Insights Into the Pathophysiology of Neurovascular Uncoupling in Patients with Brain Lesions. (NVUCVR)

February 17, 2025 updated by: Erasme University Hospital

Neurovascular uncoupling (NVU) represents a major source of potential bias for the identification of eloquent brain regions through activation procedures in blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI).

Same region shows proper pattern in glucose metabolism in victiny of brain lesions, investigated with positron emitted tomography with radiolabeled glucose (PET-FDG) This research project aims at investigating the mechanisms of NVU by using a multimodal noninvasive imaging approach in neurosurgical patients.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Brain metabolism and blood flow are tightly coupled with neuronal activity. Changes in neuronal activity result in the modulation of glucose consumption by neurons. Both glucose and lactate levels return to their baseline instantly as neuronal activity ceases, a phenomenon known as neurometabolic coupling. Given the limited energetic reserves in the central nervous system, neuronal activity heavily relies on the finely regulated supply of glucose from the bloodstream. However, the dynamic increase in cerebral blood flow (CBF) during neuronal activation far exceeds the increase in oxidative metabolism. This relative hyperemic response ensures an increased oxygen gradient between blood vessels and tissue, providing ample oxygen supply. The close temporal and regional link between changes in neuronal activity and CBF increase is referred to as neurovascular coupling (NVC) and involves a complex cascade of events. Neurotransmitters, such as glutamate, released at synapses bind to receptors on neurons and astrocytes, leading to the release of various chemical mediators, like nitric oxide and prostaglandins, which directly act on arterial smooth muscle tone. More complex and incompletely understood signaling pathways, including Na+ and Ca2+-mediated astrocyte signaling mechanisms, are also presumed to contribute to NVC.

The tight relationship between neuronal activity and both regional blood flow and metabolism has provided the basis for non-invasive functional brain imaging methods, including positron emission tomography (PET) and functional magnetic resonance imaging (fMRI). PET using [18Fluor ]-fluorodeoxyglucose (FDG) is a technique based on the accumulation of metabolized FDG (i.e., FDG-6-phosphate) in the astrocyte-neuron complex, reflecting the level of glucose consumption. Since the seminal works of Sokoloff et al., glucose utilization is considered a valid, accurate, and quantitative indicator of the level of local neuronal activity within the brain. In contrast, fMRI, which relies on the blood oxygen level-dependent (BOLD) signal, provides indirect information about neuronal activity by investigating perfusion-related changes coupled with neuronal activity. In areas of increased CBF due to modulations in neuronal activity, oxygen delivery exceeds the rate of oxygen utilization, inducing a local increase in the oxy-/deoxy-hemoglobin ratio. This leads to a detectable increase in the magnetic-susceptibility weighted MRI signal.

One of the earliest and still recognized clinical applications of fMRI has been preoperative functional mapping of the primary sensorimotor cortex in patients with brain tumors. This technique has significantly impacted surgical planning, often enabling more aggressive approaches than those considered without functional localization. fMRI has also been increasingly used in the presurgical evaluation of patients with vascular or epileptogenic lesions. However, despite the growing use of BOLD fMRI in patients with brain lesions, this technique has major limitations that must be considered when interpreting fMRI results in such populations. The main limitation is the impairment of BOLD signal changes due to lesion-related loss of normal vascular coupling with neuronal activity, a phenomenon referred to as neurovascular uncoupling (NVU). This can result in false-negative or false-positive results in critical eloquent cortex. If neuronal activity is preserved in diseased but viable cortex, NVU is presumed to occur due to astrocytic, neurotransmitter, or vascular dysfunction.

