Professor Sam Wang, associate professor of molecular biology and neuroscience at Princeton University, has spent a long time studying the cerebellum. Latin for “little brain,” the cerebellum has the appearance of a separate structure attached to the bottom of the brain, tucked underneath the cerebral hemispheres. Even though the region has been associated with only guiding movement, recently researchers have begun to assess the cerebellum in terms of non-motor function—for example, clinicians who diagnose patients with syndromes that aren’t movement-related and whose only brain damage has been to the cerebellum. He is exploring the role of the cerebellum in non-motor functions. His lab is interested in possible connections between the cerebellum and two interesting but separate phenomena: reward and autism.
BRAIN WORLD: What kind of role do you think the cerebellum plays?
Sam Wang: I think of the cerebellum as a processor of unexpected or unpredicted. For example, you walk on ice and nearly fall over, but your brain triggers a response that allows you to execute a movement saving you from landing on your face. The ice causes the unexpected event—slipping. In response, your brain sets into action a process that restores your balance. Without an intact cerebellum, these responses are far harder.
BW: “Unexpected” implies expectations. How and where are expectations generated?
SW: Tickling provides a great example of how expectations influence the brain’s response. You can’t tickle yourself. This is closely linked to the fact that your brain can predict how your own touch will feel. By the same token, if someone’s touch is ticklish, placing your hand over the top of his makes the sensation less tickly. This is a useful technique to try at the pediatrician if the doctor’s touch is causing a fit of the giggles!
Work from researchers in the UK—Sarah-Jayne Blakemore, Daniel Wolpert, and Chris Frith—indicates that the cerebellum is involved in our response to being tickled. They devised a self-tickling machine. A person operates a lever and the device brushes the palm of the other hand with a piece of foam. If the scratch occurs at exactly the same time as the lever is operated, it doesn’t tickle, but introducing even a small delay leads to a ticklish feeling. The researchers found that parts of the cerebellum are activated when this happens, suggesting the possibility that sensory prediction on short times is important for recognizing when something else is touching us—and that the cerebellum is somehow involved.
BW: Which syndromes may be linked to the cerebellum in this way?
SW: It’s not generally known that cerebellar damage has varying effects, depending on which region is damaged, and when during development [in fetuses and children]. Clinicians know about cerebellar cognitive affective syndrome (CCAS), in which thoughts and emotional responses are disorganized. Children around 6 to 8 years of age who have surgery on the vermis, the part of the cerebellum at the midline, often show language complexity that regresses to that of a 3-year old, or even lose speech entirely for a period. These are problems not related to movement. Finally, cerebellar damage around the time of birth is very often associated with autism.
BW: Can you explain the possible link between the cerebellum and autism?
SW: It’s an outstanding puzzle. Cerebellum-related structures—the cerebellar cortex, the deep nuclei and the inferior olive—are the most commonly affected brain regions in autistic persons, based on both postmortem examination and brain scans on living individuals. Researchers see an imbalance in the gray–white matter proportions, unusual growth trajectories and low cell counts. A study from McGill University in Canada, by Catherine Limperopoulos, Adré du Plessis and others, found that infants who suffer cerebellum damage before or around the time of birth are likely to be autistic by age 2. They also have low volumes in frontal cortex on the opposite side as the cerebellar damage, which makes sense, considering that there is so much connectivity between cerebellum and cerebral cortex.
BW: Putting aside the cerebellum for a moment, how do you imagine autism arises at a general level?
SW: In thinking about how this could happen, increasingly I am drawn to the classic work of David Hubel, Torsten Wiesel and their many associates. It is now generally known that brain development proceeds according to a largely automatic program, but that at certain times—called critical or sensitive periods—normal input is required or else the system does not wire itself properly. This is true for many regions of cerebral cortex, and it was first well understood for visual development.
The sensitive-period idea extends to higher functions, as well. In language acquisition, a child who learns a new language before age 6 is far less likely to speak with an accent. So nonvisual regions of cerebral cortex seem to have specific periods when they are most easily shaped by new information. For a number of developmental disorders, the sensitive periods can occur before or after birth. Children born weeks before full term are at elevated risk of autism, mental retardation and cerebral palsy. Maternal stress in the second or third trimester also increases the risk of autism. The most life-changing aspects of autism are problems of social interaction, leading me to wonder if some signal necessary for interpreting socially relevant events is lacking. If we could pinpoint which parts of the brain no longer provide this signal, it might be possible to compensate for that lost function.
BW: For example?
SW: Imagine if a baby lacked the neural circuitry to recognize a friendly touch or voice. It would be like being raised in isolation. It is well documented from Eastern European and Russian orphanages that such treatment leads to symptoms that often resemble autism. Both orphanage and autistic children may be missing out on this critical social-learning period, with consequences that last a lifetime. This might also explain how intensive therapy of young autistic children can succeed. Applied behavioral analysis (ABA), the only autism therapy with strong peer-reviewed support, involves rewards such as food each time the child is touched. After a while the child views a cuddle or a hug as being positive. Whatever the brain regions are that convey social valence in a non-autistic child, ABA seems to compensate for their lost function. If we can show that one such brain region is the cerebellum, it would give a target for early intervention. For example, we could stimulate or silence it, just as the basal ganglia are targeted for treatment in Parkinson’s disease.
BW: Let’s turn now to reward. How could the cerebellum be involved?
SW: Reward is unexpected—finding a dollar bill on the sidewalk feels good, because we weren’t anticipating it. One manifestation of unexpected reward in the brain is well known: dopamine signals originating from neurons in the ventral tegmental area (VTA). But how does the VTA figure out that an event was rewarding? As it turns out, the cerebellum probably sends signals to the VTA. Decades ago it was shown that rats preferred to press a lever that stimulated a specific part of the cerebellum—one with possible connectivity to VTA—opting for that choice in preference to sex or food. This is reminiscent of some very famous experiments that first indicated a role for the hypothalamus in relaying pleasure. And anatomical tracing has demonstrated direct connections between the deep nuclei of the cerebellum and the VTA.
BW: Could autism be based on an inability to interpret reward?
SW: That is a very interesting speculation. Unpredicted events aren’t just sensorimotor—a mother’s smile is also rewarding. The sensory information that comes into our minds has no intrinsic valence—or attractiveness/value—until we’ve made sense of it. I see a curve of light, but until I’ve processed it I don’t know whether it’s a gap between branches or a smile. Not all rectangles of paper are rewarding, but if they are pieces of money, yes. Any brain region involved in making that interpretation—the VTA, the basal ganglia, and maybe the cerebellum—could play a role in the developmental road to autism.
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