LANGUAGE, READING, & GENES Timothy C. Bates tim.bates@ed.ac.uk

LANGUAGE, READING, & GENES

Timothy C. Bates

tim.bates@ed.ac.uk

http://www.psy.ed.ac.uk/people/tbates/courses/y2

Three lectures: two main parts Patient Case Studies and Language

Box and arrow models of cognition

Genetics and cognition: Testing cognitive models using genetics Genes involved in reading: biological and

psychological explanations

Outline of part 1

How should we make models of the mind?

How can we test those models? How do we get new data to test those

models?

Where is the mind?

Where is your thinking happening? It is not obvious that your brain is important

Forward step Egyptians knew that head injury affected the mind

Backward step Aristotle (350BC)

Had a lot of the theory right, but the location… Thought mind was in the heart Head just a heat radiator

The Brain in 1836

1836: George Combe (1788-1858) 1 of 13 children to an Edinburgh Brewer. His trust founded the Edinburgh Psychology

Department with a private grant in 1906

Reported that if an injury exposed the brain, physically touching the exposed area could cause rather precise alterations in mental function Anticipates intracranial stimulation and EEG in the 1940s

Also, reported a visible swelling (increase in blood flow) during mental activity Anticipates the basis of fMRI by 150 years!

How shall we represent what is happening in the brain?

Richard Feynman:The power of a diagram

(c) J. Eric Slone www.FeynmanOnline.com

How shall we represent what is happening in the brain?

Brain as informationprocessor

Patients, boxes, and arrows

Paul Broca (1861) Patient with Brain damage: “Tan”

Dysfluent, severe problems with repetition and naming, less severe problems with auditory comprehension

Preserved memory, attention and object recognition.

Ergo: Language is localized within the brain Cognition is not unitary, but has separable

parts

Paul Broca Fractionates Cognition

CognitionOther

CognitionLanguage

X

Carl Wernicke (1874)

Broca's patient had poor language output Mildly impaired comprehension Severe fluency deficit.

By contrast, Wernicke reported a patient with comprehension difficulties: “jargon aphasia” Preserved fluency Very poor comprehension

From Broca to Wernicke

CognitionOther

CognitionLanguage

OtherCognition

Language Comprehension

Language Production

X X

Carl Wernicke’s Model: Arrows

“Schema of the Psychic Reflex” (1874)

a: Acoustic Centre: storage of “auditory word images”

b: Motor Speech Imagery

a b

Cognitive Boxes & Arrows

Lichtheim (1885) German-Jewish Physician

"The reflex arc consists in an afferent branch aA, which transmits the acoustic impressions to A; and an efferent branch Mm, which conducts the impulses from M to the organs of speech; and is completed by the commissure binding together A and M. When intelligence of the imitated sounds is superimposed, a connection is established between the auditory centre A, and the part where concepts are elaborated, B."

AM

B

am

Bastien 1888: More fractionation

Bastien (UK) reported brain damage data with preserved writing, spoken input and output, and poor reading.

OtherCognition

SpokenComprehension

SpokenProduction

WrittenComprehension

WrittenProduction

X

Bramwell’s Patient (1897)

26yr old Scottish woman. Shortly after giving birth, she had a

stroke. She was left “deaf” to speech. But said… "Is it not strange that I can hear the

clock ticking and cannot hear you speak? Now let me think what that means".

Bramwell: Auditory Agnosia“word meaning deafness”

Relevant facts She can understand print, so …

She retains knowledge of word meanings. She can hear and understand

environmental sounds, so … She is not deaf.

Why then can't she understand speech?

What we know

She can understand print: Must not have lost all

knowledge of word meanings.

She can understand environmental sounds So she is not deaf

So why can't she understand speech?

Printed words

Spoken word

Non-speech sound

Semantics

The diagrammatic notation

Boxes A system of knowledge System for processing

perceptual or cognitive information

Arrows A pathway of

communication between two systems

Printed words

Spoken word

Non-speech sound

Semantics

Claims of this diagram: 1

Single system of semantic knowledge Not one system for

each input modality Auditory stimuli have

different pathways to the semantic system spoken words non-speech sounds

Printed words

Spoken word

Non-speech sound

Semantics

Claims of this diagram: 2

Words use different pathways to the semantic system spoken words written words

Interaction is at the semantic level, not before non-speech sounds,

spoken words and written words cannot interact until they have reached the semantic level.

Printed words

Spoken word

Non-speech sound

Semantics

Building out: Auditory analysis

Both speech and non-speech sounds share early mechanisms of hearing.

