UNDERSTANDING TIIE MIGRAINE AURA: COMBINING VISUAL

D~COMFORT~S~S

A TIIES~ SUBMI'ITED TO TIIE GRADUATE DIVISION OF TIIE UNIVERSITY OF HAW AI'I IN PARTIAL FULFILLMENT OF

TIIE REQUIREMENTS FOR TIIE DEGREE OF

MASTER OF ARTS

IN

PSYCHOLOGY

MAY 2008

By

Coty James Gonzales

Thesis Committee:

Patricia A. Couvillon, Chairperson

Jason Schiffman

Kentaro Hayashi

We certify that we have read this thesis and that, in our opinion, it is satisfactory in

scope and quality as a thesis for the degree of Master of Arts in Psychology.

THESIS COMMITIEE

laL/J-

ii

Dedication

This thesis is dedicated to Edward P. Chronicle, a professor who saw promise in me, an

advisor who guided me, and a friend who is always with me. May you rest in peace.

iii

Acknowledgements

It is often said that in life we meet a few people that will have such an impact on

us that we are better people after having met them. Dr. Edward P. Chronicle was

definitely one of those people. He took me in at a time when I thought I was on my way

out. He guided me as a true advisor of life. This body of work would not have

materialized had it not been for his keen intelligence and patient heart.

I thank my parents, who have always believed in me. My mom persistently

reminded me that I have a degree to finish and always reminded me that she cared even

though I often was irritated in the moment. My dad gave me his quiet encouragement.

I thank Michelle Sagucio for always inspiring me to succeed and for always

pushing me to be the best that I can be. Her words were always uplifting and she has the

uncanny ability to provide hope when it seems like there is none. It is she who helped

me out of an unfathomable slump.

I thank Dr. Yun Chu whose concern for me "finishing up" meant a lot. In our

time together in the same lab we had heartfelt ta1ks about anything and everything, from

politics to relationships. Her fervor for life and experiencing new things will inspire me

forever. The "crash course" in statistics that she gave me was a definite life-saver.

iv

I thank Joel Sabugo, a best friend and a true brother. He provided sound

encouragement and spiritual guidance. He was my original "guinea pig", to whom aJJ of

my participants should be grateful.

I thank the undergraduates who have helped with much of the dirty work

associated with this thesis - Bryce Erich, Laurie Anne Brinkman, and Dominic Kick,

and Sabrina Favors. Their diligence and hard-word was definitely instrumental in the

recruitment of potential participants. I thank them with much sincerity.

I thank alJ of the individuals who took part in this study; the time that they gave

me is very much appreciated.

I thank the Haumana Biomedical Research Program for funding this research

and all of the supportive staff members, including HeaJani Chang, Maile Goo and

Richard Okubo, for providing guidance duriog my undergraduate and graduate years.

Finally, I thank all of the members of my thesis committee: Dr. Patricia

Couvillon, Dr. Jason Schiffman, and Dr. Kentaro Hayashi. First of all, I thank them for

being extremely patient with me. This journey that was my Masters thesis, was indeed

unforeseeably unpredicatable and not typical. I thank them very much for their

flexibility and understanding. Dr. Hayashi, is truly one of a kind. I am very fortunate to

have been able to work with him on this thesis. His assistance in helping me make sense

of my data is greatly appreciated. I thank him so much for aJJ of the meetings that we

v

had, especially the impromptu ones. At times I would come into his office, on a bad day,

and I would leave not only cheerful but also hopeful. He has a unique way of uplifting

spirits. I especially thank Dr. Couvillon for "adopting me" and becoming my major

advisor for this thesis. I truly appreciate her taking me in and working with me on my

thesis even though it was an area of neuroscience that she was not particularly familiar

with. Her steadfast attitude and encouragement made the experience of working with her

very worthwhile. It would be an understatement to say that I learned a lot from her,

because I gained so much more than can be written or said I thank her for all of the

days she spent meeting with me one-on-one in Gartley Hall and for the hours that she

spent correcting and reviewing this thesis. Without her guidance this paper would not

have been possible.

vi

Abstract

Migraine is a headache disorder of unknown origin that is characterized by

severe to very severe head pain, localization on one side of the head, sensitivity to light

and/or sound, and gastrointestinal disturbance. In previous studies, stripe-induced visual

discomfort has been shown to be aversive to migraine patients. Stress has been strongly

implicated as a migraine trigger. This study is an investigation of the effect that a

cognitive stressor may have on the migraineous brain when presented in combination

with grating patterns known to induce visual discomfort. Experimentation consisted of

the presentation of two grating patterns, 3.0 CPD (cycles per degree) and 0.5 CPD, to

subjects in the presence and absence of a cognitive stressor. The subjects within this

study included a group diagnosed as having migraine with aura and a group of non­

headache control subjects. The study used a novel computerized method for presenting

the patterns which incorporated two new measures of visual discomfort: escape and

viewing duration. Subjects with migraine anra found the 3.0 CPD pattern to be

significantly more aversive to view than the 0.5 CPD pattern and reported significantly

more illusions than control subjects. The cognitive stressor, however, did not cause a

significant increase or decrease in visual discomfort. The results of this experiment do

corroborate the findings of previous studies examining visual discomfort in the migraine

population, using a more standardized presentation procedure and more objective

measures of visual discomfort. The absence of the stress effect has implications for

future work on migraine triggers.

vii

Table of Contents

Acknowledgements ..................................................................................................... .iv

Abstract ....................................................................................................................... vii

Table of Contents ....................................................................................................... viii

List of Figures ............................................................................................................... x

List of Abbreviations .................................................................................................... xi

Introduction ................................................................................................................... 1

Clinical Features ................................................................................................. 1

Theories of Migraine ........................................................................................... 3

Visual Correlates of Migraine ............................................................................. 8

Migraine Triggers ............................................................................................. 10

Stress and Migraine .......................................................................................... 11

Method ........................................................................................................................ 15

Design ............................................................................................................... 15

Subjects ............................................................................................................. 15

Apparatus and Stimuli ....................................................................................... 17

Procedures ........................................................................................................ 18

Results ........................................................................................................................ 21

Discussion ................................................................................................................... 24

References ................................................................................................................... 28

Figures .............................................................................................................................. 35

Appendix A ................................................................................................................. 54

viii

Recruitment Advertisements for Migraine Subjects

Appendix B ................................................................................................................. 55

Recruitment Advertisements for Non-Migraine (Control) Subjects

Appendix C ................................................................................................................. 56

Cover Letter Included In Recruitment Packet

Appendix D ................................................................................................................. 57

Study Information Sheet

Appendix E ................................................................................................................. 60

Expression of Interest Form

Appendix F ................................................................................................................. 61

Migraine Questionnaire

Appendix G ................................................................................................................. 76

Exclusion Letter

Appendix H ................................................................................................................. 77

Written Informed Consent Form

Appendix I .................................................................................................................. 78

Rating Scale for Math Task

Appendix J .................................................................................................................. 79

Checklist of Visual Illusions

ix

List of Figures

Figure 1. Grating pattern of3.0 CPD and 5° subtended ................................................ 37

Figure 2. Calculations for grating pattern of 3.0 CPD and 5° subtended ...................... 38

Figure 3. Grating pattern of 0.5 CPD and 5° subtended ................................................ 39

Figure 4. Calculations for grating pattern of 0.5 CPD and 5° subtended ...................... .40

Figure 5. Grating pattern of3.0 CPD and 10° subtended. ............................................ .41

Figure 6. Calculations for grating pattern of3.0 CPD and 10° subtended ..................... 42

Figure 7. Grating pattern of 0.5 CPD and 10° subtended .............................................. 43

Figure 8. Calculations for grating pattern of 0.5 CPD and 10° subtended ..................... 44

Figure 9. Experiment Flow Chart .................................................................................... 44

Figure 10. Escape Responses ....................................................................................... 46

Figure 11. Escape and Stress ...................................................................................... .47

Figure 12. Viewing Duration ....................................................................................... 48

Figure 13. Duration and Diagnosis ............................................................................... 49

Figure 14. Duration and Stress ..................................................................................... 50

Figure 15. Interblock Pleasantness Ratings .................................................................. 51

Figure 16. Interblock Illusion Test. .............................................................................. 52

Figure 17. Interblock Illusion Descriptors .................................................................... 53

x

List of Abbreviations

C ................................................................................................ COntrol

CBF ........................................................................... Cerebral Blood Flow

CGRP ............................................................... Calciton Gene-Related Peptide

CPD ............................................................................... Cycles Per Degree

CSD ................................................................ COrtical Spreading Depression

IHS ................................................................ InternationaI Headache Society

ICHD-2 ............... InternationaI Classification of Headache Disorders, Second Edition

NY .................................................................................. Cranial Nerve V

MA .............................................................................. Migraine with Aura

TMS ............ '" ............................................ Transcranial Magnetic Stimulation

WHO .................................................................. World Health Organization

xi

Introduction

Ancient Egyptian records, dating back to 1500 B.C., are believed to be the first

to describe the debilitating effects of migraine as well as the crude methods of treating

the disorder (Martin-Araguz, Bustamante-Martinez, Emam-Mansour, & Moreno­

Martinez, 2002; Karenberg & Leitz, 2001). Migraine aura has been described in medical

literature for thousands of years (Sacks, 1992). Hippocrates first described the aura

symptoms of migraine in 400 B.C. as a shining light that usually occurs in the right eye

and is then followed by violent pain (Edmeads, 1991; Rapoport & Edmeads, 2000).

