Language & Cognitive Control (LCCMPH)

The Interaction of Cognitive Control Mechanisms and Language Processing: An Investigation With Methylphenidate

Catecholamine (CA) neurotransmitters, such as dopamine (DA) and noradrenaline (NA), have long been implicated playing a critical role in cognitive functions, such as working memory (WM), inhibition, learning, and decision making. Recent evidence from neurodegenerative patients and the healthy population suggested that CA also influences language processing. However, the question of what kind of influence that CA might exert on language is still open. Some previous studies have shown that CA can enhance semantic processing. In a recent study it was observed that CA agonists (i.e., methylphenidate) enhance participant's sensitivity to semantically incongruent information even when language processing was actually goal-irrelevant. On the other hand, the processing of semantically congruent information was enhanced while language processing was the goal. Moreover, consistent with some previous findings that there is a relation between participants' baseline characteristics and MPH effects, it was observed that participants with lower WM capacity benefited more from receiving methylphenidate. These results shed light on the relation between CA and language processing, but also lead to further questions, such as whether the interaction between CA and semantic processing is language-specific or mediated by the relation between CA and more general cognitive functions (e.g., WM, inhibition), and whether CA also has an influence on other aspects of language processing, such as syntactic processing. The present study aimed to further investigate the nature of the relation between CA and language processing by administrating methylphenidate (MPH) to healthy participants. MPH is an indirect CA agonist, which is the most commonly prescribed drug for attention deficit/hyperactivity disorder (ADHD). Previous studies have shown that MPH can efficiently increase the extracellular levels of CA in the brain by blocking their reuptake.

Objective: The primary objectives are: 1) to further investigate the effect of CA on semantic processing. The study plans to examine whether MPH interacts with processing of sentence context constraints via its influence on cognitive control operations. 2) To investigate the effects of MPH on syntactic processing. More specifically, the study is interested in whether MPH has an influence on revising syntactically temporarily ambiguous sentences.

A secondary objective is to further examine the relation between MPH effects and the baseline characteristics of individual participants.

Study design: This study will use a within-subject, double-blind, placebo-controlled, randomized, crossover design.

Study population: Approximately 40 healthy native Dutch speakers between 18 and 45 years old will be recruited. All subjects will have to complete one screening session and two separate testing sessions within three different days at the Donders Centre for Cognitive Neuroimaging (DCCN).

Intervention: Participants will either orally receive a 20mg methylphenidate or placebo capsule in each of the two testing sessions. Methylphenidate has been approved for clinical use in the Netherlands and the drug can be administered safely without any relevant risk of serious adverse events.

Main study parameters: Primary study parameters will include sentence comprehension capacity, attention and processing speed. In addition, several other measures will be included to monitor participants' baseline characteristics (e.g. working memory capacity, vocabulary size) and the general modulation effects of MPH (e.g. heart rate, blood pressure, subjective feeling).

Hypotheses:

Based on the previous finding that methylphenidate improves cognitive stability while it impairs flexible updating, the hypothesis is that methylphenidate will hinder participants' performance in resolving syntactic ambiguity, which requires an immediate updating and revising of an initial interpretation. This should be reflected in event-related potential (ERP) measures related to revision, namely the P600 effect is predicted to be reduced in the drug condition compared to placebo.

Study Overview

• Status: Completed
• Conditions: Language; Methylphenidate of Undetermined Intent
• Intervention / Treatment: Drug: Methylphenidate 20 Mg Oral Tablet; Behavioral: Language Task; Behavioral: Rest Recording; Behavioral: Go/No-Go Task; Behavioral: Processing Speed; Drug: Placebo; Behavioral: Operation Span; Behavioral: Reading Span; Behavioral: Barratt Impulsiveness Scale

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525EN
      • Donders Institute for Brain, Cognition and Behaviour, Centre for Cognitive Neuroimaging

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Native Dutch speakers
• Right-handed

Exclusion Criteria:

• Current (or history of) psychiatric disorder (e.g., psychosis, mania, severe depressive disorder)
• Current (or history of) neurological disorder (e.g. m. Parkinson, epilepsy)
• Current (or history of) endocrine / metabolic disorder
• Current (or history of) cardiac or vascular disorder
• Current (or history of) blood illness (e.g. severe anaemia, porphyria)
• Current (or history of) stomach or gastrointestinal tract disease
• History of autonomic failure (e.g., vasovagal reflex syncope)
• Experience of irregular sleep-wake rhythm
• Current (or history of) obstructive respiratory disease
• Current (or history of) clinically significant renal or hepatic disease
• (Recent treatment of) glaucoma
• Current (or history of) drug addiction (e.g. opiate, (meth)amphetamine, lysergic acid diethylamide, cocaine, solvents or barbiturate) or alcohol dependence
• One first degree or two or more second degree family members with a recent treatment of sudden death or ventricular arrhythmia
• Problems swallowing or problems with the oesophagus
• Frequent experience of headrush (vertigo)
• Current experience of an acute serious infection
• First degree family member with schizophrenia or bipolar disorder
• Abnormal hearing or (uncorrected) vision
• Use of psychotropic medication or recreational drugs weekly or more over a period of more than three months in the last 6 months
• Cannabis usage for the last 6 months
• Strong smoking behaviour starting at more than 1 package of cigarettes per week
• Hypersensitivity for e.g. beta blockers or methylphenidate
• Uncontrolled hypertension, defined as diastolic blood pressure at rest >95 mmHg or systolic blood pressure at rest >180 mmHg
• Irregular sleep/wake rhythm (e.g. regular nightshifts or cross timeline travel)
• Possible pregnancy or breastfeeding/ inadequate anticonception (for women)
• Lactose intolerance (because the placebo pill will be a lactose product)
• Language related disabilities (e.g. dyslexia, stuttering)
• Daily intense physical training

