Psychiatric and cognitive comorbidities of persistent post-traumatic headache attributed to mild traumatic brain injury

Objective To investigate the association of psychiatric and cognitive comorbidities with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). Methods A total of 100 patients with persistent PTH attributed to mild TBI and 100 age- and gender-matched healthy controls free of mild TBI were enrolled between July 2018 and June 2019. Quality of sleep was evaluated using the Pittsburgh Sleep Quality Index, while symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Cognitive impairment was evaluated using the Montreal Cognitive Assessment questionnaire, while post-traumatic stress disorder (PTSD) was assessed using the Harvard Trauma Questionnaire. Results In 100 patients with persistent PTH, 85% reported poor quality sleep, compared with 42% of healthy controls (P < 0.01). The relative frequency of probable to high risk of anxiety was 52% in the persistent PTH group vs. 8% in healthy controls (P < 0.01), while the relative frequency of probable to high risk of depression was 42% in the persistent PTH group vs. 2% in healthy controls (P < 0.01). Furthermore, 27% of the patients with persistent PTH had mild cognitive impairment while 10% had probable PTSD. Conclusions Poor quality of sleep as well as symptoms suggestive of anxiety and depression were more common in patients with persistent PTH than healthy controls. Clinicians should screen patients with persistent PTH for these comorbidities and develop treatment plans that account for their presence.


Introduction
Headache is a common sequela of mild traumatic brain injury (TBI), [1][2][3], as well as a frequent cause of chronic daily headache in the general population [4]. Few efforts have been made to assess the broader clinical picture of post-traumatic headache (PTH), [5][6][7]. The diagnosis of PTH is based on clinical criteria provided by the International Classification of Headache Disorders, 3rd edition (ICHD-3), and termed headache attributed to traumatic injury to the head [8]. Herein, PTH is characterized as either acute PTH, which develops within 7 days of the TBI and then remits within 3 months of onset, or persistent PTH, which persists beyond the 3 month-mark [8]. PTH is furthermore classified according to the severity of attributable TBI, being either mild or moderate to severe [8].
A key observation from clinic-based studies is that persistent PTH most often resembles a migraine-like headache phenotype, although some patients may report a 'pure' tension-type-like headache (TTH-like) phenotype [2,5,9]. Although the headache features of persistent PTH have been documented in multiple studies [2,5,6,9], there is a scarcity of literature on associated comorbidities [7]. These include sleep disturbances, anxiety, depression, cognitive impairment, and posttraumatic stress disorder (PTSD) [7]. From a clinical standpoint, it is important to assess comorbidities as they are likely to have an important role in the longterm management and well-being of the patient. The presence of comorbidities might also affect the choice of therapy and, thus, facilitate more informed treatment approaches.
In this cross-sectional study, we assessed quality of sleep, anxiety, depression, cognitive impairment, and PTSD as comorbidities of persistent PTH. Age-and gender-matched healthy controls were used to compare rates of poor quality of sleep, anxiety, and depression. We hypothesized that symptoms suggestive of these comorbidities would be more frequent in patients with persistent PTH, compared with healthy controls.

Study population
We enrolled patients with persistent PTH attributed to mild TBI. Patients were recruited from the outpatient clinic of the Danish Headache Center, the Danish postconcussion syndrome support group website (hjernerystelsesforeningen.dk), and from neurological departments and rehabilitation centers in the Capital Region of Denmark. Healthy non-headache controls were recruited through the Danish research subject website (forsøgsperson.dk) and posters placed at various public institutions in the Capital Region of Denmark. A trained locum doctor (HMA) was responsible for the initial screening of study eligibility by phone.
This article is part of a larger parental study that was approved by the Regional Health Research Ethics Committee of the Capital Region of Denmark (H-18011477), [5]. All participants gave written consent after receiving detailed oral and written information. The study was conducted at the Danish Headache Center in accordance with the Declaration of Helsinki [10], with later revisions. The study was also approved by the Danish Data Protection Agency.

