Advanced Space-time Resolved Techniques for Functional Neuroimaging at 7 Tesla MRI

Background Magnetic Resonance Imaging (MRI) represents a unique tool for the in vivo study of the central nervous system. With the advent of ultra-high-field technologies, such as 7 Tesla (7T) MRI, the accuracy and reproducibility of studies investigating brain structures and functions-such as visual or sensorimotor systems-have increased considerably, increasingly enabling investigations at the single-subject level in addition to group-level analyses (PMID: 29205628).

This aspect is particularly relevant in clinical practice, which increasingly promotes the use of technologies that enable personalized diagnostic and therapeutic approaches in neuroscience. Such approaches integrate structural brain information with functional, molecular, and genetic aspects (PMID: 27613521, 35021279, 36870920).

Compared with clinical field strength systems (up to 3 Tesla), 7T MRI provides a substantial gain in signal-to-noise ratio (SNR), which can be exploited to improve image quality by enhancing contrast and/or spatial and temporal resolution.

Over the last years, 7T MRI has confirmed these advantages in structural neuroimaging, for example by identifying epileptogenic malformations not visible on conventional neuroimaging (PMID: 26778405) and morphological markers of highly epileptogenic areas (PMID: 31727747).

In functional MRI (fMRI) studies, ultra-high-field MRI has enabled segmentation of subcortical structures to reveal their selectivity to specific external stimuli, exploration of the functional organization of eloquent cortical areas, investigation of the cortex at the mesoscopic (submillimetric) scale-revealing cortical columns and laminar profiles-and characterization of cortico-subcortical functional connectivity (PMID: 35384840, 34111403).

In the clinical setting, particularly in acquired pre- or perinatal brain lesions, the use of 7T has been shown to provide benefits in characterizing functional organization compared with conventional clinical MRI systems (PMID: 30595689).

These premises support the hypothesis that ultra-high-field MRI may contribute to clarifying the pathophysiological mechanisms underlying the functional organization of malformed or lesioned human cerebral cortex, with two important potential translational implications:

To investigate connectivity between epileptogenic cortical areas and subcortical structures, which appears crucial for assessing the residual functional capacity of altered cortex and its role in managing synchronized subcortical electrical activity.

To explore cortical reorganization of eloquent areas following brain lesions, in order to better understand mechanisms of neuroplasticity.

Selected patients with drug-resistant epilepsy may benefit from surgical treatment involving resection of the epileptogenic zone. Current standards for pre-surgical assessment require a multimodal approach to accurately identify the epileptogenic zone and define its functional properties (PMID: 24099054). However, when the epileptogenic area overlaps with eloquent cortex, invasive stereo-EEG techniques are often required.

In addition to resection, epilepsy surgery provides the opportunity to perform histological studies on the resected tissue. Specific genetic and molecular alterations underlying dysplastic areas (e.g., those involving the mechanistic target of rapamycin [mTOR] pathway or SLC35A2 gene variants) are associated with characteristic histological abnormalities. However, an unresolved issue concerns the possibility that histologically abnormal cells may be present without forming a mass sufficient to generate an MRI-visible dysplasia eligible for surgery (PMID: 33542949).

Although recent classification systems for cortical dysplasias integrate histological, genetic, and MRI data (PMID: 35706131), some of this information is only available post hoc and therefore cannot be considered during the critical phase of neurosurgical planning. In this context, identifying morpho-functional patterns using high spatial and temporal resolution neuroimaging techniques, such as ultra-high-field functional MRI, could facilitate pre-surgical planning, reduce the need for invasive procedures, and contribute to the implementation of personalized treatment strategies (PMID: 34145582; 34742103; 30064388).

Regarding pre- or perinatal brain lesions, it is well established that different brain structures show varying vulnerability across different stages of the pre-perinatal period. This results in distinct patterns of injury, with predominant involvement of white matter or cortical/subcortical gray matter. The topography and severity of the lesion, in turn, lead to different clinical outcomes, particularly with respect to motor or sensory deficits and the recruitment of compensatory plasticity mechanisms (PMID: 33613420; 17254004).

