Neural Bases of Motivation

Overview

Effort-based decisions are essential in daily life but strongly impaired in apathy across various brain disorders. Now, significant research to unveil the neural causes of apathy is needed. A crucial corollary to this is the need to identify the brain network and neural mechanisms underlying effort-based decisions. A fronto-striatal network and the noradrenergic system are involved in effort-based decision-making and apathy. Further, motor cortical structures may play a role in effort-based decision-making. However, the role of circuits connecting the fronto-striatal network and the noradrenergic system to the motor structures has been disregarded so far. Non-invasive brain stimulation methods provide a unique and safe means to test the causal role of connectivity changes between fronto-subcortical and motor structures in effort-based decision-making. It's now necessary to have an integrative, connectionnist framework to uncover the causal role of connectivity changes between fronto-subcortical and motor structures in effort-based decision-making. The overarching goal of the present research protocol is to establish an integrative framework testing the causal role of connectivity within recurrent, bidirectional circuits between fronto-subcortical circuits and motor structures in effort-based decision-making. To achieve this overarching goal, investigators will quantifiy the causal role of effective connectivity and oscillatory synchrony in these circuits on effort-related behavior using a non-invasive brain stimulation strategy. Further, a secondary aim is to identify potential non-invasive brain stimulation methods that could increase engagement in effortful behavior, paving the way for translational clinical applications in the context of apathy. The investigators hypothesize that effort-based decision-making in healthy subjects is governed by bidirectional interactions between fronto-subcortical circuits and motor structures such as the primary motor cortex, mediated by oscillatory synchrony in specific frequency bands (e.g., theta and gamma bands). Accordingly, they hypothesize that transient, non-invasive modulation of connectivity and oscillatory synchrony between these structures in healthy human subjects will directly modulate their decision to engage in effort. Specifically, five experiments will use complementary approaches to test the hypothesis.

Interventions

• Procedure Cortico-cortical paired-associative stimulation (ccPAS)
  Transcranial magnetic stimulation (TMS)
• Procedure Bifocal transcranial alternating current stimulation (tACS)
  Transcranial electrical stimulation (tES)
• Procedure Combining transcranial temporal interference stimulation (tTIS) and oscillatory TMS
  Transcranial electrical stimulation and transcranial magnetic stimulation
• Procedure Transcranial direct current stimulation (tDCS)
  Transcranial electrical stimulation
• Procedure Transcutaneous vagal nerve stimulation (tVNS)
  Transcutaneous vagal nerve stimulation (tVNS)
• Procedure MRI
  Magnetic Resonance Imaging
• Procedure MEG
  Magnetoencephalography
• Procedure Pupillometry
  Measurement and analysis of changes in pupil diameter over time, providing a non-invasive and straightforward method to investigate physiological and psychological processes. Using an eye tracker or pupillometer equipped with infrared cameras, pupil size is measured with high precision and temporal resolution. Pupil responses serve as a proxy for effort invigoration and are linked to multiple neuromodulatory systems, including the noradrenergic system. Recordings will be conducted throughout bot
• Behavioral Neuropsychological scales
  Different neuropsychological scales will be administered to assess various psychological and behavioral dimensions relevant to the study, such as: the Apathy Evaluation Scale (AES): To evaluate levels of apathy ; the Depression Anxiety Stress Scale (DASS): To assess depression, anxiety, and stress ; and the Snaith-Hamilton Pleasure Scale (SHAPS): To evaluate the inability to experience pleasure.
• Procedure EEG
  Electroencephalography

Primary outcome measures

• Acceptance rates (from 0 to 100 % of acceptance) for behavioral outcomes. Connectivity and oscillatory changes for neural activity [Time frame: Up to 6 months]
• Reaction times (in ms) for behavioral outcomes. Connectivity and oscillatory changes for neural activity [Time frame: Up to 6 months]

Secondary outcome measures (2)

• fMRI connectivity [Time frame: Up to 6 months]
• EEG-measured synchrony [Time frame: Up to 6 months]

Eligibility criteria

Inclusion criteria

• Healthy volunteers aged between 18 and 40 years
• Participants without confounding factors such as neural alterations related to neurological pathology, whether neurodegenerative (e.g., Alzheimer, Parkinson, Huntington, multiple sclerosis, amyotrophic lateral sclerosis), motor (e.g., dystonia, essential tremors, cerebellar syndrome), traumatic (e.g., traumatic brain injury, medulla lesion) or psychiatric pathologies, whether mood disorders (e.g., depression, bipolarity), anxious troubles (e.g., obsessional compulsive disorder, post-traumatic stress disorder), psychotic (e.g., schizophrenia, delusion), substance-related (e.g., alcool, drug or medicine addiction), food-related (e.g., anorexia, bulimia), neurodevelopmental (e.g., autism, attention-deficit with hyperactivity disorder) or personality (e.g., borderline personality disorder, antisocial personality disorder, obsessive-compulsive disorder).
• Participants affiliated with a compulsory social security scheme.

Exclusion criteria

• Persons deprived of liberty by judicial or administrative decisions.
• Pregnant women, women in labor or breastfeeding women
• Persons admitted to a health or social institution for purposes other than research.
• Adults under legal protection measures (e.g., guardianship or curatorship).
• Participation in other interventional research with an ongoing non-inclusion period.
• Neurological or psychiatric disorders.
• Use of tricyclic antidepressants (amitriptyline, clomipramine, imipramine, nortriptyline), neuroleptics (chlorpromazine, haloperidol, risperidone, olanzapine, quetiapine), or recreational drugs within the past 48 hours.
• Regular use of recreational drugs.
• Sleep deprivation (< 5 hours regularly over the last 3 months)
• Left-handedness or ambidexterity.
• Physical injuries impacting motor tasks.
• Presence of metal implants in the head (excluding oral fillings).
• Presence of implanted medical devices (e.g., pacemaker).
• Presence of metallic injuries in the eyes.
• Claustrophobia.
• Piercings incompatible with MRI procedures.
• Contraindication to MRI
• Persons who refused to be informed of eventual medical anomalies discovered by the MRI
• Personal or family history (first-degree relatives) of epilepsy or seizures. Severe and/or frequent headaches (only for participants receiving transcranial magnetic stimulation, e.g preparatory experience 1 and experience 1)
• Baldness impeding electrode placement (only for participants receiving transcranial electrical stimulation and EEG measurements, e.g experiments 2, 3 and 4)
• Facial or ear pain and/or recent ear trauma (only for participants receiving transcutaneous vagal nerve stimulation, e.g experiment 5)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Basic science

Study locations

France · 1 center

• Equipe ImpAct CRNL, INSERM U1028 CNRS UMR 5292 — Bron

Identifiers

NCT: NCT07251816 · 69HCL25_0205 · 2025-A00984-45

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