Cerebellum Studies Challenge Ancient Notions of How We Think

After centuries of being overlooked, the cerebellum is getting due recognition.

Posted Oct 25, 2018

 Wikipedia/Public Domain
This early 20th-century anatomical illustration of the human brain (from below) shows the left and right hemispheres of both the cerebellum and cerebrum. "Cerebellar" is the sister word to "cerebral" and means 'relating to or located in the cerebellum.' "Cerebro-Cerebellar" generally refers to the functional connectivity and interplay between specific regions of the cerebrum and subregions of the cerebellum. 
Source: Wikipedia/Public Domain

Until 1998, most neuroscientists adhered to the ancient notion that the cerebellum (Latin for “little brain”) was only responsible for motor functions and had nothing to do with cognition. Prior to Jeremy Schmahmann publishing three back-to-back, game-changing papers at the end of the 20th century, it was widely believed that the human cerebellum oversaw the timing and coordination of fine-tuned muscle movements, but was definitely not involved in cerebral “thinking” or cognitive thoughts.

Schmahmann’s three landmark papers about the human cerebellum's role in cognition from the late 1990s were: “The Cerebrocerebellar System” (1997), “The Cerebellar Cognitive Affective Syndrome” (1998), and “Dysmetria of Thought: Clinical Consequences of Cerebellar Dysfunction on Cognition and Affect” (1998).

Thanks to the trailblazing efforts of Schmahmann and other cerebellar pioneers over the past two decades, the misinformed “motor function only” conception of the cerebellum has been debunked. Today, most neuroscientists agree that in addition to a wide range of motor functions, the cerebellum is also involved in multiple cognitive, emotional, social, and linguistic nonmotor functions. (For more see, “Da Vinci Was Right: The Cerebellum Deserves More Recognition.”)

The recent publication of two new state-of-the-art cerebellum studies continues to inform our ever-evolving view of the “little brain” and how the whole brain works in concert to generate thoughts and coordinate thinking using cortico-cerebellar loops and cerebro-cerebellar networks.

The first new paper from Baylor College of Medicine, “A Cortico-Cerebellar Loop for Motor Planning,” was published October 17 in the journal Nature. The second paper, by researchers at the University of Washington in St. Louis and titled “Spatial and Temporal Organization of the Individual Human Cerebellum,“ was published October 25 in the journal Neuron.

This blog post is divided into two parts that explore each of these October 2018 studies separately.

Part One: “A Cortico-Cerebellar Loop for Motor Planning” by Gao et al.

Life Sciences Database/Wikipedia Commons
Cerebellum (Latin for "little brain") in red.
Source: Life Sciences Database/Wikipedia Commons

Zhenyu Gao et al. have shown that specific regions of the cerebellum are active in short-term memory, even when the body is not in motion. Remarkably, the researchers found direct evidence using a mouse model that memory activity in the frontal cortex appears to be dependent on activity in the cerebellum.

This study was conducted by an international research collaborative led by senior author Nuo Li and his lab team at Baylor College of Medicine in Houston, Texas along with neuroscientists at the Howard Hughes Medical Institute's Janelia Research Campus in Ashburn, Virginia, and first author Zhenyu Gao and colleagues at the Erasmus University Medical Center in Rotterdam, Netherlands.

The most significant aspect of the latest mouse-model study from the Nuo Li Lab is that the researchers were able to focus on neural activity in the cerebellum during periods when a test subject wasn't moving but was thinking about its next move.

Life Sciences Database/Wikipedia Commons
Frontal cortex in red.
Source: Life Sciences Database/Wikipedia Commons

“We knew that the frontal cortex and the cerebellum are anatomically connected with each other,” Li said in a statement. “We also knew that in humans, cerebellar damage has been known to cause memory or planning problems, so the two might be connected. We found that the output of the cerebellum targets the frontal cortex and vice versa. When we disrupt the communication between the two areas of the brain, memory activity is disrupted. Our results show that activity orchestrating a single behavior is coordinated by multiple regions of the brain.”

