Current knowledge on the pathophysiology

of autism

BIOS E 232

Sabina Berretta, MD

Harvard Medical School McLean Hospital

Plan for today’s class

• Today’s seminar:Current knowledge on the pathophysiology of autism

Emphasis on factors affecting emotion regulation

• Journal club presentations and discussion:

• Eva Xia

Krishnan, V. and E. J. Nestler (2010). "Linking molecules to mood: new insight into the biology of depression." Am J Psychiatry 167(11): 1305-1320.

• Carolyn Brokowski

Nestadt, G., M. Grados, et al. (2010). "Genetics of obsessive-compulsive disorder." Psychiatr Clin North Am 33(1): 141-158.

Current knowledge on the pathophysiology of

schizophrenia

Historically, the main neurotransmitter systems have been a major focus in schizophrenia

• Dopamine

• GABA

• Glutamate

• Serotonin

• Acetylcholine

Guillin et al., 2007

Guillin et al., 2007

Evidence for excess DA transmission derives from pre- and postsynaptic studies. Excess DA transmission may impair glutamatergic NMDA transmission by a D2-mediated impaired presynaptic release of glutamate and an imbalance of D1/D2 opposing effects onto NMDA transmission

Glutamate role in the pathophysiology of schizophrenia

Dissociative anesthetics, i.e. channel-blocking N-methyl-Daspartate (NMDA) receptor blockers:

• induce psychotic symptoms in healthy volunteers

• exacerbate the positive, negative, and cognitive dysfunction of patients with schizophrenia

Hayashi-Takagi and Sawa, 2010

SZ risk factors enriched in the glutamate synapse

Molecules supported by genetic information, those based on pharmacological evidence, and those with altered expression in SZ brains are described in red, blue, and green, respectively.

Marek et al., 2010

Ionotropic and metabotropic glutamate receptors in schizophrenia

Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local and long-loop pathways connecting the prefrontal cortex, thalamus, striatum, hippocampus, amygdala, and dopamine-containing brainstem neurons

Metabotropic glutamate 2/3 (mGlu2/3) receptor agonist decreases both positive and negative symptoms of schizophrenia

Abnormalities of ionotropic glutamate receptor include receptor trafficking, delivery, dendritic localization, recycling, and degradation in schizophrenia. Changes in NMDA and AMPARs in the brain in schizophrenia may thusInvolve abnormalities of specific Intracellular processes

Because of the the electrophysiological properties of GABAergic neurons, systemic administration of noncompetitive NMDA receptor antagonists would preferentially block active NMDA channels in interneurons rather than pyramidal cells, resulting in a disinhibition of circuits.

Neurons are efficient at synchronizing neuronal activity in cortical networks. Glutamatergic transmission abnormalities affecting the activity of GABAergic neurons may thus affect oscillatory patterns in cortical and subcortical brain regions. These patterns are thought to be critical for tuning the brain to the temporal dynamics of task-relevant event patterns

Gonzales-Burgos and Lewis, 2008

Inhibitory (GABAergic) interneurons abnormalities in schizophrenia

GABA-related abnormalities in schizophrenia

GAT-positive cartridges in controls and SZ; Woo et al 1998

GAD67 mRNA expression in SZHeckers et al 2002

Decreased expression of somatostatin and CCK in the DLPFC in schizophreniaHashimoto et al., 2008

AmygdalaAttribution of emotional value

Social behavior

OPFCRepresentation of reinforcer Values, Strategy generation

ACGAttention, MotivationResponse selection

DLPFCExecutive cognitive functions

Working memory

ECxAssociative memory processing

HPContext-related cognitive

processing, episodic memory

MDStimulus/significance

relationshipStriatum

Reward mechanismsIncentive salience

Glut

Glut

Glut

Glut

Glut

Glut

Glut

Glut

GABA

GABA

GABA

GABA

GABA

GABA

DA

DA

DA

DA

CNVs, which contain genes involved in neurotransmission or synapse formation and maintenance, are present in autism, schizophrenia and mental retardatiion, supporting the existence of shared biological pathways between these neurodevelopmental disorders.

Autism spectrum disorder

The term ‘autism spectrum disorder’ (ASD) is often used to encompass:• autism• Asperger's disorder• Pervasive developmental disorder not otherwise specified• Rett syndrome• Childhood disintegrative disorder

Thus the diagnosis is characterized by a great deal of heterogeneity. Although autism is often considered a disorder of childhood due to the diagnostic requirement of impairment by age three, its effects persist throughout the lifespan.