Today, it is estimated that migraine affects nearly 12% of the world's adult population.

In a recent epidemiological study from the United States, it was estimated that

approximately 6% of men and 18% of women experience migraine headaches (Lipton,

Bigal, Diamond, Freitag, Reed, & Stewart, 2007). Migraine has also been ranked among

the top 20 most debilitating diseases, ahead of diseases such as asthma and diabetes, by

the World Health Organization (Deiner, Stepper, & Tepper, 2006; Menken, Munsat, &

Toole, 2000). However, despite this high incidence, the fundamental cause of migraine

is unknown and there has been relatively little research on migraine.

Clinical Features

Migraine is classified as a primary headache disorder and can be divided into

two major sub-types, migraine without aura (formerly classified as common migraine)

and migraine with aura (formerly classified as classical migraine). Both types of

migraine are characterized by special features and associated symptoms. Migraine

without aura is described by a recurrent headache that lasts between 4 to 72 hours.

1

According to the International Headache Society's (llIS) International Classification of

Headache Disorders 2nd Edition (lCHD-2), the typical migraine headache is unilateral,

of moderate to severe intensity, and is pulsating in nature. Migraine without aura is

often associated with nausea and/or photophobia (light sensitivity) and phonophobia

(sound sensitivity). This type of migraine may be aggravated by routine physical

activity. Although most patients with migraine experience the attack exclusively without

aura, approximately 30% of patients report one or more characteristic neurological

symptoms that usually occur in advance of the head pain (Swanson, 2004). The

neurological symptoms are collectively termed the migraine aura and are comprised of

positive and negative symptoms. Positive symptoms can be thought of as ''true

hallucinations", or something that is perceived but is not present in the external world,

whereas. negative symptoms refer to a loss in sensation (Wilkinson, 2004). The aura can

be manifested in different ways, specifically through sensory and/or speech symptoms.

Positive symptoms typically appear first (e.g. flickering lights. spots, zig-zag lines,

prickling paresthesias) and are then followed by the negative symptoms, such as

decreased, or loss of, vision (scotoma) or loss of sensation (Olesen, 1993; Cutrer &

Huerter, 2007). According to Russell and Olsen (1996), the visual aura is the most

common type of aura experienced, with nearly 99% of aura patients reporting visual

aura. Patients with migraine aura may sometimes experience symptoms in other parts of

the body such as the extremities. Sensory aura, symptoms that involve numbness or

tingling in the extremities, have been reported as occurring in 30% to 54 % patients with

migraine aura (Manzoni, Farina, Lanfranchi, & Solari, 1985; Eriksen, Thomsen, &

Russell, 2004; Wilkinson, 2004). Speech disturbance, such as dysphasia, is the least

2

common form of migraine aura, occurring in 9% to 31 % of cases (Eriksen et al., 2004)

It is typical for individuals with aura to also experience attacks without aura (Cutrer &

Huerter, 2007).

The defining feature of migraine with aura is the focal neurological event that

usually precedes the headache or sometimes accompanies it. The neurological

symptoms typically develop over 5-20 minutes and last for less than 60 minutes. Visual

anras classically manifest themselves as spreading scintillations and transient blind spots

in the left or right visual field (Lashley, 1941). Visual aura is considered to be unique to

migraine and is characterized by a paracentral scotoma that gradually expands into a C­

shape with the convex edge of the scotoma containing zigzag patterns (Richards, 1971).

These symptoms are collectively known as the fortification pattern. It is generally

restricted to either the right or left visual field and can vary in size (Lashley, 1941). The

fortification pattern typically moves from the interior toward the visual periphery and

usually lasts for about 20 to 25 minutes (Richards, 1971). The disruption and partial loss

in vision is not permanent and vision continues as normal once the fortification pattern

disappears, however, in rare cases, a second consecutive fortification may occur

(poppel, 1973). Zigzag patterns comprised of lines and shapes are often described as

being located on the edge of the scotoma (Lashley, 1941; Richards, 1971).

Theories of Migraine

Although the cause of migraine is not fully understood, current research suggests

that changes in neuronal events are most likely responsible for this neurovascular

disorder (Buzzi & Moskowitz, 2005; Sanchez-del-Rio & Reuter, 2004). The literature

3

suggests three major theories of migraine: the vascular theory, the neurogenic theory

and the neurological theory. Both the vascular and neurogenic theory account for the

pain associated with the migraine attack, whereas the neurological theory focuses on the

prodromal (onset) aspects of the migraine with aura attack.

The Vascular Theory. The vascular theory originated from work done by Harold

Wolff, who, during the 1930s found that patients suffering from migraine had dilated

extracranial (temporal) arteries (Graham and Wolff, 1938). According to the vascular

theory, increased vascular pulsation in migraineurs is thought to lead to the activation of

stretch receptors, thereby activating perivascular nerves that cause the pain associated

with migraine (De Vries, Willems, Heiligers, Villalon, & Saxena, 1999).

The Neurogenic Theory. This theory asserts that migraine pain stems from the

inflammation and dilation of the meninges, the membrane (dura) that surrounds the

brain (Arulmozhi, Veeranjaneyulu, & Bodhankar, 2005; Bussone, 2004). Inflanunation

of the dura membrane is believed to be caused by neuropeptides that are released from

primary sensory nerve terminals innervating the dural vessels (Bussone, 2004). The

anatomy of the trigeminovascular system provides compelling evidence that trigeminal

innervation is a key factor in migraine pathophysiology. The trigeminal nerve (NV)

contains both sensory and motor neurons and consists of three branches, the ophthalmic,

maxillary and mandibular branches (Martini, Timmons, & Ta11itsch, 2006). The

ophtha1mic division of the trigeminal nerve is the origin of unmyelinated nerve fibers of

the trigeminovascular system. These nerve fibers contain various neuropeptides such as

calciton gene-related peptide (CORP), neurokinin A and substance P. Recent work with

CORP has demonstrated that levels of CORP are increased in individuals with migraine

4

during a migraine attack. This suggests that CGRP may be involved in the vasodilation

and increased cerebral blood flow (CBF) observed during a migraine attack (Goadsby,

Edvinsson, & Ekman, 1990). The pain pathway for the trigeminovascular system begins

in the caudal brain stem and high cervical spinal cord and is then relayed to the thalamus

via the quintothalamic tract. The thalamus is known to be a major relay station of both

sensory and motor tracts, and is known to process vascular pain. The cortical aspect in

this process is currently being investigated (Martini et aI., 2006). The serotonergic

system is one of four modulatory systems that originate in the raphe nuclei along the

brain stem midline and have nuclei that project to the lower nuclei of the spinal cord and

the upper nuclei of the brain (Silverthorn, 2007). This system is believed to have a major

impact on the events that occur during a migraine. Specifically, serotonin plays a key

role in the neurotransmission of the trigeminovascular system (Mulleners, Chronicle,

Palmer, Koehler, & Vredeveld, 2001).

The Neurological Theory. The neurological theory suggests that abnormal neural

activation (i.e. abnormal neuronal firing and neurotransmitter release due to cortical

hyperexcitability) is responsible for certain prodromal aspects of the migraine attack,

which the vascular theory and neurogenic theory have difficulty explaining. Pearce

(1984) suggests that the neurological basis of migraine is supported by the fact that

migraine attacks develop slowly and can be enhanced by factors such as stress and

hunger which is a notable characteristic in other neuronal disorders. Cortical spreading

depression (CSD) is thought to be the cause of the sensory and motor symptoms

associated with the migraine aura (Lauritzen, 1994; Parsons, 1998).

