Periodic Reporting for period 2 - MICROBRADAM (Advanced MR methods for characterization of microstructural brain damage)
Reporting period: 2017-11-01 to 2019-10-31
The former property allows repeated scanning on the same subject without safety concerns. It is a useful feature both to track a pathology or treatment in a single subject, and to develop new techniques.
The versatility of contrast is related to the fact that nuclear spins can be manipulated to make MR signal sensitive to several biophysical and biological phenomena. NMR applications are continuously evolving, and there is opportunity for many technological advances that can be easily exploited as MRI contrasts in clinical applications.
Microstructural damage is a common, key point for the characterization and understanding of many serious neurological and psychiatric diseases and disorders, including neurodegenerative diseases. In this project, we developed of a set of advanced MR techniques for the characterization of microstructural damage in some key applications, from animal models to pilot clinical studies. Albeit different pathophysiologically, many brain diseases share two common needs: the need of quantitative tools for characterizing the specific mechanisms underlying tissue damage, and the need of diagnostic tools that can: 1) identify the pathology at its earliest stages before manifestation of severe clinical symptoms, and 2) assess even subtle efficacy of experimental treatments.
Myelin sheath breakdown is the main form of microstructural damage shared by many neurological diseases. Quantification of myelin integrity is thus critical for the assessment of a variety of neurological diseases including Multiple Sclerosis (MS). The techniques we developed, based on a phenomenon called “Relaxation Along a Fictitious Field” (RAFF), showed a great sensitivity to demyelination. While we did not reach yet the endpoint of truly “tissue-composition-specific” MRI, the new techniques are a significant improvement that add information to the multiparametric approach needed to personalize treatments and care of the patients.
We developed also functional imaging methods, in order to identify the functional correlates of microstructural damage. Our efforts were focalized in two fields: steady state functional connectivity and neuromodulation. Functional connectivity is an approach that quantifies the network behavior of the brain, and is especially attractive for pathologies because it characterizes the cortex as a whole. Neuromodulation, that is a byproduct of some of the MRI techniques we developed, is important as well, because allows isolating specific neural processes, and can be used in therapeutic interventions, for instance in Deep Brain Stimulation (DBS) in Parkinson’s and in other neurodegenerative diseases.
Main results we obtained include a study on semantic network in Alzheimer ’s disease (AD), that showed that in mild AD brain regions belonging to the semantic control network are abnormally connected not only within the network, but also to other areas known to be critical for language processing. We also studied the nature of impulsive control disorder in Parkinson’s disease, which greatly exceed the previously envisioned dopaminergic pathways as the only culprit. Finally, we showed that our innovative approaches to DBS have the potential to improve the patient’s treatment, being easily tailored to the needs of each single patient.
Given the complex features of microstructural damage, it is likely that a multiparametric integration of different metrics is needed, where the new approaches we propose are intended to complement other quantitative techniques. MRI in itself lends naturally towards multiparametric studies, because it can produce images sensitized to multiple contrast mechanisms, as described above. MRI can also be combined with compatible approaches, including PET based molecular imaging, electrophysiological measurements and neuromodulation. In this project, we implemented an appropriate set of processing tools to combine different kind of information. Main results obtained with this approach are related to Parkinson Disease (PD) and the associate idiopathic REM sleep behavior disorder (iRBD). We were able to show that rotating frame relaxation methods, along with functional connectivity measures, are valuable to characterize iRBD and PD subjects, and with proper validation in larger cohorts these approaches may provide pathological signatures of iRBD and PD.
Information obtained from this project is expected to improve patient care through early disease detection and better assessment of disease progression or treatment in the future. In particular, we believe that the information gained in this investigation will be important in developing new ways to monitor for changes in the brain that occur in neurodegeneration in general.
We envisage that this process will happen in two stages. A first stage, the diffusion of the advanced methods we are developing to an increasingly wide community of neuroscientists. The availability of such sensitive tools to characterize microstructural brain damage and the relevant functional counterpart is improving the quality of the research of the involved research teams, and we committed ourselves to widen as far as possible the dissemination of our approaches.
In a second, long-term stage, our techniques (together with hardware improvements of the MRI instrumentation) have the potential to improve single patients care in the clinical routine.