Functional Neuroanatomy of

Lexical processing in children with cleft lip

and palate(CCLP)

Becker et al., 2007

Background

Males are affected more often than females.

Incidence in:• Asian population = 1 in 500 births.• Caucasian and Hispanic populations

= 1 in 1000 births.• African American population = 1 in

2000 births.(Altemus & Ferguson, 1965; Chung et al., 1986;

Natsume & Kawai, 1986; Vanderas, 1987)

Cleft Lip & PalateCleft lip may occur in

isolation or together with cleft palate and vice versa.

Incidence of cleft lip alone (15-20%) is lower than the incidence of cleft palate only (30-35%) and cleft lip and palate (50%).

(Coccia et al., 1969; Woolf et al.,

1963)

Cleft Lip & Palate

• Occurrence of cleft lip and palate together is more common in males.

• Cleft palate only is more common in females

(Calzolari et al., 1988; Womersley & Stone, 1987)

Types of CleftsCommon • Unilateral (9x as

common as bilateral and occurs more often on the left side)

• Bilateral

Often involve deformity of the nose

Unilateral

Bilateral

Types of Clefts

Rare• Median • Facial(DeMyer, 1971;

Tessier, 1976)

When do they form?

Between fourth to eight week of embryonic development.

Earlier malformations are more severe than later ones

CausesGenetic Increased incidence

in children with a parent or sibling who are similarly affected ⇒ 1 in 131 (Melnick, 1986).

Note: Individuals with cleft palate only have higher percentage of siblings that have other types of malformations than individuals with cleft lip only or cleft lip and palate (Meskin & Pruzansky, 1969. (Malformations can occur in the orbital cleft, facial asymmetry, middle ear defects, sternum).

Orbital cleft

Causes

Environmental

• Antiepileptic drug, phenytoin = 10-fold increase in the incidence of clefts.

• Smoking during pregnancy = 50% to 70% increase in clefting compared to those born to nonsmoking mothers.

• Certain viruses (rubella and influenza) increase risk of clefting.

Associated AnomaliesClefting occurs in

about 250 syndromes including Van der Woude, Stickler syndrome, microcephaly, etc.

Van der Woude

microencephalyStickler

Associated problems

1) Feeding2) Ear infection-

hearing loss3) Speech and

language disorders

4) Dental problems

TreatmentSurgery NAM – Nasal

alveolar molding

Anatomical differences

Adult males with cleft palate display:1) smaller cerebellum 2) smaller temporal lobe3) smaller occipital lobes4) larger frontal lobes

* Proportional gray and white matter(Nopoulos et al., 2000)

Language Development• Early deficits in cognitive development

(Fox et al., 1978; Snyder & Scherer, 2004; Speltz et al., 2000).

• Problems with syntax, short length of utterance and delays in expressive language (Horn, 1972; Morris, 1962;

Withcomb et al., 1976). • Articulation disorders, sometimes

even after the cleft is repaired (Jones et al., 2003; O’Gara & logemann, 1988).

Method

Participants

Experimental design

Lexical task

Auditory Visual

Rhyme generation

Verb generation

Opposite generation

Rhyme generation

Verbgeneration

Opposite generation

e.g. “cake”– “eat

e.g. “white” – “black”

e.g. “mud” –”flood”

* Presentation was jittered – stimulus was presented every 2nd, 3rd, 4th MR frame in pseudorandom fashion.

•Total of 6 runs.•Each run consisted of 21 stimuli - one

discrete task and one modality.

Movement analysisMotion in the scanner can be a problem. If more than 1.5 mm (RMS value) was

needed to realign head movement, the data was excluded.

Image analysisGeneral Linear Model for event related

data.Time = 7-level factor (BOLD measures

every 3.08 seconds).Removed outliers = time course that had

greater than 2% change in signal.

Overlap analysisCompared with Brown et al. (2005) study.

Brown et al. 2005 (used the same tasks)• Age-related regions = regions that

showed increased or decreased activity with age.

• Performance-related regions = regions that were related to performance ability.

• Age-and performance-independent regions.

Developmental analysisTo determine if age had an effect.Each CCLP was compared to an age-

matched cohort (group of 20 control individuals matched within 2 years).

Statistical analysisRepeated measures analysis – mixed

model.Between subject factor = condition or

group (with or without cleft lip and/or palate)

Within subject factor = time

Results

Results were based only on correct responses.

**Reaction time (collapsed across task and modality)Experimental: 1813 msecControl: 1804 msec** not statistically different

Main Effect of TimeTo determine how reliably each voxel was

activated by the tasks. Regions activated were similar to

previous study (Schlagger et al., 2002) looking at single word processing.

Main effect: voxels reliably activated across all subjects and all tasks

Group x time interactionThere were several regions that

displayed activation differences related to:

1) latency (CCLP > control)2) duration (CCLP >control)3) magnitude

Higher magnitude in CCLP

Left superior medial frontal gyrus

Right parietal precuneusRight inferior frontal gyrus

Lower magnitude in CCLP

Left inferior frontal gyrus* Right lateral prefrontal cortex – not shown

Right middle temporal gyrus

Similar in CCLP and controls

Left cingulate gyrus

* left paracentral lobule, right superior temporal gyrus – not shown

Not activated in CCLP

Right middle frontal gyrus

Developmental Analysis

9 out of 12 CCLP showed regions that had differences in BOLD responses from their age-matched cohorts.

Older participants (>14.5 years) showed differences consistently in the right frontal cortex (n=2) and ACC (n=1) when compared to controls.

Group x time: regions that were statistically different in BOLD response between groups

Regions that corresponded to Brown et al., 2005 study.

* Functional differences between CCLP and control increase with age.Average number of regions where the BOLD responses that differed from the controlsOlder (above 14.5 years) = 8.4Younger (below 14.5 years) = 2.6

CCLP show substantial variability in activation regions when compared to

controls

lateral

medial

posteriorPink: CCLP ≠ control (Are there more blue than pink regions in the older

participant?)

Blue: CCLP = control

posterior

DiscussionCCLP have similar but non-identical

functional neuroanatomy during language tasks at comparable levels of performance.

Regional differences in functional neuroanatomy are more apparent in age/performance related areas.

CCLP display increasing differences in age-related regions with increasing age.

CCLP display novel organization during language tasks