Since the 1990s, the Martinos Center for Biomedical Imaging at Massachusetts General Hospital has led the development and application of the powerful technique “Connectome” imaging, which reveals the organization of the human brain by tracking the movement of water molecules in the brain. In 2023, the center installed a next-generation scanner for Connectome imaging — Connectome 2.0 — building on the strengths of the original Connectome scanner, which its investigators had also developed.
In a paper published today in Nature Biomedical Engineering, Martinos Center researchers Gabriel Ramos-Llordén, PhD, Hong-Hsi Lee, MD, PhD, Susie Huang, MD, PhD, and colleagues report the design of the Connectome 2.0 scanner. They describe these advances, as well as efforts to disseminate the technology to the broader neuroscience community, in the Q&A below.
What is unique about connectome imaging?
Connectome imaging is a powerful method for mapping the brain’s structural connections — essentially, the wiring diagram of how different parts of the brain communicate. What sets it apart is its ability to look across scales: from large, long-range pathways connecting brain regions down to microscopic structures like axons and cell bodies. This multiscale approach helps us better understand how the brain is organized, not just as a network of regions, but also in terms of the fine-grained tissue properties that shape how those networks function.
The key technology behind connectome imaging is diffusion MRI, which tracks how water moves in the brain. Water diffuses differently depending on the microstructure of the tissue — for example, it moves more freely along axon bundles than across them. By capturing these patterns, we can infer detailed information about the orientation, size, and density of brain fibers and even about cell-level features — all noninvasively. This makes connectome imaging uniquely suited to bridge cellular neuroscience and systems-level brain mapping.
The applications are broad and growing. In neuroscience, it allows researchers to study how brain circuits develop, adapt with learning, or degrade with age. In medicine, it offers new ways to detect and monitor neurological and psychiatric disorders — from Alzheimer’s disease and multiple sclerosis to autism and schizophrenia — based on structural changes in brain connectivity and microstructure. Connectome imaging brings us closer to a personalized understanding of brain health and disease by revealing how structure supports function at every level.
How does Connectome 2.0 improve upon the original connectome scanner?
Connectome 2.0 represents a major leap forward in brain imaging technology. It builds upon the success of the original Connectome scanner used in the Human Connectome Project, which already had much stronger gradients than typical clinical MRI scanners. But with Connectome 2.0, we’ve pushed performance even further by designing the strongest diffusion-encoding gradients ever built for in vivo human imaging — up to 500 mT/m in amplitude and 600 T/m/s in slew rate — providing an 18-fold improvement over clinical systems. This upgrade significantly boosts the sensitivity of diffusion MRI to microscopic structures.
In addition to the ultra-strong diffusion-encoding gradients, the Connectome 2.0 system incorporates advanced RF coil and field monitoring technology to maximize image quality and spatial accuracy. For in vivo imaging, we use a high-density 72-channel head receive coil, which significantly improves signal-to-noise ratio (SNR) and enables high-fidelity spatial encoding—critical for resolving fine microstructural details in diffusion MRI. For ex vivo imaging, we developed a custom 64-channel anatomically conformal coil with integrated field monitoring and active thermal stabilization, optimized for whole-brain postmortem diffusion imaging at submillimeter resolution.
The system was carefully engineered to minimize peripheral nerve stimulation (PNS), allowing us to operate at this level of performance safely in human subjects — a major technical milestone. These advances allow us to image the brain’s wiring and microstructure with an unprecedented level of detail. We can now detect and track much smaller white matter pathways, resolve fine fiber crossings deep in the brain, and estimate features like axon diameter and cell size at near-microscopic resolution — all in living humans. This bridges the gap between ex vivo imaging and in vivo studies and enables entirely new research on how brain structure supports function and changes in health and disease.
Did you encounter any particular challenges while implement the new design in the Connectome 2.0 scanner?
The development of Connectome 2.0 was a complex, multidisciplinary project that unfolded over approximately five years. It required close collaboration between physicists, engineers, neuroscientists, and clinicians, along with support from the NIH BRAIN Initiative. Our goal was ambitious: to push the limits of human MRI performance while ensuring safety, stability, and practicality for in vivo use. Each subsystem — the gradient coil, RF hardware, cooling systems, and field monitoring — had to be designed from the ground up and integrated seamlessly.
