22
Impact of Retinal Stimulation
on Neuromodulation
Deborah Zelinsky
CONTENTS
Introduction ������������������������������������������������������������������������������������������������������������������������������������411
Retinal Function �����������������������������������������������������������������������������������������������������������������������������412
Cortical, Image-Forming Pathways (Eyesight) ������������������������������������������������������������������������� 414
Input Circuitry to the Visual Cortex ������������������������������������������������������������������������������������� 414
Output Circuitry from the Visual Cortex ������������������������������������������������������������������������������ 415
Cortical Adaptations to Change��������������������������������������������������������������������������������������������416
Subcortical Nonimage-Forming Pathways�������������������������������������������������������������������������������� 417
Subcortical Neurological Circuitry ��������������������������������������������������������������������������������������418
Subcortical Chemical Circuitry ��������������������������������������������������������������������������������������������419
Subcortical Adaptations to Change ��������������������������������������������������������������������������������������420
Retinal Structure ����������������������������������������������������������������������������������������������������������������������������421
Cell Types ���������������������������������������������������������������������������������������������������������������������������������� 422
Layers ����������������������������������������������������������������������������������������������������������������������������������������422
Sections �������������������������������������������������������������������������������������������������������������������������������������425
Thickness�����������������������������������������������������������������������������������������������������������������������������������425
Neuromodulation: A Conceptual Framework �������������������������������������������������������������������������������� 425
Combination of External and Internal Signals ��������������������������������������������������������������������������428
Cortical Interactions with Subcortical Circuitry �����������������������������������������������������������������������430
The Impact of Retinal Stimulation on Neuromodulation ��������������������������������������������������������������431
Neuro-Optometric Approaches during Rehabilitation �������������������������������������������������������������� 432
Summary of Interventions ��������������������������������������������������������������������������������������������������������� 434
Conclusion �������������������������������������������������������������������������������������������������������������������������������������434
Acknowledgments��������������������������������������������������������������������������������������������������������������������������436
References ��������������������������������������������������������������������������������������������������������������������������������������436
INTRODUCTION
Historically, experts have considered the retina as a sensory system, feeding information into the
brain’s visual cortex� However, research has now demonstrated that the retina is a bidirectional neural interface that is an actual part of the central nervous system (CNS) (Vaney 1999)� Since retinal
signals are processed by many regions of the brain—not just the visual cortex—the implication is
that retinal stimulation can affect other physical, physiological, and psychological processes, such
as motor control, biochemical activity, and cognitive abilities�
During the past decades, researchers have discovered a retinal cell type that responds to luminance
(external light) levels� These photosensitive cells combine the external luminance information with signals obtained through eyesight and not only send this combined feedforward information to the brain
but concurrently receive feedback signals from the body (Chen et al� 2011, 2013, Schmidt et al� 2011)�
The mixture of feedforward and feedback signaling enables the retina to be used as a twoway, noninvasive portal for inluencing and monitoring body functions and thought processes,
largely beneath the level of consciousness� Because of the retina’s critical role in brain function,
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therapeutic eyeglasses—an important tool in neuro-optometric rehabilitation—may be used
to modify processing in a range of physical and mental health disorders� These individualized
lenses can change the dynamic relationship between the mind’s visual inputs and the body’s
internal responses by altering spatial and temporal distribution of light on the retina� The novel
use of light to affect the nervous system has already been successfully applied to a range of disorders, including jaundice (Tayman et al� 2010), jet lag (Parry 2002), seasonal affective disorder
(Lavoie et al� 2009), brain injury (Naeser et al� 2011, Sinclair et al� 2014), and spinal cord injury
(Alilain et al� 2008, Alilain and Silver 2009)� Neuro-optometry also uses light to modulate brain
and body functions�
This chapter presents both the theoretical framework and empirical evidence to support the use
of customized eyeglasses for altering brain function� The underlying premise is that there exists a
hierarchy of separate, yet interdependent, cortical and subcortical pathways, which are linked to
various visual systems� The main emphasis of this discussion is on the retina’s complex connections
with systems other than the conscious eyesight� Those subconscious and unconscious systems can
be altered by changes in the amount, frequency, intensity, or direction of incoming light to the eye�
The following section overviews retinal function, at cortical and subcortical levels, with examples of how the mind and body adapt to environmental changes� Section 3 discusses retinal structure�
Section 4 introduces the concept of neuromodulation, and its effects on behavior and processing�
Neuromodulation is described here as the process of achieving balance between mental and physical
functions at both conscious and nonconscious levels� Section 5 describes the impact that eyeglasses
can have on the nervous system�
RETINAL FUNCTION
The retina connects with many systems other than eyesight� Its connections include structures in the
cortex, limbic system, cerebellum, midbrain, and brainstem, all of which affect systems such as the
endocrine, respiratory, circulatory, digestive, and musculoskeletal� During neuro-optometric rehabilitation, careful adjustment of light entering the retina by using lenses, prisms, and/or ilters alters
cellular activity� This biochemical activity triggers action potentials and graded potentials (Purves
and Williams 2001), affecting overall neuronal circuitry�
The basic concept outlined in the pioneering work of A�M� Skefington, O�D�, in the mid-twentieth
century, refers to a hierarchy of “Where am I?,” “Where is it?,” and “What is it?” pathways, culminating in an emergent concept of vision that gives meaning to sensory signals (Skefington 1957,
Skefington 1966)� Optometrist Jacob Liberman’s 1990 book Light: The Medicine of the Future
added pineal gland activation by retinal stimulation—a “How am I?” pathway to Skefington’s
accepted framework (Liberman 1994)� Those well-recognized retinal pathways send output signals
in response to changes in the environment� Bart Krekelberg, a brain researcher at Rutgers, postulated
a “When is It?” pathway for time judgment in 2003 (Krekelberg 2003)—a concept that has since
been documented in the past decade (Kim et al� 2014b)�
The effects of injury, disease, and stress vary from individual to individual, depending on a “Who
am I?” pathway� Altered mind and body functions limit processing of the external environment� Those
mental and physical changes often create symptoms in either the body’s internal regulation or in the
mind’s planning, attention, and judgment due to disrupted, mismatched, or dysfunctional sensory circuitry� For instance, patients with brain injuries often complain of light and sound sensitivity because
they cannot easily ilter out external sensory stimuli� Eyeglasses will affect both external sensory input
(eyesight) and internal regulation, thus inluencing executive (“What should I do about it?”) functions�
Nontraditional types of eyeglass designs can prove to be a useful tool during rehabilitation to help balance fragile biochemical and sensory systems and enhance the rehabilitative work of other professionals�
As shown in Figure 22�1, the body’s survival functions and the mind’s executive functions are
inluenced by changes in external sensory inputs� Conversely, external attention and awareness are
altered by shifts in the body and/or mind� The three domains interact�
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Impact of Retinal Stimulation on Neuromodulation
Mind
Executive functions
“What should I do about it?” is influences by
“Who am I?” (based on individual experiences)
Environment
Body
Sensory systems
Survival functions
Central
“What is it?”
Chemical
“How am I?”
Peripheral
“Where is it?” and
“When is it?”
Proprioceptive
“Where am I?”
