Tracking the Visual Guidance of Movement from Jack Eccles to Fish

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 NeedDRT1

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

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.

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

Parkinsons DiseaseThe beta straitjacket Beta activity reduces movement. Gamma activity increases it

Continuous HF stimulation eliminates low f. oscillations, hence alleviates dyskinesiasSTN stim reduces alpha & beta power

Central Neuropathic PainPain generated by central pain matrix in the absence of any peripheral nociceptionAssociated with 10-15 hz oscillations in pain networkDBS of sensory thalamus or PAG can eliminate these oscillationsThen pain goes as wellBP correlates with painAlso bronchodilation (asthma)

Anterior CingulateSomaesthetic cortex (S1)Thalamus Peri-aqueductal grey (PAG) stimulaterecordDeep brain electrodesWhen the pain network oscillates at c.10 Hz, this is felt by the patient as pain

Volume 326, Issue 8446, 13 July 1985, Pages 6973Originally published as Volume 2, Issue 8446VISUOMOTOR PERCEPTION AND READING IN DYSLEXIC CHILDRENJ. Stein, S. Fowler

Developmental DyslexiaReading and spelling significantly below that expected from a persons age and general intelligence, despite good health, adequate teaching and supportive family backgroundIt is a genetically based neurological syndrome not just involving reading. Associated with lower gamma oscillations in EEGOther poor readers may be garden variety, because of v. low intelligence, lack of home or teaching supportReading 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 suicideCommonest disability among College studentsOR through frustration, dyslexics turn to aggression and crime; 75% of those in jail are illiterate.

16Dyslexia 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 birthDelayed crawling, walking, speaking Mispronunciations, lisps, spoonerisms, glue ear when learning to speakLeft/right confusionsAssociation with autoimmunity

Genetic basis family history, gender Anatomical brain 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 & pronunciationReading is primarily a visual process

Visual processingThe visual magnocellular system inputs to the dorsal stream which directs visual attention & eye movements.

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

The visual magnocellular system and dorsal stream are impaired in dyslexics30% smaller LGN magnocells post mortem Reduced and delayed evoked brain wavesReduced gamma wavesReduced visual motion sensitivityOscillating eye controlReduced activation of cortical motion areas (FMRI) Lower sensitivity to contrastLower sensitivity to flickerLower stereoacuity Reduced visual jitterWeaker visual attention - slower visual searchVisual crowdingMini left neglect - clock drawingProlonged line motion illusionReduced Ternus effect

Abnormal magnocells in dyslexic brainUnwanted image motion, retinal slipLocks eyes on targetVisual stabilityIdentify letter orderFeedback to eye muscle control systemThe visual magnocellular system stabilises the eyes to avoid visual wobbleDetected by M- systemOrthographic skillPhonological skill

24Weak magnocellular system causes unstable vision - oscillopsiaThe letters go all blurryThe letters move over each other, so I cant tell which is whichThe letters seem to float all over the pageThe letters move in and out of the pageThe letters split and go doubleThe c moved over the r, so it looked like another cThe p joined up with the cds and bs sort of get the wrong way roundThe page goes all glary and hurts my eyesI keep on losing my placeInterventions 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 monthsAlso in older children fixation exercises can stabilise binocular fixation and greatly improve reading

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

Oxford yellow filters (negative blue) cut short wavelengths (blue) mostOxford

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

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

Blue lightM-systemhypothalamusDiurnal rhythmsBlue filters entrain the suprachiasmatic nucleus to seasonal day lengthBlue makes the letters keep still!

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

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

37Many dyslexics suffer migraine headachesBlue can relieve their headachesYellow often makes them worse!

Blue lightM-systemheadachehypothalamusDiurnal rhythms

Damien Hirst wears blue filtersChanges in single word reading after 3 months

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

The visual/orthographic and auditory/phonological pathwaysMany, but not all, dyslexics have phonological problems, probably caused by mild auditory magnocellular impairments

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

Witton, Talcott, Hansen, Richardson, Griffiths, Rees, Stein & Green, 1998

40 Hz FM

240 Hz FM2 Hz FMSlow frequency changes in speech are tracked in real time by large magnocells in the auditory systemDevelopmental Dyslexics are less sensitive to changes in sound frequency and intensity.

