A neural mechanism for exacerbation of headache by light
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Transcript of A neural mechanism for exacerbation of headache by light
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
Migraine – definition Unilateral throbbing
headache
Nausea, irritability,
fatigue
Recurring
Neurological
Migraine – definition Often aura present. Examples…
Migraine – definition - aura
Migraine – definition - aura
Migraine – definition - aura
Origin of migraines:neurological
This is not what causes migraines
This is not what causes migraines
JJ Brennan, 1990
Migraine - origin
Meninges irritated
Pain signal sent from dura to brain
Migraine - origin
Trigeminovascular pathway (TvP)
Dura mater spinal trigeminal nucleus posterior thalamus
thalamus
dura1
4
spinal trigeminalnucleus
trigeminalganglion
23
Migraine - origin
TvP sensitization during migraine
Throbbing, tenderness, allodynia
Lowered pain threshold
thalamus
dura1
4
spinal trigeminalnucleus
trigeminalganglion
23
Retinal pathways
Retinal pathwaysImage-forming pathway
Rods & cones RGCs optic nerve LGN visual cortices
Visual cortices
Visual cortices
Retinal pathways
ipRGC projects to SCN Intergeniculate
leaflet Olivary pretectal
nucleus
Intrinsically photosensitive RGC (ipRGC) pathway
Retinal pathways
Biological clock
Melatonin suppression
Pupil size
Intrinsically photosensitive RGC pathwaypurposes
Migraines and light
Migraines & light
Light ↑ migraine pain
Photophobia
Unique mechanism
Migraines & light
ipRGC pathway involved in light sensitivity in migraine
Mechanism otherwise unknown
Proposed mechanism…for light-induced increase in migraine intensity
light triggers ipRGCsoptic nerveneurons common
to pain in eyes & meninges
Fromretina
Neurons common to eye & meninges pain
Green lines: TvP
Dura mater
Proposed mechanism
Light-sensitive migraines in rod/cone damage blindness
Blind & sighted mig-raineurs equivalent
Evidence: human
Injected ipRGC-binding fluorescent protein gene virus into rat eye
2 versions: small & large amount of tracer
Evidence: ipRGC projections
RGC projections in lateral posterior thalamic nucleus group (LP)
LP: early visual area
Evidence: ipRGC projections
RGC projecting through LP toward Po
Po: dorsocaudal region of posterior thalamic nuclear group
Evidence: ipRGC projections
100μm
Some RGC projections actually in Po Po: a somatosensory region
Evidence: ipRGC projections
Fluorogold traced Po incoming signals
Signals to Po from
Dura-sensitive SpV layers: 1, 5
RGCs
Evidence: Po retrograde tracing
Top: RGCs activating PoBottom: SpV neurons activating Po
Po: 20 dura-sensitive neurons found; 14/20 also light-sensitive
Control: 14 non-dura neurons. Found also not light-sensitive.
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
Evidence: single-cell recording
Evidence: single-cell recording Dura-sensitive neuron light response varied in:
Latency (0.4-280s) Discharge time
Fire rate Decay pattern
Brightness response
A C
B
D
E
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
Evidence: cortical projections
Mapped Po projections with TMR-dextran
Fit with migraine symptoms
Primary somatosensory cortex: pain
Retrosplenial cortex: memory loss
Evidence: cortical projections Motor cortex: weakness,
clumsiness
Parietal association cortex: attention-deficits
Primary visual cortex: visual disturbances
Secondary visual cortex: aura?
Final TheoryandSummary
Final linking pathway
Migraine pain path
Dura trigeminal ganglion
(1) dura-sensitive
neurons in SpV (2) Po in thalamus (3)
Final linking pathway
Light path
ipRGC activated LP in thalamus (3) Po in thalamus (3)
Final linking pathway
Common path
Po in thalamus (3) Cortical areas that
process pain (4)
Final linking pathway
Result
Po relays migraine pain intensity
Light ↑ Po activity
Po relays more intense pain signal
Evidence summary
Blind with ipRGCs can have photophobic migraines
Staining: RGCs & SvN both connect to Po in thalamus
Evidence summary
Single-cell recordings found cells responding to both dura and light
Subjective light response variations mirror those of Po neuron responses
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 targeted regions of the brain
Woman practicing mindfulness meditation while brain is scanned by
a commercial EEG device
Future application: neurofeedback
Girl doing EEG-based neurofeedback exercises
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
Future application: neurofeedback
Simplified descriptions of types of EEG ‘waves’ recorded by EEG devices, and research-based interpretations of the waves
Thanks for coming!
Extras, don’t show
IGL: Intergeniculate leaflet
LP: lateral posterior thalamic nuclei
Po: posterior thalamic nuclear grp
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
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