Author: Julie Pryor

A multifunctional tool for cognitive neuroscience

by Jennifer Michalowski |

A team of researchers at MIT’s McGovern and Picower Institutes has advanced the clinical potential of a thin, flexible fiber designed to simultaneously monitor and manipulate neural activity at targeted sites in the brain. The collaborative team improved upon an earlier model of the multifunctional fiber, developed in the lab of McGovern Institute Associate Investigator Polina Anikeeva, to explore dynamic changes to neural signaling as large animals engage in a working memory task. The results appear Oct. 6 in Science Advances.

The new device, developed by Indie Garwood, who recently received her PhD in the Harvard-MIT Program in Health Sciences and Technology, includes four microelectrodes for detecting neural activity and two microfluidic channels through which drugs can be delivered. This means scientists can deliver a drug that alters neural signaling within a particular part of the brain, then monitor the consequences for local brain activity. This technology was a collaborative effort between Anikeeva, who is also the Matoula S. Salapatas Professor in Materials Science and Engineering and a professor of brain and cognitive sciences, and Picower Institute Investigators Emery Brown and Earl Miller, who jointly supervised Garwood to develop a multifunctional neurotechnology for larger and translational animal models, which are necessary to investigate the neural circuits that underlie high-level cognitive functions.  With further development and testing, similar devices might one day be deployed to diagnose or treat brain disorders in human patients.

Brown is the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience in the Picower Institute, the Institute for Medical Engineering and Science, and the Department of Brain and Cognitive Sciences, as well as an anesthesiologist at Massachusetts General Hospital and Harvard Medical School. Miller is the Picower Professor of Neuroscience and a professor of brain and cognitive sciences at MIT.

The new multifunctional fiber is not the first produced by Anikeeva and her team. An earlier model engineered in their lab has already reached the neuroscience community, whose members use it to simultaneously monitor and manipulate neural activity in the brains of mice and rats. But for studies in larger animals, the existing tools for delivering drugs to the brains were rigid, bulky devices, which were both fragile and prone to causing tissue damage. A better tool was needed, both to advance cognitive neuroscience research and to set the stage for developing devices that can deliver drugs directly to the brains of patients and monitor the effects.

Like the devices that Anikeeva’s team designed for rodent studies, the new tool is created by first assembling a larger version of the fiber—a preform cylinder with multiple channels that is then heated and stretched until it is thin and long. As the channels narrow, microelectrodes are incorporated into to the fiber. The final step is to link the electrodes in the fiber to a connector that will relay data collected inside the brain to a unit in the lab.

The final device is long enough to access areas deep in the brain of a large animal. It is built to withstand rigorous sterilization procedures and to stay in place even in an active animal. And it integrates directly with experimental systems that cognitive neuroscientists already use in their labs. “We really wanted this to be something that we could easily hand somebody and they’re going to know how to implement it in their system,” says Garwood, who led development of the device as a graduate student in Anikeeva’s lab.

Once the new device was developed, Garwood and colleagues in the Miller and Brown labs put it to work.  They used the tool to study changes in neural activity as an animal completed a task requiring working memory. The fluid channels in the fiber were used to deliver small amounts of GABA, a neurotransmitter that dampens neuronal activity, to the animal’s premotor cortex, a part of the brain that helps plan movement. At the same time, the device recorded electrical activity from individual neurons, as well as broader patterns of activity in this part of the brain. By monitoring these signals over time, the team learned how neural circuits adapted to the local inhibition they had applied. In another experiment, the team used the device to record neural activity from the putamen, a region deep in the brain involved in reward processing and motivation.

The data collected by the device was extensive and complex, tracking changes that unfolded in the brain over seconds to hours. Interpreting those data required the team to devise new methods of data analysis, which Garwood worked on closely with the Brown lab. Garwood says these methods will be shared with users of the new devices, providing “a roadmap for extracting all of these rich dynamics that you can get out of them.”

These successes, the researchers say, are an important step toward the development of tools to modulate and manipulate neuronal activity in the human brain to benefit patients. For example, they say, a multifunctional fiber might one day be used to more accurately pinpoint the origin of seizures in people with epilepsy, by testing the effects of activating or inhibiting specific brain cells.

 

New cellular census maps the complexity of a primate brain

by Jennifer Michalowski |

A new atlas developed by researchers at MIT’s McGovern Institute and Harvard Medical School catalogs a diverse array of brain cells throughout the marmoset brain. The atlas helps establish marmosets—small monkeys whose brains share many functional and structural features with the human brain—as a valuable model for neuroscience research.

Data from more than two million brain cells are included in the atlas, which spans 18 regions of the marmoset brain. A research team led by Guoping Feng, associate director of the McGovern Institute and member of the Broad Institute of Harvard and MIT, Harvard biologist and member of the Broad Institute of Harvard and MIT Steven McCarroll, and Princeton neurobiologist Fenna Krienen classified each cell according to its particular pattern of genetic activity, providing an important reference for studies of the marmoset brain. The team’s analysis, reported October 13, 2023, in the journal Science Advances, also reveals the profound influence of a cell’s developmental origin on its identity in the primate brain.

Regional variation in neocortical cell types and expression patterns. Image courtesy of the researchers.

Cellular diversity

Brains are made up of a tremendous diversity of cells. Neurons with dramatically different gene expression, shapes, and activities work together to process information and drive behavior, supported by an assortment of immune cells and other cell types. Scientists have only recently begun to catalog this cellular diversity—first in mice, and now in primates.

The marmoset is a quick-breeding monkey whose small brain has many of features similar to those that enable higher cognitive processes in humans. Feng says neuroscientists have begun turning to marmosets as a research model in recent years because new gene editing technology has made it easier to modify the animal’s DNA, so scientists can now study the genetic factors that shape marmosets’ brains and behavior. Feng, McCarroll, Krienen and others hope these animals will offer insights into how primate brains handle complex decision-making, social interactions, and other higher brain functions that are difficult to study in mice. Likewise, Feng says, the monkeys will help scientists investigate the impact of genetic mutations associated with brain disorders and explore potential therapeutic strategies.

To make marmosets a practical model for neuroscience, scientists need to understand the fundamental composition of their brains. Feng and McCarroll’s team have begun that characterization with their cell census, which was supported by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies (BRAIN) Initiative’s Cell Census Network (BICCN), as part a larger effort to map cellular features in the brains of mice, non-human primates, and humans. It is an essential first step in the creation of a comprehensive atlas charting the molecular, anatomical, and functional features of cells in the marmoset brain.

“Hopefully, when the BRAIN Initiative is complete, we will have a very complete map of these cells: where they are located, their abundance, their functional properties,” says Feng. “This not only gives you knowledge of the normal brain, but you can also look at what aspects change in diseases of the brain. So it’s a really powerful database.”

