Abstract
Philosophers, scientists and physicians alike have commented on the relationship of stress and headache for centuries. Many have attributed the onset or exacerbation of headache to a variety of stress-related emotional and cognitive states including suppressed anger (Junkerius, 1743), mental anxiety (Airy, 1870), repression and conversion (Breuer and Freud) or resentment and dissatisfaction (Wolff) (1,2). The 1970s ushered in several decades of well-designed, rigorous, interesting studies into the relationship of stress and many medical conditions including primary headache disorders. Today stress is well established as playing a significant role in headache. Both retrospective and prospective studies support the relationship as well as stress induction procedures and recent imaging research. In the current issue of Cephalalgia, Schramm and colleagues offer an intriguing new study to add to this rich, long, and ever expanding body of research (3).
Assessing the relationship of stress and headache is complex and multifaceted. The term “stress” itself has been defined and measured in many different ways, using a variety of study designs, over a range of time periods. Stress can be operationalized as the objective occurrence of challenging, unpleasant or threatening events (e.g. major life events or daily hassles), in subjective ratings measuring perception and appraisal, or on the level of biology, using physiologic measures such as autonomic reactivity and cortisol levels.
The relationship of stress, headache disorders and headache/migraine attacks may take various forms (4). Among hypotheses that have been proposed and tested, stress has been conceptualized as an etiologic factor, contributing to the first onset of a primary headache disorder. It has been seen as an exacerbating factor, associated with increasing headache/migraine attack frequency, severity or duration in individuals with a pre-existing headache disorder. And stress (and relaxation after stress) has been viewed as a trigger increasing the probability of a headache/migraine attack. In the case of migraine, it has been proposed that the perception of events and situations as stressful may be a result of changes in brain structure and function that are the result of experiencing migraine (5,6). Recent research also suggests that the perception of stress may be a premonitory symptom of an attack (7).
In the current study, Schramm and colleagues measured perceived stress and linked it to both the presence of primary headache subtypes and the frequency of days with headache. Using data from the German Headache Consortium longitudinal population-based study of citizens from three different German regions, researchers asked 5159 participants to rate their perceived stress over the preceding three months using a visual analog scale with scores ranging from 0 (lowest) to 100 (highest). They repeated assessments every three months for a period of two years. They gathered data necessary to classify respondents into one of five diagnostic categories based on International Classification of Headache Disorders, second edition criteria (8): migraine or probable migraine (14.0%), tension-type headache (TTH) or probable TTH (31.0%), migraine with coexisting TTH (10.6%), “unclassifiable headache” (23.6%) and no headache (20.8%).
The association of perceived stress with the presence and type of primary headache
Schramm et al. found that perceived stress ratings were higher in all four headache diagnostic groups in comparison with the no headache control group (average rating 41 ± 29). The highest average stress ratings occurred in the migraine group (62 ± 23.3) while the remaining headache groups had stress ratings in the 50s. Stress ratings were higher among younger and middle-aged respondents in all groups and lower in people over the age of 60. Many studies have examined the association of stressful events and perception with headache occurrence and type (9–17). In general, studies suggest that both occurrence and perception of stressful events are higher in people with primary headache than in individuals without a primary headache disorder. This pattern could arise if stressful events are associated with either an increased rate of onset or a prolonged duration of disease in patients with primary headache disorders. It is also possible that individuals with headache disorders are more likely to perceive events as stressful, a pattern of reverse causality. Findings from several studies have supported the hypothesis that individuals with severe headache appraise events more negatively, employ fewer or less effective coping strategies and perceive that they have less social support in response to major or minor life events than individuals without headache (15,16,18,19). Interestingly, when dividing “stressful events” into daily hassles and major life events, more pronounced differences between severe headache and control groups have been observed in daily hassles (minor life events) than in major life events (14).
