Structural and Molecular Neuroplasticity in Migraine

Alexandre F. DaSilva, DDS, DMedSc

University of Michigan, Ann Arbor, MI, Department of Biologic and Material Sciences

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

December 2008, for 3 years

Funding Amount:


Lay Summary

Imaging Neurotransmitter Receptors in Migraine

Researchers will use PET and MRI imaging in people who get migraine headaches and in healthy volunteers to identify factors that may be correlated with the severity of migraine attacks.  Migraine is a chronic disorder characterized by sudden attacks of severe headache pain that are often accompanied by nausea, vomiting, and hypersensitivity to light and sound.  Many migraine therapies do not produce long-lasting relief, suggesting that chronic migraine attacks may be due to cellular and molecular changes in the brain.  Pain perception in migraine and other chronic pain disorders has been linked to an increased number of receptors on neurons that take up opioids that are naturally produced in the brain.  Additionally, nausea has been linked to increased numbers of receptors that take up the neurotransmitter dopamine.

In previous studies of patients with migraine, the Michigan investigators found that certain brain regions that normally express high levels of these opioid and dopamine receptors also show structural changes.  The investigators hypothesize that migraine is sustained by mal-adaptive changes that occur at both the molecular and cellular levels in brain circuitry.  Specifically, they suspect that at the molecular level, the brains of migraine patients have alterations in certain subtypes of opiate and dopamine receptors; and at the cellular level, patients have cortical thickness and white matter alterations.

They will test this hypothesis using PET and MRI imaging in 20 healthy volunteers and in 20 patients with migraine.  Investigators will use PET imaging to visualize opioid and dopamine receptors in patients during a pain-free period and again within 24 hours of a migraine attack.  They will determine whether migraine severity is correlated with receptor levels in brain regions that are known to be involved either in pain perception or migraine-related disease processes or both, and will use MRI to determine whether brain regions that show altered receptor levels also exhibit structural changes.


Structural and Molecular Neuroplasticity in Migraine

The evidence that many therapeutic modalities do not provide long-lasting relief for migraineurs raises the possibility that the cause for the chronicity of this disorder is due to cellular and molecular changes in the brain.  This may include changes of specific cortical structures including the trigeminal sensory system and the periaqueductal gray matter (PAG), as well as molecular changes in opioidergic and dopaminergic neurons.

In this project, we will integrate anatomical MRI techniques with positron emission tomography (PET) for the study of structural and molecular cortical neuroplasticity in migraine.  Recent studies with PET using selective µ-opioid and dopamine D2/D3 receptor radiotracers have shown varied patterns of receptor occupancy on the disorders investigated.  These findings represent either change in occupation of receptors by endogenous ligands or loss of opioid and dopamine receptors.  Interestingly, our last results suggest that such molecular changes in refractory pain parallel cortical thickness and diffusional changes in areas related to pain perception/modulation in episodic migraine patients.

Therefore, we will test the hypothesis that migraine, during ictal and interictal phases, is sustained by mal-adaptive changes at multiple levels of the cortex by pursuing the following Aims: (1) To investigate µ-opioid and dopamine D2/D3 receptors non-displaceable binding potential (BPND) in the brain of episodic migraineurs during interictal and ictal phases; (2) To study the correlation of the attack severity in migraineurs with µ-opioid and dopamine D2/D3 BPND in specific areas of the brain associated with migraine pathophysiology; and (3) To investigate whether ictal and interictal µ-opioid and dopamine D2/D3 BPND levels in those specific brain regions of migraineurs are associated with changes in the gray and white matter. This project has significant clinical relevance, and has the support of an array of mentors, collaborators and institutions.

Investigator Biographies

Alexandre F. DaSilva, DDS, DMedSc

Dr. Alexandre DaSilva is a clinician-scientist with more than 15 years of experience in the field of chronic trigeminal pain.  He is an Assistant Professor at the Department of Biologic and Material Sciences, School of Dentistry, University of Michigan Ann Arbor.

Dr. DaSilva has received his Doctorate in Medical Science (DMedSc) degree in Oral Biology with clinical training in trigeminal pain at Harvard University, where he mapped non-invasively the somatotopic (fMRI) activation of the human trigeminal pain pathway. This training was followed by a post-doctoral fellowship on migraine neuroimaging at the Martinos Center for Biomedical Imaging, Massachusetts General Hospital, to investigate subcortical and cortical neuroplasticity in migraine patients. He was also an Instructor in the Psychiatric Department at Harvard University/McLean Hospital, as well as Assistant Clinical Investigator at the Forsyth Institute in Boston.

During his training, he collaborated with his colleagues on novel neuroimaging and non-invasive brain stimulation projects for chronic TMJD, trigeminal neuropathic pain and migraine. His original work has been published in several journals and books, and received broad media coverage.