Edited by: John J. Foxe, Albert Einstein College of Medicine, USA
Reviewed by: Rodrigo N. Romcy-Pereira, Federal University of Espírito Santo, Brazil; Janina Seubert, Monell Chemical Senses Center, USA
*Correspondence: Dave J. Hayes, Mind, Brain Imaging and Neuroethics, Institute of Mental Health Research, Royal Ottawa Health Care Group, University of Ottawa, 1145 Carling Avenue, Room 6441, Ottawa, ON, Canada K1Z 7K4. e-mail:
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The ability to detect and respond appropriately to aversive stimuli is essential for all organisms, from fruit flies to humans. This suggests the existence of a core neural network which mediates aversion-related processing. Human imaging studies on aversion have highlighted the involvement of various cortical regions, such as the prefrontal cortex, while animal studies have focused largely on subcortical regions like the periaqueductal gray and hypothalamus. However, whether and how these regions form a core neural network of aversion remains unclear. To help determine this, a translational cross-species investigation in humans (i.e., meta-analysis) and other animals (i.e., systematic review of functional neuroanatomy) was performed. Our results highlighted the recruitment of the anterior cingulate cortex, the anterior insula, and the amygdala as well as other subcortical (e.g., thalamus, midbrain) and cortical (e.g., orbitofrontal) regions in both animals and humans. Importantly, involvement of these regions remained independent of sensory modality. This study provides evidence for a core neural network mediating aversion in both animals and humans. This not only contributes to our understanding of the trans-species neural correlates of aversion but may also carry important implications for psychiatric disorders where abnormal aversive behavior can often be observed.
The ability to detect and respond appropriately to potentially harmful stimuli is essential to the well-being and self-preservation of all organisms. Avoidance behavior can be observed in both humans and animals. Even organisms with relatively simple nervous systems (e.g., worms, fruit flies) display avoidance behaviors to aversive stimuli, implying the existence of some evolutionarily conserved mechanisms (Glanzman,
Human neuroimaging studies have been key in understanding the role of many predominantly cortical regions (e.g., prefrontal, orbitofrontal, and insular cortices; e.g., Rolls et al.,
Animal studies on aversion have largely focused on various subcortical regions. In particular, aversion-related studies in animals have highlighted the importance of subcortical areas such as the periaqueductal gray (PAG), hypothalamus, bed nucleus of the stria terminalis (BNST), raphe nuclei, nucleus accumbens/ventral striatum (NAc/VS), and ventral tegmental area (VTA; e.g., Misslin,
The general aim of this study is to investigate the regions involved in aversion-related processing in both humans and non-human animals. To this end, we conducted systematic analyses of human and animal data and compared them for neuroanatomical overlaps and differences. Our specific aims were as follows. First, we aimed to conduct a meta-analysis on human imaging data. Based on the previous data, we hypothesized that this meta-analysis would associate activations in the anterior cingulate, amygdalae, anterior insula (AI), and medial or lateral prefrontal cortex with aversion. We focused on the mere passive perception of aversive stimuli (e.g., the viewing of unpleasant pictures; exposure to unpleasant, but non-painful, tactile/thermal stimuli), while excluding studies with more complex task requirements as well as those implicating additional cognitive and behavioral variables (e.g., decision-making tasks, reflex tasks, tasks specifically targeting pain, fear, or anxiety responses).
Our second aim consisted in the systematic investigation of various aversion studies in animals. Given results from prior studies, noted above, we hypothesized the predominant involvement of subcortical regions like the VTA, NAc/VS, BNST, and PAG with aversion. Because the results from both animals and humans could reflect the impact of unspecific effects associated with distinct sensory modalities, we carefully controlled for this potential confound by contrasting the aversive stimuli according to modality [i.e., auditory, tactile, and visual; olfaction (three studies included) and gustation (one study included) were not investigated in the meta-analysis due to too few studies].
Methodologically, the use of a meta-analytical approach allows for the clear distinction of areas which have been identified reliably across numerous studies – in comparison to individual brain imaging studies which may have low power and/or report a high percentage of false positive activations (Wager et al.,
To form a dataset of coordinates, we conducted multiple PubMed
Our main goal was to investigate the basic neural correlates of aversion. Therefore, we included only those studies and contrasts which used the mere passive presentation of aversive stimuli (e.g., the viewing of unpleasant pictures; exposure to unpleasant, but non-painful, tactile/thermal stimuli) but did not require any active responses. Without behavioral measures, the nature of aversive experiences were determined subjectively and often supported through physiological measures such as electrodermal activity. As such, designs whose contrasts involved explicit behavioral tasks, learning tasks, or those that did not include specific comparisons relevant to the current analysis (i.e., involving the passive perceptual component of aversion, independent of explicit cognitive processes, memory, or attention) were excluded. In addition, only studies that reported coordinates from whole-brain analysis were included (although some studies discussed region-of-interest data, those coordinates were not included here).
