Pain-motor integration in the primary motor cortex in Parkinson's disease

In Parkinson's disease (PD), the influence of chronic pain on motor features has never been investigated. We have recently designed a technique that combines nociceptive system activation by laser stimuli and primary motor cortex (M1) activation through transcranial magnetic stimulation (TMS), in a laser-paired associative stimulation design (Laser-PAS). In controls, Laser-PAS induces long-term changes in motor evoked potentials reflecting M1 long-term potentiation-like plasticity, arising from pain-motor integration

Stimulation of TRPV1 by green laser light

Low-level laser irradiation of visible light had been introduced as a medical treatment already more than 40 years ago, but its medical application still remains controversial. Laser stimulation of acupuncture points has also been introduced, and mast-cells degranulation has been suggested. Activation of TRPV ion channels may be involved in the degranulation. Here, we investigated whether TRPV1 could serve as candidate for laser-induced mast cell activation. Activation of TRPV1 by capsaicin resulted in degranulation. To investigate the effect of laser irradiation on TRPV1, we used the Xenopus oocyte as expression and model system. We show that TRPV1 can functionally be expressed in the oocyte by (a) activation by capsaicin (K 1/2 = 1.1 μM), (b) activation by temperatures exceeding 42°C, (c) activation by reduced pH (from 7.4 to 6.2), and (d) inhibition by ruthenium red. Red (637 nm) as well as blue (406 nm) light neither affected membrane currents in oocytes nor did it modulate capsaicin-induced current. In contrast, green laser light (532 nm) produced power-dependent activation of TRPV1. In conclusion, we could show that green light is effective at the cellular level to activate TRPV1. To which extend green light is of medical relevance needs further investigation

Modulation of laser-evoked pain perception and event-related potentials with non-invasive stimulation of the motor cortex

In the last two decades new techniques of non-invasive brain stimulation have been introduced that enable relatively long-lasting and reversible facilitation or inhibition of distinct cortical areas by modulating the excitability of underlying neurons. Among these methods, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are the most widespread ones. To date, both have been successfully used to modulate various perceptual, cognitive and motor functions in healthy subjects and several diseases, including chronic pain. Their efficacy regarding acute pain perception in healthy subjects, however, is still not well-established. The aims of our studies were to investigate the effects of a novel rTMS paradigm, called continuous theta-burst stimulation (cTBS), and tDCS on laser-induced acute pain perception and laser-evoked potentials (LEPs) when applied to the motor cortex of healthy adult volunteers. In two psychophysical and two electrophysiological experiments, we have compared the effects of real cTBS and two tDCS protocols (anodal and cathodal) to those of sham stimulations. We have shown for the first time that cTBS over the motor cortex significantly alleviated laser-induced pain on both hands, accentuating on the con tralateral limb. The effect of cTBS was accompanied by reduced N2-P2 LEP amplitudes in the case of medium intensity pain. In the tDCS experiments, cathodal stimulation of the motor cortex reduced mild pain contralateral to the side of stimulation. Moreover, cathodal tDCS attenuated N2-P2 LEP components, without modulating thresholds of medium intensity pain. On the contrary, anodal tDCS facilitated laser-induced warm sensation contralateral to the side of tDCS, without affecting either pain sensation or LEPs. Our results indicate that non-invasive stimulation of the motor cortex causes antinociceptive effects that depend on the parameters of stimulation and are probably due to excitability changes in remote pain-related areas such as the operculoinsular region and the anterior cingulate cortex. These findings further strengthen the application of cTBS and tDCS in pain research, which might contribute to a more efficient manipulation of brain plasticity for therapeutic purposes

