Falk Eippert

Activation of the opioidergic descending pain control system underlies placebo analgesia.

Placebo analgesia involves the endogenous opioid system, as administration of the opioid antagonist naloxone decreases placebo analgesia. To investigate the opioidergic mechanisms that underlie placebo analgesia, we combined naloxone administration with functional magnetic resonance imaging. Naloxone reduced both behavioral and neural placebo effects as well as placebo-induced responses in pain-modulatory cortical structures, such as the rostral anterior cingulate cortex (rACC). In a brainstem-specific analysis, we observed a similar naloxone modulation of placebo-induced responses in key structures of the descending pain control system, including the hypothalamus, the periaqueductal gray (PAG), and the rostral ventromedial medulla (RVM). Most importantly, naloxone abolished placebo-induced coupling between rACC and PAG, which predicted both neural and behavioral placebo effects as well as activation of the RVM. These findings show that opioidergic signaling in pain-modulating areas and the projections to downstream effectors of the descending pain control system are crucially important for placebo analgesia.

Direct evidence for spinal cord involvement in placebo analgesia.

Functional magnetic resonance imaging of the human spinal cord reveals a mechanism for placebo analgesia. Placebo analgesia is a prime example of the impact that psychological factors have on pain perception. We used functional magnetic resonance imaging of the human spinal cord to test the hypothesis that placebo analgesia results in a reduction of nociceptive processing in the spinal cord. In line with behavioral data that show decreased pain responses under placebo, pain-related activity in the spinal cord is strongly reduced under placebo. These results provide direct evidence for spinal inhibition as one mechanism of placebo analgesia and highlight that psychological factors can act on the earliest stages of pain processing in the central nervous system.

Regulation of emotional responses elicited by threat-related stimuli

The capacity to voluntarily regulate emotions is critical for mental health, especially when coping with aversive events. Several neuroimaging studies of emotion regulation found the amygdala to be a target for downregulation and prefrontal regions to be associated with downregulation. To characterize the role of prefrontal regions in bidirectional emotion regulation and to investigate regulatory influences on amygdala activity and peripheral physiological measures, a functional magnetic resonance imaging (fMRI) study with simultaneous recording of self‐report, startle eyeblink, and skin conductance responses was carried out. Subjects viewed threat‐related pictures and were asked to up‐ and downregulate their emotional responses using reappraisal strategies. While startle eyeblink responses (in successful regulators) and skin conductance responses were amplified during upregulation, but showed no consistent effect during downregulation, amygdala activity was increased and decreased according to the regulation instructions. Trial‐by‐trial ratings of regulation success correlated positively with activity in amygdala during upregulation and orbitofrontal cortex during downregulation. Downregulation was characterized by left‐hemispheric activation peaks in anterior cingulate cortex, dorsolateral prefrontal cortex, and orbitofrontal cortex and upregulation was characterized by a pattern of prefrontal activation not restricted to the left hemisphere. Further analyses showed significant overlap of prefrontal activation across both regulation conditions, possibly reflecting cognitive processes underlying both up‐ and downregulation, but also showed distinct activations in each condition. The present study demonstrates that amygdala responses to threat‐related stimuli can be controlled through the use of cognitive strategies depending on recruitment of prefrontal areas, thereby changing the subjects affective state. Hum Brain Mapp, 2007.

Trigeminal nociceptive transmission in migraineurs predicts migraine attacks.

Several lines of evidence suggest a major role of the trigeminovascular system in the pathogenesis of migraine. Using functional magnetic resonance imaging (fMRI), we compared brain responses during trigeminal pain processing in migraine patients with those of healthy control subjects. The main finding is that the activity of the spinal trigeminal nuclei in response to nociceptive stimulation showed a cycling behavior over the migraine interval. Although interictal (i.e., outside of attack) migraine patients revealed lower activations in the spinal trigeminal nuclei compared with controls, preictal (i.e., shortly before attack) patients showed activity similar to controls, which demonstrates that the trigeminal activation level increases over the pain-free migraine interval. Remarkably, the distance to the next headache attack was predictable by the height of the signal intensities in the spinal nuclei. Migraine patients scanned during the acute spontaneous migraine attack showed significantly lower signal intensities in the trigeminal nuclei compared with controls, demonstrating activity levels similar to interictal patients. Additionally we found—for the first time using fMRI—that migraineurs showed a significant increase in activation of dorsal parts of the pons, previously coined “migraine generator.” Unlike the dorsal pons activation usually linked to migraine attacks, the gradient-like activity following nociceptive stimulation in the spinal trigeminal neurons likely reflects a raise in susceptibility of the brain to generate the next attack, as these areas increase their activity long before headache starts. This oscillating behavior may be a key player in the generation of migraine headache, whereas attack-specific pons activations are most likely a secondary event.