Most studies investigating responses to specific negative emotions through face-viewing (e.g., angry or sad faces) were also excluded given the social nature of such stimuli and the ambiguous interpretations possible (e.g., inconsistent relationships to empathy or the signaling of physical contamination, for instance related to disgust; e.g., see Anderson et al.,
In addition, to control for the possible confounding effects of using aversive stimuli from different sensory modalities, we contrasted the stimuli according to modality (i.e., auditory, tactile, and visual; olfaction and gustation were not investigated due to too few studies). This resulted in the following contrasts:
We included studies reporting single group data (i.e., healthy subjects only); thus, we did not consider coordinates reporting a main effect of processing across the control and a clinical group, nor did we consider coordinates relative to functional, psychophysiological, or psychopathological correlations. Studies including individuals with psychiatric illnesses, or a history thereof, those with volumetric abnormalities or brain injuries, those taking any medications or illicit drugs, and those belonging to a group that may result in a sample bias (e.g., war veterans) were excluded. In addition, a large number of studies were excluded due to the absence of coordinates, identification of coordinate systems, and/or incomplete statistical information.
We then individually screened all the articles for the presence of Talairach or Montreal Neurological Institute (MNI) coordinates and tabulated the reported regional foci. We focused on studies that directly compared the activation of aversion-related circuitry in healthy adult subjects. These criteria resulted in the selection of 34 studies (for a total of 427 subjects; 45% male), which included 44 contrasts (see references for studies included in the meta-analysis). The authors acknowledge that these stringent inclusion/exclusion criteria have prevented the inclusion of many imaging studies investigating the processing associated with the perception of aversive stimuli. We have done this so as to reduce the number of possible confounding variables but acknowledge that some studies may have been overlooked, particularly if they did not use typical aversion-related terminology (e.g., aversion, punishment, negative).
The benefits of using the multilevel kernel density analysis (MKDA) meta-analytic approach over others, as well as an extensive elaboration of technical considerations, has been covered in-depth elsewhere (Salimi-Khorshidi et al.,
We conducted multiple PubMed (see text footnote 1) searches to initially identify all non-human animal studies related to aversion (~350 studies) published in English from 2000 to February 2010. Furthermore we searched the reference list of identified articles and several reviews. The search included keywords such as “aversion,” “aversive,” “avoidance,” “fear,” “anxiety,” “punishment,” “threat,” “reinforcement,” “c-Fos,” “Fos,” “immediate early genes,” “IEG,” “electrophysiology,” “positron emission tomography”, “PET,” “functional magnetic resonance imaging”, “fMRI.” Of the total studies identified, only those clearly showing altered brain metabolism (e.g., increased/decreased c-Fos or blood oxygenated level dependent activity, or BOLD) in mammals were included in the systematic review (i.e., 42 studies). Due to lack of methodological instruments, absence of precise standardized coordinate systems, the wide range of experimental procedures, and the diversity of regional anatomy in different species, we were not able to conduct the same rigorous meta-analysis in animals as in humans.
We looked at the following metabolic indexes of non-human animal brain activity: immediate early gene activation (e.g., c-Fos or Fos-like expression), BOLD activity in fMRI, [14C]-2-deoxyglucose, and [14C]-iodoantipyrine. Each of these indexes has previously been related to neural activity and/or metabolism. Considering the broad spectrum of animal models of aversion-related behavior (e.g., footshock exposure, conditioned taste aversion etc.), we looked at all those data that report clear effects in brain activity between control animals and those exposed to non-painful aversive stimuli.
As in humans, our main goal was to investigate the basic neural correlates of aversion. Therefore, we aimed to include only those studies which investigated changes in brain metabolism (e.g., increases in immediate early genes, such as c-Fos, or changes in BOLD activity) related to the mere passive presentation of stimuli (e.g., mild footshock, predatory odor, aversive taste), and not directly related to any behavioral task which might be involved. This is important to note given that many animal studies (including many of those noted here) involve the measurement of a behavioral variable (e.g., avoidance of a stimulus as a reflection of its aversive properties). However, the present studies were chosen for their careful controlling of such behavioral variables and their general focus on brain areas associated with the processing of aversive stimuli. Although an explicit analysis on sensory modality was not undertaken in animals (due to too few studies in each domain), the available studies were informally compared for brain activations across modalities and compared to the meta-analytic results noted in humans.
Similar to human studies, many animal studies have been excluded for their use of complex behavioral tasks, a focus on social aversion factors, or those focused mainly on memory- or learning-related mechanisms as opposed to basic aversion-related processing. Studies focused on biological/molecular changes or manipulations (e.g., locally injected drugs) related specifically to neurochemicals (which have many known functions throughout the nervous system; e.g., neurotransmitters such as dopamine and GABA), were also excluded in the present study – although the authors acknowledge that future such analyses may prove helpful. In addition, studies involving adolescent animals, chronic exposure to aversive stimuli (as considered in relation to the paradigm under investigation), and exposure to drugs of abuse and drugs which have a known direct effect on aversion- or reward-related brain circuitry, were excluded (although non-drug-exposed controls were included where appropriate). This was done in order to avoid confounding issues related to neurodevelopment and drug interactions and/or drug-induced changes in brain structure or function unrelated to the acute aversive treatment. Studies using electrical/chemical lesions or other irreversible alterations (e.g., the use of knock-out or transgenic rodents or animals bred for psychiatric disorder-related phenotypes) were also excluded for clarity.
