Common brain activations for painful and non-painful aversive stimuli

Hayes and Northoff BMC Neuroscience 2012, 13:60 http://www.biomedcentral.com/1471-2202/13/60 RESEARCH ARTICLE Open Access Common brain activations for painful and non-painful aversive stimuli Dave J Hayes* and Georg Northoff Abstract Background: Identification of potentially harmful stimuli is necessary for the well-being and self-preservation of all organisms. However, the neural substrates involved in the processing of aversive stimuli are not well understood. For instance, painful and non-painful aversive stimuli are largely thought to activate different neural networks. However, it is presently unclear whether there is a common aversion-related network of brain regions responsible for the basic processing of aversive stimuli. To help clarify this issue, this report used a cross-species translational approach in humans (i.e. meta-analysis) and rodents (i.e. systematic review of functional neuroanatomy). Results: Animal and human data combined to show a core aversion-related network, consisting of similar cortical (i.e. MCC, PCC, AI, DMPFC, RTG, SMA, VLOFC; see results section or abbreviation section for full names) and subcortical (i.e. Amyg, BNST, DS, Hab, Hipp/Parahipp, Hyp, NAc, NTS, PAG, PBN, raphe, septal nuclei, Thal, LC, midbrain) regions. In addition, a number of regions appeared to be more involved in pain-related (e.g. sensory cortex) or non-pain-related (e.g. amygdala) aversive processing. Conclusions: This investigation suggests that aversive processing, at the most basic level, relies on similar neural substrates, and that differential responses may be due, in part, to the recruitment of additional structures as well as the spatio-temporal dynamic activity of the network. This network perspective may provide a clearer understanding of why components of this circuit appear dysfunctional in some psychiatric and pain-related disorders. Keywords: Meta-analysis, Translational, Aversion, Pain, Neuroimaging, Animal models Background Aversion: painful and non-painful stimuli Identification of potentially harmful stimuli is necessary for the well-being and self-preservation of all organisms. Organisms with relatively simple nervous systems (e.g. worms, fruit flies) display motivated approach and avoidance behaviours to rewarding and aversive stimuli, respectively, implying the existence of some evolutionarily conserved mechanisms [1,2]. Aversive stimuli are those which an organism will generally expend energy to minimize or avoid [3]; in this context, aversion is operationally opposite to reward [4]. However, the strength of aversive stimuli and the context in which they occur can produce a variety of psychophysical (e.g. negative emotion, pain) and behavioural (e.g. reduced behaviour following punishment, avoidance) responses. While * Correspondence: Mind, Brain Imaging and Neuroethics Research Unit, Institute of Mental Health Research, University of Ottawa, 1145 Carling Avenue, Ottawa K1Z 7K4, Canada recent work has suggested the existence of a common aversion-related network of brain regions responsible for the basic processing of aversive stimuli [5], this work focused only on studies involving non-painful stimuli and studies including painful stimuli were not considered; as such, it is unclear if those results extend to pain-related processing. Pain-associated brain activity Pain, which typically results from activating the nociceptive system (but can also involve non-nociceptive mechanisms, such as in neuropathic pain), is experienced across mammals and is critical for survival [6]. Studies in humans and non-human animals have generally supported the notion that pain is processed differentially in the brain according to affective (e.g. amygdala, anterior insula, hippocampus) and sensory (e.g. somatosensory cortices, posterior insula) dimensions (e.g. [7-9]; though see also [10] for a review on the influential 3dimension theory of pain). Nonetheless, the assumption © 2012 Hayes and Northoff; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hayes and Northoff BMC Neuroscience 2012, 13:60 http://www.biomedcentral.com/1471-2202/13/60 that this network (sometimes referred to as the ‘Pain Matrix’) is specifically activated by painful stimuli has been questioned [11-13]. Using fMRI in humans, Mouraux et al. (2011) uncovered strong support for the notion that the typical regions of the Pain Matrix are largely involved in salience processing [12]. They showed that multimodal non-painful aversive stimuli and painful stimuli activate similar regions in the MCC, insula, thalamus, and sensory cortex and that the BOLD signals in these regions correlated largely with the perceived saliency of the stimulus (regardless of modality or stimulus type). Studies suggest shared regions for pain and non-pain aversion While much work has identified pain as a uniquely important experience (e.g. [10,14]), numerous studies using non-painful aversive stimuli (e.g. unpleasant sounds, sights, etc.) have implicated many of the same cortical and subcortical regions [5], suggesting that the processing of various painful and non-painful aversive stimuli require many of the same neurobiological substrates. In this regard, human studies have been key to understanding the role of cortical regions (e.g. prefrontal and insular cortices; e.g. [15,16]). Alternately, studies in animals have highlighted the importance of subcortical areas such as the periaqueductal grey, hypothalamus, bed nucleus of the stria terminalis, nucleus accumbens/ ventral striatum and ventral tegmental area [17-20]. While prior work has identified a network of regions involved in non-painful aversion-related processing [5], it nonetheless remains unclear which, if any, of those identified areas are also involved in processing painful stimuli. Systematic translational analysis of aversion-related circuitry The present hypothesis is that there exists a core aversion-related circuit involved in processing aversive stimuli regardless of whether they are painful or nonpainful. In an analogical sense, this network would be similar to the basic underlying (e.g. mesocorticolimbic) circuitry identified in the field of reward [21-23]. Prior meta-analyses in humans have outlined core regions associated with pain processing [6,24], and some animal work has even suggested the existence of an overlapping pain and non-pain-related aversion network [25]. Nonetheless, no investigations have used both human and animal data to directly explore the possibility of a shared network for pain- and non-pain-related processing. To this end, a translational cross-species approach was used to identify the core components of the potential aversion-related network. More specifically, our f (...truncated)