In this study, the authors report for the first time a novel 3D-Immersive & Interactive Neuronavigation (3D-IIN) through the impact of a spontaneous migraine headache attack in the μ-opioid system of a patient’s brain in vivo.
A growing body of research, generated primarily from MRI-based studies, shows that migraine appears to occur, and possibly endure, due to the alteration of specific neural processes in the central nervous system. However, information is lacking on the molecular impact of these changes, especially on the endogenous opioid system during migraine headaches, and neuronavigation through these changes has never been done. This study aimed to investigate, using a novel 3D immersive and interactive neuronavigation (3D-IIN) approach, the endogenous µ-opioid transmission in the brain during a migraine headache attack in vivo. This is arguably one of the most central neuromechanisms associated with pain regulation, affecting multiple elements of the pain experience and analgesia. A 36 year-old female, who has been suffering with migraine for 10 years, was scanned in the typical headache (ictal) and nonheadache (interictal) migraine phases using Positron Emission Tomography (PET) with the selective radiotracer [11C]carfentanil, which allowed us to measure µ-opioid receptor availability in the brain (non-displaceable binding potential – µOR BPND). The short-life radiotracer was produced by a cyclotron and chemical synthesis apparatus on campus located in close proximity to the imaging facility. Both PET scans, interictal and ictal, were scheduled during separate mid-late follicular phases of the patient’s menstrual cycle. During the ictal PET session her spontaneous headache attack reached severe intensity levels; progressing to nausea and vomiting at the end of the scan session. There were reductions in µOR BPND in the pain-modulatory regions of the endogenous µ-opioid system during the ictal phase, including the cingulate cortex, nucleus accumbens (NAcc), thalamus (Thal), and periaqueductal gray matter (PAG); indicating that µORs were already occupied by endogenous opioids released in response to the ongoing pain. To our knowledge, this is the first time that changes in µOR BPND during a migraine headache attack have been neuronavigated using a novel 3D approach. This method allows for interactive research and educational exploration of a migraine attack in an actual patient’s neuroimaging dataset.
Migraine is a chronic trigeminal pain disorder that affects nearly 16% of women and 6% of men in the United States and worldwide1-3. Repetitive migraine headache attacks have an impact on a large part of the patient’s existence, impairing quality of life and performance, costing billions of dollars in missed school/work days and healthcare utilization4. During the debilitating headache attacks, its sufferers have a marked increased sensitivity to noxious (hyperalgesia) and even nonnoxious stimuli (allodynia)5.
The µ-opioid neurotransmitter system is one of the principal endogenous pain modulatory mechanisms in our brain. It is involved in the regulation of experimental and clinical pain perception, as well as in the analgesic action of opioid drugs6-9 which have been associated with the chronification of migraine attacks10. Recent advances in Positron Emission Tomography (PET) molecular imaging allow for the study of important molecular mechanisms in the brain of chronic pain patients in vivo11. In this study, despite the challenging logistics of synchronizing the aleatory and debilitating nature of the episodic attacks with the complexity of PET/radiotracer session setup, 3D neuronavigation was used for the first time to investigate µOR availability in key pain-matrix regions of a patient’s brain during a spontaneous migraine headache.
Case Presentation
A 36 year-old Asian female was enrolled in the study. She presented with a 10 year history of migraine with visual aura. Right-sided migraine headaches occurred an average of 12 days per month, with moderate to severe pain intensity that would usually last for 72 hr (if untreated or unsuccessfully treated). There was an increased frequency of headache attacks around her menstrual cycle, which had a regular pattern throughout the study. Associated symptoms included: nausea, vomiting, photophobia, and phonophobia. During the regular headache attacks she did not present any autonomic symptoms. As treatment, she was managing her symptoms with pharmacological abortive therapy only, which was based on non-steroidal anti-inflammatory drugs, and there were no indications of medication overuse or opioid intake. The clinical examination during the screening visit was unremarkable and without abnormalities, and a review of systems was within normal limits. She was single with no children, and was not using contraceptive medication.
The study should be approved by the local Institutional Review Board, and by the Radioactive Drug Research Committee. The research subject gives written informed consent to participate in the study. The protocol is divided into three chronological steps:
The patient is responsible for filling out a headache diary, and for confirming with the research group the occurrence of a migraine attack on the day of imaging session. Both, interictal and ictal, PET scans should be scheduled during separate mid-late follicular phases of the patient (5 to 10 days after the first day of menstrual bleeding), which in this case was tracked and calculated in advance by a gynecologist with expertise in the field (Y.R.S.).
