Brain Abnormalities in Autism

N. Rajakumar, M.B.B.S., Ph.D.

University of Western Ontario

London, ON, Canada

nrajakum@uwo.ca

Autism Vs Autism Spectrum Disorders

Pervasive Developmental

Disorders

! Autism

! PDD not otherwise specified

! Asperger syndrome

! Rett syndrome

! Childhood disintegrative

disorder (“acquired autism”)

ASD

DSM IV; ICD-10

Autism - Clinical Features

Core Features:

! Impaired social interaction

! Impaired communication (verbal & non-verbal)

! Repetitive, stereotyped & restricted behavior

Certain abnormalities may be noticeable as

early as 6 months, but diagnosis is usually

made by 2.5-3 yrs

Co-morbidities:

! Intellectual disability 40-80% of patients

! Hyperactivity 60%

! Hypotonia 50%

! Anxiety 40-80%

! OCD 40%

! Aggressiveness 8-32%

! Self-injurious 35%

! Sensory abnormality 80-90%

! Seizure 5-50%

! GI symptoms 30-90%

! Sleep problem 50-70%

Lancet (2009) 374:1627-38

! Effective therapies are available for most

co-mobidity and therefore, identification and

treatment of co-morbidities are important and

will improve the quality of life

ASD - Treatment

! Outcome is better with

" early detection (?)

" intensive behavioral therapy

" special education

! No pharmacological therapy available for

core symptoms

e.g., Discrete trial training - effective in >50% of pts.

! Do not know which treatment is effective

and for whom

ASD - Prognosis

! No cure

! No remission

! Some symptoms get better with or without

treatment

! Develop coping strategies as adults

! Many need a continued support

Why study autism?

! A common psychiatric problem in children

" Prevalence 1-2 per 1000 for autism

(6/1000 for ASD)

US Prevalence

" Is it increasing?

# Changes in diagnostic practice

# Increased public awareness

# A “true increase”?

Autism - Cause

! Genetic predisposition

! Early developmental insults

! Environmental factors

? Virus/drugs/toxins at <8 weeks of gestation

? Environmental toxins (metals - Hg)

? Abnormal gut flora (endotoxins)

? Immunological/autoimmune (viral, vaccine)

Autism - Genetics

! Highly heritable traits: >0.7 for autism

>0.9 for ASD

! >60% monozygotic twins are concordant

(ASD)

! 20-50 times increased chances for the next

child to develop autism

!10-20% of ASD cases have identifiable genetic

changes

! >40 genetic abnormalities have been described

! Many are involved in synaptic development

A synapse

Those in RED are proteins of ASD candidate genes

Excess number of synapses are formed during

development and most are then eliminated

Schizophrenia diagnosis

Abnormal development of synapses may

contribute to autism

(2009) 19:231-4

What do we find in autistic patients?

! Most consistent finding is increased head

circumference

! Brain size is normal at birth, but in 20% cases

it increases and then regresses to normal size

Autism (1298 ± 88 ml)

Normal (1179 ± 71 ml)

0.9

1

1.1

1.2

1.3

1.4

Series1

Series2

Birth 6 yrs

Brain size Annual Review of Medicine (2009) 60:367-80

Neuroradiology (2010) 52:3-14

Postmortem findings

• Are inconsistent

! Increased cell packing and decreased cell

size in amygdala and hippocampus

! Decreased # of Purkinje cells in the

cerebellum

! Poor grey-white boundary

! These findings suggest some form of

Neurodevelopmental defecte.g., abnormal neurogenesis/migration

Autism Control

Volume is increased in cerebral (18%)

and cerebellar (39%) white matter, and

cerebral cortical gray matter (12%)

compared to normal children

Recent MRI studies, however, strongly

indicate that the volume increase is mainly in

the white matter in autism patients

Neurology (2001) 57:245-54

Our studies also show increased white

matter volume in autistic children

Human Brain Mapping (2009) 30:3887-900

One of our study in shows decreased size of

corpus callosum (mainly in the anterior third)

Biol. Psychiatry (2006) 60:218-25

f-MRI findings:

! Differences in patterns of activation of

brain areas and timing of synchronization

! Decreased and abnormal activation of

fusiform cortex (face area)

Control Autism

! Decreased activation of mirror neurons

Control Autism

! f-MRI studies indicate that autistic

children show Decreased functional

connectivity

i.e., abnormal connections among

functionally related brain areas

An MRI technique capable of imaging white

matter tracts, Diffusion Tensor Imaging, is

rapidly improving

We and others are beginning to employ this in autism

BRAIN TRAINING: New Hope for Children with

Developmental Delaysby Dr. Michelle Lewis MacAlpine

Scientists have learned more about how brains repair themselves in the past ten years

than they did in the previous ten thousand. New information about how the brain is

affected by sensory experiences, hormones, immune molecules and digestive

processes is helping revolutionize treatments for developmental disorders that were

once believed to be irreversible. This book guides the reader through the science and

the methods behind these new ideas and describes how to stimulate play, language,

and social development even in severely delayed children. Written in clear language

with plenty of practical advice, this book is an important resource for parents and

professionals alike. VIEW TABLE OF CONTENTS View Chapter

All kinds of “attractive things” out there …..be cautious!

e.g.,

Published online 20 April 2010 | Nature 464, 1111 (2010) | doi:10.1038/4641111a

No gain from brain training: Computerized mental workouts don't boost

mental skills, study claims.

The largest trial to date of 'brain-training' computer

games suggests that people who use the software to

boost their mental skills are likely to be disappointed.

The study, a collaboration between British researchers

and the BBC Lab UK website, recruited viewers of the

BBC science program Bang Goes the Theory to practice

a series of online tasks for a minimum of ten minutes

a day, three times a week, for six weeks. In one group,

the tasks focused on reasoning, planning and problem-

solving abilities — skills correlated with general intelligence. A second

group was trained on mental functions targeted by commercial brain-

training programs — short-term memory, attention, visuospatial abilities and

maths. A third group, the control subjects, simply used the Internet to find

answers to obscure questions. A total of 11,430 volunteers aged from 18 to

60 completed the study, and although they improved on the tasks, the

researchers believe that none of the groups boosted their performance on

tests measuring general cognitive abilities such as memory, reasoning and

learning.

Take home massage…

! Autism is a developmental brain disorder

! Heterogeneous diagnosis - based on meeting

criteria (and many of them are subjective)

! Symptoms are often loosely characterized

(?shared by other disorders, and are

deviation/deficits from normal traits)

! Autistic traits have strong genetic basis -

likely associated with rare interactions of

common mutations

! No pharmacological treatment is available for

core symptoms

! Behavioral therapy and special education

may improve certain core symptoms in

certain cases

! Treating co-morbidity may improve the quality

of life

Take home massage… (cont.)

! May involve abnormal development of

synapses

! May involve abnormal formation &

migration of neurons

! May have abnormalities of white matter

tracts of the brain

! May have “disconnection” among

functionally connected brain areas

Take home massage… (cont.)