The cerebellum makes up only around 10 percent of the mass of the human brain, yet it contains more than half of its neurons. Recent research suggests that the fist-sized structure may play a key role in autism, schizophrenia and other disorders of the brain. / CREDIT: BRAINSTEM AND CEREBELLUM FROM SELF REFLECTED / GREG DUNN AND BRIAN EDWARDS

This region of the brain is proving to exert greater influence on cognition, emotion, and other functions.

By Diana Kwon
Freelance Science Journalist

Introduction

When a 22-year-old college student turned up at the hospital after falling and hitting her head on ice, doctors conducted a CT scan that revealed a surprise: a tumor in her cerebellum, the fist-sized structure at the back of the brain. After surgeons successfully removed the mass, the woman started exhibiting strange behaviors. She was emotionally unexpressive and acted inappropriately — undressing in the hospital corridors, for example. She spoke in a fast, high-pitched, unintelligible voice and had trouble doing basic arithmetic, drawing, reading and writing. Although she began to improve after a few weeks, it took two years before she could take a remedial course through a junior college — and for more than two decades, her decision-making remained impaired.

This unusual case, which was first reported in the 1990s, defied a notion that had persisted for centuries: The cerebellum’s job is limited to coordinating movements.

For many neuroscientists, the structure took a back seat to the cerebral cortex, the thin layer of cells covering the creased, baseball-glove shaped lump that most of us think of when we imagine the human brain. The cerebellum was considered so unimportant that many scientists would simply ignore it in neuroimaging studies or, when they removed the brains of animals for many kinds of studies, they would chop the structure off and throw it away. “That’s how the field has been for a very long time,” says Krystal Parker, a neuroscientist at the University of Iowa.

Things are slowly beginning to change, however, as evidence builds that the cerebellum makes important contributions to cognition, emotion and social behavior. On top of that, studies suggest that the cerebellum may play a key role in autism, schizophrenia and other brain disorders. Researchers are now probing the brains of both mice and people to understand how the cerebellum contributes to these conditions.

Investigations of the cerebellum have really exploded over the last few years, says Catherine Stoodley, a neuroscientist at American University and a coauthor of a 2019 paper in the Annual Review of Neuroscience on the cerebellum’s role in cognition. “It’s very exciting.”

The “Little Brain”

At first glance, the cerebellum looks a bit like a wrinkly, overgrown walnut shell. A closer look reveals two hemispheres with creases on the surface that sink down into deep grooves and split off into a network of coral-like branches. Peering through a microscope reveals a uniform pattern of densely packed cells. The cerebellum makes up only about 10 percent of the mass of the human brain, but contains more than half of its neurons. Stretched out, its surface area would be nearly 80 percent that of the cerebral cortex.

The earliest experiments with the cerebellum — Latin for “little brain” — date back centuries. These investigations weren’t pretty: Scientists simply lopped off the structure from live animals then observed the effects on their behavior. Marie-Jean-Pierre Flourens, a 19th century French physiologist, for example, conducted cerebellectomies on pigeons and reported that the animals started to teeter and totter as if intoxicated. These findings led him to propose that the structure was necessary for coordinating motion. Clinical observations of people with cerebellar injuries later confirmed this hypothesis, cementing the cerebellum’s reputation as a movement-coordination structure for nearly two centuries.

For nearly two centuries, scientists considered the cerebellum — drawn here in cross-section in the 1918 Gray’s Anatomy — solely as the brain’s movement-coordination center. / CREDIT: H.V. CARTER / WIKIMEDIA COMMONS

A small number of scientists started to challenge this description in the 1980s. Lead among them was Henrietta Leiner, who initially trained in mathematics, physics and computer science, but later took an interest in neuroanatomy. She became captivated by the cerebellum as she pondered the purpose of the thick tract of nerve fibers that connect it to the cerebral cortex.

Leiner also questioned why the cerebellum evolved to be so much larger in humans than in other animals (according to one estimate, the human cerebellum is, on average, 2.8 times bigger than expected in primates our size). Why would that be so if all it did was coordinate movement? In 1986, Leiner, along with her husband, computer scientist Alan Leiner, and a neurologist named Robert Dow, proposed a radical hypothesis. The human cerebellum, they said, contributed to core thinking skills such as the ability to plan one’s actions.

