Elsevier

Brain Research Reviews

Volume 60, Issue 1, April 2009, Pages 226-242
Brain Research Reviews

Review
Forebrain pain mechanisms

https://doi.org/10.1016/j.brainresrev.2008.12.014Get rights and content

Abstract

Emotional–affective and cognitive dimensions of pain are less well understood than nociceptive and nocifensive components, but the forebrain is believed to play an important role. Recent evidence suggests that subcortical and cortical brain areas outside the traditional pain processing network contribute critically to emotional–affective responses and cognitive deficits related to pain. These brain areas include different nuclei of the amygdala and certain prefrontal cortical areas. Their roles in various aspects of pain will be discussed. Biomarkers of cortical dysfunction are being identified that may evolve into therapeutic targets to modulate pain experience and improve pain-related cognitive impairment. Supporting data from preclinical studies in neuropathic pain models will be presented. Neuroimaging analysis provides evidence for plastic changes in the pain processing brain network. Results of clinical studies in neuropathic pain patients suggest that neuroimaging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients. Recent progress in the analysis of higher brain functions emphasizes the concept of pain as a multidimensional experience and the need for integrative approaches to determine the full spectrum of harmful or protective neurobiological changes in pain.

Introduction

A multidimensional experience pain not only includes nociceptive and nocifensive but also emotional–affective and cognitive components (Fig. 1). This article will draw attention to some brain areas and functions that have been implicated in the well-documented reciprocal interactions between pain, affect and cognition (Rhudy and Meagher, 2001, de Novellis et al., 2004, Flor and Turk, 2006, Seminowicz and Davis, 2007, Tracey and Mantyh, 2007, Bacon et al., 1996). Pain hurts. Pain can lead to anxiety and depression. Conversely, patients suffering from anxiety and depression experience pain more strongly and are more likely to develop chronic pain. Pain also impairs cortical functions such as our ability to think clearly and make advantageous decisions. In turn, cognitive processes can modulate pain perception (deCharms et al., 2005, Mayer et al., 2006, Seminowicz and Davis, 2007, Rhudy et al., 2008). Understanding these complex interactions is required for improved assessment and management of pain.

Neurobiological mechanisms of the different aspects of pain are only beginning to emerge. A network of brain structures that process pain-related information has emerged based on neuroimaging studies (Casey, 1999, Seminowicz et al., 2004, Mackey and Maeda, 2004, Apkarian et al., 2004b, Mayer et al., 2006, Tracey and Mantyh, 2007, Zhuo, 2008). This so-called “pain matrix” or “homeostatic afferent processing network” consistently includes primary (S1) and secondary (S2) somatosensory cortices, insular cortex, anterior cingulate cortex (ACC), and thalamic nuclei. S1 cortex is generally associated with sensory-discriminative aspects (but see Craig, 2003), S2 likely has additional affective/cognitive functions, while the insula and ACC are important for affective–motivational and certain cognitive aspects of pain, including anticipation, attention and evaluation (Seminowicz et al., 2004, Apkarian et al., 2004b, Ohara et al., 2005, Zhuo, 2008).

It is clear now that prefrontal cortical areas other than ACC and subcortical areas such as the amygdala are also part of the brain network for pain (Neugebauer et al., 2004, Apkarian et al., 2004b, Ochsner et al., 2006, Iadarola et al., 1995, Baliki et al., 2006, Mayer et al., 2006, Kulkarni et al., 2007, Tracey and Mantyh, 2007). These brain areas may play a role in “secondary pain affect”, which includes the conscious awareness and cognitive evaluation of pain (Price, 2000). Pain-related changes in these brain areas may contribute to the emotional–affective and emotion-based cognitive consequences of pain. Conversely, pain can be modulated by emotional (fear and anxiety) and cognitive (attention, expectation, or memory) factors (deCharms et al., 2005, Mayer et al., 2006, Seminowicz and Davis, 2007, Rhudy et al., 2008). The neurobiology of these top-down processes remains to be determined and will not be discussed here. It should be noted, however, that activation of the ACC (Calejesan et al., 2000, Zhuo, 2008) or disinhibition of the insula (Jasmin et al., 2003) can facilitate nocifensive reflexes whereas stimulation of the medial PFC inhibited nocifensive responses and mixed results have been reported for orbitofrontal cortex activation (see Ohara et al., 2005).

Section snippets

Emotional–affective aspects of pain and amygdala dysfunction

The amygdala has long been known for its important role in emotions and affective disorders (Pare et al., 2004, Maren, 2005, Phelps and Ledoux, 2005). An increasing body of evidence from anatomical, neurochemical, electrophysiological and behavioral studies strongly supports the concept of the amygdala as an important player in the emotional–affective dimension of pain (Heinricher and McGaraughty, 1999, Rhudy and Meagher, 2001, Gauriau and Bernard, 2002, Neugebauer et al., 2004, Iadarola et

Cognitive impairment and cortical dysfunction in pain

Cognitive impairment, the inability to think clearly and make advantageous decisions, is one of the consequences of persistent pain but the underlying neural mechanisms are not known. A neural circuit that involves prefrontal cortical (PFC) areas and the amygdala appears to be of critical importance for cognitive functions such as decision-making.

Biomarkers of cortical dysfunction in neuropathic pain

Chronic pain is associated with functional and morphological changes in subcortical and cortical brain areas that lead to cognitive impairment. However, objective markers for pain and related dysfunctions are generally missing. Neuropathic pain resulting from peripheral nerve injury is a chronic pain condition that is difficult to manage and seriously affects quality of life. Enhanced transmission of nociceptive messages at peripheral and spinal levels occurs. Functional and morphological

Imaging cortical plasticity in clinical neuropathic pain

Until recently our understanding of pain generation, mechanisms, and transmission from the spinal cord to the brain has been based primarily on animal studies, which have yielded a wealth of knowledge about nociceptive processing, analgesia, and plasticity. Animal models often permit rapid advances in understanding many underlying disease mechanisms — understanding that can be translated to human models. However, with neuropathic pain (NP) translating what has been learned in animals to humans

Conclusions

It is clear now that the brain network for pain also includes primarily “non-sensory” forebrain areas such as PFC and amygdala that are concerned with emotional–affective and emotion-based cognitive aspects of pain. As part of the reward-aversion circuitry these brain areas play a key role in value-based decision-making that guides goal-directed behavior. Well-documented pain-related cognitive deficits may be attributed to abnormal processing in these structures.

Activation versus deactivation

Acknowledgments

Work in the authors' laboratories was supported by National Institutes of Health (NIH) grants NS38261 and NS11255 (to V.N.), Fundação para a Ciência e Tecnologia (FCT) grants POCI/SAU-NEU/63034/2004 and POCI/SAU-NEU/55811/2004 and Bial Foundation grant 84/04 (to V.G.), Ministero dell'Università e della Ricerca Scientifica (MIUR) grant PRIN-2005 (to S.M.), and NIH grant NS053961 and the John and Dodie Rosekranz Pain Research Endowment Chris Redlich Research Fund (to S.C.M.).

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