To catalog the diversity of cells in the marmoset brain, the researchers undertook an expansive analysis of the molecular contents of 2.4 million brain cells from adult marmosets. For each of these cells, they analyzed the complete set of RNA copies of its genes that the cell had produced, known as the cell’s transcriptome. Because the transcriptome captures patterns of genetic activity inside a cell, it is an indication of the cell’s function and can be used to assess cellular identity.

Gene expression across neural populations. Image courtesy of the researchers.

The team’s analysis is one of the first to compare patterns of gene activity in cells from disparate regions of the marmoset brain. Doing so yielded surprising insights into the factors that shape brain cells’ transcriptomic identities. “What we found is that the cell’s transcriptome contains breadcrumbs that link back to the developmental origin of that cell type,” says Krienen, who led the cellular census as a postdoctoral researcher in McCarroll’s lab. That suggests that comparing cells’ transcriptomes can help scientists figure out how primate brains are assembled, which might lead to insights into neurodevelopmental disorders, she says.

The team also learned that a cell’s location in the brain was critical to shaping its transcriptomic identity. For example, Krienen says, “it turns out that an inhibitory neuron in the cortex doesn’t look very anything like an inhibitory neuron in the thalamus, probably because they have distinct embryonic origins.”

Expanding the cell census

This new picture of cellular diversity in the marmoset brain will help researchers understand how genetic perturbations affect different brain cells and interpret the results of future experiments. Importantly, Krienen says, it could help researchers pinpoint exactly which cells are affected in brain disorders, and how the effects of a disease might localize to specific brain regions.

Krienen, McCarroll, and Feng went beyond their initial survey of cellular diversity with analyses of specific subsets of cells, charting the spatial distribution of interneurons in a key region of the prefrontal cortex and visualizing the shapes of several molecularly-defined cell types. Now, they have begun expanding their cell census beyond the 18 brain structures represented in the reported work. As part of the BRAIN Initiative’s Brain Cell Atlas Network (BICAN), the team will profile cells throughout the entire adult marmoset brain, including multiple data types in their analysis. Building on cell census data, NIH BRAIN Initiative has also launched BRAIN CONNECTS projects to map cellular connectivity in the brain.

This work was supported by the National Institutes of Health, the National Science Foundation, MathWorks, MIT, Harvard Medical School, the Broad Institute’s Stanley Center for Psychiatric Research, the Hock E. Tan and K. Lisa Yang Center for Autism Research at MIT, the Poitras Center for Psychiatric Disorders Research at MIT, and the McGovern Institute for Brain Research at MIT.

Thousands of programmable DNA-cutters found in algae, snails, and other organisms

by Jennifer Michalowski |

A diverse set of species, from snails to algae to amoebas, make programmable DNA-cutting enzymes called Fanzors—and a new study from scientists at MIT’s McGovern Institute has identified thousands of them. Fanzors are RNA-guided enzymes that can be programmed to cut DNA at specific sites, much like the bacterial enzymes that power the widely used gene-editing system known as CRISPR. The newly recognized diversity of natural Fanzor enzymes, reported September 27, 2023, in the journal Science Advances, gives scientists an extensive set of programmable enzymes that might be adapted into new tools for research or medicine.

“RNA-guided biology is what lets you make programmable tools that are really easy to use. So the more we can find, the better,” says McGovern fellow Omar Abudayyeh, who led the research with McGovern fellow Jonathan Gootenberg.

CRISPR, an ancient bacterial defense system, has made it clear how useful RNA-guided enzymes can be when they are adapted for use in the lab. CRISPR-based genome editing tools developed by McGovern investigator Feng Zhang, Abudayyeh, Gootenberg and others have changed the way scientists modify DNA, accelerating research and enabling the development of many experimental gene therapies.

Researchers have since uncovered other RNA-guide enzymes throughout the bacterial world, many with features that make them valuable in the lab. The discovery of Fanzors, whose ability to cut DNA in an RNA-guided manner was reported by Zhang’s group earlier this year, opens a new frontier of RNA-guided biology. Fanzors were the first such enzymes to be found in eukaryotic organisms—a wide group of lifeforms, including plants, animals, and fungi, defined by the membrane-bound nucleus that holds each cell’s genetic material. (Bacteria, which lack nuclei, belong to a group known as prokaryotes.)

Structural illustration of Fanzors.
Predicted structural image of Fanzors. Image: Jonathan Gootenberg and Omar Abudayyeh

“People have been searching for interesting tools in prokaryotic systems for a long time, and I think that that has been incredibly fruitful,” says Gootenberg. “Eukaryotic systems are really just a whole new kind of playground to work in.”

One hope, Abudayyeh and Gootenberg say, is that enzymes that naturally evolved in eukaryotic organisms might be better suited to function safely and efficiently in the cells of other eukaryotic organisms, including humans. Zhang’s group has shown that Fanzor enzymes can be engineered to precisely cut specific DNA sequences in human cells. In the new work, Abudayyeh and Gootenberg discovered that some Fanzors can target DNA sequences in human cells even without optimization. “The fact that they work quite efficiently in mammalian cells was really fantastic to see,” Gootenberg says.

Prior to the current study, hundreds of Fanzors had been found among eukaryotic organisms. Through an extensive search of genetic databases led by lab member Justin Lim, Gootenberg and Abudayyeh’s team has now expanded the known diversity of these enzymes by an order of magnitude.

Among the more than 3,600 Fanzors that the team found in eukaryotes and the viruses that infect them, the researchers were able to identify five different families of the enzymes. By comparing these enzymes’ precise makeup, they found evidence of a long evolutionary history.

Fanzors likely evolved from RNA-guided DNA-cutting bacterial enzymes called TnpBs. In fact, it was Fanzors’ genetic similarities to these bacterial enzymes that first caught the attention of both Zhang’s group and Gootenberg and Abudayyeh’s team.

The evolutionary connections that Gootenberg and Abudayyeh traced suggest that these bacterial predecessors of Fanzors probably entered eukaryotic cells, initiating their evolution, more than once. Some were likely transmitted by viruses, while others may have been introduced by symbiotic bacteria. The research also suggests that after they were taken up by eukaryotes, the enzymes evolved features suited to their new environment, such as a signal that allows them to enter a cell nucleus, where they have access to DNA.

Through genetic and biochemical experiments led by graduate student Kaiyi Jiang, the team determined that Fanzors have evolved a DNA-cutting active site that is distinct from that of their bacterial predecessors. This seems to allow the enzyme to cut its target sequence more precisely the ancestors of TnpB, when targeted to a sequence of DNA in a test tube, become activated and cut other sequences in the tube; Fanzors lack this promiscuous activity. When they used an RNA guide to direct the enzymes to cut specific sites in the genome of human cells, they found that certain Fanzors were able to cut these target sequences with about 10 to 20 percent efficiency.

