B. L. S. is a Scholar of the Child Health Research Center of Excellence in Developmental Biology at Washington University School of Medicine (HD33688)

B.L.S. is a Scholar of the Child Health Research Center of Excellence in Developmental Biology at Washington University School of Medicine (HD33688).

Cytoarchitectonic Map of Human Cerebral Cortex

Gross Development of Human Cerebrum

Why study typical and atypical brain development?

• Informs normal function

• Developmental disabilities and consequences of brain injury

• Generate rational interventions and assay their effects

A developmental context

• “our real teacher has been and still is the embryo ---who is, incidentally, the only teacher who is always right…”

• Viktor Hamburger (1900-2001)

Importance of Reading

• Straightforward predictor of success in school and later in life.

• Understanding how skilled reading is carried out and acquired…

• critical to improving strategies for reading education and
• for identifying reading disabled for early and effective remediation

Reading…

• Taught

• Not evolutionarily driven

• Disabled reading entirely consistent with normal intelligence (dyslexia).

In general…

• Reading is sub-served by a left hemisphere network of cortical regions for mapping visual (orthographic) information onto

• auditory (phonological) and conceptual (semantic) representations.

In general…

• Reading is sub-served by a left hemisphere network of cortical regions for mapping visual (orthographic) information onto

• auditory (phonological) and conceptual (semantic) representations.

Approaches/Tools

• Cognitive Psychology

• Behavioral Neurology

• Cognitive Neuroscience/Functional Neuroimaging

Initial State: Logographic Reading from Ramus

Intermediate State: Alphabetic Reading from Ramus

Final State: Orthographic Reading from Ramus

Approaches/Tools

• Cognitive Psychology

• Behavioral Neurology

• Lesion/behavior
• Alexia without agraphia (dom. medial occipital and inferior fibers of splenium of corpus callosum)
• Alexia with agraphia (dominant angular gyrus); Gerstman

• Cognitive Neuroscience/Functional Neuroimaging

Approaches/Tools

• Cognitive Psychology

• Behavioral Neurology

• Cognitive Neuroscience/Functional Neuroimaging

Functional MRI

• Safe

• FDA approved sequences
• Non-ionizing
• PET, SPECT

• Non-invasive

Conceptualization of the developing neocortex

• Conceptual framework/pendulum

• “Nature”: neocortex is entirely hard-wired at birth.
• “Nurture”: neocortex is entirely equipotent.

• Softer versions of these models emerged in the 1980’s

• Rakic: “protomap” (i.e. not a fatemap)
• O’Leary: “protocortex” (i.e. not a tabula rasa)

• Analogy with the cognitive development literature

• Chomsky, Fodor, Pinker,(Kanwisher?): nativist, “modularist”
• Elman et al, Quartz & Sejnowski, Johnson, Karmiloff-Smith: connectionist, selectionist, neuro-constructivist

Potential Developmental Scenarios

• Activation of a nascent adult organization

• nativist

• Intially “diffuse” organization becomes “specialized”

• selectionist

• Acquisition and skilled performance are sub-served by different neural mechanisms

• Neuro-constructivist/scaffolding

Regressive (and Progressive) Events in Building a Brain

• Progressive

• Cell proliferation

• Migration to definitive locations

• Selective aggregation

• Establishment of phenotypic diversity

• Establishment of complex connections

• Neuropil expansion

• Myelination

Potential Developmental Scenarios

• Activation of a nascent adult organization

• nativist

• Intially “diffuse” organization becomes “specialized”

• selectionist

• Acquisition and skilled performance are subserved by different neural mechanisms

• Neuro-constructivist/scaffolding

Where to begin to study reading development?

• Even automatic/expert reading is very complex

• Requires the coordination of multiple visual, oculomotor, and linguistic mechanisms.

• Start with reading words aloud

• Orthography to phonology
• Easy to manipulate experimentally

Functional neuroimaging and single word reading

• A wide variety of lexical tasks examined requiring not only word reading, but also performance of complex operations on single words.

• But, relatively little work has been specifically dedicated to the functional neuroanatomy of single word reading.

