These presentation notes are not for
commercial use. They are strictly for
personal use in conjunction with
Professor John Stein’s webinars from
the LDC 2017.
04/03/2017
John Stein,
Magdalen College,
Oxford University, UK
D
D
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The Magnocellular Theory of
Developmental Dyslexia
The real work was done by Sue Fowler, Tricia Riddell, Piers Cornelissen, Joel Talcott,
Priti Kashyap, Joe Taylor, Ceris Mumford, Tony Monaco, Anna Pitt
Supported by The Dyslexia Research Trust (www.dyslexic.org.uk),
Esmee Fairbairn, Garfield Weston,Tolkien & Wellcome Trusts, BBC Children in Need
Reading is primarily a visual process
Visual processing
Sequencing
Sequencing
R
T
• The essence of reading is the ability to rapidly sequence the
seen letters in a word in the right order
• Then to translate this visual sequence into an auditory
sequence of the sounds they stand for
• Background knowledge of how each spoken word can be
split into a unique sequence of separate sounds (phonemes)
• These processes require rapid signalling of the shifts of visual
attention, of the eyes and of auditory attention to the order
of the sounds in a word
• Visual and auditory ‘transient’ (‘magnocellular’) systems
mediate these sequencing computations
Many dyslexics
complain of
visual difficulties
with reading.
Often their eyes
wobble when
they try to read
This may be due
to weak visual
magnocellular
function
Magno- & parvocellular retinal
ganglion cells
The visual magnocellular system provides 90% of the input
to the ‘dorsal visuomotor stream’ which guides visual
attention & eye movements for sequencing & reading.
10% are large magnocellular
cells (<50x larger area than pcells) - for timing visual
events: fast responses, high
sensitivity to low contrast, to
motion & to flicker; control
focus of visual attention & eye
movements, highly vulnerable
Dorsal stream
Most retinal ganglion cells
are parvocellular (small):
for colour, fine detail, need
high contrast (less
vulnerable)
04/03/2017
The development of the visual
magnocellular system is impaired in poor
readers (retina & LGN)
Retina
• Lower contrast sensitivity
at low spatial and high
temporal frequencies
• Reduced visual gap
detection
• Lower flicker fusion
• Reduced spatial frequency
doubling illusion
• Reduced jitter
compensation
Retinal M- cell sensitivity is lower in dyslexics (Frequency doubling illusion Pammer & Wheatley, 2001)
Lateral Geniculate
Nucleus
• 30% smaller and
disorganised LGN
magnocell layers, post
mortem
• In vivo, thinner LGN
magnocellular layers - 7T
structural MRI
The Jitter Illusion
After exposure to an annulus of jittering random dots, retinal
magnocells adapt to discount this amount of movement. Hence
subsequently stationary dots appear to jitter until the adaptation
recovers. Hence the duration of this jitter indexes magnocellular
sensitivity. It is much shorter in dyslexics.
Left LGN M- layers were thinner
in 14 dyslexics (7T MRI)
Giraldo-Chica et al 2015
Abnormal magnocells in the LGN in a
dyslexic brain
Impaired M- cell input also compromises the dorsal
visuomotor stream
• Reduced and delayed evoked
brain waves
• Reduced visual motion
sensitivity
• Reduced visual motion
illusions
• Insensitivity to motion
defined form
• Reduced activation of cortical
motion areas (FMRI)
• Unstable visual fixation
• Saccadic intrusions during
smooth pursuit eye movts.
Inaccurate saccades
Inaccurate vergence
Slower, less accurate visual
attention
Slower, less accurate visual
sequencing
Slower visual search
Slower visual/auditory
cross modal cuing
Increased visual crowding
‘Mini’ left neglect - clock
drawing
04/03/2017
Dyslexics have reduced motion sensitivity (indexing M- cell sensitivity)
compared with both chronological and younger reading age matched
controls (Gori et al. 2015)
V5/MT (the ‘where’ system) is less active in dyslexics
V5/MT is active in
visual attention
and eye movements
Amount of V5/MT
activation in
response to
movement predicts
individuals’ reading
fluency
Dyslexics
Controls
Eden et al., 1996
40
Coherent Motion at Threshold (%)
Dyslexics are not poor at
all visual tests; most
have normal sensitivity
to static visual form
(Talcott et al. 1996)
EEG measures?
35
30
25
20
• Rapidly moving visual
stimuli set up brain
waves in the visual
cortex which can easily
be recorded from the
scalp at low cost.