With further research, Abudayyeh and Gootenberg hope that a variety of sophisticated genome editing tools can be developed from Fanzors. “It’s a new platform, and they have many capabilities,” says Gootenberg. “Opening up the whole eukaryotic world to these types of RNA-guided systems is going to give us a lot to work on,” Abudayyeh adds.

Four McGovern Investigators receive NIH BRAIN Initiative grants

by Julie Pryor |

In the human brain, 86 billion neurons form more than 100 trillion connections with other neurons at junctions called synapses. Scientists at the McGovern Institute are working with their collaborators to develop technologies to map these connections across the brain, from mice to humans.

Today, the National Institutes of Health (NIH) announced a new program to support research projects that have the potential to reveal an unprecedented and dynamic picture of the connected networks in the brain. Four of these NIH-funded research projects will take place in McGovern labs.

BRAIN Initiative

In 2013, the Obama administration announced the Brain Research Through Advancing Innovative Neurotechnologies® (BRAIN) Initiative, a public-private research effort to support the development and application of new technologies to understand brain function.

Today, the NIH announced its third project supported by the BRAIN Initiative, called BRAIN Initiative Connectivity Across Scales (BRAIN CONNECTS). The new project complements two previous large-scale projects, which together aim to transform neuroscience research by generating wiring diagrams that can span entire brains across multiple species. These detailed wiring diagrams can help uncover the logic of the brain’s neural code, leading to a better understanding of how this circuitry makes us who we are and how it could be rewired to treat brain diseases.

BRAIN CONNECTS at McGovern

The initial round of BRAIN CONNECTS awards will support researchers at more than 40 university and research institutions across the globe with 11 grants totaling $150 million over five years. Four of these grants have been awarded to McGovern researchers Guoping Feng, Ila Fiete, Satra Ghosh, and Ian Wickersham, whose projects are outlined below:

BRAIN CONNECTS: Comprehensive regional projection map of marmoset with single axon and cell type resolution
Team: Guoping Feng (McGovern Institute, MIT), Partha Mitra (Cold Spring Harbor Laboratory), Xiao Wang (Broad Institute), Ian Wickersham (McGovern Institute, MIT)

Summary: This project will establish an integrated experimental-computational platform to create the first comprehensive brain-wide mesoscale connectivity map in a non-human primate (NHP), the common marmoset (Callithrix jacchus). It will do so by tracing axonal projections of RNA barcode-identified neurons brain-wide in the marmoset, utilizing a sequencing-based imaging method that also permits simultaneous transcriptomic cell typing of the identified neurons. This work will help bridge the gap between brain-wide mesoscale connectivity data available for the mouse from a decade of mapping efforts using modern techniques and the absence of comparable data in humans and NHPs.

BRAIN CONNECTS: A center for high-throughput integrative mouse connectomics
Team: Jeff Lichtman (Harvard University), Ila Fiete (McGovern Institute, MIT), Sebastian Seung (Princeton University), David Tank (Princeton University), Hongkui Zeng (Allen Institute), Viren Jain (Google), Greg Jeffries (Oxford University)

Summary: This project aims to produce a large-scale synapse-level brain map (connectome) that includes all the main areas of the mouse hippocampus. This region is of clinical interest because it is an essential part of the circuit underlying spatial navigation and memory and the earliest impairments and degeneration related to Alzheimer’s disease.

BRAIN CONNECTS: The center for Large-scale Imaging of Neural Circuits (LINC)
Team: Anastasia Yendiki (MGH), Satra Ghosh (McGovern, MIT), Suzanne Haber (University of Rochester), Elizabeth Hillman (Columbia University)

Summary: This project will generate connectional diagrams of the monkey and human brain at unprecedented resolutions. These diagrams will be linked both to the neuroanatomic literature and to in vivo neuroimaging techniques, bridging between the rigor of the former and the clinical relevance of the latter. The data to be generated by this project will advance our understanding of brain circuits that are implicated in motor and psychiatric disorders, and that are targeted by deep-brain stimulation to treat these disorders.

BRAIN CONNECTS: Mapping brain-wide connectivity of neuronal types using barcoded connectomics
Team: Xiaoyin Chen (Allen Institute), Ian Wickersham (McGovern Institute, MIT), and Justus Kebschull of JHU

Summary: This project aims to optimize and develop barcode sequencing-based neuroanatomical techniques to achieve brain-wide, high-throughput, highly multiplexed mapping of axonal projections and synaptic connectivity of neuronal types at cellular resolution in primate brains. The team will work together to apply these techniques to generate an unprecedented multi-resolution map of brain-wide projections and synaptic inputs of neurons in the macaque visual cortex at cellular resolution.

 

Nuevo podcast de neurociencia en español celebra su tercera temporada

by Thea Singer |

Sylvia Abente, neuróloga clínica de la Universidad Nacional de Asunción (Paraguay), investiga la variedad de síntomas que son característicos de la epilepsia. Trabaja con los pueblos indígenas de Paraguay, y su dominio del español y el guaraní, los dos idiomas oficiales de Paraguay, le permite ayudar a los pacientes a encontrar las palabras que ayuden a describir sus síntomas de epilepsia para poder tratarlos.

Juan Carlos Caicedo Mera, neurocientífico de la Universidad Externado de Colombia, utiliza modelos de roedores para investigar los efectos neurobiológicos del estrés en los primeros años de vida. Ha desempeñado un papel decisivo en despertar la conciencia pública sobre los efectos biológicos y conductuales del castigo físico a edades tempranas, lo que ha propiciado cambios políticos encaminados a reducir su prevalencia como práctica cultural en Colombia.

Woman interviews a man at a table with a camera recording the interview in the foreground.
Jessica Chomik-Morales (right) interviews Pedro Maldonado at the Biomedical Neuroscience Institute of Chile at the University of Chile. Photo: Jessica Chomik-Morales

Estos son solo dos de los 33 neurocientíficos de siete países latinoamericanos que Jessica Chomik-Morales entrevistó durante 37 días para la tercera temporada de su podcast en español “Mi Última Neurona,” que se estrenará el 18 de septiembre a las 5:00 p. m. en YouTube. Cada episodio dura entre 45 y 90 minutos.

“Quise destacar sus historias para disipar la idea errónea de que la ciencia de primer nivel solo puede hacerse en Estados Unidos y Europa,” dice Chomik-Morales, “o que no se consigue en Sudamérica debido a barreras financieras y de otro tipo.”

