Association between activity in the ventral premotor cortex and spinal cord activation during force generation-A combined cortico-spinal fMRI study.

Force generation is a crucial element of dexterity and a highly relevant skill of the human motor system. How cerebral and spinal components interact and how spinal activation is associated with the activity in the cerebral primary motor and premotor areas is poorly understood. Here, we conducted combined cortico-spinal functional magnetic resonance imaging during a simple visually guided isometric force generation task in 20 healthy young subjects. Activation was localized in the right cervical spinal cord and left primary motor and premotor areas. The main finding is that spinal activation was negatively correlated with ventral premotor cortex activation. Spinal activation was furthermore significantly correlated with primary motor cortex activation, while increasing target forces led to an increase in the amount of activation. These data indicate that human premotor areas such as the ventral premotor cortex might be functionally connected to the lower cervical spinal cord contributing to distal upper limb functions, a finding that extends our understanding of human motor function beyond the animal literature.

Cortico-spinal imaging to study pain.

Functional magnetic resonance imaging of the brain has helped to reveal mechanisms of pain perception in health and disease. Recently, imaging approaches have been developed that allow recording neural activity simultaneously in the brain and in the spinal cord. These approaches offer the possibility to examine pain perception in the entire central pain system and in addition, to investigate cortico-spinal interactions during pain processing. Although cortico-spinal imaging is a promising technique, it bears challenges concerning data acquisition and data analysis strategies. In this review, we discuss studies that applied simultaneous imaging of the brain and spinal cord to explore central pain processing. Furthermore, we describe different MR-related acquisition techniques, summarize advantages and disadvantages of approaches that have been implemented so far and present software that has been specifically developed for the analysis of spinal fMRI data to address challenges of spinal data analysis.

Evidence for a spinal involvement in temporal pain contrast enhancement.

Spatiotemporal filtering and amplification of sensory information at multiple levels during the generation of perceptual representations is a fundamental processing principle of the nervous system. While for the visual and auditory system temporal filtering of sensory signals has been noticed for a long time, respective contrast mechanisms within the nociceptive system became only recently subject of investigations, mainly in the context of offset analgesia (OA) subsequent to noxious stimulus decreases. In the present study we corroborate in a first experiment the assumption that offset analgesia involves a central component by showing that an OA-like effect accounting for 74% of a corresponding OA reference can be evoked by decomposing the stimulus offset into two separate box-car stimuli applied within the same dermatome but to separate populations of primary afferent neurons. In order to draw conclusions about the levels of the CNS at which temporal filtering of nociceptive information takes place during OA we investigate in a second experiment neuronal activity in the spinal cord during a painful thermal stimulus offset employing high-resolution fMRI in healthy volunteers. Pain-related BOLD responses in the spinal cord were significantly reduced during OA and their time course followed widely behavioral hypoalgesia, but not the thermal stimulation profile. In summary, the results suggest that temporal pain contrast enhancement during OA comprises a central mechanism and this mechanism becomes already effective at the level of the spinal cord.

Functional representation of trigeminal nociceptive input in the human periaqueductal gray.

The periaqueductal gray (PAG) is located in the mesencephalon in the upper brainstem and, as part of the descending pain modulation, is considered a crucial structure for pain control. Its modulatory effect on painful sensation is often seen as a systemic function affecting the whole body similarly. However, recent animal data suggest some kind of somatotopy in the PAG. This would make the PAG capable of dermatome-specific analgesic function. We electrically stimulated the three peripheral dermatomes of the trigemino-cervical complex and the greater occipital nerve in 61 humans during optimized brainstem functional magnetic resonance imaging. We provide evidence for a fine-grained and highly specific somatotopic representation of nociceptive input in the PAG in humans and a functional connectivity between the individual representations of the peripheral nerves in the PAG and the brainstem nuclei of these nerves. Our data suggest that the downstream antinociceptive properties of the PAG may be rather specific down to the level of individual dermatomes.

Expectations and Prior Experiences Associated With Adverse Effects of COVID-19 Vaccination.

