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The brain in autism

Changes in temporal cortex may damage perception of important information for social interaction

Marie Hippenmeyer / photos from the series Preto e Branco, 2002-2007“Mummy, mummy, I have discovered that Captain Hook is a god guy. He said ‘I’ll take care of you’,” announced the boy during a consultation, interrupting his mother’s conversation with the doctor. And he repeated this discovery he had made while watching the film Peter Pan two or three times, then resuming his habitual silence and waving his hands up and down as if he wanted to release them from his arms. Unlike other children his age, the seven-year old boy seen by the child psychiatrist Marcos Tomanik Mercadante could not grasp the irony in the villain’s speech, indicated by a marked change in his tone of voice.

The signs in the boy observed by Mercadante are typical of a group of disturbances whose prevalence is still little known in Brazil and that have started to be better understood only in the last few years, thanks, partly, to the work of Brazilian researchers here and abroad. Classified as disorders of the autistic spectrum or of overall development, these neuropsychological problems appear during childhood and, to a greater or lesser extent, hinder the capacity to communicate and relate to other people throughout the lives of those who suffer from such conditions. These include a range of types:  classic autism, underscored by severe language and social interaction difficulties; Asperger’s syndrome, in which intelligence is normal or above average and the acquisition of language is problem-free, but in which repetitive gestures and a lack of control in delicate movements is common; or the savant syndrome, in which prodigious memory, mathematical or artistic skills go hand in hand with mental retardation.

A survey conducted in recent years shows a substantial growth of the number of cases of these disorders. Just slightly more than ten years ago, it was believed that autism and its variations were fairly rare. Based on research in the United States and Europe, it was estimated that one out of every 2.5 thousand children, or 0.04% of all children, had a disorder of the autistic type. Today, this figure is 20 times greater. Almost 1% of the American and English children suffer from one of these development disorders, according to recent data from the Center for Disease Control and Prevention in the United States and to research from English universities. This rate may even   be   higher. An article in the May issue of the American Journal of Psychiatry indicated that the prevalence of autistic disorders is 2.5% in South Korea.

The most likely scenario is that there is no autism epidemic. In a report presented in 2010 to the World Health Organization (WHO), Brazilian and foreign experts who analyzed almost 600 studies on the subject indicated that the increase in the rate of such disorders seems to result from using more wide-ranging diagnostic strategies and from the enhanced vigilance of healthcare professionals – although one cannot overrule the possibility of an actual growth in the number of cases.

In Brazil, however, data on the problem are practically unknown. Because of a lack of population studies, it is unclear how many children suffer from autistic conditions or where they are to be found. Even less is known about whether they receive a minimum amount of care from the healthcare and educational systems in order to lead a life as close to normal as possible.

Marie Hippenmeyer / photos from the series Preto e Branco, 2002-2007The greatest and most recent survey in Brazil – one of the few conducted in South America – suggests that autism and its variations affect one out of every 370 children or 0.3% of them. Coordinated by Mercadante, from the Federal University of São Paulo (Unifesp), and Cristiane Silvestre de Paula, a psychologist and epidemiologist from Mackenzie Presbyterian University, the study evaluated autistic signs in 1,470 children aged 7 to 12, a sample of fairly reasonable size. However, this article, published in the February Journal of Autism and Developmental Disorders, is a pilot study. Its main limitation is that it was conducted in only one Brazilian town, Atibaia, which has 126 thousand inhabitants and lies 60 km away from the city of São Paulo. “We conducted this study, financed by Mackenzie, with little money,” Mercadante explains. He plans to repeat the survey in several cities in five regions in Brazil.

In Atibaia, the psychologist Sabrina Ribeiro identified all the schools and healthcare units in the region covered by the study and trained the teachers, physicians and the professionals from the family healthcare program to recognize signs of autism in children. Out of the 1,470 that lived in the area, 94 were referred for more detailed clinical testing and 4 were diagnosed as autistic.

If the Atibaia ratio were to be extrapolated to the rest of the country, including adults, since a recent study in England showed that the prevalence of autism among adults and children was similar – one would expect to find some 570 thousand Brazilians with some form of autism. “Some studies indicate that the prevalence of autism might be lower among people of Latin origin,” comments Mercadante. “The fact that our culture demands the development of social skills to a greater extent than is the case in many Northern hemisphere countries, where epidemiological studies are usually conducted, might help people with less serious cases to lead a relatively independent life and not to be identified as autistic,” he says.

This is a favorable estimate; the figures here and in other countries may have been underestimated, as the English researcher who conducted the first study on the prevalence of adult autism suspects. The study was published in the May issue of Archives of General Psychiatry. In this study, autism signs were assessed among 7,461 adults and it was confirmed that 618 of them suffered from some form of the disorder. “In none of the cases identified in this survey did the people know that they were autistic, nor had they been officially diagnosed previously,” said Traolach Brugha, a researcher from the University of Leicester in England and the author of the study in a press release.

