The number of neurons in the amygdala normally increases during development, but not in autism.

Avino et al. point out one possible underlying cause of the characteristic difficulty that people with autism spectrum disorder have in understanding the emotional expressions of others.

Remarkably little is known about the postnatal cellular development of the human amygdala. It plays a central role in mediating emotional behavior and has an unusually protracted development well into adulthood, increasing in size by 40% from youth to adulthood. Variation from this typical neurodevelopmental trajectory could have profound implications on normal emotional development. We report the results of a stereological analysis of the number of neurons in amygdala nuclei of 52 human brains ranging from 2 to 48 years of age [24 neurotypical and 28 autism spectrum disorder (ASD)]. In neurotypical development, the number of mature neurons in the basal and accessory basal nuclei increases from childhood to adulthood, coinciding with a decrease of immature neurons within the paralaminar nucleus. Individuals with ASD, in contrast, show an initial excess of amygdala neurons during childhood, followed by a reduction in adulthood across nuclei. We propose that there is a long-term contribution of mature neurons from the paralaminar nucleus to other nuclei of the neurotypical human amygdala and that this growth trajectory may be altered in ASD, potentially underlying the volumetric changes detected in ASD and other neurodevelopmental or neuropsychiatric disorders.

Oxytocin enhances brain function in children with autism.

Fascinating observations from Gordon et al, who find that that intranasal administration of oxytocin enhances activity in the brain for socially meaningful stimuli and attenuates its response to nonsocially meaningful stimuli in children with autism spectrum disorder (ASD), as measured via functional MRI. This raises the prospect of treatments that target the core social dysfunction in ASD, and might bring about long-term behavioral improvements.:

Following intranasal administration of oxytocin (OT), we measured, via functional MRI, changes in brain activity during judgments of socially (Eyes) and nonsocially (Vehicles) meaningful pictures in 17 children with high-functioning autism spectrum disorder (ASD). OT increased activity in the striatum, the middle frontal gyrus, the medial prefrontal cortex, the right orbitofrontal cortex, and the left superior temporal sulcus. In the striatum, nucleus accumbens, left posterior superior temporal sulcus, and left premotor cortex, OT increased activity during social judgments and decreased activity during nonsocial judgments. Changes in salivary OT concentrations from baseline to 30 min postadministration were positively associated with increased activity in the right amygdala and orbitofrontal cortex during social vs. nonsocial judgments. OT may thus selectively have an impact on salience and hedonic evaluations of socially meaningful stimuli in children with ASD, and thereby facilitate social attunement. These findings further the development of a neurophysiological systems-level understanding of mechanisms by which OT may enhance social functioning in children with ASD.

Insensitivity to social reputation in autism.

Further characterization of how social cognition is changed by the autism disorder - evidence for distinctive brain systems that mediate the effects of social reputation:

People act more prosocially when they know they are watched by others, an everyday observation borne out by studies from behavioral economics, social psychology, and cognitive neuroscience. This effect is thought to be mediated by the incentive to improve one's social reputation, a specific and possibly uniquely human motivation that depends on our ability to represent what other people think of us. Here we tested the hypothesis that social reputation effects are selectively impaired in autism, a developmental disorder characterized in part by impairments in reciprocal social interactions but whose underlying cognitive causes remain elusive. When asked to make real charitable donations in the presence or absence of an observer, matched healthy controls donated significantly more in the observer's presence than absence, replicating prior work. By contrast, people with high-functioning autism were not influenced by the presence of an observer at all in this task. However, both groups performed significantly better on a continuous performance task in the presence of an observer, suggesting intact general social facilitation in autism. The results argue that people with autism lack the ability to take into consideration what others think of them and provide further support for specialized neural systems mediating the effects of social reputation.