Chomik-Morales, graduada universitaria de primera generación que creció en Asunción (Paraguay) y Boca Ratón (Florida), es ahora investigadora académica de post licenciatura en el MIT. Aquí trabaja con Laura Schulz, profesora de Ciencia Cognitiva, y Nancy Kanwisher, investigadora del McGovern Institute y la profesora Walter A. Rosenblith de Neurociencia Cognitiva, utilizando imágenes cerebrales funcionales para investigar de qué forma el cerebro explica el pasado, predice el futuro e interviene sobre el presente a traves del razonamiento causal.

“El podcast está dirigido al público en general y es apto para todas las edades,” afirma. “Se explica la neurociencia de forma fácil para inspirar a los jóvenes en el sentido de que ellos también pueden llegar a ser científicos y para mostrar la amplia variedad de investigaciones que se realizan en los países de origen de los escuchas.”

El viaje de toda una vida

“Mi Última Neurona” comenzó como una idea en 2021 y creció rápidamente hasta convertirse en una serie de conversaciones con destacados científicos hispanos, entre ellos L. Rafael Reif, ingeniero electricista venezolano-estadounidense y 17.º presidente del MIT.

Woman interviews man at a table while another man adjusts microphone.
Jessica Chomik-Morales (left) interviews the 17th president of MIT, L. Rafael Reif (right), for her podcast while Héctor De Jesús-Cortés (center) adjusts the microphone. Photo: Steph Stevens

Con las relaciones profesionales que estableció en las temporadas uno y dos, Chomik-Morales amplió su visión y reunió una lista de posibles invitados en América Latina para la tercera temporada. Con la ayuda de su asesor científico, Héctor De Jesús-Cortés, un investigador Boricua de posdoctorado del MIT, y el apoyo financiero del McGovern Institute, el Picower Institute for Learning and Memory, el Departamento de Ciencias Cerebrales y Cognitivas, y las Iniciativas Internacionales de Ciencia y Tecnología del MIT, Chomik-Morales organizó entrevistas con científicos en México, Perú, Colombia, Chile, Argentina, Uruguay y Paraguay durante el verano de 2023.

Viajando en avión cada cuatro o cinco días, y consiguiendo más posibles participantes de una etapa del viaje a la siguiente por recomendación, Chomik-Morales recorrió más de 10,000 millas y recopiló 33 historias para su tercera temporada. Las áreas de especialización de los científicos abarcan toda una variedad de temas, desde los aspectos sociales de los ciclos de sueño y vigilia hasta los trastornos del estado de ánimo y la personalidad, pasando por la lingüística y el lenguaje en el cerebro o el modelado por computadoras como herramienta de investigación.

“Si alguien estudia la depresión y la ansiedad, quiero hablar sobre sus opiniones con respecto a diversas terapias, incluidos los fármacos y también las microdosis con alucinógenos,” dice Chomik-Morales. “Estas son las cosas de las que habla la gente.” No le teme a abordar temas delicados, como la relación entre las hormonas y la orientación sexual, porque “es importante que la gente escuche a los expertos hablar de estas cosas,” comenta.

El tono de las entrevistas va de lo informal (“el investigador y yo somos como amigos”, dice) a lo pedagógico (“de profesor a alumno”). Lo que no cambia es la accesibilidad (se evitan términos técnicos) y las preguntas iniciales y finales en cada entrevista. Para empezar: “¿Cómo ha llegado hasta aquí? ¿Qué le atrajo de la neurociencia?”. Para terminar: “¿Qué consejo le daría a un joven estudiante latino interesado en Ciencias, Ingeniería, Tecnología y Matemáticas[1]?

Permite que el marco de referencia de sus escuchas sea lo que la guíe. “Si no entendiera algo o pensara que se podría explicar mejor, diría: ‘Hagamos una pausa’. ¿Qué significa esta palabra?”, aunque ella conociera la definición. Pone el ejemplo de la palabra “MEG” (magnetoencefalografía): la medición del campo magnético generado por la actividad eléctrica de las neuronas, que suele combinarse con la resonancia magnética para producir imágenes de fuentes magnéticas. Para aterrizar el concepto, preguntaría: “¿Cómo funciona? ¿Este tipo de exploración hace daño al paciente?”.

Allanar el camino para la creación de redes globales

El equipo de Chomik-Morales era escaso: tres micrófonos Yeti y una cámara de video Canon conectada a su computadora portátil. Las entrevistas se realizaban en salones de clase, oficinas universitarias, en la casa de los investigadores e incluso al aire libre, ya que no había estudios insonorizados disponibles. Ha estado trabajando con el ingeniero de sonido David Samuel Torres, de Puerto Rico, para obtener un sonido más claro.

Ninguna limitación tecnológica podía ocultar la importancia del proyecto para los científicos participantes.

Two women talking at a table in front of a camera.
Jessica Chomik-Morales (left) interviews Josefina Cruzat (right) at Adolfo Ibañez University in Chile. Photo: Jessica Chomik-Morales

“Mi Última Neurona” muestra nuestro conocimiento diverso en un escenario global, proporcionando un retrato más preciso del panorama científico en América Latina,” dice Constanza Baquedano, originaria de Chile. “Es un avance hacia la creación de una representación más inclusiva en la ciencia”. Baquendano es profesora adjunta de psicología en la Universidad Adolfo Ibáñez, en donde utiliza electrofisiología y mediciones electroencefalográficas y conductuales para investigar la meditación y otros estados contemplativos. “Estaba ansiosa por ser parte de un proyecto que buscara brindar reconocimiento a nuestras experiencias compartidas como mujeres latinoamericanas en el campo de la neurociencia.”

“Comprender los retos y las oportunidades de los neurocientíficos que trabajan en América Latina es primordial,” afirma Agustín Ibáñez, profesor y director del Instituto Latinoamericano de Salud Cerebral (BrainLat) de la Universidad Adolfo Ibáñez de Chile. “Esta región, que se caracteriza por tener importantes desigualdades que afectan la salud cerebral, también presenta desafíos únicos en el campo de la neurociencia,” afirma Ibáñez, quien se interesa principalmente en la intersección de la neurociencia social, cognitiva y afectiva. “Al centrarse en América Latina, el podcast da a conocer las historias que frecuentemente no se cuentan en la mayoría de los medios. Eso tiende puentes y allana el camino para la creación de redes globales.”

Por su parte, Chomik-Morales confía en que su podcast generará un gran número de seguidores en América Latina. “Estoy muy agradecida por el espléndido patrocinio del MIT,” dice Chomik-Morales. “Este es el proyecto más gratificante que he hecho en mi vida.”

__

[1] En inglés Science, Technology, Engineering and Mathematics (STEM)

New Spanish-language neuroscience podcast flourishes in third season

by Thea Singer |

A Spanish version of this news story can be found here. (Una versión en español de esta noticia se puede encontrar aquí.)

