John Stein, Magdalen College, Oxford University, UK

1. D R T The role of magnocellular neurones in neurodevelopmental disorders: dyslexia, dyspraxia, ADHD, autism and explosive aggression John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust (www.dyslexic.org.uk), Dyers & Colourists, Esmee Fairbairn, Garfield Weston and Wellcome Trusts, BBC Children in Need

3. Pontine visual magnocellular neurone projecting to cerebellum (1970s - Mitch Glickstein, Alan Gibson)

4. 10% are large magnocellular cells (100x p- cells in area) - for timing visual events: fast responses, high sensitivity to contrast, motion & flicker; control focus of visual attention & eye movements. They are very vulnerable. Most retinal ganglion cells are small (parvocellular): for colour, fine detail, high contrast They are less vulnerable.

5. The visual magnocellular system inputs to the ‘dorsal stream’ which directs visual attention & eye movements.

6. Parkinson’s Disease

7. The beta ‘straitjacket’ – Beta activity reduces movement. Gamma activity increases it

8. Continuous HF stimulation eliminates low f. oscillations, hence alleviates dyskinesias

9. STN stim reduces alpha & beta power

10. Central Neuropathic Pain • Pain generated by central pain matrix in the absence of any peripheral nociception • Associated with 10-15 hz oscillations in pain network • DBS of sensory thalamus or PAG can eliminate these oscillations • Then pain goes as well • BP↓ correlates with pain↓ • Also bronchodilation (asthma)

11. When the pain network oscillates at c.10 Hz, this is felt by the patient as pain Deep brain electrodes record Anterior Cingulate Somaesthetic cortex (S1) stimulate Thalamus Peri-aqueductal grey (PAG)

14. Volume 326, Issue 8446, 13 July 1985, Pages 69–73 Originally published as Volume 2, Issue 8446 VISUOMOTOR PERCEPTION AND READING IN DYSLEXIC CHILDREN J. Stein, S. Fowler

15. Developmental Dyslexia • Reading and spelling significantly below that expected from a person’s age and general intelligence, despite good health, adequate teaching and supportive family background • It is a genetically based neurological ‘syndrome’ – not just involving reading. • Associated with lower gamma oscillations in EEG • Other poor readers may be ‘garden variety’, because of v. low intelligence, lack of home or teaching support

16. Reading is difficult! 30% of US & UK pupils leave school with a reading ability that is worse than an average 11 year old! Hence 30% of adults are effectively illiterate and very ill- equipped for modern life. Reading failure is the commonest cause of childhood misery depression, even suicide Commonest disability among College students OR through frustration, dyslexics turn to aggression and crime; 75% of those in jail are illiterate.

17. Dyslexia has a real neurobiological basis; it is not just poor teaching, laziness and stupidity • Association with other neurodevelopmental disorders (SLI, ADHD, dyspraxia, autism spectrum) • Often difficult birth • Delayed crawling, walking, speaking • Mispronunciations, lisps, spoonerisms, ‘glue ear’ when learning to speak • Left/right confusions • Association with autoimmunity • Genetic basis – family history, gender • Anatomicalbrain differences – cortical ectopias, smaller thalamic magnocellular neurones, left arcuate, right cerebellum attenuation • Physiological differences: abnormal EEG oscillations, unstable visual & auditory attention - poor auditory and visual sequencing, eye control & pronunciation

18. Reading is primarily a visual process Visual processing

19. The visual magnocellular system inputs to the ‘dorsal stream’ which directs visual attention & eye movements.

20. Many children complain of visual difficulties with reading. Often their eyes oscillate when they try to read. This is due to impaired visual magnocellularfunction