Oxytocin may improve autism

I have done a large number of posts on behavioral effects of oxytocin, the 'trust hormone', notably in human studies that use an oxytocin inhaler (enter oxytocin in the blog search box in the left column to display them).  Recent studies are now suggesting that when some autistic people (who have difficulty interacting with others) inhale oxytocin, they began looking at people in the eye and recognizing social concepts like fairness in a computer game.

Debate over the term Asperger's syndrome - continued

Autism expert Simon Baron-Cohen (cousin of the comic actor Sacha Baron-Cohen) weighs in on the debate that I mentioned in my 11/4/09 post over dropping the term Asperger's syndrome.

Part of the reason the diagnostic manual can move the boundaries and add or remove “mental disorders” so easily is that it focuses on surface appearances or behavior (symptoms) and is silent about causes. Symptoms can be arranged into groups in many ways, and there is no single right way to cluster them. Psychiatry is not at the stage of other branches of medicine, where a diagnostic category depends on a known biological mechanism. An example of where this does occur is Down syndrome, where surface appearances are irrelevant. Instead the cause — an extra copy of Chromosome 21 — is the sole determinant to obtain a diagnosis. Psychiatry, in contrast, does not yet have any diagnostic blood tests with which to reveal a biological mechanism.

..science hasn’t had a proper chance to test if there is a biological difference between Asperger syndrome and classic autism. My colleagues and I recently published the first candidate gene study of Asperger syndrome, which identified 14 genes associated with the condition.

We don’t yet know if Asperger syndrome is genetically identical or distinct from classic autism, but surely it makes scientific sense to wait until these two subgroups have been thoroughly tested before lumping them together in the diagnostic manual. I am the first to agree with the concept of an autistic spectrum, but there may be important differences between subgroups that the psychiatric association should not blur too hastily.

Asperger's syndrome to become Autism spectrum disorder?

Claudia Wallis does an article on the proposal to drop the name "Asperger's syndrome,' folding it, along with the term "pervasive developmental disorder" into the term "Autism spectrum disorder." The simple fact appears to be that "nobody has been able to show consistent differences between what clinicians diagnose as Asperger’s syndrome and what they diagnose as mild autistic disorder." The not so minor problem is that the general population views "Asperger's syndrome" more positively than autism, and the term has developed its own brand identity. "The Asperger’s diagnosis is used by health insurers, researchers, state agencies and schools — not to mention people with the disorder, many of whom proudly call themselves Aspies." On the other hand Ari Ne’eman, 21 - an activist who founded the Autistic Self-Advocacy Network, a 15-chapter organization he has built while in college - notes “My identity is attached to being on the autism spectrum, not some superior Asperger’s identity. I think the consolidation to one category of autism spectrum diagnosis will lead to better services.”

Mindblindness in Asperger's syndrome

Recent work by Senju et al. is summarized in Science:

Placement of Asperger syndrome within the family of autism spectrum disorders (ASD) has always been a bit uneasy; although people with Asperger syndrome do exhibit the core impairments in social interaction and communication that are characteristic of ASD, they nevertheless perform well on tests that are thought to assess the ability to mentalize or to possess Theory of Mind skills. One of the classic tests of mentalizing ability is the false-belief task, in which subjects must be able to represent their own beliefs (true) and another's beliefs, which are false because they have not been given complete information, such as not having seen the transfer of a piece of candy from one drawer to another. People with Asperger syndrome succeed at the verbal form of the false-belief task, yet Senju et al. show that this is owing entirely to their having learned how to cope with an existing and still demonstrable deficit in an implicit version of the false-belief task. That is, the core impairment is present, but conscious and explicit learning allows them to compensate.

Here is the Senju et al. abstract:

Adults with Asperger syndrome can understand mental states such as desires and beliefs (mentalizing) when explicitly prompted to do so, despite having impairments in social communication. We directly tested the hypothesis that such individuals nevertheless fail to mentalize spontaneously. To this end, we used an eye-tracking task that has revealed the spontaneous ability to mentalize in typically developing infants. We showed that, like infants, neurotypical adults’ (n = 17 participants) eye movements anticipated an actor’s behavior on the basis of her false belief. This was not the case for individuals with Asperger syndrome (n = 19). Thus, these individuals do not attribute mental states spontaneously, but they may be able to do so in explicit tasks through compensatory learning.