1. MRI Session
2. Ictal PET Session
3. PET Data Reconstruction
4. PET Data Analysis
NOTE: Anatomically standardize images into template space using Statistical Parametric Mapping (SPM8) software following the sequence below.
Examine the activity of several bilateral regions that are engaged during the processing of pain, including:
5. 3D-Neuronavigation
6. 3D-Immersive & Interactive Neuronavigation (3D-IIN)
The patient presented to the hospital with a right temporal and occipital pulsating headache, with intensity of 6 on a 0-10 pain scale. She was having her typical migraine headache, however without aura. It had initiated upon awakening 5 hr before the (ictal) PET session, and she managed to tolerate it without any abortive pharmacotherapy. To her knowledge, the headache was not evoked by any triggering factor (e.g., alcohol, sleep deprivation). No autonomic symptoms were reported, but photophobia and phonophobia were present. Following initiation of the ictal PET session the headache intensity escalated, reaching severe levels (9 on a 0-10 pain scale) 60 min into the study; progressing to nausea and vomiting at the end of the scan session. Decrease in µOR BPND was noticed in the brain of the patient during the spontaneous migraine headache (ictal phase), as compared to the baseline (interictal phase) (Figure 2). There were patent reductions in µOR BPND in the main pain-matrix regions of the endogenous µ-opioid system, including the following thalamus nuclei: right lateral dorsal (11, -19, -16: 10.2%), right medial dorsal (6, -17, -8: 11.1%), right midline (8, -19, -16: 27%), and ventral anterior (9, -9, -12: 12.0%). In addition, changes were found in the right anterior (8, 35, 14: 13.7%) and left posterior cingulate cortex (-5, -44, 23: 11.8%), left caudate body (-11, 6, 15: 12.0%), medial globus pallidus (right: 16, -4, -3: 16.2%; left: -14, -4, -3: 22.6%), left nucleus accumbens (-9, -11, -7: 10.5%), and hippocampus (right: 30, -22, -14: 12.6%; left: -30, -22, -14: 11.5%). There was an increase in µOR BPND only in the left amygdala (-23, -4, -19: 11.7%). In the brainstem, the significant ictal reduction in µOR BPND extended from the rostral to caudal periaqueductal gray matter (PAG) (right: 4, -28, -6: 15.1%; left: -2, -28, -6: 14.6%) (Figure 3). However, the global hemispheric percentage changes in the µOR BPND during the migraine attack were modest (right: 8.5%; left: 8.29%), indicating that the decreases in the µOR BPND were specific to the pain-matrix structures in the brain.
Figure 1. Full Virtual Reality 3D Data Navigation of a Migrainous Brain. For the first time actual migraine neuroimaging data was explored in a fully immersive 3D virtual reality, which includes unrestricted navigation through the data (by students, clinicians, and researchers) regarding availability of µ-opioid receptors (µOR BPND) in the brain during the migraine headache attack in vivo.
Figure 2. μ-Opioid Brain Profile of a Migraine Headache in vivo. The ictal phase (lower row) – headache phase – shows a decrease in μ-opioid receptor availability (µOR BPND) in the pain-matrix regions (Threshold value, DV = 4.50). This result possibly represents an increase in endogenous μ-opioid release during the migraine attack, as a regulatory response to the ongoing severe headache. Key words: thalamus (Thal), nucleus accumbens (Nac), and anterior cingular cortex (ACC).
Figure 3. Midbrain/Pons/Medulla μ-Opioid Receptor Availability During a Migraine Attack in vivo. The ictal phase (right column) – headache phase – shows a decrease in μ-opioid receptor availability along the periaqueductal gray matter (PAG) (Threshold value, DV = 4.50), as compared to the interictal phase (left column) – non-headache phase. Key words: PAG: r – rostral; m – medial; c – caudal.
In this case report, actual migraine headache neuroimaging data was explored for the first time, in a fully immersive virtual 3D reality, which demonstrated a decrease in µ-opioid receptor availability (µOR BPND). Reductions in µOR BPND imply that there is a higher occupancy and/or a loss of µ-opioid receptors in the central nervous system. Acute reductions in µOR BPND in pain-matrix regions during the ictal scan as compared to the interictal scan, are expected to occur as a consequence of the release of endogenous opioids interacting with µORs as a regulatory response to the ongoing pain, making less µORs accessible to the radiotracer.
