B05 L14 AutismSchizophrenia

Is autism and schizophrenia on the same
spectrum?
Martin Vestergaard Gøtzsche

Psychologist, ph.d., senior researcher
Research Unit, Department of Child and Adolescent

Psychiatry, Copenhagen University Hospital – Psychiatry
Region Zealand, Smedegade 16, DK-4000 Roskilde, Denmark
mgoe@regionsjaelland.dk
spectrum?
Similarities and differences between autism and schizophrenia

• Genetic associations
• Cellular development
• Brain structure
• Executive dysfunctions
• Idiosyncratic language
• Social cognition and communication
• Predictive coding
spectrum?
Historical ties between schizophrenia and autism:
A century ago, the Swiss psychiatrist Eugen Bleuler considered schizophrenia

as the splitting of psychic functions in Kraepelin’s dementia praecox, and
autism, as a withdrawal from reality in people with schizophrenia.
The term autism was later redefined by Leo Kanner in 1943 build on his now
11 famous cases.
The first autism case
Born on September 8, 1933, Donald Triplett was first seen in October, 1938 when he was five
years old.
• Donald demonstrated "an unusual memory for face and names" and "could hum and sing
many tunes accurately," being able to memorize phrases that rhymed or were of a similar
nature. Donald's parents observed that "he was happiest when left alone," neither paying
much attention to anyone in the room nor reacting to the absence or homecoming of his
parents.
• What amused him was spinning round objects, such as pans and spinning blocks.
• Donald was observed shaking his head from side-to-side, repeating the same three-note
tune, spinning anything he could get his hands on, and organizing objects by color.
• Most of his actions were repetitious, "carried out in exactly the same way in which they had
been performed originally."
• Often, he would utter random words of phrases, and this formed much of his verbal output
and speech. Problems understanding the meaning of words, which had a "literal, inflexible
meaning" to Donald.
Diagnostic criteria of schizophrenia
DSM-5 Criteria for Schizophrenia
Two or more of the following symptoms must be present, at least 1 of

them must be item 1, 2, or 3:
1. Delusions
2. Hallucinations
3. Disorganized speech
4. Grossly disorganized or catatonic behavior
5. Negative symptoms, such as diminished emotional expression
Diagnostic criteria of schizophrenia
Persistent delusions of other kinds that are culturally inappropriateand completely

impossible, such as religious or political identity, or superhuman powers and abilities.
Delusions of control, influence, or passivity
Hallucinations in any modality such as hallucinatory voices
Thought disorder and disorganized speech:

• Disorganized speech or abnormal thought processes.
• Incoherent speech “word salad,” repeat things another person says back to them.
• Speech can be so disorganized that it interferes with a person’s ability to
communicate with others including neologisms.
Negative symptoms:
• Apathy, paucity of speech and blunting or incongruity of emotional responses
• Usually social withdrawal and lowering of social performance.
• There is a tendency to social isolation, flattening of affect and loss of volition.
Diagnostic criteria of Autism
DSM-5 criteria for autism spectrum disorders
Deficits in social-emotional reciprocity

• Abnormal social approach and failure of normal back-and-forth
conversation
• Reduced sharing of interests, emotions, or affect
• Failure to initiate or respond to social interactions.
Deficits in communicative behaviors used for social interaction
• Poorly integrated verbal and nonverbal communication
• Idiosyncratic language including neologisms, echolalia and stereotypical
language
• Abnormalities in eye contact, use of facial expressions, gestures and body
language
Restrictive, repetitive, rigid behavior and thinking
• Rigid behavior and thinking
• Insistence on sameness, inflexible adherence to routines, or ritualized
patterns of verbal or nonverbal behavior
• Hyper- or hyporeactivity to sensory input or unusual interest in sensory
aspects of the environment
Shared symptoms but different labels in autism and schizophrenia?
Differences in onset and psychosis between autism and schizophrenia