Estrogen receptors in the male medial amygdala disrupt social behavior.

A series of classic studies have shown that in Prairie Voles two neuropeptides, oxytocin and vasopressin, are primary modulators of pair-bond formation and parental behaviors. Genetic manipulations have been able to switch male behaviors between pair-bonding and promiscuous, and correlations between similar behaviors in human males and their genetic variations have been found. Recently Cushing et al. have made another observation on male voles which one expects will also be carried over to human males: Prosocial behavior correlates with a low density of estrogen receptors in the lateral amygdala, and genetic manipulations which increase the number of these receptors decrease pair-bonding and prosocial behaviors. It will be interesting to follow efforts to translate these findings to human social bonding, especially in relation to neuropsychiatric disorders characterized by an inability to form normal social bonds, such as autism. Here is their abstract:

Studies using estrogen receptor (ER) knock-out mice indicate that ER masculinizes male behavior. Recent studies of ER and male prosocial behavior have shown an inverse relationship between ER expression in regions of the brain that regulate social behavior, including the medial amygdala (MeA), and the expression of male prosocial behavior. These studies have lead to the hypothesis that low levels of ER are necessary to "permit" the expression of high levels of male prosocial behavior. To test this, viral vectors were used to enhance ER in male prairie voles (Microtus ochrogaster), which display high levels of prosocial behavior and low levels of MeA ER. Adult male prairie voles were transfected with ER in the MeA (MeA-ER) or the caudate–putamen (ER control) or luciferase (MeA-site-specific control), and 3 weeks later tested for spontaneous alloparental behavior and partner preference. Enhancing ER in the MeA altered/reduced male prosocial behavior. Only one-third of MeA-ER males, compared with all control males, were alloparental. MeA-ER males also displayed a significant preference for a novel female. This is a critical finding because the manipulations of neuropeptides, oxytocin and vasopressin, can inhibit the formation of a partner preference, but do not lead to the formation of a preference for a novel female. The results support the hypothesis that low levels of ER are necessary for high levels of male prosocial behavior, and provide the first direct evidence that site-specific ER expression plays a critical role in the expression of male prosocial behavior.

A novel theory of mental disorders

Benedict Carey writes a useful article on a radical new theory for explaining the psychotic spectrum:

...that an evolutionary tug of war between genes from the father’s sperm and the mother’s egg can, in effect, tip brain development in one of two ways. A strong bias toward the father pushes a developing brain along the autistic spectrum, toward a fascination with objects, patterns, mechanical systems, at the expense of social development. A bias toward the mother moves the growing brain along what the researchers call the psychotic spectrum, toward hypersensitivity to mood, their own and others’. This, according to the theory, increases a child’s risk of developing schizophrenia later on, as well as mood problems like bipolar disorder and depression.

In short: autism and schizophrenia represent opposite ends of a spectrum that includes most, if not all, psychiatric and developmental brain disorders. The theory has no use for psychiatry’s many separate categories for disorders, and it would give genetic findings an entirely new dimension.

The theory leans heavily on the work of David Haig of Harvard. It was Dr. Haig who argued in the 1990s that pregnancy was in part a biological struggle for resources between the mother and unborn child. On one side, natural selection should favor mothers who limit the nutritional costs of pregnancy and have more offspring; on the other, it should also favor fathers whose offspring maximize the nutrients they receive during gestation, setting up a direct conflict.

I strongly recommend that you read the article, which goes on to give a lucid explanation of how gene imprinting regulates this competition.

Enhanced logical consistency in autism.