To make this discovery about how cortico-cerebellar loops work during motor learning, the researchers trained mice in a learning task which required them to make a cognitive decision based on short-term memory.

The authors conclude, “In humans, cerebellar damage can cause defects in planning and working memory. Here we show that persistent representation of information in the frontal cortex during motor planning is dependent on the cerebellum. Our results support the view that persistent neural dynamics during motor planning is maintained by neural circuits that span multiple brain regions and that cerebellar computations extend beyond online motor control.”

The cerebellum is a central player when it comes to athletic performance and sports. “The cerebellum is known to guide our movement by learning from errors," Li explained in a statement. "When we learn to shoot a basketball, we initially have lots of missed shots. However, the brain can adjust our shots by adjusting our movements based on errors from the missed shots and eventually produce accurate shots. It is known that the cerebellum is responsible for this motor learning. It combines errors from the missed movements and the movement that was made to produce a more accurate movement."

The next phase of research by Li’s team will test whether or not the cerebellum uses the same “trial-and-error” learning process that is activated during motor learning in sports to master more cerebral activities like playing chess.

Part Two: “Spatial and Temporal Organization of the Individual Human Cerebellum” by Marek et al.

The press release from Washington University School of Medicine in St. Louis announcing the publication of a new cerebellar study led by postgraduate research scholar Scott Marek has an attention-grabbing title: “Mind’s Quality Control Center Found in Long-Ignored Brain Area: Cerebellum Checks and Corrects Thoughts, Movement.”

Because I’ve been trying (with limited success) to put the often-overlooked cerebellum in the spotlight for over a decade and strive to make “cerebellar” a household word, I couldn’t help nodding my head and saying “Yes! That’s exactly right” out loud as I read the lede of this press release:

“The cerebellum can’t get no respect. Located inconveniently on the underside of the brain and initially thought to be limited to controlling movement, the cerebellum has long been treated like an afterthought by researchers studying higher brain functions. But researchers at Washington University School of Medicine in St. Louis say overlooking the cerebellum is a mistake. Their findings, published October 25 in Neuron, suggest that the cerebellum has a hand in every aspect of higher brain functions — not just movement, but attention, thinking, planning and decision-making.”

For this study, WUSTL researchers in the Dosenbach Lab measured the timing of human brain activity using functional connectivity MRI and found that signals from sensory systems were processed in intermediate networks of the cerebral cortex before being sent to the cerebellum. Notably, these brain scans show that the cerebellum contains individual-specific network organization that is significantly more varied than in the cerebral cortex. As the authors explain: 

“Seminal transneuronal tracing studies have shown that the lateral posterior regions of the cerebellum form closed-looped circuits with regions of the premotor, prefrontal, and posterior parietal cortex in macaques (Dum and Strick, 2003; Kelly and Strick, 2003; Strick et al., 2009) , providing an anatomical framework for a putative role in adaptive feedback mechanisms for behavioral modification of movement and cognitive processes. Thus, the characterization of the cerebellum purely as a conserved motor structure is antiquated and inaccurate (Buckner, 2013; Caligiore et al., 2017; Fiez, 1996; Leiner et al., 1989; Schmahmann, 2004; Schmahmann et al., 2009; Strick et al., 2009). Although previous studies have provided an anatomical and functional framework for understanding cerebellar contributions to brain function, the degree of individual-specificity in cerebellar functional organization is currently unknown.”

Marek et al. speculate that as part of a cerebro-cerebellar loop brain signals undergo final quality checks in the cerebellum before being sent back to the cerebral cortex for implementation. The authors said, “Given the presence of cortico-cerebellar loops, and their purported role in error signaling and adaptive plasticity, we were particularly interested in the temporal organization of infra-slow activity (ISA) between the cerebellum and cerebral cortex.”