These inclusion and exclusion criteria resulted in the selection of almost exclusively studies involving rodents, except for a single study involving macaques (Hoffman et al.,
In order to compare aversion-related activity across the human and animal data, we listed the respective regions for both species and checked for hyper- and hypo-activity. As few studies in any domain reported hypoactivity, these are not discussed in detail here. Although a detailed comparison of commonly activated regions in both humans and animals would be informative, spatial limitations in human imaging techniques, and the absence of a clear human-to-non-human-mammal brain atlas, make this difficult beyond the descriptive level. Any comparison between human and animal data raises the question of homology of brain regions. Since they show analogous anatomy and are described by similar names, analysis of subcortical regions do not raise the problem of homology (Panksepp,
Meta-analysis results indicated the activation of core aversive brain circuitry involving the amygdala (Amyg), AI, ACC, ventrolateral orbitofrontal cortex (VLOFC), hippocampus (Hipp), and parahippocampal gyrus (Parahipp), dorsal striatum (DS), rostral temporal gyri (RTG), and thalamus (Thal). Significant clusters, extending from regions with peak activations, were also noted in the dorsomedial prefrontal cortex (DMPFC), secondary motor area (SMA), and midbrain (see Figure
Cluster | MNI | Number of peak voxels (within clusters > 10 voxels) | Region | BA | ||
---|---|---|---|---|---|---|
1 | −22 | −2 | −18 | 526 | Left amygdala, RTG, and hippocampus–parahippocampus | |
2 | −24 | 10 | −28 | 1 | Rostral temporal gyri | 38 |
3 | 20 | −4 | −14 | 386 | Right amygdala, RTG, and hippocampus–parahippocampus | |
4 | −22 | 18 | −20 | 7 | Inferior prefrontal gyrus (OFC) | 47 |
5 | −26 | 18 | −16 | 2 | Inferior frontal gyrus | |
6 | −10 | 4 | −14 | 1 | Parahippocampal gyrus | 34 |
7 | 42 | 16 | −12 | 2 | Inferior frontal gyrus | |
8 | 40 | 16 | −4 | 4 | Inferior prefrontal gyrus (OFC) | 47 |
9 | 44 | 16 | −4 | 1 | Inferior prefrontal gyrus (OFC) | |
10 | −36 | 20 | 4 | 27 | Left anterior insula | 13 |
11 | 30 | 10 | 0 | 1 | Right dorsal striatum (DS) | |
12 | −40 | 16 | 4 | 1 | Left anterior insula | 13 |
13 | 10 | −10 | 6 | 2 | Thalamus | |
14 | 10 | −12 | 10 | 1 | Thalamus |
Cluster | MNI | Size of clusters | Region | BA | ||
---|---|---|---|---|---|---|
1 | −28 | 6 | −28 | 752 | Left amygdala/left RTG | |
2 | 48 | 0 | −30 | 203 | Right middle temporal gyrus | |
3 | 32 | 22 | −18 | 1089 | Right inferior prefrontal gyrus (OFC) | |
4 | 6 | −34 | −16 | 177 | Midbrain (area of PAG) | |
5 | −20 | −44 | −6 | 229 | Left parahippocampal gyrus | |
6 | −14 | 2 | −12 | 2276 | Left hippocampus–parahippocampal gyrus | |
7 | 28 | −6 | −14 | 1486 | Right amygdala | |
8 | 38 | 16 | −4 | 1510 | Right inferior prefrontal gyrus (OFC) | 47 |
9 | −34 | 20 | −6 | 1752 | Left inferior frontal gyrus | |
10 | 10 | −24 | 0 | 578 | Thalamus | |
11 | −4 | −16 | 0 | 1603 | Thalamus | |
12 | 14 | 4 | 8 | 1367 | Dorsal striatum | |
13 | 44 | 34 | 0 | 350 | Right inferior frontal gyrus | |
14 | 4 | 24 | 30 | 1084 | ACC | 32 |
15 | 0 | 52 | 32 | 784 | DMPFC | |
16 | −2 | −10 | 38 | 1000 | midACC | 24 |
17 | 0 | 8 | 54 | 516 | SMA |
As the studies in the meta-analysis investigated the passive reception of aversive stimuli (when compared to non-aversive stimuli; and therefore required little or no action on the part of the subjects), there was no need to control for task-related effects (as related to cognitive task effects). However, the stimuli across studies were presented in various sensory modalities. As such, we attempted to control for unspecific effects associated with distinct sensory modalities (i.e., auditory, tactile, and visual; olfaction and gustation were not investigated due to too few studies) by performing contrasts between the three senses. As the number of visual contrasts was higher (33) than either tactile (5) or auditory (6), six visual contrasts were chosen (twice) at random and compared to the other modalities.