FIGURE 22.1 Three domains affected by retinal stimulation� (Courtesy of The Mind-Eye Connection,
Northbrook, IL�)
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FIGURE 22.2 Mind and body, each reacts to environmental changes� (Courtesy of The Mind-Eye Connection,
Northbrook, IL, Copyright 2015�)
It is useful to consider the cortical and subcortical pathways separately� The cortical pathways
are described in terms of retinal input into and output from the visual cortex� The subcortical (nonimage-forming) pathways are separated into neurological and biochemical systems� The multiple
feedback pathways within the retina are beyond the scope of this limited chapter�
As shown in Figure 22�2, ambient processing is everything that goes on “behind the scenes” as
opposed to conscious attention at a given moment� Chemical and muscle relexes unconsciously
govern “How am I?” and “Where am I?” systems at the body level, but those two concepts are also
processed at a cortical level, albeit subconsciously� For example, “How am I?” subcortical would
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be tired, energized, etc� At the cortical level, “How am I?” would register as happy, sad, angry, etc�
Meanwhile, the “Where am I?” subcortical response involves physical body balance against gravity, while, at the cortical level, mental awareness occurs, such as the realization of being in North
America and on the planet Earth�
CORTICAL, IMAGE-FORMING PATHWAYS (EYESIGHT)
Unfortunately, central eyesight is deemed as the most important of all the retinal pathways, even
though it is dependent on other sensory inputs� Seeing details clearly is actually the slowest retinal
pathway for information processing and occurs only after conscious attention is placed on a selected
target (O’Connor et al� 2002)� The classic image-forming eyesight pathway from the retina to the
visual cortex is only one of several visual functions� The portion of the retina that transmits clear
details is not even present in newborn infants; it develops within a few months of age, after other
retinal pathways are in place (Candy et al� 1998)� Although the “Where is it?” (peripheral eyesight) and “What is it?” (central eyesight) pathways are connected (Yeatman et al� 2014), linkage
between those cortical pathways often is not measured during eye examinations� Typically, glasses
are designed to only address the clarity of surrounding targets—the “What is it?”—central system
(Figure 22�3)�
Input Circuitry to the Visual Cortex
As they begin the journey to the visual cortex, the vast majority of signals (approximately 90%) leaving the optic nerve travel through the lateral geniculate nucleus (LGN) of the thalamus (Goldstein
2010) for further processing in the visual cortex as part of the central and peripheral eyesight pathways� Those signals lead toward attention on a selected target� Some signals branch off at the LGN
to other subcortical structures involved with neurological circuitry and others modulating chemical
circuitry as discussed in “Subcortical neurological circuitry” and “Subcortical chemical circuitry�”
Cortical
lobes
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FIGURE 22.3 Cortical where?, when?, and what? retinogeniculate tracts determining space and time judgments� (Courtesy of The Mind-Eye Connection, Northbrook, IL, Copyright 2014�)
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Impact of Retinal Stimulation on Neuromodulation
415
FIGURE 22.4 Input circuitry from retina to various cortical and subcortical locations� Nasal retinal ibers
travel to the hypothalamus; temporal retinal ibers do not� (Courtesy of The Mind-Eye Connection, Northbrook,
IL, Copyright 2015�)
Some of these subcortical structures include the intergeniculate lealet, the superior colliculus in the
midbrain, the suprachiasmatic nucleus of the hypothalamus, the pineal gland, and the habenula (part
of the limbic system connecting with motor circuitry)� New research also has demonstrated a direct
retinal pathway in humans to the brain’s pulvinar region (another portion of the thalamus) (Arcaro
et al� 2015)� Many of those locations send signals back to the LGN through feedback loops� Signals
continue from the LGN through the optic radiations that traverse the parietal and temporal lobes�
The signal content in the optic radiations depends on the originating location of the visual signal�
Signals from superior space (at or above eye level) travel through the bottom portions of each retina
and head through temporal lobes, while targets below eye level send signals through the superior
retina and interact with the parietal lobes� Meyer’s loop in the temporal lobe was originally thought
to be an anterior looping of optic radiation ibers (Jeelani et al� 2010)� However, in 2015, scientists
determined that Meyer’s loop is a conglomeration of many sensory signals (Goga and Ture 2015)
(Figure 22�4)�
Retinal input into the LGN represents approximately a ifth of its total sensory input� The LGN
is inluenced by many other sensory signals and previous memories, as presented in Figure 22�5 as
the “Who am I?” pathway� The LGN has burst modes and tonic response modes, which vary during
waking or sleep states (Weyand et al� 2001, Horng et al� 2009)� Exiting retinal signals in the optic
nerve interact with inhibitory and excitatory feedback and feedforward signaling systems from the
LGN (Guler et al� 2008, Schmidt and Kofuji 2008)� In other words, a signiicant amount of twoway signaling occurs with “Who am I?” guiding the cortical responses to subcortical reactions�
Signals from many other sensory systems also interact with retinal processing before the visual
cortex becomes involved�
Output Circuitry from the Visual Cortex
The output circuitry from the visual cortex to various cortical eye ields results in quantiiable eye
movements� Some of those movements are used to aim at a selected target, some to maintain balance, and others for thoughts� Optometrists can control inputs with various types of lenses and
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Unconscious
reflexes
Fast
Target(s)
background
Chemical
systems
Retinal
filtering
How
am
I
Mental
filtering
Thalamus
Slow
Fast
Muscular
systems
ere
Wh
am
Int. awareness
Int. attention
Subconscious
awareness
Conscious
attention
Ext. awareness
Ext. attention
Where/when is it
What is it
I
Who am I
FIGURE 22.5 “Who am I?” impacts “where am I?” (brainstem) and “how am I?” (limbic system functions)�
(Courtesy of The Mind-Eye Connection, Northbrook, IL, Copyright 2014�)
measure changes in order to deduce processing� Knowing how a person processes incoming information is helpful when developing an individualized treatment plan for rehabilitation�
Output circuitry from the visual cortex to the eye muscles is described as part of either a ventral or a dorsal stream� Signals in those streams are governed by internal awareness, attention, and
motivation� As mental priorities shift, signals travel through either the ventral or dorsal stream to
the selected target and background� The ventral stream contains information regarding the selected
target, and the dorsal stream contains information about the background to provide context for the
details of the ventral stream� In effect, the distinction between peripheral and central eyesight—or
concepts and details—depends on whether awareness and attention are on internal thoughts or external targets�
If operating properly, peripheral eyesight (background awareness) works in tandem with central
eyesight (visual attention)� This relationship between attention and awareness can be constricted
(for instance, when looking at a sliver in a inger) or expanded (e�g�, when viewing a large landscape)� Many neurodegenerative diseases such as amyotrophic lateral sclerosis, multiple sclerosis
(MS), and Alzheimer’s disease affect this peripheral/central relationship� They can be studied by
comparisons to research on glaucomatous changes in the optic nerve, which are also considered a
neurodegenerative processes (Gupta and Yucel 2007)�
Visual processing is not just a simple input/output mechanism� The visual cortex actually receives
information from other forms of internal processing in addition to the external eyesight signals
(Golomb et al� 2010) before thought-induced eye movements occur� There is feedback signaling
from the visual cortex back to the LGN (Ling et al� 2015) and eventually to the retina� These returning retinal signals are termed retinopetal signals, as compared to the retinofugal signals exiting the
retina, described in “Input Circuitry to the Visual Cortex section of this chapter�”
A simpliied viewpoint of visual output circuitry is to envision eye muscle movements as an end
result after processing multisensory inputs� Eye muscles include the eyelids, pupils, and extraocular
muscles� Movements can be quantiied by the measurements of reaction time� In addition to cortically induced eye movements addressing eyesight, there are subcortical, relexive eye movements
induced by the brainstem and limbic system activity�
Cortical Adaptations to Change
Environmental changes trigger adaptive responses in cognition, perception, and emotions at the
cortical level� Those responses are based on previous knowledge, combined with incoming sensory
information� Cognitive circuitry is dependent on perceptual circuitry, which, in turn, is altered by
emotional circuitry that is based on past experiences� Cortical activity is also inluenced by subcortical processes and can be disrupted by brain injury or disease� In some cases, cortical processes never
fully develop due to genetic mutations or other birth-related issues� However, brain plasticity allows
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Impact of Retinal Stimulation on Neuromodulation
Memory
Motivation
emotions
Cerebellum
Chemical
regulation
Retina
How am I?
Midbrain
brain stem
spinal cord
Where am I?
