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The Current Status of the Magnocellular Theory of Dyslexia John Stein, John Stein, Magdalen Magdalen College, College, Oxford Oxford University, UK 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 D R T
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The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Mar 26, 2015

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Page 1: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

The Current Status of the Magnocellular Theory of Dyslexia

John Stein, Magdalen John Stein, Magdalen College, College,

Oxford University, UKOxford 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

DDRR

TT

Page 2: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

1/3rd of English Children Leave School Unable to Read

Page 3: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Backward Reading

• Many children are poor readers simply because of low intelligence (‘garden variety’) or v. poor teaching

• Developmental dyslexia is reading significantly below that expected from child’s age and intelligence, despite good health, teaching and family support

• Dyslexia is more than reading - a neurological syndrome, involving slower processing, inattention, poor sequencing in all domains, poor short term memory

• ? caused by impaired development of ‘magnocellular’ timing neurones

Page 4: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Many possible levels of analysis

Genetics

Neuroanatomy

Neurophysiology

Psychophysiology

Cognition – phonology & orthography

Behaviour–reading & spelling

Page 5: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Definitions of Dyslexia

• Highly contentious: descriptive or aetiological?• Phonological definition purely descriptive and

tautologous – cf high blood sugar• Aetiological definitions – informed by

understanding cause eg insulin lack• Dyslexia – many possible levels; none map

perfectly onto each other• Magnocellular hypothesis is a unifying aetiological

theory linking genetics, physiology, cognition

Page 6: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Magnocellular Neurones

• Impaired m- cell development has been found in prematurity, foetal alcohol syndrome, developmental dyslexia, dyspraxia, dysphasia, ADHD, ASD, Williams, schizophrenia, depression, violent personalities

• High dynamic sensitivity requires high membrane flexibility provided by local environment of essential fatty acids, particularly omega 3s, found in fish oils

• Hence very vulnerable to omega-3 deficiency

• A system of large neurones specialised for temporal processing – tracking changes in light, sound, position etc. for direction of attention

• Large, fast conduction, fast transmission, high anisotropy

• All express same surface antigen, CAT 301

• Found throughout the whole brain: visual, auditory, skin, muscle proprioceptors, cerebral cortex, hippocampus, cerebellum, brainstem

Page 7: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Chromosome sites we have linked to reading skill

C6p ?KIAA 0319 gene - cell~cell recognition and immune control (MHC system)

Also DCD gene

Finnish pedigree

DYX1 gene

ROBO 3 gene

Page 8: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.
Page 9: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

KIAA 0319 is strongly expressed

in dorsal visual

magno- cellular

pathway

Page 10: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

C6 KIAA 0319 controls neuronal migration during early brain development in utero. Downregulation in

dyslexics may explain ectopias and other mismigrations of magnocellular neurones

Page 11: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

2nd trimester ectopias in dyslexic brain. Seen also in auto immune mice

Page 12: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Abnormal magnocells in dyslexic brain

Page 13: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Dyslexia and the Immune System

• All magnocells (visual, auditory, motor) express common surface antigen – CAT 301

• Development of magnocellular neurones is known to be regulated by the MHC cell recognition immune system on chromosome 6p

• Linkage of poor reading to surface recognition gene KIAA 319 on Chromosome 6p close to MHC genes

• 50% of BSXB ‘autoimmune’ mice exhibit ectopias that are similar to those seen in dyslexic brains

• Our evidence that serum of mothers with dyslexic children contains antimagno antibodies

• Dyslexia is associated with autoimmune anomalies – allergies, eczema, asthma, lupus

Page 14: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Autoimmune conditions in dyslexics and controls

migraineuveitis

asthma

eczema

allergies

0

5

10

15

20

25

30

1 2 3 4 5

% a

ffect

ed Dyslexic

Control

High incidence of immune anomalies in dyslexics

Page 15: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Reading is primarily a visual process

Visual processing

Page 16: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Pathways through the visual system• Parvocellular

– High Spatial, Low Temporal frequencies

– Colour sensitive

• Magnocellular– Low Spatial, High

Temporal Frequencies– Insensitive to

isoluminant changes in colour

• Magnocellular deficit theory of dyslexia:•Deficit in the magnocellular system•Parvocellular system undamaged

Page 17: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Visual magnocellular system dominates dorsal visuomotor pathway -directs visual attention &

eye movements.

Page 18: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

The visual magnocellular system is impaired in poor readers

• 30% smaller LGN magnocells post mortem

• Reduced and delayed evoked brain waves

• Unstable eye control• Reduced visual motion sensitivity• Lower sensitivity to flicker• Lower sensitivity to low spatial, high

temporal frequency contrast gratings

• Reduced activation of cortical visual motion areas (FMRI)

• Lower stereoacuity • Poor visual sequential attention -

slower visual search

• All these claims are controversial -3 problems:

• Definition of magno- system; strictly only definable anatomically in periphery

• Selectivity of stimuli• Mild deficit requires highly

sensitive test to reveal it• Nevertheless in the last 10 years

90% of new research papers have supported magnocellular deficit

• Brent Skottun has written 15 papers criticising others work!

Page 19: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Abnormal magnocells in dyslexic brain (but only 5 brains!)