There were no significant activations noted for the following contrasts:
Animal studies assessing brain activity in response to non-painful aversive stimuli implicated all of the same regions shown in humans (see Table
Rank order: Aversion (42 studies) | ||
---|---|---|
Area | Studies reporting activation | Percentage of studies reporting activation |
Amyg | 32 | 76 |
Thal | 13 | 30 |
Hyp | 12 | 29 |
NTS | 10 | 24 |
Parahipp/Hipp | 9 | 21 |
PBN | 8 | 19 |
PAG | 8 | 19 |
Ins | 7 | 17 |
PFC (PL, IL)/OFC | 7 | 17 |
BNST | 5 | 12 |
NAc | 5 | 12 |
Septal | 3 | 7 |
ACC, DR, DS, LC | 2 Each | 5 |
Motor, habenula, VTA | 1 Each | 2 |
Species | Behavioral model | Measurement type | Specific effect | Brain area(s) | References |
---|---|---|---|---|---|
Mice | LiCl-induced (130 mg/kg; i.p.) CPA (acquisition/exposure) | c-Fos | Increased expression | Cingulate, paraventricular hypothalamic n. (PVN; significant for both CPA expression and cocaine-induced CPP) | Johnson et al. ( |
Decreased expression | Dentate gyrus (significant for both CPA expression and cocaine-induced CPP) | ||||
LiCl-induced (130 mg/kg; i.p.) CPA (expression) | Increased expression (CS+ > CS−) | Cingulate, paraventricular hypothalamic n. (PVN; significant for both CPA expression and cocaine-induced CPP); paraventricular thalamic n.; PAG | |||
Wistar rats | Intra-PAG semicarbazide-induced (5 μg; GABA synthesis inhibitor) CPA | c-Fos | Increased expression (CS+ > CS−) | dmPAG, BLA, laterodorsal n. of the thal. | Zanoveli et al. ( |
Wistar rats | CTA with strawberry flavored water paired with intragastric hypertonic (5%) NaCl injection | c-Fos | Increased expression when NaCl followed CS + exposure (though not with a 30-min delay) | Intermediate n. of the solitary tract (iNST; only nucleus investigated) | Mediavilla et al. ( |
Sprague-Dawley (SD) rats | Taste-potentiated odor aversion (TPOA), simultaneous CTA, and conditioned odor aversion with saccharin combined with LiCl (0.2 M; i.p.) | c-Fos | Olfactory or taste cue: increased expression | Anterior paleocortex, posterior paleocortex, entorhinal ctx, hippocampus (CA1/3), BLA, medial n. amyg, OFC, dysgranular insula | Dardou et al. ( |
Wistar rats | CTA following arsenic administration (20 mg/kg) | c-Fos | Increased expression | Central n. amyg., BNST, NST | Garcia-Medina et al. ( |
SD rats | CTA by LiCl (0.4 M; i.p.) | c-Fos | Increased expression | Central n. amyg, BLA, PBN, BNST, gustatory thalamus | St Andre et al. ( |
SD rats | CTA by LiCl (0.15 M; i.p.) | c-Fos | Increased expression | Central n. amyg, BLA, PBN, NST, insular (gustatory) ctx | Bernstein and Koh ( |
Wistar rats | CTA by LiCl (127 mg/kg; i.p.; acquisition) | c-Fos | Increased expression | Lateral n., central n., basolateral n. amyg. | Ferreira et al. ( |
Decreased expression | NAc core | ||||
Wistar rats | CTA by LiCl (0.15 M; i.p.; expression) | c-Fos | Increased expression (CS+ > CS−) | Insula, NAc shell | Yasoshima et al. ( |
CTA by LiCl (acquisition) | Increased expression | Central n. amyg., BNST | |||
Wistar rats | CTA by LiCl (0.2 M; i.p.; expression) | c-Fos, EGR1 | Increased expression | Medial portion of the central n. amyg., BLA, NAc shell, and core, interstitial n. of the posterior limb of the anterior commissure | Dardou et al. ( |
TPOA with LiCl | EGR1 (alone) | Increased expression | BLA, insula, hippo | ||
Central n. amyg, entorhinal ctx | |||||
Long-Evans rats | CTA with LiCl (0.15 M; i.p.) | c-Fos | Increased expression | Central n. amyg, BLA, insula, NST | Wilkins and Bernstein ( |
Conditioned intra-oral aversion | Central n. amyg | ||||
Long-Evans rats | CTA with LiCl (0.15 M; i.p.) and novel stimuli | c-Fos | Increased expression | Central n. amyg, BLA, insula, iNST, PBN, | Koh and Bernstein ( |
SD rats | CTA with LiCl (81 mg/kg; i.p.; acquisition) | c-Fos | Increased expression | Central n. amyg, BLA, iNST | Mickley et al. ( |
CTA with LiCl (expression | BLA, iNST | ||||
Wistar rats | Freezing and escape behavior elicited by electrical stimulation of the dorsolateral PAG | c-Fos | Increased expression induced by freeze-inducing stimulation | Dorsomedial PAG, dorsal premammilary n. | Vianna et al. ( |
Increased expression induced by escape-inducing stimulation | Dorsomedial PAG, dorsolateral PAG, ventromedial hypothal, dorsal premammilary n., cuneiform n. | ||||
Long-Evans rats | CTA with LiCl (0.15 M; i.p.; one conditioning trial) | c-Fos | Increased expression | iNST | Navarro et al. ( |
CTA with LiCl (3 conditioning trials) | iNST, PBN, central n. amyg | ||||
Wistar rats | LiCl-induced (0.15 M; i.p.) CTA (retrieval of aversive memory following CS( exposure) | fMRI (manganese-enhanced) | Increased activity | Gustatory (insula) cortex, NAc core and shell, VP, LH, Central n. amyg, BLA | Inui-Yamamoto et al. ( |
Wistar rats | LiCl-induced (0.15 M; i.p.) CTA | c-Fos | Increased expression | Anterior nuclei of the thalamus: no change Midline and intralaminar thalamic complex: PVT | Yasoshima et al. ( |
