Effects of Subconcussive Head Impacts on Neural Integrity and Function in ADHD
Condition: Sport Injury; Attention-deficit/Hyperactivity Disorder
MeSH terms: Hyperkinesis; Athletic Injuries; Attention Deficit Disorder with Hyperactivity
Study type: Interventional

Summary: 
      The purpose of this study is to examine the acute neural responses to subconcussive head
      impacts in individuals with Attention-deficit/hyperactivity disorder (ADHD). The study is
      designed to identify the effects of 10 controlled soccer headings in college-aged soccer
      players diagnosed with ADHD and without ADHD, through the use of neural-injury blood
      biomarkers, functional and diffusion MRI, and ocular-motor function across three acute
      timepoints. The central hypothesis is that neuronal structural, physiological, and functional
      impairments from subconcussive head impacts will be amplified by ADHD. The neural-injury
      blood biomarkers neurofilament light (NF-L), glial fibrillary acidic protein (GFAP),
      ubiquitin C-terminal hydrolase-L1 (UCHL-1), and Tau will be measured in plasma, with the
      hypothesis that 10 soccer headings will significantly increase plasma NF-L levels in both
      groups at 24h post-heading compared to baseline, but this increase will be higher in the ADHD
      group; plasma UCH-L1, GFAP, and Tau levels will increase significantly after 10 headings in
      the ADHD group at 2h and 24h post-heading, but levels in the non-ADHD group will remain
      consistent throughout the time points. It is also hypothesized that repetitive subconcussive
      head impacts will impair neurocognitive function, as measured by regional changes in fMRI
      activation during working memory and attention-based tasks, in the ADHD group. Ten headings
      will significantly alter fMRI activation in the ADHD group from baseline. This impairment
      will not be observed in the non-ADHD group, rather the non-ADHD group will show consistent
      fMRI activation even after 10 headings. White matter microstructure will be measured by
      diffusion imaging metrics, with the hypothesis that 10 soccer headings will significantly
      disrupt microstructure in the ADHD group compared to baseline, but not in the non-ADHD group.
      The study will also assess neuro-ophthalmologic function as measured by the King-Devick test
      (KDT) and oculomotor function as measured by the near-point-of-convergence (NPC) in response
      to subconcussive head impacts. The hypothesis is that NPC performance will be significantly
      impaired and persist for longer than 24 hours in both groups, but this impairment will be
      greater in the ADHD group, and that the learning curve and expected improvement of KDT will
      be significantly blunted in both groups, with a display of worsening in the ADHD group.
    

Detailed description: 
      We will recruit participants on a first-come, first-served basis for the ADHD group. We will
      select age- and sex-matched controls (e.g., matched to 1st, 3rd, 5th, and 7th ADHD
      participants since this is 1:2 frequency-matched sampling) for the non-ADHD group. We propose
      to include a total of 60 participants in the study (ADHD n= 40, non-ADHD n=20).

      The study consists of 3 data collection time points in a 2-day period. The 1st day will last
      approximately 4.75 hours and 2nd day will last approximately 1.5 hours. This study design
      will enable to test outcome measures over 2 acute phases.

        -  The 1st test session takes place right before the soccer heading intervention

        -  Participants will perform the soccer heading intervention

        -  The 2nd test session takes place 2 hours after the soccer heading intervention

        -  The 3rd test session takes place approximately 24 hours after the intervention

      When written informed consent is obtained, we will use a self-reported health questionnaire
      to obtain demographic information. The information includes age, sex, BMI, race/ethnicity,
      years of soccer playing and heading experience, number and age of previous concussions, and
      sleep habits, as well as assessment of other neurological conditions to screen participants'
      eligibility. Participants who meet the inclusion criteria and are free of exclusionary
      factors will advance to the testing procedures. From 3 days before the study until the 24h
      post-heading time point, participants will be instructed to (1) take ADHD medication (for the
      ADHD Cohort), (2) refrain from consuming alcohol and recreational drugs, and (3) refrain from
      activities that involve head impacts.

      Soccer Heading Intervention:

      A standardized and reliable soccer heading protocol will be used for the experiment. A
      triaxial accelerometer and gyroscope (Triax Technologies) embedded in a head-band pocket and
      positioned back of the head to monitor linear and rotational head accelerations. A JUGS
      soccer machine will be used to simulate a soccer throw-in with a standardized ball speed of
      25mph across both groups. The ball speed is similar to when soccer players make a long
      throw-in from the sideline to mid-field. Soccer players frequently perform this maneuver
      during practice and game. Participants will stand approximately 40ft away from the machine to
      perform soccer ball headings. An average linear head acceleration from a header sits around
      20 g, while regular corner or goal kicks (~50mph) yield accelerations above 50 g.
      Participants in both groups will perform 10 headers with 1 header per minute.

