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)

In our previous in vivo proton magnetic resonance spectroscopy ((1)H 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 (1)H 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).

[1]  Anthony K. P. Jones,et al.  The cortical representation of pain , 1999, PAIN.

[2]  C. Spielberger,et al.  Manual for the State-Trait Anxiety Inventory , 1970 .

[3]  Karen Faith Berman,et al.  Unilateral decrease in thalamic activity observed with positron emission tomography in patients with chronic neuropathic pain , 1995, Pain.

[4]  J. Mann,et al.  The functional neuroanatomy of mood disorders. , 1997, Journal of psychiatric research.

[5]  J. Kessler,et al.  Relation Between 1H MR Spectroscopic Imaging and Regional Cerebral Glucose Metabolism in Alzheimer's Disease , 2001, The International journal of neuroscience.

[6]  J. Coyle,et al.  Quantitative in vivo 1H nuclear magnetic resonance spectroscopic imaging of neuronal loss in rat brain , 1995, Neuroscience.

[7]  G. Moore,et al.  Neuroplasticity and cellular resilience in mood disorders , 2000, Molecular Psychiatry.

[8]  B. Miller.  A review of chemical issues in 1H NMR spectroscopy: N‐acetyl‐l‐aspartate, creatine and choline , 1991, NMR in biomedicine.

[9]  D. Perani,et al.  Chronic pain: a PET study of the central effects of percutaneous high cervical cordotomy , 1991, Pain.

[10]  M. Raichle,et al.  Subgenual prefrontal cortex abnormalities in mood disorders , 1997, Nature.

[11]  L. Selemon,et al.  Reductions in neuronal and glial density characterize the dorsolateral prefrontal cortex in bipolar disorder , 2001, Biological Psychiatry.

[12]  J C Froment,et al.  Allodynia after lateral-medullary (Wallenberg) infarct. A PET study. , 1998, Brain : a journal of neurology.

[13]  H C de Vet,et al.  Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy. , 2000, The New England journal of medicine.

[14]  A. Vania Apkarian,et al.  Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study , 2000, Pain.

[15]  Yasuhiro Shimada,et al.  ANGIOTENSIN - CONVERTING ENZYME GENE POLYMORPHISM IN PATIENTS WITH NEUROPATHIC PAIN , 1998 .

[16]  B. Roth,et al.  Morphometric evidence for neuronal and glial prefrontal cell pathology in major depression∗ ∗ See accompanying Editorial, in this issue. , 1999, Biological Psychiatry.

[17]  Krishna Kumar,et al.  Deep brain stimulation for intractable pain: a 15-year experience. , 1997, Neurosurgery.

[18]  M. Altemus,et al.  Biochemical Hypotheses of Mood and Anxiety Disorders , 1999 .

[19]  Mark A. Brown,et al.  Clinical MR Spectroscopy: First Principles , 1997 .

[20]  J. Mazziotta,et al.  Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder. , 1988, The American journal of psychiatry.

[21]  Jen-Chuen Hsieh,et al.  Central representation of chronic ongoing neuropathic pain studied by positron emission tomography , 1995, PAIN®.

[22]  P. Molinoff,et al.  Basic Neurochemistry: Molecular, Cellular and Medical Aspects , 1989 .

[23]  Jen-Chuen Hsieh,et al.  Right-lateralised central processing for pain of nitroglycer-induced cluster headache , 1996, PAIN.

[24]  H. Sackeim,et al.  Functional brain circuits in major depression and remission. , 2001, Archives of general psychiatry.

[25]  G. Rajkowska,et al.  Postmortem studies in mood disorders indicate altered numbers of neurons and glial cells , 2000, Biological Psychiatry.

[26]  H. Tallan.  Studies on the distribution of N-acetyl-L-aspartic acid in brain. , 1957, The Journal of biological chemistry.

[27]  Karl J. Friston,et al.  Statistical parametric mapping with 18F-dopa PET shows bilaterally reduced striatal and nigral dopaminergic function in early Parkinson’s disease , 1999, Journal of neurology, neurosurgery, and psychiatry.

[28]  A. Apkarian,et al.  Cortical representation of pain: functional characterization of nociceptive areas near the lateral sulcus , 2000, Pain.

