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