How can we add a shared component for speech and non-speech sound?

Printed words

Spoken word

Non-speech sound

Semantics

Auditory processing?

Rules for Arrows

We will need two arrows from auditory processing…

1 for speech 1 for non-speech

Is that OK?

Printed words

All sounds

Semantics

Auditory processing

The diagrammatic notation

Boxes A system of knowledge system for processing

perceptual or cognitive information

Arrows

A pathway of communication between two systems

Printed words

All sounds

Semantics

Auditory processing For

speechFor non-speech

One box per process

If we want to be able to dissociate non-speech from speech, we will need more boxes: More separate processes:

Printed words

All sounds

Semantics

Early Auditory processing

For speech

For non-

speech? ?

Three things, then, might explain Bramwell’s patient

• We need to:• Eliminate meaning for

spoken words• But…• Preserve meaning and

hearing for environmental sounds & printed words

• Preserve speech

Printed words

All sounds

Semantics

Early Auditory processing

Non-speech

Speech sounds

x

x

x

“turbid”Bramwell’s patient & the lexicon

•There are spoken words you can recognize as being “real” though you cannot define them.•So…

•A store of spoken-forms (words we can recognize) must be separate from a store of word meanings (semantics)

for non-speechsound

Bramwell’s patient & the lexicon

•Path from Auditory Processing to Input Lexicon?

•Phonological Input Lexicon itself?

•Path from Input Lexicon to Semantic System?

non-speechsound

?

?

?

A new fact from Bramwell

"I asked her … the question:`Do you like to come to Edinburgh?'

She did not understand it. I then communicated that I wished her to

repeat what I had said: She did so without hesitation.

I then asked her to write down the words she had just said.

She did so without the words having to be repeated a second time, and she then undoubtedly understood the question.”

Which of three lesions preserves spelling?

How can she write down “You” and “Edinburgh”? not “Yoo”

or“Edinburra” How does she

know how these are spelled?

Bramwell’s patient & the lexicon

•Path from Auditory Processing to Input Lexicon?

•Phonological Input Lexicon itself?

•Path from Input Lexicon to Semantic System?

non-speechsound

?

?

?

The necessary lesion

for non-speechsounds

Lexicon

Non-verbal acoustic Lexicon?

•Is there a complementary non-verbal acoustic lexicon?

•We need another patient…

•Wait 100 years.

Albert et al (1972)

Comprehension of spoken words tested “Point to the X” (shown a range of pictures)

100% correct. Comprehension of sounds

Played a tape recording of sounds made objects “Point to object whose sound you are hearing”

10% correct.

Lexicon

Final Model

here, here or here

Revision

What do boxes do? When do we know we need a new black

box? What can arrows do? List the tests given by Bramwell

Build the diagram from the tests Next: Association, Dissociation, Double

dissociation

A case of associated deficits

A patient comes in who cannot: Tell left-right from right

“Show me your left hand” (cannot do correctly) Calculate (dyscalculia)

“What is 100 - 7?” (cannot answer accurately) Express thoughts in writing (dysgraphia)

“Write a sentence” (cannot write) Distinguish Fingers (finger agnosia)

“Touch your nose with your index finger”

Is this association evidence for a left-right-writing-number-finger module?

Printed and spoken, and pictorial information

Telling left from right, and writing, and calculating and

telling one finger from another

Moving and talking and writing and moving fingers and hands

Gerstmann’s Syndrome (1924) Spatial location, finger knowledge,

calculation, and writing are associated. Association is evidence for shared

processes or shared anatomy It does not, however, support the

hypothesis that the processes are the same: it merely does not rule it out.

Tim Shallice (1988) From Neuropsychology to Mental Structure

What can we tell if one task is OK, and one is imperfect? This is called Dissociation

Prima-facie evidence that two tasks differ…

But… what if one task is just harder than another?

% c

orre

ct

Amount of Damage

Double Dissociation

Subject A: Significantly better at task 1 than task 2

Subject B: Significantly better at task 2 than task 1

Plausible inference: there are two modules: One is important for task 1 (but not task 2) One is important for task 2 (but not task 1).

Summary

Association: Compatible with shared function but also with shared

location, blood supply, biochemistry. Not much help for finding new boxes and arrows

Dissociation: Compatible with separate functions Also with compatible differential dependency on a single

function (differential task difficulty) Double Dissociation:

Supports modeling tasks as functionally distinct: two boxes

III: Genetic Neuropsychology Building on Cognitive neuropsychology

by incorporating genetics Examine genetic & environmental

influences on cognition Model separate paths to cognition in

genetic and environmental terms. Test & build new models using genetics

Bates (2008a)

Purpose of Genetic Neuropsychology Describe the functional architecture of

the mind using genetic dissociations Deduce information about how these

processes are implemented neurally Do the genes that build phoneme

extractors also build speech processing systems?