FIGURE 22.6 Retinal connections with neurological and chemical circuitry� (Courtesy of The Mind-Eye
Connection, Northbrook, IL, Copyright 2014�)
for many adaptations when provided with proper stimuli� Customized eyeglasses can uniquely provide such stimuli, especially when combined with other disciplines during rehabilitation�
When describing sensory systems (such as visual and auditory), “Where is it?” and “What is
it?” pathways are commonly referenced� They are often mistakenly termed “ambient and focal”
processing, respectively� However, the “Where is it?” pathway is only the external portion of ambient processing� There is a second, more primitive, internal portion of ambient processing termed
“Where am I?�” Although the visual cortex is usually thought of as being activated by external
sensory signals, prior research has determined how it is also activated by other sensory signals and/
or mental imagery activities, even without the presence of actual external visual stimuli (Vetter
et al� 2014)� In other words, feedback information is abundant in the visual cortex, more so than
feedforward information from the external environment� In autistic patients, sensory pathways are
often hyperactive, and the classic eyesight pathways are often dysfunctional (Grossman et al� 2009,
Tillmann et al� 2015)�
Adaptation to environmental changes at the cortical level depends on such factors as motivation,
propensity for risk taking, comfort, sense of security, interest, mood, appetite, anxiety level, and
libido� Visual circuitry, combined with “Who am I?” internal experiences, plays an important role
in assessments of time and space� Thus, cortical adaptations to change encompass many signaling
processes—not simply eyesight (Figure 22�6)�
SUBCORTICAL NONIMAGE-FORMING PATHWAYS
Retinal connections at an unconscious level affect chemical and muscular reactions through the
retino-hypothalamic and retinotectal tracts, respectively� Research on the parvocellular (“What is
it?”) pathway from the ventral stream and the external magnocellular (“Where is it?”) pathway from
the dorsal stream show that deiciencies in those pathways are found in patients who have schizophrenia, Parkinson’s disease (Altintas et al� 2008), epilepsy (van Baarsen et al� 2009), diabetes, drug
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addiction, autism, and Alzheimer’s disease� Changes in retinal function, such as judgments in space
and time, can be used as a biomarker for psychiatric disorders (Lavoie et al� 2014)�
Connections build themselves on the basis of need� For instance, the auditory cortex reorganizes
itself to be able to process visual motion (Shiell et al� 2014)� Visual ields develop differently in deaf
people than in either people who hear normally or people who have learned signing from infancy�
The inferior and right visual ields are most effective for processing sign language signals (Bosworth
and Dobkins 2002)� People with normal hearing prefer central eyesight pathways, while those who
are deaf prefer peripheral eyesight pathways� These differences are attributed to changes in retinal
plasticity rather than to cortical neuroplasticity� For example, when reading was tested in children
using colored ilters, researchers found that those children with normal hearing did not choose the
same visual ilters as children who were deaf (Hollingsworth et al� 2015)� Therefore, in the case of
auditory sensory deprivation, neuroplasticity of the retina was again exhibited�
The effects of retinal stimulation can be quantiied by measuring eye movements and pupil functions—part of which are relexive from brainstem and limbic system activity� Other measurements
are cortically induced, relecting both conscious and subconscious thought� Signals contributing to
the subcortical reactions are faster than those triggering cortical responses� For instance, convergence (aiming the eyes inward) is a measurement that has several triggers� The most common source
is when a patient is engaged in the environment, consciously aiming at a selected target� A second
mechanism of convergence occurs when head position is shifted� Habitual head position might be
downward (creating an “eyes outward” posture), when the head tilts upwards, eyes converge� A third
mechanism involves internal thoughts� Eyes converge when people are thinking about details or are
stressed and diverge when they are conceptualizing or relaxed� A fourth mechanism is an internal,
physiological state—eyes pull outward during sleep� Pupil reactions also can change due to external
(light) or internal stimuli (fear, arousal in the mind, or drugs and chemicals in the body)�
Relationships between retinal activity—more speciically the peripheral retina—and physical
and physiological body functions have been identiied in recent research—for instance, the oculocardiac relex (Stathopoulos et al� 2012) or the adrenal glands (Kiessling et al� 2014)� Impairments in
retinal processing affecting predictive mechanisms have been implicated in the disrupted eye movements noted in schizophrenia (Sprenger et al� 2013)� Retinal stimulation in humans has been shown
to affect migraines and photophobia (Maleki et al� 2012)� A study of 40,000 men during a 25 year
period showed a 43% increase in open angle glaucoma in those who had gum disease� Their possible hypothesis is that toxins released from the gums travel to the eye� Patients with glaucoma also
are noted as often having sleep problems attributed to loss of the retinal cells linked with circadian
rhythms� Electroretinogram testing of people with seasonal affective disorder shows measureable
changes in rod and cone activity (Lavoie et al� 2009)�
Subcortical Neurological Circuitry
Signals that travel to the nucleus of the optic tract are used for smooth pursuit movement� Other pathways for pursuit movements exist as well, all of them interconnected (Nuding et al� 2008)� Other pretectal nuclei govern relexive eye movements and visual stability, such as optokinetic nystagmus relexes
and visual–vestibular interactions� Regions in the cortex, such as the middle, temporal, and the medial
superior temporal lobes, link their signaling with subcortical structures, including parts of the accessory
optic system for stable pursuit (tracking) movements (Heinen and Watamaniuk 1998) (Figure 22�7)�
The Edinger–Westphal nucleus is an accessory nucleus of the oculomotor nerve and receives
input for pupillary constriction from external light� This nucleus also receives internal information from the olivary pretectal nuclei, which also receive signals from a subtype of the intrinsically
photosensitive retinal ganglion (ipRGC) cells� The olivary pretectal nuclei are involved in linking
internal metabolism with external luminance—through the suprachiasmatic nuclei (SCN) of the
hypothalamus and intergeniculate lealet (IGL) of the thalamus (Ishikawa 2013)�
That light stimulation on one part of the visual ield would affect the corresponding portion
of the subcortical superior colliculus make sense, because the retina is mapped onto the superior
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Impact of Retinal Stimulation on Neuromodulation
Vestibular nuclei
Superior colliculi
Basal ganglia
Frontal eye fields
Supplementary eye fields
E-W nuclei
Pretectal nuclei
Nuclei of the optic tract
Cerebellum
Cerebellum
Midbrain
brain stem
spinal cord
Where am I?
Muscular
survival
functions
FIGURE 22.7 Retino-tectal tract—Where am I? (Courtesy of The Mind-Eye Connection, Northbrook, IL,
Copyright 2014�)
colliculus� The superior colliculus responses are different depending on the stimulus’ location
(Ghose and Wallace 2014)� Retinal signals travel to the top three layers (supericial superior colliculus), rather than to the bottom four layers (deep superior colliculus), which are simultaneously
receiving information from other sensory systems (Ghose et al� 2014)�
The subcortical superior colliculus also is involved in spatial attention (Schneider and Kastner 2009)�
Studies have shown that the superior colliculus/pretectal area and the visual cortical areas are each
affected by changes in light (Miller et al� 1998)� The superior colliculus pathway is independent of the
classic cone pathway of seeing (Leh et al� 2010)� Yet, the superior colliculus is still responsive to colors
(Zhang et al� 2015)� Sensory systems interact with the basal ganglia (Prescott et al� 2006)� A clinical
trial demonstrated that patients given placebo glasses were not as effectively treated as those prescribed
actual glasses with prisms (Bowers et al� 2014)� In other words, varying the dispersion of light onto the
retina affected the patients’ reactions� New research shows that prism glasses altering the “Where is it?”
