Functional imaging of subcortical nociceptive structures in response to treatment of chronic daily headache

Abstract

The objective was to provide objective imaging evidence of functional changes in brainstem structures involved in chronic daily headache (CDH). Over time, episodic migraine (EM) patients may develop CDH known as transformed migraine (TM). Using analysis of transverse relaxation rates, R2, R2* and R2' (R2* values are reflective of blood oxygen level dependence; R2' is a measure of non-heme iron in tissues) we have reported activation (hyperoxia) of red nucleus (RN) and substantia nigra (SN) (decreased R2* and R2') in CDH patients studied during headache, and dysfunction of periaqueductal grey (PAG) based on increased iron levels (elevated R2') [1]. We now report a patient with CDH who, upon treatment, reverted to EM, permitting studies when headache free and an objective analysis of treatment response. SP is a female aged 48 years. She presented with daily headaches for 6 months. Episodic headaches, meeting IHS criteria for migraine without aura, began in her 20s. At the time of presentation she was taking 5 tablets of ergotamine tartarate in the form of Ercaf and 6 extra-strength acetaminophen daily. Repeated dosages of intravenous dihydroergotamine for three days during withdrawal of all medications successfully achieved clinical reversion from CDH to EM. She was studied both during CDH and when headache free after reverting to EM, using high-resolution MR techniques to map the transverse relaxation rates R2, R2* and R2' in RN, SN and PAG. For technical reasons, PAG was not imaged during the CDH phase of her illness. During the CDH phase of her illness, respective R2* values were reduced compared to normal in the RN and SN to 30.1 m/s and 31.45 m/s. Similarly, R2' in RN and SN were abnormally low at 6.62 m/s and 6.72 m/s compared to normal. Subsequent headache free studies demonstrated that R2* and R2' in the RN became 40.1 m/s and 15.47 m/s respectively, and in the SN, 40.25 m/s and 15.19 m/s respectively. These values were similar to EM patients and normal controls. The R2' in PAG during EM for this subject was increased at 6.88 m/s but elevated compared to controls. Daily headache in this patient was associated with chronic activation of pain networks that included RN and SN. Resolution of headache was associated with resolution of activation, although there was evidence for persistent PAG dysfunction, as previously reported. To the best of our knowledge, this case represents the first objective correlation of functional changes in brainstem nociceptive networks with clinical features of TM and its response to treatment.

Cortical Inhibition Is Reduced in Chronic and Episodic Migraine and Demonstrates a Spectrum of Illness

“…Some preliminary work along these lines has already been reported: brain stem changes in PCM appear to resolve after effective treatment. 25 A complete picture of brainstem-cortex relationships in PCM, over the evolution of the disorder, should be the goal of investigators in this area: we feel that the goal is attainable with the appropriate techniques of both neuroimaging and TMS-based functional studies as reported here.…”

Brainstem Dysfunction in Chronic Migraine as Evidenced by Neurophysiological and Positron Emission Tomography Studies*

“…Some preliminary work along these lines has already been reported: brain stem changes in CM appear to resolve after effective treatment. 36 A complete picture of brainstem-cortex relationships in CM, over the evolution of the disorder, should be the goal of investigators in this area: we feel that the goal is attainable with the appropriate techniques of both neuroimaging and TMS-based functional studies as reported here.…”

Red nucleus structure and function: from anatomy to clinical neurosciences

“…Recent pathophysiological theories suggest that migraine may be a disorder of the neurovegetative and nociceptive brainstem, and that local imbalances in the activity of hypothalamic and brainstem circuitry could be implied in the initiation and termination of migraine attacks (May 2017 ). Although the involvement of RN in such circuitry in the human brain is yet to be clarified, some fMRI studies report intense activation and hyperoxia of bilateral RN during both spontaneous and visually-triggered migraine (Welch et al 1998 ; Cao et al 2002 ; Aurora et al 2004 ). More recently, resting-state fMRI has been used to study functional connectivity of brainstem structures in migraineurs, reporting altered functional connectivity between RN, parietal lobe and cerebellum (Huang et al 2019 ).…”