Inclusion and exclusion criteria
The diagnosis of persistent PTH attributed to mild TBI was established by a trained locum doctor (AI) using a semi-structured interview and made in accordance with the ICHD-3 criteria for persistent headache attributed to mild traumatic injury to the head [8]. Table 1 sets out the ICHD-3 criteria for mild traumatic injury to the head. Other inclusion criteria for individuals with persistent PTH were: 1) mild TBI to have occurred at least 12 months prior to study participation and 2) age between 18 and 65 years. Exclusion criteria were 1) any history of primary headache disorder (except infrequent TTH), 2) any history of whiplash injury or more than one TBI, 3) pregnant or nursing women, 4) cardiovascular or cerebrovascular disease, 5) pre-trauma psychiatric disorder (unless well-regulated), and 6) medicationoveruse headache. To ensure eligibility for inclusion, medical records were reviewed to cross-check for any formal medical or psychiatric diagnosis. Moreover, we required no intake of analgesics within 24 h of study participation because study participants were scheduled for functional magnetic resonance imaging and blood sampling as part of the larger parental study. Some of the data from the larger parental study have been published elsewhere [5,11,12].
Inclusion criteria for healthy controls were 1) age between 18 and 65 years, 2) no history of known head trauma or whiplash injury, 3) no history of primary headache disorder (except infrequent episodic TTH), 4) no first-degree relatives with primary headache disorder, 5) no daily intake of medicine other than oral contraceptives, 6) no history of neurological or psychological Imaging evidence of a traumatic head injury such as skull fracture, intracranial haemorrhage and/or brain contusion 2. Associated with one or more of the following symptoms and/or signs transient confusion, disorientation or impaired consciousness loss of memory for events immediately before or after the head injury two or more of the following symptoms suggestive of mild traumatic brain injury: disorders, 7) no history of structural heart disease. An in-person structured interview was performed by a trained locum doctor (AI) to determine study eligibility. Medical records were reviewed to cross-check for any formal medical or psychiatric diagnosis.

Measures
An in-person semi-structured interview was used to record data on demographics, medical history, and full clinical course. The assignment of headache phenotypes was based on review of clinical features in patients with persistent PTH and without consideration of the ICHD-3 criterion for primary headache disorders, which states "not better accounted for by another ICHD-3 diagnosis".
As study inclusion was based on a diagnosis of persistent PTH attributed mild TBI, we used terms such as migraine-like and TTH-like to describe assigned headache phenotypes. The case definitions, that were used to classify migraine-like and TTH-like days, have been published elsewhere [13].

Pittsburg sleep quality index
The Pittsburg Sleep Quality Index (PSQ-I) is a 19-item self-report instrument that comprises 7 components used to assess quality of sleep [14]. Each component is scored on a scale of 0 to 3, which is then used to calculate a global score of 0 to 21. Poor quality of sleep is defined as global scores of 5 or higher. The appraisal period is the past 30 days.

Hospital anxiety and depression scale
The Hospital Anxiety and Depression Scale (HADS) is a 14-item self-report instrument used to screen for anxiety and depression separately [15]. The range of the scale is 0 to 21, with scores of 8 to 10 being indicative of a probable risk of anxiety or depression, whereas scores of 11 to 21 indicate a high risk of anxiety or depression. The appraisal period is the past 7 days.

Montreal cognitive assessment
The Montreal Cognitive Assessment (MoCA) questionnaire is a 30-item instrument used to screen for cognitive impairment [16]. The range of the scale is 0 to 30, and scores of 26 or less are indicative of cognitive impairment. The degree of cognitive impairment is denoted as mild if scores are between 18 to 25. The MoCA questionnaire was only administered to patients with persistent PTH.

