Kazuaki Nagasaka

Central post-stroke pain (CPSP) is a neuropathic pain condition that can substantially impact sensory function, daily activities, and participation in rehabilitation after stroke. Although CPSP has traditionally been associated with thalamic lesions, accumulating evidence indicates that it is associated with disruption of a broader nociceptive network involving multiple brain regions and the white matter pathways connecting them. This network-based view has shifted the focus of neuroimaging research from individual lesion locations to the neural pathways and networks underlying CPSP. Experimental studies have further identified the potential roles of glial activation, altered γ-aminobutyric acidergic signaling, and maladaptive plasticity in the development of abnormal pain. Clinically, CPSP may emerge following the acute phase of stroke, raising the possibility of identifying patients at risk before pain becomes apparent. Quantitative sensory testing, particularly the assessment of cold sensation, may provide an early functional marker of subsequent CPSP. Furthermore, pain quality may provide information about the underlying mechanisms of pain and its subsequent clinical course. This review summarizes current evidence linking brain lesions, disrupted neural pathways, sensory dysfunction, and CPSP and discusses the potential of integrating neuroimaging with sensory assessment for early risk stratification.

The locus coeruleus (LC) neurons send extensive projections to the somatosensory cortex and release noradrenaline (NA) at synaptic terminals, which is thought to regulate the activation of sensory‐related cells by acting on three types of receptors (α1, α2 and β). Although previous studies have examined the effects of LC stimulation on single‐unit sensory neurons, their impact on somatosensory evoked potentials (SEPs) and their temporal variations, as well as the specific roles of NA receptors, remain unclear. Herein, we investigated how SEPs are modulated by tonic LC stimulation at physiological frequencies (0.1, 1 and 4 Hz) and identified the receptors involved in these changes. Forepaw stimulation‐induced amplitudes in SEP were enhanced in response to 1 Hz stimulation of the LC but not in response to 0.1 and 4 Hz stimulation. Interestingly, the enhancement of SEPs after LC stimulation persisted for tens of minutes following the cessation of stimulation. Optical imaging using a voltage‐sensitive dye showed an increase in the depolarizing response in the somatosensory cortex after 1 Hz stimulation. Prazosin (α1 receptor antagonist) and propranolol (β receptor antagonist) inhibited SEP enhancement following 1 Hz LC stimulation, whereas yohimbine (α2 receptor antagonist) had no effect. This suggests that the enhancement in SEP observed is primarily mediated by the activation of cortical excitatory α1 and β receptors. These findings provide insight into the impact of the NA system on sensory information processing and the pathophysiology of sensory disorders related to the disruption of the NA system.

The locus coeruleus (LC) neurons send extensive projections to the somatosensory cortex and release noradrenaline (NA) at synaptic terminals, which is thought to regulate the activation of sensory-related cells by acting on three types of receptors (α1, α2 and β). Although previous studies have examined the effects of LC stimulation on single-unit sensory neurons, their impact on somatosensory evoked potentials (SEPs) and their temporal variations, as well as the specific roles of NA receptors remain unclear. Herein, we investigated how SEPs are modulated by tonic LC stimulation at physiological frequencies (0.1, 1 and 4 Hz) and identified the receptors involved in these changes. Forepaw stimulation-induced amplitudes in SEP were enhanced in response to 1 Hz stimulation of the LC but not in response to 0.1 and 4 Hz stimulation. Interestingly, the enhancement of SEPs after LC stimulation persisted for tens of minutes following the cessation of stimulation. Optical imaging using a voltage-sensitive dye showed an increase in the depolarizing response in the somatosensory cortex after 1 Hz stimulation. Prazosin (α1 receptor antagonist) and propranolol (β receptor antagonist) inhibited SEP enhancement following 1 Hz LC stimulation, whereas yohimbine (α2 receptor antagonist) had no effect. This suggests that the observed enhancement in SEP observed is primarily mediated by the activation of cortical excitatory α1 and β receptors. These findings provide insight into the impact of the NA system on sensory information processing as well as the pathophysiology of sensory disorders related to the disruption of the NA system.

