Cerebellar Involvement in Cognitive Sequencing

Investigation of Cerebellar Involvement in Cognitive Sequencing

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.

Study Overview

• Status: Recruiting
• Conditions: Effects of Cerebellar Stimulation on Brain Activation
• Intervention / Treatment: Procedure: TMS during sequence-demanding task; Procedure: No TMS during sequence-demanding task; Procedure: TMS during non-sequence-demanding task; Procedure: No TMS during non-sequence-demanding task

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.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: John E Desmond, Ph.D.; Phone Number: 410-502-3583; Email: jdesmon2@jhmi.edu
• Study Contact Backup: Name: Rida Saeed, BS; Phone Number: 410-502-2150; Email: rsaeed5@jhu.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Recruiting
      • Johns Hopkins University School of Medicine
      • Contact: John E. Desmond, Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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
• 9) Additional exclusion criteria recommended by Wassermann for TMS neuromodulation, including: History of seizure or a family history of epilepsy, heart disease, intracardiac lines, increased intracranial pressure, history of head trauma, and history of respiratory disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Procedure: 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; Other Names: Transcranial magnetic stimulation; Procedure: No TMS during sequence-demanding task; TMS is not administered during the execution of sequence-demanding task.; 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; Procedure: No TMS during non-sequence-demanding task; TMS is not administered during the execution of non-sequence-demanding task
Active Comparator: 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.	Procedure: 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; Other Names: Transcranial magnetic stimulation; Procedure: No TMS during sequence-demanding task; TMS is not administered during the execution of sequence-demanding task.; 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; Procedure: No TMS during non-sequence-demanding task; TMS is not administered during the execution of non-sequence-demanding task

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
functional magnetic resonance imaging brain activation	functional magnetic resonance imaging brain activation. For the sequential task, a sequence of letters is presented and the subject is presented with number signs, one at a time, to guide rehearsal of the sequence. At some point a probe letter is presented and the subject indicates by button press if the probe is the next letter in the sequence. For the non-sequential task, subjects do not have a guided rehearsal, and the response to the probe indicates if the probe was one of the letters originally presented. Brain activation in response to the probe will be measured with brain stimulation vs no brain stimulation for each task	during scan up to 1 hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
percent correct of behavioral responses	percent correct of behavioral responses. For the sequential task, a sequence of letters is presented and the subject is presented with # signs, one at a time, to guide rehearsal of the sequence. At some point a probe letter is presented and the subject indicates by button press if the probe is the next letter in the sequence. For the non-sequential task, subjects do not have a guided rehearsal, and the response to the probe indicates if the probe was one of the letters originally presented. Behavioral accuracy consists of the percent of correct responses to the probe, with higher numbers indicating better performance	during scan up to 1 hour
behavioral reaction time (milliseconds)	behavioral reaction time to respond to the probe. Increases in reaction time indicate greater difficulty for the subject to respond	during scan up to 1 hour

Collaborators and Investigators

• Sponsor: Johns Hopkins University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: John E Desmond, Ph.D., Johns Hopkins University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2024
• Primary Completion (Estimated): July 31, 2026
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: October 25, 2023
• First Submitted That Met QC Criteria: October 25, 2023
• First Posted (Actual): October 31, 2023

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: functional MRI; fMRI; cerebellum; TMS; sequencing; transcranial magnetic stimulation; verbal working memory
• Other Study ID Numbers: IRB00328214; R01MH128278 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No