      Health Questionnaire Screening:

      When written informed consent is obtained, we will use a self-reported health questionnaire
      to obtain demographic information. The information includes age, sex, BMI, race/ethnicity,
      years of soccer playing and heading experience, number and age of previous concussions, and
      sleep habits, as well as assessment of other neurological conditions to screen participants'
      eligibility. Before the first and final test session, participants will be asked to verify
      that they have slept longer than 4 hours the prior night, did not consume alcohol or
      recreational drugs within 3 days before the start of the study, did not participant in
      activities that involve head impacts within 3 days before the start of the study, and for the
      ADHD group they will be asked to provide the time of when they took their prescribed ADHD
      medication for the day. In addition, participants will complete a Participant Health
      Screening Checklist with the Imaging Research Facility (IRF) operator prior to participating
      in the imaging procedures. This checklist will screen participants for symptoms related to
      COVID-19.

      ADHD Diagnosis and Screening of Psychiatric Factors and Substance Misuse:

      We will use a two-step validation of ADHD diagnosis for both groups. Upon signing the consent
      form, ADHD participants will be instructed to submit confirmation of the ADHD diagnosis
      evaluated and assigned by their physicians. During a follow-up meeting, we will conduct a
      semi-structured diagnostic interview for both groups using the Adult ADHD Investigator
      Symptom Rating Scale (AISRS), which is a robust, valid efficacy measure of ADHD symptoms in
      adult patients. The assessment will be given by a trained examiner (a clinical social
      worker), who will be blinded from the participants' diagnosis status. We will also assess (1)
      depression, anxiety, and panic symptoms using the PHQ-9; (2) alcohol use disorder using
      AUDIT; and (3) cannabis use disorder using CUDIT.

      NPC and KDT:

      During each test session, various assessments will be conducted on each participant. First,
      ocular assessments consisting of near point of convergence (NPC) and the King-Devick Test
      (KDT) will be used to assed ocular-motor function and neuro-ophthalamolgic function,
      respectively. The NPC measures the closest point to which one can maintain convergence while
      focusing on an object before double vision occurs. Assessment will be repeated twice, and
      mean NPC scores will be used for statistical analyses. After they have finished NPC,
      participants will complete the KDT. The KDT assesses neuro-ophthalamogic function due to it's
      design of saccadic eye movements coupled with multiple facets of brain functions such as
      attention, language, and concentration. It will be administrated on a hand- held tablet.
      Participants will be given one trial "demonstration" card to practice the task. Following the
      demonstration card, participants will tap through 3 test cards. Participants will be asked to
      read aloud, left to right and top to bottom, a series of numbers on the test cards as fast
      and as accurate as they can while refraining from using his/her fingers as a reading guide.
      The 3 test cards progress in difficulty (i.e. guideline disappearance, numbers become more
      dense). The KDT records the total time, in seconds, participants spent to complete the task
      (all 3 test cards). Accuracy will be recorded by a lab personnel member who will stand behind
      the participant and record any errors (incorrect number, missed number, etc.) made during the
      testing.

      Eye Reflex Assessment (Blinktbi):

      The blink reflex is elicited when a stimulus is applied to or near the cornea, immediate area
      surrounding the canthus, the eyelashes, or directly to the peri-orbital nerves. This reflex
      is facilitated by stimulation to nerves that enter into the brainstem, loops through a number
      of brainstem and basal ganglia structures, including the reticular formation and the
      dopaminergic systems, and then out to the facial nerves as the actual blink. This provides a
      non-invasive way to monitor the integrity of the deep brain structures. It is postulated that
      by precisely measuring metrics associated with blink, data can be gathered on the field that
      will assist in detecting alterations in brain function suggestive of concussion or more
      severe brain injury. An FDA approved Eyestat device will be used for this testing.

      Blood Biomarkers:

      Antecubital vein blood draws will be performed each test session to help determine serum
      biomarker concentrations. A trained phlebotomist will thoroughly clean the inner elbow
      surface with an alcohol swab and draw 7 ml of whole blood into sterile Vacutainer tubes with
      21G butterfly needle. After the blood draw, the participant will use gauze to maintain direct
      pressure and a bandage will be provided. Plasma will be assessed by the 4-plex Simoa assay
      platform (Quanterix), which is a magnetic bead-based ELISA that allows detection of
      biomarkers in femtomolar concentrations.