Marek’s research unearthed an amazing new statistic: Only 20 percent of the cerebellum is solely devoted to motor functions; the remaining 80 percent appears to be occupied by nonmotor cerebellar regions involved in higher-order cognition. “The executive function networks are way overrepresented in the cerebellum,” Marek said in a statement. “Our whole understanding of the cerebellum needs to shift away from it being involved in motor control to it being more involved in general control of higher-level cognition.”

“The biggest surprise to me was the discovery that 80 percent of the cerebellum is devoted to the smart stuff,” senior author Nico Dosenbach added. “Everyone thought the cerebellum was about movement. If your cerebellum is damaged, you can’t move smoothly ­— your hand jerks around when you try to reach for something. Our research strongly suggests that just as the cerebellum serves as a quality check on movement, it also checks your thoughts as well — smoothing them out, correcting them, perfecting things.”

One unexpected aspect of this cerebellar research is related to the cerebellum's sensitivity to alcohol. The researchers speculate that the poor judgement and lack of impulse control that occurs after someone drinks too much alcohol may be rooted in the cerebellum. Everybody knows that being intoxicated makes people’s physical movements discombobulated as marked by slurred speech and inability to walk a straight line. Interestingly, the latest findings by Marek and his team suggest that the poor decision-making fueled by alcohol consumption may be a reflection of the cerebellum losing its ability to monitor and control the quality of executive functions.

“Many people who are looking at links between brain function and behavior just ignore the cerebellum,” Dosenbach said in a statement. “They slice off that data and throw it away, because they don’t know what to do with it. But there are four times as many neurons in the cerebellum as in the cerebral cortex, so if you’re leaving out the cerebellum, you’ve already shot yourself in the foot before you started. The promise of imaging the whole human brain at once is to understand how it all works together. You can’t see how the whole circuit works together when you’re missing a major piece of it.”

The authors conclude, “[Our] findings suggest a domain-general function of the cerebellum may be the ultimate correction of all cortical motor and cognitive processes.”

The next step for Marek and the research team in Dosenback’s Lab is to investigate how individual differences in cerebellar structure and functional connectivity are correlated with various types of intelligence, behavior, personality traits, and psychiatric disorders.

References

Scott Marek, Joshua S. Siegel, Evan M. Gordon, Ryan V. Raut, Dillan J. Newbold, Mario Ortega, Timothy O. Laumann, Derek B. Miller, Annie Zheng, Katherine C. Lopez, Jeffrey J. Berg, Rebecca S. Coalson, Annie L. Nguyen, Donna Dierker, Andrew N. Van, Catherine R. Hoyt, Kathleen B. McDermott, Scott A. Norris, Joshua S. Shimony, Abraham Z. Snyder, Steven M. Nelson, Deanna M. Barch, Bradley L. Schlaggar, Marcus E. Raichle, Steven E. Petersen, Deanna J. Greene, Nico U.F. Dosenbach. "Spatial and Temporal Organization of the Individual Human Cerebellum." Neuron (First published: October 25, 2018) DOI: 10.1016/j.neuron.2018.10.010

Zhenyu Gao, Courtney Davis, Alyse M. Thomas, Michael N. Economo, Amada M. Abrego, Karel Svoboda, Chris I. De Zeeuw, and Nuo Li. "A Cortico-Cerebellar Loop for Motor Planning" Nature (First published: October 17, 2018) DOI: 10.1038/s41586-018-0633-x

Jeremy D. Schmahmann and Deepak N.Pandyat. "The Cerebrocerebellar System." International Review of Neurobiology (1997) DOI: 10.1016/S0074-7742(08)60346-3

Jeremy D. Schmahmann and Janet C. Sherman. "The Cerebellar Cognitive Affective Syndrome." Brain: A Journal of Neurology (1998) DOI: 10.1093/brain/121.4.561

Jeremy D. Schmahmann. "Dysmetria of Thought: Clinical Consequences of Cerebellar Dysfunction on Cognition and Affect." Trends in Cognitive Sciences (1998) DOI: 10.1016/S1364-6613(98)01218-2

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