pathway by shifting apparent target location also have an effect on the “How am I?” chemical pathway�
Subcortical Chemical Circuitry
Chemical measurements can be made to evaluate changes in the immune system by assessing the color of the sclera, luid in the conjunctiva, and the quantity and content of the tears� The
retino-hypothalamic pathway alters adrenaline levels quickly via the hypothalamic–pituitary–adrenal axis before the slower signals from central eyesight have even focused on the target� External
and internal systems come together in the retino-hypothalamic tract, where retinal changes inluence
body functions both muscularly and chemically (Figure 22�8)�
The habenula (part of the limbic system) has direct connections with a small percentage of retinal
ganglion cells and multiple connections in the brainstem� Its circuitry connects the cortex with the
brainstem (Aizawa 2012) by registering changes in light� It is involved in modulation of both dopamine and serotonin systems, playing a role in sleep, depression, and schizophrenia� Dysfunction in the
habenular circuit contributes to decreased REM sleep and is often linked to insomnia and depression
(Aizawa et al� 2013)� It is also involved in the suppression of motor control (Beretta et al� 2012)�
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Hippocampus
Amygdala
Hypothalamus
Pituitary gland
Pineal gland
Intergeniculate leaflet
Habenula
Motivation
emotions
Chemical
regulation
Chemical
survival
functions
FIGURE 22.8 Retino-hypothalamic tract—How am I? (Courtesy of The Mind-Eye Connection, Northbrook,
IL, Copyright 2014�)�
Intergeniculate lealet, a small section of the LGN (part of the thalamus), contributes feedforward information to the SCN regarding body metabolism and sensory conditions� It receives input
from the vestibulo–visuomotor system� Thus, head movement might inluence circadian rhythms
(Horowitz et al� 2004, Blasiak and Lewandowski 2013, Saderi et al� 2013)� “How am I?” signals
from biochemical regulation are linked to “Where am I?” signals determined from the head position
(Horowitz et al� 2004)� Signals from the IGL to contralateral IGL are more activated in the light
(Blasiak and Lewandowski 2013)�
The hippocampus is one of many components that regulate adrenocortical activity at the hypothalamic level (Jacobson and Sapolsky 1991)�
The amygdala is activated during eye contact� A small experiment showed that the amygdala in
a cortically blind person was activated by direct gaze rather than averted gaze� The study concluded
that the amygdala pathway is part of a larger network involving facial expressions (Burra et al� 2013)�
The retino-hypothalamic pathway is involved at the subconscious level in circadian rhythms�
While the existence of the retino-hypothalamic pathway has been known for some time, scientists
have not explored how optometry can use retinal pathways to link the internal environment with
external stimuli, relecting both conscious and non-conscious pathways� Research is beginning to
show how treatments using speciic light wavelengths can profoundly change the response of circadian rhythms (Mure et al� 2009)�
Subcortical Adaptations to Change
Pupil and eye movement relex assessments are often used as biomarkers for neurological integrity�
The relationship between the retina and the nervous system means that the eye also can be used as
a noninvasive approach determining brain function� One way to assess balance in systems is with
pupil measurements� The pupil is controlled by the synthesis of three photoreceptive inputs—rods,
cones, and ipRGC cells—and also by nonphotoreceptive inputs such as stimulation by the autonomic nervous system (ANS)� The more stressed a person is, the larger his or her pupils become�
Chemical circuitry plays a large role in visual processing� For instance, someone on pain medications having hallucinations as a side effect or someone with schizophrenia who has too much
dopamine present are not fully aware of their surroundings�
The critical role that the retina performs, its interconnections with brain systems other than simple eyesight, and its relationship to disease and treatment of disease can be best understood by having some familiarity with how the retina is structured� This next section will provide a brief overview
of that structure�
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Impact of Retinal Stimulation on Neuromodulation
RETINAL STRUCTURE
The retina receives information from both external and internal sources, with the inal goal
of directing action� It contains pathways linking exogenous stimuli and endogenous processes,
including having its own immune system (Benhar et al� 2012) and a localized circadian clock
(Zele et al� 2011)� At the simplest level, the eye channels light onto the retina, triggering chemical reactions in the outer retina that convert the light into electrical signals in the inner retina�
Pupil responses generated by internal retinal signals are separate from responses generated by
external light (Lee et al� 2014)� Various diseases can be diagnosed by changes in the retinal
structure� During development, the structure changes depending on need� For example, retinal
plasticity, not cortical plasticity, has been found in deaf people, as mentioned in “Retinal function” (Figure 22�9)�
The estimated 126 million photoreceptors in each eye (Jonas et al� 1992) receive light information and funnel signals through ten retinal layers into approximately 1,200,000 ganglion axon
ibers, which exit each eye as the optic nerve (Medeiros et al� 2013)� The exiting signals are not
all involved in cortical eyesight� Even in blind persons, functional optic nerve ibers have been
observed� Although the eyesight portions were not functioning, between 5% and 15% of the millionplus axons were still active (Cursiefen et al� 2001)�
The complex iltering structure of the retina can be described in various ways—by its cell types,
which serve different functions; its layers through which the signals travel; its sections, which arise
from different transcription factors (Tombran-Tink and Barnstable 2008); and its thickness� Various
types of chemical receptors, such as dopaminergic, serotonergic, cholinergic, and glutaminergic, are
involved in signal transmission for excitatory and inhibitory signaling� For instance, when activated,
dopaminergic neurons send more signals through retinal cone circuits and fewer signals through rod
circuits (Witkovsky 2004)� Eyeglasses can selectively stimulate various cell groups, thereby affecting informational iltering processes and, thus, output signals� Different diseases affect speciic cell
types, altering overall retinal function�
10 retinal
layers
Eyesight
126 million
entering signals
1.2 million
exiting signals
Cor
l
tica
Sub cort
ic
Chemical
systems
al
Neurological
systems
To
eye muscles
FIGURE 22.9 Retinal iltering to direct action and behavior� (Courtesy of The Mind-Eye Connection,
Northbrook, IL, Copyright 2015�)
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CELL TYPES
There are more than 50 cell types in the retina (Raviola 2002), each contributing to a different aspect
of retinal processing before signals leave the eye to the brain’s subcortical and cortical pathways�
The main cells in the retina include the straightforward pathway—from photoreceptors to bipolar
cells to ganglion cells, with horizontal and amacrine cells interspersed in between to inhibit the
overlow of incoming information� There are also Mueller glial cells, which run the entire depth
of the retina� This star-shaped type of glial cell (astrocyte) is found in the brain and the spinal cord
and once was able to help in maintaining support structure� However, as of 2000, research has demonstrated that astrocytes are involved in metabolic transfers between extracellular environments�
Disruptions in their signaling may play a possible role in neuropsychiatric disorders (Molofsky et al�
2012) and brain plasticity (Araque and Navarrete 2010, Perea and Araque 2010)�
Another recent research has demonstrated that many subtypes of each kind of retinal cell exist�
For instance, three types of cones, L, M, and S, respond to long, medium, and short wavelengths of
light, respectively� Bipolar cells are separated into midget and diffuse general groupings, with many
subtypes of those, but, functionally, they are considered to be activated by central or surrounding
targets� There are ON cone bipolar cells (for each type of cone cell grouping) and OFF cone bipolar
cells as well as ON and OFF rod bipolar cells� As for the inhibitory horizontal and amacrine cells,
three types of horizontal cells have been identiied in the human retina as of 1994 (Ahnelt and Kolb
1994), and more than 20 kinds of amacrine cells are separated into wide and narrow ield classiications� The most commonly researched of these cells are the starburst amacrine and the AII cells� The
AII cells link some rod and cone information before signals exit the eye, and the starburst cells are
involved in directional sensitivity involved by optokinetic relexes (Yoshida et al� 2001)�
In addition to rods and cones, a third receptor (discovered in 2002) reacts to the luminance level
of light� When light strikes the retina, the ipRGC cells in the ganglion layer send rudimentary eyesight signals directly to the hypothalamus (Canteras et al� 2011)� This process is signiicantly faster
than the classic eyesight pathway� Melanopsin-containing ipRGC cells are more sensitive to blue
light and are more damaged in glaucoma (Bessler et al� 2010)� Those cells also receive light from
the rods and cones� Patients who have macular degeneration, with damage in their retinal layers,
respond better to red lighting (Ishikawa 2013)� The earlier-mentioned ipRGC cells receive information from both cones and rods, but show more effect with rod (peripheral retinal) information (Lall
et al� 2010, Schmidt and Kofuji 2010) (Figure 22�10)�
The melanopsin-containing ganglion cells have been shown to inluence circuits of luminance
and spatial information (Ecker et al� 2010)� In 2005, the melanopsin retinal pathway was not considered a contributor to spatial vision (Schmucker et al� 2005)� However, further research on mice
demonstrated that the ipRGC pathway does contribute to spatial vision by mixing signals with rod
and cone pathway information� The rods respond differently depending on cone information via
