Emotion and Memory in Chronic Neuropathic Pain

Recruiting

• Conditions: Facial Pain; Trigeminal Neuralgia
• Interventions: Behavioral: Neuropsychological assessments; Diagnostic Test: MR Imaging

• Registration Number: NCT06518421
• Lead Sponsor: University Health Network, Toronto

Brief Summary

Chronic pain affects one in four Canadians, leading to severe personal and societal costs. Over 70% of chronic pain patients report memory difficulties and fear having unexpected pain. Abnormalities in brain structures associated with emotion and memory, including the hippocampus and amygdala, can be affected by chronic pain. Understanding the relationship between chronic pain, structural brain changes, and cognitive functioning will lead to improved diagnosis, treatment, and outcomes in chronic pain disorders. In this project, the investigators will use advanced brain imaging techniques that assess the structure and function of the brain along with cognitive assessments to examine the overlap between chronic pain and emotion-memory processes. The study team will conduct the study using an excellent model of chronic pain-trigeminal neuralgia, a severe form of facial pain that responds well to surgical treatment. Brain images and cognitive data will be collected from participants before and after surgical treatment for pain. This information will be analyzed and compared with age- and sex-matched healthy individuals. This study will be the first to thoroughly investigate relationships between brain structure and function, cognition (memory, emotion), and promises to impact our understanding of chronic neuropathic pain conditions.

Detailed Description

Chronic pain affects 1 in 4 Canadians leading to severe personal and societal consequences. Over 70% of patients with chronic pain report cognitive deficits including memory difficulties and fear of having unexpected pain. However, the impact of chronic pain on cognition has not been adequately studied. Trigeminal neuralgia (TN), a severe facial pain with clear surgical outcomes, is an ideal model to address this question. Limbic structures, including the hippocampus (HPC) and amygdala (AMG), link emotion-memory and pain. Our prior CIHR-funded research revealed significant HPC volume reduction that normalized with successful treatment and abnormal HPC activity and AMG volume in chronic pain. These findings provide the foundation for a better understanding of the limbic subcortical structures and neuronal mechanisms of chronic pain.

Multimodal neuroimaging techniques have emerged as important tools for studying brain abnormalities in TN - seeking to elucidate the underlying neural mechanisms of HPC and AMG alterations, along with emotion-memory processes. This will be the first comprehensive study of limbic subcortical structural alterations and cognition in chronic pain.

Goal(s)/Research Aims

Our overall goal is to uncover the underlying neural mechanism of HPC and AMG alteration in TN and how these relate to chronic pain pathophysiology and cognition. Our specific aims are:

1. To characterize abnormalities in HPC subfields and their associated link with memory-specific performance in TN patients and their potential resolution following surgery.

2. To investigate the role of the AMG in pain-related fear in TN patients pre- and post-surgery and their associated link with the treatment outcomes.

3. To determine the relationship between the alterations in HPC subfields and the amygdaloid complex, and emotion-memory processes in TN patients pre- and post-surgery.

Methods/Approaches/Expertise The investigators will prospectively analyze brain imaging, clinical, and cognitive data from 340 participants (170 TN and 170 healthy age-/sex-matched controls). Patients will be scanned and assessed pre- and 6 months post-surgical treatment for TN.

In Aim 1, HPC subfield volumes will be extracted to characterize regional abnormalities in TN patients. The investigators will use HPC-sensitive memory tasks, including the mnemonic similarity task and the Rey Auditory Verbal Learning Test , to explore whether the HPC-specific memory processes correlate with structural abnormalities outlined.

In Aim 2, AMG nuclei volumes will be extracted to characterize regional abnormalities in TN patients. Fear of pain questionnaires and the Pain Catastrophizing Scale will be used to explore the link between pain-related fear and chronic pain.

In Aim 3, a validated fMRI task designed for episodic simulation based on novel word-pain associations will be used to examine the relationship between the abnormalities in the HPC subfields and AMG nuclei, and emotion-memory processes in TN patients pre- and post-surgery.