[29]  M. Hallett,et al.  Mechanism of action of deep brain stimulation. , 2000, Neurology.

[30]  Michael J. Berridge,et al.  Neural and developmental actions of lithium: A unifying hypothesis , 1989, Cell.

[31]  F. Mauguière,et al.  Parietal and cingulate processes in central pain. A combined positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) study of an unusual case , 2000, Pain.

[32]  E. Adalsteinsson,et al.  Decreased dorsolateral prefrontal N-acetyl aspartate in bipolar disorder , 1998, Biological Psychiatry.

[33]  A. Apkarian,et al.  Dissociating anxiety from pain: mapping the neuronal marker N-acetyl aspartate to perception distinguishes closely interrelated characteristics of chronic pain , 2001, Molecular Psychiatry.

[34]  M. Castillo,et al.  Proton MR spectroscopy in neoplastic and non-neoplastic brain disorders. , 1998, Magnetic resonance imaging clinics of North America.

[35]  W. Drevets,et al.  Functional neuroimaging studies of depression: the anatomy of melancholia. , 1998, Annual review of medicine.

[36]  A. Beck,et al.  Beck Anxiety Inventory. , 1997 .

[37]  W. Willis.  Hyperalgesia and allodynia , 1992 .

[38]  C. L. Kwan,et al.  Thalamic stimulation and functional magnetic resonance imaging: localization of cortical and subcortical activation with implanted electrodes. Technical note. , 1999 .

[39]  N. Alpert,et al.  Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. , 1994, Archives of general psychiatry.

[40]  K. Wilson,et al.  Alternative diagnostic criteria for major depressive disorder in patients with chronic pain , 2001, Pain.

[41]  Ronald Melzack,et al.  The short-form McGill pain questionnaire , 1987, Pain.

[42]  A. Kupsch,et al.  Striatal dopaminergic metabolism is increased by deep brain stimulation of the subthalamic nucleus in 6-hydroxydopamine lesioned rats , 2001, Neuroscience Letters.

[43]  Stuart W. G. Derbyshire,et al.  Meta-Analysis of thirty-four independent samples studied using PET reveals a significantly attenuated central response to noxious stimulation in clinical pain patients , 1999, Current review of pain.

[44]  C. Frith,et al.  Central nervous pathways mediating angina pectoris , 1994, The Lancet.

[45]  N. Logothetis,et al.  Neurophysiological investigation of the basis of the fMRI signal , 2001, Nature.

[46]  A. Pfefferbaum,et al.  N-Acetyl Aspartic Acid (NAA) and N-Acetyl Aspartylglutamic Acid (NAAG) in Human Ventricular, Subarachnoid, and Lumbar Cerebrospinal Fluid , 1999, Neurochemical Research.

[47]  Yudong D. He,et al.  Microarrays—the 21st century divining rod? , 2001, Nature Medicine.

[48]  J. Kleinman,et al.  Reduced frontal cortex inositol levels in postmortem brain of suicide victims and patients with bipolar disorder. , 1997, The American journal of psychiatry.

[49]  A. Apkarian,et al.  Anxiety in healthy humans is associated with orbital frontal chemistry , 2000, Molecular Psychiatry.

[50]  K. Berman,et al.  Global Cerebral Blood Flow Decreases during Pain , 1998, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[51]  F Gonzalez-Lima,et al.  Energy Hypometabolism in Posterior Cingulate Cortex of Alzheimer's Patients: Superficial Laminar Cytochrome Oxidase Associated with Disease Duration , 2001, The Journal of Neuroscience.

[52]  C. Weiller,et al.  Brain stem activation in spontaneous human migraine attacks , 1995, Nature Medicine.

[53]  J. Gybels,et al.  Positron emission tomography study of a chronic pain patient successfully treated with somatosensory thalamic stimulation , 2000, Pain.

[54]  J. Dostrovsky,et al.  Activation of the anterior cingulate cortex by thalamic stimulation in patients with chronic pain: a positron emission tomography study , 2000 .

[55]  Simon R. Cherry,et al.  Deficits in Striatal Dopamine D2 Receptors and Energy Metabolism Detected by in Vivo MicroPET Imaging in a Rat Model of Huntington's Disease , 2000, Experimental Neurology.