Harvard trauma questionnaire
The Harvard Trauma Questionnaire (HTQ) is a 16-item instrument used to screen for PTSD [17]. Each item is rated on a four-point Likert scale, and total mean scores of 2.5 or higher are indicative of probable PTSD. The appraisal period is the past 7 days. The HTQ questionnaire was only administered to patients with persistent PTH.

Statistical analysis
Descriptive statistics were used to summarize baseline characteristics. Continuous variable were reported as means and standard deviations (SDs), whereas categorical variables were summarized as proportions and/or percentages. Comparisons were performed using a t test for continuous variables and a χ 2 test for categorical variables. For analyses of correlation, we used the Spearman rank correlation coefficient (r s ). All statistical analyses were conducted using IBM SPSS Statistics for Windows, Version 25.0, Armonk, NY, USA.

Results
A total of 100 patients with persistent PTH and 100 ageand gender-matched healthy controls were enrolled between July 2018 and June 2019. Of 100 participants in both groups, 83 were females and 17 were males. The mean age (SD) was 36.0 (11.6) years in patients with persistent PTH and 35.8 (11.3) years in healthy controls. Furthermore, the mean BMI (SD) was 24.5 (4.1) kg/m 2 in patients with persistent PTH and 24.3 (3.7) kg/m 2 in healthy controls. A more detailed summary has been published elsewhere [5] and is also presented in Tables  2, 3 and 4. In brief, patients with persistent PTH had a mean (SD) headache frequency of 25.4 (7.1) days per month. The most common headache phenotypes were chronic migraine-like (n = 61) followed by combined episodic migraine-like and episodic/chronic TTH-like (n = 29), 'pure' chronic TTH-like (n = 9), and episodic migraine-like headache (n = 1), (Table 3).  Episodic migraine-like combined with frequent TTH-like 2 Episodic migraine-like combined with infrequent TTH-like 2 Chronic TTH-like 9 Self-Rated Health, %

Associated comorbidities
Tables 5 and 6 summarize outcome rates for poor quality of sleep, anxiety, depression, mild cognitive impairment, and PTSD. In 100 patients with persistent PTH, 85% had poor quality of sleep, 52% had at least probable risk of anxiety, 42% had at least probable risk of depression, 27% had mild cognitive impairment, and 10% had probable PTSD. Compared with healthy controls, patients with persistent PTH had a higher relative frequency of poor quality of sleep (85% vs. 42%, P < 0.01), anxiety (52% vs. 8%, P < 0.01), and depression (42% vs. 2%, P < 0.01). Another observation was that 28% of patients with persistent PTH had poor quality of sleep, as well as at least probable risk of both anxiety and depression.
In 91 patients with a migraine-like phenotype, 88% had poor quality of sleep, 56% had at least probable risk of anxiety, and 43% had at least probable risk of depression. The corresponding figures for 61 patients with a chronic migraine-like phenotype were 93%, 46%, and 56% (Table 6).