Footshock-induced avoidance | Increased expression | Anterior nuclei of the thalamus: Anterodorsal n. Midline and intralaminar thalamic complex: PVT | |||
SD rats | CTA with LiCl (0.15 M; i.p.); investigation of amyg only using laser capture and RT-PCR | c-Fos, Fra-2 | Increased expression | Central n. amyg (c-Fos, Fra-2), BLA (Fra-2) | Kwon et al. ( |
SD rats | Exposure to predatory fox odor compared to control, butyric acid | c-Fos | Increased expression | Olfactory bulb, lateral septal n, septohypothalamic n, anteromedial and oval nuclei of the BNST, CeA, the anteroventral, anterodorsal, and medial preoptic nuclei, the anterior, dorsomedial, lateral, supramammillary, dorsal premammillary and paraventricular hypothalamic nuclei, the external lateral PBN, LC, NST | Day et al. ( |
Wistar rats | Exposure to predatory cat odor compared to control | c-Fos | Increased expression | Posteroventral medial amygdaloid nucleus, the premamillary nucleus (dorsal part), ventromedial hypothalamic nucleus (dorsomedial part), dorsomedial hypothalamic nucleus, periaqueductal gray (dorsomedial, dorsolateral, and ventrolateral parts), and the cuneiform nucleus | Dielenberg et al. ( |
Wistar rats | Odor-conditioned (to footshock) | c-Fos | Increased activity | Olfactory bulb, infralimbic cortex, OFC, perirhinal–entorhinal ctx, BLA | Funk and Amir ( |
Wistar-Kyoto rats | Cold chamber (4°C/3 h) | c-Fos | Increased activity | Rostral thal, zona incerta, midline thalamic, hypothal dorsomedial, supramamillary and lateral PBN, PVN hypothal, arcuate, CeA, NST | Baffi and Palkovits ( |
SD rats | Hypercarbic chamber | c-Fos | Increased activity | Hypothalamus (DMH, PeF, PVN, PMd), PAG, rostroventrolateral medulla, lateral paragigantocelluar n. | Johnson et al. ( |
Wistar rats | Exposure to footshock-paired chamber | c-Fos | Increased activity | PL/IL | Lemos et al. ( |
SD rats | Intragastrically administered bitter tasting-receptor ligands (10 mM) | c-Fos | Increased activity | Area postrema, NST, PBN, PVN hypothal, CeA | Hao et al. ( |
Wistar rats | Social defeat | c-Fos | Increased activity | Arcuate n, ventromedial n of the hypothal, and medial amygdala | Fekete et al. ( |
SD rats | Cue-associated footshock and footshock alone | c-Fos | Increased activity | Core of the rostromedial tegmental n (projecting to VTA), SNR | Jhou et al. ( |
Mice | LiCl-induced (0.14 M; i.p.) CTA | c-Fos and Zif268/Egr1 | Increased activity | Amyg (Zif268 only) | Baumgartel et al. ( |
Wistar rats | Playback of 22 kHz aversive vocalizations | c-Fos | Increased activity | perirhinal cortex, amygdalar nuclei, PAG | Sadananda et al. ( |
Wistar rats | Conditioned freezing to footshock-paired compartment | c-Fos | Increased activity | M2 ctx, PVN, BLA, CeA, MeA, CA1, DG, DRN | Lehner et al. ( |
Mice | Tone-conditioned footshock-induced aversion | c-Fos | Increased activity | Ventrolateral septum, dorsolateral septum | Calandreau et al. ( |
Footshock-induced aversion | Ventrolateral septum, medial septum | ||||
Wistar rats | Elevated plus maze exposure | c-Fos | Increased activity | PL, IL, BLA, CeA, ACC | Albrechet-Souza et al. ( |
SD rats | Predator (fox) scent | MnCl2-enhanced fMRI (aversive scent > neutral scent) | Increased act. ipsil. | Thal, hypothal, amyg | Chen et al. ( |
Decreased act. Ipsil. | PFC | ||||
Increased act. contra. | None | ||||
Decreased act. contra. | PFC | ||||
Wistar rats | Social defeat | c-Fos | Increased activity | Hippocampus (CA1, CA2, CA3, DG) | Calfa et al. ( |
Macaques | Threatening faces | fMRI (threat > pleasant) | Increased activity | BLA | Hoffman et al. ( |
SD rats | Visual exposure to predator (ferret) | c-Fos | Increased activity | MeA, CeA, BLA, Lat habenula, PVN of the thal, hypothal (lat n, dorsal premammillary n) | Roseboom et al. ( |
Wistar rats | Open field exposure | c-Fos | Increased activity | MeA, CeA | Badowska-Szalewska et al. ( |
Wistar rats (bred for high vs. low anxiety) | Airjet (compressed air) | c-Fos | Increased activity (both high and low anxiety) | mPFC, ACC, caudate putamen, NAc, lat septum, PVN of the thal, hypothal, amyg, PAG, VTA, DR, latPBN, LC | Salchner et al. ( |
Increased activity (high > low anxiety) | Anterior hypothal, med preoptic area, dorsolateral PAG, LC | ||||
Wistar rats | Tone-conditioned footshock; avoidance of footshock | c-Fos, P-ERK | Increased activity | Lat dorsal amyg (ventral portion) | Radwanska et al. ( |
SD rats | Footshock exposure | c-Fos | Increased activity | Amyg, thal, hypothal | Nikolaev et al. ( |
Wistar rats | IC electrical stimulation causing: Freezing Escape | c-Fos | Increased activity | Frontal ctx, BLA, dorsal hippo, entorhinal, CeA | Lamprea et al. ( |
Increased activity | Frontal ctx, BLA, dorsal hippo, dPAG, cuneiform n, IC | ||||
SD rats | Footshock exposure | NGFI-B | Increased activity | Lat dorsal amyg, hippo (CA1), neocortex | Malkani and Rosen ( |