Placebo Analgesia: A Predictive Coding Perspective

This Perspective reviews recent findings in placebo hypoalgesia and provides a conceptual account of how expectations and experience can lead to placebo hypoalgesia. In particular, we put forward the idea that the ascending and the descending pain system resembles a recurrent system that allows for the implementation of predictive coding-meaning that the brain is not passively waiting for nociceptive stimuli to impinge on it but is actively making inferences based on prior experience and expectations. The Bayesian formulation within the predictive coding framework can directly account for differences in the magnitude but also the precision of expectations that are known to influence the strength of placebo hypoalgesia. We discuss how modulatory neurotransmitters such as opioids might be related to the characterization of expectations with an emphasis on the precision of these expectations. Finally, we develop experimental strategies that are suited to test this framework at the behavioral and neuronal level.

Attention Modulates Spinal Cord Responses to Pain

Reduced pain perception while being distracted from pain is an everyday example of how cognitive processes can interfere with pain perception. Previous neuroimaging studies showed distraction-related modulations of pain-driven activations in various cortical and subcortical brain regions, but the precise neuronal mechanism underlying this phenomenon is unclear. Using high-resolution functional magnetic resonance imaging of the human cervical spinal cord in combination with thermal pain stimulation and a well-established working memory task, we demonstrate that this phenomenon relies on an inhibition of incoming pain signals in the spinal cord. Neuronal responses to painful stimulation in the dorsal horn of the corresponding spinal segment were significantly reduced under high working memory load compared to low working memory load. At the individual level, reductions of neuronal responses in the spinal cord predicted behavioral pain reductions. In a subsequent behavioral experiment, using the opioid antagonist naloxone in a double-blind crossover design with the same paradigm, we demonstrate a substantial contribution of endogenous opioids to this mechanism. Taken together, our results show that the reduced pain experience during mental distraction is related to a spinal process and involves opioid neurotransmission.

Corticocortical connections mediate primary visual cortex responses to auditory stimulation in the blind.

Blind individuals have to rely on nonvisual information to a greater extent than sighted to efficiently interact with the environment, and consequently exhibit superior skills in their spared modalities. These performance advantages are often paralleled by responses in the occipital cortex, which have been suggested to be essential for nonvisual processing in the blind. However, it is currently unclear through which pathways (i.e., thalamocortical or corticocortical connections) nonvisual information reaches the occipital cortex of the blind. Here, we used functional magnetic resonance imaging to study blind and matched sighted humans with an auditory discrimination paradigm and used dynamic causal modeling to investigate the effective connectivity underlying auditory activations in the primary visual cortex of blind volunteers. Model comparison revealed that a model connecting the medial geniculate nucleus (MGN), primary auditory cortex (A1), and primary visual cortex (V1) in a bidirectional manner outperformed all other models in both groups. Regarding inference on model parameters, we observed that basic auditory mechanisms (i.e., sensory input to MGN and connections from MGN to A1) did not differ significantly between the two groups. In contrast, we found clear evidence for stronger corticocortical connections from A1 to V1 in the blind, whereas results with regard to thalamocortical enhancement (from MGN to V1 and, in a control analysis, from the lateral geniculate nucleus to V1) were not consistent. These results suggest that plastic changes especially in corticocortical connectivity allow auditory information to evoke responses in the primary visual cortex of blind individuals.