• Moving visual stimulus:
signal reaches the brain
20 ms more slowly in
dyslexics
15
10
5
0
Con (n = 29)
Dys (n = 16)
Coherent Form at Threshold (%)
40
35
30
25
20
15
10
5
0
25
Visual cortex brain waves responding to
a moving visual stimulus
Con (n = 29)
Dys (n = 16)
Frequency analysis of interoccipital EEGs
20
Controls
(magno)
Dyslexics
(parvo)
“These results show … a causal
relationship between magnocellulardorsal route deficits and developmental
dyslexia, virtually closing a 30-year long
debate”
15
Power µwatt/Hz
10
5
0
0
5
10
15
Frequency (Hz)
20
25
Average steady state VEP spectra (microwatt/hz) in response to chequer
board stimulation at 5 Hz.
F1/F2 Biomarker?
Gori, S., Seitz, A. R., Ronconi, L., Franceschini, S., & Facoetti,
A. (2015). Multiple causal links between a magnocellulardorsal pathway deficit and developmental dyslexia. Cerebral
Cortex (New York, N.Y.)
04/03/2017
Visual instability blurs vision
The visual magnocellular system stabilises
the eyes to avoid visual ‘wobble’ & enables
you to remember the order of letters in a word
Unwanted
image motion,
‘retinal slip’
Feedback to
eye muscle
control system
Detected by Msystem
Visual
stability
Locks eyes
on target
Orthographic
skill
Identify letter
order
Phonological
skill
A weak magnocellular system causes
unstable vision - oscillopsia
Vergence instability
• The eyes also have to
converge for near vision
when reading
“The letters go all blurry”
“The letters move over each other, so I can’t tell
which is which”
• Control of vergence eye
movements is dominated by
the visual magno system
“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 vergence eye movement
control system is the most
vulnerable to drugs and
disease
“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”
• Many poor readers have
unstable vergence control
Reading (s score)
Eye discrepancy
Spelling (s score)
Eye discrepancy
Motion sensitivity (M- cells) predicts orthographic
reading skill in everyone
Vergence
instability impairs
reading; the
greater a child’s
vergence
wobble, the
worse is his
reading
READING
S SCORE
100.00
80.00
60.00
r = - 0.43**, n= 71
Honney R. et al, 2006
Orthographic Discrimination (% Correct)
120.00
100
80
60
40
20
n = 792; r = - 0.38
0
0
0.00
2.00
4.00
6.00
8.00
Eye wobble degs.
10.00
12.00
10
20
30
40
50
60
Coherent Motion at Threshold (%)
70
80
04/03/2017
Summary (vision)
• The visual system needs to be able to identify letters
and their order in a word
• Letter identification is ok in dyslexics, but letter
ordering is not
• M- system stabilises vision and indicates when eyes
move
• Thus a rapid and accurate M- system is crucial for
sequencing the letters in a word correctly
• The M- system is impaired in dyslexics
• Hence their letter ordering is impaired
• Therefore their orthographical memory is impaired
• Hence their phonological memory is affected too
The auditory/phonological pathway
Many, but not all,
poor readers also
have phonological
problems, partly
caused by auditory
magnocellular
impairments
Auditory Sequencing for Reading
• Need to be able to sequence words in
sentences, syllables in words, phonemes in
syllables
• Requires hearing accurately the changes in the
amplitude and/or frequency of the sounds and
remembering their order
• Which enables you to sequence the sounds
correctly
• Dyslexics are slower and less accurate at this
sequencing
• Probably due to impaired development of their
auditory magnocellular system
• Improving their detection of sound amplitude
& frequency changes improves their reading
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
3
40 Hz FM
2 Hz FM
0.16
40 Hz FM
p<0.001
p=0.027
0.12
2
0.08
1
500 Hz
pure tone
0.04
0.00
0
Dyslexics (N=21)
Controls (N=23)
Dyslexics (N=21)
Detection Threshold (M od. Index )
•
Detection Threshold (M od. Index)
2nd formant ascends in frequency for ‘b’;
but descends for ‘d’ & ‘g’. Subtle auditory processing
impairments in dyslexics may reduce sensitivity to these
changes in sound frequency and amplitude, hence they may
underlie their phonological problems
240 Hz FM
0.012
p=0.360, N.S.
Controls (N=23)
240 Hz FM
0.008
0.004
0.000
Dyslexics (N=21)
Controls (N=23)
Witton, Talcott, Hansen, Richardson, Griffiths, Rees, Stein & Green, 1998
04/03/2017
FM sensitivity determines phonological skill
Meltham 10 year olds (N = 32); rs = 0.7; p< 0.001
Nonword Naming (max. 30)
30
25
20
15
10
5
0
0
2
4
6
8
10
12
14
16
18
Sensitivity to rhythm predicts reading skills in both
dyslexics and controls
Auditory FM Threshold (Mod. Index) Witton et al 1996
L. arcuate link to Broca’s increases in size after successful
auditory remediation of backward reading (MEG)
ARCUATE
Auditory (AM & FM) and visual (motion) magnocellular
sensitivity explains over half of the differences
between individual children’s reading abilities
Thus magnocellular sensitivity seems to be the most important
determinant of overall reading ability; this is v. encouraging
because M- sensitivity can be improved by simple techniques:
coloured filters, rhythm training
Impaired auditory magnocells
in dyslexics?