Similar to the human analysis, brain activations resulting specifically from aversive stimuli in each sensory modality were noted in studies across animals. However, in comparison to human studies, the majority of animal studies (done mostly in rodents) use gustatory or olfactory aversive stimuli. Despite this difference, and similar to the meta-analysis results, there are no areas overlapping with humans which can clearly be identified as modality specific (see Table
Comparing the regions found in the human meta-analysis (see figure
The present work aimed to clearly identify a network of brain regions involved in the processing of aversive stimuli using a cross-species translational approach. A comparison was made between studies investigating the passive reception of aversive stimuli in humans (using a meta-analysis; see Figure
This translational analysis has identified a core cross-species aversion-related network of brain regions which include cortical (i.e., ACC, AI, DMPFC, RTG, SMA, and VLOFC) and subcortical (i.e., Amyg, DS, Hipp, Parahipp, Thal, and midbrain) areas (see Figure
The first aim was to identify brain regions associated with the processing of aversive stimuli in humans. These results revealed activations (figure
While the systematic review of animal studies also identified the same regions as in humans, additional subcortical activations were noted predominantly in animals, including the BNST, Hab, Hyp, NTS, NAc, PAG, PBN, and septal nuclei (see Table
For instance, while the hypothalamus is rarely found to be activated during aversion-related processing in the human literature (e.g., Herwig et al.,
Although regions such as the amygdala, AI, and areas of the prefrontal cortex show robust activations across both animals and humans (see further discussion below), it remains unclear what role the subcortical areas, identified mainly in the animal studies, play in the core aversion-related network. This is likely due, in part, to the fact that the role of subcortical areas in human imaging studies are largely underestimated as these techniques typically focus on whole-brain analysis and have lower subcortical and subregional resolution (see Logothetis,
Taken together, this translational analysis identified a core cross-species aversion-related network of cortical and subcortical areas, including the Amyg, ACC, VLOFC, DMPFC, secondary motor cortex, Hipp/parahipp, DS, RTG, Thal, and midbrain (see Figure
Although the precise role of the amygdala is not fully understood, there is good evidence to suggest that it is involved in processing the saliency (Ewbank et al.,
The variety of functional roles is similarly seen in other regions noted in the present study. For instance, the functions of the ACC and orbitofrontal cortex are equally complex in that they are incompletely understood although they appear to be broadly implicated in functions such as error processing (Simons,
The present investigation demonstrated the amygdala, OFC, and AI as common regions in aversion in both humans and animals. If these regions are indeed core regions of aversion-related processing, one would assume that their activation remains independent of a specific sensory modality. This is so because aversive stimuli can occur in different sensory modalities, for instance visually (e.g., using complex scenes or images), as used predominantly in human studies, or olfactorily or gustatorily as is the case especially in animal studies. In order to rule out sensory modality-specific effects, we controlled for them in our meta-analysis. As indicated in the Section
However, there are a few important caveats to note. While there may indeed be a common cross-species neural network for basic aversion-related processing, given the differential reliance on sensory systems across species (e.g., humans rely more heavily on visual information, while rodents rely more heavily on olfactory cues from the environment), the present study cannot comment on the impact of likely species-specific responses to aversive stimuli from the different senses. The specific impact, for instance, of aversive gustatory or olfactory stimuli in humans could have been explored more thoroughly had studies investigating the disgust response been included in the present study (these were left out, as described above, in an attempt to limit potential confounds related to ambiguous and/or higher-order processing such as the response to physical contaminants). Nonetheless, studies included in the meta-analysis which used these sensory stimuli (e.g., Rolls et al.,
