Impact of Epilepsy on the Brainstem Adenosine Pathway and Its Relation With Arousal and Respiratory Reactivity

Conditions

• Drug-resistant Focal Epilepsy
• Epilepsy
• Healthy Controls

Eligibility Criteria

Sex

ALL

Age

18 Years - 55 Years

Healthy Volunteers

Accepted

Interventions

• 1 Hypercapnic challenge while participant is awake — PROCEDURE
  The healthy patient/subject breathes through the mouth, using a mouthpiece and a nose clip, through a device fitted with a hermetically sealed bag that measures the various parameters of his/her breathing. At the start of the test, the healthy patient/subject breathes ambient air and his or her breathing is measured. Then, after a few minutes, the healthy patient/subject is connected to the bag, breathing in a closed circuit. This causes a gradual increase in carbon dioxide (CO2) in the inspired air. During this time, breathing parameters will be measured and gas exchanges studied with each breath. The test is stopped when the end-tidal carbon dioxide pressure (PetCO2) reaches 60 mm Hg, or in the event of intolerance
• PET/MRI acquisition — PROCEDURE
  The PET/MRI acquisition will be organized into 3 parts for a total duration of 120 minutes from the injection of the radiotracer 1. Baseline (0-70 min) 2. Respiratory challenge (70-100 min) : Subjects will perform three series of expiratory breath holds (six repeats during each run). A green dot will be shown for 30 seconds, indicating that the patient can still breathe normally for 30 seconds. Then, a yellow dot appears for two seconds, indicating that the patient needs to prepare himself for an expiratory BH that shall start at the end of an expiration, and at the end of the two seconds. Then a red dot appears indicating that the patient must hold his breath while being in full expiration or inspiration. The red dot remains until the patient decides to breath again and push a button to alert us of re-breathing. Screen turns black for 60 seconds before another sequence starts (30 sec. green dot). 3. Return to equilibrium (100-120 min).

Study Details

Despite the continuous development of new antiseizure medications over the past 25 years, 30% of patients with epilepsy suffer from drug-resistant seizures and are at risk of epilepsy-related complications, like cognitive dysfunctions, sleep-disordered breathing or Sudden and Unexpected Death in Epilepsy (SUDEP). SUDEP typically occurs during sleep, after a nocturnal seizure, and primarily results from a postictal central respiratory dysfunction in patients with generalized convulsive seizure (GCS), suggesting that interaction between respiratory dysfunction and sleep state may play a role in its pathophysiology. Post-mortem data in SUDEP patients showed alteration of neuronal populations involved in respiratory control in the medulla. Accordingly, pharmacologic strategies aimed at reducing the severity of postictal respiratory dysfunction has appeared as one of the most promising way to prevent SUDEP. However, no encouraging result has hitherto been reported. Interconnections between the complex network that regulates arousal and sleep and the respiratory network are numerous. They primarily include the relation between chemosensitive regulation and arousal system to ensure asphyxia-induced arousal (i.e. arousal to elevated CO2), especially through serotonin (5HT)-dependent connections in brain stem. The link between alterations of the brainstem networks involved in arousal regulation and respiratory dysfunction has not been characterized in patients with epilepsy yet. Like 5HT, adenosine is deeply implicated in the regulation of sleep and central respiratory control. Seizures transiently increase adenosine extracellular levels. Adenosine physiological effects in the brain are mediated through the activation of two types of Adenosine receptors (ARs), A1Rs and A2ARs. Extracellular adenosine promotes sleep via A1R-dependant inhibition of glutamatergic neurons in the basal forebrain, but also via A2AR-dependant activation of neurons in the nucleus accumbens. Respiration is also inhibited by A1R and A2AR. Most importantly, it has been shown that drug-resistant epilepsy is associated with long-term alterations of ARs cortical expression. However, whether or not a similar epilepsy-related plasticity of ARs occurs in the brainstem and may participate to chronic arousal and respiratory dysfunction in epilepsy has never been investigated. Considering the tight interplay between central respiratory control, arousal regulation and brainstem adenosine, the main hypothesis of the BRAVE study is that epilepsy might result in alterations of the distribution of A1Rs in the brainstem structures involved in respiratory regulation and/or arousal control, especially in the brainstem structures involved in respiratory regulation under hypercapnic condition. The study combines clinical respiratory characterization, morphological, functional and metabolic imaging, using the hybrid simultaneous 3T MRI-PET scanner (Siemens Biograph mMR) of the CERMEP. Combining PET with anatomical and functional MR imaging enables non-invasively in vivo mapping of receptor binding and functional neuronal assessment of a physiological task in the entire brain with high spatial resolution. Investigators already performed fMRI study of respiratory centers, showing number of functional changes in brainstem regions participating to the central control of respiration, including reduced activation during breath-holding fMRI, in patients with epilepsy. The BRAVE study will use the same respiratory paradigm as the one used in this past study. PET imaging will be focused on A1R, using \[18F\]CPFPX, a selective A1R antagonist.

Key Dates

First listed

Nov 25, 2025

Start date

Jan 1, 2026

Status verified

Sep 2025

Primary completion

Jan 1, 2028

Completion

Mar 1, 2028

Study Design

Enrollment

50 participants (estimated)

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Arms

• Experimental: Patients with drug-resistant epilepsy
  Diagnosis of refractory focal epilepsy or of refractory idiopathic generalized epilepsy, as defined by the International League Against Epilepsy. The following procedures will be carried out as part of the research: * Hypercapnic challenge * PET/MRI acquisition with \[18F\]-CPFPX Baseline (0-70 min) Hypercapnic challenge (Breath holding) (70-100 min) Return to equilibrium (100-120 min)
• Experimental: Healthy subjects
  Selection of healthy subjects will be performed to ensure age and sex matching. The following procedures will be carried out as part of the research: * Hypercapnic challenge * PET/MRI acquisition with \[18F\]-CPFPX Baseline (0-70 min) Hypercapnic challenge (Breath holding) (70-100 min) Return to equilibrium (100-120 min)

Primary Outcome Measure

Comparison of the [18F]-CPFPX BPND in the brainstem structures involved in respiratory regulation under hypercapnic condition in patients with drug-resistant epilepsy with the one of healthy subjects [ Time Frame: Emission will be acquired over 90 minutes post-injection ]

Central Contacts

• Sylvain RHEIMS, PUPH
  +33472357106
  [email protected]
• Mathilde LECLERCQ, CP
  +33472355838
  [email protected]

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