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Editorial
. 2012 Aug;32(11):803-12.
doi: 10.1177/0333102412453952. Epub 2012 Jul 13.

The enigma of the dorsolateral pons as a migraine generator

D Borsook, R Burstein
Editorial

The enigma of the dorsolateral pons as a migraine generator

D Borsook et al. Cephalalgia. 2012 Aug.

Abstract

In this editorial, we integrate improved understanding of functional and structural brain stem anatomy with lessons learned from other disciplines on brainstem function to provide an alternative interpretation to the data used to support the brainstem migraine generator theory.

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Figures

Figure 1
Figure 1
Anatomical correlation with dorsal pons activation. To re-examine the dorsal pons activation images from (6) we superimposed them on MRI anatomical and brainstem atlas slices [adapted from Duvernoy's Atlas of the Human Brainstem and Cerebellum (34)] of the same region. The area highlighted by dashed lines (in red) corresponds to the bold signal in the fMRI images on top. It can be seen that there is minimal, if any, activation in the PAG. Instead, activation is seen in the cuneiform nucleus, rostral trigeminal nuclear complex, the locus coeruleus and the inferior colliculus. N., nucleus.
Figure 2
Figure 2
Activation in the DLP across different conditions as measured by functional magnetic resonance imaging (fMRI). Examples of DLP activation in migraine (top, reproduced from (65) with permission), neuropathic pain in response to cold (middle left image, reproduced from (27) with permission), and experimentally induced pain (middle right image, reproduced from (26) with permission) and in breath holding (bottom, reproduced from (32) with permission). Note that the horizontal slice for breath holding has been flipped vertically from the original to align with the other figure. The x and y coordinates are provided in the top left hand corner for each slice. The diagram on the right provides a reference point to the level of the 3 horizontal sections. White arrows indicate location of DLP. N, nucleus.
Figure 3
Figure 3
Detailed anatomy of the rostral dorsolateral pons and caudal midbrain. Identification of nuclei follow reference (34). N, nucleus.
Figure 4
Figure 4
(A) The migraine circuit, showing peripheral and central structures involved in nociceptive drive (dura, trigeminal afferents, trigeminal ganglion and trigeminal nucleus), modulation of nociceptive inputs (DLP, PAG) and cortical processing (thalamus, primary somatosensory cortex). (B) Principles that govern brainstem modulation of nociceptive drive during migraine. Activation of nociceptors, for example by cortical spreading depression (CSD), mild head trauma in migraine patients or inflammation, triggers activity in central trigeminovascular neurons. The magnitude of activation is then enhanced by insufficient synaptic inhibition due to PAG deficiency or due to abnormally enhanced synaptic strength caused by overactive pain facilitatory neurons in the PAG. (C) Brainstem ‘state of tone’ can limit afferent nociceptive drive in migraine-susceptible individuals. Brainstem activity, like that in other parts of the brain, fluctuates over time and such fluctuations may correlate with functional processing (66) that may be adaptive or not. This applies to modulation of nociceptive signals. The effectiveness or gating of these signals (whether they exceed brainstem tone and are therefore inhibited) depends on the threshold of neural networks that modify these afferent signals. Thus, the robustness of the ‘gate’ that allows nociceptive signals to drive central trigeminovascular neurons (and thus headache) is dictated by brainstem tone. Since tone may vary over time (diurnal, stress, hormonal, sympathetic drive, cortical and subcortical influences, etc.), the threshold to limit afferent signals will vary: when the brainstem tone is high (red dot below line of migraine threshold (MT), nociceptive signals are inhibited or limited; and when the brainstem tone is low (red dot above MT), afferent signals are not effectively blocked. Three functional brainstem states are defined in this model: 1) normal state: when cyclical phase brainstem activity is high (less sensitive to stimuli), the potency of pain facilitation (enhanced synaptic strength in the dorsal horn) is too high to allow normal nociceptive signals from the periphery to ‘drive’ the central neurons into the active state (left); 2) threshold state: At threshold, the system has reached a primed state that could tip into a functional state that would allow for nociceptive drive from the dura to activate the central trigeminovascular neurons (middle); 3) migraine state: When cyclical brainstem activity is high (more sensitive to stimuli), nociceptive signals from the periphery ‘drive’ the central neurons into the active state (right). In migraineurs, the state of brainstem tone may be unstable or less robust than in healthy individuals by prophylactic and thus they may be susceptible to activation of the cascade of networks that trigger the migraine attack by normal afferent nociceptive signals, which would be inhibited in healthy individuals or prophylactic treatment.
Figure 5
Figure 5
CNS cyclical process and brainstem thresholds. Genetic, physiological, pharmacological, social and other interactions define migraineurs’ susceptibility. When processes are in synchrony (a harmonic or repetitive frequency), the model suggests that the migraine potential is sub-threshold (red circle); however, when these are altered either in magnitude, phase or duration, the system becomes unstable and the migraine threshold is exceeded. These components affect the brainstem tone as shown on the right of the figure for the interictal state: 1) cortical processes affect subcortical processing; 2) afferent input through the trigeminal ganglion is normal; 3) trigeminal nucleus function is normal/unchallenged; 4) DLP function is normal or not activated; 5) PAG functioning is not challenged; 6) brain systems acting on the brainstem are in a balanced tone. During migraine, however, we postulate the following cascade of events: 1) normal cortical inhibition of brainstem pathways is altered; 2) there is an afferent barrage of nociceptive input from trigeminal ganglion neurons to 3) the spinal trigeminal nucleus; 4) there is increased activation of the DLP; 5) there is diminished brainstem inhibition of nociceptive signals resulting from altered modulatory/inhibitory tone by the PAG; and 6) all this results in increased afferent inputs to higher brain centers that themselves may be sensitized or affected by brainstem nuclei.
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