500 Hz pure toneKatia Lehongre , Franck Ramus , Nadige Villiermet , Denis Schwartz , Anne-Lise Giraud - Neuron Volume 72, Issue 6 2011 1080 - 90

Altered gamma sampling in Auditory Cortex in Dyslexia

Impaired auditory magnocells in dyslexia?Large magnocellular neurones in the auditory brainstem signal changes in sound frequency and amplitudeDyslexics have smaller magnocellular neurones in medial geniculate N.They have lower AM & FM sensitivityPoorer gamma samplingThus dyslexics poor phonology may result from impaired development of their auditory magnocellsAuditory and visual magnocellular sensitivity determines over half of differences in childrens reading ability

Magnocellular sensitivity seems to be the most important determinant of overall reading abilityEncouraging because can be improved by trainingMagnocellular systems also project strongly to the cerebellum the brains autopilot.

Cerebellum

Decreased activation in cerebellum of adult dyslexics learning visual tracking52

Balancing on one leg, eyes openControlHead movement DyslexicThe Cerebellum & Neural DevelopmentThe cerebellum is the brains autopilot for timing and motor prediction, balance and skilled movementsMagnocellular systems all project to the cerebellum Cerebellum is part of the magno systemCerebellum is underactive in many dyspraxics, dyslexics, autisticsExplains coordination and pronounciation problems and may contribute to reading difficultiesSensorimotor Basis of DyslexiaLow visual magnocellular sensitivity - orthographic weaknessLow auditory magnocellular sensitivity - phonological problemsLower motor magnocellular sensitivity in coordination, poor balanceLower kinaesthetic magnocellular sensitivityMagnocellular Neurones Very vulnerable genetics, immune attack, poor nutrition. Impaired m- cell development has been found in prematurity, foetal alcohol syndrome, developmental dyslexia, dyspraxia, dysphasia, ADHD, ASD, Williams syndrome, Tourettes schizophrenia, depressionM- cell high dynamic sensitivity requires high membrane flexibility provided by local environment of essential fatty acids, particularly omega 3s, found in fish oilsHence particularly vulnerable to omega-3 deficiencyA system of large neurones specialised for temporal processing tracking changes in light, sound, position etc. for direction of attentionLarge, fast conduction, fast transmission, high anisotropy All derive from same lineage, express same surface antigen, CAT 301Found throughout the whole brain: visual, auditory, skin, muscle proprioceptors, cerebral cortex, hippocampus, cerebellum, brainstemParticularly important for synchronising EEG gamma oscillations, reducing low frequencies

Pathological low frequency oscillations in ADHD, Tourettes, autismnormalWhat causes this general magnocellular impairment?GeneticImmune SystemNutrition

Sir John Bell, Magdalen,1974-Are particular chromosomal markers/sites associated with poor reading? Analyse the DNA of father, mother and their dyslexic and normally reading children >400 Oxford; 100 Boulder (US) familiesEU consortium; 1000 families, 2000 cases, 2000 controls, 50,000 markers per case Genetic linkage/associations

Dyslexia is highly hereditary; 7 genes associated so farC6p ? KIAA 0319 gene migration, cell~cell recognition and immune control (MHC system) C18p, omega 3s?APOB?ZNF804AROBODCDC2KIAA 0319 is strongly expressed in dorsal visual cortical (magnocellular) pathway

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C6 KIAA 0319 gene controls neuronal migration during early brain development in utero. Underexpression in dyslexics may explain ectopias and impaired development of magnocellular neurones

3 dyslexia genes (KIAA, DCDC2, ROBO) control neuronal migration and may cause these ectopias

Left hemisphere language areas that activate less in dyslexics

High incidence of immune anomalies in dyslexics & ADHDThe Immune System & NeurodevelopmentDevelopment of magnocellular neurones is known to be regulated by the MHC cell recognition immune system on short arm of chromosome 6 (C6p)Linkage of poor reading and ADHD to DCDC2 and KIAA0319 genes on C6pImmune disorders in dyslexics, ADHD and their familiesBSXB autoimmune mice exhibit cortical ectopias similar to those seen in dyslexicsEvidence for antimagno antibodies in serum of mothers with dyslexic & autistic children

?Melanocortin receptor 5Cod Liver Oil Queue, 1949

Most Britons were better fed in 1943 at the height of the Atlantic blockade than in 1983 Dr Hugh Sinclair, Magdalen College, Oxford

