Nocebo is the counterpart to the better known placebo phenomenon.1–3 In a precise and narrow sense, nocebo effects refer to new or worsening symptoms that develop after placebo treatments.4 More broadly, nocebo effects arise in response to negative health-related information, beliefs, and/or experiences that lack any specific biological impact on health or illness but can nevertheless influence outcomes through their contextualized, psychosocial significance.5,6 Many nocebo effects are due to misattribution of normal background symptoms, which can lead to treatment nonadherence, unnecessary clinic visits, or even use of additional medications to treat adverse effects.7–10 Nocebo effects have been elsewhere implicated in sick building syndrome11 and the perception of symptoms after exposure to wind turbines and powerlines.12–14
Nocebo effects may also play an important role in concussion. Until recently, concussions were largely underrecognized and dismissed, but of late, new evidence has elucidated their underlying pathophysiology and begun associating repetitive head injury among American-style football players with chronic traumatic encephalopathy (CTE), a purportedly progressive tauopathy.15,16 As such, representations of concussion have undergone a substantial transformation over the past decade, perceived nowadays as more hazardous to health than ever before. Concussion-related research has been widely publicized and ignited debates not only between scientists but also among patients, athletes, and schools,17,18 resulting in new mandates for concussion education, monitoring and treatment, changes in game play rules,19 as well as a number of litigation suits aimed at professional and amateur sporting organizations.17
While advancements in concussion-related research and clinical care are of great importance, we might also wonder whether the increasing publicity and negative representation of concussion carries any latent costs. Though worthwhile and necessary, could these efforts be unwittingly contributing to a societal nocebo effect?
In this article, we explore whether and how nocebo effects may be impacting concussions. We begin by reviewing the literature on nocebos, describing several underlying psychological and neurobiological processes.20,21 We then present a series of clinical studies supporting a role for nocebos in concussions and speculate on additional ways nocebo may impact concussion symptomatology both clinically and societally. We conclude with a discussion of how one may try to minimize nocebo effects in concussion-related care.
Psychological and Neurobiological Mechanisms of Nocebo
Over the past several years, a growing body of research has aimed to explore precisely how it is that nocebos exert their effects. Some of the primary underlying psychological and neurobiological mechanisms that have been identified include verbal suggestion, social learning, cognitive reframing, somatization, nonconscious processing, anxiety, Bayesian brain, prediction processing, and genetics.1,3,7,22–27 Below we summarize what is known behaviorally and mechanistically about nocebo effects.
Evidence From Placebo Treatments in Randomized Controlled Trials
A primary source of evidence for nocebos comes from pooled data on individuals randomized to the placebo arms of pharmaceutical trials. The development of adverse responses to placebos in clinical trials, is believed to be psychosocially and contextually mediated through nocebo effects—as inert drugs themselves do exert direct biological actions.
Adverse responses to placebos are common, occurring in approximately a quarter of subjects across various clinical trials.7 Converging evidence suggests that nocebos may even account for most adverse effects reported in clinical trials.28,29 In one systematic review on randomized, blinded, placebo-controlled trials of β-blockers, rates of adverse effects for 28 of the 33 most widely recognized complaints were nearly equivalent between those receiving placebos versus β-blockers.29 Discontinuation rates due to intolerable symptoms among individuals in the placebo arms of clinical trials are also substantial, ranging from 0.33% in acute migraine treatments, 4.75% in preventative migraine treatments,30 4.7% for antidepressants,31 and up to 10.9% in treatments for fibromylagia.32
Several factors may influence the frequency and/or type of adverse effects experienced by an individual. For instance, nocebo adverse effects seem to be more common among subjective symptoms and certain medical entities, such as pain, neurological conditions, and depression.33,34 Expectations and anticipation also likely play a role, as adverse responses to placebos in clinical trials often mirror those associated with the active drug—among depressive patients, dry mouth and drowsiness are more common with placebo tricyclic antidepressants than with placebo selective serotonin reuptake inhibitors35; among migraineurs, anorexia and memory complaints are more common with placebo antiepileptic drugs than placebos for differing drug classes36; and for subjects with arm pain, sham acupuncture is more likely to cause pain, redness, and swelling, whereas placebo amitriptyline is more likely to cause drowsiness, dry mouth, and dizziness.37