Dolan's group has an interesting open access article in J. Neuroscience showing:

behavioral evidence that autism spectrum disorder (ASD) subjects show a reduced susceptibility to the framing effect and psycho-physiological evidence that they fail to incorporate emotional context into the decision-making process.

From their introduction:

Logical consistency across decisions, regardless of how choices are presented, is a central tenet of rational choice theory and the cornerstone of modern economic and political science. Empirical data challenge this perspective by showing that humans are highly susceptible to the manner or context in which options are cast, resulting in a decision bias termed the "framing effect". We have previously shown that the amygdala mediates this framing bias, a finding that highlights the importance of incorporating emotional processes within models of human decision making. An ability to integrate emotional contextual information into the decision process provides a useful heuristic in decision making under uncertainty. This is a factor that is likely to assume considerable importance during social interactions in which information about others is often incomplete, ambiguous, and not easily amenable to standard inferential reasoning processes.

In this study, we investigated the effect of contextual frame on choice behavior of individuals with autistic spectrum disorder (ASD). Autism is a neurodevelopmental disorder characterized by deficits in social interaction, qualitative impairments in communication, and repetitive and stereotyped patterns of behavior, interests, and activities. From Kanner's earliest description, it has been recognized that individuals with ASD have a strong tendency to focus on parts rather than global aspects of objects of interest and are unable to integrate disparate information into a meaningful whole (weak central coherence theory).

We previously proposed that susceptibility to a framing bias reflects the operation of an affect heuristic. Here, we show that individuals with ASD, a condition characterized by marked behavioral inflexibility, demonstrate a decreased susceptibility to framing resulting in an unusual enhancement in logical consistency that is paradoxically more in line with the normative prescriptions of rationality at the core of the current economics theory. Furthermore, insensitivity in these subjects to a contextual framing bias was associated with a failure to express a differential autonomic response to contextual cues as indexed in skin conductance responses (SCRs), a standard measure of emotional processing. Our findings suggest that a more consistent pattern of choice in the ASD group reflects a failure to incorporate emotional cues into the decision process, an enhanced economic "rationality" that may come at a cost of reduced behavioral flexibility.

Autistic people have the visual acuity of hawks.

Ashwin et al. have come up with a fascinating observation during their testing of 15 men with autism-spectrum disorders using the Freiburg Visual Acuity and Contrast Test. They found them to have, on average, 20:7 vision. This means they can see the same detail on an object 20 meters away that a person with average vision can see at 7 meters. Birds of prey have roughly 20:6 vision. What gives these people with autism hawk-like vision isn't known.

High-Functioning Autism: a neural phenotype in the cingulate cortex

A review by Chris and Uta Frith discusses and important paper in Neuron from Montague's group in Houston, who:

...have measured brain activity (using fMRI) while volunteers, who are classified as being at the high-functioning end of the autistic spectrum, were engaged in a simple social interaction. The task was an iterated trust game in which two subjects take turns as investor or trustee. The investor chooses how much to money to invest. This chosen amount is tripled on its way to the trustee, and the trustee then chooses how much to repay to the investor. Read Montague and his colleagues have studied this game extensively in large groups of volunteers and have observed a characteristic pattern of brain activity in the anterior cingulate cortex. When making an investment (self phase), transient increases in activity are seen in an area of mid cingulate cortex (−7 <>A graphic from the Chiu et al paper showing the diminished "self" response in autism spectrum patients:


