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Diet-Based Epilepsy Therapy May Offer Hope for Children with Autism

Susan MasinoA dietary therapy known to be highly effective at reducing epileptic seizures may independently reduce behaviors associated with autism spectrum disorders, new research on mice has shown. The high-fat, low-carbohydrate food regimen, known as a “ketogenic” diet, has been prescribed to treat epilepsy patients — most often in children — for nearly 100 years.

Research in recent years has suggested that the diet may benefit neurological conditions besides epilepsy, including neurodegenerative disorders. However, these new findings provide the first translational evidence in an established animal model that a ketogenic diet can reverse multiple symptoms that characterize a developmental disorder such as autism.

The research was conducted by an international team of scientists, led by Susan Masino, professor of psychology and neuroscience at Trinity College, and published in the June 5 issue of the open-access peer reviewed journal, PLOS ONE (http://dx.plos.org/10.1371/journal.pone.0065021). Researchers at the Legacy Research Institute in Portland, OR; at the Jikei University School of Medicine in Tokyo, Japan; and at the University of Calgary in Alberta, Canada, contributed to this work.

“Although treatment strategies for children with autism spectrum disorders are under development, the ketogenic diet is available now and could offer multiple benefits,” Masino noted. “For example, children with autism and uncontrolled seizures have few options, and this research suggests a ketogenic diet could reduce seizures and improve behavior.”

It is well established that autism rates are increasing, and are now estimated at 1 in 88 children. Currently, there are no biologically validated treatments for autism’s core symptoms of poor social behavior and communication and restricted interests. Although dietary approaches for treating autism are not uncommon – for example, a gluten-free, casein-free diet remains popular – none of these special diets have proven to be effective in controlled clinical studies. Furthermore, most available medical treatments address co-morbid conditions, such as anxiety, seizures and aggression rather than the core behavioral symptoms that result in an autism diagnosis.

A ketogenic diet is administered under medical supervision and was developed based on the historical observation that fasting reduces seizures. Because of very restricted carbohydrates and limited proteins, the ketogenic diet forces the body to use fat rather than glucose as an energy source and thus produces a metabolic state similar to fasting. Ketogenic diets have been used successfully to treat epilepsy in people since 1921, and can sometimes stop seizures when drugs are ineffective.

A small study a decade ago demonstrated that some children with autism on an intermittent ketogenic diet experienced a significant reduction in autistic symptoms, but this initial work did not lead to controlled clinical or animal studies. Masino and her colleagues have been studying the ketogenic diet for a variety of neurological disorders, and working on hypotheses that the anti-seizure molecule, adenosine, may be key to the diet’s effects and may also be helpful in alleviating symptoms of autism.

Masino and her team tested the behavioral effects of a ketogenic diet using a model known as the BTBR mouse, a mouse strain that shows multiple characteristics of autism, including low sociability, poor perception of social cues and highly repetitive behaviors. As expected, the group confirmed that BTBR mice fed a normal diet displayed behavioral symptoms of autism.

Surprisingly, however, after feeding a ketogenic diet to a matched group of BTBR mice for three to four weeks, autistic behaviors reversed significantly and BTBR mice behaved like normal mice. For example, BTBR mice fed a ketogenic diet were more social and opted to spend more time with another mouse rather than time alone; they were also successful at perceiving social communication cues regarding food choice. Ketogenic diet-fed BTBR mice also spent significantly less time grooming, indicating reduced repetitive self-directed behavior.

“Together, these behaviors represent the complement of core symptoms used to diagnose autism, and all were reversed by the ketogenic diet,” said Masino.

Because seizures are common in persons with autism spectrum disorders, it was important to determine if the effects of the diet were related to the ketogenic diet’s well-known ability to treat epilepsy. Based on a battery of tests, including EEG recordings and evoked seizures, the researchers found that the BTBR mice do not have epilepsy, and are not generally vulnerable to seizures. Therefore, the behavioral effects of the diet are independent of its anti-seizure effects.