The NPA is a neurosurgeon and scientist with a strong clinical research focus on chronic pain. The team has expertise in chronic pain, brain imaging, cognition, and multivariate statistics.

Expected Outcomes Our innovative proposal interfaces brain imaging with cognition. Knowledge of the relationships between limbic structures, cognition, and pain will revolutionize pain assessment and treatment decisions. Uncovering neural mechanisms of HPC- and AMG-related structures in pain may improve healthcare delivery and patient outcomes by providing objective insights complementing current clinical care.

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2024-02-12
• Study First Submitted: 2024-03-01
• Status Verified: 2024-07
• Study First Submitted QC: 2024-07-23
• Last Update Submitted: 2024-07-23
• Study First Posted: 2024-07-24
• Last Update Posted: 2024-07-24
• Primary Completion: 2027-02-12
• Study Completion: 2029-02-12

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 400

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Trigeminal Neuralgia	Neuropsychological assessments	Trigeminal Neuralgia is the most common chronic neuropathic facial pain disorder, characterized by the sudden onset of intermittent, intense, shock-like pain in distributions of the trigeminal nerve branches. TN has several unique features that distinguish it as an ideal model for the study of chronic pain: TN is largely unilateral; is severe in its nature; has stereotypical presentation among patients; and is not associated with other sensory deficits observed in other chronic pain disorders, such as numbness. Brain imaging, clinical data, and cognitive data will be prospectively collect and analyze in both healthy control and patients with trigeminal neuralgia groups. Prospective data collection for TN group includes: * MRI scan (2 timepoints; pre- and 6-month post-surgery) * Neuropsychological assessments (2 timepoints; pre- and 6-month post-surgery)
Healthy Controls	MR Imaging	Brain imaging, clinical data, and cognitive data will be prospectively collect and analyze in both healthy control and patients with trigeminal neuralgia groups. Prospective data collection for control group includes: * MRI scan (1 timepoint) * Neuropsychological assessments (1 timepoint)
Trigeminal Neuralgia	MR Imaging	Trigeminal Neuralgia is the most common chronic neuropathic facial pain disorder, characterized by the sudden onset of intermittent, intense, shock-like pain in distributions of the trigeminal nerve branches. TN has several unique features that distinguish it as an ideal model for the study of chronic pain: TN is largely unilateral; is severe in its nature; has stereotypical presentation among patients; and is not associated with other sensory deficits observed in other chronic pain disorders, such as numbness. Brain imaging, clinical data, and cognitive data will be prospectively collect and analyze in both healthy control and patients with trigeminal neuralgia groups. Prospective data collection for TN group includes: * MRI scan (2 timepoints; pre- and 6-month post-surgery) * Neuropsychological assessments (2 timepoints; pre- and 6-month post-surgery)
Healthy Controls	Neuropsychological assessments	Brain imaging, clinical data, and cognitive data will be prospectively collect and analyze in both healthy control and patients with trigeminal neuralgia groups. Prospective data collection for control group includes: * MRI scan (1 timepoint) * Neuropsychological assessments (1 timepoint)