the AII type of amacrine cell (Alam et al� 2015)� There are other types of ganglion cells such as the
bistratiied ones whose signals travel to the koniocellular layers of the LGN (Dacey and Lee 1994)�
Of the 1�2 million ganglion cells, approximately 90% are parvocellular, 5% are magnocellular, and
5% are koniocellular (Freberg 2010)�
LAYERS
Each of the cell types has a dendrite, cell body, and axon� Many scanning and electrophysiological
devices are available to analyze retinal layers� If any problem exists, the abnormal cells will distort
the layers, creating system breakdowns� As depicted in Figure 22�11, retinal layers ilter information
using both inhibitory and excitatory mechanisms, taking into account feedback and feedforward
signals� Deposits of cholesterol plaques also have been found in different retinal layers (Zheng et al�
2012)� In the case of sleep disorders and glaucoma, the specialized melanopsin-containing ganglion
cells are involved (Gracitelli et al� 2015)�
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Impact of Retinal Stimulation on Neuromodulation
Ambient light for
non-image-forming signal
To opt
ic
ner ve
Ambient light for
image of background
Focal light ray
for image of target
Macula
Retinal pigment epithelium
FIGURE 22.10 Three groups of retinal cells sensitive to light� (From Zelinsky, D�, Functional Magnetic
Resonance Imaging: Advanced Neuroimaging Application, InTech, 2013, p� 91� With permission�)
The retinal layers are also associated with different types of chemical transmitters� Glutamate
is used through the feedforward pathway mentioned here, while GABA and glycine receptors are
found in the inhibitory layers of horizontal and amacrine cells (Dutertre et al� 2012)� Melatonin
is produced by the retina in the dark, and dopamine is produced in the light� However, prolonged
exposure to the dark lessens the effect, reducing the production of melatonin (Adler et al� 1992,
Danilenko et al� 2009)�
The most familiar of the retina’s ten layers is the one with photoreceptors, split into the outer and
inner segments of rods and cones� Photoreceptors need nourishment from another retinal layer, the
retinal pigment epithelium (RPE)� The constant interaction between the RPE and the rod photoreceptors is termed the visual cycle, triggered by lighting changes� Cones have a chemical interchange
with Mueller cells� The external limiting membrane (or outer limiting membrane) separates the cell
bodies of the photoreceptors from their outer and inner segments� The line of cell bodies is termed
the outer nuclear layer of the retina� Oftentimes, a photoreceptor integrity line is evaluated on retinal
imaging, but it is not a retinal layer� It simply represents the junction between the outer and inner
segments of the photoreceptors, and its assessment is useful for determining the progress of various
diseases�
A large amount of retinal processing occurs at synaptic junctions� The outer plexiform layer of
the retina is where electrical signals from the photoreceptors interact with bipolar cells� This outer
layer includes dendrites from bipolar and horizontal cells as well as axons from photoreceptors�
The inner nuclear layer contains the cell nuclei of horizontal, bipolar, and amacrine cells� The inner
plexiform layer contains axons of bipolar cells, many types of amacrine cells, and dendrites of
ganglion cells (Roska et al� 2006)� A web of iltered excitatory and inhibitory signals in the inner
plexiform layer detects motion and suppresses eye movements (Baccus 2007)� The combination of
those signals affects judgments in space and time (Kim et al� 2014a, Robinson 2014) and results in
the inal exiting signal from the ganglion cell�
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Neurophotonics and Brain Mapping
Visual cycle in retinal rods
Axons to
optic nerve
Eye
Amacrine cell
Ganglion cell
Blood
vessel
Light
Bipolar cell
Retinal
pigment epithelium
Disc of rod cell
Horizontal cell
Dietary
intake
Cone cell
Rod cell
H 3C
Ttr
Blood
vessel
Retinol
metabolism
ye
of
th
ee
ck
Ba
CH3
H3C
CH3
CH3
CH3
Light
Photoreceptor
N
Opsin
D
i
s
c
N
H3C
C
O
C
H3C
500 nm
CH3 H C
3
O
CH3
O
CH3
CH3
CH3 H3C
O
Na+
all-trans-Retinal
CH3
O
Na+/Ca2+
Exchanger
Ca2+
Ca2+
H
Lumi11-cis- Rhodopsin
Retinal
Na+
Ca2+
Na+
cGMP-Gated
Channel
Calm
Ca2+
Open
(Dark)
C
MetaH
Rhodopsin-I
MetaRhodopsin-II 480 nm
C
O
C Rhodopsin
C
H
CH3 CH
3
CH3
O
3
H3C
CH3
cGMP
CH3 CH3
C
C
H
RGS9
H
all-trans-Retinal
all-trans-Retinal
CH3
N
AT
CH3
P
P N
Gα
GDP
GTP
n
ADP
PDE
sti
re
GαT
PKC
GRK4
Ar
Arres
tin
DAG
Rc
HpcaL
RHOK
CaBP
v1
F2
E
P
P
Ca2+
IP3
I
P
Disc
3
Ca2+ R
C
R
Front of the eye
Na+
Rod membrane
Batho-Rhodopsin
C
O
CH3 CH
CH3
3
C
all-trans-Retinal
CH3
N
CH3
543 nm
C
all-trans-Retinyl ester
CH3
H
Isomerization
H3C CH
CH3
3
CH3
H
IRBP
CH3
LRAT
RDH
Rhodopsin
H3C
cRBP
Vitamin-A
(all-trans-Retinol)
RPE65
11-cisretinal
CH3
CH2OH
H 3C
C
O
C
CH3
Vitamin-A
(all-trans-Retinol)
CH3
CRALBP
CH3 H3C
11-cis-Retinal
RBCs
CH2OH
sion
CH3
Retinal
pigment
epithelium
CH3
pRBP
Diffu
CH3
H3C
CH3
CH3
GCAPs
H
GC
GTP
PLCβ
Closed
(Light)
PIP2
Na+
GMP
Ca2+
Ca2+
Na+
cGMP-Gated
Channel
FIGURE 22.11 Visual cycle in rods © 2009 QIAGEN, all rights reserved� Qiagen testing is available for pathway
speciic siRNA’s real-time polymerase chain reactions (PCR)� (From QIAGEN, Visual cycles in rods, 2009� With
permission�)
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Impact of Retinal Stimulation on Neuromodulation
425
The ganglion cell layer and the axons from the ganglion cells, termed the nerve iber layer, are
next in the progression of retinal layers toward the inside of the eyeball� Loss of nerve iber layer
tissue is found to be an early biomarker for neurodegenerative diseases, such as Alzheimer’s disease
and glaucoma (Valenti 2011)� The inal layer is the porous internal limiting membrane separating the
retina from the vitreous� From there, 1�2 million signals travel through the optic nerve further into
the brain for processing (Figure 22�12)�
SECTIONS
Retinal development arises from several different transcription factors and different portions of DNA�
During gestation, the sections develop separately and then later link� Various sections of the retina
react to light differently� For instance, the concentration of cone photoreceptors in the nasal retina
was found to be higher than in other regions (Jonas et al� 1992)� Studies as far back as 1948 identify
differences in saccadic ixation abilities and melatonin production (Braendstrup 1948, Ruger et al�
2005, Johannesson et al� 2012)� The ganglion cell axon diameter has been found to vary depending on
its location in the retina (FitzGibbon and Taylor 2012)� Studies also have shown that the nasal portion
of the human retina suppresses melatonin more than the temporal portion (Visser et al� 1999)� The
nasal portion of the retina sends signals to the hypothalamus, while the temporal portion does not�
Differences between the inferior and superior retinal sections also have been identiied� In
humans, blood low is reduced in the inferior retina when certain types of stress are applied (Harris
et al� 2003)� In 1985, a study demonstrated that the upper retina shows more signiicant contrast sensitivity than the inferior retina (Skrandies 1985)� Flicker sensitivity is more closely associated with
the peripheral retina (Solomon et al� 2002)� In dementia, with Lewy bodies, eye movements during
sleep are not normal (McCarter et al� 2013)�
THICKNESS
Retinal thickness changes with either degenerative conditions or swelling� Assessments of retinal
thickness have recently been developed as a simple method to follow objective changes (Choi et al�
2008, Grazioli et al� 2008)� Thickness of retinal cell layers has been watched closely in glaucoma
for years (Shin et al� 2014)� In patients with Parkinson’s disease, the parafoveal inner nuclear layer
is thinner than the same layer in normal patients, and in those Parkinson’s patients who also have
dementia, the retinal layer is even thinner than in those with Parkinson’s alone (Lee et al� 2014)� In
schizophrenic patients, the right nasal quadrant of the schizoaffective group is thinner than in the
general schizophrenia group (Chu et al� 2012)� New research is correlating retinal thickness with
brain atrophy in patients with MS (Abalo-Lojo et al� 2014)� In fact, studies show degeneration of the
thalamus and retinal thickness in MS (Zivadinov et al� 2014)�
Now that the retinal structure and function have been reviewed in detail, the remainder of this
chapter will focus on neuromodulation—the continual search for homeostasis between conscious
and nonconscious functions, the relationship between neuromodulation and the retina, and the overall impact of this relationship and its interplay with other brain and nervous system processes� These
relationships affect human behavior, environmental response, and progression and intervention of
disease processes�
NEUROMODULATION: A CONCEPTUAL FRAMEWORK
After prolonged stress, shock, injury, or disease, behavior, perception, and responses to environmental changes are frequently affected, often creating abnormal neuromodulation� One common compensatory mechanism to sensory overload is to ignore outside environmental stimuli� People have
individual acceptance levels to change; how much it takes to push them over the edge varies with
their “How am I?” and “Who am I?” pathways� Sensory systems interact with each other, and each
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Cell types
Ganglion
Cell bodies
Light
Retinal layers
Internal limiting membrane
Ganglion axon (nerve fiber) layer
Ganglion cell body layer
Internal plexiform layer
Amacrine
Bipolar
Cell bodies
Inner nuclear layer
Horizontal
Outer plexiform layer
Mueller
Photoreceptors
Outer nuclear layer
Inner segment
External limiting membrane
Photoreceptor layer
Pigment epithelial layer
Bruch’s membrane
Choroidal circulation
FIGURE 22.12
Retinal cells and layers� (Courtesy of The Mind-Eye Connection, Northbrook, IL, Copyright 2016�)
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Integrity line
Outer segment
427
Impact of Retinal Stimulation on Neuromodulation
Interaction between central nervous system and peripheral nervous systems
Central
Nervous system
Conscious
attentions
Peripheral
nervous system
Awareness
Autonomic
(visceral)
Central
Peripheral
Body
functions
Brainstem