Certain negative beliefs have also been associated with a greater likelihood of experiencing adverse medication effects, such as modern health worries, perceived individual sensitivity to medications,38,39 and perception of receiving a generic versus brand or biologic versus biosimilar drug.40–42 Furthermore, there is some evidence to suggest that rates of nocebo effects may be increasing over time.43 In the case of more high-risk drugs, this observation may correspond with the contemporary trend of more thoroughly describing all potential drug toxicities on research consent forms.44
Evidence From Randomized Controlled Trials Comparing Two Types of Information About Adverse Effects
A handful of studies have also assessed whether medication-related information provided directly to individuals could impact the frequency of adverse effect reporting. In a multicenter study evaluating aspirin or sulfinpyrazone for unstable angina, the possibility of gastrointestinal adverse effects was mentioned in the consent forms at some clinical sites but not others. Correspondingly, withdrawal rates due to gastrointestinal adverse effects were six times greater among individuals warned about these adverse effects in advance.45
In another large analysis of statins, subjects participated in one of two clinical phases: a placebo-controlled, doubled-blinded, randomized phase versus a nonblinded, nonrandomized, open-label phase. Rates of statin-associated muscle symptoms were equivalent between those receiving statins and placebos in the blinded, randomized portion of the study, but significantly higher among statin users versus nonusers in the nonblinded, nonrandomized portion.46
The impact of adverse information regarding medications has also been prospectively evaluated. In one study, sexually active men with a history of benign prostatic hyperplasia were randomized to receive finasteride labeled as “compound X” either with or without counseling on its potential sexual adverse effects. One year later, those who had been forewarned of sexual adverse effects reported sexual dysfunction nearly three times as often as those who had not (43.6% vs. 15.3%).47 In a second study, men newly diagnosed with cardiovascular disease were randomized to start atenolol under three different conditions. Group A was not informed of the drug's name, group B was informed of the drug's name, and group C was told of the drug's name and potential sexual adverse effects. Three months later, the incidence of erectile dysfunction was 3.1% in group A, 15.6% in group B, and 31.2% in group C.48
Studies such as these demonstrate how information about adverse effects can be an active component of any treatment.49 When patients (and/or prescribers) are cognizant of the perceived adverse effects of a drug or are explicitly informed of specific adverse effects, additional symptoms may develop.
Evidence From Randomized Clinical Experiments
Another body of nocebo literature has prospectively generated clinical nocebo effects through behavioral experiments. Psychological mechanisms used here include direct verbal suggestion, learning through experience, social learning, and classical conditioning.
Verbal Suggestion
Direct verbal suggestion is among the most straightforward means for generating a nocebo effect. Studies has demonstrated, for example, that giving asthmatics nebulized saline labeled as an irritant can worsen respiratory function and precipitate bronchoconstrictive attacks50 and that injecting saline labeled as an allergen into patients with food allergies can cause allergic symptoms.51 Furthermore, among laboratory studies involving healthy subjects, headaches have been induced by simulating passage of an electrical current through one's head along with the false message of its headache-promoting effects,52 and symptoms of headache, nausea, itchy skin, and drowsiness have been elicited after exposure to an inert substance paired with advance warning of these specific symptoms.53,54
Negative verbal suggestion can even negate the effectiveness of valid treatments. Administering nitrous oxide or topical analgesia along with the false message that these interventions worsen rather than alleviate pain results in increased rather than decreased pain.55,56 A similar pattern of worsened rather than improved muscle tension has been observed when pairing negative information with a commonly used muscle relaxant.57
Previous Experience and Classical Conditioning
Nocebos can also be learned through previous experience. Experimenters in one study induced a positive or negative treatment experience with an inert “topical analgesic patch” and then exposed healthy subjects to a novel, inert “topical analgesic patch” days later. In response to the new patch, those with the negative treatment history reported higher pain ratings than those with a positive treatment history.58 Failure to benefit from one treatment was found to carry forward and negatively affect outcomes from a subsequent treatment in this study.
