Laminar fMRI and resting state fMRI in the somatosensory system - effect of peripheral nerve injury on cortical circuits

Understanding how information is processed in the brain and how this is impaired in neurological and psychiatric conditions is one of the greatest challenges in science. Functional magnetic resonance imaging (fMRI) is a non-invasive method for investigating brain function. The way information flows in cortical circuits consisting of multiple interconnected brain areas, and the processing of information by these circuits is fundamental to brain function. Being able to measure how information flows in the brain would be of great advantage in rehabilitation after peripheral nerve injuries, where the brain reorganizes itself, but in an imperfect way that often prevents full recovery or leads to chronic pain. We currently lack effective ways to study brain circuits in humans because current imaging methods are too coarse. The commonly used fMRI methods can provide information about which brain areas are active when a person performs a certain task, but cannot show how information flows in the brain.

A potential way of overcoming these limitations to the study of cortical circuits is the use of ultra high-resolution fMRI, that is fMRI that has sufficient resolution to resolve the layers (laminae) of the cortex. Resolving these layers is essential to understanding cortical circuits and their connectivity because different functions in the circuit are assigned to neurons in different layers. We propose to develop and refine fMRI to attain a resolution that is sufficient to provide information about functional activation and connectivity in the different layers using laminar fMRI and laminar resting state (rs) fMRI. Rs-fMRI is based on the principle that if two areas are connected, their activity fluctuates together (they are 'functionally connected'). Knowledge of which cortical layers are active and how they are connected makes it possible to establish those sending and those receiving information.

Laminar rs-fMRI will be optimized in humans at ultra high magnetic field (7T). We will optimize the acquisition techniques, enhance resolution and develop methods for data analysis. We will evaluate activity and functional connectivity in the cortical layers of the sensorimotor cortex in healthy volunteers and in patients with peripheral nerve injury. Peripheral nerve injuries are common and intensely painful. Complex microsurgical reconstruction helps, but recovery is slow and very incomplete, with incomplete recovery of function, despite that the nerve regenerates. The lack of recovery is thought to be because brain circuitry has reorganized in the long time it takes for the nerve to heal. We will use laminar fMRI to investigate how the processing in the brain circuits changes by comparing the circuitry just after injury, and follow the changes in the cortex over time, as the nerve reconnects. Initially after nerve damage there is a loss of sensory input, which leads to brain reorganization. To understand how reorganization of brain circuits in response to sensory deprivation and the subsequent reconnection of the nerve change over time, we will carry out laminar fMRI and rs-fMRI at different times after injury and compare it to the recovery of function of the hand. We will then investigate how brain sensorimotor circuits further change in cases of good functional recovery or when recovery is less optimal. The timing of changes in cortical circuits will be correlated with measures of returning function.

We expect the study to lead to new approaches for the non-invasive interrogation of brain function and provide new information about the function of brain sensorimotor areas. In addition, it will illuminate plastic mechanisms in the brain highly relevant to understanding adaptive functional recovery, rehabilitation strategies utilizing activity-dependent plasticity and the limitations that brain plasticity imposes on functional recovery after peripheral nerve repair.

The goal of this project is to understand function and information flow in cortical laminar circuits, by using laminar resting-state fMRI (rs-fMRI) and fMRI to study the sensorimotor circuits in the human cortex at 7T. We aim to apply this technology to investigate plastic changes in cortical circuits after peripheral nerve injury. Despite regeneration and reinnervation, full functional recovery is impaired by cortical plasticity occurring during the long period of axonal regeneration. A better understanding of the changes in these circuits after nerve injury may help improve prognostics and guide future improvements in rehabilitation strategies. Because ultra-high-resolution fMRI and rs-fMRI can visualize the cortical layers, it offers the possibility of measuring input-output connectivity of cortical circuits, and the direction of information flow between brain areas. We will implement and optimize the technology and evaluate its potential for investigating processing in sensorimotor cortical circuits in healthy volunteers. Subsequently we will employ laminar fMRI and rs-fMRI to investigate plastic reorganization of cortical circuits resulting from interruption of sensory input after peripheral nerve injury. We will investigate changes in laminar functional activity and connectivity acutely after injury, and following subsequent regeneration and re-innervation after peripheral nerve regeneration. This project will improve our ability to interpret fMRI and rs-fMRI signals and provide an important tool for obtaining mechanistic insight into normal brain function and plastic reorganization in response to injury.

Understanding neural circuits, such as laminar circuits in the cortex is critical to understanding brain function. However, tools suitable for studying laminar cortical circuits in humans are lacking because current technologies have insufficient spatial resolution. Laminar stimulus evoked and resting state (rs) fMRI can potentially allow study of processing in cortical layers and between areas, allowing separation of feedforward-feedback or input-output connections. Cortical circuits underlie a broad range of brain functions and thus this technique could have significant impact on neuroscience research in many areas. The development of better tools to study brain circuits also has implications for research into a wide range of neurological conditions, increasing the probability of finding new treatments for a variety of neural disorders.

This project is expected to provide important insights into the function of sensorimotor cortical circuits and injury- and plasticity-induced changes to these circuits. Peripheral nerve and spinal cord injury result in devastating loss of function. The damaged CNS does not regenerate but modest spontaneous functional recovery is attributed to compensatory plasticity in the brain and spinal cord. Development of rehabilitative strategies aimed at maximizing return of function by driving activity-dependent plasticity is a rapidly growing research area relevant to peripheral nerve and spinal cord injury, brain injury and stroke. Following peripheral nerve injury successful repair and regeneration can occur but functional recovery is slow (1-5 years) and incomplete. Cortical plasticity is thought to be one of the main factors limiting return of function. In addition, neuropathic pain is common following peripheral nerve and spinal cord injury. This pain is difficult to treat, and although the underlying mechanisms remain poorly understood, it is attributed partly to maladaptive plasticity. Little is known about how brain circuits adapt after nerve or spinal cord injuries, but a better mechanistic understanding is likely to flow from study of these circuits in healthy volunteers and patients, and has the potential to advance treatments. For instance, better understanding of the alterations to cortical circuits after injury could lead to improved methods of monitoring regeneration and evaluating the efficacy of rehabilitation. Plasticity is also implicated in phantom sensations and neglect disorders so that understanding somatosensory and motor circuits can potentially benefit clinicians and scientists studying a range of conditions. If improved understanding feeds through into improved treatment options then the ultimate beneficiaries would be patients.

Furthermore, the project can potentially drive development of high-resolution MRI-technology. Developing methodology and improving our understanding of fMRI-mechanisms can facilitate application of high-resolution fMRI in humans. Understanding laminar cortical circuit processes that underlie rs-fMRI would allow scientists and clinicians who use rs-fMRI to improve their inferences about cognitive processing or disease processes, and may lead to wider use of rs-fMRI in clinical research and diagnosis, and improved interpretation of its findings. Laminar fMRI is a key goal behind the acquisition of many human 7T scanners, and enhancing the spatial resolution to accurately visualize cortical layers can potentially impact MR-physics research and further technological development of ultra-high field human scanners. Demonstrating the feasibility and utility of laminar fMRI and rs-fMRI in patients may provide an incentive for researchers and manufacturers to increase the spatial resolution of scanners by improving the hardware and software capabilities of current scanners. Ability to show feedforward and feedback connectivity conclusively would be a major step in the utility of rs-fMRI, and one large enough to warrant such technological development.