In addition to sensory modality-specific effects, we also ruled out possible behavioral and cognitive confounding effects. This was accomplished by including only human and animal studies which focused on the passive reception of stimuli, where aversive and non-aversive stimuli had to be merely perceived but not acted upon. Our results of a common aversion-related core network must thus reflect the neural processing of aversive stimuli when compared to non-aversive ones rather than some unspecific task-related effects associated with the presentation of the stimuli. We are aware however that despite our careful selection of studies, we are not completely able to rule out task-related effects since even during passive perception some implicit task-related effects may occur. For instance, implicit judgment or attention effects may be greater in aversive (compared to non-aversive) stimulus processing. Future studies focusing on the interaction between aversive (vs. non-aversive) stimuli and task-related effects (like judgment, attention or anticipation) may therefore need to be conducted. Additionally, the degree of aversion from moderate to severe should also be considered in future, as should the comparison to pain-related activations. Nonetheless, it is important to point out that a recent set of experiments by Mouraux et al. (
Taken together, these results demonstrate that this core aversion-related network is activated independent of sensory modality and is not related explicitly to cognitive or behavioral effects. In addition, while no single brain area is responsible for the processing of aversive stimuli, there may be at least some differentiation at the subregional (e.g., rostrocaudal/anteroposterior gradations) and/or neuronal level. Regardless, these results raise many questions and leave open numerous possibilities for future studies, including: Is this aversion-related network specific for aversive stimuli? How does the network differentially encode the anticipation and reception of aversive stimuli? And what neurochemical mechanisms are involved?
Is this aversion-related network specific for the processing of aversive stimuli? Given the fact that the observed core aversion-related network appears to remain independent of sensory, cognitive, and behavioral processing, one may raise the question of exactly what kind of processing is mediated by this network. Although we aimed to remove any potential cognitive effects by focusing on studies employing the use of passive aversive stimuli, we cannot completely eliminate the possible impact of “top-down” processes (such as cognitive reappraisal). In particular, as event-related fMRI designs generally use the repetition of stimuli across many trials, subjects may be consciously or automatically/unconsciously using coping strategies to help control their emotional responses to the unpleasant stimuli. Although we suspect that each of the regions presently identified are involved in basic aversion-related processing, it is probable that some are also particularly involved in higher-order cognitive processing as well. As such, future studies should continue to investigate the impact of stimulus anticipation and trial repetition, especially as a few studies have already suggested differential activities within regions such as the amygdala and areas of the prefrontal cortex (Wright et al.,
Another suggestion is that this network processes stimulus saliency (i.e., the importance of a stimulus to a particular organism, irrespective of valence), especially given that the amygdala, for instance, is involved in processing the saliency of emotional stimuli (Ewbank et al.,
Both reward- and aversion-related stimuli are highly salient – a fact that might be reflected in the common activation of many brain regions such as the OFC, ACC, and NAc, as noted above. Nonetheless, there are many regions which are currently thought to be selectively or predominantly activated during the presentation of either rewarding or aversive stimuli. For instance, some areas that appear to be more selective for reward include the ventromedial prefrontal cortex, nucleus basalis, ventral pallidum, and dorsal VTA (Tindell et al.,
One major limitation of the present study in addressing these issues, as noted above, is the fact that brain imaging techniques typically have lower subcortical and subregional resolution. However, consideration of some imaging studies identifying subcortical areas in aversion-related processing (e.g., Jensen et al.,
Like with reward, there may be subregional and neuronal differentiations which correspond to other processing and/or behavioral aspects of aversion such as fear, anxiety, and pain. While the exclusion of studies looking at these specific aversion-related concepts in the present study have allowed for the control of complex behavioral and cognitive factors, it is nonetheless clear that future investigations should include these studies in comparison to the present core aversion-related network. Although studies from these respective fields have largely implicated the involvement of brain areas which are in general agreement with the present study (for example, see the discussion of work by Seymour et al.,
In turn, these open questions lead to another question: How is the anticipation/expectation of aversive stimuli coded by the aversion-related network? To what degree are these processes separate? (For a discussion of the latter question, see Bermpohl et al.,
Examples of studies that have implicated aversion-related processing as being dysfunctional in some psychiatric disorders.