Additional studies suggest that these carry-over effects can generalize to novel, dissimilar treatments. After a negative experience with an analgesic patch, negative experience with an analgesic ointment may be more likely.58,59 Both conscious and nonconscious mechanisms (eg, associative learning) may be at play here. A number of psychological variables, including anxiety, depression, and locus of control, may further contribute to this form of learning.60
At least one study has evaluated associative learning with regard to adverse medication effects. When participants were given amitriptyline or a placebo paired with a novel-tasting drink for four nights, those receiving amitriptyline developed more adverse effects than those receiving placebo. After a washout period, although subjects in both groups subsequently received placebos and the novel-tasting drink, those originally assigned to the amitriptyline group reported more adverse drug effects.61 At this time, the persistence of such effects is not known.
Nocebos can also be generated through more standard classical conditioning paradigms. In the pain literature, visual cues repeatedly paired with experimentally delivered thermal pain can subsequently trigger pain when administered in isolation.62 Similar results have been demonstrated after repetitively pairing a foul-smelling odor with carbon dioxide (inciting transient, distressing respiratory symptoms) such that individuals later exposed to the odor alone experience respiratory distress.63 Further imaging studies on conditioned nocebos have shown that the neural pathways for these effects can be elicited independent of conscious awareness.64 The associative strength between stimulus and response depends on numerous factors, including the frequency of association, intensity of the adverse outcome, and the relevance of cues.8
Within the clinic, anticipatory nausea and vomiting among chemotherapy patients may be the best known example of a classically conditioned nocebo. After repeated exposure to chemotherapy paired with consistent environmental cues (the oncology clinic, a nurse administrating chemotherapy), the environmental stimulus alone can trigger emesis.65,66
Social Contagion
Social processes have also been identified as means of generating and propagating nocebos. Observational learning is one such mechanism. Viewing video clips of itch-related images or people scratching has been found to induce itchiness and spontaneous scratching.67,68 Subjects exposed to a demonstrator feigning yawning, scratching, and wincing after inhalation of an inert substance can elicit similar symptoms after exposure to the same substance.53,54 The social phenomenon of mirroring, which will be described further hereinafter, may be at play here.
One study explicitly demonstrated how nocebos can be transmitted from peer-to-peer. In this study, a single member of a group of subjects was falsely informed of the risk of altitude headache before relatively low-altitude hike. Before the ascent, this information was spontaneously shared with some, but not all participants. Those exposed to the negative information, constituting a “nocebo group,” reported much higher rates of headache than those who had not been exposed to this information.69 One might imagine such social infection becoming even more powerful in the present era of instantaneous information and mass social media.
Evidence Concerning Broad Societal-Wide Nocebo Effects, Implications for Public Health
Nocebos can also exert their influence more broadly in communities, as suggested by cases of public health scares subsequently attributed to psychogenic mechanisms.
During the late 1990s, a high school teacher in Tennessee developed headaches, nausea, shortness of breath, and dizziness after noticing a gas-like smell. The school was subsequently evacuated and nearly 100 students and staff presented to the local emergency department for what was subsequently believed to represent a case of mass psychogenic illness.11 Several years ago in Western New York State, 19 teenagers presented with the sudden onset of tic-like symptoms. Despite much initial fear regarding the possibility of environmental contamination, the symptoms were ultimately deemed psychogenic in origin, a functional neurologic disorder disseminated among peers.70
To our knowledge, the last systematic documentation of mass sociogenic illness was performed 44 yrs ago: it reported more than 200 cases.71 Some common features of this phenomenon includes significant anxiety, membership in a cohesive group, female sex, rapid onset and recovery of symptoms, spread of symptoms through sight, sounds, or oral means, as well as chronologic transmission of symptoms from individuals of higher social status to lower social status.72
