Comprehensive Evaluation of Healthy Volunteers Using Multi-Modality Brain Injury Assessments: An Exploratory, Observational Study

Abstract

Introduction: Even though mild traumatic brain injury is common and can result in persistent symptoms, traditional measurement tools can be insensitive in detecting functional deficits after injury. Some newer assessments do not have well-established norms, and little is known about how these measures perform over time or how cross-domain assessments correlate with one another. We conducted an exploratory study to measure the distribution, stability, and correlation of results from assessments used in mild traumatic brain injury in healthy, community-dwelling adults. Materials and Methods: In this prospective cohort study, healthy adult men and women without a history of brain injury underwent a comprehensive brain injury evaluation that included self-report questionnaires and neurological, electroencephalography, sleep, audiology/vestibular, autonomic, visual, neuroimaging, and laboratory testing. Most testing was performed at 3 intervals over 6 months. Results: The study enrolled 83 participants, and 75 were included in the primary analysis. Mean age was 38 years, 58 were male, and 53 were civilians. Participants did not endorse symptoms of post-concussive syndrome, PTSD, or depression. Abnormal neurological examination findings were rare, and 6 had generalized slowing on electroencephalography. Actigraphy and sleep diary showed good sleep maintenance efficiency, but 21 reported poor sleep quality. Heart rate variability was most stable over time in the sleep segment. Dynavision performance was normal, but 41 participants had abnormal ocular torsion. On eye tracking, circular, horizontal ramp, and reading tasks were more likely to be abnormal than other tasks. Most participants had normal hearing, videonystagmography, and rotational chair testing, but computerized dynamic posturography was abnormal in up to 21% of participants. Twenty-two participants had greater than expected white matter changes for age by MRI. Most abnormal findings were dispersed across the population, though a few participants had clusters of abnormalities. Conclusions: Despite our efforts to enroll normal, healthy volunteers, abnormalities on some measures were surprisingly common. Trial Registration: This study was registered at www.clinicaltrials.gov, trial identifier NCT01925963.

Keywords: brain imaging; healthy volunteers; mild traumatic brain injury; neuroepidemiology; neurological evaluation; white matter hyperintensities.

Figures

Figure 1

Study design and CONSORT diagram.

Figure 2

Heatmap of abnormalities over selected measures for age and gender subgroups. The following methods were used to generate this figure: 1. Neurobehavioral Symptom Inventory (NSI) total score: green if ≤10, yellow to red from 11 to 63 (maximum possible score). 2. PTSD Checklist–Civilian Version (PCL-C) total score: green if ≤29, yellow to red from 30 to 85 (maximum possible score). 3. Pittsburgh Sleep Quality Index (Sleep) total score: green if ≤4, yellow to red from 5 to 24 (maximum possible score). 4. Neurological Examination: green if normal, red if abnormal (findings present on exam). 5. Sharpened Romberg Test (SRT): green if normal, red if abnormal (unable to perform to 30 seconds on any of 4 attempts). 6. Near Point of Convergence: green if ≤12.7 cm, red if >12.7 cm. 7. Brief Smell Identification Test (B-SIT): green if normal for age, red if abnormal for age. 8. Sustained Grip Strength: green if within 2SD of mean for age (70). 9. Heart Rate Variability (HRV): identified by subject matter expert as having abnormal HRV measures on 24-h Holter monitoring. 10. Electroencephalography (EEG): green if normal, red if abnormal. All abnormalities identified by clinical EEG testing in this population were generalized slowing. 11. Quantitative Electroencephalography (qEEG): green if normal, red if abnormal. 12. Eye Tracking: green if normal, yellow if abnormal performance on circular, horizontal ramp, or reading tasks 2 or 3 times over 3 testing intervals, red if abnormal 4 or more times over 3 testing intervals. 13. Vestibular: green if normal, yellow if identified by subject matter expert as having findings warranting clinical concern and further evaluation, red if identified by subject matter expert as having clinically abnormal vestibular testing. 14. Computed Tomography Angiography (CTA): cerebral blood flow and cerebral blood volume green if normal. Yellow if abnormal blood flow in 1 of 16 brain regions, red if abnormal in 2 regions (maximum observed). All abnormalities were were focal non-uniformities representing decreased arterial flow and volume. Regions were right and left frontal, parietal, temporal, occipital, basal ganglia, cerebellum, pons, and brain stem. 15. Overall MRI Impression: based on white matter lesion burden (clinical interpretation based on lesion count and size). Green if no lesions or lesions consistent with normal aging. Yellow if lesion burden greater than expected for age but unlikely to be seen at routine imaging. Orange if lesion burden greater than expected for age and likely to be seen at routine imaging. Red if severe/significant lesion burden. 16. Hippocampal and global atrophy: graded as normal (green), mild (yellow), moderate (orange), severe (red). 17. Cavum Septum, Size of Largest White Matter Hyperintensity, Encephalomalacia, Gliosis, Hypoxia/Ischemic Injury, Pineal Cyst, and Dilated Perivascular Spaces: graded as normal (green), tiny (0–3 mm) (yellow-green), small (4–6 mm) (yellow), medium (8–10 mm), large (>10 mm) (red). 18. Number of white matter hyperintensities. 19. Number of Regions with White Matter Hyperintensities: green if normal, red if abnormal in 7 of 19 regions (maximum observed). Regions were right and left frontal, parietal, temporal, occipital, cerebellum, corpus collosum genu, body, and splenium, midbrain, pons, and medulla. 20. Diffusion Tensor Imaging (DTI): green if normal, red if abnormal (fractional anisotropy and radial diffusivity >2 standard deviations outside the mean). 21. Empty Sella: green if normal, red if abnormal.

Figure 3

Age and white matter hyperintensities. Radiologists are commonly taught that one lesion per decade of life is considered normal (50).