Central post-stroke pain (CPSP) is a chronic pain resulting from a lesion in somatosensory pathways. Neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS) that target the primary motor cortex (M1), have shown promise for the treatment of CPSP. High-frequency (Hf) rTMS exhibits analgesic effects compared to low-frequency (Lf) rTMS; however, its analgesic mechanism is unknown. We aimed to elucidate the mechanism of rTMS-induced analgesia by evaluating alterations of tactile functional magnetic resonance imaging (fMRI) due to Hf- and Lf-rTMS in a CPSP monkey model. Consistent with the patient findings, the monkeys showed an increase in pain threshold after Hf-rTMS, which indicated an analgesic effect. However, no change after Lf-rTMS was observed. Compared to Lf-rTMS, Hf-rTMS produced enhanced tactile-evoked fMRI signals not only in M1 but also in somatosensory processing regions, such as the primary somatosensory and midcingulate cortices. However, the secondary somatosensory cortex (S2) was less active after Hf-rTMS than after Lf-rTMS, suggesting that activation of this region was involved in CPSP. Previous studies showed pharmacological inhibition of S2 reduces CPSP-related behaviors, and the present results emphasize the involvement of an S2 inhibitory system in rTMS-induced analgesia. Verification using the monkey model is important to elucidate the inhibition system.

Contexte: Nous avons précédemment développé un modèle de douleur centrale post-AVC (DCPA) chez le macaque et confirmé l’implication d’une activité accrue du cortex insulaire postérieur (CIP) et du cortex somatosensoriel secondaire (SII) dans l’allodynie mécanique, observée en cas de DCPA, en associant une inactivation pharmacologique de ces régions corticales et des techniques d’imagerie. Cependant, on ne sait pas si cette inactivation joue un rôle dans l’hyperalgésie thermique. Par conséquent, en utilisant ce modèle de macaque, nous avons examiné les réponses comportementales aux stimuli thermiques après une inactivation pharmacologique du CIP/SII.Méthodes: Une DCPA a été créée chez deux macaques en induisant des lésions hémorragiques unilatérales dans le noyau ventral postérolatéral du thalamus, par injection de collagénase. Pour évaluer la perception de la douleur, la latence de retrait des mains à des stimuli thermiques de 37, 45, 50, 52 et 55 °C a été mesurée. Quelques semaines après l’induction de la lésion, une inactivation pharmacologique des CIP/SII par micro-injection de muscimol a été réalisée. L’effet de l’inactivation sur la latence de retrait a été évalué par comparaison avec la latence de retrait après injection de placebo.Résultats: Quelques semaines après l’induction des lésions thalamiques, on observe une réduction des latences de retrait à la stimulation thermique (< 50 °C) de la main controlatérale de l’emplacement de la lésion chez les deux macaques, indiquant l’apparition d’une hyperalgésie thermique. Lorsque les CIP/SII sont inactivés par lemuscimol, les latences de retrait à des stimuli thermiques de 50 et 52 °C sont significativement augmentées par rapport à celles après injection de placebo.Conclusion: Nos données soulignent qu’une activité accrue dans les CIP/SII après lésion thalamique peut contribuer à une douleur anormale en réponse à de multiples modalités et que la modulation de cette activité peut être une approche thérapeutique pour l’hyperalgésie thermique.Signification: La DCPA est causée par des lésions cérébrales du système somatosensoriel et se caractérise par une allodynie mécanique ou une hyperalgésie thermique. Il a été démontré que l’inactivation pharmacologique de l’activité des CIP/SII a un effet analgésique sur l’allodynie mécanique ; cependant, l’efficacité de cette inactivation pour réduire l’hyperalgésie thermique n’était pas claire. Dans ce travail, en utilisant deux macaques, nous avons démontré que l’inactivation de ces régions corticales réduit l’hypersensibilité aux stimuli thermiques. Ce résultat souligne qu’une activité accrue des CIP/SII peut contribuer à une douleur anormale en réponse à de multiples modalités.