• Autism has an onset typically in childhood, Schizophrenia in late
adolescence and early adulthood
• Schizophrenia is characterized by psychotic symptoms, autism is not
Thought disorder and disorganized speech in schizophrenia:

• Incoherent speech “word salad,” repeat things another person says back to
them.
• Speech can be so disorganized that it interferes with a person’s ability to
communicate with others including neologisms.
Verbal communication in autism:

• Neologisms
• Echolalia
• Stereotypical language
Negative symptoms in schizophrenia:

• Apathy
• Paucity of speech and blunting or incongruity of emotional responses,
usually resulting in social withdrawal
• Lowering of social performance
• There is a tendency to social isolation
• Flattening of affect and loss of volition
Restricted behavior and lower reciprocity in autism:

• Unmodulated eye contact, facial expressions, use of gestures and monotonic
voice
• Deficits in social-emotional reciprocity
• Reduced sharing of interests, emotions, or affect; to failure to initiate social
contact
• Deficits in developing and maintaining relationships
• Difficulties adjusting behavior to suit various social contexts
• Absence of interest in peers.
Genetic and environmental contributions to autism and schizophrenia
Only a limited number of genotypes and polymorphisms have been identified.
The genetic load is similarly high for Schizophrenia and autism

Schizophrenia shares genetic load with most diagnoses, autism mainly with schizophrenia
Today it is acknowlegded that schizphrenia has a developmental trajectory and

that psychosocial factors and stress predisposes psychosis-onset.
Cellular morphological development
Synaptogenesis peaks in childhood while pruning is ongoing through
adolescence
Synaptogenesis peaks in childhood while pruning is ongoing through

adolescence
The volume of the cell soma peaks within the first year or so.
Dendrites peaks early in life too.
Layers of PFC in a child 11 years of age. Length of dendritic segment as a function of age.
Dendrites peaks early in life too.

Myelination however, is an ongoing process.
Axons in corpus callosum in the adult rat at day 84 (A and C) and a young rat at day 21 (B and D).
The axons in the adult rat are visually substantially larger and more mylinated.
Synapse density in autism and schizophrenia
Increased density of synaptic spines is observed in autistic persons in frontal,

temporal og parietal cortices, specificlally in layer II, which connects
intracortical areas.
In Schizophrenic persons lower density of synaptic spines are observed,

specifically in layer III.
Hypothical model about autism and schizophrenia.
However, we do not know the exact timing and whether cellular mechanisms
related to axonal development is coupled to autism and schizophrenia.
Macroscopic brain development with MRI
Macroscopic brain structure in autism and schizophrenia
Early studies found that the cortical volume in young people with
Schizophrenia grew smaller over time.
Accelerated gray matter volume loss in very early-onset schizophrenia.

Schizophrenia is associated with reduced volume of the gray matter.
The question is what cellular processes drive these differences?
Grey matter reductions were more frequent in the insula, medial prefrontal, medial temporal
and striatal regions.
Psychosis is associated with cortical thinning in frontolimbic and

Venstre hemisfære
associative language areas.
The brain and white matter is larger in toddlers with autism, after
which white matter volume decreases through adolescence.
DWI and DTI measures the diffusion of water, which is higher in

more mature white matter
Schizophrenia is associated with diffuse reductions in white matter

anisotropy measured with DTI
Fibre tracts that connect language areas and the frontolimbic system
show atypical trajectories in autism.
Schizophrenia is associated mainly with reduced gray matter,

whereas autism is mainly related to increases in gray matter -
more so in the frontolimbic system and laterally in associative
areas.
The question is what cellular processes drive these differences?
Changes in synaptic density cannot readily explain observed

differences at the macroscopic level because the total volume of
synapses in the brain are hardly detectable with MRI.
The question remains whether the observed cellular and macroscopic
differences seen in autism is associated with an underlying predispostion or
experiential factors.
The question remains whether the observed cellular and macroscopic

differences seen in autism and schizophrenia are associated with an underlying
predispostion or experiential factors.
Autobiographical
memory
Verbal
Semantic cognition
communication
Mentalizing Executive functions

Executive dysfunctions in autism and schizophrenia
Studies confirm general executive dysfunctions in a subgroup of autistic persons.

