# Investigation of cerebellar involvement in cognitive sequencing

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $803,364

## Abstract

Although there is increasing recognition that the cerebellum is involved in cognition as well as motor function,
the manner in which the cerebellum contributes to cognition is uncertain. The cerebellar sequencing
hypothesis posits that the cerebellum acquires sequence information, makes sequence predictions, and
detects sequence violations via a forward model. Sequencing requirements are prominent in both verbal
working memory (VWM) and language acquisition. Although cerebellar activation has been observed in many
VWM and language investigations, the brainstem/cerebellar neural correlates of sequencing in cognition, and
the influence of cerebellar sequence predictions on neocortical targets, are poorly understood. In Aim 1, we will
investigate the cerebellar sequencing hypothesis in VWM. Our preliminary data indicate inferior olive (IO)
involvement in sequence acquisition, whereas sequence violations are characterized by large increases in
cerebro-cerebellar functional connectivity (FC). We hypothesize that cerebellar ataxia patients, who exhibit
gray and white matter degeneration, should exhibit neural and behavioral abnormalities in sequencing-
dependent VWM performance. Using fMRI, we hypothesize group differences in IO activation during sequence
acquisition and FC between cerebellum and known critical forebrain regions (CFRs) for VWM (left inferior
frontal gyrus [LIFG], supplementary motor area, and left temporal/parietal cortex) during sequence violation.
Using structural neuroimaging, we predict group differences in cerebellar gray matter and peduncle integrity,
as well as in structural connectivity between cerebellum and CFRs. We will correlate these structural and
functional measures with task performance to infer brain-behavior relationships. In Aim 2, we will test the
generalization of cerebellar sequencing in a statistical learning/language acquisition paradigm. Ataxia and
control subjects will receive fMRI during a learning phase in which they listen to a pseudo language to learn
transition probabilities of sequences of phonemes, and a test phase in which they will detect phoneme
sequence violations. We hypothesize that ataxia patients will be impaired in detecting incorrect sequences or
novel transitions of syllables. As in Aim 1, we hypothesize group differences in IO activation during sequence
acquisition and changes in FC between cerebellum and known CFRs during sequence violation, but for
statistical learning those CFRs are left superior temporal gyrus, striatum, and LIFG. Finally, the cerebellum is
hypothesized to provide its sequence prediction computation to neocortical targets, and in Aim 3, using
cerebellar transcranial magnetic stimulation (TMS) with concurrent functional MRI, we will test the hypothesis
that TMS disruption during a sequencing task will produce greater changes in neocortical activation relative to
an analogous control task that does not have the predictive component. These investigations will improve our
un...

## Key facts

- **NIH application ID:** 10892200
- **Project number:** 5R01MH128278-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** JOHN E DESMOND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $803,364
- **Award type:** 5
- **Project period:** 2022-08-16 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10892200

## Citation

> US National Institutes of Health, RePORTER application 10892200, Investigation of cerebellar involvement in cognitive sequencing (5R01MH128278-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10892200. Licensed CC0.

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