Neuroimaging studies of skilled word reading

• Variables manipulated:

• frequency, regularity, lexicality, letter case, word length, stimulus degradation, rate, duration

• Context:

• lexical decision, verb & past tense generation, object naming, simple reading.

• Control tasks (for “baseline comparison”):

• resting with eyes closed, visual fixation, passive viewing of words, silent reading of words , uttering a pre-determined word in response to consonant strings, false fonts.

• Responses:

• vocalization, “silent” mouthing, silent reading.

Common brain regions for skilled word reading

• Encouragingly, despite these experimental differences, a set of brain regions common to single word reading has emerged (Fiez and Petersen 1998, Turkeltaub et al 2002, Palmer et al, in press)

Digression; What is the goal of functional imaging?

• “In contrast to a localist assumption of a one-to-one mapping between cortical regions and cognitive operations, an alternative view is that cognitive task performance is subserved by large-scale cortical networks that consist of spatially separate computational components, each with its own set of relative specializations, that collaborate extensively to accomplish cognitive functions.” Carpenter et al 2001

Localization of Cognitive Operations in the Human Brain Posner, Petersen, Fox, and Raichle 1988 Science

• “The hypothesis is that elementary operations forming the basis of cognitive analyses of human tasks are strictly localized. Many such local operations are involved in any cognitive task. A set of distributed brain areas must be orchestrated in the performance of even simple cognitive tasks. The task itself is not performed by any single area of the brain, but the operations that underlie the performance are strictly localized…

Localization of Cognitive Operations in the Human Brain Posner, Petersen, Fox, and Raichle 1988 Science

• “…This form of localization of function differs from the idea that cognitive tasks are performed by a particular brain area. Visual imagery, word reading, and even shifting visual attention from one location to another are not performed by any single brain area. Each of them involves a large number of component computations that must be orchestrated to perform the cognitive task.

What is an area? How about a region?

• A neocortical area is defined by its afferents, efferents, architecture (cyto-, chemo-, myelo-) and function (e.g. primary motor cortex versus primary somatosensory cortex).

• FMRI does not (necessarily) show activation in “areas”.

• Check out “The anatomical basis of functional localization in the cortex” by Passingham et al, Nat Rev Neuro 2002

Methodological Issues in Studying the Development of Reading with fMRI

Perceived Barriers

• Variability of child brain

• too variable to be compared directly with the adult brain.

• Performance mismatch on cognitive tasks; children will not perform as well as adults on most tasks.

• performance versus processing

• These issues are relevant to any group-wise comparison

• Adults versus Children
• Princeton versus Yale

Issues

• Anatomical variability across development

• Physiological variability across development

• Performance differences between adults and children

• “Task B problem”

• choosing appropriate comparison tasks

Strategy

• Child-friendly (yet adult-challenging) tasks

• lexical processing tasks with overt responding

• Event-related design

• Relate performance to fMRI measures on trial-by-trial basis.
• Code and analyze only correct responses.
• Compatible with overt verbal responding.

Strategy

• Child-friendly (yet adult-challenging) tasks

• lexical processing tasks with overt responding

• Event-related design

• Relate performance to fMRI measures on trial-by-trial basis.
• Code and analyze only correct responses.
• Compatible with overt verbal responding.

Transformation of adult and pediatric brains into a common stereotactic space

• 1. Anatomical Variability

• 2. Functional Variability

Comparison of primary sulcus location and general brain shape in children and adults Burgund et al Neuroimage 2002

Transformation of adult and pediatric brains into a common stereotactic space

• 1. Anatomical Variability

• 2. Functional Variability

Methods

Anatomical and functional variability exists, but is“small” after transformation of pediatric and adult brains into the same stereotactic space.

• “Small” is in reference to the spatial resolution of fMRI data (~6-7mm)

• Offset is rarely greater than 4 mm. When variability is less than 5 mm, the likelihood of false-positive functional differences is very low.

• Hence, the degree to which post-transformed brains differ between children and adults, by this measurement, is beneath the resolution of fMRI.