• Large ‘magnocellular’ neurones in the auditory brainstem
signal changes in sound frequency and amplitude
• Dyslexics have smaller magnocellular neurones in the
medial geniculate nucleus
• They have lower frequency, AM & FM sensitivity
• Frequency sensitivity predicts their non word reading skills
• Poor phonological skill may result from impaired
development of auditory magnocells
• Musical training, particularly in rhythm, may improve
auditory m- cell responses, hence improve reading
The magnocellular systems project strongly to
the cerebellum – the ‘brain’s autopilot’
Cerebellum
04/03/2017
Cerebellum controls balance: one leg, eyes open
Control
Head movement
Dyslexic
Cerebellar areas whose volume predicts reading ability in
110 TD participants from 8-18 yrs old (PING database)
Connects with
left hemisphere
language areas
Decreased activation in cerebellum of adult
dyslexics learning visual tracking
R. Cerebellum assists
speech comprehension
Dyslexics R. cerebellum
activates well for slow
frequency changes, but
poorly for rapid ones.
Difference between fast
and slow changes
predict individuals’
phonological skills
Confirms that the
cerebellum is involved in
reading and its activity is
reduced in dyslexics
Embodied Cognition & Dyslexia
• The brain represents cognitive processes by subliminal activation of
sensorimotor systems, eg. the foot area of the motor cortex is activated
when reading the word ‘foot’; this ‘Embodied cognition’helps us to
understand and use the word
• The cerebellum is the brain’s autopilot for balance, skilled movements
and embodied cognition
• The magnocellular systems for timing and sequencing all project to the
cerebellum
• The cerebellum is underactive in many dyslexics
• This explains their coordination problems, and their poor embodied
cognition
• Hence training children to be aware of how their body moves (mindfull
movement) can greatly help their cognitive development, including
reading and social interactions
Low visual magnocellular
sensitivity - orthographic
weakness
Low auditory magnocellular
sensitivity - phonological
problems
Sensorimotor Basis of
Dyslexia
Lower motor magnocellular
sensitivity – incoordination,
poor balance, impaired
embodied cognition
Lower kinaesthetic and
proprioceptive magnocellular
sensitivity
04/03/2017
Magnocellular Neurones
• Very vulnerable. Impaired m• A system of large neurones
specialised for temporal processing
cell development has been
and sequencing– tracking changes
found in prematurity, foetal
in light, sound, position etc. for
alcohol syndrome,
direction of attention
developmental dyslexia,
dyspraxia, dysphasia, ADHD,
ASD, Williams syndrome,
schizophrenia, depression
• M- cell high dynamic
sensitivity requires high
membrane flexibility provided
by local environment of
essential fatty acids,
particularly omega 3s, found
in fish oils
• Found throughout the whole brain:
visual, auditory, skin, muscle
proprioceptors, cerebral cortex,
hippocampus, cerebellum,
brainstem
• Large, fast conduction, fast
synaptic transmission
• All derive from same lineage; they
all express the same surface
antigen, CAT 301
Genetic
vulnerability
Neurobiological
Level
Magnocellular
deficit
Slow
temporal
sequencing
Visual
processing
speed
Physiological
Level
Auditory
processing
speed
Slow graphemephoneme
translation
What causes
this general
magnocellular
impairment?
Genetic
Immune System
Nutrition
Genetic
linkage/association
• Are particular chromosomal markers/sites
associated with poor reading?
• Analyse the DNA of father, mother and
their poor and normally reading children
Behavioural
Level
• >500 Oxford (UK); 100 Boulder (US)
families
• EU consortium; 1000 families, 2000 cases,
2000 controls, 50,000 markers per case
Poor Reading
Dyslexia is highly hereditary; 15 chromosomal sites
and 9 genes have so far been discovered; these
strongly imply a neurological basis
Genetic Linkage in 400 Oxford Families
Chromosome 6p21, KIAA 0319, DCDC2
C6p ? KIAA
0319 gene cell~cell
recognition
and immune
control (MHC
system); also
DCDC2
C18p,
omega
3s?
Monaco et al 2000
04/03/2017
C6 KIAA 0319 gene controls neuronal migration
during early brain development in utero.