Based on previous research on the ketogenic diet and on the causes of autism, multiple possible cellular changes may underlie these behavioral improvements. In addition to Masino’s hypothesis regarding adenosine, inflammation is emerging as an important factor in causing autism: a general decrease in inflammation due to the ketogenic diet could underlie its effectiveness against autistic symptoms. In a prior paper in PLOS ONE, Masino’s laboratory showed for the first time that a ketogenic diet can reduce inflammation in rats. Inflammation, adenosine, and other possible mechanisms are under investigation by several research groups.

At this time, with increasing prevalence and few treatment options, new treatment strategies for autism are needed. Based on these findings, additional research on the ketogenic diet may offer clues to reversing symptoms of autism.

Added Masino: “We hope this research draws attention to ketogenic diets as a promising, non-pharmaceutical treatment for children with autism spectrum disorders. These diets may be particularly useful for children with autism and co-morbid uncontrolled seizures. This is a clinical population known to have particularly poor outcomes. If other treatments are not working, a ketogenic diet should be offered as an option.”

Masino’s laboratory is funded by the National Institutes of Health (National Institutes of Neurological Disorders and Stroke), and the National Science Foundation.

For more information, please contact Masino at susan.masino@trincoll.edu or at 860-748-7746.

Founded in Hartford, CT, in 1823, Trinity College is an independent, nonsectarian liberal arts college with more than 2,300 students from 47 states and 54 countries. It is home to the eighth-oldest chapter of Phi Beta Kappa in the United States. The faculty and alumni include recipients of the Pulitzer Prize, the MacArthur award, Guggenheims Rockefellers and other national academic awards. Trinity students integrate meaningful academic and leadership experience at all levels on the College’s celebrated campus in the capital city of Hartford, and in communities all over the world.

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First major CUGS publication focuses on secondary cities

In the autumn of 2007, Xiangming Chen arrived at Trinity to become the founding dean and director of the College’s Center for Urban and Global Studies (CUGS), which began that year thanks to a major donation from the Andrew W. Mellon Foundation. Chen brought with him strong credentials—a distinguished 18-year career at the University of Illinois at Chicago and an impressive body of scholarship. He was precisely the sort of leader that the new center, the first of its type at a top liberal arts college in the United States, required.

CUGS is at the epicenter of Trinity’s strategic mission to integrate urban and global education in Hartford and globally. And Chen wasted no time tackling that mission. In November 2008, he convened the new center’s first major conference. It was a two-day program that drew speakers, panelists and participants from all over the region, including 13 prominent scholars from Harvard, Brown, MIT, Yale, and other major universities, plus a large, interdisciplinary contingent of Trinity faculty.

The collective focus of the conference—Rethinking Cities and Communities: Urban Transition Before and During the Era of Globalization—signaled Chen’s determination that the center would lead, rather than follow, in defining new and innovative ways of thinking about the role of cities in the future of the planet. And the subjects of many of the papers, inspired by that focus, spoke volumes about his vision for the new center, which seeks to balance Trinity’s commitment to international learning opportunities with the College’s commitment to employing Hartford and the region as an experiential learning laboratory.

Now, four years later, a book—Rethinking Global Urbanism: Comparative Insights from Secondary Cities (2012, Routledge)—has emerged from that seminal conference. Edited by Chen and Ahmed Kanna, assistant professor in the School of International Studies at the University of the Pacific, the book’s 12 chapters are expanded from papers presented at the 2008 conference.

Not surprisingly, some papers presented at the conference focused on issues related to the Connecticut River Valley and the historic impact of economic change on Springfield and Hartford. But several papers ranged far abroad, tackling such diverse subject matter as social accountability systems in African cities; the intersection of global politics and community politics in San Francisco’s Chinatown during World War II and the Cold War; the struggle of Black women for land rights in Brazilian cities; and the community-based nature of women’s activism in response to global economic and political change.

Those themes are explored in depth in Rethinking Global Urbanism. “Today cities play a more important role in the connection and organization of global economic activities and everyday activities than ever before,” asserts Chen, “but scholars often do not explore the importance of cities beyond a handful of mega-metropolises. This is a narrow-minded and short-sighted view of the interconnected world of cities. Many secondary cities are playing increasingly stronger roles in the global economy than many people might imagine. They deserve more focused scholarship.”

