2022 MSC Poster Contest Presentation: Functional Brain and Trigeminovascular Changes in Migraine Using a New Neuroimaging Approach: Functional Ultrasound Imaging (fUSI)

Title: Functional brain and trigeminovascular changes in migraine using a new neuroimaging approach: Functional ultrasound imaging (fUSI)

Presenter: Lauriane Delay, PhD, postdoc, Physics for Medicine Laboratory, INSERM, France

Methodology, findings and conclusions of the research
Migraine is a common chronic, neurovascular brain disorder characterized by recurring, often highly disabling attacks of severe headache, nausea, vomiting, photophobia, phonophobia and widespread tactile hypersensitivity. The pathophysiology of migraine is complex as it involves several clinical phases in which the physiopathology evolves and differs. The most accepted mechanisms include an alteration of brain excitability, intracranial arterial dilatation, and recurrent activation and sensitization of the trigemino-cervical complex.

In our study, we used functional ultrasound imaging (fUSI) as a unique neuroimaging approach, developed by my laboratory, ‘Physics for Medicine’. Thanks to the high sensitivity to cerebral blood volume (CBV) changes and its high spatial and temporal resolutions (100 µm and 10 Hz, respectively), this technique led to major breakthroughs in the field of neuroscience. Its high adaptability allows the study of evoked hemodynamic responses to external stimuli and functional connectivity in anesthetized and awake rodents. Due to the vascular nature of the signals measured with fUSI, it is a unique tool to study pathophysiology in models of migraine.

Due to a lack of comprehensive and widespread characterization of the cerebral hemodynamic changes and measures of brain network functional connectivity during the various phases of migraine attacks, we characterized the hemodynamic and functional changes (FC and functional responses to allodynic and visual stimuli) using fUSI in a preclinical model of migraine in rats induced by repeated injections of a nitric oxide donor (isosorbide dinitrate; ISDN). Facial mechanical threshold sensitivity was monitored using von Frey hair filaments before the model induction, 48 hours after the skull thinning and before the fUSI to confirm the manifestation of allodynia, the marker used widely to assess the migraine attack in the models.

Our first set of data validates the use of functional ultrasound imaging to explore hemodynamic changes and functional connectivity during migraine crisis induced by repeated systemic injection of a nitric oxide donor. ISDN-sensitive rats (4/7 rats) exhibited facial mechanical allodynia, and strong cerebral blood flow changes in several parts of the pain matrix (e.g., cingulate cortex, retrosplenial system, thalamus, somatosensory cortex), in the limbic system known to regulate the motivational or behavioral responses to pain, and in photophobia-associated cortical areas, immediately after the fifth injection of ISDN and 2h30 later. These results were not seen in ISDN non-sensitive control rats (2/7 rats). In the next experiment, we will compare males and females and assess the impact of migraine therapies on this dynamic. Following our recent publication describing a somatotopic functional activation of the trigeminal ganglion (TG) by orofacial stimuli, we will also investigate this key structure in trigeminal sensitivity using functional ultrasound localization microscopy (fULM) to capture changes at the micron-scale.

Implications of the research for understanding migraine and/or its comorbidities
Functional ultrasound imaging is transforming the field of neuroimaging, providing a unique technology that is portable, easy-to-use, and cost-efficient to visualize cerebral activity and trigeminovascular system activity at high spatio-temporal sensitivity (100 µm and 10 Hz, respectively); an alternative to fMRI. In preclinical research, this technique offers an incredible advantage because it can be used in anesthetized or awake (head-fixed or freely-moving) small animals. My research has implications for understanding migraine disease by exploring the hemodynamic cerebral changes and functional connectivity before, during, and after migraine crisis, enabling the study of a potential sexual dimorphism and the impact of antimigraine therapies on this dynamic. We are also assessing comorbidity-related cerebral changes, especially the functional responses to mechanical stimulation (allodynia) and visual stimulation (photophobia).