In typically developing children, executive functions are predictive of the

quality in peer relations, social likability and having conflicts with others.
However, executive dysfunctions cannot explain the origin of symptoms in

neither autism or schizophrenia but likely worsen the course and level in
functioning.
The executive network

Mentalizing in autism and schizophrenia
"Theory of mind" based on theory of Uta Frith.
"Mentalizing" based on psychodynamic tradition, particularly

associated with Peter Fonagy's theory on personality disorder and
attachment.
Mentalizing: the ability to understand your own toughts and feelings, and the
thoughts and feelings of others.
To mentalize we need to read the verbal and nonverbal signals of others,

understand what is going on the specific contect, take a persons past, traits etc
into account to understand their possible motives, needs and intentions.
The Movie for the Assessment of Social Cognition (MASC) measures
hypermentalizing and hypomentalizing
Studies using social cognitive laboratory experiments have shown that both
schizophrenic and autistic persons hypo- and hypermentalize when they are
prompted to mentalize on the MASC.
Social cognitive problems in Schizophrenia and autism may underlie some of
the structural brain differences
The social cognitive network

Autobiographical memory in autism and schizophrenia
• The recollection of moments and experiences from our personal past a connected and
infused with meaning that shapes how we perceive ourselves and others.
• Autobiographical memories are critical for our sense of having a continuous self.
• We communicate and share our personal past with each other to facilitate social
relationships and secure attachments.
• Autobiographical memories are directive in guiding our values and beliefs, our
decision-making, problem-solving and goal-oriented behavior
• The discourse of narratives is shaped by cultural trends and social norms, and like
language, narration is a skill that needs to be nurtured and trained through social
interplay.
Directive function Self function Social function

Narrative coherence in autism and schizophrenia
Autobiographical memories are more generalized with less episodic details
in children with autism.
Up to 20% of children with autism were not able to recall an autobiographical

memory or coming up with a study.
The ability to narrate autobiographical memories and fictional stories

coherently develops through childhood and adolescence and is critical for social
interaction and communication.
A coherent narrative provides the listener with sufficient context leading up to

the story, it structures the story with a causal, logical, and temporal flow, and
it evaluates what happened in the story by conveying the point, theme or
morale of the story.
Context: necessitates mentalizing

Structure: necessitates mentalizing and the ability to keep a logical flow
Evaluation: necessitates mentalizing and abstract thinking.
Studies show that autistic persons and adults on the schizophrenic spectrum
display lower coherence when narrating.
Lower narrative coherence on storytelling in children with autism is coupled to

lower adaptive functioning, more social-communication problems with peers
and adults, more atypical language, more stereotypical behavior and thought,
more sensory sensitivity and more anxiety/depression and somatic complaints.
Storytelling are used in autism research and in clinical practice to examine
the communication skills of autistic children.
The picture book "Tuesday" is part of the screening with ADOS-2

Mentalizing and narration in autism and schizophrenia
When we narrate a memory or a fictional story we mentalize. More coherent
narration is coupled to more complex mentalizing.
1.5 age_group
Children
Adolescents
Young adults
1.0 Middle-aged adults
complexity
R2 Linear = 0.217
.5
X_ment_narr
.0
Mentalizing
-.5
-1.0
-1.5
-2 -1 0 1 2
Y_ment_narr
Narrative coherence
Mentalizing and autobiographcial memory in autism and
schizophrenia
Both mentalizing and autobiographical memory is associated with frontolimbic

and associative functioning, the same areas that show apparent differences in
autism and schizophrenia.
Semantic language in autism and schizophrenia
Thought disorder and disorganized speech in schizophrenia:

• Incoherent speech “word salad,” repeat things another person
says back to them.
• Speech can be so disorganized that it interferes with a person’s
ability to communicate with others including neologisms.
Verbal communication in autism:

• Neologisms
• Echolalia
• Stereotypical language
Similar to autistic persons, adults with schizophrenia show

vagueness in speech.
Words are connected to each other through the semantic
relationships or semantic networks.
Semantic network for animals
The purple nodes mainly contain farm animals; the blue nodes are mainly water animals;
the red nodes are mainly zoo animals, etc
Speech networks while telling a story
Speech networks in persons with schizophrenia (first episode psychosis) are
more disconnected than in controls
Schizophrenia
Control
Different words are more representative or typical to a category than other

words.
Frequency distribition of the category animal and fruits.