AUTISM - DSM V(A) Persistent deficits in social communication and social interaction across contexts:1. Deficits in social-emotional reciprocity; ranging from abnormal social approach and failure of normal back and forth conversation through reduced sharing of interests, emotions, and affect and response to total lack of initiation of social interaction

2. Deficits in nonverbal communicative behaviors used for social interaction; ranging from abnormalities in eye contact and body-language, or deficits in understanding and use of nonverbal communication, to total lack of facial expression or gestures

3. Deficits in developing and maintaining relationships, appropriate to developmental level (beyond those with caregivers); ranging from difficulties adjusting behavior to suit different social contexts through difficulties in sharing imaginative play and  in making friends  to an apparent absence of interest in people

(B) Restricted, repetitive patterns of behavior, interests, or activities (at least two of  the following):

AUTISM - DSM V

1. Stereotyped or repetitive speech, motor movements, or use of objects (such as simple motor stereotypies, echolalia, repetitive use of objects, or idiosyncratic phrases). 

2. Excessive adherence to routines, ritualized patterns of verbal or nonverbal behavior, or excessive resistance to change(such as motoric rituals, insistence on same route or food, repetitive questioning or extreme distress at small changes).3. Highly restricted, fixated interests that are abnormal in intensity or focus (such as strong attachment to or preoccupation with unusual objects, excessively circumscribed or perseverative interests). 4. Hyper-or hypo-reactivity to sensory input or unusual interest in sensory aspects of environment (such as apparent indifference to pain/heat/cold, adverse response to specific sounds or textures, excessive smelling or touching of objects, fascination with lights or spinning objects).

Social Deficits• Social orienting:children with ASD are less likely to look preferentially or orient toward social stimuli (e.g., hands clapping and a voice calling their name)

• Joint attention:The ability to share awareness with others by sharing, following, and/or directing attention typically emerges during the first year of life and supports the development of subsequentlinguistic and social skills. Children with ASD show well-documented deficits in both initiation and following of joint attention• Processing of facial information and emotional cues from othersLack of attention to faces is among the earliest indicators of ASD. Difficulties in recognition of emotions based on visual and vocal cues

A and B: gaze distribution of 20 persons on a painting (“Piipunsytyttäjät/Lighting pipes” by Juho Rissanen, 1902; copyright Ateneum Art Museum, Central Art Archives/Hannu Aaltonen,

Finland).

Hari R , Kujala M V Physiol Rev 2009;89:453-479

©2009 by American Physiological Society

Communication Deficits

Some children diagnosed with ASD remain mute throughout their lives. Others may be delayed. Those who do speak often use language in unusual ways. They seem unable to combine words into meaningful sentences. Some speak only single words, while others repeat the same phrase over and over. Some ASD children parrot what they hear, a condition called echolalia. Some children only mildly affected, or even seem to have precocious language, but have great difficulty in sustaining a conversation. Another difficulty is often the inability to understand body language, tone of voice, or “phrases of speech.”

Oh, that’s just great …

Theory of Mind / Empathy

• 'The man thinks that someone is putting a gun in his back, but it's a guitar'

• 'The couple don't realize that they are making the man think he is being robbed'

• 'The couple are waiting for a bus and the man is jumping to reach something'

• 'The couple are trying to push the man over with the guitar so that they can get on the bus first'

Marjoram et al., 2005

Heider and Simmel's paradigm (1944)Social Attribution Task

http://www.youtube.com/watch?v=76p64j3H1Ng&feature=related

What happened was that the larger triangle, which was like a bigger kid or a bully and he had isolated himself from everything else until two new kids come along and the little one was a bit more shy, scared, and the smaller triangle more like stood up for himself and protected the little one. The big triangle got jealous of them, came out, and started to pick on the smaller triangle. The little triangle got upset and said like ``what's up? '' ``Why are you doing this ? '' …

The big triangle went into the rectangle. There were a small triangle and a circle. The big trianglewent out. The shapes bounce off each other. The small circle went inside the rectangle. The big triangle was in the box with the circle. The small triangle and the circle went around each other a few times. They were kind of oscillating around each other, maybe because of a magnetic field. After that, they go off the screen. The big triangle turned like a star like a Star of David and broke the rectangle.

Klin et al., 2000

Brain regions differentially involved during ToM in people with autism as compared to normal controls

PET study - Greater activation in control v/s autistic subjects in occipital and temporal pole/amygdaloid regions (1), superior temporal sulcus (2), and medial prefrontal cortex (3). Abbr. LO, lateral occipital cortex; IT, inferior temporal gyrus; V3, extrastriatal cortex

1 2 3

Castelli et al., 2002