The media and lay press have also been recognized for their role in disseminating sociogenic illness.5 For example, several symptom outbreaks initially attributed to environmental sources, including infrasound (subaudible) from wind turbines,6 electromagnetic field emission from powerlines,12 and aerial spraying of pesticides,73 were later believed to be psychogenically mediated.74 In these specific cases, epidemiologists subsequently observed that the frequency of complaints tended to increase after significant media coverage,75 with density of symptom reporting geographically clustering in regions receiving the most negative press.5 Public distrust, controversy, and uncertainty regarding the diagnosis seemed to further augment the potency of nocebo responses in these cases.70,74,76
The impact of negative publicity regarding medication adverse effects has also been recognized. After negative press about a pharmaceutical company's decision to change one of the inert ingredients in a thyroid medication in New Zealand, rates of adverse effect reporting for the drug rose 2000-fold and then dropped again after the company announced plans for a new formulation.77,78 Further studies associate statin adverse effect reporting and discontinuation with the intensity of negative statin-related coverage79 and a negative tone in statin-related news stories.80
Evidence From Neurological Laboratory Experiments
Several central and peripheral biological mechanisms are believed to underlie nocebos. Functional magnetic resonance imaging for one has enabled a glimpse into some of the higher-order brain mechanisms implicated in nocebo effects. Studies on nocebo hyperalgesia have shown activation in circuits engaged in the cognitive evaluation and sensory experience of pain—including the prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, thalamus, insula, and periaqueductal gray.81–84 Regarding the role of negative cognition specifically, one study used negative expectancy to abolish the effectiveness of the μ-opioid agonist remifentanil and observed increased activity in the hippocampus, a pattern markedly different from when remifentanil administration was delivered with positive expectancy.85
Emotional circuitry also seems to be involved in nocebo hyperalgesia with studies demonstrating activation of the amygdala and hippocampus during pain anticipation and painful stimulation.83,84 Downstream effects of nocebo-generated anxiety have been observed in several studies. This includes release of the stress-hormone cortisol86,87 and cholecystokinin (CCK), a peptide hormone facilitating pain neurotransmission.87,88 Further studies have elaborated discrete steps along this biochemical pathway, demonstrating that the benzodiazepine diazepam, by lessening anxiety, can block both hypothalamic-pituitary-adrenal axis hyperactivity and CCKergic effects, and administration of proglumide, a CCK receptor antagonist, mediates the CCK-hyperalgesic component of nocebo effects, but not the anxiety components.87 Further positron emission topography studies have associated nocebo hyperalgesia with decreased release of endogenous opioids and dopamine.89,90
Neurobiological Theories on Somatization and Prediction Processing
Other theories of somatization and misattribution have been used to account for how negative information can influence individuals' interpretation of and/or response to their bodily sensations. Sensations (tingling or warmth) and symptoms (fatigue, dizziness, discomfort, etc.) are a natural part of everyday life, occurring commonly even among members of the general, healthy population.14 However, in context of negative beliefs and cognitive framing, expectations, and fears, one may be led to preferentially attend to specific symptoms and sensations, which may be benign or may have otherwise gone unnoticed.91–94 Downstream, this can cause symptom misattribution and/or amplification. Several factors, in addition to negative beliefs and anxiety, may increase the likelihood of this occurrence, including one's degree of baseline symptoms available for misattribution and traits of negative affectivity, such as neuroticism.8,95–97
Novel theories in computational neuroscience have attempted to further explain this process through discussions of the Bayesian brain.27,34,98–101 Bayesian probability theory offers a normative framework for modeling how an observer combines information from multiple cues and prior knowledge in the world to make perceptual inferences. The brain is thereby perceived as a “prediction processing” or “interferential device.”27,101 When a mismatch occurs between top-down neutrally encoded predictions and bottom-up sensory input, a “prediction error” occurs and hypotheses are revised. Much of this activity takes place nonconsciously.