The association of perceived stress with the frequency of headache/migraine attacks
Within each headache diagnostic group, Schramm et al. found that higher stress ratings were associated with more headache days per month. In the group with TTH, a 10-point increase in stress was associated with a 6.4% increase in headache days/month. For the migraine and combined groups, a 10-point increase in stress was associated with approximately a 4% increase in headache days per month. The association between stress and headache frequency was stronger in younger and middle-aged respondents than in older adults. Interestingly, higher perceived stress ratings were not associated with increased headache days in respondents over the age of 60, suggesting a weaker relationship between perceived stress and headache expression with increasing age Examining a similar question from a different perspective, an analysis of data from the American Migraine Prevalence and Prevention (AMPP) Study found differential reporting of both the frequency of major events and the perception of the major events as being stressful by respondents with chronic migraine (CM) versus episodic migraine (EM). Respondents with CM reported a higher number of objective major life events in the preceding year than respondents with EM and they rated those events as more stressful (20).
Stress and “letdown” as headache triggers
Though Schramm et al. did not examine stress as a trigger, many recent studies have focused on stress as an exacerbating factor or trigger for individual headache/migraine attacks. In an excellent review of triggers of migraine and TTH, Wöber and Wöber-Bingöl (21) found seven studies reporting stress as a trigger for migraine in 16%–50% of respondents and six studies found that it was a trigger for ≥50% of respondents. Among studies of TTH, they reported three studies in which stress was a reported trigger for 10%–50% of individuals and four studies in which stress was a trigger for ≥50% of individuals. There have also been five studies in migraine and two in TTH reporting that relaxation following stress is a trigger for attacks. The majority of these studies used a paper-pencil methodology, but a recent electronic diary study also provided support for the hypothesis that “letdown” following a period of stress is a potent migraine trigger using prospectively entered, time-stamped data (22).
Stress may interact with other trigger factors. Houle et al. recently reported on the complex relationship of stress, sleep duration and headache experience among participants with CM and chronic TTH and found that two consecutive days of either high stress or short sleep duration were strongly predictive of a headache/migraine attack (23). They found an additive effect where the greatest chance of an attack occurred following high stress and low sleep. They also found a “letdown” effect in that a high-stress day followed by a low-stress day was more predictive of higher headache activity the following day. Importantly, they found that two days of low stress or adequate sleep were protective against an attack.
The biology of stress and the relationship to primary headache
Psychological stress can be defined as a state of mental or emotional strain or tension resulting from the perception of adverse, demanding, threatening or dangerous circumstances. The stress response system includes components of the central nervous system, located in the hypothalamus and the brainstem, the peripheral limbs of the hypothalamic pituitary-adrenal axis, the efferent sympathetic-adrenomedullary system and components of the parasympathetic system (24,25). The system uses a range of hormones and neurotransmitters in its attempt to maintain homeostasis and activate survival responses when necessary. As Schramm et al. review, there are several models that may help us understand the interplay of the physiologic response to a perceived stressor and primary headache.
Recent imaging evidence during the premonitory phase suggests that the experience of stress may be a manifestation of the premonitory stage of an impending migraine (5). There are also theories that individuals with primary headache disorders may process stressful events and situations differently and their responses can become deregulated and maladaptive over time due to allostatic load. Individuals with migraine are continually exposed to stressors (including the migraine attack itself), resulting in changes to central and peripheral physiology and function (26). The experience of migraine itself may result in changes in functional connectivity leading to an enduring predisposition to the perception of events and situations as stressful (6,7). Some neurophysiologic studies of individuals with migraine have detected abnormal cortical excitability and information processing between attacks, whereas cortical habituation was seen as a protective mechanism against overstimulation of physiological stress. Stress might produce additional chemical changes in the cerebral cortex of sufficient degree to promote migraine attacks. However, other studies have not shown evidence of differential serotonergic, sympathoadrenomedullary, or cerebrovascular response of individuals with migraine to stressful stimuli as compared to non-migraineurs (27,28).