...the results suggest that the abnormality associated with autism is restricted to only one phase of the interactive game: the point where the autistic volunteer makes an investment, not the point where the autistic volunteer is told about the repayment made by their partner. Additional results from Read Montague's group give further clues as to the implications of this result. First, the same pattern of activity in cingulate cortex is observed when volunteers are shown pictures of people engaged in athletic activities and asked to imagine themselves taking part. This is further evidence as to the nature of the cognitive process associated with this pattern of activity: it involves thinking about the self acting in a social context. Second, the characteristic patterns of activity in the cingulate cortex are only observed when the trust game is played with a human partner. No such distinct patterns emerge when the game is played in the absence of a responsive social partner...At least part of the imagining must involve thinking about how one would fit in with the group, and how other group members would evaluate one's performance. Actually, this is a question about the kind of reputation one might gain in the eyes of the others. Likewise, in the self phase of the trust game, the amount one invests can be seen as a measure of how much one trusts one's partner. It is not just giving an amount of money; it is giving a signal to the other person: “trust me” and “I trust you.”
In other words, at the point of investment we are predicting what the effect of our investments is going to be on the behavior of our partners. In the other phase of the game, we are also evaluating a signal. But there is a difference. The evaluation is after the fact. We know what the investment is. We are not at this point trying to build our reputation in the other player's eyes.

Impairment of action chains in autism.

When we observe the start of an action sequence that can end in two possible ways (in the figure shown a piece of food is placed in the mouth or in a container on the shoulder) appropriate sympathetic muscle EMG signals are detected at the start of the sequence. Thus, if the sequence will end in food to the mouth, activity is observed in the mouth-opening mylohyoid (MH) muscle at the onset. Rizzolatti and collaborators find that typically developing children show an activation of their MH muscle already when they observe the experimenter's initial motor act, food reaching. This activation reflects their understanding of the final goal of the observed action. In children with autism this action-understanding motor activation is lacking. Further, when typically developing children actually perform the observed action, MH muscle activation is observed at the very beginning of the sequence, while in children with autism, the activation is not observed until immediately before the muscle is actually used.

Figure - Schematic representation of the tasks. (Upper) The individual reaches for a piece of food located on a touch-sensitive plate, grasps it, brings it to the mouth, and finally eats it. (Lower) The individual reaches for a piece of a paper located on the same plate, grasps it, and puts into a container placed on the shoulder.

They suggest that high-functioning autistic children may understand the intentions of others cognitively but lack the mechanism for understanding them experientially because they lack the chains of action-constrained neurons that code specific motor acts (e.g., grasping) according to the final goal of the action in which the motor act is embedded.

Plasticity and learning in the human mirror neuron system

I pass on a review by Welberg of an interesting study by Catmur et al. [Catmur, C., Walsh, V. & Heyes, C. Sensorimotor learning configures the human mirror system. Curr. Biol. 17, 1527–1531 (2007)]:

Neurons in the frontoparietal mirror system fire when one performs an action and when one observes someone else performing that same action. This system is thought to have a role in social cognition and, perhaps, in language acquisition. How the mirror neurons map sensory input onto its motor representation is unknown, but Catmur et al. demonstrate that these representations are not innate and can be altered by training.

The authors used transcranial magnetic stimulation (TMS) to stimulate the motor cortex of volunteers who were watching a video of a hand. When the volunteers watched the hand's index finger move, the TMS-induced motor-evoked potential (MEP) was greater in the abductor muscle of their own index finger than when they watched the little finger move; conversely, the MEP of their little finger's abductor muscle was greatest when they watched the little finger move. In other words, a muscle showed MEP enhancement when its owner watched a movement that is normally performed by that muscle; this 'mirror effect' is thought to reflect activity of the mirror neuron system.

Half of the volunteers then underwent incongruent training trials, in which they were asked to extend their little finger if the video showed a hand extending the index finger, and vice versa. People in congruent trials simply had to repeat the movement they saw in the video. The incongruent trials were assumed to train the mirror system to associate an observed finger movement with movement of a different finger of the volunteer's own hand.

Measuring TMS-induced MEPs after training, the authors found that volunteers who had undergone the incongruent training now showed greater MEPs in the muscle of one finger when watching the 'wrong' finger move in the video, indicating that a reversal of muscle-specific MEP enhancement during action observation had taken place.

