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Although brain gray matter (GM) plastically changes during short-term training, it is still unclear whether brain structures are stable for short periods (several months). Therefore, this study aimed to re-test the short-term variability of GM volumes and to clarify the effect of factors (gender and BDNF-genotype) expected to contribute to such variability. The subjects comprised 41 young healthy adults. T1-weighted images were acquired twice with an interval of approximately 4 months using a 3 T-MRI scanner. Voxel-based morphometry (VBM) was used to calculate GM volumes in 47 regions. The intraclass correlation coefficient (ICC) and Test–retest variability (%TRV) were used as indices of variability. As a result, the ICCs in 43 regions were excellent (ICC > 0.90) and those in 3 regions were good (ICC > 0.80), whereas the ICC in the thalamus was moderate (ICC = 0.694). Women had a higher %TRV than men in 5 regions, and %TRV of the Val66Val group was higher than that of the Met carrier group in 2 regions. Moreover, the Female-Val66Val group had a higher %TRV than the Male-Met carrier group in 3 regions. These results indicate that although the short-term variability of GM volumes is small, it is affected by within-subject factors.

Compensatory plastic changes in the remaining intact brain regions are supposedly involved in functional recovery following stroke. Previously, a compensatory increase in cortical activation occurred in the ventral premotor cortex (PMv), which contributed to the recovery of dexterous hand movement in a macaque model of unilateral internal capsular infarcts. Herein, we investigated the structural plastic changes underlying functional changes together with voxel-based morphometry (VBM) analysis of magnetic resonance imaging data and immunohistochemical analysis using SMI-32 antibody in a macaque model. Unilateral internal capsular infarcts were pharmacologically induced in 5 macaques, and another 5 macaques were used as intact controls for immunohistochemical analysis. Three months post infarcts, we observed significant increases in the gray matter volume (GMV) and the dendritic arborization of layer V pyramidal neurons in the contralesional rostral PMv (F5) as well as the primary motor cortex (M1). The histological analysis revealed shrinkage of neuronal soma and dendrites in the ipsilesional M1 and several premotor cortices, despite not always detecting GMV reduction by VBM analysis. In conclusion, compensatory structural changes occur in the contralesional F5 and M1 during motor recovery following internal capsular infarcts, and the dendritic growth of pyramidal neurons is partially correlated with GMV increase.

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.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.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.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.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.

Central post-stroke pain (CPSP) is a chronic pain caused by stroke lesions of somatosensory pathways. Several brain imaging studies among patients with CPSP demonstrate that the pathophysiological mechanism underlying this condition is the maladaptive plasticity of pain-related brain regions. However, the temporal profile of the regional plastic changes, as suggested by brain imaging of CPSP patients, as well as their cellular basis, is unknown. To investigate these issues, we performed voxel-based morphometry (VBM) using T1-weighted magnetic resonance imaging and immunohistochemical analysis with our established CPSP monkey model. From 8 weeks after a hemorrhagic lesion to the unilateral ventral posterolateral nucleus of the thalamus, the monkeys exhibited significant behavioral changes that were interpreted as reflecting allodynia. The present VBM results revealed a decrease in gray matter volume in the pain-related areas after several weeks following the lesion. Furthermore, immunohistochemical staining in the ipsilesional posterior insular cortex (ipsi-PIC) and secondary somatosensory cortex (ipsi-SII), where the significant reduction in gray matter volume was observed in the VBM result, displayed a significant reduction in both excitatory and inhibitory synaptic terminals compared to intact monkeys. Our results suggest that progressive changes in neuronal morphology, including synaptic loss in the ipsi-PIC/SII, are involved in theCPSP.

The different cortical activity evoked by a mechanical tactile stimulus depends on tactile stimulus patterns, which demonstrates that simple stimuli (i.e., global synchronous stimulation the stimulus area) activate the primary somatosensory cortex alone, whereas complex stimuli (i.e., stimulation while moving in the stimulus area) activate not only the primary somatosensory cortex but also the primary motor area. Here, we investigated whether the effects of a repetitive mechanical tactile stimulation (MS) on somatosensory evoked magnetic fields (SEFs) and cortical oscillations depend on MS patterns. This single-blinded study included 15 healthy participants. Two types interventions of MS lasting 20 min were used: a repetitive global tactile stimulation (RGS) was used to stimulate the finger by using 24 pins installed on a finger pad, whereas a sequential stepwise displacement tactile stimulation (SSDS) was used to stimulate the finger by moving a row of six pins between the left and right sides on the finger pad. Each parameter was measured pre- and post-intervention. The P50m amplitude of the SEF was increased by RGS and decreased by SSDS. The modulation of P50m was correlated with its amplitude before RGS and with the modulation of beta band oscillation at the resting state after SSDS. This study showed that the effects of a 20-min MS on SEFs and cortical oscillations depend on mechanical tactile stimulus patterns. Moreover, our results offer potential for the modulation of tactile functions and selection of stimulation patterns according to cortical states.

The intraparietal sulcus region, which is part of the posterior parietal cortex (PPC), has been shown to play an important role in discriminating object shapes using the fingers. Transcranial random noise stimulation (tRNS) and anodal transcranial pulsed current stimulation (tPCS) are noninvasive strategies widely used to modulate neural activity in cortical regions. Therefore, we investigated the effects of tRNS and anodal tPCS applied to left or right PPC on the tactile discrimination performance of the right index finger in 20 neurologically healthy subjects. A grating orientation task (GOT) was performed before and immediately after delivering tRNS (stimulus frequency 0.1-640 Hz) in Experiment 1 or anodal tPCS (pulse width 50 ms and inter-pulse interval 5 ms) in Experiment 2. Performing tRNS over the right PPC significantly improved discrimination performance on the GOT. Subjects were classified into low and high baseline performance groups. Conducting tRNS over the left PPC significantly reduced the GOT discrimination performance in the high-performance group. By contrast, anodal tPCS delivered to the PPC of the left and right hemispheres had no significant effect on the tactile GOT discrimination performance of the right hand. We show that transcranial electric stimulation over the PPC may improve tactile perception but the effect depends on stimulus modality, parameters, and on the stimulated hemisphere.