Importance: Uptake of vaccination against COVID-19 is strongly affected by concerns about adverse effects. Research on nocebo effects suggests that these concerns can amplify symptom burden. Objective: To investigate whether positive and negative expectations prior to COVID-19 vaccination are associated with systemic adverse effects. Design, Setting, and Participants: This prospective cohort study analyzed the association of expected benefits and risks of vaccination, adverse effects at first vaccination, and observed adverse effects in close contacts with severity of systemic adverse effects among adults receiving a second dose of messenger RNA (mRNA)-based vaccines between August 16 and 28, 2021. A total of 7771 individuals receiving the second dose at a state vaccination center in Hamburg, Germany, were invited to participate; of these, 5370 did not respond, 535 provided incomplete information, and 188 were excluded retrospectively. The mobile application m-Path was used for data collection. Main Outcomes and Measures: Primary outcome was a composite severity index of systemic adverse effects in 12 symptom areas measured once daily with an electronic symptom diary over 7 consecutive days. Data were analyzed by mixed-effects multivariable ordered logistic regression adjusted for prevaccine symptom levels and observation times. Results: A total of 10 447 observations from 1678 individuals receiving vaccinations (BNT162b2 [Pfizer BioNTech] in 1297 [77.3%] and mRNA-1273 [Moderna] in 381 [22.7%]) were collected. The participants' median age was 34 (IQR, 27-44) years, and 862 (51.4%) were women. The risk for more severe adverse effects was higher for persons expecting a lower benefit of vaccination (odds ratio [OR] for higher expectations, 0.72 [95% CI, 0.63-0.83]; P < .001), expecting higher adverse effects of vaccination (OR, 1.39 [95% CI, 1.23-1.58]; P < .001), having experienced higher symptom burden at the first vaccination (OR, 1.60 [95% CI, 1.42-1.82]; P < .001), scoring higher on the Somatosensory Amplification Scale (OR, 1.21 [95% CI, 1.06-1.38]; P = .004), and if the vaccine mRNA-1273 was given rather than BNT162b2 (OR, 2.45 [95% CI, 2.01-2.99]; P < .001). No associations were seen for observed experiences. Conclusions and Relevance: In this cohort study, several nocebo effects occurred in the first week after COVID-19 vaccination. The severity of systemic adverse effects was associated not only with vaccine-specific reactogenicity but also more negative prior experiences with adverse effects from the first COVID-19 vaccination, more negative expectations regarding vaccination, and tendency to catastrophize instead of normalize benign bodily sensations. Clinician-patient interactions and public vaccine campaigns may both benefit from these insights by optimizing and contextualizing information provided about COVID-19 vaccines.

Opioid analgesia alters corticospinal coupling along the descending pain system in healthy participants.

Opioids are potent analgesic drugs with widespread cortical, subcortical, and spinal targets. In particular, the central pain system comprising ascending and descending pain pathways has high opioid receptor densities and is thus crucial for opioid analgesia. Here, we investigated the effects of the opioid remifentanil in a large sample (n = 78) of healthy male participants using combined corticospinal functional MRI. This approach offers the possibility to measure BOLD responses simultaneously in the brain and spinal cord, allowing us to investigate the role of corticospinal coupling in opioid analgesia. Our data show that opioids altered activity in regions involved in pain processing such as somatosensory regions, including the spinal cord and pain modulation such as prefrontal regions. Moreover, coupling strength along the descending pain system, that is, between the anterior cingulate cortex, periaqueductal gray, and spinal cord, was stronger in participants who reported stronger analgesia during opioid treatment while participants that received saline showed reduced coupling when experiencing less pain. These results indicate that coupling along the descending pain pathway is a potential mechanism of opioid analgesia and can differentiate between opioid analgesia and unspecific reductions in pain such as habituation.

Generalization of placebo pain relief.

ABSTRACT: Efficacy of treatment is heavily dependent on experience and expectations. Moreover, humans can generalize from one experience to a perceptually similar but novel situation. We investigated whether and how this applies to pain relief, using ecologically valid tonic pain stimuli treated by surreptitiously lowering the applied temperature. Using different face cues, participants experienced better treatment from one physician than another. Participants were then tested on 6 additional face cues perceptually lying between both faces. Our data from 2 independent samples (N = 18 and N = 39) show a treatment experience effect, ie, for physically identical treatments, the initially superior physician was reported to deliver stronger pain relief. More importantly, the other faces on the perceptual continuum showed a graded effect of pain relief, indicating placebo generalization. Introducing a paradigm feasible to induce placebo pain relief, we show that the generic learning principle of generalization can explain carryover effects between learned and novel treatment situations.

Observation of others' painful heat stimulation involves responses in the spinal cord.

Observing others' aversive experiences is central to know what is dangerous for ourselves. Hence, observation often elicits behavioral and physiological responses comparable to first-hand aversive experiences and engages overlapping brain activation. While brain activation to first-hand aversive experiences relies on connections to the spinal cord, it is unresolved whether merely observing aversive stimulation also involves responses in the spinal cord. Here, we show that observation of others receiving painful heat stimulation involves neural responses in the spinal cord, located in the same cervical segment as first-hand heat pain. However, while first-hand painful experiences are coded within dorsolateral regions of the spinal cord, observation of others' painful heat stimulation involves medial regions. Dorsolateral areas that process first-hand pain exhibit negative responses when observing pain in others. Our results suggest a distinct processing between self and others' pain in the spinal cord when integrating social information.

On the role of the anterior prefrontal cortex in cognitive 'branching': An fMRI study.

The most anterior portion of prefrontal cortex (aPFC), more specifically Brodman Area 10 (BA10), has been implicated in 'branching operations', or the ability to perform tasks related to one goal, while keeping in working memory information related to a secondary goal. Such findings have been based on fMRI recordings under complex behavioral paradigms that compare 'branching' tasks with tasks where one goal is pursued at a time, but are limited by their complete reliance on verbal working memory and by small sample sizes. Here, we test the specificity of BA 10 to branching in similar behavioral paradigms but with a larger sample and in two different conditions involving verbal and visual working memory respectively. We find that BA 10 and other frontal and parietal brain areas are activated in all tasks, with an extent and level of significance increasing with the complexity of the task. We conclude that the activation of BA 10 is not specific to branching as previously hypothesized, but is related to the level of complexity of working memory performance. For further insight into the specific role of anterior portions of the frontal cortex we highlight the importance of simple control tasks with gradual and incremental increase in complexity.