Behavioral Data in the Scanner; critical for developmental studies

• Relate fMRI measures to concurrent behavior

• Assure compliance with task

• Acquire performance data

• Accuracy and reaction time
• Contend with performance confound

• Performance can be discrepant for the comparison task, as well

• Relevant to the “Task B” problem

Digression: Task B problem

• Very difficult methodological issue

• Relevant to any group-wise comparison

Choosing appropriate comparison tasks

• Assumption: Task A - Task B = Activity of interest

• (Task Achild - Task Bchild) vs (Task Aadult - Task Badult)

• Interpreted as Task Achild vs Task Aadult
• Assumed that Task Bchild = Task Badult

• But Task Bchild vs Task Badult is rarely presented

The Task B Problem

The Task B Problem

The Task B Problem

Lexical Task Conditions

• * “ Passive presentation”

• “Simple”

• Single word reading

• Single word repetition

• “Controlled”

• *Verb Generate nose --> “smell”

• *Opposite Generate good --> “bad”

• *Rhyme Generate book --> “look”

• * both auditory and visual modalities

Trial Design: Visual Stimuli Run

Task cond. Adult RT (%) Child RT (%)

• Task cond. Adult RT (%) Child RT (%)

• Simple Read 665 (100) 668 (100)

• Controlled Read 1471 (86) 1880 (75)

Task cond. Adult RT (%) Child RT (%)

• Task cond. Adult RT (%) Child RT (%)

• Simple Read 665 (100) 668 (100)

• Controlled Read 1471 (86) 1880 (75)

Task cond. Adult RT (%) Child RT (%)

• Task cond. Adult RT (%) Child RT (%)

• Simple Read 665 (100) 668 (100)

• Controlled Read 1471 (86) 1880 (75)

Some Interim Conclusions

• Developmental studies in children 7 years of age and up appear to be tractable using methods similar to those used in adults.

• Many changes in functional anatomy from 7 to adulthood do not appear to be related to simple performance variables. These changes seem to be more extensive in tasks with more complex demands.

• These changes do not seem to relate to a single type of mechanism, but rather reflect both “progressive” and “regressive” phenomena.

Some Interim Conclusions

• A strategy incorporating:

• direct statistical comparison

• transformation to a common stereotactic target atlas

• event-related design with overt verbal responding

• performance matching

• can be implemented successfully to study cognitive development from age 7 to adulthood.

A handful of recent developmental fMRI studies of “reading”

Disruption of posterior brain systems for reading in children with developmental dyslexia. Shaywitz et al 2002

• Goal: to differentially tap the component processes in normal and impaired reading.

• TASKS

• Line: / / / \ - / \ / / (visuo-spatial)

• Case: t - V (letter identification)

• Single Letter Rhyme: “t” vs “v” (sounding out letters)

• Non-word Rhyme: jete vs leat (sounding out non-words)

• Semantic Category Judgement: rice vs corn (semantics)

Shaywitz et al study

• 144 right handed children (70 dyslexic), m-13.3 years for dys, 10.9 for normals.

• 1.5 T magnet

• Standard EPI imaging

• Standardized anatomical space

• Generate image for each contrast for each subject and then generate composite image

NWR-Line CAT-Line

Positive correlation between reading skill (Word Attack) and activation across all subjects (normal and dyslexics). Highlight the left occipito-temporal cortex

Positive correlation between age and activation in normal readers; left inferior frontal cortex for the CAT task No correlations mentioned in temporoparietal nor occipitotemporal cortex.

Children disengage posterior right hemisphere visual representations that interfere with proper word identification (which is in posterior left hemisphere). Orton 1925

• Children disengage posterior right hemisphere visual representations that interfere with proper word identification (which is in posterior left hemisphere). Orton 1925

• Children preferentially engage the dorsal (temporoparietal) decoding system and then transition to the ventral word form area with reading expertise. E.g. Pugh, Shaywitz

How do the neural systems responsible for reading change throughout the period of its acquisition?

