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A neural mechanism for exacerbation of headache by light
- 1. A neural mechanism for exacerbation of headache by light Rodrigo Noseda, Vanessa Kainz, Moshe Jakubowski, Joshua J Gooley, Clifford B Saper, Kathleen Digre, & Rami Burstein
- 2. Migraine – definition Unilateral throbbing headache Nausea, irritability, fa tigue Recurring Neurological
- 3. Migraine – definition Often aura present. Examples…
- 5. Migraine – definition - aura
- 6. Migraine – definition - aura
- 7. Migraine – definition - aura
- 8. Origin of migraines: neurological This is not what causes migraines This is not what causes migraines JJ Brennan, 1990
- 9. Migraine - origin Meninges irritated Pain signal sent from dura to brain
- 10. Migraine - origin Trigeminovascular thalamus 4 pathway (TvP) 1 dura Dura mater spinal trigeminal nucleus posterior thalamus trigeminal ganglion spinal 2 trigeminal nucleus 3
- 11. Migraine - origin TvP sensitization thalamus 4 during migraine 1 dura Throbbing, tendern ess, allodynia Lowered pain trigeminal ganglion spinal threshold 2 trigeminal nucleus 3
- 12. Retinal pathways
- 13. Retinal pathways Image-forming pathway Rods & cones RGCs optic nerve LGN visual cortices Visual cortices Visual cortic es
- 14. Retinal pathways Intrinsically photosensitive RGC (ipRGC) pathway ipRGC projects to SCN Intergeniculate leaflet Olivary pretectal nucleus
- 15. Retinal pathways Intrinsically photosensitive RGC pathway purposes Biological clock Melatonin suppression Pupil size
- 17. Migraines & light Light ↑ migraine pain Photophobia Unique mechanism
- 18. Migraines & light ipRGC pathway involved in light sensitivity in migraine Mechanism otherwise unknown
- 19. Proposed mechanis …for light- minduced increase in migraine intensity
- 20. Proposed mechanism light triggers ipRGCs Dura mater optic nerve neurons common to pain in eyes & meninges From retina Neurons common to Green lines: eye & meninges pain TvP
- 21. Evidence: human Light-sensitive migraines in rod/cone damage blindness Blind & sighted mig- raineurs equivalent
- 22. Evidence: ipRGC projections Injected ipRGC-binding fluorescent protein gene virus into rat eye 2 versions: small & large amount of tracer
- 23. Evidence: ipRGC projections RGC projections in lateral posterior thalamic nucleus group (LP) LP: early visual area
- 24. Evidence: ipRGC projections RGC projecting through LP toward Po Po: dorsocaudal region of posterior thalamic nuclear group
- 25. Evidence: ipRGC projections 100μm Some RGC projections actually in Po Po: a somatosensory region
- 26. Evidence: Po retrograde tracing Fluorogold traced Po incoming signals Signals to Po from Dura-sensitive SpV layers: 1, 5 RGCs Top: RGCs activating Po Bottom: SpV neurons activating Po
- 27. Evidence: single-cell recording Po: 20 dura-sensitive neurons found; 14/20 also light-sensitive Control: 14 non-dura neurons. Found also not light-sensitive.
- 28. Evidence: single-cell recording If any dura stimulation produces firing, neuron dura-sensitive Dura-sensitive units: 2X firing for ambient light, 4X for bright Dorsal Po had 9/13 dura & light-sensitive neurons
- 29. Evidence: single-cell recording Dura-sensitive neuron light response varied in: Latency (0.4-280s) Fire rate Brightness Discharge time Decay pattern response A C D B E
- 30. Evidence: single-cell recording Variations fit migraine profile. Explains: occasional worsening w/ lower light variation in persistence of light-induced pain wave-like pain intensity
- 31. Evidence: cortical projections Mapped Po projections with TMR-dextran Fit with migraine symptoms Primary somatosensory cortex: pain Retrosplenial cortex: memory loss
- 32. Evidence: cortical projections Motor cortex: weakness, clumsiness Parietal association cortex: attention-deficits Primary visual cortex: visual disturbances Secondary visual cortex: aura?