Although most of the cases were light, the finding is akin to a yellow light: even in countries with well-structured health services, many cases go undiagnosed. Should Brazilian rates be as high as those in the United States, there might be as many as 1.9 million autistic Brazilians. “This would be a bomb for the public coffers,” says Cristiane. “It would be necessary to increase significantly the capacity to deal with the problem.”

Marie Hippenmeyer / photos from the series Preto e Branco, 2002-2007“Autistic people require ongoing and costly treatment,” Maria Cecilia Mello tells us. She is the mother of Nicholas, a 19-year old who was diagnosed with Asperger’s syndrome just three years ago. “They also need specialized monitoring to leverage their specific skills and develop those with which they have difficulty,” says the federal judge who,  along with Mercadante and other parents and researchers, founded the Autismo & Realidade NGO in 2010, which aims to disseminate information on the disorder and raise funds to finance research in the field.

In the United States, where statistics for almost anything are available, Michael Ganz from Harvard University calculated, years ago, that the cost of maintaining an autistic person throughout his or her life, taking into account medical and educational expenses and the loss of work productivity, was US$3.2 million.

In Brazil’s public health service, suspected autism cases are meant to be identified by pediatricians in the basic healthcare units and referred for specialized care to one of the 128 centers of psychosocial care for children (CAPsi). However, these centers are concentrated in the Southeast and the Northeast. There are five Brazilian states with no CAPsi, while another seven states only have one, according to a recent Ministry of Health report.

Even in the city of São Paulo, which has the best services of this kind in Brazil, only 9 of the 16 CAPSi are qualified to care for autistic people, according to Cristiane. Given this state of affairs, Mercadante believes that most cases are seen to by associations of parents and friends of intellectually impaired children, the AMAs and APAEs. In São Paulo, a 2001 court ruling   established that the State Health Bureau should pay for the specialized education, assistance and treatment of autistic patients.

Without a broader survey, such as that which he and Cristiane are planning, one faces a vicious circle. “As no wide-ranging studies are available in the country, one is unable to show that the problem exists. And the absence of proof makes it hard to demand care,” states the epidemiologist, who is working on a survey of mental health problems among children in five Brazilian capital cities. This is a project of the National Institute of Psychiatry for Development of Children and Adolescents, which has FAPESP and federal government support.

Early and good quality medical care is essential to influence the development of autism, so much so that researchers worldwide are looking for strategies to identify autism with certainty in the first year of life. “The earlier the signs are identified, the better the chances of intervening to try and recover the child’s capacity to relate to others and to develop its construction of significant language,” states the psychologist and psychoanalyst Maria Cristina Kupfer, from the Psychology Institute of the University of São Paulo (USP), and the founder of Lugar de Vida, an organization that for the last 20 years has been providing care for autistic individuals. “Early intervention also enables listening to the parents, who suffer because they don’t get from their children the same attention that they give them.”

016-023_autismo_184NOVO2Ever since autism was described in the 1940s, its diagnosis has been clinical. In general, a neurologist or psychiatrist examines the child and evaluates his or her life history looking for signs of late development in the capacity to interact socially and to communicate, as well as delays in motor development, as described in the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association and in the World Health Organization’s International Classification of Diseases.

Although some symptoms emerge very early, in the first few months of life, most cases are usually confirmed only around the age of three, once the brain has already undergone one of its most intense growth phases, under the best hypothesis. Mercadante, however, believes that identification in Brazil tends to occur only around the age of five or six, once a fundamental stage of child development has already been missed. In the Atibaia study, for example, only one of the four cases of autism had been identified previously and had received specialized care. “We need to improve the training of pediatricians to identify the signs as early as possible,” states Cristiane.

Leonardo Posternak, a pediatrician at the Albert Einstein Hospital in the city of São Paulo, plans to start a multi-center study this year, together with a Unifesp team, to assess the effectiveness of a training program for pediatricians that has been developed by a French care organization, PréAut, with the help of the Brazilian psychoanalyst Marie Christine Laznik. Posternak, who already offers this training to physicians from Instituto da Família, a social organization that provides care for low-income children and their families, plans to train, initially, pediatricians from the town of Embu and then measure their capacity to identify autism and other psychiatric problems that lead to early suffering. “The pediatrician must be aware of the relation between parents and children and of the family’s day-to-day life,” says Posternak.

Years ago, Maria Cristina Kupfer tried to establish a bridge with pediatricians and to help early detection of autism. Although psychoanalysis does not employ the identification protocols of psychiatry, in 1999, a group of nine experts under her coordination, with FAPESP support, developed a series of 31 indicators for the early detection of risks to psychiatric development, the IRDI protocol, at the request of the pediatrician Josenilda Brant, a children’s healthcare consultant to the Ministry of Health. The protocol was meant to be part of the Manual para o acompanhamento do crescimento e desenvolvimento[Growth and Development Monitoring Manual] that the ministry distributes to the doctors of the public healthcare network.