• Implicit word-processing task

• “although subjects are not instructed to read the words, reading occurs obligatorily without conscious effort, resulting in comparable brain activity to that associated with explicit reading tasks.”

• In adults

• “Even novice readers can perform the task accurately because subjects are not explicitly required to read the words…”

• Explicit vs implicit task performance

Methods

• 57 right handed subjects (ages 6-22)

• 16 excluded for various reasons

• Neuropsychology battery

• Correlate brain activity with measures in this battery.

• Button press with right hand “ascenders”, left hand “not”

Results

• Although task performance was related to age…

Results

• …accuracy and RT differences between words and false font strings were not related to age

• Accuracy and RT differences were not related to reading ability

Results

• Post-test forced choice recognition to confirm implicit processing of stimuli

• 65% words
• 51% false fonts
• Age effects ?

• Word recognition accuracy correlated with the letter/word identification subtest (single word reading task)

• Strong correspondence between implicit word processing and reading ability

Implicit Reading

• Contrasts

• Words vs fixation
• False fonts vs fixation
• Words versus false fonts
• “the contrast of words versus false font strings revealed those structures engaged by the implicit processing of words”

Reading Acquisition

• Voxel wise regression between word-false font image and reading ability

• Composite score
• Reading of single words
• Novel word decoding
• Passage reading rate and accuracy

• Positive correlations with left hemisphere regions

• Negative correlations with right hemisphere regions

Reading Acquisition

• No relationship between reading ability and activity in the word form area.

• Development of ventral extrastriate via disengagement of right sided regions

Age-related changes in single word reading

• One hundred eleven right-handed subjects (ages 7 to 35)

• single word reading

• event-related fMRI

• overt verbal responses

• A subset of 75 subjects with well-matched performance

• accuracy – 100%, and reaction time – ~ 665ms
• grouped by age: (1) 7-10 yrs (n=30); (2) 11-17 yrs (n=24); (3) 19-35 yrs (n=21).

• Voxel and region-wise ANOVA were implemented to identify age-related regions.

Age-related changes in single word reading

• The majority of age-related regions showed decreases in activation across maturation.

• relatively greater activation in the youngest subjects transitioning to little or no activation in adults
• bilateral precuneus & posterior cingulate, left angular gyrus
• relatively little (de)activation in the youngest subjects transitioning to robust deactivation in the older groups
• anterior cingulate, left caudate.

• Decreasing regions reached “mature” levels of activation in the 11-17 year old group (based on post hoc ANOVA).

Age-related changes in single word reading

• In the context of prior findings, these results demonstrate that the functional anatomy of simple lexical processing, as for controlled tasks, differs across development, independent of task performance.

Some Take Home Messages

• “identical” performance can be supported by non-identical functional neuroanatomy.

• The Strategy can help alleviate some of the methodological issues in studying development

• And group comparison, per se

B.L.S. is a Scholar of the Child Health Research Center of Excellence in Developmental Biology at Washington University School of Medicine (HD33688).

Repeat vs Read

fMRI identifies regional specialization of neural networks for reading in young children Gaillard et al 2003

• 16 normal right handed children (m = 7.2 years)

• 1.5T magnet

• Boxcar design: experimental reading task and control visual task (looking at dot patterns).

• Reading tasks were skill-adjusted

• Silent task; unmonitored. Post task test for comprehension (pop-quiz)

• Collected neuropsychological data

• No adult comparison built in

Gaillard et al 2003

• Children showed most activation in the left midtemporal (implicated in semantic processing) and inferior temporal gyri (fusiform and lingual; implicated in word form), left inferior and mid frontal gyrus (implicated in grammatic decoding, verbal working memory and speech planning), and SMA

Gaillard et al 2003

• Children showed most activation in the left midtemporal (implicated in semantic processing) and inferior temporal gyri (fusiform and lingual; implicated in word form), left inferior and mid frontal gyrus (implicated in grammatic decoding, verbal working memory and speech planning, and SMA

Gaillard et al 2003

• “The neural networks that process reading are strongly lateralized and regionally specific by age 6-7 years.”

• “Neural networks in early readers are similar to those in adults.”