Jeremy Schmahmann, then a neurology resident at Boston City Hospital, also developed a fascination for the cerebellum around that time. His interest stemmed from emerging evidence that another part of the brain once thought to be involved solely in motor control — the basal ganglia — also contributed to cognition. This led Schmahmann to wonder whether the same could be true of the cerebellum.

To address this question, Schmahmann set out on what he describes as an “archeological dig” through the stacks at Harvard’s Countway Library of Medicine. There, he discovered manuscripts dating to the 1800s documenting instances of cognitive, social and emotional impairments in patients with cerebellar damage — and in rare cases where people were born without a cerebellum at all. “There was a little counterculture going back right to the beginning that was completely neglected,” says Schmahmann, now a neurologist at Massachusetts General Hospital and a coauthor of the recent review with Stoodley.

The historical reports persuaded Schmahmann to investigate further. In experiments with monkeys, he and his adviser, neuroanatomist Deepak Pandya, found evidence that the cerebellum receives input via the brainstem from areas in the cerebral cortex that parallel areas in humans that are involved in functions such as language, attention and memory. “This flew in the face of accepted wisdom,” Schmahmann says. “We had some very strong opponents — but most, once the data became available, came around.”

While the cerebral cortex’s role in cognition has long been recognized, the cerebellum’s role has largely been ignored. But these two parts of the brain share an elaborate network of connections. Some 40 million neurons in the cerebral cortex have fiber-like axons extending to the pontine nuclei in the brainstem, an area intimately connected to the cerebellum. Extensive connections go in the other direction, too, from the cerebellum up to the cortex.

Around this time, another group, led by University of Pittsburgh neurobiologist Peter Strick, traced the connections going the other direction — from the cerebellum to the rest of the brain. This two-way communication bolstered the case that the cerebellum does much more than coordinate movements.

A Broad Repertoire

Subsequent clinical observations and neuroimaging studies have strengthened the argument further.

In the late 1990s, Schmahmann reported the first description of cerebellar cognitive affective syndrome after observing that people with cerebellar damage — due to degeneration or after tumor removal, strokes and infection — exhibited a wide array of impairments in cognition and behavior. These included difficulties with abstract reasoning and planning, changes in personality — such as the flattened emotions and inappropriate behaviors he observed in the college student with the cerebellar tumor — and problems with speech. Some patients recovered after several months; in others, symptoms persisted for years. This condition, which was later dubbed “Schmahmann’s syndrome,” strengthened the evidence that the cerebellum was indeed involved in a variety of cognitive processes.

Rare cases of people born missing parts of their cerebellum have also hinted at broader functions. In addition to difficulty coordinating their movements, these individuals exhibit signs of Schmahmann’s syndrome, as well as autistic-like traits such as obsessive rituals and trouble understanding social cues.

In another influential study, neuroscientist Randy Buckner at Harvard University and his colleagues mapped communication between the cerebral cortex and the cerebellum in humans. By scanning the brains of healthy people using functional magnetic resonance imaging, the team revealed that activity in the majority of the cerebellum was in sync with activity in parts of the cerebral cortex responsible for cognitive functions — and not with cortical areas involved in movement. “That paper was incredible for showing that the majority of the cerebellum can actually be accounted for by non-motor functions,” says Ann Shinn, a psychiatrist at McLean Hospital in Massachusetts.

The cerebellum plays a role in several motor and cognitive tasks. Neuroscientists used functional magnetic resonance imaging to scan people’s brains while they carried out a wide variety of activities. The researchers then mapped key functions associated with different regions of the cerebellum. Stronger associations are indicated by larger text in this flattened version of the cerebellum’s surface.

These studies and others are making it increasingly clear the cerebellum has many roles. But a big question remains: What, exactly, is its overall function?

