gujrat, India; Dristi Anusandhana Sansthana, c/o NiceTech Computer Education Institute,
Pendra, Bilaspur, C.G. 495119, India; and Dristi Anusandhana Sansthana, Sai Niwas, East of
Hanuman Mandir, Betiahata, Gorakhpur, U.P. 273001, India. His URL:
http://sites.google.com/site/rlpvimal/Home.
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