The novelty of our ictal migraine neuroimaging study lies in the new 3D neuronavigation approach to investigate a patient’s actual brain data in virtual reality. PET radiotracer technology was used to measure changes in µORs availability with [11C]carfentanil. When examined during the headache event, the brains of migraineurs are usually scanned following an attack trigger (e.g., glyceryl trinitrate, photostimulation)16,17, or under the technical demand of a specific evoked stimulus (e.g., pain, brush, light, and odor)18-20. All those studies corroborate the knowledge that the disorder is associated with cortical and subcortical hyperexcitability during the headache phase. However, such a plethora of stimuli in the neuroimaging protocols introduces multiple factors that cloud our understanding of the sole impact of an acute migraine attack on the central nervous system. From the few previous functional studies without the presence of exogenous stimulation, there is indication of increased regional cerebral flow in areas such as the cingulate cortex, hypothalamus, and brainstem21, which can persist even after acute therapy22. Hitherto, the neuroimaging technologies applied have not allowed for the molecular characterization of neurotransmitter/receptor processes involved in the migraine attack, such as the endogenous µ-opioid mechanism, one of most important analgesic resources in the brain. Moreover, our method allowed these processes to be explored using 3D neuronavigation in a virtual environment.
The descending pain modulatory system is a complex network that regulates pain processing to a great extent via μ-opioid receptors throughout the brain, including spinal to supra-spinal areas. These areas are known to be involved in endogenous anti-nociception, stress-induced analgesia, and in the action of opioid drugs commonly used for chronic pain and migraine treatment. In fact, the dural neurogenic vasodilation associated with migraine can be inhibited by morphine and subsequently reversed by the opioid antagonist naloxone, indicating that the effects of morphine on neurogenic inflammation are mediated specifically via activation of µ-opioid receptors23. Interestingly, the magnitude of endogenous opioid/µORs regional activations in humans is related to the individual’s capacity to suppress sensory and affective elements of the pain experience24.
In our study, the brain regions that showed reductions in µ-opioid receptor availability during the ictal phase are responsible for both elements of the migraine headache experience and its modulation. They are the ACC, thalamus, basal ganglia (e.g., NAcc), hippocampus, and the PAG. In addition to sensitization due to abnormal trigeminal afferent traffic, one solid hypothesis for migraine pathophysiology is the dysfunction of the modulatory system. In this case, projections from/to brainstem structures, such as the PAG, where there is a high expression of opioid receptors, would inefficiently produce their anti-nociceptive effect on ascending sensory neurons. In addition, other higher cortical structures participate in this faulty pain-modulatory mechanism in migraine. A recent interictal resting-state study reported changes in the connectivity of migraineurs versus healthy controls in the ventrolateral PAG and most of the (sub)cortical structures in the modulatory pain system and correlated these with the frequency of the headache attacks13. The regions with connectivity changes found in this study are the same as those with changes in µOR BPND found in our own study. The same PAG location was originally reported as encompassing microstructural neuroplasticity in migraineurs14, and here had a considerable decrease in µOR BPND during the attack.
Further studies with larger cohorts are necessary to confirm and extend the findings presented in this case report. For instance, it is currently unknown why the system does not properly respond to the long-term use of exogenous opioids frequently prescribed in migraine clinics. Nonetheless, our study provides important mechanistic information, on the impact of a migraine headache in the µ -opioid system, and uses a novel 3D immersive and interactive neuronavigation (3D-IIN) approach for the first time. In the future, this exploratory 3D method could provide a much more immersive and interactive perspective for examining the brains of patients in research and the clinic.
The authors have nothing to disclose.
This work was supported by the following grants (DaSilva AF): National Institute of Health – National Institute of Neurological Disorders and Stroke – K23 NS062946, Dana Foundation’s Brain and Immuno-Imaging Award, and the Migraine Research Foundation Research Grant Award. The authors acknowledge the PET Center Nuclear Medicine Technologists (Jill M. Rothley, Edward J. McKenna, Andrew R. Weeden, Paul Kison, and Caitlin Hendricks) and the personnel of Functional MRI Laboratory (Scott Peltier and Keith Newnham). Dr. Alexandre DaSilva, the principal investigator, had full access to all the data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors declare no conflicts of interest related to this study.