- 34. Final linking pathway Migraine pain path Dura trigeminal ganglion (1) dura-sensitive neurons in SpV (2) Po in thalamus (3)
- 35. Final linking pathway Light path ipRGC activated LP in thalamus (3) Po in thalamus (3)
- 36. Final linking pathway Common path Po in thalamus (3) Cortical areas that process pain (4)
- 37. Final linking pathway Result Po relays migraine pain intensity Light ↑ Po activity Po relays more intense pain signal
- 38. Evidence summary Blind with ipRGCs can have photophobic migraines Staining: RGCs & SvN both connect to Po in thalamus
- 39. Evidence summary Single-cell recordings found cells responding to both dura and light Subjective light response variations mirror those of Po neuron responses
- 40. Future application: neurofeedback Neurofeedback to reduce brain activity in affected regions? Mental exercises guided by neuroimaging (especially EEG) that can specifically reduce or increase activity in Woman practicing mindfulness targeted regions of the meditation while brain is scanned by a commercial EEG device brain
- 41. Future application: neurofeedback Girl doing EEG-based neurofeedback exercises
- 42. Future application: neurofeedback Simplified descriptions of types of EEG ‘waves’ recorded by EEG devices, and research-based interpretations of the waves. Certain waveforms may be migraine-specific & could be reduced with neurofeedback
- 43. Future application: neurofeedback Simplified descriptions of types of EEG ‘waves’ recorded by EEG devices, and research-based interpretations of the waves
- 47. IGL: Intergeniculate leaflet LP: lateral posterior thalamic nuclei Po: posterior thalamic nuclear grp
- 48. Acronyms defined APT: anterior pretectal nucleus Au1: primary auditory cortex; AuD, secondary auditory cortex, bsc: brachium superior colliculus CTB: Cholera toxin subunit B – used for anterograde labelling DLG, dorsal part of lateral geniculate nucleus. ec: external capsule IGL: intergeniculate leaflet – involved in circadian rhythm entrainment ipRGCs: intrinsically photosensitive retinal ganglion cells LDDM: laterodorsal thalamic nucleus, dorsomedial. LDVL: laterodorsal thalamic nucleus, ventrolateral LP: lateral posterior thalamic nuclei LPLC: lateral posterior thalamic nucleus, laterocaudal LPLR: lateral posterior thalamic nucleus, laterorostral LPMC: lateral posterior thalamic nucleus, mediocaudal LPMR: lateral posterior thalamic nucleus, mediorostral M1: primary motor cortex M2: secondary motor cortex OPT: olivary pretectal nucleus PoT: posterior thalamic nuclear group, triangular Pli: posterior limitans thalamic nucleus
- 49. Acronyms defined PLR: Pupillary light response PtA: parietal association cortex Po: Posterior thalamic nuclear group (dorsocaudal Po NB because it contains anterograde-labeled retinal neurons, and is also dura-sensitive) rAAV-GFP: recombinant adeno-associated virus containing a green fluorescent protein reporter gene (rAAV-GFP). RGCs: retinal ganglion cells RSA: retrosplenial agranular cortex RT: Thalamic reticular nucleus S1: primary somatosensory cortex S1BF: primary somatosensory barrel field S1Tr: primary somatosensory trunk region S1DZ: primary somatosensory dysgranular region SCN: Suprachiasmatic nucleus SpV: Spinal trigeminal nucleus TMR-dextran: anterograde tracer tetramethylrhodamine-dextran conjugate V1B: binocular area of the primary visual cortex V2L: lateral area of the secondary visual cortex V2M: mediolateral area of the secondary visual cortex VPL: ventral posterolateral thalamic nucleus VPM: ventral posteromedial thalamic nucleus
Editor's Notes
- 2:
- These are sensory disturbances, usually visual that last seconds to minutes, and mark the onset of a migraine
- What a scintillating scotoma aura looks like
- What a scintillating scotoma aura looks like
- What a scintillating scotoma aura looks like
- What a scintillating scotoma aura looks like
- On the left is an artist’s proposed causeof migraines, the migraine monsterSource: J.J. Ignatius Brennan, Migraine Man Suffers Again, 1990The bottom right is another thing that is not the cause of migraines.