Sympathetic
O
r
g
a
n
s
Parasympathetic
Ref
rne
d
An
tici
pat
or y
Int
ent
ion
al
Refl
ex
Enteric
lex
r
e
c
e
p
t
o
r
s
Mind
Peripheral
nervous system
Somatic
(skeletal)
Lea
S
e
n
s
o
r
y
Move
ment
FIGURE 22.13 Internal/external interactions� (Courtesy of The Mind-Eye Connection, Northbrook, IL,
Copyright 2014�)
person has an optimal load and also an upper threshold of tolerance before a breakdown is reached�
Retinal stimulation via nontraditional eyeglasses or contact lenses can be extremely beneicial in
helping patients regain a sense of internal comfort�
Figure 22�13 depicts how the CNS, which is composed of the brain, spinal cord, and retina, sends
and receives information from the two peripheral nervous systems—the ANS and the somatosensory�
The autonomic system has three portions —sympathetic, parasympathetic, and enteric�
Sensory (afferent) and motor (efferent) signals are sent to and from the CNS through both visceral and skeletal systems� The efferent pathways can be either voluntary or involuntary� The involuntary motor pathways can be either in sympathetic (ight/light/fright) mode or parasympathetic
(rest/digest mode)� The enteric nervous system produces the majority of serotonin in the body and
relates to the digestive system� Normal functioning of the CNS depends on the balanced interplay of
both excitatory and inhibitory neurons in the body (Dutertre et al� 2012)�
Cognitive reserves are limited, and in the presence of confusion or distraction from too many
sensory inputs, comfort is reduced� The mind can usually “tune out” unwanted peripheral/background auditory and visual inputs and disengage eye aiming at targets in external surroundings� That
selective iltering ability is often hindered when the body systems are in survival mode� Attentional
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Neurophotonics and Brain Mapping
Comfort, tolerance and protective ranges
The more interest in activities, the more effort expended to stay on task
Too little stimuli
Breakdown
Attention on body
Too much stimuli
Fight or Flight
Tolerance
Comfort Tolerance
Fight or Flight
Less attention on task Attention on task Less attention on task
Adrenaline
Thyroid
Breakdown
Attention on body
Adrenaline
FIGURE 22.14 Comfort, tolerance, and protective mechanisms which can arise from either endogenous or
exogenous sources� (Courtesy of The Mind-Eye Connection, Northbrook, IL, Copyright 2014�)
pathways are shut down or become hypersensitized in people when the internal pathways are out of
balance� In other words, if the internal “How am I?” and “Where am I?” pathways are not in a range
of comfort, the external perception of the “Where is it?” and “What is it?” pathways will be hindered
or skewed� The degree of comfort inluences actions, behavior, and attention� Typically, the mind is
not aware of bodily sensations until they are out of the range of comfort�
Most patients have large ranges of comfort and tolerance, and they simply adapt to the changes�
In those who are not able to adapt, such as people with brain injuries, protective mechanisms hinder
cognitive processing� Something as simple as a slight tint in everyday eyeglasses might be helpful
in calming a sensitive nervous system by iltering out extraneous, irritating stimuli� Comfort ranges,
tolerance ranges, and protective mode form intricate circuitry that governs perception� The more
comfortable a person is, the less effort is expended and the more attention paid to whatever the mind
wants� If any systems are disrupted or stressed past the comfort threshold, more effort is required to
deal with the outside information (Figure 22�14)�
Once past tolerance ranges, the body goes into chemical and muscular protective modes� For
instance, after brain injury, primitive survival relexes emerge� Some protective mechanisms include
iltering of environmental stimuli� Living near a jackhammer or lashing neon lights triggers protective signaling pathways� By comparison, when a person feels safe and comfortable, he or she can
become habituated to repetitive stimuli, such as a cuckoo clock� Humans are born with certain builtin survival mechanisms (muscular relexes), such as an asymmetrical tonic neck relex� Those primitive survival relexes reemerge after trauma� The role of doctors and therapists often becomes one of
teaching patients how to reintegrate those relexes� This can be achieved by movement reeducation
strategies through variations of integrative manual therapy�
COMBINATION OF EXTERNAL AND INTERNAL SIGNALS
Consider what happens to adrenaline levels if a sudden movement is “caught” out of the corner of
the eye, such as glimpsing an unexpected mouse running across a room� Instantly, beneath conscious control, internal chemical and muscular systems react, triggered by a moving shadow on the
peripheral retina� Aiming, focusing, and classic central eyesight (“seeing”) are processed after panic
(chemical) and tension (muscular) reactions occur� Feedforward retinal signals are sent to two main
processing sections in the brain—biochemical (How am I?) and muscular (Where am I?)� Feedback
signals to the retina from subcortical and cortical limbic structures are based on a person’s experiences (Who am I?)� Thus, the “How am I?” and “Where am I?” pathways are inluenced by the
“Who am I?” primarily beneath the conscious awareness�
Visceral systems also are affected beneath cortical control by input from temperature sensors,
like sweating or shivering in response to heat or cold� Humans have built-in protective mechanisms
so that, when they pass their individual comfort range and go into a tolerance range, some attention
and mental energy are diverted to the discomfort or imbalance� For instance, beneath conscious
awareness, some people remove a jacket without thinking about it, while others, at a conscious level,
might seek a jacket to wear�
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Impact of Retinal Stimulation on Neuromodulation
Int. awareness
Int. attention
Subconscious
awareness
Conscious
attention
Ext. awareness
Ext. attention
Where/When is it
What is it
FIGURE 22.15 Awareness and attention� (Courtesy of The Mind-Eye Connection, Northbrook, IL,
Copyright 2014�)
External signals have an effect on internal systems, and the altered internal signals can inluence
the iltering ability of external sensory systems� One example is how exposure to external noise
affects retinal sensitivity (Dantsig and Diev 1986)� Running with a peaceful water scene in the
visual background elicits different stress chemicals than running while being chased by wild animals� People with fragile sensory integration or hypersensitive peripheral retinas visceral reactions
induced daily simply by normal objects moving in their environments� These types of reactions and
responses to environmental changes are part of a two-way transfer of information (Figure 22�15)�
Attention and awareness can be focused on either external or internal stimuli� Eyeglasses designed
to address peripheral awareness and/or body functions can affect responses to environmental changes�
When internal systems are dysregulated, external awareness (including peripheral eyesight) tends
to shut down and become less sensitive to the surrounding environment� This processing beneath
a conscious level varies with individual interests and energy levels� For example, a person at a fun
party wanting to stay up might ight off a tired sensation� On the other hand, if the party is boring,
that person might choose to surrender to the fatigue�
People differ in their experiences, temperaments, perceptions, motivations, and organizational skills�
For that reason, they have different ranges of comfort before breakdowns occur� The “Who am I?” component determines whether they will activate their ight or light mode or simply disengage from the outside
environment� If a sound of a dog collar jingling is heard and the person hearing it had previous bad experiences with dogs, the memories from the cortical limbic system will “tell” the subcortical limbic system
“You’re not safe”—the body becomes stressed and muscles freeze or muscles run� However, the same,
exact stimuli of a dog collar jingling heard by another person who has pleasant memories of dogs will create a signal indicating “This is great! Where is it?”—muscles turn toward the sound and the body relaxes�
Each system has its own comfort and stress levels� One person can eat a lot of sugary desserts
and not experience a mood change; another can eat one small piece of candy and experience a sugar
high� Each system can be modulated to regain stability and return to the habitual position where it
feels “normal�” The systems work concurrently, all vying for conscious attention� Depending on the
task, sometimes the body receives attention and sometimes the mind�
The mind and body react and respond to environmental changes by activating both cortical and
subcortical circuitries� Constant interaction occurs between internal and external stimuli, involving
measureable shifts in eye movement� Shifting light inluences the interplay between incoming signals
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Neurophotonics and Brain Mapping
from the outside environment (exogenous sources) and returning signals from the inside environment
(endogenous sources)� For instance, no single “blood pressure center” exists� Rather, networks of
external and internal signals from the various nervous systems regulate blood pressure by using many
factors to determine when to release hormones and retain or excrete luids from the body� The same is
true of retinal stimulation� The many visual systems use numerous factors to determine when to pay
attention to changes in the external environment and when to ignore those changes�
CORTICAL INTERACTIONS WITH SUBCORTICAL CIRCUITRY
Eye movements are an observable and quantiiable result of signiicant brain processing at unconscious, subconscious, and conscious levels; no simple input/output system of visual acuity is at play�
Instead, considerable planning and redundancy are built-in for survival� As an example, several eye
ield regions in various cortices connect with each other and the brainstem to govern initiation and
control of eye movements (Lynch and Tian 2006) (Figure 22�16)�
Simplified central nervous system
Cortical
lobes
Executive
functions
Focal
How will I act on it?