In addition to Chen, the book includes chapters by two other Trinity faculty members, Associate Professor Beth Notar of the Anthropology Department and Assistant Professor Scott Tang of the American Studies Program. And several of Chen’s former students left Trinity with a credential few undergraduates, in any discipline, are able to boast, a citation in a significant scholarly book.

This story was extracted from an article that appeared in the spring 2013 issue of The Trinity Reporter. Read the full article here.  

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Sean Cocco examines historical accounts of Mt. Vesuvius

The 1631 eruption of Mt. Vesuvius—the famed volcano situated outside the city of Naples, Italy—altered more than just the natural landscape of the Italian coast; it left a cultural mark by becoming the first natural event in modern history to be scientifically documented by human observers, according to Associate Professor of History Sean Cocco.

In his new book, Watching Vesuvius: A History of Science and Culture in Early Modern Italy (University of Chicago Press, December 2012), Cocco tells the story of Mt. Vesuvius through historical records of the volcano left by Renaissance-era scholars during what is considered to be the first period of modern scientific discovery.

Mt. Vesuvius had been dormant since the 12th century until 1631. Because of this long period of inactivity, said Cocco, the eruption was recognized first by scholars of history who were knowledgeable of ancient texts. “There was the famous eruption that destroyed the Roman cities of Pompeii and Herculaneum, and this would have been on the minds of Renaissance humanists,” he explained.

Cocco became interested in Vesuvius more than 12 years ago when he discovered a letter by a man in Naples written to his brother in Rome, days after the December 16, 1631 eruption of Vesuvius. “The man had woken, like thousands of others, to a volcano erupting less than six miles away, and he registered that what he was looking at was exactly what the ancient Romans had seen,” Cocco said. “He had a very historical understanding of nature, and he used this knowledge of the past to understand modern events.”

Although modern volcanologists largely dismiss the scientific merit of these documents, Cocco argues the opposite, citing the complexity and thoroughness of the historical accounts highlighted in Watching Vesuvius. “The eruption was not met with superstition—people from Europe had been exploring Central America during this time and had encountered volcanoes there. Natural philosophers—the scientists of the day—also theorized that earthquakes and eruptions operated something like weather in the system of nature. These accounts show that educated people during the 17th century had a complex understanding of natural causation. They had a sophisticated sensibility of landscapes and nature and the ways that human beings relate to them. In many ways, the observations that these people made were admirably precise.”

Cocco was interviewed about Watching Vesuvius for the spring 2012 issue of the Trinity Reporter. Read the full interview here.

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New book by Zayde Antrim uncovers the “Power of Place”

As a complement to popular scholarship on globalization, a new book by Associate Professor of History and International Studies Zayde Antrim explores the historical significance of identities formed through attachments to geographic locations.

Published in September, Routes and Realms: The Power of Place in the Early Islamic World (2012, Oxford University Press) examines early texts produced by Muslims during the ninth through eleventh centuries, paying specific attention to how the authors conveyed attachment to the lands in which they lived. This attachment created what Antrim describes as “widely resonant categories of belonging.”

“Representing plots of land as homes, cities, and regions in texts…was a powerful way to claim loyalty, authority, and belonging in the early Islamic world,” said Antrim, who teaches courses on Islamic civilizations, Middle Eastern history, nationalism, and geography. “I have always been interested in geography and the ways in which the geographical imagination shapes the way we see and act in the world.”

The information contained in these millennium-old texts may help us better interpret current events in the Arab region. Antrim points out that Western analysis of these events de-emphasizes individual and cultural ties to physical locations and instead promotes a characterization of Arabs and Muslims as motivated by kinship and larger religious affiliations.

“Political rhetoric about the global dimensions of the ‘War on Terror’ is dominated by the threatening figure of the ‘Muslim terrorist,’ loyal only to a worldwide network of like-minded Muslims committed to otherworldly and utopian (or dystopian) goals rather than local, national, or geopolitical agendas,” Antrim says. “These assumptions have distracted from the modes in which territories, imagined in new ways and deployed in new forms of discourse, have retained wide relevance in the geographical imagination as well as on the ground in the late twentieth and twenty-first centuries–not just among Muslims or in the Middle East, but everywhere.”

