Decreased Levels of N-Acetylaspartate in Dorsolateral Prefrontal Cortex in a Case of Intractable Severe Sympathetically Mediated Chronic Pain (Complex Regional Pain Syndrome, Type I)

doi:10.1006/brcg.2001.1489

Brain and Cognition

Volume 49, Issue 1, June 2002, Pages 102-113

https://doi.org/10.1006/brcg.2001.1489 Get rights and content

Abstract

In our previous in vivo proton magnetic resonance spectroscopy (¹H MRS) study we found reduced levels of N-acetylaspartate in dorsolateral prefrontal cortex of chronic back pain patients. This study tests whether these chemical abnormalities can be detected in other pain states. Using ¹H MRS, we measured levels for N-acetylaspartate and other identifiable chemicals relative to creatine in four bilateral brain regions, including dorsolateral prefrontal cortex, orbitofrontal cortex, cingulate, and thalamus, in a case of intractable severe sympathetically mediated chronic pain [complex regional pain syndrome (CRPS) type I]. The subject's chemical variations in the brain were compared to the same regional chemicals in 10 normal subjects (age- and sex-matched). Univariate statistics showed reduced levels of N-acetylaspartate in bilateral dorsolateral prefrontal cortex and increased levels of myo-inositol in left orbitofrontal cortex of the patient with intractable severe CRPS type I. These data support our original hypothesis that depletion of N-acetylaspartate in dorsolateral prefrontal cortex is a chemical marker of chronic pain, indicating for neuronal degeneration. Unpredicted changes of orbitofrontal myo-inositol may be related to the specific mood/affective state in an extreme pain perception. This is the first report, which identifies chemical markers in the prefrontal cortex for objective measurement and monitoring of CRPS type I. This information might lead to valuable insights into diagnosis and future effective interventions of CRPS type I (e.g., prefrontal brain stimulation).