      MRI Techniques:

      Once completing the MRI screening procedure, participants will undergo the following
      standardized MRI protocols.

      Diffusion tensor imaging (DTI) is the most widely used technique to study the microstructural
      integrity of white matter in vivo. DTI provides simple markers, such as mean diffusivity (MD)
      and fractional anisotropy (FA), that have been used to reflect microstructural tissue change
      during aging, neurological disorders, and traumatic brain injury (i.e., concussion). However,
      despite their sensitivity, MD and FA represent cellular diffusivity estimated by basic
      statistical descriptions that do not directly correspond to biophysiological parameters of
      the neural cellular integrity. DTI assumes Gaussian diffusion within a single microstructural
      compartment and thus has proven non-specific to axonal structural damage. To address this
      limitation, neurite orientation dispersion and density imaging (NODDI) has been characterized
      to assess microstructural integrity of axons using a non-Gaussian model with multiple
      compartments. NODDI allows researchers to measure axonal density within white matter,
      orientation of axonal dispersion, and free water diffusion. The combined approach using NODDI
      and DTI will uncover greater depth of progressive axonal degeneration in response to
      repetitive subconcussive head impacts.

      Flanker Task: The Flanker test measures participants' ability to focus attention and ignore
      irrelevant information. Therefore, the Flanker task will assess the changes in attention in
      participants over time. For this task, while in the scanner, participants will be presented
      with a set of 5 arrows above the fixation point. They will be instructed to only respond to
      the direction of the central arrow. If the arrow is pointing to the left, participants will
      be instructed to press the index button of the controller in their left hand. If the arrow is
      pointing to the right, participants will be instructed to press the index button of the
      controller in their right hand. Participants will be read instructions prior to the test and
      will be permitted to press both index buttons to assure there is an understanding. The task
      will run for a total of approximately 10 minutes.

      N-Back Tasks: The n-back task will be used to asses both verbal (letters) and visual (blocks)
      memory. For the verbal n-back tasks, while in the scanner, participants will be presented a
      series of letters, with letters being displayed on the screen one at a time. Participants
      will be instructed to answer whether the target letter is the same or different from the
      letter presented, if it the presented target is the same or different from the letter
      presented 1-back or 2-back letters prior. If the target letter is the same, participants will
      be instructed to press the index button of the controller in their left hand and if the
      letter is different, participants will be instructed to press the index button of the
      controller in their right hand. For the visual n-back tasks, the design and instructions will
      be the same, but letters will be replaced with simple abstract objects. Participants will be
      read instructions prior to the test and will be permitted to press both index buttons to
      assure there is an understanding. The n-back tasks are performed as a block design, with a
      total duration of about 15 minutes.
    

Intervention name(s): Soccer Heading; Soccer Heading
Intervention type(s): Other; Other
Intervention description(s): A standardized and reliable soccer heading protocol will be used for the experiment. A triaxial accelerometer embedded in a head-band pocket and positioned directly below the external occipital protuberance (inion) to monitor linear and rotational head accelerations. A JUGS soccer machine will be used to simulate a soccer throw-in with a standardized ball speed of 25mph. The ball speed is similar to when soccer players make a long throw-in from the sideline to mid-field. Soccer players frequently perform this maneuver during practice and games. Subjects will stand approximately 40ft away from the machine to perform the heading. Participants perform 20 standing headers with 1 header per 30 seconds. The subjects will be instructed to direct the ball back toward the JUGS soccer machine in the air.; A standardized and reliable soccer heading protocol will be used for the experiment. A triaxial accelerometer embedded in a head-band pocket and positioned directly below the external occipital protuberance (inion) to monitor linear and rotational head accelerations. A JUGS soccer machine will be used to simulate a soccer throw-in with a standardized ball speed of 25mph. The ball speed is similar to when soccer players make a long throw-in from the sideline to mid-field. Soccer players frequently perform this maneuver during practice and games. Subjects will stand approximately 40ft away from the machine to perform the heading. Participants perform 20 standing headers with 1 header per 30 seconds. The subjects will be instructed to direct the ball back toward the JUGS soccer machine in the air.
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Other
Keywords: Soccer Heading; Subconcussive Head Impacts; Attention-deficit/hyperactivity disorder