This was a cross-sectional cohort study in which participants were prospectively enrolled from November 2015 until February 2018. The data reported within this manuscript were collected as part of a larger United States Department of Defense funded study that aimed to compare clinical characteristics and brain imaging findings amongst those with PPTH vs. migraine (24-26) .
Subjects
Participants were enrolled from the Mayo Clinic Department of Neurology and from the Phoenix VA Health Care System. The Ohio State University TBI Identification Method was used to assess for a history of TBI (27). Patients who had PTH attributed to mTBI for at least three months were included in the PPTH group regardless of their mechanism of brain injury. Patients with migraine were enrolled from the Mayo Clinic Headache Center or were recruited via advertisements posted at the Mayo Clinic in Phoenix, Arizona. Healthy controls were recruited from the Phoenix area via advertisements and word-of-mouth. All participants were between 18 and 65 years of age. Headache diagnoses were made by a certified headache specialist (TS) using ICHD-3 beta diagnostic criteria (28). Patients with PPTH were excluded if they had a personal history of moderate or severe TBI, migraine, or any other headache type prior to their injury (except infrequent episodic tension-type headaches). Those with migraine were excluded if they had a personal history of TBI. Healthy control subjects had no history of any headache type (except infrequent episodic tension-type headaches) and no history of TBI.
This study was reviewed and approved by the Mayo Clinic Institutional Review Board, the Phoenix VA Health Care System Institutional Review Board, and the US Department of Defense Human Research Protection Office.
All participants provided written informed consent prior to study participation.
Sleep questionnaire
Symptoms of insomnia were assessed using the Insomnia Severity Index (ISI) questionnaire (29). The ISI is a 7-item self-report questionnaire that evaluates sleep onset, sleep maintenance, early morning awakening, sleep dissatisfaction, noticeability of sleep problems by others, degree of distress, and impact of sleep disturbance on daily functioning. Each of the ISI items is rated on a scale of 0–4; total ISI scores range between 0 to 28 with higher scores indicating greater insomnia severity. The ISI total raw score is interpreted as follows: 0-7=absence of insomnia; 8-14=sub-threshold insomnia; 15-21=clinical insomnia with moderate severity; 22-28=clinical insomnia with severe severity (29-31). Individuals answer the ISI questions based on their symptom during the last two weeks.
Headache questionnaires
Those with migraine and those with PPTH provided detailed information about their headaches including age at onset, headache duration, headache frequency, presence of aura, headache characteristics, localization, headache intensity, associated features, comorbidity, and medical and family history, using a standardized headache questionnaire developed for this research study. Participants completed the Migraine Disability Assessment Scale (MIDAS) to assess headache-related disability during the prior 90 days (32).
Hypersensitivity questionnaires
To investigate sensory hypersensitivities, all subjects completed the following: Hyperacusis Questionnaire (HQ) for assessing hypersensitivity to sound (33), Allodynia Symptom Checklist (ASC) for assessing cutaneous allodynia (34), and Photosensitivity Assessment Questionnaire (PAQ) for assessing photosensitivity (35). The HQ consists of 14 items designed to assess auditory symptoms and sound sensitivity. Items are rated on a 4-point scale (scores 0-3), with higher scores indicating greater sensitivity (ranging from 0 to 42) (33). The ASC is a 12-item questionnaire that assesses for symptoms of cutaneous allodynia during headaches. A total ASC score ≥3 suggests the presence of cutaneous allodynia, with higher scores indicating greater severity (34, 36). The PAQ consists of 16 questions that identify behaviors that are consistent with avoiding light, termed photophobia, or that are consistent with searching for light, described as photophilia. In this study, only the eight items related to photophobia were included, with higher scores indicating greater photophobia severity (ranging from 0 to 8) (35, 37).
Mood-related questionnaires
Mood-related questionnaires included the Beck Depression Inventory (BDI) for assessing depression (38), the State-Trait Anxiety Inventory for assessing anxiety (39), and the Post-traumatic Stress Disorder (PTSD) checklist in primary care (PC-PTSD) for assessing PTSD (40). The BDI includes 21 items, each rated from 0 to 3, with higher scores indicating greater symptoms of depression (38). The State-Trait Anxiety Inventory consists of 20 questions that assess how the individual feels "right now" and 20 questions assessing how the individual "generally feels". Each item is rated on a scale from 1 to 4, with higher scores suggesting greater levels of anxiety (39). The PC-PTSD is the 4-item screen for PTSD, with a total score ≥3 suggesting the presence of PTSD (40).
Cognitive function evaluation
The Trail Making Test (TMT, A and B) (41) and The Rey Auditory Verbal Learning Test (RAVLT) (42) were used to evaluate cognitive function. The TMT is a test of executive function, speed of processing, and attention. The participants were instructed to draw lines connecting letters and numbers in an order that alternated between increasing numerical value and alphabetic order (43). Trails A was presented first, followed by Trails B. The time in seconds and the logarithm of the time to complete each test were included in the TMT data (41, 43). The RAVLT is an assessment of auditory verbal learning and memory. A list of 15 words is read aloud to the participant, and then the participant is immediately asked to recall as many words as they remember (42). After 30-minutes of interpolated testing, the participant is again asked to recall the words from the first list (delayed recall) (44). For the TMT and RAVLT, each participant’s test score was converted to a z-score based on age-matched normative data (41, 42, 44).
Statistical Analyses
Descriptive statistics were used to compare demographic data and headache characteristics among groups. Frequencies were used for description of categorical variables. Fisher’s exact test was used to assess group differences for categorical data, and one-way ANOVA followed by Tukey tests were used for continuous data. The diagnostic plots showed no violation of assumptions. According to the one-way ANOVA, age was not significantly different across the three groups. Thus, age was not corrected for in subsequent analyses. Spearman’s rank correlations between independent variables and total ISI scores were calculated to assess the relationship between insomnia severity and clinical factors. A stepwise logistic regression analysis was conducted to identify clinical variables associated with insomnia symptoms. The total ISI score was the dependent variable, while the independent variables included headache characteristics, sensory hypersensitivity scores, scores on psychological questionnaires, and cognitive test results. Statistical significance was set at p-value < 0.05, and 95% confidence intervals (CI) were reported as appropriate. All analyses were performed with SPSS 25.0 (Chicago, IL, USA) software.