Distinct Roles of Anterior and Posterior Insula Glutamate in Chronic Pain

Richard E. Harris, Ph.D.

University of Michigan, Ann Arbor, MI, The Chronic Pain and Fatigue Research Center

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

December 2008, for 3 years

Funding Amount:


Lay Summary

Severity of Pain and Mood Disturbance in Patients Diagnosed with Fibromyalgia May Relate to Insular Glutamate Levels as Measured by H-MRS Imaging

Researchers will use H-MRS imaging in patients with fibromyalgia to determine whether reduction of the excitatory neurotransmitter glutamate in the insula (a specific area of the brain) is associated with decreased sensations of pain and related mood dysfunction in this disorder.

Fibromyalgia is a chronic pain disorder thought to result from a disturbance in the way the central nervous system processes pain.  These patients spontaneously report pain throughout their bodies even though there is no inflammatory or anatomical damage.  In addition to chronic pain, patients also suffer from related mood disturbances such as anxiety and depression.  The Michigan investigators and others have recently shown that fibromyalgia patients may have heightened neural activity in a region of the brain called the insula, and that this excess activity may be related to elevated levels of the excitatory neurotransmitter glutamate.  The insula is a complex brain structure with diverse functions that include processing pain, regulating emotion, and facilitating the sense of self-awareness.

Recent research suggests that the anterior and posterior portions of the insula carry out different functions, with posterior neurons coordinating sensory aspects of pain while anterior neurons process related mood disturbances and anxiety.  The Michigan researchers hypothesize, therefore, that reducing glutamate in these separate portions of the insula will correlate with reduced pain and anxiety, respectively.  They will explore this hypothesis using H-MRS imaging (proton magnetic resonance spectroscopy).  This imaging method measures concentrations of specific brain metabolites, in this case glutamate, in defined brain areas.  They will undertake H-MRS imaging in 20 fibromyalgia patients before and following a one-month course of acupuncture treatment, which has been demonstrated to reduce pain within a relatively short period.  Changes in glutamate levels in the anterior and posterior insula will be correlated with measures of patients’ anxiety and pain levels, respectively.


Distinct Roles of Anterior and Posterior Insula Glutamate in Chronic Pain

The insula is a complex brain structure that has developed rapidly throughout primate evolution. Its functions are diverse, ranging from pain processing and emotional regulation to more complex behaviors such as interoception or the sense of “self-awareness.” Topographically, pain and emotional processing within this structure are thought to occur in different regions. Posterior insula neurons are thought to coordinate sensory discriminative aspects of pain, whereas more anterior regions are thought to process affective dimensions of pain as well as anxiety and possibly interoception. Recently our group and others have shown that the insula is a locus of heightened neural activity in fibromyalgia (FM), a common chronic pain syndrome. This finding may result from the presence of elevated levels of glutamate (Glu), an excitatory neurotransmitter, within the cerebrospinal fluid and insulae of these patients.

The aim of this proposal is to demonstrate in FM patients that reduction of Glu within the posterior insula is associated with decreases in the sensory discriminative aspects of pain whereas reduction of Glu within in the anterior insula parallels decreases in co-morbid mood disturbance. To achieve our aim we will use proton magnetic resonance spectroscopy (H-MRS), a non-invasive neuroimaging method that can measure in vivo concentrations of specific brain metabolites. H-MRS will be done before and following a non-pharmacological treatment designed to reduce pain and anxiety in FM patients. Results from this trial will point towards a topographic distribution of insular glutamatergic neurotransmission for processing separate dimensions of pain and mood disturbance in chronic pain patients.

Investigator Biographies

Richard E. Harris, Ph.D.

Richard Harris, Ph. D., is a research assistant professor in the Department of Anesthesiology at the University of Michigan.  His background is in basic science and clinical research in alternative medicine.  He received his B.S. degree in genetics from Purdue University in 1992 and his Ph. D. in molecular and cellular biology from UC Berkeley in 1997.

Following his graduate work, he completed a postdoctoral fellowship at NIH studying the rhythmic properties of neural cultures.  In 2002 he graduated from the Maryland Institute of Traditional Chinese Medicine where he studied acupuncture and other aspects of Chinese medicine.  In 2005 he completed an M.S. degree from the University of Michigan in clinical research and statistical analysis.  He is currently investigating central neurobiological mechanisms of acupuncture and pharmacologic therapy in the treatment of chronic pain conditions.