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Novel Evaluation of Cerebrovascular Response in Chronic Mild Traumatic Brain Injury

Key findings

  • Functional magnetic resonance imaging (fMRI) was used to map the cerebrovascular responses to the dynamic changes in respiratory gas exchange metrics during a breath-hold challenge in patients with chronic mild traumatic brain injury (TBI)
  • The respiratory gas metrics, including the breath-by-breath changes in partial pressure of O2 (ΔPO2), CO2 (ΔPCO2) and their ratio, O2-CO2 exchange ratio (bER), were compared with cerebrovascular responses
  • Compared with controls, patients with chronic mild TBI showed significantly reduced correlations between cerebrovascular responses and bER in brain regions responsible for attention, memory, visual processing, auditory processing and more
  • Dynamic coupling of cerebrovascular responses with bER and ΔPO2 was stronger than with ΔPCO2 in both patients and controls; no significant differences were found between the two groups for correlations of cerebrovascular responses with ΔPO2 or ΔPCO2 alone
  • Average changes in bER and ΔPO2 during breath-holding significantly decreased with an increase in burden severity, and no relationship was observed between ΔPCO2 and burden severity

Reduced or delayed cerebrovascular reactivity (CVR) in adults with traumatic brain injury (TBI) is associated with poor outcomes. One way CVR can be assessed is with a breath-hold challenge during a functional MRI scan. Changes in the partial pressure of carbon dioxide (ΔPCO2) were traditionally compared with changes in cerebral blood flow and blood oxygenation level-dependent (BOLD) signals to evaluate cerebrovascular responses to the breath-hold.

Suk-tak Chan, PhD, and Kenneth Kwong, PhD, both faculty members in the Martinos Center for Biomedical Imaging at Massachusetts General Hospital, and colleagues have previously shown that change in oxygen-carbon dioxide (O2-CO2) exchange ratio is more useful than ΔPCO2 to assess cerebrovascular response to a breath-hold challenge or to characterize the low-frequency spontaneous fluctuations in brain activities of healthy individuals. The breath-by-breath O2-CO2exchange ratio (bER) is defined as the ratio of the change in the partial pressure of oxygen (ΔPO2) to ΔPCO2 between end-inspiration and end-expiration.

Building on this research with healthy participants, the team and colleagues from the Department of Neurology at Mass General recently demonstrated for the first time that this respiratory gas exchange metric of bER is better than DPCO2 for characterizing cerebrovascular responses during a breath-hold challenge in a patient group with chronic mild TBI. The researchers describe their observations in the Journal of Neurotrauma.

Study Methods

The team studied 20 individuals, 20 to 57 years old: 10 patients diagnosed with chronic mild TBI at least three months previously and 10 control subjects with no history of brain injury.

All participants engaged in a brief breath-hold challenge while functional MRI was used to measure the blood oxygenation level–dependent (BOLD) signal in the brain. PO2, PCO2 and respiration were measured simultaneously with MRI acquisition. The participants also completed the Rivermead Post-concussion Symptoms Questionnaire (RPQ) for the burden severity.

Cerebrovascular Responses to the Synergistic Effect of Oand CO2 Changes

  • Breath-hold is not a simple hypercapnic challenge
  • While cerebrovascular responses to breath-hold challenge are traditionally assessed by comparing ΔPCO2 with changes in cerebrovascular responses described by BOLD signals measured with functional MRI, dynamic coupling of BOLD signals with bER and ΔPOwas stronger than that with ΔPCO2 in both patients with chronic mild TBI and control participants who did not have a history of brain injury

Reduced Brain-Body Interaction Between Respiratory Gas Exchange and Brain Activity

  • bER is a metric related to the homeostasis of systemic arterial gases
  • In patients with chronic mild TBI, the bER–ΔBOLD correlation during the breath-hold challenge was significantly reduced in multiple brain regions when compared with control participants

Contribution of Respiratory Gas Exchange to the Severity of Post-Concussive Symptoms

In patients with chronic mild TBI, the averaged changes in bER and ΔPO2 during breath holds decreased with an increased burden severity indicated by the total scores on the Rivermead Post-Concussion Symptoms Questionnaire, and no relationship was observed between those scores and ΔPCO2.


bER is a new and useful metric for characterizing cerebrovascular response to the breath-hold challenge in patients with chronic mild TBI. Compared with ΔPCO2, bER is less affected by ventilatory volume fluctuations resulting from isolated deep breaths. The correlation between bER changes and symptom severity during breath-holding suggests a relationship between respiratory gas exchange and post-concussive symptoms. Evaluating the brain-body interaction between bER and brain activity will increase the understanding of the progression of TBI recovery and the relationship of bER with the symptomatology of TBI, potentially helping to improve the diagnosis, monitoring and rehabilitation planning for post-concussive symptoms.

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