One of the biggest challenges we faced was safely achieving ultra-high gradient strengths without causing PNS, which occurs when rapidly switching magnetic fields stimulate nerves in the body. To overcome this, we designed a novel three-layer head-only gradient coil optimized to redistribute electric fields and minimize PNS. This allowed us to reach 500 mT/m gradient amplitudes and operate safely within human tolerance — something that had never been done before at this scale.
Other challenges included managing heat and mechanical stress from the powerful gradients, controlling acoustic noise, and maintaining precise timing and geometric fidelity for advanced diffusion protocols. We implemented innovative cooling strategies, vibration isolation, and real-time field monitoring to address these issues. Through careful engineering and validation, we delivered a scanner that sets a new benchmark in human brain imaging — enabling researchers to study brain microstructure and connectivity at scales that were previously out of reach.
Can you describe the dissemination efforts outlined in the BRAIN U24 grant you have received? What is your broader goal in introducing these efforts?
The BRAIN U24 dissemination program for the Connectome 2.0 scanner is designed to expand access to next-generation diffusion MRI (dMRI) technology by making the unique capabilities of this system available to the broader neuroscience community. As part of this effort, we’re providing funded pilot scan time, subject recruitment support, on-site technical staff, and remote scanning capabilities to both domestic and international investigators. Our goal is to lower barriers for researchers aiming to leverage ultra-strong diffusion gradients and high-resolution imaging to study brain connectivity and microstructure in ways that were previously impractical or inaccessible.
Beyond providing access, we are focused on methodological standardization, protocol harmonization, and community training:
- We are releasing open-source imaging protocols and reconstruction pipelines optimized for Connectome 2.0, ensuring reproducibility and interoperability across sites.
- We are supporting multi-site harmonization efforts, enabling investigators with access to advanced 3T systems to benefit from our protocols and contribute to a unified connectomics framework.
- Through hands-on workshops, we’re training the next generation of researchers in high-gradient dMRI acquisition, field monitoring, and microstructural modeling.
The broader goal is to democratize access to cutting-edge diffusion imaging, accelerate the development of microstructure-informed biomarkers, and facilitate a collaborative research environment that bridges engineering innovation, neuroscience, and clinical translation. By sharing tools, expertise, and infrastructure, we aim to catalyze discoveries across neurodevelopment, aging, psychiatric disease, and precision neurotherapeutics.
Have you already begun the dissemination efforts?
Yes, dissemination efforts are actively underway and already yielding impactful collaborations. Since launching the U24 program, we’ve onboarded multiple investigator-led pilot projects spanning diverse neuroscience applications — including sleep and memory consolidation, post-stroke motor recovery, glioblastoma microstructure, spinal cord injury, glial imaging in pain, and multiple sclerosis. These projects come from both U.S. and international institutions, including MGH, Spaulding Rehabilitation Hospital, the National Institute on Aging, University of Washington, University of Lausanne, Max Planck Institute, UT Southwestern, and Tsinghua University.
To support this growing network:
- We’ve provided tailored onboarding for each project, including protocol adaptation, remote scanning access, and technical support for advanced sequences and reconstruction workflows.
- Several teams have begun collecting data or completed initial feasibility scans, with strong early feedback on the imaging quality and support structure.
- Internally, we’ve created a structured data pipeline that incorporates real-time field monitoring, advanced image reconstruction, and harmonized output formats to facilitate downstream analysis and collaboration.
Community engagement has also been strong. At recent conferences, our dissemination talks and training sessions have attracted broad interest, particularly from early-career researchers eager to access the Connectome 2.0 system. We’re currently planning additional training workshops and shared publication efforts to disseminate lessons learned and amplify scientific return.
Overall, we’re encouraged by the scientific diversity, technical feasibility, and momentum of the current dissemination efforts — and we’re actively expanding support to ensure that the Connectome 2.0 platform becomes a shared resource for microstructural neuroscience.