In a predictive system, previous negative experiences with medical treatments/interventions are important. Previous exposure to medical treatment and its adverse effects will generate a set of probabilities associated with sensory cues (eg, pill shape, color, and taste). These associatively learned patterns then create a framework by which stimuli from new incoming sensory information (pill, capsule, injection) are incorporated and experienced. As such, especially in the case of chronic, subtle symptoms in certain contexts, minimal interoceptive signals could be perceived as significant symptoms in some cases, or in others, the brain could nonconsciously induce a visceral symptom that matches a top-down hypothesis.27
Evidence Concerning Genetics
A small growing body of research has also begun looking at the impact of genetics on nocebo responses. Much attention here has focused on an enzyme involved in dopamine catabolism, catechol-O-methyltransferase, for which varying combinations of valine-methionine (val/met) alleles can impact enzymatic activity, dopamine availability, and thus nocebo and placebo responses.102 The majority of the population possesses the val/met polymorphism. Those possessing the val/val polymorphism have increased enzymatic activity, decreased dopamine activity, and are more likely to exhibit nocebo responses,103 whereas those possessing met/met polymorphism have the opposite pattern leading to more robust placebo responses.26 In one study, val homozygotes reported greater specific drug adverse effects, general adverse effects, and score higher on somatosensory amplification scales compared with those carrying other allele combinations.103 In this same study, no differences in psychological variables (eg, anxiety) were noted between groups.103 The list of genes potentially related to placebo continues to expand, most recently from 11 genes102 to now nearly 30 genes.104
Nocebos in Clinical Concussion Care
Having outlined several of the psychological and neurobiological mechanisms underlying nocebo effects, we will now review several means by which nocebo effects may impact concussion outcomes. Here, we review available literature and speculate on several additional hypothetical mechanisms. A summary of the various ways nocebos may play out in concussion is presented in Table 1.
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TABLE 1: Nocebo effects in concussion
Negative Expectations
Converging evidence from both epidemiological and clinical trials suggest that negative expectations may adversely affect concussion outcomes. For example, in a series of cross-cultural studies, it was noted that although Canada, Greece, and Lithuania report similar rates of head injury, Canadians generally expect concussion symptoms to last for months to years longer than Greeks or Lithuanians, and corresponding experience a much higher rate of persistent postconcussive symptoms.105,106 In a series of prospective clinical studies, beliefs that symptoms will negatively impact one's life, last a long time, or be beyond one's control have all been associated with less favorable concussion outcomes.107–109
Verbal Suggestion and the Therapeutic Encounter
The specific words spoken during a clinical encounter may also impact outcomes after concussion. For example, calling attention to one's history of traumatic injury and its potential adverse cognitive effects just before neuropsychological testing has been associated with lower self-rated cognitive function,110 as well as performance on indices of attention and/or working memory,110–113 consistent with the construct stereotype or diagnosis threat as defined elsewhere.114
Furthermore, although per medical definitions, “concussions” are considered synonymous “mild traumatic brain injuries,” members of the public typically believe that the latter reflects a greater injury severity.115–117 As such, it is possible that referring to a head injury as a “traumatic brain injury” rather than a “concussion” might actually worsen clinical outcomes.
Misattribution
The role of misattribution, through what has been referred to as the “expectation as etiology” or “good old days bias,” has also been frequently discussed with regard to concussion symptoms. Individuals may overestimate their preinjury to postinjury symptom change, endorsing current symptom rates similar to that reported in the general population, while underestimating their preinjury prevalence of symptoms.118–121
Misattribution is a common phenomenon, whereby ordinary aches and complaints of daily life that are easily overlooked become more prominent because of worry and anxiety. In certain settings after an injury has occurred, these symptoms and complaints can commonly be attributed to the injury. Misattribution is likely more frequent with clinical entities, such as concussion, where symptoms are nonspecific, diffuse, and exist at high base rates in the general population.122–124 Misattribution may also be more common when accompanied by concrete negative beliefs of expectations (“I have a brain injury”).
As a hypothetical case, if an individual with strongly held concussion-related concerns sustained the most minimal of force impacts to the head, negative thoughts and feelings could bolster what would-have-been subthreshold sensations into consciously experienced symptoms. A sporadic, benign headache could thereafter be interpreted as evidence of ongoing injury, or normal everyday forgetfulness could be perceived as resurgence of neuronal dysfunction.