NVU has been mainly reported in patients with high-grade glial tumors and meningiomas. In such patients, the volume of task-based fMRI signal increases has been shown to be reduced adjacent to the tumor compared to homologous fMRI signal changes in the contralesional hemisphere, despite the absence of neurological deficit. In line with experimental data in healthy subjects showing that BOLD signal may decrease as cerebral blood volume (CBV) increases, impaired cerebrovascular reactivity (CVR) in brain tumor patients may be explained by changes in local perfusion. In hypervascularized tumors such as high-grade gliomas and meningiomas, local hyperperfusion has been suggested to explain the decreased BOLD signal on task-based fMRI. However, recent studies have demonstrated that NVU may also occur in low-grade gliomas. Given the absence of hyperperfusion in this tumor type, different mechanisms need to be considered. In low-grade gliomas, the observed NVU is currently thought to be, at least in part, due to disruption of astrocyte-vascular coupling (gliovascular uncoupling). Patients with arteriovenous malformations may exhibit impaired peri-nidal cerebrovascular reserve due to high-flow shunting, making perfusion-dependent mapping signals unreliable. Epilepsy patients may also exhibit regional impairment of CVR due to dramatic increases in brain metabolism and CBF during the ictal period, disruption of the brain-blood barrier, and an acute loss of cerebral pressure autoregulation.

According to previous research, CVR can be studied through the "hypercapnia challenge" during fMRI recordings, including breath-hold fMRI (BH fMRI) and carbogen inhalation fMRI. Hypercapnia is a potent vasodilator that increases the BOLD baseline signal by detecting an increase in tissue oxygenation resulting from increases in CBF while oxidative metabolism demands are considered to remain constant. However, the influence of hypercapnia on neural activity and neurometabolic/neurovascular couplings is not well understood and remains debated. In practice, areas of reduced or absent hypercapnia-induced increase in fMRI signal on CVR maps compared to homologous contralateral activation are assumed to indicate NVU. Recent studies suggest potential advantages in using resting-state (rs) fMRI as a preoperative technique. rs-fMRI is a functional neuroimaging technique that allows the measurement of spontaneous brain activity in patients at rest. Spontaneous BOLD signal fluctuations are highly correlated in distinct and long-ranged brain regions, indicating functional connectivity within specific and highly organized neuroanatomical networks. Functional connectivity studies have also demonstrated a high degree of spatial correlation between rs-fMRI functional brain connectivity and those studied during a hypercapnia challenge. Interestingly, recent research suggests that rs-BOLD signal may be impaired in patients in whom task-based increases in fMRI signals are reduced or absent due to NVU. Therefore, alterations in functional brain connectivity studied with rs-fMRI might provide insights into the presence of NVU as studied with CVR during hypercapnia. Such findings would be of interest in clinical practice as they could avoid the need for CVR-mapping with a hypercapnia challenge.

Study Type

Interventional

Enrollment (Estimated)

40

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • patients in the study include prior imaging showing a potentially resectable intra-cerebral mass lesion. Patient has to be included before surgery, chemotherapy and radiation

Exclusion Criteria:

  • previous brain surgery
  • respiratory failure
  • Asthma
  • Claustrophobia
  • Previous adverse reaction to gadovist (contrast agent)
  • Pregnancy and Breath feeding
  • Diabetes (type I and II)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Glioma patient
As compared to the pre-surgical evaluation that brain tumor patients routinely undergo in our institution, patients are asked to undergo some additional examinations.
Diagnostic test: Functional MRI

11 minutes of Functional MRI alternating breathing Air-Room and gaz mix (5%CO2 21%O2 74%N2).

All procedure are acquired simultaneously on a single acquisition on the PET/MRI camera in the institution.

Diagnostic test: FDG-PET

Some patients who did not benefit from a FDG-PET in their clinical evaluation or more than 1 month before the inclusion in the present study will be ask to also undergo a brain FDG-PET , the dose is set at 2 Mega becquerel per Kg.

All procedure are acquired simultaneously on a single acquisition on the PET/MRI camera in the institution.

Diagnostic test: Structural MRI

Patient will benefit Different anatomical sequence of acquisition listed here : T1 , T1 with contrast agent (gadovist) , T2 flair , T2 and DSC (Dynamic susceptibility contrast) , and Time Of Flight .

