Cerebellar Involvement in Cognitive Sequencing

NCT ID: NCT06108336

Last Updated: 2026-01-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: NA
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-01
• Study Completion Date: 2027-07-31

Brief Summary

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. One theory that might account for both motor and cognitive contributions of the cerebellum is that the cerebellum is involved in sequencing of relevant events or stimuli. Previous experiments have suggested that disruption of the cerebellum impairs the prediction of the next event in a sequence. The present experiment will examine the impact of cerebellar stimulation on brain activation during the performance of both sequence-demanding and non-sequence-demanding tasks.

Detailed Description

Although there is increasing recognition that the cerebellum, which contains half of the brain's neurons, is involved in cognition as well as motor function, the manner in which the cerebellum contributes to cognition is uncertain. The uniform circuitry of the cerebellum and the extensive connectivity of the cerebellum with numerous neocortical regions has suggested to some researchers that there is a common computation that the cerebellum performs for both motor and cognitive functions. The cerebellar sequencing hypothesis posits that the cerebellum acquires sequence information, makes sequence predictions, and detects sequence violations. These functions, executed via a forward model, could underlie cerebellar involvement in both motor and cognitive behavior. In motor control, such predictions can be used to guide limb trajectory without reliance on movement-generated sensory feedback. In cognition, sequencing requirements are prominent in both verbal working memory (VWM) and language acquisition; eg, in VWM, keeping a phone number in mind requires encoding and rehearsing a sequence of digits. In language, words consist of sequences of syllables, and the learning of syllable transition probabilities is an important component of recognizing legal words in a language. Importantly, prominent cerebellar activation has been observed in many functional MRI (fMRI) VWM and language studies. However, the brainstem/cerebellar neural correlates of sequencing in cognition, and the influence of cerebellar sequence predictions on neocortical targets, are poorly understood. In this experiment, studying healthy individuals the investigators will Investigate the cerebellum as a source of sequence prediction and its influence on forebrain areas. The cerebellum is hypothesized to provide its forward model sequence prediction to forebrain targets, but to date no study has attempted to visualize with concurrent TMS/fMRI the consequences of disrupting this cerebellar input on forebrain activation. In the investigators previous work, the investigators show that transcranial magnetic stimulation (TMS) during the rehearsal of a sequence of letters results in errors in determining if a probe letter matches the next letter in the sequence, suggesting that TMS disrupted this predictive input. In accordance with this finding, the investigators hypothesize that, using concurrent TMS/fMRI, 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 brought out by sequencing demands. The investigators further hypothesize that different patterns of neocortical activations in response to cerebellar TMS will be observed depending on whether a probe letter matches the expected next letter in a sequence.

Conditions

Effects of Cerebellar Stimulation on Brain Activation

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Cerebellar Stimulation

TMS will be administered to the cerebellum on half the trials of a sequence-demanding task, and on half the trials of a non-sequence-demanding task. Task order will be counterbalanced.

Group Type: EXPERIMENTAL

TMS during sequence-demanding task

Intervention Type: PROCEDURE

TMS is administered during the execution of sequence-demanding task. Transcranial magnetic stimulation (TMS) is a safe and non-invasive technique for transiently modulating brain activity

No TMS during sequence-demanding task

Intervention Type: PROCEDURE

TMS is not administered during the execution of sequence-demanding task.

TMS during non-sequence-demanding task

Intervention Type: PROCEDURE

TMS is administered during the execution of non-sequence-demanding task. Transcranial magnetic stimulation (TMS) is a safe and non-invasive technique for transiently modulating brain activity

No TMS during non-sequence-demanding task

Intervention Type: PROCEDURE

TMS is not administered during the execution of non-sequence-demanding task

Occipital Stimulation

TMS will be administered to an occipital control region on half the trials of a sequence-demanding task, and on half the trials of a non-sequence-demanding task. Task order will be counterbalanced.

Group Type: ACTIVE_COMPARATOR

TMS during sequence-demanding task

Intervention Type: PROCEDURE

TMS is administered during the execution of sequence-demanding task. Transcranial magnetic stimulation (TMS) is a safe and non-invasive technique for transiently modulating brain activity

No TMS during sequence-demanding task

Intervention Type: PROCEDURE

TMS is not administered during the execution of sequence-demanding task.

TMS during non-sequence-demanding task

Intervention Type: PROCEDURE

TMS is administered during the execution of non-sequence-demanding task. Transcranial magnetic stimulation (TMS) is a safe and non-invasive technique for transiently modulating brain activity

No TMS during non-sequence-demanding task

Intervention Type: PROCEDURE

TMS is not administered during the execution of non-sequence-demanding task

Interventions

TMS during sequence-demanding task

TMS is administered during the execution of sequence-demanding task. Transcranial magnetic stimulation (TMS) is a safe and non-invasive technique for transiently modulating brain activity

Intervention Type: PROCEDURE

No TMS during sequence-demanding task

TMS is not administered during the execution of sequence-demanding task.

Intervention Type: PROCEDURE

TMS during non-sequence-demanding task

TMS is administered during the execution of non-sequence-demanding task. Transcranial magnetic stimulation (TMS) is a safe and non-invasive technique for transiently modulating brain activity

Intervention Type: PROCEDURE

No TMS during non-sequence-demanding task

TMS is not administered during the execution of non-sequence-demanding task

Intervention Type: PROCEDURE

Other Intervention Names

Transcranial magnetic stimulation

Eligibility Criteria

Inclusion Criteria

• 1) Age 18-50;
• 2) educational attainment of at least 8 years;
• 3) capable of giving informed consent;
• 4) fluent speaker of English by self-report;
• 5) right handed.

Exclusion Criteria

• 1) illicit drug use within 30 days of MRI scanning;
• 2) neurological or systemic disorder which can cause dementia or cognitive dysfunction;
• 3) history of an Axis I psychiatric disorder including substance use disorder;
• 4) history of definite stroke;
• 5) focal lesion on MRI exam;
• 6) uncorrected visual deficits by self-report
• 7) contraindications for MRI scanning
• 8) use of anxiolytic, antidepressant, neuroleptic, or sedative medication

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

John E Desmond, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Johns Hopkins University

Locations

Johns Hopkins University School of Medicine

Baltimore, Maryland, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

John E Desmond, Ph.D.

Role: CONTACT

jdesmon2@jhmi.edu

410-502-3583

JoAnna Mathena, MS

Role: CONTACT

labnim@jh.edu

443-571-0947

Facility Contacts

John E. Desmond, Ph.D.

Role: primary

Other Identifiers

R01MH128278

Identifier Type: NIH

Identifier Source: secondary_id

View Link

IRB00328214

Identifier Type: -

Identifier Source: org_study_id