Anticipatory brainstem activity predicts neural processing of pain in humans

Department of Physiology, Anatomy and Genetics, Department of Clinical Neurology, University of Oxford, Oxford OX1 3QX, United Kingdom.
Pain (Impact Factor: 5.21). 04/2007; 128(1-2):101-10. DOI: 10.1016/j.pain.2006.09.001
Source: PubMed


Previous neuroimaging studies have shown brain activity during not only the application of noxious stimuli, but also prior to stimulation. The functional significance of the anticipatory response, however, has yet to be explored. Two theoretical responses involve either a decrease or an increase in sensitivity of the nociceptive system. In a functional magnetic resonance imaging (fMRI) study, brainstem responses during anticipation and processing of thermal noxious stimuli were investigated. Twelve healthy subjects were warned prior to and then received noxious stimulation to their left hand. Behavioral data showed a positive correlation between the intensity of anticipation and pain. FMRI data revealed brainstem activation in the PAG during the anticipation period. When correlated with individual anticipation ratings, activation during anticipation included significant clusters within the entorhinal cortex and ventral tegmental area (VTA). During receipt, activation within the brainstem included the PAG, VTA, rostral ventromedial medulla (RVM), and the parabrachial nucleus (PB), all elements of descending pain pathways. Using a backward model approach, we explored the functional significance of the anticipatory neural response for subsequent pain processing. Results of this regression analysis revealed that insula activity during receipt was predicted by activity in both the entorhinal cortex and VTA during anticipation. We suggest that activation in both regions before and during pain may underlie anticipation and subsequent pain modulatory responses, possibly involving the appraisal and control of attention necessary for pain modulation. Together, the results suggest a possible role of brainstem areas in anticipatory mechanisms involved in the maintenance of chronic pain.

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    • "This finding corroborates previous studies that have reported decreased nociceptive processing when fasting (Davidson et al. 1992; de los Santos-Arteaga et al. 2003; McGivern et al. 1979; McGivern and Berntson 1980). A contribution by parahippocampal cortex (or very closely related areas) to evoked pain responses has been postulated previously in EEG source analysis studies (Stancak et al. 2013; Stancak and Fallon 2013; Valeriani et al. 1996, 2000, 2002), and experiments with fMRI have cited PHG as being involved in processes such as reactivating memories of pain (Kattoor et al. 2013), pain anticipation (Fairhurst et al. 2007), and pain sensitivity (Piche et al. 2010). Interestingly, in the present study the effects of session on PHG activation were not correlated with pain ratings but rather with ratings of food photograph hedonicity. "
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    ABSTRACT: Hunger and pain are basic drives that compete for a behavioral response when experienced together. To investigate the cortical processes underlying hunger-pain interactions, we manipulated participants' hunger and presented photographs of appetizing food or inedible objects in combination with painful laser stimuli. Fourteen healthy participants completed two EEG sessions: one after an overnight fast, the other following a large breakfast. Spatio-temporal patterns of cortical activation underlying the hunger-pain competition were explored using 128-channel EEG recordings, and source dipole analysis of laser evoked potentials (LEPs). We found that initial pain ratings were temporarily reduced when participants were hungry compared to when fed. Source activity in parahippocampal gyrus was weaker when participants were hungry, and activations of operculo-insular cortex, anterior cingulate cortex, parahippocampal gyrus, and cerebellum were smaller in the context of appetitive food photographs than in that of inedible object photographs. Cortical processing of noxious stimuli in pain-related brain structures is reduced and pain temporarily attenuated when people are hungry or passively viewing food photographs, suggesting a possible interaction between the opposing motivational forces of the eating drive and pain. Copyright © 2014, Journal of Neurophysiology.
    Journal of Neurophysiology 12/2014; 113(5):jn.00504.2014. DOI:10.1152/jn.00504.2014 · 2.89 Impact Factor
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    • "Their coordinates were based on previous studies. We specified the sgACC (x = 0, y = 22, z = −6) (Fairhurst et al., 2007) and PAG (left: x = − 2, y = -28, z = − 8; right: x = 3, y = -28, z = − 6) (Yoshida et al., 2013). In each ROI, the peak value per subject and per contrast was obtained with a homemade Matlab program. "
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    ABSTRACT: The human brain responds both before and during the application of aversive stimuli. Anticipation allows the organism to prepare its nociceptive system to respond adequately to the subsequent stimulus. The context in which an uncomfortable stimulus is experienced may also influence neural processing. Uncertainty of occurrence, timing and intensity of an aversive event may lead to increased anticipatory anxiety, fear, physiological arousal and sensory perception. We aimed to identify, in healthy volunteers, the effects of uncertainty in the anticipation of uncomfortable rectal distension, and the impact of the autonomic nervous system (ANS) activity and anxiety-related psychological variables on neural mechanisms of anticipation of rectal distension using fMRI. Barostat-controlled uncomfortable rectal distensions were preceded by cued uncertain or certain anticipation in 15 healthy volunteers in a fMRI protocol at 3T. Electrocardiographic data were concurrently registered by MR scanner. The low frequency (LF)-component of the heart rate variability (HRV) time-series was extracted and inserted as a regressor in the fMRI model ('LF-HRV model'). The impact of ANS activity was analyzed by comparing the fMRI signal in the 'standard model' and in the 'LF-HRV model' across the different anticipation and distension conditions. The scores of the psychological questionnaires and the rating of perceived anticipatory anxiety were included as covariates in the fMRI data analysis. Our experiments led to the following key findings: 1) the subgenual anterior cingulate cortex (sgACC) is the only activation site that relates to uncertainty in healthy volunteers and is directly correlated to individual questionnaire score for pain-related anxiety; 2) uncertain anticipation of rectal distension involved several relevant brain regions, namely activation of sgACC and medial prefrontal cortex and deactivation of amygdala, insula, thalamus, secondary somatosensory cortex, supplementary motor area and cerebellum; 3) most of the brain activity during anticipation, but not distension, is associated with activity of the central autonomic network. This approach could be applied to study the ANS impact on brain activity in various pathological conditions, namely in patients with chronic digestive conditions characterized by visceral discomfort and ANS imbalance such as irritable bowel syndrome or inflammatory bowel diseases. Copyright © 2014 Elsevier Inc. All rights reserved.
    NeuroImage 12/2014; 107. DOI:10.1016/j.neuroimage.2014.11.043 · 6.36 Impact Factor
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    • "Coordinates for small volume correction were based on peak coordinates obtained from previous studies on pain processing and pain modulation. The PAG65, the ventral striatum62 were corrected using spheres of 4 mm radius. The anterior MPFC66 and the pregenual rostral anterior cingular cortex (rACC)67 were corrected using spheres of 9 mm radius. "
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    Scientific Reports 09/2014; 4:6482. DOI:10.1038/srep06482 · 5.58 Impact Factor
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