Beyond Feeling: Chronic Pain Hurts the Brain, Disrupting the Default-Mode Network Dynamics

I have read with great interest the report by Baliki and colleagues describing increased prefrontal activity (“decreased deactivation”) during a cognitive paradigm in patients with chronic low back pain (Baliki et al., 2008). While the authors suggest their findings indicate that chronic pain alters brain function, by their own admission, study design disallows definitive mechanistic explanations. Excitatory prefrontal afferents preferentially target interneurons that inhibit mesolimbic projections (Carr & Sesack, 2000), while attenuated dopaminergic activity within the striatum augments nociceptive behavior (Altier & Stewart, 1999; Saadé et al, 1997). One would therefore anticipate that a predisposition towards increased prefrontal activity (i.e. “hyperfrontality”) would produce a proportional decrease in mesolimbic activity thereby augmenting nociception and, ostensibly, placing one at increased risk for developing chronic pain. Indeed, relative increases in prefrontal activity among healthy subjects correlate with increased subjective pain ratings (Coghill et al., 2003), and clinical pain states are likewise associated with prefrontal hyperactivity (Apkarian et al, 2001; Cook et al., 2004). Conversely, the inverse relationship between prefrontal activation and mesolimbic reactivity may underlie the observation that schizophrenia, which is associated with both hypofrontality (Andreasen et al., 1997) and mesolimbic hyperactivity (Bertolino et al., 1999), is also associated with hypoalgesia (Potvin & Marchand, 2007). Thus, chronic pain might be the result of increased prefrontal activity rather than its cause.

References

Altier N, Stewart J (1999) The role of dopamine in the nucleus accumbens in analgesia. Life Sci. 65:2269-2287.

Andreasen NC, O'Leary DS, Flaum M, Nopoulos P, Watkins GL, Boles Ponto LL, Hichwa RD (1997) Hypofrontality in schizophrenia: distributed dysfunctional circuits in neuroleptic-naïve patients. Lancet 349:1730- 1734.

Apkarian AV, Thomas PS, Krauss BR, Szeverenyi NM (2001) Prefrontal cortical hyperactivity in patients with sympathetically mediated chronic pain. Neurosci Lett 311:193-197.

Baliki MN, Geha PY, Apkarian AV, Chialvo DR (2008) Beyond feeling: chronic pain hurts the brain, disrupting the default-mode network dynamics. J Neurosci 28:1398-1403.

Bertolino A, Knable MB, Saunders RC, Callicott JH, Kolachana B, Mattay VS, Bachevalier J, Frank JA, Egan M, Weinberger DR (1999) The relationship between dorsolateral prefrontal N-acetylaspartate measures and striatal dopamine activity in schizophrenia. Biol Psychiatry 45:660- 667.

Carr DB, Sesack SR (2000) Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci 20:3864-3873.

Coghill RC, McHaffie JG, Yen YF (2003) Neural correlates of interindividual differences in the subjective experience of pain. Proc Natl Acad Sci U S A. 100:8538-8542.

Cook DB, Lange G, Ciccone DS, Liu WC, Steffener J, Natelson BH (2004) Functional imaging of pain in patients with primary fibromyalgia. J Rheumatol 31:364-378.

Potvin S, Marchand S (2007) Hypoalgesia in schizophrenia is independent of antipsychotic drugs: A systematic quantitative review of experimental studies. Pain [in press]

Saadé NE, Atweh SF, Bahuth NB, Jabbur SJ (1997) Augmentation of nociceptive reflexes and chronic deafferentation pain by chemical lesions of either dopaminergic terminals or midbrain dopaminergic neurons. Brain Res 751:1-12.