As in cortical malformations, in vivo knowledge of mechanisms underlying reorganization of eloquent brain functions in acquired lesions may contribute to better understanding clinical presentations and identifying personalized rehabilitation pathways based on morpho-functional characteristics of the lesion.

The current project aims to develop and evaluate novel advanced 7T functional neuroimaging methods with very high spatial and temporal resolution to investigate minimal MRI signal fluctuations. Two complementary approaches will be pursued in parallel.

The first approach will focus on improving and optimizing the quality of structural and functional images using Deep Learning (DL) techniques for image correction and acceleration, as well as magnetic field monitoring through a field camera to characterize and correct local field perturbations responsible for image distortions and artifacts.

The second approach will involve the development of novel functional neuroimaging sequences (cine-fMRI) capable of detecting signal variations at temporal resolutions approaching that of neuronal action potentials. Cine-MRI techniques have thus far been applied primarily in animal models and in two-dimensional imaging (PMID: 36227975; 36227975).

Cine-fMRI will be implemented on the 7T MRI system for whole-brain studies. This technique enables dynamic imaging based on the assumption of repeated signal behavior following a specific trigger, such as an external or internal stimulus in functional MRI. Such stimuli may include neuronal events elicited externally or generated internally, such as epileptogenic activity.

Because these neuronal events are unpredictable, pseudo-random spatial encoding is required for retrospective data sorting and reconstruction into consistent images for subsequent processing.

For data acquisition, ZTE and Looping Star sequences will be explored, as both are compatible with the cine-fMRI approach. ZTE is a 3D sequence with spiral sampling that enables detection of potential direct functional fluctuations (i.e., not dependent on the BOLD effect as in conventional fMRI sequences). Looping Star is based on a multi-gradient echo sequence that allows pseudo-random data sampling with conventional T2*-weighted BOLD contrast.

After validation and optimization in phantoms and healthy volunteers, these techniques will be applied in functional studies in both basic neuroscience and two clinical populations: patients with drug-resistant epilepsy who are candidates for epilepsy surgery, and patients with acquired brain lesions.

The study will be structured into four Work Packages (WPs). WP1 and WP2 will focus on the technological development of novel processing techniques and imaging sequences for brain imaging. These two WPs will operate in close interaction, continuously informing each other and exchanging results bidirectionally throughout the project.

WP1 - Development and implementation of state-of-the-art image correction approaches. IMAGO7 and IRCCS Stella Maris, in collaboration with GEHC and THI, will develop and implement on the 7T MRI scanner new methods to enhance image quality based on: a) Deep learning (DL) algorithms to accelerate acquisition, reduce noise, and mitigate subject motion effects; b) Correction of geometric distortions through offline monitoring of local magnetic field inhomogeneities using a dynamic field camera, a device capable of directly recording the magnetic field during pulse sequences and simulating the presence of the subject without the subject being physically inside the magnet.

WP2 - Development and implementation of cine-fMRI sequences. GEHC and THI, in collaboration with IMAGO7, will lead WP2, which will focus on the development, implementation, and optimization of innovative cine-fMRI sequences on the 7T MRI scanner.

WP3 - Implementation of UHF-MRI techniques for Neuroscience. WP3 and WP4 will provide data to support and validate the implementations developed in WP1 and WP2 through their application in basic neuroscience and clinical studies. Activities within WP3, conducted in collaboration between the University of Pisa, IRCCS Stella Maris, and IMAGO7, will involve translating the newly developed functional neuroimaging methods into advanced neuroscience applications, including both task-related studies and investigations of cortico-cortical and cortico-subcortical connectivity.

WP4 - Validation and clinical translation of advanced 7T MRI methods in subjects with epilepsy or malformed/lesioned brain areas. AOU Meyer IRCCS, together with IRCCS Stella Maris and the University of Pisa, will conduct WP4. This WP will focus on the clinical application of the advanced fMRI techniques developed in WP1 and WP2 for: non-invasive localization of cortical responses, characterization of epileptogenic areas, genotype-phenotype correlations.

The application of the techniques developed in WP1 and WP2 across two substantially different contexts-basic neuroscience studies in highly cooperative healthy volunteers and clinical pediatric populations, where intrinsic image noise may be considerable-is essential to evaluate the robustness, versatility, and added value of these methods under markedly different experimental conditions.