Introduction
Between two outstretched hands lies a distance shaped by the forces of neural and social differences, pulling them apart even as they reach for connection. This dynamic mirrors the experiences of those with Autism Spectrum Disorder (ASD), a neurodevelopmental condition where neural differences underlie challenges in social communication, restricted interests, and repetitive behaviors. ASD symptoms are not fixed, but rather exist on a spectrum with affected individuals exhibiting a variety of behaviors that differ in type and intensity. Although common ASD behaviors are well-known, the neural underpinnings of this disorder remain a puzzle, complicating efforts to develop effective treatments.
The Tangible Divide: Exploring the Behavioral Manifestations of ASD
According to Dr. Leslie Carver, the principal investigator of the Developmental Neuroscience Lab at UC San Diego, traditional perspectives on ASD often portray social difficulties as stemming from a “broken” social brain, characterized by difficulties in understanding or responding to social cues. Many modern researchers, like Dr. Carver, are not focused on “fixing” ASD with a cure or treatment, but are rather interested in better understanding the disorder itself. This perspective promotes the notion that the difficulties in social situations faced by autistic people arise from a mismatch in their neurological wiring and the demands of living in a largely neurotypical world where social cues and expectations are processed normatively. Specifically, individuals with autism require predictability in a socially unpredictable world. This makes social dynamics confusing and anxiety-inducing, leading to differences in behavior that are situational rather than intrinsic.
The key behavioral characteristics of ASD broadly fall into three categories: differences in language, social issues, and repetitive/restrictive behaviors. Regarding language, many of the differences pertain to awareness, or lack thereof, of contextual cues. For instance, children with ASD have difficulty understanding jokes or sarcasm and comprehending intentional differences in verbal tonality. Autistic children also typically present with flatter, or more monotone, language and often experience delays in language development. Individuals with ASD experience different social issues based on their age. Preadolescent children have difficulty sharing their attention with others, picking up on social cues, and typically do not respond to their own names. Older individuals with ASD have difficulty understanding and making predictions based on other people’s thoughts and intentions. Additionally, autistic individuals exhibit restrictive and repetitive behaviors as demonstrated by a narrow range of interests. For instance, they may develop an intense focus on specific objects, fascinated by their shape, texture, or motion. This attraction to familiarity clashes with the unpredictability of our social world, where interactions are fluid and often require adjustment.
Based on these patterns in social behavior, current research at the Carver Lab focuses on how six to nine-year old neurotypical and autistic children respond to social versus non-social stimuli through electroencephalogram recordings, or EEG. Social stimuli may include an image of a human face, while non-social stimuli may feature images of inanimate objects. Neurons, cells of the nervous system, orchestrate basic behaviors including our ability to move, talk, or process and react to information. When we think, groups of neurons fire in our brains to create waveforms. Measured by EEG, these waveforms are a representation of electrical activity in the brain, and are characterized by their frequency, amplitude, shape, and location on the scalp. In neurotypical children, the waveform shows greater activation when anticipating human faces, as the observed activity is localized to reward centers in the brain associated with dopamine, the “feel-good” hormone. On the other hand, children with ASD exhibit reduced activation in the brain’s reward centers when anticipating a face in a sequence of images. In contrast, children with ASD showed reduced activation in these reward centers when predicting a human face, with waveforms that appear nearly identical whether predicting a face or an object. This difference between the children may be rooted in the anxiety-inducing unpredictability of social stimuli. The resulting social disconnect contributes to the stigma surrounding neurodevelopmental disorders like ASD. These insights underscore the importance of rethinking how ASD is perceived—not as a condition that needs to be “fixed” but as a different way of experiencing and interacting with the world.
The Physiological Divide: Unraveling the Brain in ASD
Researchers at the Carver Lab are striving to paint a clearer picture of the social and behavioral aspects of ASD, but to fully explore its mysteries, we must zoom in on its neurological basis. Dr. Melissa Campbell, the principal investigator of the Campbell Lab in the Department of Neurosciences at UC San Diego is taking this microscopic approach by focusing on the neurons that shape how we think, feel, and behave.
Bridging sensory and motor neurons, interneurons receive signals from the nervous system and pass them along to the motor system, transferring messages from the brain to the rest of the body. Two primary types of interneurons are parvalbumin (PV) and somatostatin (SST). PV interneurons participate in synaptic depression, or the inhibition of neuronal activity, while SST neurons participate in synaptic facilitation, or the excitation of neuronal transmission. Neurons can also be broadly classified as either excitatory or inhibitory. Excitatory neurons initiate neural activity by releasing neurotransmitters that prompt neurons to fire, while inhibitory neurons act oppositely, blocking neuronal firing. Excitatory neurons are critical for the survival of interneurons during brain development. Deficits in PV interneurons, a feature commonly linked to ASD, are associated with abnormal excitatory neuronal connectivity in social and personality-based brain regions, specifically the prefrontal cortex.
The Campbell Lab investigates the neuronal framework of various neurodevelopmental disorders, with a particular focus on the mechanisms underlying ASD. Within the lab, post-doctoral scholar Dr. Yujie Cao focuses on receptor-like kinase (Ryk) proteins, which are crucial in determining PV interneuron cell fate. Ryk proteins facilitate the evolution of unspecified progenitor cells, which divide, mature, and specialize into specific interneurons. Fascinated by interneuron differentiation, Dr. Cao looks into cell transplantation, where embryonic stem (ES) cells that readily differentiate to any cell type are used to generate neural progenitor cells. These progenitor cells can then be transplanted into the brain, where they can migrate to appropriate regions and differentiate into interneuron subtypes like PV neurons. The ideal window of transplantation would likely be during the embryonic stage, which assists in rebuilding neuron plasticity, the ability of the nervous system to change its structures and functions. This process has shown some potential in mouse models, effectively altering the neural circuitry of the brain positively and allowing the possibility of adaptation. By manipulating Ryk proteins and promoting the development of PV interneurons, which are deficient in individuals with ASD, Dr. Cao’s work at the Campbell Lab helps uncover new strategies to address the neuronal imbalances seen in ASD.
The field of ASD research is vast but many questions remain unexplored. The Campbell Lab is working toward understanding the interactions that fail to give rise to sufficient PV interneurons in the brains of individuals with ASD. Alterations to the interneuron balance within these areas of the brain can result in behavioral shifts, as shown in individuals with ASD. However, there is no definite test to predict ASD during the embryonic stage, though family history and genetics can provide clues concerning the risk of later development. Those with ASD typically perceive and interact with the world through a unique lens, resulting in an increased stigma and therefore a greater divide in social connection with others.
While innovations like cell transplantation may not “fix” ASD, they offer the potential for mitigating the neurological imbalances that are thought to result in the manifestation of the linguistic, social, and behavioral issues exhibited by individuals with ASD. Research at the Campbell Lab underscores the importance of investigating the neurological blueprint for ASD before neuronal imbalances become deeply established. Simultaneously, research at the Carver Lab emphasizes the importance of understanding the behavioral manifestations that shape this disorder. By approaching ASD from both neural and behavioral perspectives, the researchers at the Campbell Lab and the Carver Lab are moving towards a more comprehensive approach to understanding this disorder—one that goes beyond the idea of a cure and instead focuses on recognition, intervention, and a deeper understanding of ASD.