Primary Outcome Measures

Name	Time	Method
Behavioural Inhibition System	For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria	The Behavioural Inhibition System (BIS) will be included in our battery of neuropsychological assessments that will be conducted on both HC and TN groups to screen for study inclusion and exclusion criteria. The BIS is a 20 question, self-assessment that measures trait sensitivity levels of the behavioral inhibition and activation systems.
Beck's Hopelessness Scale	For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria	The Beck Hopelessness Scale (BHS) will be included in our battery of neuropsychological assessments that will be conducted on both HC and TN groups to screen for study inclusion and exclusion criteria.
Childhood Trauma Questionnaire	For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria	The Childhood Trauma Questionnaire (CTQ) will be included in our battery of neuropsychological assessments that will be conducted on both HC and TN groups to screen for study inclusion and exclusion criteria.
Pain Catastrophizing Scale	For HC > pain-related fear and anxiety assessments at baseline. For TN >> pain-related fear and anxiety assessments at baseline (pre-surgery) and at 6-month post-surgical	The Pain Catastrophizing Scale (PCS) will be used as one of the pain-related fear and anxiety assessments to assess pain-related fear and anxiety in TN and HC groups. The investigators will assess whether the abnormalities of the AMG nuclei volume will be normalized after surgery and will correlate these findings with validated pain-related fear and anxiety assessments. The PCS will help investigators quantify an individual's pain - how they feel and what they think about when experiencing something painful.
Beck Depression Inventory	For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria	The Beck Depression Inventory (BDI) will be included in our battery of neuropsychological assessments that will be conducted on both HC and TN groups to screen for study inclusion and exclusion criteria. The BDI consists of 21 questions on which patients must score themselves on a scale from zero to three. The BDI is scored out of 63 with a score over 31 representing severe depression.
Pain Anxiety Symptoms Scale	For HC > pain-related fear and anxiety assessments at baseline. For TN >> pain-related fear and anxiety assessments at baseline (pre-surgery) and at 6-month post-surgical	The Pain Anxiety Symptoms Scale (PASS-20) will be used as one of the pain-related fear and anxiety assessments to assess pain-related fear and anxiety in TN and HC groups. The investigators will assess whether the abnormalities of the AMG nuclei volume will be normalized after surgery and will correlate these findings with validated pain-related fear and anxiety assessments. The Pass-20 is a 20 item assessment that measures 4 distinct components of pain-related anxiety.
Anxiety Sensitivity Index	For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria	The Anxiety Sensitivity Index (ASI) will be included in our battery of neuropsychological assessments that will be conducted on both HC and TN groups to screen for study inclusion and exclusion criteria. The ASI is a six item scale that can outline different concerns someone could have regarding their anxiety.
Structural magnetic resonance imaging (MRI)	For HC > MRI at baseline. For TN > MRI at baseline (pre-surgery) and at 6-month post-surgical)	The investigators will acquire prospective longitudinal structural imaging data in 170 Trigeminal Neuralgia (TN) (pre-/6-months post-surgery) and 170 healthy controls (HC) and obtain topologies and volumes of the hippocampus (HPC) subfields using the brain imaging analysis software including HippUnfold and FreeSurfer. The investigators will also analyze amygdala (AMG) nuclei volumes using FreeSurfer. The group comparisons of the HPC and AMG will be done in both inter-group (TN vs. HC) and intra-group (pre- vs. post-surgery).
Mnemonic Similarity Test	For HC > MRI at baseline. For TN > MRI at baseline (pre-surgery) and at 6-month post-surgical)	The Mnemonic Similarity Test will be used to compare HPC-dependent memory performance between TN and HC and examine the effect of surgery (pre- and post-) on performance. The investigators will assess whether HPC-dependent memory and HPC volumes/topologies normalize following surgical TN pain relief.
Recalled pain memory interview	For HC > recalled pain at baselines. For TN >> recalled pain at baseline (pre-surgery) and at 2 weeks and 6-month post-surgery	The recalled pain interview, focused on the recall of pain events, will be conducted and analyzed with a specific focus on the discrepancies in pain recall (referred to as autobiographical memory, AM). Recalled Pain questionnaires will take place at baseline (\~1 week prior to surgery, for the recall of pain onset and experience), acute recovery (2 weeks post-surgery) and 6 months post-surgery for recalled pain. These interview questionnaires will assess pain frequency, duration, intensity, fear, anxiety, unpleasantness, and interference.
Marlowe Crowne Scale	For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria	The Marlowe Crowne Scale (MCS) will be included in our battery of neuropsychological assessments that will be conducted on both HC and TN groups to screen for study inclusion and exclusion criteria.
Fear of Pain Questionnaire III	For HC > pain-related fear and anxiety assessments at baseline. For TN >> pain-related fear and anxiety assessments at baseline (pre-surgery) and at 6-month post-surgical	The Fear of Pain Questionnaire III (FPQ-III) will be used as one of the pain-related fear and anxiety assessments to assess pain-related fear and anxiety in TN and HC groups. The investigators will assess whether the abnormalities of the AMG nuclei volume will be normalized after surgery and will correlate these findings with validated pain-related fear and anxiety assessments. The FPQ-III is a 30 item assessment on which individuals rate how fearful they are of certain pain experiences on a scale from one to five.
State-Trait Anxiety Inventory	For HC > pain-related fear and anxiety assessments at baseline. For TN >> pain-related fear and anxiety assessments at baseline (pre-surgery) and at 6-month post-surgical	The State-Trait Anxiety Inventory (STAI) will be used as one of the pain-related fear and anxiety assessments to assess pain-related fear and anxiety in TN and HC groups. The investigators will assess whether the abnormalities of the AMG nuclei volume will be normalized after surgery and will correlate these findings with validated pain-related fear and anxiety assessments. The STAI is commonly used to measure trait and state anxiety. This assessment consists of 20 items for assessing trait anxiety and 20 for state anxiety, each of which are rated on a 4-point scale.
Functional Magnetic Resonance Imaging (fMRI)	For HC >ES task-fMRI at baseline. For TN >> ES task-based fMRI at baseline (pre-surgery) and 6-months post-surgery	The experimental functional magnetic resonance imaging (fMRI) task that is specifically designed to measure episodic simulation (ES) using both neutral and pain-related cues will be conducted. ES measures the capacity to imagine specific future personal events and is heavily dependent on limbic integrity. This, along with the recalled pain memory interview will allow the investigators to correlate task-based fMRI findings with pain-recall discrepancies (discrepancies between recalled and initial pain ratings) and surgical response.