Page 20: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

DTI - Fewer large axons in left angular gyrus in dyslexics. Successful remediation increases their size

Page 21: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Delayed Brain Potentials Evoked by Moving Visual Stimulus (10 hz component)

Page 22: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Control

Dyslexic

Phase

Amplitude

Spectral Analysis(FFT) of steady state EEG

Page 23: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

***

Page 24: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Dyslexics have lower sensitivity to ‘jitter’, hence unstable vision

Page 25: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

0.00 2.00 4.00 6.00 8.00 10.00 12.00

60.00

80.00

100.00

120.00

Reading (s score)Eye discrepancy

Spelling (s score)Eye discrepancy

Vergence instability impairs reading; the greater the wobble, the worse is children’s reading

r = - 0.43

Page 26: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.
Page 27: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

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”

Page 28: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Although they do not mediate colour vision magnocells are most sensitive to yellow light. So in many children yellow filters can improve magnocellular function, hence visual motion sensitivity

and binocular control, hence improve reading

magnocells

Page 29: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.
Page 30: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Yellow filters can improve reading

Increase in literacy in 3 months

0

1

2

3

4

5

6

7

8

reading spelling

month

s

yellow

placebo

Page 31: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.
Page 32: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

B - Dull Shifting Y - Highly Labile

Blue light

M-system

headachehypothalamus

Diurnal rhythms

Page 33: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Blue makes the letters keep still!

Page 34: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Blue filters improve reading even more

Increase in literacy

0

2

4

6

8

10

12

14

reading spelling

month

s

blue

placebo

Page 35: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Blue or yellow filters can improve magno function hence binocular control

Convergence

beforebefore

afterafter

0

5

10

15

20

25

30

cms

Page 36: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.
Page 37: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

• Also blue can improve migraine headaches

• Many dyslexics suffer severe migraine

• Yellow often make them worse!

Improvement

Page 38: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

B - Dull Shifting Y - Highly Labile

Blue light

M-system

headachehypothalamus

Diurnal rhythms

Page 39: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Reduction of melatonin secretion by blue light at night confirms it affects suprachiasmatic clock

0

20

40

60

80

100

120

neutral blue

%

Page 40: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

The colour choice of 297 reading disabled 9 year olds

no colour preference49%

blue 25%

yellow 26%

1

2

3

Page 41: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Reading age increase in 3 months

0

1

2

3

4

5

6

7

8

nil grey normal,readingrecovery

(phonology)

yellow occlusion search blue omega 3sRA

in

cr.

(mo

nth

s)Elucidating the role of the visual system in reading has enabled us to develop

techniques for helping most of the dyslexics we see

*

* *

****

Page 42: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Many, but not all, dyslexics

have phonological

problems; these may be caused

by mild auditory magnocellular impairments

Page 43: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

2nd and 3rd formants ascend in frequency for ‘b’;

but descend for ‘d’.

Subtle auditory impairments may reduce sensitivity to these changes in sound frequency

Page 44: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

FM sensitivity determines phonological skill

Page 45: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Impaired auditory magnocells in dyslexia?

• Large neurones staining for CAT 301 in the auditory brainstem signal changes in sound frequency and amplitude

• Dyslexics have smaller magnocellular neurones in medial geniculate N.

• Lower AM & FM sensitivity, correlate with phonological deficit

• Reduced brainstem auditory evoked potentials correlate with reading deficit

• Thus dyslexics’ poor phonology may result from impaired development of auditory magnocells

Page 46: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Auditory and visual magnocellular sensitivity determines over half of differences in children’s reading ability

Thus the most important determinant of overall reading ability appears to be low level magnocellular sensitivity. Encouraging because this can be improved by training

Page 47: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Sensorimotor Basis of Dyslexia

Low visual magnocellular sensitivity - orthographic weakness

Low auditory magnocellular sensitivity - phonological problems

Lower motor magnocellular sensitivity – in coordination, poor balance

Lower kinaesthetic magnocellular sensitivity

Page 48: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Fish oils

C18 melanocortin receptor 5

Omega-3s protect neuronal function - 50% of the membrane enclosing this magnocellular nerve cell consists of a long chain omega 3 fatty acid (DHA); improves neuronal function because very flexible

Page 49: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Modern Western diet is a disaster!

• Too much: salt, sugar, saturated fat, omega 6s (from corn and soya bean oil)

• Too little: minerals, fibre, vitamins A & D, omega 3s from fish

• Far too much omega 6 - ratio of omega 6/omega 3 should be 1/1; currently it is 7/1!

Page 50: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Not very romantic!

Page 51: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Fatty acid deficiency in dyslexia and young

offenders?• Many children with

neurodevelopmental probems and young offenders have clinical signs of omega 3 deficiency:

• Low blood and brain n-3 FAs

• Omega 3 FA (fish oil) supplements can v. significantly improve m- function, attention, reading and violent offences

Page 52: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

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

and their reading (Richardson & Montgomery)

Increase in Reading age in 3 months

0

1

2

3

4

5

6

7

8

9

10

n-3 placebo

RA

incr

ease

n-3

placebo

Page 53: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Omega–3, vitamins & mineral supplements reduced offences in Young Offenders by 1/3rd (Gesch et al.)

1133 offences: ITT- Active vs Placebo: -26.3 % (p ‹ 0.03)

0

0.2

0.4

0.6

0.8

1

1.2

1.4

Before Supplementation During Supplementation

Rat

io o

f R

ate

of D

isci

plin

ary

Inci

dent

s S

uppl

emen

tatio

n/B

asel

ine

Active

Placebo

Error bars at 2SE to indicate the 95% confidence interval

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

Page 54: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

Conclusions Conclusions

• Most dyslexics have impaired magnocellular function

• may result from:GeneticGenetic vulnerability

AntibodyAntibody attack Fatty Fatty acid acid (fish oil)(fish oil) deficiency

• This knowledge is exciting because these weaknesses cancan be remedied: auditory and phonological training, eye exercises, coloured filters, fish oil supplements

Page 55: The Current Status of the Magnocellular Theory of Dyslexia John Stein, Magdalen College, Oxford University, UK Supported by The Dyslexia Research Trust.

John SteinJohn Stein

Visit The Dyslexia Research Trust

(www.dyslexic.org.uk)

Wobbles, warbles & fish!

DDRR

TT