In this study, we compared the differences in brain activation associated with the different types of objects using functional magnetic resonance imaging (fMRI). Twenty-six participants in their 20s underwent fMRI while grasping four different types of objects. After the experiment, all of the participants completed a questionnaire based on the Likert Scale, which asked them about the sensations they experienced while grasping each object (comfort, hardness, pain, ease in grasping). We investigated the relationship between brain activity and the results of the survey; characteristic brain activity for each object was correlated with the results of the questionnaire, indicating that each object produced a different sensation response in the participants. Additionally, we observed brain activity in the primary somatosensory cortex (postcentral gyrus), the primary motor cortex (precentral gyrus), and the cerebellum exterior during the gripping task. Our study shows that gripping different objects produces activity in specific and distinct brain regions and suggests an “action appraisal” mechanism, which is considered to be the act of integrating multiple different sensory information and connecting it to actual action. To the best of our knowledge, this is the first study to observe brain activity in response to tactile stimuli and motor activity simultaneously.

Background: We previously established a macaque model of central post‐stroke pain (CPSP) and confirmed the involvement of increased activity of the posterior insular cortex (PIC) and secondary somatosensory cortex (SII) to somatosensory stimuli in mechanical allodynia by a combination of imaging techniques with local pharmacological inactivation. However, it is unclear whether the same intervention would be effective for thermal hyperalgesia. Therefore, using the macaque model, we examined behavioural responses to thermal stimuli following pharmacological inactivation of the PIC/SII.Methods: Two CPSP model macaques were established based on collagenase‐induced unilateral hemorrhagic lesions in the ventral posterolateral nucleus of the thalamus. To evaluate pain perception, withdrawal latencies to thermal stimuli of 37, 45, 50, 52, and 55 °C to hands were measured. Several weeks after the lesion induction, pharmacological inactivation of the PIC/SII by microinjection of muscimol was performed. The effect of inactivation on withdrawal latency was assessed by comparison with withdrawal latency after vehicle injection.Results: Several weeks after induction of the thalamic lesions, both macaques demonstrated a reduction in withdrawal latencies to thermal stimulation (<50 °C) on the contralesional hand, indicating the occurrence of thermal hyperalgesia. When the PIC/SII were inactivated by muscimol, the withdrawal latencies to thermal stimuli of 50 and 52 °C were significantly increased compared to those after vehicle injection.Conclusions: Our data emphasize that increased activity in the PIC/SII after appearance of thalamic lesions can contribute to abnormal pain of multiple modalities, and the modulation of PIC/SII activity may be a therapeutic approach for thermal hyperalgesia.Significance: CPSP is caused by stroke lesions in the sensory system and characterized by mechanical allodynia or thermal hyperalgesia. Inactivation of the PIC/SII has an analgesic effect on mechanical allodynia; however, it is not clear whether the same intervention could reduce thermal hyperalgesia. Here, using the macaque model, we demonstrated that inactivation of these cortices reduces hypersensitivity to thermal stimuli. This result emphasizes that increased PIC/SII activity can contribute to abnormal pain of multiple modalities.

Two-point discrimination (2PD) test reflects somatosensory spatial discrimination ability, but evidence on the relationship between 2PD and cortical gray matter (GM) volume is limited. This study aimed to analyze the relationship between cortical GM volume and 2PD threshold in young healthy individuals and to clarify the characteristics of brain structure reflecting the individual differences in somatosensory function. 2PD was measured in 42 healthy (20 females) volunteers aged 20–32 years using a custom-made test system that can be controlled by a personal computer. The 2PD of the right index finger measured with this device has been confirmed to show good reproducibility. T1-weighted images were acquired using a 3-T magnetic resonance imaging scanner for voxel-based morphometry analysis. The mean 2PD threshold was 2.58 ± 0.54 mm. Whole-brain multiple regression analysis of the relationship between 2PD and GM volume showed that a lower 2PD threshold (i.e. better somatosensory function) significantly correlated with decreased GM volume from the middle temporal gyrus to the inferior parietal lobule (IPL) in the contralateral hemisphere. In conclusion, a lower GM volume in the middle temporal gyrus and IPL correlates with better somatosensory function. Thus, cortical GM volume may be a biomarker of somatosensory function.