Aged 28, he persuaded the WWII government to provide free cod liver oil and orange juice to all pregnant mothers and young children20% of the brain consists of omega-3, mainly Docosahexanoic acid (DHA, 22-6) Your brain contains 100 grams of DHAEssential for flexible membranes rapid neural responsesBut less than 25% of young males eat any fish at all!Treatment with 3 FAs can improve reading, attention, impulsivity, antisocial behaviour

Modern Western diet is appalling! Too much of the 4 dangerous Ss: sugar, saturated fat, salt, omega-6sNot enough micronutrients: omega 3 from fish, vitamins A&D, Fe, I, Zn, Se

Omega-3s enable fast neuronal function - 50% of the membrane enclosing this magnocellular nerve cell consists of DHA Fast magnocellular neurones are especially vulnerable to lack of fish oil omega 3 (n-3) fatty acids

In order to open and signal fast, their ionic channels need flexible n-3 fatty acids in the surrounding membrane

Durham RCT - Omega 3 EPA & DHA supplements helped dyspraxic & dyslexic children to improve their concentration and their reading

Intermittent explosive disorder (IED) is associated with high beta EEG, poor discrimination of emotional signal, poor sociability! Also reduced gamma power74

Improving diet can reduce violent criminal behaviour by one third! Omega3, vitamins & mineral supplements reduced offences in Aylesbury Young Offenders Institute by 1/3rd1133 offences: ITT- Active vs Placebo: -26.3 % (p 0.03)

Supplementation for at least 2 weeks: -34.0% Violent offences only: -37.0%

Fish is good for the heart & brain!By increasing membrane flexibility, omega 3 DHA & EPA speed up neuronal Na, K, NMDA, GABAa currents; ie accelerate neuronal responsesEnhance magnocellular timing functions?Improve gamma samplingIncrease neurite outgrowth and synapse formationIncrease neurogenesis; decrease apoptosis Hence improve memory (Alzheimers)Strengthen hemispheric lateralisation Increase good cholesterol (HDL)Protect against inflammation Reduce pain transmission (TRPV1 receptors)Cooking fish has made my brother a celebrity!

April 14th, St Catherines College, Oxford - Neurobiology and Treatment of Dyslexia www.oxfordkobe.comThe Dyslexia Research Trust has taken advantage of the presence of the many international experts gathered in Oxford for the 3rd Oxford Kobe Symposium on Dyslexia in different scripts, to ask some of them to give overview lectures for a non specialist audience. Al Galaburda (Harvard), Ken Pugh (Yale), Trichur Vidyasagar (Melbourne U), Kristen Pammer (Australian National U.), Nina Kraus (NorthWestern U, Chicago) and John Stein (Oxford) will give lectures on dyslexia genetics, neurology, visual and auditory processing and treatments. These will enable important outcomes of the Symposium to be shared with dyslexics themselves, teachers, SEN practitioners, doctors, and parents.DRTTake home messagesMagnocellular neurones are vital for the brains rapid timing functions, particularly gamma (>40 hz) wavesGamma waves bind and synchronise brains separate processing functions visual, auditory, motor etc.Excess delta, theta, alpha, beta waves are pathologicalSeen in Parkinsons, Dystonia, Dyspraxia, Dyslexia, ADHD, Tourettes, AutismMagnocellular deficit found in these conditionsAssociated with too much low frequency power and reduced high frequency gamma wavesDue to a combination of genetic and environmental factors Consequences of visual magnocellular deficit can also be alleviated using blue or yellow filtersM- function can often be improved by omega 3 supplements78

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L coneM coneS coneWavelength (nm)Relative Activation of ConesFowler Yellow Lenses - D 65 Illuminant

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L coneM coneS coneWavelength (nm)Relative Activation of ConesFowler Yellow Lenses - D 65 Illuminant

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Chart1716.80.9

yellowplacebomonthsIncrease in literacy in 3 months

Sheet1readingspellingyellow76.8placebo10.9

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yellowplacebomonthsIncrease in literacy

Sheet2

Sheet3

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L coneM coneS coneWavelength (nm)Relative Activation of ConesFowler Blue Lenses - D 65 Illuminant

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coneL coneM coneS coneL coneM coneS coneL coneM coneS coneL coneM coneS coneL coneM coneS coneL coneM coneS coneL coneM coneS 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