Underexpression in dyslexics may explain their
ectopias and the impaired development of their
magnocellular neurones
One gene
we’ve
discovered,
KIAA 0319, is
strongly
expressed in
the visual
magnocellular
system
3 dyslexia genes
(KIAA, DCDC2,
ROBO) control
neuronal migration
and may cause
these ectopias in a
dyslexic brain
Abnormal magnocells in dyslexic LGN
Dyslexia genes & neuronal migration
30
in dyslexics and
HighAutoimmune
incidence conditions
of controls
immune
anomalies in
dyslexics & their families
allergies
• Underexpression of KIAA, DCDC2, ROBO genes
all disrupt neuronal migration early in brain
development
25
• Later many of these genes seem to help to
control immune function
• This may cause magnocells to fail to develop
properly, to successfully contact with other
magnocells, and to remain immunologically highly
vulnerable
% affected
20
• Control the expression of cell surface recognition
(signature) molecules such as CAT 301
Dyslexic
15
Control
eczema
10
asthma
uveitis
5
migraine
0
1
2
3
4
5
04/03/2017
Dyslexia and the Immune System
• Development of magnocellular neurones is known to be
regulated by the MHC cell recognition immune system on
Chromosome 6p – eg KIAA 0319
• Linkage of poor reading to these surface recognition genes on
Chromosome 6p
• BSXB ‘autoimmune’ mice exhibit ectopias that are identical to
those seen in dyslexics
• Evidence for antimagno antibodies in serum of mothers with
dyslexic children
Melanocortin receptor
5 (MCR5)?
Monaco et al 2000
MCR5? - Cod Liver Oil Queue, 1949
‘Most Britons were better fed
in 1943 at the height of the
German blockade, than in 1983’
Dr Hugh Sinclair, Magdalen College,
Oxford
•
Aged 28, he persuaded the
WWII government to provide
free cod liver oil, malt and
orange juice to all pregnant
mothers and young children
20% of yr. brain membranes
(5 G) is docosahexanoic acid
(DHA – 22,6 n-3)
Essential for flexible and
electrostatic membranes –
rapid neural responses
You lose 5 mgm DHA/day
•
•
•
•
Now 75% of 18 yr olds eat
no fish at all. Av. IQ of
western populations is now
decreasing!
Fish Diet
Humans evolved in or near water
– providing a plentiful supply of
fish – main source of calories &
protein. The fish oils that were
incorporated into our nerve
membranes allowed our 10 fold
expansion of brain size and 100
fold increase in connections
compared with chimpanzees.
Even 100 years ago fish was our
main source of protein
But now 75% of 18 yr olds eat
no fish at all!
Modern diet is appalling!
Too much dangerous 3 S’s: sugar, salt, omega-6s
Not enough micronutrients: omega 3 from fish, vitamins A&D, I, Zn, Fe, Se
04/03/2017
A terminal effect of the 3 S’s
Long chain omega 3 polyunsaturated fatty acid (DHA)
enables fast neuronal function
DHA forms 20% of the
membrane enclosing this
magnocellular nerve cell
In order to open and signal
fast, ionic channels need
these flexible n-3 fatty acids in
the surrounding membrane
Fast magnocellular neurones
are therefore especially
vulnerable to lack of fish oil
omega 3 (n-3) fatty acids in
the diet.
•
•
•
•
•
•
•
•
•
Fish is essential for the heart & brain!
DHA increases membrane
flexibility, speeds up neuronal
Na, K, NMDA, GABAa
currents; ie accelerates
neuronal responses
This improves magnocellular
timing functions
Increases neurogenesis;
decreases apoptosis
Increases neurite outgrowth
(syntaxin) and synapse
formation
Hence improves memory
(Alzheimer’s)
Strengthens hemispheric
lateralisation
EPA protects against
inflammation
Reduces pain transmission
(TRPV1 receptors)
Prevents accumulation of
insoluble amyloid precursor
protein (Alzheimer’s)
Conclusions 1
Conclusions 2
• Weak magnocellular function results from:
Genetic vulnerability
Antibody attack
Fatty acid (fish oil) deficiency
• This knowledge is exciting because these
weaknesses can be remedied: auditory and
phonological training, coloured filters, fish oil
supplements
BUT…
•
Fundamental auditory, visual & motor temporal sequencing
requirements for successful communication, speech, reading,
attention, coordination and social ineractions are mediated by
magnocellular neuronal systems in the brain
•
Visual magnocellular weakness may cause visual perceptual
instability, hence letter position confusions fuzzy orthographic
representations, leading to poor orthographic skill for reading,
together with poor social communication
•
Auditory magnocellular weakness impedes breakdown of word
sounds into phonemes
low phonological skill
•
Magno systems also involve the cerebellum, so that dyslexics tend to
be incoordinated & clumsy with impaired embodied cognition
The ‘dyslexia
genes’ would not
be so common
unless they
provided some
selective
advantage. Many
dyslexics are
unusually creative
and excel when
‘holistic’ thinking
is required
04/03/2017
D
John Stein
R
T
Wobbles, Warbles &
Fish: the Magnocellular
Theory of Dyslexia
Visit
The Dyslexia Research Trust
(www.dyslexic.org.uk)