5

Aristedes Leao (1944), a Brazilian neurophysiologist, first discovered the CSD

phenomenon in 1943 while investigating cortical epilepsy in animals. This early

research led to Milner and Lashley's hypothesis that CSD is the underlying

pathophysiological phenomenon of the migraine aura (Milner, 1958; Lashley, 1941).

CSD is the process of the expanding depolarization of cortical neurons and glial cells

and can be described as a wave-like propagation of depression of electrical activity

across the cortex with a speed of2-8 = per minute (Arulmozhi et al., 2005).

Essentially, CSD can be described simply as a burst of neuronal activity that is then

followed by the prolonged depression of neuronal activity that spreads along the cortical

surface. Arulmozhi et al. (2005) demonstrated that CSD is simultaneously accompanied

by an increase in regional CBF that is short-lasting followed by a long-lasting CBF

hypoperfusion (decreased blood flow). CBF typically begins posteriorly and then

spreads anteriorly. Recent functional magnetic resonance imaging (tMRJ) studies

strongly support the occurrence of CSD during visual migraine aura (Hadjikhani et al.,

2001).

Functional hyperexcitability of the visual cortex has been implicated as a major

factor in why the migrainous brain is more susceptible to CSD. Previous research has

produced compelling convergent evidence that the visual cortex of the human brain is

hyperexcitable to stimulation in those with migraine (Chronicle, Wilkins, & Coleston,

1995; Chronicle & Mulleners, 1996; Palmer & Chronicle, 1998; Palmer, Chronicle,

Rolan, & Mulleners, 2000; Mulleners, et al., 2001; Mulleners, Chronicle, Palmer,

Koehler & Vredeveld, 2001). Migraine patients have been shown to be more susceptible

to visual discomfort when viewing square-wave grating patterns (Wilkins, Nimmo-

6

Smith, Tait, McManus, Della Sala, Trilley, Arnold, Barrie, & Scott, 1984; Marcus &

Soso, 1989; Mulleners et al., 2001). A later study by Chronicle, Wilkins, & Coleston

(1995) placed more focus on controlling for the possibility of the over-emphasizing of

symptoms by migraineurs. They utilized a target-detection method to compare

migraineurs with controls. The target-detection method focused on the detection of the

presence or absence of a target stimulus, presented on a background of stripes (similar to

those that cause illusions and discomfort). Results from the Chronicle et al. (1995) study

demonstrated increased target threshold detection by migraine with aura patients as

compared to migraine without aura patients.

Work with transcranial magnetic stimulation (TMS) provides further supporting

evidence for hyperexcitability in migraine patients. TMS utilizes powerful magnetic

fields to induce electrical fields in the brain by electromagnetic induction in a non­

invasive manner. A number of researchers have shown that the threshold for elicitation

of visual phosphenes by single-pulse TMS over the posterior portion of the head (i.e.

occipital lobe of the brain) is significantly lower in migraine (Aurora, 1998; Mulleners

et aI., 2001). Furthermore, Palmer et aI. (2000) used metacontrast masking, a

psychophysical technique in which a target is superimposed upon a patterned

background thereby causing it to become difficult to see. Palmer demonstrated that

migraine patients showed significantly less masking than controls. It should be noted

that a few studies suggest the opposite, hypoexcitability in the migraine patient,

although the consensus in the literature seems to support the notion that the visual cortex

is hyperexcitable in migraine (Afra, Cecchini, De Pasqua, Albert, & Schoenen, 1998;

7

Bohotin, Fuma\, Vandenheede, Gerard, Bohotin, Maertens de Noordhout, & Schoenen,

2002).

Both the vascular and neurogenic theories of migraine focus on the origin of the

pain associated with the migraine attack, whereas the neurological theory accounts for

the onset symptoms (Le. the migraine aura). However, there has been no theory of

migraine that explains both the occurrence of the migraine aura and the pain that

follows. Recent progress in understanding the role of cortical spreading depression in

migraine (parsons, 1998) permits the emergence of a unifying hypothesis (E.P.

Chronicle, personal communication, 2006). The brain is hyperexcitable in migraine,

which is probably genetically predetermined. In response to psychological or

physiological stress, excessive sensory stimulation, or a combination of these, inhibitory

processes in the cortex fail to maintain an equilibrium, and CSD may result. The

widespread physiological disroption that follows can then potentially cause the pain and

autonomic features of the attack to occur as an aftereffect.

Visual Correlates of Migraine

One question that has been relatively under-researched relates to the onset of

each migraine attack. It has been well documented in the literature that the visual system

is implicated in migraine (Chronicle & Mulleners, 1996). The visual cortex has been

shown to be hyperexcitable in migraineurs by a wide array of electrophysiological,

psychophysical, and 1MS studies (Chronicle etal., 1995; Chronicle & Mulleners, 1996;

Palmer & Chronicle, 1998; Palmer et al., 2000; Mulleners et al., 2001; Mulleners et al.,

2001).

8

Grating Patterns as Visual Stimuli. Since Lashley (1941) first reported his

findings, there have been numerous psychophysiological studies that have focused on

the primary visual cortex in migraine, specifically, examining visual discomfort in

migraine patients using a variety of psychophysiological methods (Wilkins et aI., 1984;

Marcus & Soso, 1989; Khalil, 1991; Coleston & Kennard, 1995). Many of these studies

involved the use of high -contrast square-wave grating patterns varying in spatial

frequency, that is, the number of pairs of bars within a given distance on the retina

(Wilkins et aL, 1984; Marcus & S080, 1989; Khalil, 1991). These investigators

examined the unpleasantness of striped patterns, the spatial properties of these patterns,

the specificity of these properties and the extent to which they produced visual

discomfort. Wilkins et aI. (1984) noted that individuals with frequent headaches were

more likely to experience discomfort when viewing the striped grating patterns

compared to individuals without headaches. They found that patients with unilateral

headaches were more likely to report illusions in a 3-4 cycles per degree (CPD) grating

pattern. Their findings suggested that certain grating patterns can induce significant

discomfort in individuals with headaches. Marcus and Soso (1989) published a similar

study in which they examined visual discomfort among three groups (migraine, non­

migraine, and non-headache subjects) by recording and analyzing behavioral responses

such as grimacing with eye narrowing, turning away, or refusal to look at the stimuli.

Subjects with migraine found certain grating patterns to be significantly more aversive

to view compared to the non-migraine headache groups and the non-headache group.

The results of Khalil (1991) added to the fmdings of Wilkins et aI. (1984) and Marcus

and Soso (1989) by showing that headache patients overall saw more illusions than

9

controls when shown grating patterns of various sizes and experienced more discomfort

in response to these patterns. Furthermore, illusions and discomfort were more frequent

in migraine aura patients than those without the aura. In a later study, Coleston and

Kennard (1995) required that subjects not only rate the presence or absence of an

illusion, but also the intensity of the illusion seen in a grating pattern. They also varied

the fundamental spatial frequency of the stimulus grating and observed the effects on the

intensity of the illusion. Overall, migraine patients experienced more intense illusions

than did controls. Furthermore, those with migraine aura reported the most intense

illusions among the three groups (migraine with aura, migraine without aura, and non­

headache controls).

There is ample evidence supporting the notion that visual discomfort can be

induced by the presentation of grating patterns. Furthermore, the visual discomfort as

measured by ratings or behavioral reactions appears to be greater in migraine than non­

migraine subjects. These results also indicate that migraine subjects experience more

illusions when viewing these patterns. However, simple viewing of a striped pattern,

while uncomfortable and occasioriaIly aversive for migraine subjects, does not

automatically induce an aura (Wilkins et al., 1984).

Migraine Triggers

The pathogenesis of migraine has been reasonably wel1 understood for many

years (see above for a review of migraine theories), however, it is stil1 unclear how

migraine attacks are triggered. A variety of factors have been implicated as migraine

trigger factors, including menstruation, sleep disturbances, fatigue, alcohol consumption

10

and nutrition. Environmental and psychological fators have also been mentioned as

trigger factors to migraine (Wober, Holzhammer, Zeitlhofer, Wessel, & Wober-Bingol,

2006). Sensory stimuli, such as flickering light and glare, are particularly related to

migraine with aura and less often to migraine without aura (Scharff, Turk, & Marcus

1995; Spierings, Ranke, & Honkoop 2001; Chabriat, Danchot, Joire, & Henry, 1999;

Russel, Rasmussen, Fenger, & Olsen, 1996; Ulrich, Olesen, Gervil, & Russell, 2000).