What is it?
Where is it, When is it?
Thalamus
Motivation
emotions
Cerebellum
Chemical
regulation
Retina
Ambient
Memory
Who am I?
How am I?
Midbrain
brain stem
spinal cord
Where am I?
Survival
functions
FIGURE 22.16 Retinal connections within the CNS� (Courtesy of The Mind-Eye Connection, Northbrook,
IL, Copyright 2014�)
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Impact of Retinal Stimulation on Neuromodulation
431
The retina is connected with the thalamus (for cortical eyesight) and the hypothalamus (for subcortical chemical circuitry) and the brainstem (for subcortical muscular circuitry)�
Stress, injury, or disease can cause neurological, metabolic, and/or perceptual changes� Injury and
disease disrupt electrical signaling pathways in the nervous system and alter biochemistry, affecting
cognition and behavior� Diseases can occur many years after injury� Oftentimes, ocular symptoms
(an end result of much processing) precede the diagnosis of CNS disorders (London et al� 2013) and
separate the “Where am I?” and “How am I?” into relex (subcortical) and subconscious cortical
levels� Memory and visual perception (Khan et al� 2011) also have speciic malleable circuitry� The
entire ield of brain plasticity is growing, as evidenced in such books as The Brain that Changes
Itself and The Brain’s Way of Healing by Norman Doidge (2016)� Neuroplasticity is an emerging
ield, as is neurophotonics—the use of light to affect neurological systems�
THE IMPACT OF RETINAL STIMULATION ON NEUROMODULATION
Typically, after a brain injury, neurological systems are disrupted and comfort ranges are constricted�
Signaling pathways can be rerouted, relying on the plasticity in brain wiring when creating new
connections� In developing children, this circuitry can be modiied to avoid dysfunctional patterns
before habitual patterns become embedded�
Executive function skills develop by age 25� However, skills can be lost during aging and disease
processes� These skills are based on the “Who am I?” experiences� Cognitive responses are dependent
on lower-level cortical processes, such as perception and emotions, as well as on unconscious reactions
at the proprioceptive and chemical levels� In fact, in addition to the right and left brain, some people discuss a top and bottom brain concept of how gray matter is organized (Kosslyn and Miller 2015)� Since
input circuitry to the visual cortex is routed through right, left, top (parietal), and bottom (temporal) of
the cortex, therapeutic eyeglasses can be used on an individual basis to stimulate one or the other�
Neuromodulation is a continual process occurring far beneath a conscious level and involving the
retina as well as the eye muscles (think of REM sleep)� Even during sleep, chemical changes occurr
in the retinal layers� If a person sleeps with the television on, or with surrounding noise, the brain is
not able to fall into as deep a sleep and restorative properties are not as good� Recent research shows
that the concept of systemic tolerance is useful in pharmacological treatment of such diseases as MS
and diabetes (Graham et al� 2013, Lutterotti et al� 2013)� Instead of treating symptoms, researchers have achieved better results from allowing neuroplasticity of the immune system to develop
antibodies�
The eye is not isolated from the other sensory, motor, emotional, and cognitive systems� As
research on retinal signaling pathways continues to progress, the concept that multiple pathways
exist between the eye and the body, with a great deal of activity occurring beneath the conscious
awareness, will gain wider acceptance� These pathways can be both excitatory and inhibitory, involving both feedback and feedforward mechanisms� The small portion of information that reaches conscious awareness is actually a conglomeration of inputs from several senses—visual, auditory, etc�
(Eagleman 2011)�
Priorities continually shift among body, mind, and environment until achieving a comfortable
balance� This interaction is termed homeodynamics� As stated earlier, quantiiable metrics such as
eye movements, habitual eye position, pupil size, blink rate, and tear layer quality can be used to
assess visual processing� Central 20/20 eyesight (classic visual acuity) is only one of several of
these measurements� However, changes in perceived clarity in central eyesight can arise due to the
multiple steps that occur before attention shifts to targets�
Hand–eye coordination is a good example� It is not simply sensory/motor input/output—see a
ball and reach out to catch it� Rather, many other processes are involved� If they were not, people
would be able to play catch endlessly� Instead, the limbic system’s involvement concerning interest,
fear, or pleasure, the autonomic system’s activation once stress levels are reached, hunger or fatigue,
and other processes all play pivotal roles�
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NEURO-OPTOMETRIC APPROACHES DURING REHABILITATION
Neuro-optometry uses a noninvasive approach to brain function and has been shown helpful
in the treatment of multiple types of disorders, including those that are visual and neurological� Evaluations include possible hidden dysfunctions in mind–eye connections and dysfunctions that can affect social, academic, and sports performance� When incoming visual signals
are altered by particular types of ilters, these pathways can be either disrupted or enhanced
(Figure 22�17)�
Various mechanisms are triggered by different kinds of retinal stimulation� Depending on whether
the pathways are disrupted or enhanced, individualized lenses can be prescribed to assist in treating
symptoms�
Major optical treatments include the following:
Lenses: They disperse light toward the edges or the center of the retina, tending to make objects
appear larger or smaller by emphasizing or muting the background� This change in light primarily
alters the balance between central and peripheral circuitry by having the target and background
occupy different percentages of the retinal input� Depending on the type of lenses used, the treatment can enhance attention or mute peripheral distractions�
Nonyoked prisms: They can be categorized into two types: lateral and vertical� They angle light
toward either nasal/temporal retinal sensors or superior/inferior receptors� The eyes will relexively
point toward the light, but the inward or outward movement prompted by these prisms will, in turn,
affect different visual and postural mechanisms, affecting the placement of shoulders by shifting
apparent object locations� The nasal stimulation (from base-in prism, commonly prescribed after
traumatic brain injuries) affects chemical retino-hypothalamic signaling�
Yoked prisms: They angle light toward a speciic section of the retinal sensors� Angling light toward
one edge of the retina initially affects the body’s positional sense (proprioceptive sense), because
relexive eye movements will point toward the incoming light, triggering internal postural mechanisms in the hips for stability of balance� These prisms promote a shift of the hips as the center
of gravity relexively changes� These prisms can be divided into two main categories—those that
make the person comfortable, so their attention can shift to external targets, and those designed
to make the person slightly uncomfortable to induce a mental reorganization� Depending on the
stability of the person’s sense of balance, mental attention may be shifted off of body position and
onto external targets� Cortical mechanisms regarding internal perception of limb location modulate
the actual temperature of the hands (Moseley et al� 2013)�
Filters: They alter either spatial or temporal retinal input and affect internal processing and external
perception� Tints ilter out selected wavelengths of light, stimulating speciic retinal cells, which
then alter retinal chemistry (and thus body chemistry)� Graded occlusion ilters, such as Bangerters,
alter the spatial components of incoming light� For instance, binasal ilters reduce stimulation to the
temporal retina� Neutral density ilters alter the temporal components�
Mirrors: They induce a sensory mismatch in the retina between central (target) and peripheral (background)� They are used in many aspects of patient treatments, such as rehabilitation of patients who
have experienced strokes or visual ield defects�
Alteration of corneal tear layer: When in ight or fright stage, the sympathetic nervous system is
stressed and the eyes become drier� When calm, the eye and neck muscles relax and the eyes moisten
as the parasympathetic system becomes dominant� By using punctual plugs to artiicially moisten
the eyes with the body’s own tears, feedback mechanisms register moisture from tears, thereby activating the parasympathetic system�
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Accommodation
Vergence
Executive
functions
Target
Habitual
Mind
0
<
0
Fixation
Attention
Eye
muscles
Anticipatory
Saccades
Pursuits
Optokinetic nystagmus (OKN)
Vestibulo-ocular reflex (VOR)
Awareness
Pupilary reaction
Rapid eye movement (REM)
Unconscious
(shoulders)
Movement
Chemical
Conscious
Body
Reflex
(Hips)
Neurological
Organs and
other muscle
groups
Survival functions
External
(sensory inputs)
Unconscious
Skeletal
Internal
(sensory inputs)
Cardiac
Visceral
Impact of Retinal Stimulation on Neuromodulation
K23139_C022.indd 433
Conscious
Intentional
Conscious
Neck, shoulders,
hips and ankles
(Limbs)
Heartbeat
G-I tract
other organs
blood vessels
Unconscious
FIGURE 22.17
