Evidence for Thalamic Involvement in the Thermal Grill Illusion: An fMRI Study

Perceptual illusions play an important role in untangling neural mechanisms underlying conscious phenomena. The thermal grill illusion (TGI) has been suggested as a promising model for exploring percepts involved in neuropathic pain, such as cold-allodynia (pain arising from contact with innocuous cold). The TGI is an unpleasant/painful sensation from touching juxtapositioned bars of cold and warm innocuous temperatures.To develop an MRI-compatible TGI-unit and explore the supraspinal correlates of the illusion, using fMRI, in a group of healthy volunteers.We constructed a TGI-thermode allowing the rapid presentation of warm(41°C), cold(18°C) and interleaved(41°C+18°C = TGI) temperatures in an fMRI-environment. Twenty volunteers were tested. The affective-motivational (“unpleasantness”) and sensory-disciminatory (“pain-intensity”) dimensions of each respective stimulus were rated. Functional images were analyzed at a corrected α-level <0.05.The TGI was rated as significantly more unpleasant and painful than stimulation with each of its constituent temperatures. Also, the TGI was rated as significantly more unpleasant than painful. Thermal stimulation versus neutral baseline revealed bilateral activations of the anterior insulae and fronto-parietal regions. Unlike its constituent temperatures the TGI displayed a strong activation of the right (contralateral) thalamus. Exploratory contrasts at a slightly more liberal threshold-level also revealed a TGI-activation of the right mid/anterior insula, correlating with ratings of unpleasantness(rho = 0.31).To the best of our knowledge, this is the first fMRI-study of the TGI. The activation of the anterior insula is consistent with this region's putative role in processing of homeostatically relevant feeling-states. Our results constitute the first neurophysiologic evidence of thalamic involvement in the TGI. Similar thalamic activity has previously been observed during evoked cold-allodynia in patients with central neuropathic pain. Our results further the understanding of the supraspinal correlates of the TGI-phenomenon and pave the way for future inquiries into if and how it may relate to neuropathic pain

Ultrastructure and synaptic connectivity of main and accessory olfactory bulb efferent projections terminating in the rat anterior piriform cortex and medial amygdala

Neurons in the main olfactory bulb relay peripheral odorant signals to the anterior piriform cortex (aPir), whereas neurons of the accessory olfactory bulb relay pheromone signals to the medial amygdala (MeA), suggesting that they belong to two functionally distinct systems. To help understand how odorant and pheromone signals are further processed in the brain, we investigated the synaptic connectivity of identified axon terminals of these neurons in layer Ia of the aPir and posterodorsal part of the MeA, using anterograde tracing with horseradish peroxidase, quantitative ultrastructural analysis of serial thin sections, and immunogold staining. All identified boutons contained round vesicles and some also contained many large dense core vesicles. The number of postsynaptic dendrites per labeled bouton was significantly higher in the aPir than in the MeA, suggesting higher synaptic divergence at a single bouton level. While a large fraction of identified boutons (29 %) in the aPir contacted 2-4 postsynaptic dendrites, only 7 % of the identified boutons in the MeA contacted multiple postsynaptic dendrites. In addition, the majority of the identified boutons in the aPir (95 %) contacted dendritic spines, whereas most identified boutons in the MeA (64 %) contacted dendritic shafts. Identified boutons and many of the postsynaptic dendrites showed glutamate immunoreactivity. These findings suggest that odorant and pheromone signals are processed differently in the brain centers of the main and accessory olfactory systems. © 2013 Springer-Verlag Berlin Heidelberg.1

Corticotropin-releasing Factor Receptor 2 Mediates Sex-Specific Cellular Stress Responses