Repercussions of Fear and Anxiety
Anticipatory anxiety is another primary driver of the nocebo effect. A handful of studies to date has associated postconcussive symptom burden with experimentally induced stress, daily stress, and anxiety sensitivity.125–127 Studies have also associated tendencies toward somatization with postconcussive symptom burden.128–131
When anxiety leads to avoidant behavior, concussion recovery can be affected in a more downstream fashion as well. The case of cogniphobia can be illustrative here.132 The phenomenon originally referred to headache sufferers who worried that because of a personal vulnerability, pushing through concentration or problem-solving difficulties could be unsafe and/or detrimental to health.133 In concussion, cogniphobia has been associated with avoidance of physical activity and traumatic stress triggers, as well as lower performance on memory testing.132 Analogous patterns may play out with photophobia or cervical kinesiophobia after concussion.
While often making one more comfortable in the short term, avoidant behaviors ultimately tend to worsen symptoms. Theoretically, we may consider whether some degree of “learned nonuse” has occurred, whereby because of habituated avoidance of a specific behavior (eg, mental exertion), one's function remains far below one's potential.134 Such behaviors may prevent resiliency through utilization of one's cognitive reserve. Corresponding brain networks could subsequently atrophy or undergo negative neuroplastic changes with protracted disuse or avoidance.135
In support of this notion, studies of prolonged complete rest after concussion have generally shown worse outcomes when compared with relative rest,136,137 and multiple studies now support a role for practice-based therapy as a primary treatment basis for rehabilitation.138
Societal Nocebos in Concussion
A role for society-wide nocebo effects also deserves consideration in the context of concussion. As mentioned previously, with emerging data on the pathophysiology and implications of a head injury,15,16 concussions have undergone a major reconceptualization in recent years, viewed as significantly more hazardous than in the past. Emerging concussion-related data and knowledge have been disseminated to the public in two parallel routes, a coordinated public health campaign and media coverage focused predominantly on CTE. Hereinafter, we describe these efforts, situate data on public perceptions of concussion in this context, and entertain whether some forms of negative concussion-related publicity may be unintentionally fostering nocebo effects.
Public Health Campaigns on Concussion
In the past decade, several public health campaigns have aimed to increase concussion-related awareness and surveillance.139 Through coordinated efforts between public health institutions, sporting organizations and schools, protocols for concussion monitoring, and care have been mandated across many levels of play.140–142 In most initiatives, before a season's start, athletes are taught the mechanisms and consequences of concussion in the form of didactic presentations or case-based videos143,144 such that if they subsequently sustain a head strike, they will be more aware of what to expect.
The educational success of concussion-related public health campaigns has been mixed. Some preliminary data suggest that these initiatives have reached their intended audience.145 However, in some studies, those receiving concussion training have not demonstrated improved concussion-related knowledge compared with those who have not.146 In one study, having sustained a previous concussion, undergone formal concussion training, or participated in collegiate or semiprofessional athletics were all associated with lower, rather than higher accuracy of concussion-related knowledge.147
Media Representation of CTE
The media has played a parallel role in disseminating concussion-related information to the public. Discussions of CTE148,149 in American-style football players and athletes specifically have received a remarkable degree of attention in the lay press. In one study assessing online news trends, CTE was found to be the most frequently reported consequence of concussion.150 This predominance likely reflects a variety of factors. Professional athletes and professional sports tend to be inherently newsworthy, and secondly, the CTE storyline—progressive psychological and cognitive deterioration of former professional athletes—tells a compelling human interest narrative.
Although the evolving science of CTE is of great significance,151–153 its representation in the media has been criticized by some as biased, overly simplified, and alarming. A primary argument contends that by having most news articles on concussion discuss CTE as a consequence provides an excessively negative representation of a single concussive injury,18,154 as the far more common trajectory after concussion, for example, headache and/or dizziness followed by recovery, is largely absent from these reports.