Pediatricians at 11 healthcare centers in nine Brazilian cities applied the indicators to 726 children aged one and a half or younger. Presented in 2009 in the Latin American Journal of Fundamental Psychopathology Online, the results showed that 15 of these indicators, which assessed simple interactions such as “mother and baby exchange looks or the child reacts (smiles, vocalizes) when the mother or another person talks to it,” could predict, as of the sixth month of life, if there was a risk of developing psychiatric problems. “The indicators of the IRDI protocol, after adaptation, actually became part of the Child Healthcare Bulletin, designed to provide guidance for the parents, in 2006, 2007 and 2008, but they were subsequently eliminated,” Maria Cristina explains. “However, the research-validated indicators were not included in the development monitoring records used by pediatricians in consultations in the public healthcare system.”

Despite this setback, Maria Cristina did not give up. “If one door closes, we look for another one,” says the psychoanalyst, who plans to test her indicators in 29 daycare centers in the São Paulo city district of Butantã. “Using this tool in daycare centers is an interesting alternative, because children spend eight hours a day there and have much more contact with the teachers than with pediatricians,” she explains.

art4432img2-290x300Marie Hippenmeyer / photos from the series Preto e Branco, 2002-2007Actually, it was as a problem of affective contact that the first cases of what would come to be known as autism were described by the Austrian psychiatrist Leo Kanner, from the Johns Hopkins Hospital in the United States. In October 1938, Kanner examined an American boy from Missouri, Donald Gray Triplett, who from his earliest days had had difficulty interacting with people while also having a fixation for certain objects and a great capacity for memorization. Although the indications were reminiscent of a severe psychiatric problem, schizophrenia, Kanner was unable to establish a definitive diagnosis. In subsequent years, he identified nine similar cases and presented them in a 1943 article called “Autistic disturbances of affective contact.” Here, Kanner borrowed the term autism to describe the distancing and self-centered behavior typical of schizophrenia. One year later, another Austrian psychiatrist, Hans Asperger, described slightly different cases, involving children of normal intelligence and learning capabilities who had difficulty interacting socially – indicators that became characteristic of Asperger’s syndrome, one of the disorders of the autistic spectrum.

Whereas Asperger believed that these disorders had a biological basis, Kanner saw them as problems of psychic causes, the result of being raised by cold, distant parents. As a result of the influence of researchers such as the psychologist Bruno Bettelheim, this view prevailed for years, becoming known as the “refrigerator mother theory.” “An entire generation of parents, and of mothers in particular, was lead to feel guilty for their children’s autism,” writes the English neurologist Oliver Sacks in his book An Anthropologist on Mars, published [in translation] in Brazil by Companhia das Letras.

This weight would only come to be lifted from parents’ shoulders in the 1960s, when evidence began arising in support of the notion that changes in the central nervous system might be behind autism. However, it still took quite a while for the biological view to gain strength. The first group to identify the abnormal functioning of autistic children’s brains was that of the Brazilian physician Monica Zilbovicius, a researcher at France’s National Institute of Health and Medical Research. Using positron emission tomography (PET), which measures the blood flow and therefore the level of activity in different areas of the central nervous system, Monica analyzed the brain of 21 boys who were autistic and of 10 who were not. Autism is four times more common among boys than among girls.

She found that the children in the first group had less activity in the superior temporal sulcus, a small area of the temporal lobe, according to results presented in 2000 in the American Journal of Psychiatry. “Four groups attempted this before us, but they found nothing,” Monica tells us. “At that time, we didn’t even know what the function of this area was in the normal brain.” Besides being less active, the cortex of the superior temporal sulcus, in the area of the temples, right above the ears, was less thick.

At first, scientists thought that the temporal lobe was only important for perceiving sounds. More detailed studies, however, showed that both the superior temporal sulcus and another area of the temporal lobe, the fusiform gyrus, were involved in the processing of two types of relevant information for social interaction, capturing auditory information about the voice of the interlocutor, as well as visual information, such as eye movements, gestures and facial expressions. These areas then process this data and distribute them to other brain areas associated with emotions and logical thinking.