Psychiatric disorder | Evidence of altered aversion-related processing | References |
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Depression | Compared with healthy controls, patients with major depressive disorder (MDD) show increased activation in the right amygdala, and decreased activations in PAG, ACC, prefrontal cortex to the reception of painful > non-painful stimuli; they also show increased activation in the right anterior insula, dorsal ACC, and right amygdala during the anticipation of painful > non-painful stimuli. Also, recovered patients with a history of MDD showed decreased ventral striatal activity to rewarding stimuli and increased dorsal striatal (i.e., caudate nucleus) activity to aversive stimuli. In addition, anticipation of aversive stimuli in patients with depression results in greater activations within the sublenticular extended dorsal amygdala compared to controls, with no differences in the expectation of positive stimuli. | Abler et al. ( |
Addiction | Although little research has been done specifically regarding aversion-related processing and addiction, there is an abundance of research in both humans and animals regarding how stressful/aversive stimuli and drug-associated cues (which are often reported to be highly aversive) can trigger drug seeking and relapse. For instance, one study by Wheeler et al. ( |
Weiss et al. ( |
Schizophrenia | Compared with healthy controls, patients show inappropriately strong ventral striatal activations to neutral stimuli in an aversive learning paradigm. Behaviorally, they also show an inability to properly identify neutral stimuli (reporting them as aversive) which is also consistent with their abnormal autonomic reactivity to these stimuli (e.g., galvanic skin responses). This abnormal aversion-related processing may also be reflected behaviorally by their lack of loss aversion (i.e., the typical behavior of assigning greater value to that which can be lost over that which can be gained). | Jensen et al. ( |
Borderline personality | Few imaging studies have been performed in this group, however, altered aversion-related processing may be involved in the pathophysiology as behaviorally these patients show increased pain thresholds and often engage in self-mutilation. However, one fMRI study by Herpertz et al. ( |
Herpertz et al. ( |
Anxiety disorders | Converging evidence in humans and animals suggests that some anxiety disorders (particularly post-traumatic stress disorder; PTSD) may be related to an inability to inhibit aversion-related signaling. A functional neuroimaging meta-analysis by Etkin and Wager ( |
Etkin and Wager ( |
A related consideration involves the potential role of intrinsic brain activity, or the so-called resting state, on aversion-related processing. Though nearly all of the studies included in the meta-analysis contrasted known aversive stimuli to their neutral equivalent (e.g., aversive vs. neutral pictures), only a few used what could be considered true resting state conditions (e.g., viewing a static image of a fixation-cross; e.g., Liberzon et al.,
Finally, future studies (especially in humans) should further investigate the possible neurochemical mechanisms of aversion-related processing. Glutamate, GABA, dopamine, and serotonin have all been implicated (as have other neurotransmitters), but given the complexity of possible interactions much more work is needed. For instance, numerous animal studies have demonstrated a role for glutamate and GABA (particularly the NMDA and GABAA receptors, respectively) in the ACC (Lei et al.,
To our knowledge, this is the first report using a systematic translational approach investigating aversion-related processing in humans and other animals. It was demonstrated that humans and animals have a common core aversion-related network, consisting of similar cortical and subcortical regions, and that its activity is largely independent of sensory modality and cognitive (e.g., task-related) effects. The identification of this core network helps to explain the reported overlap of neural substrates noted across aversion-related concepts (e.g., pain, fear, punishment). This perspective, in conjunction with future work to identify the precise subregional and neurochemical mechanisms involved, will contribute to a better understanding of how aversive stimuli are processed in both animals and healthy individuals as well as those subjects with psychiatric disorders (like addiction or depression) displaying dysfunctional aversion processing (see
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors would like to thank Niall W. Duncan for his assistance with the MKDA meta-analysis and his critical reading of the manuscript. Georg Northoff holds a Canada Research Chair for Mind, Brain imaging and Neuroethics as well as an EJLB-CIHR Michael Smith Chair in Neurosciences and Mental Health. Dave J. Hayes holds a Postdoctoral Fellowship from the Canadian Institutes of Health Research (CIHR).
ACC, anterior cingulate cortex; AI, anterior insula; amyg, amygdala; BNST, bed n of the stria terminalis; ctx, cortex; d, dorsal; DMPFC, dorsomedial prefrontal ctx; DR, dorsal raphe; DS, dorsal striatum; Hab, habenula; Hipp, hippocampal area; Hyp, hypothalamus; IC, inferior colliculus; IL, infralimbic ctx; Ins, insula; lat, lateral; LC, locus coeruleus; n, nucleus; NAc, nucleus accumbens; NTS, n of the solitary tract; OFC, orbital frontal ctx, PAG, periaqueductal gray; Parahipp, parahippocampal gyrus; PBN, parabrachial n; PFC, prefrontal ctx; PL, prelimbic; RTG, rostral temporal gyri; SC, superior colliculus; Sens, sensory ctx; Sep, septal n; SMA, secondary motor area; Thal, thalamus; VLOFC, ventrolateral orbitofrontal ctx; VTA, ventral tegmental area.
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