Although visual stimuli sometimes trigger migraine, it is a more common clinical

observation that combinations of events (e.g. "I had a rea11y bad day in the office, then I

drove home with the sun low on the horizon") are potent triggers.

Stress and Migraine

Psychological factors, such as stress, have long been thought to be facilitating

factors in migraine attacks (Wang, Timsit-Berthier, & Schoenen, 1996; Kropp,

Siniatchkin, & Gerber, 2002; Fanciullacci, Alessandri, & Fanciullacci, 1998).

Specifically, mental stressors have been considered to be a major precipitant of migraine

(Chabriat et al., 1999) and have been found to do so in controlled studies (Holm,

Lokken, & Myers, 1997; De Benedittis & Lorenzetti, 1992). Although stress is

considered a common trigger of migraine, there are no experimental data to directly

relate the possible interaction between stress and visual discomfort in the precipitation

of migraine attacks (Schoonman, Evers, Ba1lieux, de Geus, de Kloet, Terwindt, van

Dijk, & Ferrari, 2006). The experiment reported here examines how two factors,

psychological stress and visual stimulation, may interact in migraine subjects.

11

According to Hassinger, Semenchuk. and O'Brien (1999), there have been a

number of studies that have examined the vascular responses of migraineurs to a variety

oflaboratory stressors. The results of these studies, however, have been inconclusive

and inconsistent. Arena, Blanchard, Andrasik, Appelbaum, & Myers (1985), Drummond

(1982), Drummond (1985) and Rojahn & Gerhards (1986) each found support for

vasodilation in response to stress while Ahles, Martin, Gaulier, Cassens, Andres, &

Shariff (1988), Morley (1985), and Passchier, Goudswaard, & Orlebeke (1993) reported

vasoconstriction in response to stress. Numerous other investigators have reported no

difference in vascular response in migraine and control subjects as a function of stress.

Some investigators have focused on the cardiovascular system based on the hypothesis

that there is a heightened level of autonomic arousal in response to stress. However, like

the research examining vascular response, results have been inconsistent. Some

researchers have reported greater heart-rate reactivity to stress (Cohen, Williamson,

Monguillot, Hutchinson, Gottlieb, & Waters, 1983; Gannon, Haynes, Safranek, &

Hamilton, 1981) while the majority have reported no difference between migraine and

control subjects. Although these studies are inconsistent, Hassinger et at. (1999)

suggests that the cause for the inconsistency is due to the fact that these studies

essentially measure just two responses, heart rate (HR) and blood pressure (BP).

Hassinger et at. (1999) looked beyond just HR and BP and instead looked at individual

difference in hemodynamic response to stressors since subjects may exhibit reliable

differences in hemodynamic response even when both their HR and BP are similar. The

measurement of multiple cardiovascular components was accomplished by using

impedance cardiography. The results of the Hassinger et at. (1999) study supported the

12

hypothesis that individuals with migraine have physiologically different responses to

stress than control subjects.

Psychophysiological studies examining stress in migraineous individuals

typically utilize a physiological, cognitive or mental stressor (Hassinger, et aI., 1999).

According to de Kloet, Joels, & Holsboer (2005) mental stressors are psychological

events that threaten the homeostasis of a living organism. It has been suggested that

migraineurs experience heightened reactivity when exposed to stressful stimuli

(passchier, 1994). Physiological stress can involve auditory stimulation, acute pain (i.e.

the cold pressure test or the radiant heat test), or visual stimulation (i.e. stressful

imagery). Typical cognitive stressors include intelligence tests, time estimation tasks

and mathematical stressors. Mathematical stressors often used include mental arithmetic

problems where subjects are given a series of mathematical problems and are asked to

verbally solve them out loud or serial subtraction where they are asked to subtract

continuously from a starting number verbally out loud.

In a serial subtraction problem reported by Hassinger et aI. (1999) migraine

subjects had a different physiological respouse from control subjects. The task was

found to be an effective stressor, producing significant changes in cardiovascular

reactivity as measured by systolic blood pressure, diastolic blood pressure, heart rate,

stroke volume, total peripheral resistance, and cardiac output. Migraineurs showed

increased heart rate reactivity to stress, and, furthermore, migraineurs have differences

in cardiovascular reactivity in response to cognitive stressors. Thus, it is plausible that

the pairing of heightened reactivity to stressful stimuli and cortical hyperexcitability

may serve as a trigger to a migraine attack.

13

Although there has been considerable research done to examine the

physiological role of cardiovascular reactivity to stress in migraineurs, there has been a

no research to explore the interactions between stress and striped grating patterns known

to induce significant visual discomfort in migraineurs. It seems likely that psychological

factors interact to generate a migraine attack; for example, it is possible that visual

stimuli (e.g. striped patterns, flickering light, etc.) may only trigger a migraine attack if

the subject is already experiencing psychological stress. Debney (1984) supports this

notion with a catastrophe model of the initiation of an attack:, in which various

environmental factors may sum to exceed the critical threshold of brain stimulation for

the onset of an attack.

By investigating the effect of combining grating patterns known to induce visual

discomfort with a potential stressor, it may be possible to gain some insight into how a

migraine with aura attack might be initiated. Here, grating patterns of varying cycles per

degree (3.0 CPD vs. 0.5 CPD) were paired with a cognitive stressor (mathematical task)

designed to induce a stressful state.

The aim of the experiment reported here was to demonstrate that combining

grating patterns known to induce visual discomfort with a cognitive stressor will

increase the aversiveness of viewing the grating pattern. A secondary aim of this work is

to increase the methodological precision of this kind of study by: 1) using computer­

generated stimuli presented on a computer monitor instead of the usual paper format; 2)

providing subjects with an escape response; and 3) measuring the actual viewing

durations in addition to pleasantness ratings.

14

Method

Design

The independent variables of this experiment are the diagnosis of the subject

(migmine with aura [MAl or control [CD, the presence or absence of a psychological

stressor and the spatial frequency of the grating patterns, 3.0 CPD or 0.5 CPD. The

dependent measure is the level of discomfort experienced by the subjects to the grating

pattern presented. Each subject was presented with each grating pattern an equal number

of times in both the stress and no stress conditions. The order of the stress and no stress

conditions was counterbalanced across subjects.

Subjects

Subjects were recruited through advertisements posted on the University of

Hawaii at Manoa campus (Appendix A and Appendix B). All potential subjects were

sent a packet containing a cover letter (Appendix C), study information sheet (Appendix

D), expression of interest form (Appendix E) and migmine questionnaire that asked

about headache symptoms (Appendix F). The questionnaire had been used previously in

studies involving migmine (Chronicle, 1993) and had been formulated in accordance

with the diagnostic criteria for migraine set out by the Headache Classification

Committee of the International Headache Society (lCHD-2). It has been suggested,

however, that diagnosis based on questionnaire responses may not correspond well with

those made by clinicians (Rasmussen et ai, 1991). Therefore, the questionnaire was used

as a screening tool for those who probably had migraine. After review of the migraine

questionnaire, potential subjects not fidfilling inclusion criteria were mailed an

exclusion letter (Appendix G) indicating why they were not suitable for participation.

15

Before participating in the experiment, all subjects were interviewed by the

experimenter to assess headache and aura symptoms and to verify that their symptoms

fulfilled the diagnostic criteria. During the interview, subjects were further screened for

exclusionary criteria, such as history of neurological pathology or neurosurgery.

Individuals with a history of epilepsy were excluded as were those on drugs such as

antidepressants, tranquilizers, lithium, anti-epileptic drugs, anti-parkinsonian drugs,

muscle relaxants, systemic anticholinergics, migraine prophylactics, Ca-entry blockers,

anti-emetics, betahistamine, cinnarizine, piracetam and hormone replacement therapy.

All subjects were tested for visual acuity using the Snellen Eye Chart #2867-1264

(Graham-Field, Atlanta, Georgia) and had normal visual acuity after correction. All

subjects fulfilling participation criteria completed a written informed consent form

(Appendix H).