The human amygdala is sensitive to the valence of pictures and sounds irrespective of arousal: an fMRI study

With the advent of studies showing that amygdala responses are not limited to fear-related or highly unpleasant stimuli, studies began to focus on stimulus valence and stimulus-related arousal as predictors of amygdala activity. Recent studies in the chemosensory domain found amygdala activity to increase with the intensity of negative and positive chemosensory stimuli. This has led to the proposal that amygdala activity might be an indicator of emotional arousal, at least in the chemosensory domain. The present study investigated amygdala activity in response to visual and auditory stimuli. By selecting stimuli based on individual valence and arousal ratings, we were able to dissociate stimulus valence and stimulus-related arousal, both on the verbal and the peripheral physiological level. We found that the amygdala was sensitive to stimulus valence even when arousal was controlled for, and that increased amygdala activity was better explained by valence than by arousal. The proposed difference in the relation between amygdala activity and stimulus-related arousal between the chemosensory and the audiovisual domain is discussed in terms of the amygdalas embedding within these sensory systems and the processes by which emotional meaning is derived.

Down-Regulation of Insular Cortex Responses to Dyspnea and Pain in Asthma

RATIONALE Dyspnea is the impairing cardinal symptom of asthma but its accurate perception is also crucial for timely initiation of treatment. However, the underlying brain mechanisms of perceived dyspnea in patients with asthma are unknown. OBJECTIVES To study brain mechanisms of dyspnea in asthma. METHODS By using functional magnetic resonance imaging we compared the neuronal responses to experimentally induced dyspnea in patients with asthma and healthy controls. These brain activations were compared with neuronal responses evoked by pain to study neuronal generalization processes to another, similarly unpleasant, physiological sensation. MEASUREMENTS AND MAIN RESULTS While lying in the scanner, fourteen patients with mild-to-moderate asthma and fourteen matched healthy controls repeatedly underwent conditions of mild dyspnea, severe dyspnea, mild pain and severe pain. Dyspnea was induced by resistive loaded breathing. Heat pain of similar intensity was induced by a contact thermode. Whereas the sensory intensity of both sensations was rated similar by patients and controls, ratings of the affective unpleasantness of dyspnea and pain were reduced in patients. This perceptual difference was mirrored by reduced insular cortex activity, but increased activity in the periaqueductal gray (PAG) in patients during both increased dyspnea and pain. Connectivity analyses showed that asthma-specific down-regulation of the insular cortex during dyspnea and pain was moderated by increased PAG activity. CONCLUSIONS The results suggest a down-regulation of affect-related insular cortex activity by the PAG during perceived dyspnea and pain in patients with asthma. This might represent a neuronal habituation mechanism reducing the affective unpleasantness of dyspnea in asthma, which generalizes to other unpleasant physiological sensations such as pain.

Blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans.

The endogenous opioid system is involved in fear learning in rodents, as opioid agonists attenuate and opioid antagonists facilitate the acquisition of conditioned fear. It has been suggested that an opioidergic signal, which is engaged through conditioning and acts inhibitory on unconditioned stimulus input, is the source of these effects. To clarify whether blockade of endogenous opioid neurotransmission enhances acquisition of conditioned fear in humans, and to elucidate the neural underpinnings of such an effect, we used functional magnetic resonance imaging in combination with behavioral recordings and a double-blind pharmacological intervention. All subjects underwent the same classical fear-conditioning paradigm, but subjects in the experimental group received the opioid antagonist naloxone before and during the experiment, in contrast to subjects in the control group, who received saline. Blocking endogenous opioid neurotransmission with naloxone led to more sustained responses to the unconditioned stimulus across trials, evident in both behavioral and blood oxygen level-dependent responses in pain responsive cortical regions. This effect was likely caused by naloxone blocking conditioned responses in a pain-inhibitory circuit involving opioid-rich areas such as the rostral anterior cingulate cortex, amygdala, and periaqueductal gray. Most importantly, naloxone enhanced the acquisition of fear on the behavioral level and changed the activation profile of the amygdala: whereas the control group showed rapidly decaying conditioned responses across trials, the naloxone group showed sustained conditioned responses in the amygdala. Together, these results demonstrate that in humans the endogenous opioid system has an inhibitory role in the acquisition of fear.