How do neurons extract phonemes?

Dyslexia

Dyslexia = “difficulty with words” (Berlin, 1884)

Prevalence Affect up to 17.5% of children despite adequate

intelligence, education, and social environment (Shaywitz & Shaywitz, 2005).

Onset The disorder begins in childhood, continuing into

adulthood (Bates, Castles, Coltheart, Gillespie et al., 2004)

Important negative social impact (Maughan, etal, 1996).

Dyslexia is familial

Hallgren, 1950 Thomas, 1905 Qu: What does familial mean? Qu: Why might reading look familial?

Genes, shared environments Twins allow us to compare these two

MZ twins = Identical genes and Identical family DZ twins = 50% genes and Identical family Different families = random genes, random

families

Heritability: Twins Reared Together Components of Individual Differences

Random or Unique Environment effect E = 1 - rmz

Heritable effect (Additive genetic effect) A = 2 * (rmz - rdz)

Shared or Common Environment C = (rmz - A)

Concepts of Genetic Modeling

A

“Reading”

Reading as the sum of genes, family, and unique effects

A = Additive genetic = 2* (rMZ-rDZ)C = Common (family) environment = A- rMZ

E = Unique effects and noise = 1-rMZ

C E

Basic Behavior Genetics

Most of the familial similarity is due to shared genes Heritability of around 0.7

DeFries, Fulker, & LaBuda, 1987; Bates et al., 2006; Gayan & Olson, 2003.

Family environment effects prior to school starting

Baker et al, 1997

Few family effects after school begins Olson etal (2002); Bates et al 2006

Dual Route Cascaded Model (DRC) (Coltheart et al. 2003)

Two tasks in reading aloud:

Access to your store of words Activate known words from

a store “lexicon” What happens if you look up

“GOP” ? Decoding new words

What sounds (phonemes) correspond to the letters?

How do you say: GOP ? How do you say: YACHT ?

Abstract letter units

Orthographic lexicon

Letter-sound conversion

Phonological lexicon

Phoneme units

Genetic Model of Reading (Bates et al 2007)

NonwordReading

Ag

Irregular Reading

.77

Eg

.33

.49.26

.38

.44

Airr Anon

EnonEirr

Summary of Genetic modeling Because variance in reading is heritable,

normal twins can inform us about the genetic neuropsychology of reading

Association Genes that influence all types of reading

Double dissociation Genes for lexical (whole word) processing

(and not for graphemes) Genes for sub-lexical (grapheme)

processing (and not for whole words)

Dual-route models and genes The next step is to move to gene

identification Identifying risk early in development

Understanding the connections and disconnections that might lead to reading difficulties

Deoxyribonucleic acid (DNA) James Watson, Francis Crick Maurice Wilkens, Rosalind Franklin

February 21, 1953

James Watson

Born 6th April 1928-

Francis Crick: 8/6/1916 – 28/7/2004

Genes

Origins What genes influence reading? How do they influence development? Are the genes used in other abilities, like

language, or face recognition? Treatment

What period is neural growth influenced? Early recognition, if neural growth can be

affected?

(p34-p36)

(p11-p16)

(p12-q13)

DYX8

DYX3

DYX5

(p21.3-p22)

(q13-q16)

(p15)

(q15-q21)

(p11)

(q27.3)

DYX2

DYX4DYX7

DYX1DYX6

DYX9

q12

Linkage: 11 Dyslexia Susceptibility Loci

DYX1C1 Dyslexia susceptibility 1 candidate 1

1. DCDC2 Doublecortin domain2. KIAA0319

ROBO1 Roundabout

Eleven Genes for reading

1p34-36 (Grigorenko et al., 2001; Rabin et al.,

1993; Tzenova et al., 2004 ; Bates et al, 2007)

2p15-16 (Chapman et al., 2004; Fagerheim, 1999;

Francks et al., 2002; Kaminen et al., 2003; Petryshen, et al., 2002 ; Bates et

al, 2007) 2q22.3

(Raskind et al. 2005 ; Bates et al, 2007),

3p12-q13 (Nopola-Hemmi et al., 2001; Taipale et

al., 2003 ; Bates et al, 2007)