Although females suffer twice as much as males from stress-related disorders, sex-specific participating and pathogenic cellular stress mechanisms remain uncharacterized. Using corticotropin-releasing factor receptor 2–deficient (Crhr2(−/−) ) and wild-type (WT) mice, we show that CRF receptor type 2 (CRF(2)) and its high-affinity ligand, urocortin 1 (Ucn1), are key mediators of the endoplasmic reticulum (ER) stress response in a murine model of acute pancreatic inflammation. Ucn1 was expressed de novo in acinar cells of male, but not female WT mice during acute inflammation. Upon insult, acinar Ucn1 induction was markedly attenuated in male but not female Crhr2(−/−) mice. Crhr(2)(−/−) mice of both sexes show exacerbated acinar cell inflammation and necrosis. Electron microscopy showed mild ER damage in WT male mice and markedly distorted ER structure in Crhr2(−/−) male mice during pancreatitis. WT and Crhr2(−/−) female mice showed similarly distorted ER ultrastructure that was less severe than distortion seen in Crhr2(−/−) male mice. Damage in ER structure was accompanied by increased ubiquitination, peIF2, and mistargeted localization of vimentin in WT mice that was further exacerbated in Crhr2(−/−) mice of both sexes during pancreatitis. Exogenous Ucn1 rescued many aspects of histological damage and cellular stress response, including restoration of ER structure in male WT and Crhr2(−/−)mice, but not in females. Instead, females often showed increased damage. Thus, specific cellular pathways involved in coping and resolution seem to be distinct to each sex. Our results demonstrate the importance of identifying sex-specific pathogenic mechanisms and their value in designing effective therapeutics

Reappraising neuropathic pain in humans—how symptoms help disclose mechanisms

Neuropathic pain--that is, pain arising directly from a lesion or disease that affects the somatosensory system--is a common clinical problem, and typically causes patients intense distress. Patients with neuropathic pain have sensory abnormalities on clinical examination and experience pain of diverse types, some spontaneous and others provoked. Spontaneous pain typically manifests as ongoing burning pain or paroxysmal electric shock-like sensations. Provoked pain includes pain induced by various stimuli or even gentle brushing (dynamic mechanical allodynia). Recent clinical and neurophysiological studies suggest that the various pain types arise through distinct pathophysiological mechanisms. Ongoing burning pain primarily reflects spontaneous hyperactivity in nociceptive-fibre pathways, originating from 'irritable' nociceptors, regenerating nerve sprouts or denervated central neurons. Paroxysmal sensations can be caused by several mechanisms; for example, electric shock-like sensations probably arise from high-frequency bursts generated in demyelinated non-nociceptive Aβ fibres. Most human and animal findings suggest that brush-evoked allodynia originates from Aβ fibres projecting onto previously sensitized nociceptive neurons in the dorsal horn, with additional contributions from plastic changes in the brainstem and thalamus. Here, we propose that the emerging mechanism-based approach to the study of neuropathic pain might aid the tailoring of therapy to the individual patient, and could be useful for drug development.Neuropathic pain - that is, pain arising directly from a lesion or disease that affects the somatosensory system - is a common clinical problem, and typically causes patients intense distress. Patients with neuropathic pain have sensory abnormalities on clinical examination and experience pain of diverse types, some spontaneous and others provoked. Spontaneous pain typically manifests as ongoing burning pain or paroxysmal electric shock-like sensations. Provoked pain includes pain induced by various stimuli or even gentle brushing (dynamic mechanical allodynia). Recent clinical and neurophysiological studies suggest that the various pain types arise through distinct pathophysiological mechanisms. Ongoing burning pain primarily reflects spontaneous hyperactivity in nociceptive-fibre pathways, originating from 'irritable' nociceptors, regenerating nerve sprouts or denervated central neurons. Paroxysmal sensations can be caused by several mechanisms; for example, electric shock-like sensations probably arise from high-frequency bursts generated in demyelinated non-nociceptive Aβ fibres. Most human and animal findings suggest that brush-evoked allodynia originates from Aβ fibres projecting onto previously sensitized nociceptive neurons in the dorsal horn, with additional contributions from plastic changes in the brainstem and thalamus. Here, we propose that the emerging mechanism-based approach to the study of neuropathic pain might aid the tailoring of therapy to the individual patient, and could be useful for drug development. © 2013 Macmillan Publishers Limited