Antrim was interviewed about Routes and Realms for the spring 2012 issue of The Trinity Reporter. Read the full interview here. 

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Sensual perception in the work of Johann Georg Hamann

Language is a structured way through which human beings communicate with one another and more easily conceptualize the world around them. At the same time, each of us has unique experiences that account for variations in how we understand the words we use. To what extent do these variations occur? And what does this mean in terms of the universality of language?

In her recent book, Body Language: Corporeality, Subjectivity, and Language in Johann Georg Hamann (Peter Lang Pubilshing, Inc., 2011), Visiting Lecturer in Language and Culture Studies Julia Goesser Assaiante addresses questions like these through the perspective of 18th century German philosopher Johann Georg Hamann. The book details the central role that sensual perception plays in the work of Hamann, who was interested in “the constitution of subjectivity and the resulting relationship between subjectivity and language.”

Faculty Highlights: What specifically attracted you to the work of Johann Georg Hamann?

Julia Goesser Assaiante: I first encountered Hamann in a graduate school, and it was not love at first sight. I was tasked with presenting his essay “Aesthetica en Nuce” (aesthetics in a nutshell) to the class, and after a week of intense preparation I found myself less confident that I even understood the basics of what he was saying! But the opacity of his writing is what eventually drew me in. It is a puzzle with labyrinthian twists and turns and the deeper you go, the more you see. And it’s all by design—Hamann meant his readers to be puzzled, intrigued, infuriated even, at the withholding of meaning! But there are also moments of great beauty in his writing, and the challenge to the reader is to connect all of the disparate parts.

Faculty Highlights: To clarify, does “sensual perception” simply refer to the ways that individuals process through their senses the world around them?

Julia Goesser Assaiante: Yes, I mean it in its most concrete form. In focusing on sensual perception, Hamman is an heir to the empiricist skepticism of David Hume. Hamann argues that all we can really rely on is our sensual perception of the world, and when it comes down to it, this is something we must take on faith. Ergo, our very encounter with the world around us through our senses becomes a “leap of faith” that we are really seeing/feeling/smelling/touching/tasting the object of our inquiry.

Faculty Highlights: What do you mean by “abstraction of language” and “finite subjectivity?” How does the latter shape the former?

Julia Goesser Assaiante: Hamann views language as inherently abstract and metaphorical, in much the same way that Friedrich Nietzsche explains that when we use the word “leaf” to denote the green objects hanging on trees, we are using a catch-all abstraction that covers over the individuality of each single leaf. What Hamann—and here he prefigures Nietzsche quite closely—wishes to uncover is the lost, creative specificity of language. Hamann is arguing for a use of language that makes more room for creative and individual ways of communicating the sense of “leaf,” without using the crutch of that tired abstraction. And since our encounter with the world is conditioned by our finite, organic existence, a language that reflects more of each individual’s experiences would be more in keeping with the creative use of language for which Hamann is arguing.

Faculty Highlights: In what ways do Hamann’s ideas run counter to the Enlightenment tradition?

Julia Goesser Assaiante: Hamann was deeply suspicious of knowledge that was not empirical, and he felt that an increasing turn toward the rationalization of human affairs represented a turn from the divinely granted human qualities of individuality and creativity to the false idol of reason. Hamann feared that a purely rationalist understanding of the human condition could not account for the messiness and unpredictability of human affairs, and it is precisely that messiness which makes us so wonderfully human. One anecdote to illustrate this point is Hamann’s crusade against various proposed orthographic reforms of the time that were designed to make the German language more “rational.” Hamann argues that the moments in which written and spoken language differ, when curious formulations arise, when languages contaminate one another—these are the moments in which human language briefly comes into contact with the divine unity of word and act. Arresting that movement of language would be like gutting its divine spirit and origins.

Read a full description of Body Language here.

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Hebe Guardiola-Diaz partners with UConn Health Center

Associate Professor of Biology and Neuroscience Hebe Guardiola-Diaz recently teamed up with researchers at the University of Connecticut to study the development and stability of oligodendrocytes, cells in the brain that produce the myelin required for nervous system function.