- 1: The migraine process usually begins when the meninges around the brain are irritated in some way. This is usually chemical in origin.2: Following this, nociceptive signals are transmitted from the dura mater to the brain via the (switch slide) trigeminovascular pathway
- 2: This pathway’sfirst order neurons project to the spinal trigeminal nucleus, and the second from laminae 1 and 5 (that is, layers 1 and 5) of the spinal trigeminal nucleus to the posterior thalamus. trigeminal ganglion spinal trigeminal nucleus
- 1 – This pathway is activated for a very prolonged period during a migraine attack, which causes it to sensitize. The result of this overactivation is…2 – a throbbing headache, scalp and neck muscle tenderness, and pain in response to normally benign stimuli. In other words, this pain pathway emerging from the skull is so hyperactive that it takes very little to set it off, so heartbeat, which normally isn’t even consciously registered, becomes a painful stimulus due to the greatly lowered threshold of activation required for this nerve to register a sensation as pain – thus the mild throb of blood pumping through veins is enough to make the nerves in the trigeminovascular pathway fire – and in a lot of patients, the same can go for things like light touches on the skin. The pain threshold drops for everything connected to this nerve pathway.
- So, in order to link this up with light, a bit of background on retinal pathways.
- 1: This is the standard visual pathway that takes in light via the rods and cones, then transmits the signals to the retinal ganglion cells, which then relay the information down the optic nerve, through the lateral geniculate nucleus of the thalamus, then to the visual cortex for processing.
- (after title) It’s called such because the retinal ganglion cells involved in this pathway respond directly to light via a photopigment they contain named melanopsin. They can also be activated by rods and cones – but are nonetheless not involved in generating images from light. It projects to the suprachiasmatic nucleus aka the brain’s primary circadian rhythm controller, the intergeniculate leaflet, which is also involved in the light/dark cycles, and the olivarypretectal nucleus, involved in involuntary pupil response. So, not surprisingly, this pathway’s main functions are (flip slide)
- entraining the biological clock, including suppressing melatonin release in response to light, and adapting the size of the pupil to the level of ambient light.
- 1 – extreme pain increase in response to light2 – Pain in the eyes also appears in response to light during a migraine, which is known as photophobia – so not only does the regular migraine pain worsen, eye pain is added on.3 – The way this occurs is to be unique to migraine – the characteristics of the light sensitivity associated with migraine don’t match those seen with most of the other causes of photophobia, which are usually either directly related to problems with the eye itself, things that cause eyestrain including disorders like dyslexia, and cranial pathologies like meningitis. In light of this, the researchers hypothesized a new mechanism to account for these differences, essentially, that…(switch slides) (beginning of next slide) photic signals transmitted from the retina through the optic nerve eventually find their way to central neurons that process nociception in the meninges. This would be a completely unique photophobia etiology that has no precedent in other photophobia-inducing disorders.
- Intrinsically photosensitive RGC (ipRGC) pathway is hypothesized to be the one involved in the light-sensitivity, and this was generally accepted, though not quite provenBeyond the fact that this pathway was probably involved (which wasn’t even proven), the mechanism through which this worsening occurs was otherwise unknown until this publication
- Proposed pathway:1 – Light activates the Intrinsically photosensitive retinal ganglion cell pathway, which then sends photic signals through the optic nerve, which eventually find their way to central neurons that process nociception in the meninges. This would be a completely unique photophobia etiology that has no precedent in other photophobia-inducing disorders.This can be seen on the image, essentially, the red line shows an incoming pathway from the retina that links to the same set of nociceptive neurons that the trigeminovascular pathway from a few slides back (TvP) had as an endpoint. The green line is the TvP. This common endpoint has projections throughout the brain, especially the cortex, which are shown by the blue lines.However, in order to understand the first segment, it’s important to note that
- ~20 blind and sighted migraine sufferers were compared, and found to display no significant differences in age of onset, time of first migraine, incidence of auras, or level of increase in pain in response to light. It should be noted that these blind subjects had very disparate causes for their blindness. The majority still had eyes, but those who only had sockets, and those with complete retinal haemorrhaging (so no retina at all) didn’t have migraine photophobia.Shows that image-forming pathways are not involved in migraines, which essentially proves that the mechanism occurs through the intrinsically photosensitive RGC (ipRGC) pathway, unless there’s a yet-undiscovered retinal pathway – but this seems really unlikely.