Secondary Outcome Measures

Name	Time	Method
The Rey Auditory Verbal Learning Test (RAVLT)	For HC > RAVLT at baseline. For TN > RAVLT at baseline (pre-surgery) and at 6-month post-surgical)	Group correlation between other HPC subfield volumes and a second HPC-specific memory task using the Rey Auditory Verbal Learning Test (RAVLT) will be performed to evaluate multiple episodic memory functions in both inter-group (TN vs. HC) and intra-group (pre- vs. post-surgery).
Whole brain cortical-based analysis	For HC > MRI at baseline. For TN > MRI at baseline (pre-surgery) and at 6-month post-surgical)	Group comparisons of other limbic structures will be performed, using the whole brain cortical-based analysis with a focus on the thickness of the anterior cingulate (ACC), insular, and medial prefrontal cortex (mPFC) cortices. The investigator will be focused on the dynamic changes of the cortical thickness in TN between i) TN vs. HC, and ii) pre- vs. post-surgical time points.
Sex- and gender-based analysis (SGBA)	For HC ad TN > SGBA at baseline as a part of the demographic data	The investigator will target enrollment of a 50% male-to-female ratio. The investigator will also collect the gender identity data. SGBA will be conducted in all Aims and the distribution of gender data will determine whether we have sufficient power for detailed analyses.
Structural Magnetic Resonance Imaging Cont.	For HC > MRI at baseline. For TN > MRI at baseline (pre-surgery) and at 6-month post-surgical)	Group correlation between other AMG nuclei volumes and pain-related fear and anxiety questionnaires will be performed. The investigators will assess whether the abnormalities of other AMG nuclei volumes will be normalized after surgery and/or correlated with the validated pain-related fear and anxiety assessments.
Impact of COVID-19 on pain population	For HC > COVID-19 related data at baseline. For TN > COVID-19 related data at baseline (pre-surgery) and at 6-month post-surgical)	Medical and medication history including COVID-19-related experiences will be collected. The investigator will also address the biopsychological impacts of COVID-19 in our study cohort.

Trial Locations

Locations (1)

Toronto Western Hospital; 🇨🇦 Toronto, Ontario, Canada