37 subjects took part in the experiment In one group, there were 20 subjects (7

men and 13 women) diagnosed with migraine with aura (MA). The age range of

subjects in the MA group was 18-41 years with a mean of 24. All migraineurs took

medication for their migraines only during an attack, because potential subjects on

migraine prophylactics had been excluded from the study. 17 control subjects (5 men

and 12 women) completed the same questionnaire as the MA group and none gave

responses to the questions that were indicative of any headache disorder, and none had

any history indicative of migraine at the interview. The age range of subjects in the

control group was 18 - 34 years with a mean of24. Controls were approximately age

and sex matched to the MA subjects.

16

Apparatus and Stimuli

The striped grating patterns (see Figures 1,3,5, and 7) were generated in Adobe

Photoshop CS (Adobe Systems Incorporated, San Jose, California). Calculations for

how these images were derived can be found in Figures 2, 4, 6, and 8. The striped

grating patterns were presented to subjects via Super Lab Pro (Cedrus Corporation, San

Pedro, California), an experiment management software application designed for the

presentation of experimental stimuli. Stimuli were presented on a 19" digital flat panel

computer monitor (Dell Computer Corporation, Round Rock, Texas) with a DPI of 86, a

resolution of 128Oxl024, a horizontal width of 14.8 inches and a vertical width of 11.85

inches. A Dell Pentium 4 computer (Dell Computer Corporation, Round Rock, Texas)

running Microsoft Windows XP Service Pack 2 was used to run the program.

Striped grating patterns were utilized to measure the degree of visual discomfort

of the subjects. The grating patterns seen in Figures 1,3,5 and 7 differ in the number of

cycles (pairs of white and black bars of equal widths) of the grating per degree of visual

angle, thus they are each said to have a different fundamental spatial frequency. The

duty cycle for these gratings was set at 50%, meaning brightness for these grating

patterns was at its maximum for 50% of each cycle (i.e. for each pair of black and white

bars). The brightness of these gratings, measured along a line perpendicular to the bars

of the grating, varied according to a square waveform, therefore, these grating are said

to have a square waveform. Figure 1 shows the 3.0 CPD grating pattern. This pattern

has a fundamental spatial frequency of3.0 CPD. 50% duty cycle and a square wave

lumjnance profile. This type of grating had previously been demonstrated to induce

discomfort in migraineurs (Wilkins et al., 1984; Marcus & Soso, 1989). Figure 3 shows

17

the 0.5 CPD grating pattern. This pattern has a fundamental special frequency of 0.5

CPO, 50% duty cycle and a square wave luminance profile. This low spatial frequency

grating pattern had previously been shown to induce little or no pattern sensitivity in

either migraineurs or control subjects (Wilkins et al., 1994). The grating patterns seen in

Figures 1 and 3 are both subtended 5°. The diameter of each grating pattern is

determined by the distance from which it is displayed to the subject and the angle from

which it is subtended. Therefore, it is possible to increase the diameter of the grating

pattern by increasing the subtended angle. Figures 5 and 7 show grating patterns that are

subtended 10°. All grating patterns were viewed from a fixed distance of 50 em.

Subjects were positioned on a chin rest in order to maintain a fixed position of 50 cm

from the monitor that presented the stimuli.

Procedures

Testing took place in a testing room at the Psychology Department at the

University of Hawaii at Manoa interictally (no headache for at least 3 days prior to the

appointment). Subjects were tested one at a time. Subjects were seated in front of the

computer monitor with their chin placed on a chin rest to maintain the viewing distance

from the computer monitor. A testing session for each subject lasted approximately 20

minutes.

Testing was conducted in two blocks, the order of which was counterbalanced

across subjects. In one block, subjects were given either a stressful mental arithmetic

task (A) or a non-stressful mental arithmetic task (B) that lasted three minutes. Prior to

the administration of the mental arithmetic task, subjects were asked to complete a 7-

point rating scale (see Appendix I), in which they were asked to mte their current level

18

of stress. Subjects then were instructed to complete either math task A or B (math task A

consisted of serially subtracting backwards by 17 from a beginning number of 7000 and

math task B consisted of serially subtracting backwards by 1 from a beginning number

of 100). Subjects were asked to work as quickly and accurately as possible. If subjects

were silent for a period of 30 seconds, they were prompted by the experimenter to

continue. If subj ects lost their place they were asked to begin again at a different number

(a number of 100 less than their last starting point if doing math task A or a number of

10 less than their last starting point if doing math task B). Upon completion of the task,

subjects were again asked to rate their level of stress using the same 7-point rating scale.

Subjects were then shown 10 grating patterns that randomly alternated between

fundamental spatial frequencies of3.0 CPD (Figure 1) and 0.5 CPD (Figure 3). Each

grating was randomly presented five times (for a total often presentations) and each

time was on the screen for a maximum of 15 seconds. Subjects were asked to press a

key (designated as the U key) on the computer keyboard as soon as the grating pattern

being shown became uncomfortable to view. If subjects pressed the U key, they would

then escape from viewing the current pattern and move on to the next pattern. If they did

not press the U key then the pattern would stay on the screen for a maximum of 15

seconds, after which, the next pattern would appear. The duration spent looking at each

of the grating patterns and the number of escapes (presses of the U key) were recorded.

At the end of the first block, subjects were shown two more gratings (shown in Figure 5

and Figure 7) separately for 10 seconds, during an interblock period. They were then

asked to complete a checklist after viewing each of the grating patterns (Appendix J) to

indicate the visual illusions experienced while viewing the gratings. The checklist

19

included categories relating to the color (red, green, yellow, blue) and shape (blurring,

shimmering, flickering, bending of the lines, shadowy shapes) of the illusion. Subjects

were also allowed to indicate illusions that were not on the checklist. Subjects were then

asked to rate the grating patterns on a scale of 1 to 5 (1- very unpleasant, 3 - moderately

pleasant, 5 - very pleasant). Following the completion of the illusion checklist, the

second test block began and subjects were again asked to rate their current level of stress

using the same 7 -point rating scale used prior to the presentation of the first

mathematical task. Subjects were then presented with the second mathematical task

(math task B if they began block one by doing math task A or math task A if they began

block one by doing math task B). The math task again lasted for a duration of three

minutes. Subjects presented with math task B were instructed to seria1ly subtract by 1

from a beginning number of 100 and subjects presented with math task A were

instructed to serially subtract by 17 from a beginning number of 7000. Subjects were

asked to work as quickly and accurately as possible. If subjects were silent for a period

of 30 seconds, they were prompted by the experimenter to continue. If subjects lost their

place they were asked to begin again at a different number (a number of 10 less than

their last starting point if doing math task B or a number of 100 less than their last

starting point if doing math task A). Subjects were informed that they were being

evaluated on the speed and accuracy of their responses. Upon completion of the task,

subjects were asked to rate their level of stress using the same 7-point rating scale.

Immediately after the presentation of the mental arithmetic problem, subjects were again

presented with the visual discomfort task, exactly as in the first block, in which they

20

were again presented with 10 grating patterns that alternated between 3.0 CPD (Figure

1) and 0.5 CPD (Figure 3).

Once subjects completed testing they were informed that the mental arithmetic

tasks were not an intelligence test and that responses to this task were not recorded but

simply presented to induce minor psychological stress. They were also informed once

more that they should contact the experimenter(s) should they experience any adverse

reactions within 12 hours of testing. Following this, the experimenter then answered

subjects' questions and reimbursed them $24 for their time. Please refer to Figure 9 for a

procedural flow chart for this experiment.

Results

Stress mtings obtained from math task A (counting backwards from 7000 by 17)

indicate that the task was effective in inducing a stressful state in both rnigmineurs and

controls. Univariate analysis of variance was performed on the post math retings in both

block 1 and block 2. The hard math task (A) was found to be significantly more difficult

than the easy math task (B). There was a significant effect of stress in block 1 (F[I, 33]

= 13.902; P = .001) and block 2 (F[I,33] = 8.372; p = .007).

Shown in Figure 10 are the mean total escapes for the MA and C subgroups in

the two stress sequences (stress to no stress and no stress to stress). The performance in

the two sequences was very much the same and therefore the subgroups were combined

in the statistical analysis. The effect of the stressor on the number of escapes from

viewing the grating patterns are shown in Figure 11 for the rnigmine and control groups.