It is the proper functioning of these areas that allows one to become aware of the intention and disposition of the person with whom one is interacting. When one of these areas is altered, the perception of both visual and auditory information becomes deficient, as in the case of the boy who could not grasp the vicious undertones in Captain Hook’s voice. These discoveries led Monica to propose, in 2006, that modifications in these areas of the brain during development might be responsible for difficulties with social interaction, the most frequent autism symptom.

art4432img3Marie Hippenmeyer / photos from the series Preto e Branco, 2002-2007While certain brain regions involved in autism were being mapped, another Brazilian researcher, the psychologist Ami Klin, began identifying why autistic children failed to perceive important information for interaction with other people. During his PhD in psychology at the London School of Economics, Klin created a simple experiment that allowed him to verify that autistic babies have an abnormal reaction when they hear voices. He created a device with two buttons – one reproduced a recording of the voice of the baby’s mother and the other, a mixture of voices – and presented it to babies less than one year of age. In most cases, the healthy babies pressed the button that would play their mother’s voice. The autistic babies, however, showed no preference: they pressed both buttons indistinctly. At Yale University in the United States, where he headed a program of studies on autism, Klin started using a technique that allows one to track eye movement to find out where people with autism focused their vision during contact with other people. “If we really want to understand what is going on in their head, we need to see the world through their eyes,” said Klin, who is now a researcher at Emory University, in an interview he gave years ago.

In a test with healthy adolescents and autistic adolescents, he found that most of the time, the former paid attention to the eyes of the speaker, a pattern that humans and other large primates develop in their first weeks of life. This is believed to have been of evolutionary importance because it allows one to distinguish the members of the same species (and their intent) from predators. Autistic people, however, focused their eyes around the mouth or the hair, areas that do not provide relevant information about the social context. In autism, apparently, the capacity to look for these social clues is lost very early in life, as Klin showed when he repeated the experiment with two-year olds. “It is likely that, for this reason, autistic people are unable to decipher the expression on the faces of other people or show expressions that are appropriate to their social situation,” comments Monica.

At present, there is a consensus that the inadequate formation of the neuronal networks connected with perception and the processing of social information – the so-called social brain – is due to defects in genes. “It is believed that autism has a substantial genetic origin and that the manifestation of the problem depends predominantly on the genetic constitution of the individual,” comments Maria Rita Passos Bueno, a geneticist from USP who is investigating the disorder.

To date, changes in more than 200 genes, distributed along almost all human chromosomes, have been associated with autism. Defects in a small number of these (10%), however, apparently explain the problem entirely. Despite a certain pattern of clinical symptoms, from the genetic point of view each patient seems to have his or her own form of autism, according to Maria Rita. Her group at USP, which described, in 2009, alterations in the genes of two receptors of the neurotransmitter serotonin, has developed a DNA chip to look for small alterations in the 250 genes responsible for neuron connections in 500 autistic children, most of them diagnosed by the team of psychiatrist Estevão Vadasz. Twenty percent of the 70 children already tested by Cíntia Marques Ribeiro have defects in one of these genes at least.

Mercadante and the geneticist Patricia Braga, also from USP, are taking a different path. Instead of working with a large group of autistic people with varied clinical characteristics, they selected just a few patients with similar symptoms, to see whether they share the same genetic alterations.

“A more general classification reveals that the gene alterations already found interfere with three biochemical pathways responsible for the development of neurons, one of the types of brain cells,” explains the Brazilian neuroscientist Alysson Muotri, from the University of California in San Diego, in the United States. The affected biochemical pathways control the proliferation and maturing of neurons and the formation of connections (synapses) among these brain cells.

Last year, Muotri’s team made significant progress in their investigation of what is the matter with neurons in autism. As it is unethical to extract cells from a child’s brain, the Brazilian researcher and his group took skin cells from children with Rett syndrome (one of the disorders of the autistic spectrum) and from normal children to then convert them into stem cells using a process called genetic reprogramming. These cells were then stimulated in a laboratory to become neurons. Muotri observed that the neurons from the Rett syndrome children had approximately 50% fewer projections (spines) connecting one cell to the next. In association with Maria Rita’s group, he repeated the experiment with cells from the tooth pulp of classically autistic children and observed similar results. Preliminary data indicate a smaller number of spines in the neurons developed from the cells of autistic children (see Autism connection, Pesquisa FAPESP issue 173).

“We’ll never know whether what we observed in these neurons taken from a culture is the same as that which happens in the brain,” explains Muotri. “Nevertheless, I believe that one can get important information from this model.” Despite this doubt, this cellular model of autism is promising. Using two compounds, the antibiotic gentamicin and a growth factor similar to insulin 1 (IGF-1) during neuronal development, Muotri changed the structure of the neurons obtained from autistic cells, which began looking like healthy neurons. “By showing that these changes can be reversed, we proved that there is a biological problem and we broke the stigma that autism isn’t curable,” says the neuroscientist.

He is well aware that the strategy used with a culture of cells cannot yet be applied to humans. Gentamicin is relatively toxic and IGF-1, if applied to the blood stream, does not reach the brain efficiently. The result, however, raises hopes that one day, in what might still be the distant future, it may be possible to develop pharmacological treatment to diminish the characteristics of autism, for which there is no cure at present.

Mutations behind autism are also a feature at Nature News this month