Discussion
This study presents data on comorbidities in 100 patients with persistent PTH and 100 age-and gendermatched healthy controls. When comparing the two groups, poor quality of sleep (85% vs. 42%), at least probable risk of anxiety (52% vs. 8%), and at least probable risk of depression (42% vs. 2%) were more frequently observed in patients with persistent PTH. In addition, mild cognitive impairment was present in 27% of patients with persistent PTH, whilst probable PTSD was found in 10%. These findings underscore that patients with persistent PTH often experience symptoms suggestive of psychiatric and cognitive comorbidities. An initial screening for comorbid conditions should be used in clinical practice to facilitate treatment schemes that are more carefully matched to patients. This, in turn,   would be a much needed move away from the conventional one-size-fits-all approach. Our finding of poor quality of sleep in most patients with persistent PTH is in accord with previous observations [7,18]. A recent clinic-based study found that 26% of patients with persistent PTH had a severe degree of insomnia, whilst 40% had a moderate degree of insomnia [18]. The same study also found that insomnia was more frequent in patients with persistent PTH, compared with patients with migraine [18]. This is an interesting observation because a recent web-based survey reported that insomnia is more common in individuals with migraine than non-migraine controls [19]. A meta-analysis has estimated that sleep disturbances are experienced by about 50% of individuals who sustain a TBI [20], Taken together, it is evident that poor quality of sleep is prevalent in patients with persistent PTH attributed to mild TBI.
Besides poor quality of sleep, we found that anxiety and depression are more frequent in patients with persistent PTH, compared with healthy controls. These associations have several possible explanations. For example, anxiety and depression may be independent risk factors for the development of TBI-related sequelae, such as persistent PTH. Another option is that anxiety and depression are sequelae of TBI that are unrelated to persistent PTH per se. Lastly, they could indeed be linked to persistent PTH. Many studies indicate that that anxiety and depression are common sequela in patients with TBI [21,22]. A prospective cohort study found that the relative frequency of anxiety and depression was higher in patients with persistent PTH, compared with those who had sustained a mild TBI but did not report headache [23]. Longitudinal data is required to resolve the timing of PTH, anxiety, depression following mild TBI.
An interesting finding from our study is that mild cognitive impairment was experienced by 27% of patients with persistent PTH. This is in line with findings from a prospective cohort study of patients with mild TBI [24]. The authors reported that about 60% of patients, who had sustained a mild TBI, reported at least one cognitive symptom at 6 months and 12 months post-trauma [24]. Furthermore, another study found that cognitive performance at 2 weeks postinjury was lower in patients with mild TBI when compared with healthy controls [25].
Although there are robust data that the risk of PTSD is increased after mild TBI [22,26,27], it remains unclear to what extent individuals with persistent PTH are affected by PTSD. Two small clinic-based studies have  found that about 30% of patients with persistent PTH have PTSD [28,29]. In contrast, we found that 10% of patients with persistent PTH had probable PTSD. The discordant findings could be due to differences in methodology or the pre-injury characteristics of the study populations. Nonetheless, it should be noted that some experimental data does support a possible bidirectional relation between PTH and PTSD, possibly attributed to dysfunction in pain modulatory circuits [30].

Limitations
Several limitations should be noted before considering the implications of our findings. First, we excluded individuals with a personal history of primary headache disorder (except infrequent episodic TTH) from inclusion in the control group [8]. This might have affected the observed relative frequencies of poor quality of sleep, anxiety, and depression. Indeed, there is evidence to suggest an association of migraine and TTH with these comorbidities [19,[31][32][33]. Another point, that merits emphasis, is the occurrence of pre-trauma psychiatric history in 23% of patient with persistent PTH, compared with none in the control group. This might yield higher comorbidity scores for patients with persistent PTH. However, it should be mentioned that none of the patients with persistent PTH received treatment for any psychiatric disorder at the time of the mild TBI. Second, we used questionnaires for screening of comorbidities rather than diagnostic instruments. This could result in an over-or underestimation of the caseness prevalence.
In addition, we are not able to provide a detailed clinical description of the assessed comorbidities when using screeners. Third, we used a cross-sectional design, which therefore does not allow for causality to be inferred. This study should, therefore, be considered a first step in the investigation of comorbidities associated with persistent PTH. Causation should be ascertained in future prospective cohort studies. Lastly, we recruited patients with persistent PTH who had sought medical care or were involved with patient-support groups. Thus, it is plausible that our study population is skewed towards more adversely affected individuals with persistent PTH.

Conclusions
Poor quality of sleep, anxiety, and depression are more common in patients with persistent PTH, compared with healthy controls. In addition, some patients with persistent PTH have symptoms suggestive of mild cognitive impairment and PTSD. These findings underscore that patients should be screened for common comorbidities during the initial clinical assessment. Recognition of these might, in turn, affect choice of therapy and highlight the need for more active follow-up. In addition, effective management of comorbidities might be useful in improving treatment outcomes for persistent PTH.