The mean number of escapes is plotted for each pattern for the stress condition (upper

21

panel) and no stress condition (lower panel). There was a higher level of escapes in the

migraine group than in the control group for both the 3.0 CPD and 0.5 CPD patterns in

both stress conditions. Mean values for the number of escapes when looking at the

grating pattern were analyzed with a mixed-effects analysis of variance with diagnosis

as the between-groups factor and with both grating pattern (0.5 CPD, 3.0 CPD) and

stress (stress or no stress) as the within-groups factors. There was a significant main

effect of diagnosis (F[I, 35] = 10.54; P = .0026). There was also a significant main

effect of grating pattern (F[I, 35] = 11.66; p = .0016). No interaction was found between

grating pattern and diagnosis (F[I, 35] = 1.17; p = .2870) or stress and diagnosis (F[I,

35] < 1.00). A three-way analysis of variance found no significant interaction among

stress, grating pattern and diagnosis (F[I, 35] < 1.00).

The effects of the stressor on duration spent looking at the grating patterns in

block I and block 2 are shown in Figure 12 for the migraine and control groups. The

mean duration spent looking at each grating pattern is plotted by trial. Durations are

generally lower in the migraine group compared to the control group. Mean values for

the duration spent looking at the grating patterns were analyzed with a mixed-effects

analysis of variance with diagnosis as the between-groups factor and both grating

pattern (0.5 CPD, 3.0 CPD) and stress (stress and no stress) as the within-groups factors.

There was a significant main effect of diagnosis (F[I, 35] = 8.83; P = .0053). There was

a significant main effect of grating pattern (F[l, 35] = 14.49; P = .0005). No interaction

was found between grating pattern and diagnosis (F[I, 35] = 2.29; p = .01396). There

was found to be no significant stress effect (F[l, 35] = 1.03; p = 0.3173). A three-way

analysis of variance found no significance between stress, grating pattern and diagnosis

22

(F[I, 35] < 1.00). Since there was no effect of stress, the trial by trial curves were

pooled and are shown Figure 13. Figure 14 further shows the overall mean duration for

both the MA and C groups in the no stress and stress conditions.

Results of the pleasantness ratings (Appendix J) taken during the interblock are

shown in Figure IS for the MA and C groups. Mean values were analyzed with a

repeated measures analysis of variance. There was no significant main effect of

diagnosis (F[I,33] = 3.289; P = .079) or stress (F[I,33] = .026; P = .873). There was no

interaction between diagnosis and stress (F[I, 33] < 1.00). There was a significant main

effect of grating (F[1,33] = 14.527; P = .001). Although the migraine group appeared to

rate the two patterns as somewhat less pleasant than the control group, no interaction

was found between grating pattern and diagnosis (F[I, 33] = 1.332; P = .257).

Furthermore, there was no interaction between grating pattern and stress (F[I, 33] =

3.24; P = .081). A three-way analysis of variance found no significant interaction among

grating pattern, stress and diagnosis (F[1, 33] < 1.00).

During the interblock, new 10· subtended patterns were presented to all SUbjects.

Each subject responded to the illusion checklist immediately after viewing the new

patterns. The responses to the illusion checklist (Appendix J) are shown in Figure 16

plotted as percent of subjects in each group who reported seeing illusions for both the

new 0.5 CPD and 3.0 CPD patterns. There was no difference between the migraine

group and the control group. Furthermore, there was no effect of stress on percent

seeing illusions. A Chochran-Mantel-Haenszel test, an extension of a chi-squared test,

was performed to detect a relationship among grating pattern, stress and diagnosis in

seeing illusions during the presentation of the gratings during the interblock. Across

23

different diagnoses, grating pattern and stress were not related in tenns of the frequency

in which illusions were experienced (r= 1.7418, p = 0.1869).

The mean number of illusion descriptors used by subjects in the two groups are

shown in Figure 17 for the new 10· subtended 3.0 CPD and 0.5 CPD grating patterns in

the interblock. There was a noticeable increase in the number of descriptors used by

migraineurs when viewing the 3.0 CPD grating. The number of descriptors used by

control subjects did not change between the 3.0 CPD and 0.5 CPD grating patterns.

Mean values for the number of illusion descriptors mentioned by the MA and C group

were analyzed with a mixed-effects analysis of variance. There was a main effect of

diagnosis (F[1,33] = 7.649, p = .009. There was no main effect of stress (F(1, 33] <

1.00). There was no interaction between diagnosis and stress (F(1, 33] < 1.00). There

was a significant main effect of grating pattern (F[1,33] = 26.229; p < .001) and an

interaction between grating pattern and diagnosis (F[1,33] = 9.026; P = .005). No

interaction was found between grating pattern and stress (F(1, 33] = 2.890; p = .099). A

three-way analysis of variance found no significant interaction among grating pattern,

stress and diagnosis. In none of these measures did a stress effect appear. The results are

interesting because the stressor was effective.

Discussion

The primary purpose of this work was to demonstrate that combining a cognitive

stressor with grating patterns known to induce visual discomfort would increase the

aversiveness of viewing the grating pattern. Specifically, the introduction of a cognitive

stressor was expected to accentuate the effects of visual discomfort when viewing the

24

3.0 epn grating pattern. Examination of both the number of escapes when viewing the

grating patterns and duration spent looking at the grating patterns revealed that stress did

not increase the number of escapes performed nor did it reduce time spent looking at the

grating patterns. The MA subjects did not experience a heightened level ofvisua1

discomfort with the introduction of stress as compared to when stress was not presented.

It should be noted that pilot work on the stressor alone produced stress levels that were

significantly higher than baseline after the introduction of the difficult math task.

Furthermore in this experiment, the stress task produced a significant difference in stress

ratings as compared to the non-stressful task in both MA and e subjects. Thus, the

difficult math task was an effective stressor. Therefore the failure to find an effect of

stress on visual discomfort cannot be due to lack of an effective stressor. This indicates

that the difficult math task was indeed significantly more stressful than the easy math

task and thus made for an effective stressor. Overall, migraineurs found the two grating

patterns used to be significantly more aversive than control subjects, thereby, supporting

the findings ofWi1kins et al (1984). However, there was no evidence to support the

notion that the stress task had any effect on intensifying the discomfort felt when

viewing the 3.0 epn grating pattern in migraineurs.

The finding that stress did not produce changes in visual discomfort raises

questions as to why this might be so. One possibility is that stress does not affect visual

discomfort in migraineurs. It is difficult to take that possibility seriously since stress has

been reported as a trigger of migraine attacks in the literature by both researchers and

migraine sufferers. Furthermore, in this study many subjects noted during the pre­

experimental interview that stress is a major precipitant of their migraine attacks. Mental

25

stress is regarded as a psychological event that disrupts homeostasis (KIoet et aI., 2005),

therefore a more likely possibility is that the cognitive stressor used in this study,

although shown to be effective in inducing a feeling of stressfuiness, did not produce the

level of stressfuiness required to initiate a migraine in a real world setting. It might be

reasonable to change the approach and use a battery of stressful tasks, thereby creating a

cascade of stressful events strong enough to stimulate the necessary threshold to trigger

a migraine attack. This idea corresponds with Debney's (1984) Catastrophe Model in

which various environmental factors may sum to exceed the critical threshold ofbrain

stimulation for the onset of an attack. It is also possible that the effect of the stressor was

short-lived, with the effectiveness of the stressor dissipating with the presentation of

each grating pattern. In future work it may be worthwhile to assess the stress levels after

each trial or each block. It is worth mentioning that subjects were told prior to testing

that they would be presented with a mathematical stressor. Perhaps that resulted in a

heightened baseline state of stress (because of ethical considerations as requested by the

Committee on Human Studies at the University of Hawaii, it was advised that

notification of the use of a stressor should be given to subjects). Another methodological

suggestion would be to include more objective measures of stress such as measuring

blood pressure and heart rate. It is possible that these measures may be taken,

unobtrusively, before and after the stressor is administered.

The work presented here utilizing stimuli shown to induce visual discomfort in

migraineurs paired with a cognitive stress task confirmed that there are differences in

the way migraineurs react to viewing certain grating patterns compared to controls. The

visual gratings have been shown, repeatedly, to be a highly replicable task that produces

26

differences between migraineurs and controls. A secondary goal of this work was to test

a novel computerized method for presenting the visual stimuli and to introduce more

precision in the visual discomfort measures. The results validate the new technique.

Both the escape and duration measures of visual discomfort produced clean evidence

that migraineurs experienced the gratings as more aversive than controls. This new

procedure should contribute to the standardization and precision of future work on

visual discomfort in the migraine population.

