Connectome-guided Onco-functional Resection With Tractography-Extended Neuronavigation in Brain Tumor Surgery (CORTEx)

Connectome-guided Onco-functional Resection With Tractography-Extended Neuronavigation in Brain Tumor Surgery Involving Eloquent Regions: a Prospective Single-centre Cohort Study Integrating Advanced Diffusion MRI Into Clinical Neuronavigation for Gliomas and Metastases

Brain tumor surgery in so-called "eloquent" brain areas aims to remove as much tumor as possible while preserving neurological functions. Standard surgical planning typically focuses on discrete, anatomically defined cortical regions. However, modern neuroscience demonstrates that most brain functions arise from distributed networks of interconnected areas rather than isolated spots - a concept that standard navigation tools do not fully capture.

The CORTEX study evaluates a surgical workflow - termed "connectome-guided network-based navigation" - in which advanced diffusion MRI processing is used to reconstruct patient-specific maps of white matter pathways and large-scale brain networks. These maps are imported into a clinical neuronavigation system to guide preoperative planning and intraoperative decision-making for patients with gliomas or brain metastases in eloquent regions.

The primary aims are to determine how often network-based information leads to meaningful changes in surgical strategy compared with conventional anatomy-based planning, and to assess early neurological outcomes. Secondary objectives include characterizing the extent of tumor removal, the proximity of the resection to critical white matter tracts, and the feasibility of implementing this pipeline in a high-volume clinical setting.

Study Overview

• Status: Recruiting
• Conditions: Glioma; Brain Connectivity; Brain (Nervous System) Cancers; Brain Metastasases
• Intervention / Treatment: Procedure: Connectome-guided network-based neuronavigation; Diagnostic test: Advanced diffusion MRI tractography and connectome pipeline

Detailed Description

The CORTEX study is a prospective, single-centre cohort study conducted at the Unit of Neurosurgery of A.R.N.A.S. Civico Di Cristina Benfratelli, Palermo, Italy. Consecutive eligible patients are enrolled from January 2022 onwards.

Background and Rationale:

Contemporary understanding of brain organization emphasizes the distributed, network-based nature of neurological and cognitive functions. Surgical planning centered exclusively on anatomical landmarks - a "localist" approach - may fail to account for the role of long-range white matter pathways, association fasciculi, and large-scale cortico-subcortical networks in sustaining higher-order functions. The concept of "extended eloquence" extends surgical risk stratification beyond classical primary cortices to include associative and integrative networks, whose disruption may produce clinically relevant higher-order deficits even in the absence of damage to traditional eloquent areas.

Diffusion MRI Processing Pipeline:

Preoperative high-direction diffusion MRI is processed using an open-source pipeline integrating MRtrix3 (denoising, Gibbs correction, multi-tissue constrained spherical deconvolution, anatomically constrained tractography with the iFOD2 algorithm, SIFT2 tractogram filtering), FSL (eddy current and motion correction, susceptibility distortion correction), and FreeSurfer (cortical and subcortical segmentation, atlas-based parcellation). In a subset of patients with optimal data quality, an HCP-style surface-based analysis is performed using the Ciftify framework. Workflow automation is achieved through custom Bash and Python scripts, reducing operator-dependent variability.

Neuronavigation Integration:

Tractograms and volumetric overlays of clinically relevant white matter tracts - including the corticospinal tract, arcuate and superior longitudinal fasciculi, inferior fronto-occipital fasciculus, optic radiations, and frontal aslant tract - are co-registered to anatomical space and imported into neuronavigation platform. These overlays are used during preoperative planning to define craniotomy location, surgical corridor, and intended extent of resection relative to critical network architecture.

Intraoperative Integration:

Where applicable, connectome-guided navigation is integrated with intraoperative neurophysiological monitoring and, in selected cases, awake craniotomy with direct electrical stimulation. Concordance between tractographic predictions and intraoperative stimulation findings is recorded prospectively.

Outcome Assessment:

Postoperative MRI is obtained within 48-72 hours of surgery. Neurological assessment is performed at discharge and at 3-month follow-up by the treating neurosurgical team.

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

• Study Contact: Name: Giovanni Tringali, M.D.; Phone Number: +390916661111; Email: giovanni.tringali@arnascivico.it

Study Locations

• Italy
  • PA
    • Palermo, PA, Italy, 90127
      • Recruiting
      • Unit of Neurosurgery - A.R.N.A.S. Civico Di Cristina Benfratelli - 90127, Palermo - Italy
      • Contact: Giovanni Tringali, M.D.; Phone Number: +390916661111; Email: giovanni.tringali@arnascivico.it
      • Principal Investigator: Giovanni Tringali, M.D.
      • Sub-Investigator: Umberto Emanuele Benigno, M.D.
      • Sub-Investigator: Lapo Bonosi, M.D.
      • Sub-Investigator: Giuseppe Roberto Giammalva, M.D. PhD
      • Sub-Investigator: Gabriele Costantino, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Consecutive adult patients referred to the Unit of Neurosurgery of A.R.N.A.S. Civico Di Cristina Benfratelli (Palermo, Italy) for surgical treatment of supratentorial gliomas or brain metastases involving or adjacent to eloquent cortical or subcortical regions, enrolled prospectively from January 2022.

