Emotion and Memory in Chronic Neuropathic Pain
ID: NCT06518421
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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.
Read Full Scientific Objectives & Methods
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.
* Pain questionnaires such as Numerical Pain Rating Scale is one of the most widely used multidimensional pain scales to assesses a person's pain based on the words they use to describe their pain. * Battery of Cognitive questionnaires = The cognitive test battery was designed to assess key cognitive abilities including attention, concentration, verbal learning and memory, verbal fluency, working memory and executive function as well as global cognitive functioning and fear and anxiety * Mnemonic Simulation Test and Rey Auditory Verbal Learning Test are the neuropsychological assessments designed to evaluate recognition and verbal memory, respectively. Both tasks have been shown to be very sensitive to hippocampal engagement and damage. * Memory-recall interview is an interview for the interviewees to recall the event from different perspectives, such as from the preadmission date, 2-week post- and 6-month post-surgical date. This supports the memory retrieval process.
Magnetic Resonance Imaging is a noninvasive medical imaging test that produces detailed images of almost every internal structure in the human body, including the organs, bones, muscles and blood vessels. MRI scanners create images of the body using a large magnet and radio waves.
Treatment Arms Description
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 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)
- Age between 35 and 60 years old
- Absence of other active major neurological or psychiatric disorders
- Absence of MRI contraindications
- Able to communicate sufficiently to complete tasks and questionnaires
- Montreal Cognitive Assessment (MoCA) score greater than 23/30 (MoCA ≤23/30 could indicate severe cognitive impairment)
- Experiencing TN pain over a period of 6 months
- Stable medication use
- Meet established diagnostic criteria for TN (ICHD-3)
- Presence of other chronic pain/headache conditions
- Untreated hypertension or diabetes mellitus
- History of chronic drug or substance use disorder, chronic use of opioids or steroids, head trauma affecting cognitive performance,
- History/presence of active psychiatric illness and/or current use of psychoactive medication
- History of multiple sclerosis, skull base injury or tumours
Primary Outcome Measures
- Beck Depression Inventory — Time Frame: 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.
- Behavioural Inhibition System — Time Frame: 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.
- Anxiety Sensitivity Index — Time Frame: 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.
- Beck's Hopelessness Scale — Time Frame: 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.
- Marlowe Crowne Scale — Time Frame: 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.
- Childhood Trauma Questionnaire — Time Frame: 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.
View Secondary Outcome Measures (5)
- Structural Magnetic Resonance Imaging Cont. — Time Frame: 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.
- The Rey Auditory Verbal Learning Test (RAVLT) — Time Frame: 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 — Time Frame: 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.
- Impact of COVID-19 on pain population — Time Frame: 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.
- Sex- and gender-based analysis (SGBA) — Time Frame: 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.
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- Hung PS, Noorani A, Zhang JY, Tohyama S, Laperriere N, Davis KD, Mikulis DJ, Rudzicz F, Hodaie M. Regional brain morphology predicts pain relief in trigeminal neuralgia. Neuroimage Clin. 2021;31:102706. doi: 10.1016/j.nicl.2021.102706. Epub 2021 May 25.PubMed ↗
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- Waisman A, Pavlova M, Noel M, Katz J. Painful reminders: Involvement of the autobiographical memory system in pediatric postsurgical pain and the transition to chronicity. Can J Pain. 2022 Jun 3;6(2):121-141. doi: 10.1080/24740527.2022.2058474. eCollection 2022.PubMed ↗
View Official Medical/Scientific Title
The Role of Limbic Subcortical Structures and Cognition in Chronic Neuropathic Pain