___

Sylvia Abente, a clinical neurologist at the Universidad Nacional de Asunción in Paraguay, investigates the range of symptoms that characterize epilepsy. She works with indigenous peoples in Paraguay, and her fluency in Spanish and Guarni—the two official languages of Paraguay—allows her to help patients find the words to describe their epilepsy symptoms so she can treat them.

Juan Carlos Caicedo Mera, a neuroscientist at the Universidad Externado de Colombia, uses rodent models to research the neurobiological effects of early life stress. He has been instrumental in raising public awareness about the biological and behavioral effects of early-age physical punishment, leading to policy changes aimed at reducing its prevalence as a cultural practice in Colombia.

Woman interviews a man at a table with a camera recording the interview in the foreground.
Jessica Chomik-Morales (right) interviews Pedro Maldonado at the Biomedical Neuroscience Institute of Chile at the University of Chile. Photo: Jessica Chomik-Morales

Those are just two of the 33 neuroscientists in seven Latin American countries that Jessica Chomik-Morales interviewed over 37 days for the expansive third season of her Spanish-language podcast, “Mi Ultima Neurona” (“My Last Neuron”), which launches Sept. 18 at 5 p.m. on YouTube. Each episode runs between 45 and 90 minutes.

“I wanted to shine a spotlight on their stories to dispel the misconception that excellent science can only be done in America and Europe,” says Chomik-Morales, “or that it isn’t being produced in South America because of financial and other barriers.”

A first-generation college graduate who grew up in Asunción, Paraguay and Boca Raton, Florida, Chomik-Morales is now a postbaccalaureate research scholar at MIT. Here she works with Laura Schulz, professor of cognitive science, and Nancy Kanwisher, McGovern Institute investigator and the Walter A. Rosenblith Professor of Cognitive Neuroscience, using functional brain imaging to investigate how the brain explains the past, predicts the future, and intervenes on the present.

“The podcast is for the general public and is suitable for all ages,” she says. “It explains neuroscience in a digestable way to inspire young people that they, too, can become scientists and to show the rich variety of reseach that is being done in listeners’ home countries.”

Journey of a lifetime

“Mi Ultima Neurona” began as an idea in 2021 and grew rapidly into a collection of conversations with prominent Hispanic scientists, including L. Rafael Reif, a Venezuelan-American electrical engineer and the 17th president of MIT.

Woman interviews man at a table while another man adjusts microphone.
Jessica Chomik-Morales (left) interviews the 17th president of MIT, L. Rafael Reif (right), for her podcast while Héctor De Jesús-Cortés (center) adjusts the microphone. Photo: Steph Stevens

Building upon the professional relationships she built in seasons one and two, Chomik-Morales broadened her vision, and assembled a list of potential guests in Latin America for season three.  With research help from her scientific advisor, Héctor De Jesús-Cortés, an MIT postdoc from Puerto Rico, and financial support from the McGovern Institute, the Picower Institute for Learning and Memory, the Department of Brain and Cognitive Sciences, and MIT International Science and Technology Initiatives, Chomik-Morales lined up interviews with scientists in Mexico, Peru, Colombia, Chile, Argentina, Uruguay, and Paraguay during the summer of 2023.

Traveling by plane every four or five days, and garnering further referrals from one leg of the trip to the next through word of mouth, Chomik-Morales logged over 10,000 miles and collected 33 stories for her third season. The scientists’ areas of specialization run the gamut— from the social aspects of sleep/wake cycles to mood and personality disorders, from linguistics and language in the brain to computational modeling as a research tool.

“This is the most fulfilling thing I’ve ever done.” – Jessica Chomik-Morales

“If somebody studies depression and anxiety, I want to touch on their opinions regarding various therapies, including drugs, even microdosing with hallucinogens,” says Chomik-Morales. “These are the things people are talking about.” She’s not afraid to broach sensitive topics, like the relationship between hormones and sexual orientation, because “it’s important that people listen to experts talk about these things,” she says.

The tone of the interviews range from casual (“the researcher and I are like friends,” she says) to pedagogic (“professor to student”). The only constants are accessibility—avoiding technical terms—and the opening and closing questions in each one. To start: “How did you get here? What drew you to neuroscience?” To end: “What advice would you give a young Latino student who is interested in STEM?”

She lets her listeners’ frame of reference be her guide. “If I didn’t understand something or thought it could be explained better, I’d say, ‘Let’s pause. ‘What does this word mean?’ ” even if she knew the definition herself. She gives the example of the word “MEG” (magnetoencephalography)—the measurement of the magnetic field generated by the electrical activity of neurons, which is usually combined with magnetic resonance imaging to produce magnetic source imaging. To bring the concept down to Earth, she’d ask: “How does it work? Does this kind of scan hurt the patient?’ ”

Paving the way for global networking

Chomik-Morales’s equipment was spare: three Yeti microphones and a Canon video camera connected to her laptop computer. The interviews took place in classrooms, university offices, at researchers’ homes, even outside—no soundproof studios were available. She has been working with sound engineer David Samuel Torres, from Puerto Rico, to clarify the audio.

No technological limitations could obscure the significance of the project for the participating scientists.

Two women talking at a table in front of a camera.
Jessica Chomik-Morales (left) interviews Josefina Cruzat (right) at Adolfo Ibañez University in Chile. Photo: Jessica Chomik-Morales

“‘Mi Ultima Neurona’ showcases our diverse expertise on a global stage, providing a more accurate portrayal of the scientific landscape in Latin America,” says Constanza Baquedano, who is from Chile. “It’s a step toward creating a more inclusive representation in science.” Baquendano is an assistant professor of psychology at Universidad Adolfo Ibáñez, where she uses electrophysiology and electroencephalographic and behavioral measurements to investigate meditation and other contemplative states. “I was eager to be a part of a project that aimed to bring recognition to our shared experiences as Latin American women in the field of neuroscience.”

“Understanding the challenges and opportunities of neuroscientists working in Latin America is vital,”says Agustín Ibañez, professor and director of the Latin American Brain Health Institute (BrainLat) at Universidad Adolfo Ibáñez in Chile. “This region, characterized by significant inequalities affecting brain health, also presents unique challenges in the field of neuroscience,” says Ibañez, who is primarily interested in the intersection of social, cognitive, and affective neuroscience. “By focusing on Latin America, the podcast brings forth the narratives that often remain untold in the mainstream. That bridges gaps and paves the way for global networking.”

For her part, Chomik-Morales is hopeful that her podcast will generate a strong following in Latin America. “I am so grateful for the wonderful sponsorship from MIT,” says Chomik-Morales. “This is the most fulfilling thing I’ve ever done.”