Linking pain and the body: neural correlates of visually induced analgesia

The visual context of seeing the body can reduce the experience of acute pain, producing a multisensory analgesia. Here we investigated the neural correlates of this “visually induced analgesia” using fMRI. We induced acute pain with an infrared laser while human participants looked either at their stimulated right hand or at another object. Behavioral results confirmed the expected analgesic effect of seeing the body, while fMRI results revealed an associated reduction of laser-induced activity in ipsilateral primary somatosensory cortex (SI) and contralateral operculoinsular cortex during the visual context of seeing the body. We further identified two known cortical networks activated by sensory stimulation: (1) a set of brain areas consistently activated by painful stimuli (the so-called “pain matrix”), and (2) an extensive set of posterior brain areas activated by the visual perception of the body (“visual body network”). Connectivity analyses via psychophysiological interactions revealed that the visual context of seeing the body increased effective connectivity (i.e., functional coupling) between posterior parietal nodes of the visual body network and the purported pain matrix. Increased connectivity with these posterior parietal nodes was seen for several pain-related regions, including somatosensory area SII, anterior and posterior insula, and anterior cingulate cortex. These findings suggest that visually induced analgesia does not involve an overall reduction of the cortical response elicited by laser stimulation, but is consequent to the interplay between the brain's pain network and a posterior network for body perception, resulting in modulation of the experience of pain

Fine-grained nociceptive maps in primary somatosensory cortex

Topographic maps of the receptive surface are a fundamental feature of neural organization in many sensory systems. While touch is finely mapped in the cerebral cortex, it remains controversial how precise any cortical nociceptive map may be. Given that nociceptive innervation density is relatively low on distal skin regions such as the digits, one might conclude that the nociceptive system lacks fine representation of these regions. Indeed, only gross spatial organization of nociceptive maps has been reported so far. However, here we reveal the existence of fine-grained somatotopy for nociceptive inputs to the digits in human primary somatosensory cortex (SI). Using painful nociceptive-selective laser stimuli to the hand, and phase-encoded fMRI analysis methods, we observed somatotopic maps of the digits in contralateral SI. These nociceptive maps were highly aligned with maps of non-painful tactile stimuli, suggesting comparable cortical representations for, and possible interactions between, mechanoreceptive and nociceptive signals. Our findings may also be valuable for future studies tracking the timecourse and the spatial pattern of plastic changes in cortical organization involved in chronic pain

Pain perception and migraine

Background: It is well-known that both inter-and intra-individual differences exist in the perception of pain; this is especially true in migraine, an elusive pain disorder of the head. Although electrophysiology and neuroimaging techniques have greatly contributed to a better understanding of the mechanisms involved in migraine during recent decades, the exact characteristics of pain threshold and pain intensity perception remain to be determined, and continue to be a matter of debate.Objective: The aim of this review is to provide a comprehensive overview of clinical, electrophysiological, and functional neuroimaging studies investigating changes during various phases of the so-called "migraine cycle" and in different migraine phenotypes, using pain threshold and pain intensity perception assessments.Methods: A systematic search for qualitative studies was conducted using search terms "migraine," "pain," "headache," "temporal summation," "quantitative sensory testing," and "threshold," alone and in combination (subject headings and keywords). The literature search was updated using the additional keywords "pain intensity," and "neuroimaging"to identify full-text papers written in English and published in peer-reviewed journals, using PubMed and Google Scholar databases. In addition, we manually searched the reference lists of all research articles and review articles.Conclusion: Consistent data indicate that pain threshold is lower during the ictal phase than during the interictal phase of migraine or healthy controls in response to pressure, cold and heat stimuli. There is evidence for preictal sub-allodynia, whereas interictal results are conflicting due to either reduced or no observed difference in pain threshold. On the other hand, despite methodological limitations, converging observations support the concept that migraine attacks may be characterized by an increased pain intensity perception, which normalizes between episodes. Nevertheless, future studies are required to longitudinally evaluate a large group of patients before and after pharmacological and non-pharmacological interventions to investigate phases of the migraine cycle, clinical parameters of disease severity and chronic medication usage

Prepontine non-giant neurons drive flexible escape behavior in zebrafish

Many species execute ballistic escape reactions to avoid imminent danger. Despite fast reaction times, responses are often highly regulated, reflecting a trade-off between costly motor actions and perceived threat level. However, how sensory cues are integrated within premotor escape circuits remains poorly understood. Here, we show that in zebrafish, less precipitous threats elicit a delayed escape, characterized by flexible trajectories, which are driven by a cluster of 38 prepontine neurons that are completely separate from the fast escape pathway. Whereas neurons that initiate rapid escapes receive direct auditory input and drive motor neurons, input and output pathways for delayed escapes are indirect, facilitating integration of cross-modal sensory information. These results show that rapid decision-making in the escape system is enabled by parallel pathways for ballistic responses and flexible delayed actions and defines a neuronal substrate for hierarchical choice in the vertebrate nervous system