Emotion and Memory in Chronic Neuropathic Pain

Official title

The Role of Limbic Subcortical Structures and Cognition in Chronic Neuropathic Pain

Overview

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.

Interventions

• Behavioral Neuropsychological assessments
  * 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 * Mnemoni
• Diagnostic test MR Imaging
  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.

Primary outcome measures

• Beck Depression Inventory [Time frame: For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria]
• Behavioural Inhibition System [Time frame: For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria]
• Anxiety Sensitivity Index [Time frame: For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria]
• Beck's Hopelessness Scale [Time frame: For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria]
• Marlowe Crowne Scale [Time frame: For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria]
• Childhood Trauma Questionnaire [Time frame: For HC and TN > Neuropsychological assessments at baseline to screen for inclusion/exclusion criteria]
• Structural magnetic resonance imaging (MRI) [Time frame: For HC > MRI at baseline. For TN > MRI at baseline (pre-surgery) and at 6-month post-surgical)]
• Mnemonic Similarity Test [Time frame: For HC > MRI at baseline. For TN > MRI at baseline (pre-surgery) and at 6-month post-surgical)]
• Fear of Pain Questionnaire III [Time frame: 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]
• Pain Catastrophizing Scale [Time frame: 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]

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)]
• 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)]
• 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)]
• 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)]
• Sex- and gender-based analysis (SGBA) [Time frame: For HC ad TN > SGBA at baseline as a part of the demographic data]

Eligibility criteria

Inclusion Criteria (for HC and TN):

• 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)

Inclusion Criteria for TN:

• Experiencing TN pain over a period of 6 months
• Stable medication use
• Meet established diagnostic criteria for TN (ICHD-3)

Exclusion Criteria (both HC and TN):

• 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

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

Healthy volunteers: Yes

Study design

Observational model

Cohort

Study locations

Canada · 1 center

• Toronto Western Hospital — Toronto

Publications

• Noorani A, Hung PS, Zhang JY, Sohng K, Laperriere N, Moayedi M, Hodaie M. Pain Relief Reverses Hippocampal Abnormalities in Trigeminal Neuralgia. J Pain. 2022 Jan;23(1):141-155. doi: 10.1016/j.jpain.2021.07.004. Epub 2021 Aug 8. PMID 34380093
• 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. PMID 34087549
• Vaculik MF, Noorani A, Hung PS, Hodaie M. Selective hippocampal subfield volume reductions in classic trigeminal neuralgia. Neuroimage Clin. 2019;23:101911. doi: 10.1016/j.nicl.2019.101911. Epub 2019 Jun 26. PMID 31491821
• Audrain S, McAndrews MP. Schemas provide a scaffold for neocortical integration of new memories over time. Nat Commun. 2022 Oct 2;13(1):5795. doi: 10.1038/s41467-022-33517-0. PMID 36184668
• 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. PMID 35692557
• Noel M, Rosenbloom B, Pavlova M, Campbell F, Isaac L, Page MG, Stinson J, Katz J. Remembering the pain of surgery 1 year later: a longitudinal examination of anxiety in children's pain memory development. Pain. 2019 Aug;160(8):1729-1739. doi: 10.1097/j.pain.0000000000001582. PMID 31335643

Identifiers

NCT: NCT06518421 · 14-7350

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