- 1 – So for their next experiment, they injected a recombinant adeno-associated virus carrying a green fluorescent protein reporter gene set up to bind specifically to retinal ganglion cells - into the eyes of living rats. It causes the entirety of the RGCs to glow green after blue light is applied to them, and this includes their projecting axons and dendrites. It is thus possible to identify what areas of the rest of the brain the cell projections innervate.2 – With a small amount of the tracer, the axons and dendrites of the retinal ganglion cells are very clearly outlined, but many will be completely missed. With a larger amount, considerably fewer cells will be missed, but the virus will start being taken up by cells that are not intrinsically photosensitive retinal ganglion cells.The tissue was stained post-mortem, turning the projections black, so keep that in mind for upcoming images
- 1 – So there was clear innervation of early visual regions in the thalamus, specifically the lateral posterior thalamic nuclei (LP), among others. This was exactly as expected, no surprisesAt first glance, it looks like the projections really only reach the lateral posterior thalamic nucleus group,{{[switch slide]}}but if we zoom out a bit…
- {[end of last]}, and examine the large tracer quantity stains, there’s a very clear descent of these fibres towards the lower region, that is, the dorsocaudal region of the posterior thalamic nucleus group, or Po, as they labelled it. Also, when they zoomed in on the small tracer quantity stains in Po, {{[switch slide]}}
- …it became very clear that the RGCs were not merely projecting toward the dorsocaudal region of the posterior thalamic nuclear group - they were in fact also present there, albeit to a lesser degree than in the LP region lateral posterior thalamic nucleus group (LP) above it. I encircled the visible neurons in this particular subsection of the slice with red lines, because they were a bit tricky to pick out compared with the lateral posterior thalamic nucleus group (LP)
- They next wanted to ensure that region Po was actually receiving signals from both dura-sensitive and light-sensitive regions on a neuronal level. Theythus injected the retroactive tracer Fluorogold into the Po region, which resulted in labelling of cells in the spinal trigeminal nucleus or SpV for a reason I don’t fathom, and also retinal ganglion cells, especially intrinsically photosensitive retinal ganglion cells. You can see a bit of their results in the image: on top are individual RGCs that lit up in response to Fluorogold, on the bottom are spinal trigeminal nucleus neurons labelled in the same way. This confirmed that the light-sensitive and dura-sensitive pathways intersect here. However, this doesn’t prove that the two necessarily interact despite their intersection in this region. To do this, individual cells must be found that respond to both light and dura stimulation.
- With extracellular single-cell recordings, 20 posterior thalamus neurons found that responded both to dura stimulation, and to light. 14 neurons not dura-sensitive were found as controls, and they also happened to be unresponsive to both bright light and ambient light. The image is of a single cell and a simulated microelectrode being attached to it to measure its electrophysiological activity - and thus its action potentials when they occur - just to give those of you who don’t know a basic idea of how single-neuron electrophysiological recording works.
- So, this I how the groups were determined: neurons that responded to electrical, mechanical, and/or chemical irritation of the dura mater were determined to be dura sensitive neurons. Those that had a massive increase in firing rate in response to light were light-sensitive. 14 that had neither were used as controls. Most of these neurons were in the dorsal border of the posterior thalamic nuclear group. Those in other regions were usually unresponsive to light, more ventral = less likely to be responsive to both. The responsive to neither controls were found in every location checked.
- Within these dura-sensitive neurons, there was incredible variation in how they responded to light. There are 5 examples of this at the bottom. Different neurons would respond at different rates to different levels of brightness – some would respond to quickly to bright light, others slowly, and sometimes vice versa for mid-range or low-light. For example, the neuron D on the middle right and B on the bottom left took 280 and 0.3s to respond respectively, but each was exposed to the same mid-level brightness of 3000 lx. Some would respond quickly regardless, other slowly no matter what, although brightness often modulated responses in consistent ways within each neuron, but it was not consistent across neurons. Length of discharge was all over the place, but again consistent within each neuron at each brightness: IE neurons A and C each had exposure to extremely bright light, but A discharged for ~20s, while C responded for around 540s. The decay pattern in the rate of firing was also chaotic, IE neuron C had a gradual decline and almost asymptotic rate of firing, that doesn’t even return halfway to baseline after 540s of firing, whileneuron A responded strongly and erratically for around 20 seconds, then its firing dropped off as suddenly as it began. Number of action potential per second in response went from a peak of 6, like neuron D, to as high as 50-ish for neuron C. Some neurons would gradually increase in firing rate in response to light, like neuron E, others would start firing suddenly, as with C, with everything in between. And so on – it was erratic, but usually consistent in a single neuronThe latency had huge range – IE the one on the bottom-left took around 367ms to response to the light stimulation, while the one on the middle-right took 280s.