Study decodes surprising approach mice take in learning

by David Orenstein |

Neuroscience discoveries ranging from the nature of memory to treatments for disease have depended on reading the minds of mice, so researchers need to truly understand what the rodents’ behavior is telling them during experiments. In a new study that examines learning from reward, MIT researchers deciphered some initially mystifying mouse behavior, yielding new ideas about how mice think and a mathematical tool to aid future research.

The task the mice were supposed to master is simple: Turn a wheel left or right to get a reward and then recognize when the reward direction switches. When neurotypical people play such “reversal learning” games they quickly infer the optimal approach: stick with the direction that works until it doesn’t and then switch right away. Notably, people with schizophrenia struggle with the task. In the new study in PLOS Computational Biology, mice surprised scientists by showing that while they were capable of learning the “win-stay, lose-shift” strategy, they nonetheless refused to fully adopt it.

“It is not that mice cannot form an inference-based model of this environment—they can,” said corresponding author Mriganka Sur, Newton Professor in The Picower Institute for Learning and Memory and MIT’s Department of Brain and Cognitive Sciences (BCS). “The surprising thing is that they don’t persist with it. Even in a single block of the game where you know the reward is 100 percent on one side, every so often they will try the other side.”

While the mouse motif of departing from the optimal strategy could be due to a failure to hold it in memory, said lead author and Sur Lab graduate student Nhat Le, another possibility is that mice don’t commit to the “win-stay, lose-shift” approach because they don’t trust that their circumstances will remain stable or predictable. Instead, they might deviate from the optimal regime to test whether the rules have changed. Natural settings, after all, are rarely stable or predictable.

“I’d like to think mice are smarter than we give them credit for,” Le said.

But regardless of which reason may cause the mice to mix strategies, added co-senior author Mehrdad Jazayeri, Associate Professor in BCS and the McGovern Institute for Brain Research, it is important for researchers to recognize that they do and to be able to tell when and how they are choosing one strategy or another.

“This study highlights the fact that, unlike the accepted wisdom, mice doing lab tasks do not necessarily adopt a stationary strategy and it offers a computationally rigorous approach to detect and quantify such non-stationarities,” he said. “This ability is important because when researchers record the neural activity, their interpretation of the underlying algorithms and mechanisms may be invalid when they do not take the animals’ shifting strategies into account.”

Tracking thinking

The research team, which also includes co-author Murat Yildirim, a former Sur lab postdoc who is now an assistant professor at the Cleveland Clinic Lerner Research Institute, initially expected that the mice might adopt one strategy or the other. They simulated the results they’d expect to see if the mice either adopted the optimal strategy of inferring a rule about the task, or more randomly surveying whether left or right turns were being rewarded. Mouse behavior on the task, even after days, varied widely but it never resembled the results simulated by just one strategy.

To differing, individual extents, mouse performance on the task reflected variance along three parameters: how quickly they switched directions after the rule switched, how long it took them to transition to the new direction, and how loyal they remained to the new direction. Across 21 mice, the raw data represented a surprising diversity of outcomes on a task that neurotypical humans uniformly optimize. But the mice clearly weren’t helpless. Their average performance significantly improved over time, even though it plateaued below the optimal level.

In the task, the rewarded side switched every 15-25 turns. The team realized the mice were using more than one strategy in each such “block” of the game, rather than just inferring the simple rule and optimizing based on that inference. To disentangle when the mice were employing that strategy or another, the team harnessed an analytical framework called a Hidden Markov Model (HMM), which can computationally tease out when one unseen state is producing a result vs. another unseen state. Le likens it to what a judge on a cooking show might do: inferring which chef contestant made which version of a dish based on patterns in each plate of food before them.

Before the team could use an HMM to decipher their mouse performance results, however, they had to adapt it. A typical HMM might apply to individual mouse choices, but here the team modified it to explain choice transitions over the course of whole blocks. They dubbed their modified model the blockHMM. Computational simulations of task performance using the blockHMM showed that the algorithm is able to infer the true hidden states of an artificial agent. The authors then used this technique to show the mice were persistently blending multiple strategies, achieving varied levels of performance.

“We verified that each animal executes a mixture of behavior from multiple regimes instead of a behavior in a single domain,” Le and his co-authors wrote. “Indeed 17/21 mice used a combination of low, medium and high-performance behavior modes.”

Further analysis revealed that the strategies afoot were indeed the “correct” rule inference strategy and a more exploratory strategy consistent with randomly testing options to get turn-by-turn feedback.

Now that the researchers have decoded the peculiar approach mice take to reversal learning, they are planning to look more deeply into the brain to understand which brain regions and circuits are involved. By watching brain cell activity during the task, they hope to discern what underlies the decisions the mice make to switch strategies.

By examining reversal learning circuits in detail, Sur said, it’s possible the team will gain insights that could help explain why people with schizophrenia show diminished performance on reversal learning tasks. Sur added that some people with autism spectrum disorders also persist with newly unrewarded behaviors longer than neurotypical people, so his lab will also have that phenomenon in mind as they investigate.

Yildirim, too, is interested in examining potential clinical connections.

“This reversal learning paradigm fascinates me since I want to use it in my lab with various preclinical models of neurological disorders,” he said. “The next step for us is to determine the brain mechanisms underlying these differences in behavioral strategies and whether we can manipulate these strategies.”

Funding for the study came from The National Institutes of Health, the Army Research Office, a Paul and Lilah Newton Brain Science Research Award, the Massachusetts Life Sciences Initiative, The Picower Institute for Learning and Memory and The JPB Foundation.

One scientist’s journey from the Middle East to MIT

by Thea Singer |

Smiling man holidng paper in a room.
Ubadah Sabbagh, soon after receiving his US citizenship papers, in April 2023. Photo: Ubadah Sabbagh

“I recently exhaled a breath I’ve been holding in for nearly half my life. After applying over a decade ago, I’m finally an American. This means so many things to me. Foremost, it means I can go back to the the Middle East, and see my mama and the family, for the first time in 14 years.” — McGovern Institute Postdoctoral Associate Ubadah Sabbagh, X (formerly Twitter) post, April 27, 2023

The words sit atop a photo of Ubadah Sabbagh, who joined the lab of Guoping Feng, James W. (1963) and Patricia T. Poitras Professor at MIT, as a postdoctoral associate in 2021. Sabbagh, a Syrian national, is dressed in a charcoal grey jacket, a keffiyeh loose around his neck, and holding his US citizenship papers, which he began applying for when he was 19 and an undergraduate at the University of Missouri-Kansas City (UMKC) studying biology and bioinformatics.

In the photo he is 29.