Implications and future directions
Studying stress is a complex undertaking. There are several ways to operationalize and measure “stress,” including objective events believed to be stressful by researchers or participants, subjective reports of the experience of stress by respondents, and biologic data. There are also several potential effects of stress on headache disorders including initiation of the disease, prolonging the disease, exacerbating the disease or triggering individual attacks, and several variables in the perception of stress that may be affected by factors ranging from sex, early childhood experiences, psychological and cognitive variables and the experience of migraine itself on the brain. Each kind of stress exposure can be measured over a range of time periods using a number of data-capture methodologies.
Schramm et al. found that the influence of stress on headache day frequency was strongest in younger and middle-aged respondents and that it lost significance over the age of 60, suggesting that perhaps older adults have learned to moderate their perception, resulting in non-stressful cognitive and physiological responses to potentially stressful events. It is vital to remember that it is perception not an objective event that causes the psychological and physiological stress response in the individual. Epictetus, a Greek sage and Stoic philosopher who lived during the first century AD, is credited with first proposing this concept. He is credited as saying “People are not disturbed by things, but by the view they take of them.” This concept has been repeated by philosophers and teachers for millennia, and today it forms a central tenant of cognitive behavioral therapy (CBT) (29,30). This provides additional support for the role of empirically supported biobehavioral treatments (i.e., stress management training, cognitive behavioral therapy, biofeedback and relaxation training) for individuals with primary headache (29–31). Other therapies gaining evidence for improving migraine management include mindfulness-based stress reduction (MSBR) and mindfulness-based cognitive therapy (MBCT) (32,33). A recent randomized controlled trial of behavioral management of triggers of recurrent headache found that a graduated exposure to selected triggers to promote desensitization (the “Learning to Cope with Triggers” program) was more effective than avoidance of triggers on measures of headache and medication consumption (34). The authors wisely noted that events that cause stress may not always be avoided; however, learning to effectively respond to those events is essential in effectively managing a chronic headache condition.
To the best of our knowledge, the Schramm et al. manuscript is the first longitudinal, population-based study to evaluate the role of perceived stress on headache frequency among several types of primary headache. The large sample size, the use of validated questionnaires and the careful analysis are notable strengths. One limitation imposed by the design of the study was that the questionnaires assessed stress as a subjective single item summary over a three-month period. The study design did not allow for a finer analysis of the relationship between stress levels and headache or migraine attacks on a shorter time scale (e.g. daily or hourly), which could yield useful information. Nonetheless, this interesting, large-scale study by Schramm and colleagues study sets the stage for exciting future work to continue to illuminate and unravel the relationship between stress and primary headache disorders as well as testing interventions that may buffer or uncouple this relationship. Future work to expand our understanding of the relationship between stress and primary headache may incorporate the following:
Footnotes
Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Conflicts of interest
Dawn C. Buse, PhD, has received grant support and honoraria from Allergan Pharmaceuticals, Endo Pharmaceuticals, GlaxoSmithKline, MAP Pharmaceuticals, Merck & Co. Inc, NuPathe, Novartis, Ortho-McNeil, Zogenix, the American Headache Society, and the National Headache Foundation.
Richard B. Lipton, MD, receives research support from the National Institutes of Health (NIH): PO1 AG003949 (Program Director), PO1AG027734 (Project Leader), RO1AG025119 (Investigator), RO1AG022374-06A2 (Investigator), RO1AG034119 (Investigator), RO1AG12101 (Investigator), K23AG030857 (Mentor), K23NS05140901A1 (Mentor), and K23NS47256 (Mentor), the National Headache Foundation, and the Migraine Research Fund; serves on the editorial boards of Neurology and Cephalalgia and as senior advisor to Headache, has reviewed for the National Institute on Aging (NIA) and National Institute of Neurological Disorders and Stroke (NINDS), holds stock options in eNeura Therapeutics (a company without commercial products); and serves as consultant, advisory board member, or has received honoraria from: Alder, Allergan, American Headache Society, Autonomic Technologies, Boston Scientific, Bristol Myers Squibb, Colucid, Dr Reddy’s, ElectroCore, Eli Lilly, Endo, eNeura Therapeutics, Informa, Labrys, Merck, Novartis, Teva, and Vedanta.