Effects of retinal stimulation on eye movements� (Courtesy of The Mind-Eye Connection, Northbrook, IL, Copyright 2016�)
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Neurophotonics and Brain Mapping
SUMMARY OF INTERVENTIONS
A range of treatments is available to modulate nervous system responses� Methods include behavioral,
electrical, pharmacologic, and magnetic approaches� Behavioral methods have been used for decades
in the treatment of such diseases as autism� Electrical methods include the electroconvulsive shock
therapy of the 1950s, cardiac pacemakers in the 1960s, deep brain stimulation devices in the 1990s,
and vagus nerve stimulation in the 2000s� Now, since 2010, deep brain stimulation is being considered
in Parkinson’s treatment, using less risky versions—closed loop versus open loop (Beuter et al� 2014)�
Pharmacologic methods also are commonly used to control chemical signaling pathways� Examples
include L-dopa for Parkinson’s, ritalin for attention deicit disorder, and a variety of drugs for depression, epilepsy, and bipolar conditions� Other diagnostic methods and treatments of signaling pathways
include magnetic ields, such as fMRIs, MEG, and transcranial magnetic stimulation� Combining
assessment methods of “when signals are processed,” such as the use of EEGs or fMRIs when signals
are active, can provide a plethora of information regarding brain processing� Measurements of licker
sensitivity have been shown to chart disease progress (Falsini et al� 2000)� Optogenetics—using light
to modulate the nervous system—has become a new technique of brain assessment�
These approaches do not by any means exhaust the range of treatments� In addition to neuro-optometric rehabilitation methods, some optometrists use classic visual therapy activities and direct and
indirect syntonic lens therapies� Available as well are some useful tools designed to enhance auditory
feedback, such as the talking pen from Wayne Engineering (now known as Eye Carrot), or, from South
Africa, the Sebezaphone, a self-ampliication tool that enables the user to be both speaker and listener to
his/her own voice, thereby enhancing language development and reading luency (www�sebezaphone�
co�za)� New instruments have been developed to quantify subtle changes in eye movements, such as
video pupillometers and RightEye�com’s computerized testing batteries intended for patients who have
sustained brain injury or have autism� An invaluable treatment instrument for any optometric ofice is
the Germany Fusiobox (www�fusiobox�com)� It contains an astoundingly large array of stimuli and
feedback to individualize patient treatments for lazy eyes and crossed eyes�
Since 2007, literature has been demonstrating the importance of visual/auditory linkages and Z-BellSM
testing (Zelinsky 2007)� Just as hand–eye coordination develops with age and experience, so do eye/ear
connections� Monica Gori, a researcher in Italy, has a body of work that indicates visual/auditory linkages
develop rapidly until approximately age 8 (Gori et al� 2008, Gori et al� 2012, Tonelli et al� 2015)�
What should be noted is not all studies have found improvements from neuro-optometric treatments� However, tests that have failed often have not considered particular variables� For instance,
one study included more than 5500 children with reading impairments� They were evaluated for eye
problems involving image-forming (eyesight) circuitry� Conclusion was that no optometric vision
rehabilitation would be helpful� Strabismus, motor fusion, sensory fusion at a distance, refractive
error, amblyopia, convergence, accommodation, or contrast sensitivity were not signiicantly different in those children when they were compared to children with normal reading ability (Creavin et
al� 2015)� However, this study did not take into account all the linkages between the eyes and other
sensory systems� For instance, dyslexia involves auditory/visual interactions�
Vision is complex� The chart in Figure 22�18 separates and explains the various stages of visual
development and summarizes expected responses to different optometric interventions� Nonstandard
responses can provide information useful in identifying any deicient visual pathway(s) and determining the appropriate treatment or referral�
CONCLUSION
Neuromodulation via retinal stimulation is a new and promising technology that can be applied to
humans today by specially trained eye care professionals� The use of eyeglasses to modulate the frequency, amount, and direction of light dispersed on the retina allows neuro-optometric rehabilitation
to accelerate recovery from brain injury and provide improvement in patient comfort and tolerance
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435
Impact of Retinal Stimulation on Neuromodulation
Brainstem,
cerebellum
and limbic
system
Yoked
prism
(phoria
measurements)
Yoked
prisms
also modify
environmental
awareness
Peripheral
(Where Is it?)
Central
(What Is it?)
Environment
Perception
Non-yoked
prism
(vergence ranges)
Lenses
Occipital,
temporal and (accommodative
ranges)
parietal lobes
and limbic
system
Occlusion
(sensory
integration)
Expected responses and perceptions
BD
Eyes up and outward
Leans on heels
BU
Eyes down and inward
Leans on toes
BR
Eyes left
Rotates left
BL
Eyes right
Rotates right
BD
Uphill, farther
and bigger
BU
BR
Perceptions
Balance
(Where am I?)
Body
Optometric intervention
Expands space left
and contracts right
BI
Objects appear farther
and bigger
Shoulders
back
Objects appear closer
and smaller
Panoramic view
emphasizes background
Shoulders
forward
Neck muscles
loosen
Tunnel vision
emphasizes figure
Neck muscles
tighten
+
–
Tints
Longer
wave
lengths
Mind
Cognition
(What Will I
do about It?)
Limbic system
frontal lobe
Visual
thinking
games
Organization
skills
Alters peripheral or
central input
Shorter
wave
lengths
Emotions
(What do I
feel?)
Motor
skills
Downhill, closer
and smaller
Expands space right
and contracts left
BL
BO
Skills affected
Calming
( parasympathetic)
accommodation
Alter apparent
speed of input
Stimulating
( sympathetic)
accommodation
Differentiation of “big picture” versus details
enhanced control over actions
improved range of flexibility
altering self-image
Visualization
skills
FIGURE 22.18 Intervention response chart� (Courtesy of The Mind-Eye Connection, Northbrook, IL,
Copyright 2004�)
ranges to environmental changes� It can also lessen the hypersensitivity to sensory stimuli often seen
in patients with brain injury, developmental disabilities, mental illnesses, and posttraumatic stress
disorders� The classic use of optometric techniques to sharpen central eyesight to 20/20 impacts a
patient’s attention at a conscious level, with high-contrast, nonmoving targets� This approach is not
suficient in patients with neurodegenerative conditions or fragile connections between systems�
As compared to traditional behavioral and pharmacological treatments, neuro-optometric rehabilitation is safe and noninvasive� This treatment is different from classic visual therapy because it
addresses the brainstem and subcortical reactions� Such therapeutic stimulation can be easily and
inexpensively applied via individualized eyeglasses that cost well below other treatment options�
The treatment causes no risk of life-threatening complications and no side effects� Patient compliance is good, and patients are more comfortable when they wear the glasses� This type of retinal
stimulation can also be used as an adjunct to other treatments�
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Neurophotonics and Brain Mapping
In the future, development of highly advanced eyeglasses that selectively stimulate retinal pathways
may be possible� This tool could be used in treating patients with drug-resistant epileptic seizures
or patients who have Parkinson’s, Alzheimer’s, or other neurodegenerative conditions as well as in
patients with autism, genetic disorders, and/or mental illness� Future research may also ind ways to
apply this technology to metabolic disorders and alteration of gene expression� As computer/brain
interfaces become more than the norms during rehabilitation, customized lenses may prove useful for
developing brain plasticity and for attention training after brain injury using robotics�
In conclusion, retinal stimulation via therapeutic eyeglasses can be applied to a wide range
of medical problems as an adjunct to other treatment processes to maximize rehabilitative outcomes� Doctors and scientists interested in applying these techniques are encouraged to team
with neuro-optometric practitioners� Such collaboration will quickly develop a whole range of
new, effective, and inexpensive therapies for an array of physical, physiological, and psychological dysfunctions�
ACKNOWLEDGMENTS
Sincere appreciation for Babak Kateb, M�D�—a true visionary� Dr� Kateb was one of the very few
medical professionals who understood the tremendous diagnostic and therapeutic potential of retinal
stimulation from the moment I met him� This chapter would not exist without his continuous and
cheerful encouragement over the years� I would also like to acknowledge the support of Jonathan
Q� Hall, Jr�, O�D�—a future optometric leader—whose eye care constantly includes consideration of
multiple system interactions in all of his patients� Also, appreciation goes to Dorothy Mason, Paul
Zelinsky, Mara Sachs, Martha David, and Adam Boin for their abilities to create clearly descriptive
illustrations and to Mike Maggio for his help with precise grammar�
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Deborah Zelinsky
TheMind-Eye Connection