The media has been critiqued for prematurely representing symptoms attributed to CTE and the neuropathology of CTE as causally related and for downplaying the role of a significant selection bias in the current case series literature.18,147,154 These actions may inappropriately suggest to the public that nearly anyone with a connection to American-style football, or history of playing contact sport, have reason for extensive alarm.155,156
Still, others have criticized the media for its failure to acknowledge the many additional factors that could enhance the true risk of repetitive trauma or adversely impact the long-term neurologic health of professional football players, including sleep apnea, depression, chronic pain, number of previous exposures to anesthesia, comorbid cardiac and medical conditions, untreated mental health conditions, performance-enhancing drugs, and/or substance abuse.18,154,157–159
Taken as such, the media's representation of CTE in present-day America is likely raising public concern over CTE and arguably may be doing so to a greater degree than is currently warranted based on the state of the science. Elsewhere, it has been noted that in times of great public fear, controversy, and mistrust, as is the case with CTE presently, societal nocebo effects are more likely to manifest.70,74,76
Public Perceptions of Concussion
The public likely derives its concussion-related information from a variety of sources. According to a number of surveys, Internet searches, television (including football games and boxing matches), and films were among the most common means for gathering information about head injury.146,160 Researchers have further noted the persistence of blatant misperceptions regarding head injury among the public. For instance, in one survey, a third of respondents believed that a second blow to the head could help individuals remember things previously forgotten.147 In another, more than 90% of respondents endorsed the possibility that after brain injury, an individual could be normal in every way aside from being able to recognize family members or past events.160 Rather than representing any neurobiological possibility, such notions resemble popular Hollywood storylines,161 suggesting further the likely potency of media representations.
On the whole, it seems that the public's perception of concussion is more negative than that of the biomedical community's.162,163 Although most individuals sustaining a concussion are known to fully recovery within several weeks,164 a predominance of lay people expect symptoms to last months to years and believe that concussions symptoms can “never be cured,” symptoms reflect permanent brain damage, and symptoms may worsen over time.146,147,165 Many also believe symptom exacerbation after concussion to be dangerous although no empirical data exist to support this notion.166
Empirical findings, such as these, do raise the question as to whether the way in which concussions are framed to the public may contribute to a collective nocebo response or a collective worsening of symptoms among concussed individuals.167 Explicitly stated here, we are not stating that CTE pathology is related to nocebo effect, but rather that the public perception of the likelihood of CTE from a single concussive exposure is overstated.
The Potential for Even Bleaker Consequences
An additional, albeit highly controversial, role for nocebo in concussion concerns the relationship between CTE and suicide. This topic should be discussed in an academic manner. In the past several years, reports of American-style football players posthumously diagnosed with CTE after death by suicide have been widely publicized in the media. Given the possibility that suicide rates within this population of athletes may have increased in recent years,157,168,169 questions have arisen regarding the role of exposure to negative information as a co-contributor along with complex comorbid biopsychosocial issues and primary brain pathology.
At present, CTE is not diagnosable in living persons. However, dismal representations of CTE may fuel a fatalistic attitude among certain at-risk individuals.170,171 For the past few years, former players, who have recently attempted or died by suicide, have disclosed fears about CTE in advance,172,173 although no one can be certain of the specific role if any of those nocebo effects could have in any of these cases.
Heavy media coverage of celebrity suicides is elsewhere known to be a major risk factor in suicide contagion, steering highly vulnerable individuals toward completion of the act.174,175 The question of a copycat element has been raised with regard to the suicide of former football players as well. Several have died by gunshot wound to the chest. Before death, one player expressed a desire to end his life by this means as opposed to another, so as to preserve his brain for autopsy evaluation of CTE.176 Two others have subsequently died by similar means, including a former high school player who also, before his death, requested his brain be evaluated for CTE.177,178 Any role for a “copycat” phenomena in this population is unclear, and ascribing all such events to “copycat” actions could be overly simplistic.156,179 No strong data exist in this debate, yet caution mandates a transparent yet logical approach to discussion and symptom-based treatment in those believed to have an elevated risk of CTE.
Strategies for Dealing With Nocebo Effects in Concussion
In light of the heightened concern surrounding concussions in the present day, it may be of benefit for clinicians to make conscious efforts to minimize the impact of nocebos. Some of these practices are already part of standard multidisciplinary care.
Working With Beliefs and Expectations
Given the lay public's view of concussion symptoms as more functionally limiting and persistent than what has been demonstrated in research studies,146,147,165 careful elicitation of a patient's expectation regarding concussion recovery may be a useful starting point in a given clinical encounter. False beliefs should be carefully corrected. Framing may be important as well, emphasizing (positively) that a large majority recovers fully within weeks to months, as opposed to (negatively) that a minority does not recover within week to months.