21. The visualmagnocellularsystem and dorsal stream are impaired in dyslexics • 30% smaller LGN magnocellspost mortem • Reduced and delayed evoked brain waves • Reduced gamma waves • Reduced visual motion sensitivity • Oscillating eye control • Reduced activation of cortical motion areas (FMRI) • Lower sensitivity to contrast • Lower sensitivity to flicker • Lower stereoacuity • Reduced visual jitter • Weaker visual attention - slower visual search • Visual crowding • Mini left neglect - clock drawing • Prolonged line motion illusion • Reduced Ternus effect

22. Abnormal magnocells in dyslexic brain

23. The visual magnocellular system stabilises the eyes to avoid visual wobble Unwanted image motion, ‘retinal slip’ Feedback to eye muscle control system Detected by M- system Visual stability Identify letter order Locks eyes on target Orthographic skill Phonological skill

25. Weak magnocellular system causes unstable vision - oscillopsia “The letters go all blurry” “The letters move over each other, so I can’t tell which is which” “The letters seem to float all over the page” “The letters move in and out of the page” “The letters split and go double” “The c moved over the r, so it looked like another c” “The p joined up with the c” “d’s and b’s sort of get the wrong way round” “The page goes all glary and hurts my eyes” “I keep on losing my place”

26. Interventions that improve visual magnocellular function can often improve eye control, hence reading In half of all dyslexics viewing through yellow or blue coloured filters can rebalance input to the visual M- system. Reading improves by av. 6 months in 3 months Also in older children fixation exercises can stabilise binocular fixation and greatly improve reading

27. Although they do not mediate colour vision magnocells are most sensitive to yellow light. Soin some children yellow filters canboost magnocellular input, hence improve visual motion sensitivity and binocular control, hence improve reading

28. Oxford Oxford yellow filters (negative blue) cut short wavelengths (blue) most

30. Yellow filters can significantly improve reading in c. 25% of dyslexics

32. Oxford blue filters (negative yellow) cut long wavelengths (red and green) most

33. Blue filters entrain the suprachiasmatic nucleus to seasonal day length hypothalamus Blue light Diurnal rhythms M-system

34. Blue makes the letters keep still!

35. Blue filters can greatly improve reading in another 25% of dyslexic children

36. Blue filters at 3am reduced melatonin secretion in undergraduates by 27%

38. Many dyslexics suffer migraine headaches • Blue can relieve their headaches • Yellow often makes them worse!

39. headache hypothalamus Blue light Diurnal rhythms M-system

40. Damien Hirst wears blue filters

41. Changes in single word reading after 3 months

42. Visual magno deficit causes many dyslexics to confuse the order of letters!

43. The visual/orthographic and auditory/phonological pathways

44. Many, but not all, dyslexics have phonological problems, probably caused by mild auditory magnocellular impairments

45. 2nd formant ascends in frequency for ‘b’; but descends for ‘d’. Subtle hearing impairments may reduce sensitivity to these changes in sound frequency

47. Developmental Dyslexics are less sensitive to changes in sound frequency and intensity. • Slow frequency changes in speech are tracked in real time by large magnocells in the auditory system 2 Hz FM 40 Hz FM 500 Hz pure tone 240 Hz FM Witton, Talcott, Hansen, Richardson, Griffiths, Rees, Stein & Green, 1998

48. Altered gamma sampling in Auditory Cortex in Dyslexia Katia Lehongre , Franck Ramus , Nadige Villiermet , Denis Schwartz , Anne-Lise Giraud - Neuron Volume 72, Issue 6 2011 1080 - 90

49. Impaired auditory magnocells in dyslexia? • Large ‘magnocellular’ neurones in the auditory brainstem signal changes in sound frequency and amplitude • Dyslexics have smaller magnocellular neurones in medial geniculate N. • They have lower AM & FM sensitivity • Poorer gamma sampling • Thus dyslexics’ poor phonology may result from impaired development of their auditory magnocells

50. Auditory and visual magnocellular sensitivity determines over half of differences in children’s reading ability Magnocellular sensitivity seems to be the most important determinant of overall reading ability Encouraging because can be improved by training