A clarity of vision

Sabbagh’s journey from the Middle East to his research position at MIT has been marked by determination and courage, a multifaceted curiosity, and a role as a scientist-writer/scientist-advocate.  He is particularly committed to the importance of humanity in science.

“For me, a scientist is a person who is not only in the lab but also has a unique perspective to contribute to society,” he says. “The scientific method is an idea, and that can be objective. But the process of doing science is a human endeavor, and like all human endeavors, it is inherently both social and political.”

At just 30 years of age, some of Sabbagh’s ideas have disrupted conventional thinking about how science is done in the United States. He believes nations should do science not primarily to compete, for example, but to be aspirational.

“It is our job to make our work accessible to the public, to educate and inform, and to help ground policy,” he says. “In our technologically advanced society, we need to raise the baseline for public scientific intuition so that people are empowered and better equipped to separate truth from myth.”

Two men sitting at a booth wearing headphones.
Ubadah Sabbagh is interviewed for Max Planck Forida’s Neurotransmissions podcast at the 2023 Society for Neuroscience conference in San Diego. Photo: Max Planck Florida

His research and advocacy work have won him accolades, including the 2023 Young Arab Pioneers Award from the Arab Youth Center and the 2020 Young Investigator Award from the American Society of Neurochemistry. He was also named to the 2021 Forbes “30 under 30” list, the first Syrian to be selected in the Science category.

A path to knowledge

Sabbagh’s path to that knowledge began when, living on his own at age 16, he attended Longview Community College, in Kansas City, often juggling multiple jobs. It continued at UMKC, where he fell in love with biology and had his first research experience with bioinformatician Gerald Wyckoff at the same time the civil war in Syria escalated, with his family still in the Middle East. “That was a rough time for me,” he says. “I had a lot of survivor’s guilt: I am here, I have all of this stability and security compared to what they have, and while they had suffocation, I had opportunity. I need to make this mean something positive, not just for me, but in as broad a way as possible for other people.”

Child smiles in front of scientific poster.
Ubadah Sabbagh, age 9, presents his first scientific poster. Photo: Ubadah Sabbagh

The war also sparked Sabbagh’s interest in human behavior—“where it originates, what motivates people to do things, but in a biological, not a psychological way,” he says. “What circuitry is engaged? What is the infrastructure of the brain that leads to X, Y, Z?”

His passion for neuroscience blossomed as a graduate student at Virginia Tech, where he earned his PhD in translational biology, medicine, and health. There, he received a six-year NIH F99/K00 Award, and under the mentorship of neuroscientist at the Fralin Biomedical Research Institute he researched the connections between the eye and the brain, specifically, mapping the architecture of the principle neurons in a region of the thalamus essential to visual processing.

“The retina, and the entire visual system, struck me as elegant, with beautiful layers of diverse cells found at every node,” says Sabbagh, his own eyes lighting up.

His research earned him a coveted spot on the Forbes “30 under 30” list, generating enormous visibility, including in the Arab world, adding visitors to his already robust X (formerly Twitter) account, which has more than 9,200 followers. “The increased visibility lets me use my voice to advocate for the things I care about,” he says.

“I need to make this mean something positive, not just for me, but in as broad a way as possible for other people.” — Ubadah Sabbagh

Those causes range from promoting equity and inclusion in science to transforming the American system of doing science for the betterment of science and the scientists themselves. He cofounded the nonprofit Black in Neuro to celebrate and empower Black scholars in neuroscience, and he continues to serve on the board. He is the chair of an advisory committee for the Society for Neuroscience (SfN), recommending ways SfN can better address the needs of its young members, and a member of the Advisory Committee to the National Institutes of Health (NIH) Director working group charged with re-envisioning postdoctoral training. He serves on the advisory board of Community for Rigor, a new NIH initiative that aims to teach scientific rigor at national scale and, in his spare time, he writes articles about the relationship of science and policy for publications including Scientific American and the Washington Post.

Still, there have been obstacles. The same year Sabbagh received the NIH F99/K00 Award, he faced major setbacks in his application to become a citizen. He would not try again until 2021, when he had his PhD in hand and had joined the McGovern Institute.

An MIT postdoc and citizenship

Sabbagh dove into his research in Guoping Feng’s lab with the same vigor and outside-the-box thinking that characterized his previous work. He continues to investigate the thalamus, but in a region that is less involved in processing pure sensory signals, such as light and sound, and more focused on cognitive functions of the brain. He aims to understand how thalamic brain areas orchestrate complex functions we carry out every day, including working memory and cognitive flexibility.

“This is important to understand because when this orchestra goes out of tune it can lead to a range of neurological disorders, including autism spectrum disorder and schizophrenia,” he says. He is also developing new tools for studying the brain using genome editing and viral engineering to expand the toolkit available to neuroscientists.

Microscopic image of mouse brain
Neurons in a transgenic mouse brain labeled by Sabbagh using genome editing technology in the Feng lab. Image: Ubadah Sabbagh

The environment at the McGovern Institute is also a source of inspiration for Sabbagh’s research. “The scale and scope of work being done at McGovern is remarkable. It’s an exciting place for me to be as a neuroscientist,” said Sabbagh. “Besides being intellectually enriching, I’ve found great community here – something that’s important to me wherever I work.”

Returning to the Middle East

Profile of scientist Ubadah Sabbagh speaking at a table.
McGovern postdoc Ubadah Sabbagh at the 2023 Young Arab Pioneers Award ceremony in Abu Dhabi. Photo: Arab Youth Center

While at an advisory meeting at the NIH, Sabbagh learned he had been selected as a Young Arab Pioneer by the Arab Youth Center and was flown the next day to Abu Dhabi for a ceremony overseen by Her Excellency Shamma Al Mazrui, Cabinet Member and Minister of Community Development in the United Arab Emirates. The ceremony recognized 20 Arab youth from around the world in sectors ranging from scientific research to entrepreneurship and community development. Sabbagh’s research “presented a unique portrayal of creative Arab youth and an admirable representation of the values of youth beyond the Arab world,” said Sadeq Jarrar, executive director of the center.

“There I was, among other young Arab leaders, learning firsthand about their efforts, aspirations, and their outlook for the future,” says Sabbagh, who was deeply inspired by the experience.

Just a month earlier, his passport finally secured, Sabbagh had reunited with his family in the Middle East after more than a decade in the United States. “I had been away for so long,” he said, describing the experience as a “cultural reawakening.”

Woman hands man an award on stage.
Ubadah Sabbagh receives a Young Arab Pioneer Award by Her Excellency Shamma Al Mazrui, Cabinet Member and Minister of Community Development in the United Arab Emirates. Photo: Arab Youth Center

Sabbagh saw a gaping need he had not been aware of when he left 14 years earlier, as a teen. “The Middle East had such a glorious intellectual past,” he says. “But for years people have been leaving to get their advanced scientific training, and there is no adequate infrastructure to support them if they want to go back.” He wondered: What if there were a scientific renaissance in the region? How would we build infrastructure to cultivate local minds and local talent? What if the next chapter of the Middle East included being a new nexus of global scientific advancements?