Although this work is a good starting point for research examining the effects of

stress in migraineurs using visual discomfort, it is obvious that further work needs to be

done in this area. Nonetheless, given the presence of stress as a likely trigger of

migraine, research in this area is important and will lead to a better understanding of the

association between visua1 triggers and stress in migraineurs. Individuals suffering from

migraine make up a significant part of the world population and their disability

undoubtedly has a major effect on their level of function and permeates every aspect of

their lives. Thus, if we can further understand how stress is involved in the initiation of a

migraine attack then it may be possible to shed new light on the pathophysiology of

migraine.

27

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36

Figure 1. Grating pattern of3.0 CPD and 5° subtended.

37

y

Calculations:

5 degrees subtended 3 cycles per degree diameter = 4.37 cm width per bar = .1456 cm

tan8=y Ix y=xtan8 y = (50cm) (tanS°) y = 4.37 cm = diameter of the grating

x=50cm

diameter of grating I degrees subtended = total width per cycle 4.37 cm I 5° = 0.874 cm

total width per cycle I bars per cycle = width per bar 0.874 em I 6 bars per cycle = 0.1456 cm

Figure 2. Calcu1ations for grating pattern of 3.0 CPD and 5° subtended.

38

Figure 3. Grating pattern of 0.5 CPO and 5° subtended.

39

y

Calculations:

0.5 cycles per degree diameter = 4.37 cm width per bar = .1456 em

tane =y Ix y=xtanO y = (50cm) (tanS') y = 4.37 em = diameter of the grating

x=50cm

diameter of grating I degrees subtended = total width per cycle 4.37 cm I S' = 0.874 em

total width per cycle I bars per cycle = width per bar 0.874 cm 11 bar per cycle = 0.874 cm 5 degrees subtended

Figure 4. Calculations for grating pattern of 0.5 CPD and 5° subtended.

40

Figure 50 Grating pattern of300 CPD and 10° subtendedo

41

y

Calculations:

10 degrees subtended 3 cycles per degree diameter = 8.82 cm width per bar = .147 em

tan!l=y Ix y =xtan!l Y = (50cm) (tanIO·) y = 8.82 em = diameter of the grating

II = 10·

x=50cm

diameter of grating I degrees subtended = total width per cycle 8.82 em I 10· = 0.882 em

total width per cycle I bars per cycle = width per bar

Figure 6. Calculations for grating pattern of3.0 CPD and 10° subtended.

42

Figure 7. Grating pattern ofO.S CPD and 10° subtended.

43

y

Calculations:

10 degrees subtended 0.5 cycles per degree diameter = 8.82 cm width per bar = .882 cm

tan8=y Ix y=xtan8 y = (50cm) (tan 1 00

)

y = 8.82 cm = diameter of the grating

A= 100

x=50cm

diameter of grating I degrees subtended = total width per cycle 8.82 cm 1100 = 0.882 cm

Figure 8. Calculations for grating pattern of 0.5 CPD and 10° subtended.

44

~ U1

R&eruitment

BJockOne

llliJ~ns

GnceK" 9t

• Pre-Slress Rallng

Sc;!I(JOf 1,7

GrAlI/\O ponofn 2

Experiment Flow Chart

Math Task A (01 B)

Cc. rl Ux,~w.3rds b:~

17's ~ la1Iflg:11 70(;':)

(Ot ty l 's S(:l1 f"I9 OJ1 -COl

A U$IOr\S C"IOO<fIGt

• Post-Stress ---. Rating

$caiC or 1,1

Grotll"tQ PQttern 1 O.S CPt) (01 3.0 CPO)

VICW 10 Gor<:!tlf'IQ pane'os J.a CPU and 0.5 CPD 5 ocgrees SUOIC1(]CO

(5 or cacn) Ro'\Com l OO

Press key w1"£n tJI"ICOO11ortatlIO Of w ill move 10 nc-xt pattern

after 15 sec

I IlIlO - 3.0 C~O IO~ 0,' CPOJ

10 degroe, "J01cndOCl RondOmlzOCI

"orooo 10 ViOW to! 10 ~c

.......-- Qna .......-- 10-dog'OOSSlJDtondCc! .......-- Imerbloc/r PIColllnlncsa

Scale

Bloc/r Two • Pre-Slress Rating

SeJI~ Of ' ·1

•

PlcaSllntf\C5$ Secto

Math Ta'k B (01 A)

CQU i l !.3aC('o\.Ol':lS r:ty - 's

SUor:!;g at 1 GO

(or I!y In, St!l1 '19,lt 10CO)

RIl.:'IOOMZOQ FO'COCl10 View 101 lt1 sec

• Post-Stress ---. Rating

Scnlco' 1-1

Figure 9. Procedural flow chart of the steps fo llowed for thi s experiment.

VICW ro Grabng pancTIS 3:0 CPO and 0.5 CpO 5 degrccs s!Jbtc'lClcd

(5 Of eaCh) Ha"ldOm zoo

Press key when uncornlortablC or v. II move 10 next pattem 'IIter

15 sec

• End of E)(perJmenr

on 2.5 GI on I:

8. 2 on ~

8. ~ 1.5 GI

'0 .. 1 1: E :J I: 0.5 I: .. GI :I: o

Escape Responses

MA No Stress MA Stress C No Stress C Stress then then Stress then No Stress then Stress No Stress

Group

. 0.5 CPD Grating

3.0 CPD Grating

Figure 10. Mean total escapes from the two grating patterns for the MA and C

subgroups are shown for the two stress sequences (stress then no stress and no stress

then stress) .

46

VI

" 3

Ii 2,5 u VI au 2 '0 .. Z 1.5

E " 1 Z

" : 05 :E

Escape and Stress

Stress

• O +--------~~-------~

3

~ 2,5 Co

e ~ 2 ... o .. Z 1.5

E " Z 1

" .. " :E 0,5

0 ,5 3

Grating Pattern ( CPO)

No Stress

.-O +---------------~------------~

0,5 3

Grating Pattern (CPO)

__ MA

C

Figure II, Mean number of escapes in the stress (upper panel) and no stress (lower

panel) conditions for the two grating patterns for the MA and C groups,

47

Viewing Duration

16000

14000 '- • - .. ~ • -E 12000 ~

c 10000 --+--- MA 3.0 0 ;; MA 0.5 .. 8000 ~ C 3.0 " Q

6000 C 0.5 c .. " 4000 Block One Block Two :E

No St ress Stress 2000

0 1 2 3 4 5 6 7 8 9 10

Trial

16000

14000 -...... ~ ~ • E 12000 ~

c 10000 --+--- MA 3.0 0 ;; MA 0.5 .. 8000 ~ C 3.0 " Q 6000 C 0.5 c .. " 4000 Block One Block Two :E Stress No Stress

2000

0 1 2 3 4 5 6 7 8 9 10

Trial

Figure 12. Mean durations spent looking at each grating pattern for both the MA and C

groups across trial s in the two blocks.

48

Duration and Diagnosis

16000

* 14000

'i 12000 ---- / --.. -. ~

c 10000 __ MA3.0 0 .;: MA 0 .5 (! 8000

" C 3.0 0 6000 C 0.5 c .. .,

4000 :I:

2000

0 1 2 3 4 5 6 7 8 9 10

Trial

Figure 13 . Mean durations spent looking at each grating pattern for both the MA and C

groups after pooling the stress conditions.

49

Duration and Stress

15000

14000

~ .. E ~ .... c 13000 - -+- MA 3.0 CPD 0 -:;; -- MA 0.5 CPD .. .... ... C 3.0 CPD :I Q

c 12000 C 0.5 CPD .. II :E

11000

10000 +------------------.----------------~

No Stress Stress

Condit ion

Figure 14. Mean durations spent looking at each grating pattern for both the MA and C

groups in the no stress and stress conditions.

50

4

3.5

iii 3 , ... '0 2.5 .!! ~ 2 ~

~ 1.5 .. ~ 1

0.5

Interblock Pleasantness Ratings

--+-MA - No Stress

MA - Stress

C- No Stress

C - Stress

o +------------------.------------------~ 0.5 3

Grating Pattern (CPO)

Figure 15. Mean rating given by the MA and C groups for the 0.5 CPD and 3.0 CPD

grating pattern (now 10° subtended). Subjects rated each of the two patterns in terms of

pleasantness using a 5-point scale (I = very unpleasant and 5 = very pleasant).