Study Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Drug Session; In this arm of the study participants receive the drug (Methylphenidate - 20mg), administered prior to completion of the primary and secondary tasks for the study. Electroencephalography (EEG) is measured for the duration of the primary and secondary tasks. Participants complete both arms of the study, and the order in which participants are assigned to this and the other arm of the study is randomized.	Drug: Methylphenidate 20 Mg Oral Tablet; 20mg methylphenidate or placebo capsule - one per session (counterbalanced) approximately 1 week apart; Behavioral: Language Task; The core part of the experiment is the language task, in which the aim is to investigate two critical aspects of language processing: semantic and syntactic processing. In this task, participants will be asked to read a list of sentences.; Behavioral: Rest Recording; Brain activity in the EEG is recorded at rest with eyes open and eyes closed to obtain baseline measures of alpha power as a proxy for attention and control under conditions of drug and placebo.; Behavioral: Go/No-Go Task; A Go/No-Go task will be implemented in the study design to investigate the functional properties of spatial selective attention and response inhibition. An adapted cued Go/No-Go paradigm from Randall & Smith (2011) will be employed.; Behavioral: Processing Speed; A speeded button response task will be included to measure participants' general processing speed. In this task, participants will be instructed to respond to a simple shape presented in the centre of the screen as fast and accurately as possible through pressing a corresponding button.
PLACEBO_COMPARATOR: Placebo Session; In this arm of the study participants receive the a placebo, administered prior to completion of the primary and secondary tasks for the study. Electroencephalography (EEG) is measured for the duration of the primary and secondary tasks. Participants complete both arms of the study, and the order in which participants are assigned to this and the other arm of the study is randomized.	Behavioral: Language Task; The core part of the experiment is the language task, in which the aim is to investigate two critical aspects of language processing: semantic and syntactic processing. In this task, participants will be asked to read a list of sentences.; Behavioral: Rest Recording; Brain activity in the EEG is recorded at rest with eyes open and eyes closed to obtain baseline measures of alpha power as a proxy for attention and control under conditions of drug and placebo.; Behavioral: Go/No-Go Task; A Go/No-Go task will be implemented in the study design to investigate the functional properties of spatial selective attention and response inhibition. An adapted cued Go/No-Go paradigm from Randall & Smith (2011) will be employed.; Behavioral: Processing Speed; A speeded button response task will be included to measure participants' general processing speed. In this task, participants will be instructed to respond to a simple shape presented in the centre of the screen as fast and accurately as possible through pressing a corresponding button.; Drug: Placebo; 20mg methylphenidate or placebo capsule - one per session (counterbalanced) approximately 1 week apart
OTHER: Intake Session; In this arm of the study participants are screened for suitability to participate in the experiment based on specified inclusion and exclusion criteria. They also complete some baseline tasks to assess working memory capacity, impulsiveness, and subjective mood.	Behavioral: Operation Span; In the operation span task, participants are instructed to solve math operations (e.g., (1*2) +1=?) as soon as possible and then remember a single letter. This to-be-remembered letter is followed by either another math-word combination or a recall screen, which will show up at the end of each set. When the recall screen is presented, participants have to recall all the letters in the correct order they were presented. The experimental trials contain three sets at each set size (i.e., the number of math-word pairs), with set sizes ranging from 3 to 7 items. This results in a total of 75 sets with 75 letters and 75 math problems. The order of set sizes is random for each participant. Participants' operation span will be evaluated by the total number of letters recalled in the correct serial position regardless of whether the entire trial was recalled correctly.; Behavioral: Reading Span; Participants are instructed to judge whether a presented sentence makes sense or not. After each sentence, a to-be-remembered letter will be shown on the screen, which is followed by either another sentence-word combination or the final recall screen. The set size ranges from 3 to 7 items. At the end of each set of sentences, participants will be required to recall all the letters in the current set in order. There will be a total of 75 letters and 75 sentence judgements. The order of the set sizes will be at random for each participant. Participants' performance will be evaluated by calculating the total number of correctly recalled letter sets.; Behavioral: Barratt Impulsiveness Scale; The Barratt impulsiveness scale (BIS-11) will be used in the experiment to measure participants' trait impulsivity. Participants will be required to rate themselves on 30 items that are related to attention, motor, self-control, cognitive complexity, perseverance, and cognitive instability impulsiveness.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Language Task ERP Drug Session	This measure will assess the P600 ERP effect (amplitude difference between correct and syntactic ambiguity conditions) just after the target word in the sentences being read.	First or second testing session depending on which session corresponds to the session where the drug was administered.