In addition to correcting incorrect beliefs as they emerge in clinic, clinicians can also make deliberate efforts to provide positive and realistic expectations for recovery. In support of this effort, the literature regarding support and positive-expectation setting after acute concussion has, on the whole (though not in all cases), been favorable.180–184 In these studies, clinicians offered emotional support and provided reassurance that symptoms are generally benign and temporary shortly after presentation to the emergency department, resulting in reduced symptom burden, decreased anxiety, and improved functional outcomes as compared with standard care.180–182 Whether positive expectations could be of benefit to those with persistent, prolonged symptoms known to have a poorer prognosis185 is not known. Generally, expectations need to be balanced by trust and honesty. Setting inappropriately positive expectations can ultimately hurt patients, leading to a downward spiral and belief that one's particular condition is untreatable.34
Additional strategies for generating positive expectations may include attempts to foster learning through example or by observation. Here, clinicians could offer stories of similar patients who recovered from their injury within weeks or provide more formalized examples, for example, showing video clips of patients describing their successful recovery. Again here, honesty is important in terms of the degree to which these vignettes truly match the present patient's clinical outlook.
Discussing Fears
It may also be worthwhile to ask patients open-ended question regarding their specific fears. Anecdotally, we find that many individuals, athletes in particular, harbor worries regarding CTE and their long-term physical and psychological health. We make a conscious effort to counteract such fears as appropriate or, in cases where lifetime burden of concussion is substantial, discuss the state of the current CTE literature along with a discussion on the potential risks of continued play.
Clinicians may also consider describing the impact of stress and anxiety on concussion symptom exacerbation, as characterized in a handful of clinical trials.125–127 This could be paired with a discussion of the potential utility of stress management strategies.
Fears and anxieties can also influence outcomes by adversely impacting behaviors. As described previously, specific fears regarding the dangerousness of symptoms can lead to avoidant behavior via cogniphobia, photophobia, and kinesiophobia. For these individuals, clinicians may want to explicitly relay the message that mild provocation of symptoms is benign—no empirical evidence exists to suggest otherwise.166 Clinicians may further want to explicitly name these fear-avoidance patterns, educating patients on how avoidance can ultimately worsen rather than improve function.
In cases where negative beliefs and behavioral patterns are particularly fixed, referrals for psychotherapy, physical therapy, or occupational therapy may be indicated. Psychologists can spend additional time with patients, reworking negative thoughts, feelings, and behaviors. Supervised physical or occupational therapy programs can function as graded exposure to triggers, helping patients move beyond old associations previously forged and start building new ones. Actively trying to address symptoms also likely has an empowering effect.
Care Around Disclosure of Negative Information
Clinicians may also want to take care so as to avoid unwittingly causing or exacerbating nocebo effects. Awareness of what is or is not said during the clinical encounter is of importance here. A simple example of this effort may include care around use of terminology. For example as was described previously, among the general population, the term “mild traumatic brain injury” currently retains more negative connotations than the term “concussion.”115–117 Referring to one's concussion as a “mild traumatic brain injury” as such may inadvertently worsen outcomes.
Another strategy concerns the extent of detail that we disclose when assessing concussion symptoms. Frequently, clinicians will inquire on an exhaustive list of the most common postconcussive symptoms, which may include upward of 20 individual symptoms. We know from meta-analyses on nocebo responses to placebo medications as described previously that negative expectations about specific adverse effects increase their likelihood of occurrence and that directly warning an individual about a specific effect increases the likelihood even further.7,36,47,73 With this knowledge, we ask the provocative question of whether it may be more prudent to ask a patient to report all bothersome symptoms and, unless diagnostically or therapeutically necessary, refrain from probing for the exhaustive list of possibilities.
CONCLUSIONS
In this article, we have speculated on ways in which negative concussion-related publicity may be contributing to a societal nocebo response. Growing evidence suggests that nocebos may exacerbate or prolong concussion-related symptoms via negative expectancy, diagnosis threat, misattribution, fostering of fear and anxiety, behavioral avoidance, and conditioning. Nocebo effects warrant careful consideration by clinicians working in the field.
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