Children with autism show difficulties with semantic fluency and name more
idiosyncratic words than their peers.
Recall for semantically connected words are reduced in children with autism.
So are the problems with idiosyncratic language, lower mentalizing and incoherent
communication underlying the observed social symptoms in schizophrenia and autism?
Negative symptoms in schizophrenia:

• Apathy
• Paucity of speech and blunting or incongruity of emotional responses, usually
resulting in social withdrawal
• Lowering of social performance
• There is a tendency to social isolation
• Flattening of affect and loss of volition
Restricted behavior lower reciprocity in autism:

• Unmodulated eye contact, facial expressions, use of gestures and monotonic voice
• Deficits in social-emotional reciprocity
• Reduced sharing of interests, emotions, or affect; to failure to initiate social contact
• Deficits in developing and maintaining relationships
• Difficulties adjusting behavior to suit various social contexts
• Absence of interest in peers.
Predictive coding in autism and schizophrenia
Predictive coding framework (the new kid on the block)
Predictive coding theory may account for both autistic and schizophrenic symptoms
but are so far mostly speculated.
A: V is reward prediction, ! is reward, " is learning rate, and t is trial. B: typical

learning curve, generated by gradually declining prediction errors [!(t) - V(t)]
Prior beliefs are the expected probability that something occurs based in prior
expreience (Bayesian inference).
Bayesian statistical inference
• Prior probability: the believed probability of an event.
• Posterior probability: The corrected probability of an event after updating the prior
probability using Bayes' theorem.
• Based on experience, the cell, organism or brain, makes prior belief about
the outcome of an event termed a prediction.
• The discrepancy between prior beliefs and the acutal outcome (reality) is
termed the prediction error.
A: V is reward prediction, ! is reward, " is learning rate, and t is trial. B: typical

learning curve, generated by gradually declining prediction errors [!(t) - V(t)]
1. To differentiate whether prediction errors are due to noise or signal, the precision
of a prediction error is attributed a weight.
2. Sensory precision increase when sensory inputs are regular and decrease when
sensory input becomes noisy.
3. Precision is assumed to be the mechanism of attention within the predictive

coding framework. High sensory precision should have a large impact on our prior
beliefs.
Following the prediction codin gframework:

"The brain must flexibly change the precision weights on noise and
signals in order to adapt to changing environments and contexts."
The mismatch negativity (MMN) measures the difference in brain response to regular
sensory input and novel input. Discriminating regularity from novelty is critical for
sensory filtering.
Persons with schizophrenia and autism tend to have lower MMN

Predictive coding can be assessed by examining how a person completes a task by predicting
what will happen.
In the change-point condition, where surprising errors are indicative of change-points and
thereby predictive of future outcomes, high levels of surprise drive the model to use high
learning rates. In contrast, in the oddball condition, where surprising errors are indicative of
one-off outliers that do not predict future outcomes, high levels of surprise lead to
reductions in prescribed learning rate.
People with schizophrenia are more prone to completely ignore new information and persist
on previous responses, but when they do update, tend to do so completely. This updating
strategy limits the integration of information over time, reducing both the flexibility and
precision of beliefs and provides a potential explanation for how patients could
simultaneously show over-sensitivity and under-sensitivity to feedback in different
paradigms.
A lowered brain response is observed in autism for unpredictive sensory input
Control ASD
It is assumed that lack of updating prediction errors in autism is the