The highly organized, grid-like architecture of cells in the cerebellum has inspired some scientists to suggest that it carries out a single computation. Schmahmann has dubbed this hypothesis the “universal cerebellar transform.” What core computation could account for the cerebellum’s involvement in movement, cognition and emotion remains an open question. But scientists have proposed a variety of possibilities, such as making and updating predictions or the precise timing of tasks.

A Role in Schizophrenia, Autism, and Beyond?

Given the cerebellum’s myriad roles, some scientists suspect the structure may be involved in several brain-related disorders. The two conditions for which there is currently the most evidence are autism and schizophrenia.

Cerebellar abnormalities are some of the most common neuroanatomical differences seen in people with autism, and physicians have observed that injuries to the cerebellum at birth considerably increase the risk that a child will develop the condition. Recent studies also suggest that the cerebellum may have an outsize influence on development and that irregularities in this structure early on may predispose people to conditions like autism.

Sam Wang, a neuroscientist at Princeton University, and his team have shown that inactivating the cerebellum in mice during development using chemogenetics — a method for manipulating specific neural circuits using engineered molecules injected into the brain — leads to characteristics in the animals that mirrored those seen in humans with autism. The mice lost the preference to spend time around another mouse instead of an inanimate object and had difficulty adjusting to a new task. The same manipulation in adult mice had no such effects.

Other researchers have found that it may be possible to modify some of these traits by targeting the cerebellum. Stoodley and her colleagues have demonstrated that stimulating the cerebellum with chemogenetics can reverse social deficits in genetically engineered mice that show autism traits. Her lab is now assessing whether they can modify social learning in autistic and neurotypical people by targeting the cerebellum with a technique called transcranial direct current stimulation, which uses electrodes placed on the head to modulate brain activity.

Purkinje cells (green), are recognizable by their flask-like bodies and long branching extensions, which enable the cells to integrate large amounts of information. These nerve cells are primarily responsible for carrying out cerebellar computations; each cell’s dense tree of branches receives approximately 175,000 inputs from cells in the granule layer (pink). / CREDIT: THOMAS DEERINCK, NCMIR / SCIENCE SOURCE

The idea that the cerebellum might be involved in schizophrenia has been around for decades, but until recently there was little experimental evidence in humans. In 2019, however, a group including Schmahmann reported that stimulating the cerebellum with a method called transcranial magnetic stimulation (TMS), which uses magnets to create electrical currents in the brain, could alleviate the negative symptoms of schizophrenia, which include a lack of motivation and anhedonia, the inability to feel pleasure. If TMS therapy proves to be effective, it could fulfill a long-standing need: Antipsychotic medications can successfully reduce the positive symptoms of schizophrenia, such a hallucinations and delusional thoughts, but effective therapies for negative symptoms remain elusive.

“There’s a lot of things we need to work out before this would become a therapeutic,” says Roscoe Brady, a psychiatrist at the Beth Israel Deaconess Medical Center in Boston who was involved in that trial. That said, he adds, TMS is one of most promising options he’s seen in the published research.

Brady and his colleagues are now carrying out a follow-up study with a larger group of people. They’re also tackling the question of how, exactly, cerebellar stimulation leads to improvement. At the University of Iowa, Parker and her colleagues are also testing whether cerebellar TMS can improve mood and cognition in people with disorders including schizophrenia, autism, bipolar disorder, depression and Parkinson’s disease. The abnormalities in working memory, attention and planning are very similar in many of these conditions, says Parker. Ultimately, she hopes that teasing apart the cerebellar contribution to these conditions will lead to the development of new treatments.

Whether cerebellum-based therapies can help people with these wide-ranging conditions remains to be seen. What’s clear, however, is that the cerebellum can no longer be ignored — and that its connections throughout the brain and contributions to brain function may be much broader than scientists had initially imagined.

“What I’m hoping comes out of all of this is that people can’t get away with eliminating the cerebellum from the research that they’re doing,” Parker says. “It’s almost always doing something related to whatever people are studying.”

Originally published by Knowable Magazine, 09.30.2020, under the terms of a Creative Commons Attribution-NoDerivatives 4.0 International license.