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In some cases, these structural abnormalities were correlated with pain catastrophizing or other clinical characteristics.38 These findings are corroborated by magnetic resonance spectroscopy studies that have found decreased levels of N-acetyl-aspartate—a putative measure of neuronal viability—in the DLPFC in chronic back pain32 and complex regional pain syndrome.33 In some cases, these structural abnormalities were correlated with pain catastrophizing or other clinical characteristics.38
The dorsolateral prefrontal cortex (DLPFC) is a functionally and structurally heterogeneous region and a key node of several brain networks, implicated in cognitive, affective, and sensory processing. As such, the DLPFC is commonly activated in experimental pain studies, and shows abnormally increased function in chronic pain populations. Furthermore, several studies have shown that some chronic pains are associated with decreased left DLPFC gray matter and that successful interventions can reverse this structural abnormality. In addition, studies have indicated that noninvasive stimulation of the left DLPFC effectively treats some chronic pains. In this article, we review the neuroimaging literature regarding the role of the DLPFC and its potential as a therapeutic target for chronic pain conditions, including studies showing the involvement of the DLPFC in encoding and modulating acute pain and studies demonstrating the reversal of DLPFC functional and structural abnormalities after successful interventions for chronic pain. We also review studies of noninvasive brain stimulation of the DLPFC showing acute pain modulation and some effectiveness as a treatment for certain chronic pain conditions. We further discuss the network architecture of the DLPFC, and postulate mechanisms by which DLPFC stimulation alleviates chronic pain. Future work testing these mechanisms will allow for more effective therapies.
The structure and function of the DLPFC is abnormal in some chronic pain conditions. Upon successful resolution of pain, these abnormalities are reversed. Understanding the underlying mechanisms and the role of this region can lead to the development of an effective therapeutic target for some chronic pain conditions.
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Over the past two decades, modern brain imaging techniques such as functional magnetic resonance imaging, positron emission tomography (PET), magnetoencephalography (MEG), and electroencephalography (EEG) have revolutionized our understanding of pain. Using such tools, in conjunction with carefully conceived experimental manipulations and sophisticated image analysis methods, scientists have begun unraveling the complexities of the neural processes underlying the pain experience as well as its modulation by a variety of factors (e.g. cognitive or emotional state, genetic makeup, and pharmacological or behavioral interventions). Brain imaging studies are also contributing to a change in the way we perceive chronic pain, as they have revealed that the brains of patients with pain disorders are characterized by structural, functional, and neurochemical alterations, some of which might have causal roles in the pathophysiology of pain conditions. In this chapter, we will discuss the advances that neuroimaging studies have brought to our understanding of pain, as well as the limitations and future implications of research in this field. In particular, this chapter concentrates on magnetic resonance imaging (MRI) studies, with brief mention of other imaging techniques. While tools such as PET, single-photon emission computed tomography, MEG, EEG, and other techniques have undoubtedly provided significant contributions to this field, MRI has arguably been proved to be among the most powerful techniques for the investigation of pain processing, given that it allows for the assessment of functional, structural, perfusion, connectivity, and neurochemical correlates of pain.
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Furthermore, the vSM deviation did not correlate with pain intensity in the present or in previous studies [50,51,54]. Particularly in CRPS, unilateral pain was demonstrated to (bilaterally) suppress the sensory processing of sensory stimuli in the somatosensory cortex from the affected hand rather than exaggerating it [16,24,29,30,38,45]. In the construction of the egocentric reference frame, the hand plays an important role as visuomotor transformation device, providing an arm-centred reference frame [15,48,54].
Recently, a shift of the visual subjective body midline (vSM), a correlate of the egocentric reference frame, towards the affected side was reported in patients with complex regional pain syndrome (CRPS). However, the specificity of this finding is as yet unclear. This study compares 24 CRPS patients to 21 patients with upper limb pain of other origin (pain control) and to 24 healthy subjects using a comprehensive test battery, including assessment of the vSM in light and dark, line bisection, hand laterality recognition, neglect-like severity symptoms, and motor impairment (disability of the arm, shoulder, and hand). Statistics: 1-way analysis of variance, t-tests, significance level: 0.05. In the dark, CRPS patients displayed a significantly larger leftward spatial bias when estimating their vSM, compared to pain controls and healthy subjects, and also reported lower motor function than pain controls. For right-affected CRPS patients only, the deviation of the vSM correlated significantly with the severity of distorted body perception. Results confirm previous findings of impaired visuospatial perception in CRPS patients, which might be the result of the involvement of supraspinal mechanisms in this pain syndrome. These mechanisms might accentuate the leftward bias that results from a right-hemispheric dominance in visuospatial processing and is known as pseudoneglect. Pseudoneglect reveals itself in the tendency to perceive the midpoint of horizontal lines or the subjective body midline left of the centre. It was observable in all 3 groups, but most pronounced in CRPS patients, which might be due to the cortical reorganisation processes associated with this syndrome.
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^☆

Address correspondence and reprint requests to Igor D. Grachev, Department of Anesthesiology, SUNY Upstate Medical University, 750 E. Adams St., 4109 IHP, Syracuse, NY 13210. Fax: (315) 464-8476. E-mail: [email protected].

We thank N. Horton and G. Tillapaugh-Fay for technical assistance. This work was funded, after application, by the Hendricks Fund for Medical Research (Drs. Grachev and Ramachandran) and Research Initiative Fund in Radiology (Dr. Grachev) at SUNY Upstate Medical University, Syracuse, New York.

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Regular ArticleDecreased Levels of N-Acetylaspartate in Dorsolateral Prefrontal Cortex in a Case of Intractable Severe Sympathetically Mediated Chronic Pain (Complex Regional Pain Syndrome, Type I)☆

Abstract

Experimental Neurology

Cell

Magnetic Resonance Imaging Clinics of North America

Pain

Pain

Neuroscience

Pain

Pain

Pain

Pain

Neuroscience Letters

Pain

Pain

Biological Psychiatry

Biological Psychiatry

Biological Psychiatry

Lancet

Journal of Psychiatric Research

Pain

Pain

Pain

Biological Psychiatry

New directions for studying human brain pathophysiology of chronic pain states

Disability

Biochemical hypotheses of mood and anxiety disorders

Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder

American Journal of Psychiatry

Beck Depression Inventory

Beck Anxiety Inventory

Mechanism of action of deep brain stimulation

Neurology

The treatment of hyperalgesia following neural injury

Global cerebral blood flow decreases during pain

Journal of Cerebral Blood Flow Metabolism

Regular Article
Decreased Levels of N-Acetylaspartate in Dorsolateral Prefrontal Cortex in a Case of Intractable Severe Sympathetically Mediated Chronic Pain (Complex Regional Pain Syndrome, Type I)☆