Da Vinci Was Right: The Cerebellum Deserves More Recognition

Neonatal cerebellar damage may have multiple neurodevelopmental consequences.

Posted Oct 20, 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

In 1504, Leonardo da Vinci (1452-1519) made wax castings inside the cranium and discovered two miniature brain hemispheres neatly tucked underneath the Goliath-sized cerebral hemispheres we commonly refer to as "left brain-right brain." Da Vinci recognized that these two, often-overlooked, kumquat-shaped brain hemispheres were noteworthy because they seemed symmetrical and interconnected with both cerebral hemispheres.

According to my neuroscientist father, Leonardo da Vinci coined the term “cerebellum” (Latin for “little brain”) as a direct and cogent response to the term “cerebrum” (Latin for “brain”). Within the cranial globe, our "whole-brain" has a total of four hemispheres: Two cerebral hemispheres north of the midbrain, and two cerebellar hemispheres south of the midbrain. Using the "cranial globe" analogy of northern and southern hemispheres, the midbrain is akin to the equator. Notably, the cerebellum is less than 10% of total brain volume but houses almost 80% of the brain's total neurons.

Da Vinci put "cerebellum" in the spotlight. Unfortunately, the cerebellum remained underestimated and overlooked for centuries. Thankfully, as the timeline below maps out, the cerebellum is finally getting the recognition it deserves. 

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

In the 19th century, Marie Jean Pierre Flourens (1794–1867) identified that the cerebellum was directly linked to motor functions. He observed that damage to the cerebellum resulted in a lack of coordination and inability to precisely time finely-tuned muscle movements. Today, we refer to these cerebellar deficits as ataxia and dysmetria.

Until the very end of the 20th century, most experts adamantly believed that the cerebellum was directly involved in coordinated motor control, but was not involved in any nonmotor functions or cognitive processes. 

1998 Was a Pivotal Year in the Historical Timeline of Cerebellum 

The "motor function only" concept of the cerebellum began to change in 1998, when Jeremy Schmahmann of Harvard Medical School’s Massachusetts General Hospital published two landmark papers. The first paper, "The Cerebellar Cognitive Affective Syndrome," was co-authored with Janet Sherman and published in the journal Brain. (CCAS is also referred to as "Schmahmann's Syndrome.") The second groundbreaking paper by Schmahmann from 1998, "Dysmetria of Thought: Clinical Consequences of Cerebellar Dysfunction on Cognition and Affect," was published in the journal Trends in Cognitive Sciences.

Based on his ongoing work with ataxia patients at MGH that began in the late 20th century, Schmahmann was able to pinpoint specific ways that cerebellar damage can result in a constellation of deficits within the cognitive domains of executive function, spatial cognition, language, and behavior. 

Since the beginning of the 21st century, our understanding of how the cerebellum is structured and how specific subregions within each cerebellar hemisphere (and vermis) influence motor and nonmotor functions in conjunction with the cerebrum is evolving at breakneck speed.

 Xavier Guell et al./eLife 2018 (Creative Commons)
Cerebellum gradients and relationship with discrete task activity maps (from Guell et al., 2018a) and resting-state maps (from Buckner et al., 2011)
Source: Xavier Guell et al./eLife 2018 (Creative Commons)

Recently, Schmahmann along with Xavier Guell and John Gabrieli of the McGovern Institute for Brain Research at MIT created exquisitely detailed maps of the cerebellum that link specific cerebellar "microzones” with motor tasks, working memory task, emotion processing task, social processing task, language processing task, and a cerebellar region that has language/social overlap. (For more see, “Mapping the Human Cerebellum Reframes Whole-Brain Functions.”) 

Now, a new systematic review of how damage to isolated regions of the cerebellum in newborns influences their neurodevelopment offers fresh clues about cerebellar functions. This paper, “Neurodevelopmental Consequences of Preterm Isolated Cerebellar Hemorrhage: A Systematic Review,” was published October 19 in the journal Pediatrics

Based on detailed analysis of infants with isolated cerebellar hemorrhage, the review found that the incidence of severe delays in (1) cognition, (2) motor skills, (3) language, and (4) behavioral development was 38%, 39%, 41%, and 38%, respectively. 

First author Lisa Hortensius from the Department of Neonatology at UMC Utrecht Brain Center Rudolf Magnus in the Netherlands and co-authors conclude, "Of infants with isolated cerebellar hemorrhage, 43% to 75% were severely delayed in cognition, motor, language, and/or behavioral development, with the highest incidence with vermis involvement and with large bleeds." 

The latest findings about the impact of neonatal cerebellar hemorrhage on neurodevelopmental outcome (NDO) sheds light on just how much damage to the cerebellum can affect both motor and nonmotor domains. That said, exactly how the cerebellum works and everything our "little brain" does remains largely unknown. For many researchers around the globe, solving the untold mysteries of the cerebellum has become a type of holy grail. 

Years from now, history may reveal that Leonardo's wax castings from 1504 represent a much more significant neuroscience-based "Da Vinci code" on the cerebellum timeline than we realize today. Hopefully, state-of-the-art technology will help us better understand the enigmatic cerebellum in the near future. Cutting-edge, 21st-century cerebellar research could lead to interventions and best practices for optimizing neurodevelopment outcomes, cerebro-cerebellar functional connectivity, and other cerebellum-based functions across the human lifespan. Stay tuned!

References

Lisa M. Hortensius, Aicha B.C. Dijkshoorn, Ginette M. Ecury-Goossen, Sylke J. Steggerda, Freek E. Hoebeek, Manon J.N.L. Benders, Jeroen Dudink. “Neurodevelopmental Consequences of Preterm Isolated Cerebellar Hemorrhage: A Systematic Review." Pediatrics (First published: October 19, 2018) DOI: 10.1542/peds.2018-0609

Xavier Guell, Jeremy D. Schmahmann, John D.E. Gabrieli, Satrajit S. Ghosh. "Functional Gradients of the Cerebellum." eLife (First published: August 14, 2018) DOI: 10.7554/eLife.36652

Xavier Guell, John Gabrieli, and Jeremy Schmahmann. "Triple Representation of Language, Working Memory, Social and Emotion Processing in the Cerebellum: Convergent Evidence from Task and Seed-Based Resting-State fMRI Analyses in a Single Large Cohort." NeuroImage (First published online: February 2, 2018 ) DOI: 10.1016/j.neuroimage.2018.01.082

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

Fatos Belgin Yildirim and Levent Sarikcioglu. "Marie Jean Pierre Flourens (1794–1867): An Extraordinary Scientist of His Time" Journal of Neurology, Neurosurgery & Psychiatry (2007) DOI: 10.1136/jnnp.2007.118380