All procedure are acquired simultaneously on a single acquisition on the PET/MRI camera in the institution.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Effects of Hypercapnia administration on fMRI data
Time Frame: end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
For brain fRMI data: BOLD signal variation (Arbitrary Unit from a percent change from baseline).
end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
Effects of Hypercapnia administration on PET-FDG regional standardized data.
Time Frame: end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
For brain PET-FDG: regional SUV value (Standardized Uptake Ratio) .The SUV is a mathematically derived ratio of tissue radioactivity concentration at a point in time at a specific region of interest and the injected dose of radioactivity per kilogram of the patient's body weight
end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
Effects of Hypercapnia administration on PET-FDG global data
Time Frame: end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
For brain PET-FDG: Statistical Parametric Mapping analysis (SPM) for voxel-wise comparison and multiple correlations (t-score)
end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
Effects of Hypercapnia administration on oxygen saturation (SpO2)
Time Frame: end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
SpO2 Variation: Measured in percentage points (%), reflecting the change from baseline levels.
end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
End tidal CO2
Time Frame: end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
End Tidal CO2 during the experiment allow the modelisation and quantification of MRI signal among brain tissue. End tidal CO2 pressure is measured in mmHg
end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
Breathing Rate
Time Frame: end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
Breathing Rate during the experiment allow the modelisation and quantification of MRI signal among brain tissue. Breathing rate is measure in respiration per minute
end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
Regional Cerebral Blood Volume
Time Frame: end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
CBV represents the volume of blood present in 100 grams of brain tissue at a given time. It is used to assess the vascular capacity of the brain. unit are in mL per 100g of brain tissue .A DSC (Dynamic susceptibility contrast) -MRI is needed, the sequence involves the intravenous injection of a contrast agent, usually gadolinium-based. The contrast agent passes through the brain, and changes in the MRI signal are recorded over time.
end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
Regional Cerebral Blood Flow
Time Frame: end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)
CBF measures the amount of blood flowing through 100 grams of brain tissue in one minute. This is a crucial measure for assessing cerebral perfusion and identifying areas of under- or hyperperfusion.(mL/100g/min)A DSC-MRI is needed, the sequence involves the intravenous injection of a contrast agent, usually gadolinium-based. The contrast agent passes through the brain, and changes in the MRI signal are recorded over time.
end of acquisition ( group of 40 subject estimated at 10 months after first subjet acquisition)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Tumor Grading
Time Frame: up to 2 week after last acquisition to allow Multidisciplinary oncologic commission to fix the grading status
Tumor Grading, respectively with the World Health Organisation (WHO) 2021 guideline about brain neoplasm
up to 2 week after last acquisition to allow Multidisciplinary oncologic commission to fix the grading status
Tumor Histology
Time Frame: up to 2 week after last acquisition to allow Multidisciplinary oncologic commission to fix the grading status
respectively with the WHO 2021 guideline about brain neoplasm from the surgery clinically planned
up to 2 week after last acquisition to allow Multidisciplinary oncologic commission to fix the grading status
Cerebrovascular reactivity mapping
Time Frame: up to 1 month after the last acquisition to allow processing time , all the 40 patient together
Integration of the variation in fMRI signal and end tidal CO2, and breathing rate into a quantification . The produced data are in % of MRI signal change per mmHg of CO2
up to 1 month after the last acquisition to allow processing time , all the 40 patient together
Correlation map
Time Frame: up to 1 month after the last acquisition to allow processing time , all the 40 patient together
Correlation on coregistration of fMRI and PET procedure among the brain and plotted in a linear regression. Correlation will be expressed in Spearman's "R".
up to 1 month after the last acquisition to allow processing time , all the 40 patient together
Functional connectivity
Time Frame: up to 1 month after the last acquisition to allow processing time , all the 40 patient together
Measured on resting state data acquired during the experiment , allowing to construct a functional "FC" measure of the hub connected together in the brain. Measured in arbitrary unit.
up to 1 month after the last acquisition to allow processing time , all the 40 patient together

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Erasme University Hospital

Investigators

  • Study Chair: Xavier De Tiège, MD,PhD, Laboratoire de Neuroanatomie et Neuroimagerie translationnelles Université Libre de Bruxelles

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 17, 2025

Primary Completion (Estimated)

June 1, 2026

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

January 23, 2025

First Submitted That Met QC Criteria

January 23, 2025

First Posted (Actual)

March 25, 2025

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

February 17, 2025

Last Verified

January 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SRB2024304

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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