This study shows that the 'mirror properties' of the mirror system are not innate. Rather, they can be trained, through sensorimotor experience, to transform observation into action. These findings imply that insufficient social interaction and consequent inadequate sensory experience might affect the development of the mirror neuron system, for example, in children with autism.

Self-Referential Cognition in Autism

Individuals with autism spectrum conditions (ASC) have profound impairments in the interpersonal social domain, but it is unclear if individuals with ASC also have impairments in the intrapersonal self-referential domain. Lombardo et. al. give an interesting introductory discussion of the "absent self" model of Frith. They then evaluate performance of 30 subjects and:

"conclude that individuals with ASC have broad impairments in both self-referential cognition and empathy. These two domains are also intrinsically linked and support predictions made by simulation theory. Our results also highlight a specific dysfunction in ASC within cortical midlines structures of the brain such as the medial prefrontal cortex."

Figure:. Image showing the overlap in peaks of activation from studies of self-referential cognition, other-referential cognition, and theory of mind within the medial prefrontal cortex and posterior cingulate/precuneus.

Boundaries are 16mm from within midline. All peaks are taken from exemplary studies in the literature. Brain is depicted on a representative sagittal slice of the Montreal Neurological Institute (MNI) template

Savant Autism - part 1

I thought this two part sequence on autism was worth passing on....

Savant Autism - part 2

An Autistic Savant - The Living Camera

Steven is an autistic savant living in London who did not speak until he was five and now has great difficulty with language as an adult. When he was eleven he drew a perfect aerial view of London after flying over it only once. Here is a windows media player movie describing his Rome flyover and drawing.

A "mind reading" prosthesis for autistic people?

Another clip from the NYTimes Magazine "Ideas" issue:

"The Emotional-Social Intelligence Prosthesis, developed by Rana el Kaliouby and Rosalind Picard, consists of a small camera mounted on a cap or glasses that monitors a conversation partner’s facial expressions and feeds the data into a hand-held computer. Software tracks the movement of facial features and classifies them using a coding system developed by the psychologist Paul Ekman, which is then correlated with a second taxonomy of emotional states created by the Cambridge autism researcher (and Ali G cousin) Simon Baron-Cohen. Almost instantaneously, the computer crunches each raised eyebrow and pucker of the lips, giving a whispered verdict about how the person is feeling. (Another version of the device, meant to be used separately, points back at users, allowing them to better understand — and perhaps modify — the face they present to the world.)" (CLICK to enlarge image below).

A striking difference in brain function in autism: Failure to deactivate.

Kennedy et al report interesting functional magnetic resonance imaging (fMRI) data on normal compared with autistic brains. From their article:

Internally directed processes, such as self-reflective thought and most higher-order social and emotional processes, consistently activate a medial cortical network involving several brain regions, namely, the medial prefrontal cortex (MPFC) and adjacent rostral anterior cingulate cortex (rACC), posterior cingulate cortex (PCC), and precuneus (PrC). Interestingly, this network is active when normal subjects are passively resting, leading many to speculate that these internally directed thoughts dominate the resting state. Self-reports from subjects while at rest further support this interpretation, wherein they typically describe "autobiographical reminiscences, either recent or ancient, consisting of familiar faces, scenes, dialogues, stories, and melodies". Conversely, activity in this midline "resting network" is reduced when subjects perform externally directed, attention-demanding, goal-oriented tasks (such as the Stroop task or math calculations), and the resulting "deactivation" of this network is thought to be an indicator of an interruption of ongoing internally directed thought processes. Thus, measuring deactivation provides a means by which rest-associated functional activity can be quantitatively examined.

Applying this approach to autism, Kennedy et al found that the autism group failed to demonstrate this deactivation effect. Furthermore, there was a strong correlation between a clinical measure of social impairment and functional activity within the ventral medial prefrontal cortex. They speculate that the lack of deactivation in the autism group is indicative of abnormal internally directed processes at rest, which may be an important contribution to the social and emotional deficits of autism.