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Cerebro-Cerebellar Circuits May Play a Role in Depression

Ketamine research unearths how cerebellar-cortical loops may inhibit depression.

Key points

  • Until the 1990s, the human cerebellum was mistakenly considered a motor-function-only brain region that didn't play a role in cognition.
  • Since the early 2000s, accumulating evidence suggests that the cerebellum is involved in many non-motor cognitive functions.
  • New ketamine-based fMRI research shows how neural circuits that connect the cerebellum to cortical areas may be linked to depression.
Both hemispheres of the cerebellum (Latin: "little brain') are tucked beneath the much larger hemispheres of the cerebrum, commonly referred to as "left brain-right brain." Cerebellar is the sister word to cerebral and means "relating to the cerebellum." Cerebro-cerebellar circuits and cerebellar-cortical loops connect specific neural networks within the cerebrum to microzones in each hemisphere of the cerebellum.
Source: SciePro/Shutterstock

Until recently, most neuroimaging research into major depressive disorders (MDD) focused on cortical hubs within the cerebrum's forebrain and completely overlooked the cerebellum.

A new brain imaging study from UCLA breaks this trend by investigating how clinically-administered ketamine infusions modulate cerebro-cerebellar circuitry during response inhibition in MDD patients. These open-access findings (Loureiro et al., 2021) were published online ahead of print on Sept. 9 in the journal NeuroImage: Clinical.

Historically, both cerebellar hemispheres were mistakenly viewed as motor-function-only brain regions that primarily held muscle memory and coordinated movements. Prior to 1998, most experts didn't realize that the cerebellum also plays a role in non-motor functions and cognition. Until about twenty years ago, nobody thought the cerebellum was involved in how we think or in our emotions.

For example, as a young tennis player in the 1970s, my neuroscientist father coached me by saying things like, "Practice, practice, practice is key to hammering and forging automatic muscle memory into your cerebellar Purkinje cells." But, back then, he didn't talk about the cerebellum much beyond the realm of sports and athletic peak performance.

Throughout most of the 20th century, brain scientists didn't view the cerebellum as playing any role in our mental health or neuropsychiatric disorders. This changed in 1998 when Jeremy Schmahmann of Harvard Medical School's Massachusetts General Hospital published two landmark papers that coined the terms, "Cerebellar Cognitive Affective Syndrome," and "Dysmetria of Thought."

Since the early 21st century, we've known that the cerebellum and the multiple cerebro-cerebellar circuits connecting specific areas of the "big brain" to microzones in the "little brain" play an important role in non-motor functions related to emotions, cognition, and executive functions. (See, "Cerebro-Cerebellar Circuits Remind Us: To Know Is Not Enough.")

Newfound Ways Cerebro-Cerebellar Circuits May Be Linked to Depression

In their recent (2021) paper, Joana Loureiro and co-authors wrote, "This research implicates the contribution of cerebro-cerebellar circuitries in MDD pathophysiology and the need to further investigate these circuitries and their role in executive control processes in depression and its treatment."

 Clinical/Creative Commons (CC BY-NC-ND 4.0)
Zstat maps for the cortical surface (top left), subcortical regions (bottom left), and cerebellum surface (right) obtained from the one-sample t-test performed across healthy controls and MDD at the first time point for the NoGo>Go contrast. Upper right cerebellar surface is a posterior view (dorsal is up), and lower right cerebellar surface is a ventral view (posterior is up). Dorsal is up in the flattened cerebellar surface at left.
Source: Loureiro et al., 2021 from NeuroImage: Clinical/Creative Commons (CC BY-NC-ND 4.0)

For this study, the researchers from the Ahmanson-Lovelace Brain Mapping Center at UCLA examined how ketamine, which has been shown to elicit rapid therapeutic effects in patients with major depressive disorder, modulates cerebro-cerebellar circuitry during a response-inhibition task while undergoing an fMRI brain scan. The cohort for this study involved MDD patients (N = 46) who received four ketamine infusions and a group of healthy controls (N = 32).

Loureiro et al. focused on cerebro-cerebellar connectivity to three functional networks: frontoparietal networks (FPN), sensory-motor networks (SMN), and salience networks (SN).

"The primary findings from this study indicate that low-dose ketamine infusion therapy, a rapidly acting treatment for MDD, served to decrease the connectivity between the posterior cerebellum and both the FPN and SMN in patient remitters, but not non-remitters," the authors explain. Interestingly, the researchers also found that cerebro-cerebellar connectivity between the cerebellum and the SN decreased for both remitters and non-remitters.

Ketamine's Antidepressant Effects May Be Tied to Cortico-Cerebellar Circuitry

Taken together, the researchers conclude that ketamine appears to modulate the connectivity between the cerebellum and multiple large-scale cortical networks in the cerebrum, including the FPN, SMN, and SN. Previous research has implicated all three of these neural networks in the pathophysiology of major depressive disorders.

"These findings support that ketamine may regulate higher-order function through cerebellar-cortico loops, which are involved in a number of functions including executive control, emotion regulation, motor learning and impulsive behavior in MDD," the authors conclude. "This study generates new insights into the neural mechanisms associated with response inhibition processes in MDD and the antidepressant effects of single and serial ketamine therapy, where cortico-cerebellar circuitry at the systems level may be used as ketamine biomarkers."


Joana R. A. Loureiro, Ashish K.Sahib, Megha Vasavada, Amber Leaver, Antoni Kubicki, Benjamin Wade, Shantanu Joshi, Gerhard Hellemann, Eliza Congdon, Roger P. Woods, Randall Espinoza, Katherine L. Narr. "Ketamine’s Modulation of Cerebro-Cerebellar Circuitry During Response Inhibition in Major Depression." NeuroImage: Clinical (First available online: September 09, 2021) DOI: 10.1016/j.nicl.2021.102792

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