During a 2009-2010 sabbatical, Guardiola-Diaz spent time as a visiting faculty member at the UConn Health Center, working with Rashmi Bansal, a professor of neuroscience at UConn. Guardiola-Diaz spent this time focused on a process known as oligodendrocyte differentiation. Guardiola-Diaz explained, “Oligodendrocyte are cells in the brain that make myelin, which is a fatty substance that protects nerve cells and makes it possible for them to communicate efficiently with their targets.”

The deterioration of myelin around neurons can lead to a number of degenerative nerve diseases, the most common example of which is multiple sclerosis. “Because of this, it is important to understand how oligodendtocytes develop and the properties that allow them to survive in dynamic interaction with their axons,” Guardiola-Diaz said.

One result of this research partnership was an article that was co-authored by Guardiola-Diaz, Bansal, and Akihiro Ishii, a postdoctoral fellow at UConn and advisee of Bansal. The article specifically examines a signaling network of proteins inside neurons that convey information from the cell’s environment. “The paper describes selective use of the signaling proteins Erk1/2MAPK and mTOR during different stages of oligodendrocyte development,” says Guardiola-Diaz. “We’re asking questions like, ‘What is it that mTOR does inside cells that is so essential? Why does interfering with this protein disrupt the developmental process of oligodendrocytes?’”

Guardiola-Diaz and her co-authors carried out their research on isolated cells in culture under controlled conditions. She points out that colleagues in the field of neuroscience are currently carrying out similar research in vivo—or within a living organism—by using new technologies that enable scientists to disrupt genes in animal models for human disorders. “As we find out more about the signaling requirements at different stages of oligodendrocyte development, we will better understand their functional interaction with neurons in the healthy and diseased brain.”

Click here to read the abstract.

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David Cruz-Uribe discusses recent publications

We recently sat down with Professor of Mathematics David Cruz-Uribe to discuss two articles that were published earlier this year, both of which were part of an extensive effort to solve what is referred to as the A2 problem in harmonic analysis. The first of these articles was co-authored by Cruz-Uribe and longtime collaborators José María Martell from the Instituto de Ciencias Matematicas in Madrid, Spain, and Carlos Peréz from the Universidad de Sevilla in Sevilla, Spain. The second paper was co-authored by Cruz-Uribe and Kabe Moen, assistant professor of mathematics at the University of Alabama. Please see the bottom of this post for full citations.

Faculty Highlights: What is the A2 problem in harmonic analysis and where did it originate?

David Cruz-Uribe: The A2 problem was first posed in the mid-1990s by Professor Robert Fefferman at the University of Chicago. He asked for the sharpest constant in certain inequalities—more precisely, in weighted Lp norm inequalities for singular integrals. The problem soon expanded to include similar questions for the other kinds of operators in harmonic analysis.

Faculty Highlights: How did the two articles you worked on address this problem?

David Cruz-Uribe: The first paper yielded a very elementary proof of the conjectured result for a special family of singular integrals—the Hilbert transform, Riesz transforms, and the Beurling-Ahlfors transform. These results were previously known, but our approach yielded a unified proof that was considerably simpler than all known proofs. The second paper extended these ideas to a family of operators called commutators.

Faculty Highlights: What was the outcome of these papers?  

Cruz-Uribe: In very basic terms, my colleagues and I vastly simplified what had previously required a 45-page proof into a couple of pages. Though we were not able to refine our argument to get the complete solution, the two papers still marked an advance over what had been done previously.

Faculty Highlights: Has any work been done on this topic since?

David Cruz-Uribe: Yes, shortly after these papers were completed the full A2 conjecture was solved by Tuomas Hytonen of the University of Helsinki using different methods. More recently, however, Andrei Lerner of Bar-Ilan University extended our approach to give a very elegant proof of the conjecture.

 

David Cruz-Uribe, José María Martell, and Carlos Peréz. “Sharp Weighted Estimates for Classical Operators.” Advances in Mathematics 229, no. 1 (January 15, 2012): 408-441.

David Cruz-Uribe. Kabe Moen. “Sharp Norm Inequalities for Commutators of Classical Operators.” Publicacions Mathematiques 56, no. 1 (2012): 147-190.

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