Language Task ERP Placebo Session	This measure will assess the P600 ERP effect (amplitude difference between correct and syntactic ambiguity conditions) just after the target word in the sentences being read.	First or second testing session depending on which session corresponds to the session where the placebo was administered.
Language Task Alpha Power Drug Session	This measure will assess the alpha power effect (relative power difference between high and low sentence constraint conditions in the alpha frequency band, 8-12 Hz) just before the target word in the sentences being read.	First or second testing session depending on which session corresponds to the session where the drug was administered.
Language Task Alpha Power Placebo Session	This measure will assess the alpha power effect (relative power difference between high and low sentence constraint conditions in the alpha frequency band, 8-12 Hz) just before the target word in the sentences being read.	First or second testing session depending on which session corresponds to the session where the placebo was administered.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Default Mode Alpha Power Drug Session	This measure will assess alpha power (8-12 Hz) at rest (relative difference between alpha power measured over the duration of the eyes open to that measured over the duration of the eyes closed recordings).	First or second testing session depending on which session corresponds to the session where the placebo was administered.
Default Mode Alpha Power Placebo Session	This measure will assess alpha power (8-12 Hz) at rest (relative difference between alpha power measured over the duration of the eyes open to that measured over the duration of the eyes closed recordings).	First or second testing session depending on which session corresponds to the session where the placebo was administered.
Go-NoGo Task Alpha Power Drug Session	This measure will assess alpha power (8-12 Hz) at response and no-response cues to obtain a measure of attentional control.	First or second testing session depending on which session corresponds to the session where the placebo was administered.
Go-NoGo Task Alpha Power Placebo Session	This measure will assess alpha power (8-12 Hz) at response and no-response cues to obtain a measure of attentional control.	First or second testing session depending on which session corresponds to the session where the placebo was administered.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peabody Picture Vocabulary Test	The Peabody Picture Vocabulary Test (PPVT) is used to measure vocabulary size. Raw scores are converted to standardized scores based on normative age-matched data (μ = 100; σ = 15). A higher score indicates better performance.	First testing session.
General Processing Speed Drug Session	Participants respond as fast as possible via button-press to a shape presented on the screen. Reaction time (RT) and accuracy are combined to obtain a single measure of performance, with faster RTs indicating better performance.	First or second testing session depending on which session corresponds to the session where the placebo was administered.
General Processing Speed Placebo Session	Participants respond as fast as possible via button-press to a shape presented on the screen. Reaction time (RT) and accuracy are combined to obtain a single measure of performance, with faster RTs indicating better performance.	First or second testing session depending on which session corresponds to the session where the placebo was administered.
Barratt Impulsiveness Scale	The Barrat Impulsiveness Scale (BIS) is used to assess the trait of impulsivity. Individual responses are scored on a 4-point scale (Rarely/Never = 1; Occasionally = 2; Often = 3; Almost always/Always = 4) and higher scores correspond to greater impulsivity.	Intake Session, 1-4 weeks prior to the intervention sessions
Reading Span Task	Participants are required to memorize letters presented between sentences that have to be read. The outcome measure is the number of letters correctly recalled in the correct order in a subsequent memory test. Set sizes range from 3-7 letters before memory is tested. This provides a measure of working memory capacity. More letters recalled indicates better working memory performance.	Intake Session, 1-4 weeks prior to the intervention sessions
Operation Span Task	Participants are required to memorize letters presented between math operations that have to be solved as quickly as possible. The outcome measure is the number of letters correctly recalled in the correct order in a subsequent memory test. Set sizes range from 3-7 letters before memory is tested. This provides a measure of working memory capacity. More letters recalled indicates better working memory performance.	Intake Session, 1-4 weeks prior to the intervention sessions

Collaborators and Investigators

• Sponsor: Donders Centre for Cognitive Neuroimaging
• Collaborators: Radboud University Medical Center; Max Planck Institute for Psycholinguistics
• Investigators: Principal Investigator: Peter Hagoort, PhD, Donders Centre for Cognitive Neuroimaging

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 26, 2019
• Primary Completion (ACTUAL): December 2, 2021
• Study Completion (ACTUAL): December 2, 2021

Study Registration Dates

• First Submitted: February 7, 2022
• First Submitted That Met QC Criteria: February 28, 2022
• First Posted (ACTUAL): March 9, 2022

Study Record Updates

• Last Update Posted (ACTUAL): April 1, 2022
• Last Update Submitted That Met QC Criteria: March 21, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: Cognitive Control; Reading; Methylphenidate; Language Processing; Catecholaminergic Neurotransmitters
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Dopamine Agents; Dopamine Uptake Inhibitors; Central Nervous System Stimulants; Methylphenidate
• Other Study ID Numbers: NL69700.091.19

Drug and device information, study documents

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