6p23-21.3 (Cardon et al., 1994; Fisher et al., 1999;

Gayan et al., 1999; Grigorenko et al., 1997; Kaplan et al., 2002a; Chapman et al., 2004; Turic et al., 2003; Luciano, et al. 2007),

6q11.2 (Petryshen et al., 2001 ; Bates et al, 2007)

7q32 (Kaminen et al., 2003 ; Bates et al, 2007)

11p15.5 (Hsiung, Kaplan, Petryshen, Lu, & Field, 2004)

15q21.1 (Grigorenko et al., 1997; Morris et al., 2000;

Nopola-Hemmi et al., 2000; Nothen et al., 1999; Schulte-Körne et al., 1998 ; Bates et al, 2007)

18p21 (Chapman et al., 2004; Fisher et al., 2002;

Marlow et al., 2003; Bates et al, 2007)

Xq27.3 (de Kovel et al., 2004; Fisher et al., 2002 ; Bates

et al, 2007)

+DYX1C1 and DCDC2

Paracchini and Monaco (2007)

Building a brain that can read Guiding the growth of Neurons Neuronal Proliferation/connectivity

DCDC2 (Cope et al. 2005; Bates et al 2007)

KIAA0319 (Cope et al. 2005, Luciano et al 2007)

DYX1C1 (Bates et al 2007)

Nerves Crossing the midline ROBO1 (Hanula-Jouppi, 2005)

+KIAA0319; DCDC2; DYX1C1

All Linked to neuronal migration: (LoTurco 2007; Wang et al, 2006; Schumacher, 2006)

+Genes for Normal Reading

3839 twins, siblings and parents (768 families) 47.1% male; 98% Caucasian (~82% Anglo-Celtic)

Components of Reading Examination (CORE) Six reading and spelling tests of regular, irregular (e.g.,

yacht) and non-word (e.g., torlep) stimuli (Bates et al, 2004)

Significant associations of normal reading to DCDC2, DYX1C1, and KIAA0319

+DYX1C1 SNPs

marker position NONWORD IRREGULAR Prin Comp

rs685935 53.558203 . 0.0638 .

rs8043049 53.56508 . . .

rs6493791 53.568018 . . .

rs17819126 53.577202 0.0003 0.0086 0.007

rs3743204 53.577602 0.0089 . .

rs3743205 53.577822 . . .

rs8040756 53.585891 . . .

Mutation (GLY-SER)

+Genes for Reading

The models from cognitive neuropsychology are reflected in the genetic transmission of difference in ability to acquire whole word and sounding-out forms of reading

These modules appear to depend on early developmental cortical and subcortical neuronal migration

Dyslexia and normal reading associated with genes for neuronal migration in the cortex (DCDC2, DYX1C1, and KIAA0319) and across the midline of the brain (ROBO1)

Summary: Cognitive Neuropsychology Cognitive Neuropsychology uses deficits

to tell us about the structure of the mind Broca, Wernicke, Bramwell

Represent this structure using boxes and arrows Lichtheim

Summary: Box and arrow rules Boxes represent a store of information or

a process acting on information Arrows communicate information, but do

not transform it. Only needed in our models, because

patient data suggests that information can go to different places independently

Rules for claiming that two processes are different Association ✗ Dissociation ✓ Double Dissociation

A model of language

Bramwell’s patient Her symptoms His questions The boxes and arrows we must draw to

capture the abilities and disabilities that Bramwell identified

Genetic model

Boxes and arrows for Dyslexia Dual route model (Coltheart 2003)

Study similarities of Twins Genes show biological basis of different

modules Study DNA

Molecular biology describes the neuronal basis of language and its evolution.

Advanced Material

Double Dissociation

Subject A: Significantly better at task 1 than task 2

Subject B: Significantly better at task 2 than task 1

Plausible inference: there are two modules: One is important for task 1 (but not task 2) One is important for task 2 (but not task 1).

What other possibilities exist?

Assumptions of Double dissociation People are fundamentally the same

If people could differ in their basic mental architecture, then we might see a double dissociation where there was in fact only one module, but it was optimized for task 1 in person A, and task 2 in person B

Limitations and Problems

The box and functions are the level of analysis The algorithm of the box can often be deduced The actual circuits inside cannot be

Relies on cases of functional dissociation Things that do not dissociate in nature cannot be

distinguished with cognitive neuropsychology. Transcranial Magnetic Stimulation changes this

Lack of tools for replication and falsification Replication depends on (often rare) cases Wrong or false clinical observations of dissociation

not readily removed from the literature