“I felt so inspired,” he says. “I have a longing, someday, to meaningfully give back.”

Unpacking auditory hallucinations

by Thea Singer |

Tamar Regev, the 2022–2024 Poitras Center Postdoctoral Fellow, has identified a new neural system that may shed light on the auditory hallucinations experienced by patients diagnosed with schizophrenia.

Scientist portrait
Tamar Regev is the 2022–2024 Poitras Center Postdoctoral
Fellow in Ev Fedorenko’s lab at the McGovern Institute. Photo: Steph Stevens

“The system appears integral to prosody processing,”says Regev. “‘Prosody’ can be described as the melody of speech — auditory gestures that we use when we’re speaking to signal linguistic, emotional, and social information.” The prosody processing system Regev has uncovered is distinct from the lower-level auditory speech processing system as well as the higher-level language processing system. Regev aims to understand how the prosody system, along with the speech and language processing systems, may be impaired in neuropsychiatric disorders such as schizophrenia, especially when experienced with auditory hallucinations in the form of speech.

“Knowing which neural systems are affected by schizophrenia can lay the groundwork for future research into interventions that target the mechanisms underlying symptoms such as hallucinations,” says Regev. Passionate about bridging gaps between disciplines, she is collaborating with Ann Shinn, MD, MPH, of McLean Hospital’s Schizophrenia and Bipolar Disorder Research Program.

Regev’s graduate work at the Hebrew University of Jerusalem focused on exploring the auditory system with electroencephalography (EEG), which measures electrical activity in the brain using small electrodes attached to the scalp. She came to MIT to study under Evelina Fedorenko, a world leader in researching the cognitive and neural mechanisms underlying language processing. With Fedorenko she has learned to use functional magnetic resonance imaging (fMRI), which reveals the brain’s functional anatomy by measuring small changes in blood flow that occur with brain activity.

“I hope my research will lead to a better understanding of the neural architectures that underlie these disorders—and eventually help us as a society to better understand and accept special populations.”- Tamar Regev

“EEG has very good temporal resolution but poor spatial resolution, while fMRI provides a map of the brain showing where neural signals are coming from,” says Regev. “With fMRI I can connect my work on the auditory system with that on the language system.”

Regev developed a unique fMRI paradigm to do that. While her human subjects are in the scanner, she is comparing brain responses to speech with expressive prosody versus flat prosody to find the role of the prosody system among the auditory, speech, and language regions. She plans to apply her findings to analyze a rich data set drawn from fMRI studies that Fedorenko and Shinn began a few years ago while investigating the neural basis of auditory hallucinations in patients with schizophrenia and bipolar disorder. Regev is exploring how the neural architecture may differ between control subjects and those with and without auditory hallucinations as well as those with schizophrenia and bipolar disorder.

“This is the first time these questions are being asked using the individual-subject approach developed in the Fedorenko lab,” says Regev. The approach provides superior sensitivity, functional resolution, interpretability, and versatility compared with the group analyses of the past. “I hope my research will lead to a better understanding of the neural architectures that underlie these disorders,” says Regev, “and eventually help us as a society to better understand and accept special populations.”

Using the tools of neuroscience to personalize medicine

by Thea Singer |

Profile picture of Sadie Zacharek
Graduate student Sadie Zacharek. Photo: Steph Stevens

From summer internships as an undergraduate studying neuroscience at the University of Notre Dame, Sadie Zacharek developed interests in areas ranging from neuroimaging to developmental psychopathologies, from basic-science research to clinical translation. When she interviewed with John Gabrieli, the Grover Hermann Professor of Health Sciences and Technology and Cognitive Neuroscience, for a position in his lab as a graduate fellow, everything came together.

“The brain provides a window not only into dysfunction but also into response to treatment,” she says. “John and I both wanted to explore how we might use neuroimaging as a step toward personalized medicine.”

Zacharek joined the Gabrieli lab in 2020 and currently holds the Sheldon and Janet Razin’59 Fellowship for 2023-2024. In the Gabrieli lab, she has been designing and helping launch studies focusing on the neural mechanisms driving childhood depression and social anxiety disorder with the aim of developing strategies to predict which treatments will be most effective for individual patients.

Helping children and adults

“Depression in children is hugely understudied,” says Zacharek. “Most of the research has focused on adult and adolescent depression.” But the clinical presentation differs in the two groups, she says. “In children, irritability can be the primary presenting symptom rather than melancholy.” To get to the root of childhood depression, she is exploring both the brain basis of the disorder and how the parent-child relationship might influence symptoms. “Parents help children develop their emotion-regulation skills,” she says. “Knowing the underlying mechanisms could, in family-focused therapy, help them turn a ‘downward spiral’ into irritability, into an ‘upward spiral,’ away from it.”

The studies she is conducting include functional magnetic resonance imaging (fMRI) of children to explore their brain responses to positive and negative stimuli, fMRI of both the child and parent to compare maps of their brains’ functional connectivity, and magnetic resonance spectroscopy to explore the neurochemical environment of both, including quantities of neurometabolites that indicate inflammation (higher levels have been found to correlate with depressive pathology).

“If we could find a normative range for neurochemicals and then see how far someone has deviated in depression, or a neural signature of elevated activity in a brain region, that could serve as a biomarker for future interventions,” she says. “Such a biomarker would be especially relevant for children given that they are less able to articulately convey their symptoms or internal experience.”

“The brain provides a window not only into dysfunction but also into response to treatment.” – Sadie Zacharek

Social anxiety disorder is a chronic and disabling condition that affects about 7.1 percent of U.S. adults. Treatment usually involves cognitive behavior therapy (CBT), and then, if there is limited response, the addition of a selective serotonin reuptake inhibitor (SSRI), as an anxiolytic.

But what if research could reveal the key neurocircuitry of social anxiety disorder as well as changes associated with treatment? That could open the door to predicting treatment outcome.

Zacharek is collecting neuroimaging data, as well as clinical assessments, from participants. The participants diagnosed with social anxiety disorder will then undergo 12 weeks of group CBT, followed by more data collection, and then individual CBT for 12 weeks plus an SSRI for those who do not benefit from the group CBT. The results from those two time points will help determine the best treatment for each person.

“We hope to build a predictive model that could enable clinicians to scan a new patient and select the optimal treatment,” says Zacharek. “John’s many long-standing relationships with clinicians in this area make all of these translational studies possible.”