- These variations actually fit really well with how migraines are experienced. The variation in how these dura and light sensitive cells respond to different variations in intensity of light explains some odd characteristics of migraines. Oftentimes migraines will actually worsen in response to lower light, sometimes the increase in pain brought on by light exposure will be very lasting, other times disappear as soon as the light is gone – it seems likely that this is caused by the number of cells a migraine-sufferer has that respond in a particular way to a particular brightness. Since even subtle, and perhaps indetectable variations in brightness can bring on variations in these thalamic cellular responses, it seems likely that the erratic nature of stimulus-induced worsening of migraines may in fact be due to cell response variation, and not simply be random.The wave like pain-intensity fits nicely with the wave like responses to light and dura stimulation many of the dorsocaudal posterior thalamic nuclear groupneurons display. This provides still further evidence for this model
- 1 – they were found to project to the primary somatosensory cortex, which is strongly involved with pain2 -
- 1 – this is straightforward, disruptinig the primary brain area responsible for movement would naturally cause lack of coordination, and muscle weakness makes sense, since a lack of coordinated response in this area would make it diffucult to send strong enough signals to the muscles to make them move effectively – that is, the signals passing down to the muscles would be weak if the area is disrupted..3 – this has to do with the basic visual disturbances, like the disruption of single – I guess you’d call them “pixels” of visual imagery. I suspect this manifests in tandem with disruptions to the secondary visual cortex. It may have to do with the simple vision disregulations that occur with some migraines, such as loss of parts of vision. Actually, I suspect this works in tandem with the secondary cortex to form the migraine aura, with the precise manifestation of the aura having to do with whether the main disruption is in the primary or secondary visual cortex.4 - The secondary visual cortex is invovled with piecing together basic, almost pixel-based information passed through the primary visual cortex, and arranging it into simple patterns like lines and circles – otherwise known as “phosphenes”. Disturbances in this area produce “phosphenepseudohallucinations”, in which one might see floating dot, lines or circles, or “waviness,” random colours, etc. This fits extremely well with the sort of symptoms experienced with a large portion of migraine aura. Both images on the right are, again, auras, since I didn;’t show enough of them at the beginning of the talk – but this time, note their simlilarities with phosphenes. The one on the bottom is small dots, which is again, a phosphene. In fact, when I was at SfN, there was a TMS demonstration, and I volunteered. They used it to disrupt my secondary visual cortex, and the net result looked remarkably like a single dot in the bottom right image. The one on the top right may represent a primary visual cortex aura, wherein the part of the ability to see is simply lost.
- This includes modifications of their original hypothesis, which were largely correct.
- Something irritates or is irritating the dura mater, which results in noicafferent pathways from the meninges
- Intrinsically photosensitive retinal ganglion cells are activated by light, resulting in a projection to the thalamus that travels through the lateral posterior thalamic nuclei, then to the Posterior thalamic nuclear group, specifically the dorsocaudal. Same location the dura activation arrived from.
- This is a somatosensory region that has links with the dura mater.
- 3 – single neuron electrophysiological recordings found neurons that respond both RGCs were exposed to light, and when the dura mater was stimulated in some way.
- 1 – migraine-sufferingblind subjects who lack the ability to form images, but still have intact intrinsically photosensitive retinal ganglion cells can still have a painful response to light during a migraine, while blind migraineurs who have complete destruction of the retina do not exhibit this response.2 – Neuron staining and labelling techniques found projections from the dura-sensitive regions and from retinal ganglion cells that both reached the same location in the thalamus – the Dorsocaudalposterior thalamic nuclear group.