underlying cause:
• "prediction errors in autism are not corrected except for extremely
uniform environments."
• "Each event is experienced as novel and contexutal learning is therefore
not generalized."
It is similarly assumed that delusions and even hallucinations in

schizophrenia is related to an inflexible updating of prediction errors:
• "overly precise representations of prior knowledge, which in turn lead
beliefs to become insensitive to feedback."
• "a tendency to interpret prediction errors as indicating meaningful
change, leading to the assignment of aberrant salience to noisy or
misleading information."
Summary
Both autism and schizophrenia are associated with lower mentalizing,
problems with autobiographical memory, narrative coherence, functions
processed by associative areas and the frontolimbic network
Summary
Autobiographical
memory
Verbal
Semantic cognition
communication
Mentalizing Executive functions

B05 L14 AutismSchizophrenia

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Is autism and schizophrenia on the same

Martin Vestergaard Gøtzsche

Research Unit, Department of Child and Adolescent

Similarities and differences between autism and schizophrenia

Historical ties between schizophrenia and autism:

A century ago, the Swiss psychiatrist Eugen Bleuler considered schizophrenia

DSM-5 Criteria for Schizophrenia

Two or more of the following symptoms must be present, at least 1 of

Persistent delusions of other kinds that are culturally inappropriateand completely

Delusions of control, influence, or passivity

Hallucinations in any modality such as hallucinatory voices

Thought disorder and disorganized speech:

DSM-5 criteria for autism spectrum disorders

Deficits in social-emotional reciprocity

Differences in onset and psychosis between autism and schizophrenia

Thought disorder and disorganized speech in schizophrenia:

Verbal communication in autism:

Negative symptoms in schizophrenia:

Restricted behavior and lower reciprocity in autism:

Only a limited number of genotypes and polymorphisms have been identified.

The genetic load is similarly high for Schizophrenia and autism

Today it is acknowlegded that schizphrenia has a developmental trajectory and

Synaptogenesis peaks in childhood while pruning is ongoing through

Dendrites peaks early in life too.

Dendrites peaks early in life too.

Myelination however, is an ongoing process.

Increased density of synaptic spines is observed in autistic persons in frontal,

In Schizophrenic persons lower density of synaptic spines are observed,

Accelerated gray matter volume loss in very early-onset schizophrenia.

Schizophrenia is associated with reduced volume of the gray matter.

The question is what cellular processes drive these differences?

Psychosis is associated with cortical thinning in frontolimbic and

DWI and DTI measures the diffusion of water, which is higher in

Schizophrenia is associated with diffuse reductions in white matter

Schizophrenia is associated mainly with reduced gray matter,

The question is what cellular processes drive these differences?

Changes in synaptic density cannot readily explain observed

The question remains whether the observed cellular and macroscopic

Mentalizing Executive functions

Studies confirm general executive dysfunctions in a subgroup of autistic persons.

In typically developing children, executive functions are predictive of the

However, executive dysfunctions cannot explain the origin of symptoms in

The executive network

"Theory of mind" based on theory of Uta Frith.

"Mentalizing" based on psychodynamic tradition, particularly

To mentalize we need to read the verbal and nonverbal signals of others,

The social cognitive network

Directive function Self function Social function

Up to 20% of children with autism were not able to recall an autobiographical

The ability to narrate autobiographical memories and fictional stories

A coherent narrative provides the listener with sufficient context leading up to

Context: necessitates mentalizing

Lower narrative coherence on storytelling in children with autism is coupled to

The picture book "Tuesday" is part of the screening with ADOS-2

Both mentalizing and autobiographical memory is associated with frontolimbic

Thought disorder and disorganized speech in schizophrenia:

Verbal communication in autism:

Similar to autistic persons, adults with schizophrenia show

Different words are more representative or typical to a category than other

Frequency distribition of the category animal and fruits.

Negative symptoms in schizophrenia:

Restricted behavior lower reciprocity in autism:

A: V is reward prediction, ! is reward, " is learning rate, and t is trial. B: typical