51

100

90 .,

80 r:: 0 'iii 70 ::J .. 60 01 r::

50 'Qj III III 40 ... r:: III 30 ~ III 20 II.

10

0

Interblock Test

~~

D,S 3

Grat ing Pattern ( CPO)

__ MA - No Stress

MA - Stress

C- No Stress

C - Stress

Figure 16, Percent of subjects in the MA and C groups who reported seeing illusions

whi le viewing the 10° subtended grating pattern in the interb lock test.

52

3.5

3 III ... .s 2.5 Q. .;: U III 2 .. c ... 0 1.5 It c

'" 1 .. :E

0.5

0

Interblock Illusion Descriptors

0.5 3

Grating Pattern (CPO)

-+-MA - No Stress

MA - Stress

C- No Stress

C - Stress

Figure 17. Mean number of illusion descriptors reported during the interblock test with

the 10° subtended grating pattern by both the migraine and control groups in the stress

and no stress conditions.

53

Appendix A

Recruitment Advertisements for Migraine Subjects

MIGRAINE RESEARCH University of Hawaii at Manoa Department of Psychology

----

Do you suffer from MIGRAINE?

Do you experience AURA (visual changes or disturbances) prior

to your migraine attack?

Are you between the ages of 18 and 451

Coty G'a!rzales IIJniioeosity 01' Hawaii, Dep:. ot; ..... -,droIogy 1t00000001lll1u,t Hawaii Phooe (808) 956,· 6465 E- m~il: cot~haWililledul

-, , J , . ~ j !oj ;-

• ~ ,

J. c . . ~ f

, " ; Ji •

~

54

If so.. th"rl you 'rloP,' he e g iI):e to panlJpate- <1150 ~ ",.Q'C I"l ee'f ir ~ Ifi~rc ne s,"ud)' tt • .t '" 'e ng "" O!:d<d Oy lhe ?s)'C.nOOgj' Depa-:n1:"Tt a1 tt-.e U'l r ... 'ef5I':y cJ ltc~i·.'2 I i ~ l13T1ce.

- t e r~erd1 fft.'O\.'eS'

:; Conple"tl rg a s..~~ i1g Qlll~stQJl1a Ire

:;. Ans:.·.Efi19 SorT'E' (;J.JeS.~JrDr ~ a:tot.-1: you,. r,g'a flES

=- Cornple':l rg d s:ri!l.;tI"'ior",'crd W1T'p!.U1e.~· te~ S':TJ!C) '

fo:pll.Orl'l;rof-fts ' ...... ·. 1 ze- ama1~:erl a':l el t rne: r.lJ,.r..en il!:l~ ttJ 'fOIl!

'5-24.fJ"J l1tCl"q:ell 53t o l tw l lo~ '·,ure spen'1 rl

1hll!:!: laJ01iItc('l1 <il rd ~o ttrt-'ff tnp.~ E'JCt!ofSei

10 ilrd frt.m ihe n "'6'5 ty Cof "'fi·t\·~j i ·.,,",1 I:~'

j!a d if }'Ut.1 ~ rf" ~~'H,:et1 lOr ~'e: studf l-d 1tr.~i -'9 [01rtAe~cn r;J ' .'he q l..&ofl r-.eh!

~"'''' __ w \ •• -• . :~" ...... .,. •.• ,., . ~ " ," • .- •.• w. .~ , .... " ....... . . . 'ri " ,'-_ ..,.' ~ " •

q .... . . - "", . ., .•

....... , ............. ' .. , , " .. _ ....... ,." ..... . ,

" " " ~ ; .' u ~ ~ ,

~ .~ ;

~ { :,: ~

Appendix B

Recruitment Advertisements fo r Non-Migraine (Control) Subjects

PARTICIPANTS NEEDED University of Hawaii at Manoa Department of Psychology

-----

Do you NOT suffer from headaches?

Are you between the ages of 18 and 45?

If _"II!' iartJ!'l!sted pr ...... , cont3r:.t:

Coty GOmaIes Illni lllll!ll5ity of' Hawaii, Dept_ afi hyd rology H""",rulu, Hawa ii Phone (808) 9~6465 E-m"il: artyOh"w;o;li.edUi

'!-' ;' ~

~ ., !

-g ~ , , ;\

. g ~ \' ~

55

---

If so, !hen ;oU may be elog ible to participate as a control in a 'grainc srudy that is being conducted by the Psyt:hclbgf Depart rot at the University of ~'1lii at ~'aooa_

The ' CS<.'ar.:n irwo M!s.: • Comjpl'ct:ing a sc.reening

Questionnaire

Ci Arns"'t.l!f~ sorre questio ns, Gibout '!,our 11'edcal li5!nr,'

c· CompfeJiJng a stragirtf". ",,,,,d col11lutcr-bc5cd .tu:ly

Apjpoirrt",,,,,ts ",ill be arranged at a tiTre co llIicfiicnt ",. ;oU $1~ .. 1IIl rom pel15G,oofl tolll i luf lure SIl"ll'd inl !he lcOO,atOlf'( ..-d tD em",r moel ""penscs til, and rrom t '" Unj~e,sity of Hc, .... ii will be ,pcid d yw are seicaro lor 111" stlldt' fuUrr" .' iny "'11'~IeIi:i:ln IJf tile Qocstion.ra · e

.• , ... ·.L \"'-"', '" ......... -..• ' " . ~ '"' . .... ~ ' • .., ,, -II . .... ', . .. ' r -, - . " " "C- .. . , - .... '", ,.. •

~ ,...." . , -. ~. ,,' .,., f ·.·· .. ,.- _.~ .• -... ~ .. ,. ..

.. '· ' ......... 1 , ."" . f " ,"

, , . , • , <

~ , .;;.

~ 1

~

Appendix C

Cover Letter Included In Recruitment Packet

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(';:" : 1 I

56

Appendix D

Study Information Sheet

l~ t:O K-' I .. \ 110 _' :-' II U : r

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57

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58

(fro:. '.4, J1 ~ uli lu somt'~'n~' :Lbo.ILll lh • .'> f't's CoJC. h r n'1t' ~"1 or h:m: :1:".:- c,ues lill::s l.lK' Lllhl~ n:so::an:h prq .:r;lnl. )'l:i:l m:Ly .... <r..tK1 '! hI: fol ll~'::',~ :

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59

Appendix E

Expression of Interest Form

SJD.fC"'t If

(!'OR OI'FICE CSEJ

El.pr~sion af Intu e:tor f or lll

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60

Appendix F

Migraine Questionnaire

:'1 iJ!r3l0e Q Ilt1tio nnaire

SUDjt\,"t OJ

'FOROFI:< r_ l ~ I.

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61

Appendix F

Migraine Questionnaire

~l i~ raioe Que-st ioonai re

Subit:'..::t N

:HJROFU r. L ~k )

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D YES (pk.:b(' b1Q 10 q uc~iol1 2)

o ~!O (p~ .. ;:.~ ~jp to ~tU"Jl 3)

~. :\n.~ ~ cur h~.:joj.tLb'!. ~il ol \..;:d 1U> illlt" i.1fI.J11'l n:. l:l If.t) }1lU h":,,, t: m.vrc llwl cu t l ind u f h "l· 1~ ·· ·h .t· '

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61

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73

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74

75

Appendix G

Exclusion Letter

Cot~ {i ~xr_~!l. k:!t. l j r.1d-;: a.l ~ ~uCl-nt

l!t.I· .. ~rsl ty uf I !a .... -;ul a t \~ iJr.oJo

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U()f.l ' h.lu. tH %b21

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76

Appendix H

Written Informed Consent Form

Writl~. In forrru:d C(lnll4.'Ilt For m

Dr. Ed ... ·..., P. C'h!lJn lC L: Prir':': lpii ~·""'l j l.c(l f

~ 6(!!- 1 1)56-6·~(o'?

CN~ G(l.:tl.J~ .. ( 'o-l r.\'(" tifJ.:or f~l! i :).;&-(''':6:0

Subject :J

~ FOROHTF. l S E)

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Appendix I

Rating Scale for Math Task

Mockf'41.d y lo'ln:~::.cJ

78

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S i Dje-l"l [) IfO R OFF I( f: L~ I"

Appendix J

Checkli st of Visual Illusions

Subj::1..1 II 'FOR on J . t-. L SI: '

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