Description

Inclusion Criteria:

• Indication for supratentorial brain tumor surgery (glioma or metastasis)
• Lesion located within or adjacent to eloquent cortical or subcortical regions (motor, language, visual, or higher-order associative networks, as defined by clinical and neuroimaging criteria)
• Availability of standardized preoperative and early postoperative brain MRI (including high-direction diffusion tensor imaging, ≥64 directions)
• Consistent postoperative clinical follow-up planned at the treating centre
• Provision of informed consent for use of anonymized clinical and imaging data

Exclusion Criteria:

• Inability to undergo pre- or postoperative MRI
• Significant comorbidities precluding surgery
• Incomplete imaging or clinical data
• Purely infratentorial lesions or non-tumoral pathologies

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

CORTEx cohort; Consecutive patients undergoing resection of supratentorial gliomas or brain metastases in eloquent or adjacent regions, enrolled in the CORTEX study and treated with integration of advanced diffusion MRI tractography and connectome-based network overlays into the clinical neuronavigation workflow.

Procedure: Connectome-guided network-based neuronavigation; Integration of patient-specific white matter tractography and large-scale brain network overlays, derived from advanced diffusion MRI processing, into a clinical neuronavigation platform for preoperative planning and intraoperative guidance of brain tumor resection in eloquent regions; Diagnostic test: Advanced diffusion MRI tractography and connectome pipeline; Open-source multi-tissue constrained spherical deconvolution tractography, cortical parcellation and segmentation, diffusion preprocessing and brain connectivity mapping with automated Bash/Python scripting for streamlined and reproducible clinical implementation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Major Change in Surgical Plan	Proportion of surgical procedures in which integration of network-based tractography information results in a major modification of the initial anatomy-centered surgical plan, defined as a change in the surgical corridor, the planned extent of resection, or the operative indication. Assessed by the operating neurosurgeon at the time of surgical planning.	Intraoperative (day of surgery)
Incidence of major neurological deficit at 3-month follow-up	3 months after surgery	Proportion of patients with persistent major neurological deficits with functional impact (motor, language, or visual deficits) 3-month post-op, as evaluated by the treating neurosurgical team using standardized neurological examination

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Extent of Resection	Proportion of procedures achieving supratotal resection, gross-total resection, or partial resection, as determined on early postoperative contrast-enhanced MRI reviewed by the treating neurosurgeon	Within 72 hours after surgery
Minimum Distance Between Resection Cavity and Key White Matter Tracts	Minimum distance (mm) between the resection cavity and functionally relevant white matter tracts (corticospinal tract, arcuate fasciculus, inferior fronto-occipital fasciculus, optic radiations), estimated intraoperatively from subcortical stimulation thresholds and cross-validated by postoperative tractographic reconstructions.	Intraoperative and within 72 hours after surgery
Rate of Intraoperative Mapping and Awake Surgery	Proportion of procedures performed with awake craniotomy and/or continuous intraoperative neurophysiological monitoring; rate of concordance between intraoperative stimulation-induced responses and preoperative tractographic predictions.	Intraoperative (day of surgery)
Pipeline Implementation Feasibility	Proportion of enrolled patients in whom the full connectome-guided pipeline (diffusion MRI processing, tractogram generation, neuronavigation import) was successfully completed within the clinical workflow and used for preoperative planning.	Preoperative (day of surgical planning)

Collaborators and Investigators

• Sponsor: ARNAS Civico Di Cristina Benfratelli Hospital
• Investigators: Principal Investigator: Giovanni Tringali, M.D., Unit of Neurosurgery - A.R.N.A.S. Civico Di Cristina Benfratelli - 90127, Palermo - Italy

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: July 16, 2026
• First Submitted That Met QC Criteria: July 16, 2026
• First Posted (Actual): July 21, 2026

Study Record Updates

• Last Update Posted (Actual): July 21, 2026
• Last Update Submitted That Met QC Criteria: July 16, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: glioma; brain metastasis; tractography; white matter; diffusion MRI; neural networks; extent of resection; neuronavigation; brain tumor surgery; connectome; eloquent cortex; onco-functional balance; network neuroscience; CORTEx
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Site; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Central Nervous System Neoplasms; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Neoplasms; Neurologic Manifestations; Glioma; Brain Neoplasms
• Other Study ID Numbers: ARNAS_NCH_2022_1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be made available due to patient privacy considerations. Deidentified aggregate results will be reported in future publications.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No