The psychological characteristic of having difficulty expressing emotions, known as alexithymia, is associated with hypervigilance to pain and is considered one of the risk factors for chronic pain. The correlation between alexithymia and hypervigilance to pain can be observed even in healthy individuals. However, the factors influencing this correlation remain unknown. We explored the dopamine system, which is known to be involved in emotion and pain. The dopamine-degrading enzyme catechol-O-methyltransferase (COMT) has a genetic polymorphism known to influence dopamine metabolism in the prefrontal cortex. COMT polymorphism reportedly affects various aspects of pain and increases pain sensitivity in Met allele carriers. Therefore, we investigated whether the correlation between alexithymia and hypervigilance to pain is influenced by COMT polymorphism in healthy individuals. The results revealed a significant positive correlation between the “difficulty describing feelings” of the 20-item Toronto Alexithymia Scale and the “attention to changes in pain” of the pain vigilance and awareness questionnaire in COMT Met carriers but not in Val/Val individuals. This finding suggests that the correlation between alexithymia and hypervigilance to pain is influenced by COMT polymorphism.

Background: Autonomous sensory meridian response (ASMR) is used by young people to induce relaxation and sleep and to reduce stress and anxiety; it comprises somatosensation caused by audiovisual stimuli (triggers) that lead to positive emotions. Auditory stimuli play the most important role among the triggers involved in ASMR and have been reported to be more triggering than visual stimuli. On the other hand, classical music is also known to have a relaxing effect. This is the first study to clarify the difference in brain activation associated with relaxation effects between ASMR and classical music by limiting ASMR to auditory stimulation alone.Methods: Thirty healthy subjects, all over 20 years of age, underwent fMRI while listening to ASMR and classical music. We compared the differences in brain activation associated with classical music and ASMR stimulation. After the experiment, the subjects were administered a questionnaire on somatosensation and moods. After the experiment, the participants were asked whether they experienced ASMR somatosensation or frisson. They were also asked to rate the intensity of two moods during stimulation: “comfortable mood,” and “tingling mood”.Result: The results of the questionnaire showed that none of the participants experienced any ASMR somatosensation or frisson. Further, there was no significant difference in the ratings given to comfort mood, but there was a significant difference in those given to tingling mood. In terms of brain function, classical music and ASMR showed significant activation in common areas, while ASMR showed activation in more areas, with the medial prefrontal cortex being the main area of activation during ASMR.Conclusion: Both classical music and the ASMR auditory stimulus produced a pleasant and relaxed state, and ASMR involved more complex brain functions than classical music, especially the activation of the medial prefrontal cortex. Although ASMR was limited to auditory stimulation, the effects were similar to those of listening to classical music, suggesting that ASMR stimulation can produce a pleasant state of relaxation even if it is limited to the auditory component, without the somatic sensation of tingling. ASMR stimulation is easy to use, and appropriate for wellness purposes and a wide range of people.

The Pain Vigilance and Awareness Questionnaire (PVAQ) is a questionnaire for non-clinical and clinical cases of patients, such as those suffering from chronic pain. Moreover, it is used for evaluation of two aspects of habitual attention to pain: attention to pain and attention to changes in pain. As the PVAQ assesses two different aspects of attention function, different neural basis may present. However, it remains unclear which brain regions are involved. Here, we performed voxel-based morphometry (VBM) in 30 healthy participants to determine the regional morphology associated with the two attention states. Multiple regression analysis was conducted between each score and the regional grey matter (GM) volume, which revealed that a decreased GM volume in the left anterior insular cortex (AIC) was associated with a higher attention to pain score. In contrast, no brain region was correlated with the attention to changes in pain score. Our VBM results demonstrate that attention to pain scores assessed by PVAQ are associated with morphological features of the left AIC. Moreover, they may contribute to the elucidation of the complex psychological and neurophysiological characteristics of patients with chronic pain.

Central post-stroke pain (CPSP) can occur as a result of a cerebrovascular accident in the ventral posterolateral nucleus (VPL) of the thalamus. Developing therapeutic interventions for CPSP is difficult because its pathophysiology is unclear. Here we developed and characterized a macaque model of CPSP. The location of the VPL was determined by magnetic resonance imaging (MRI) and extracellular recording of neuronal activity during tactile stimulation, after which a hemorrhagic lesion was induced by injecting collagenase type IV. Histological analysis revealed that most of the lesion was localized within the VPL. Several weeks after the injection, the macaques displayed behavioral changes that were interpreted as reflecting the development of both mechanical allodynia and thermal hyperalgesia. Immunohistochemistry revealed that microglial and astrocytic activation in the perilesional areas lasted at least 3 months after injection. The present model reproduced the symptoms of patients suffering from CPSP, in which both mechanical allodynia and thermal hyperalgesia often develop several weeks after cerebrovascular accident. Further, the long-lasting glial activation revealed here may be characteristic of primate brains following injury. The present model will be useful not only for examining the neurological changes underlying CPSP, but also for testing therapeutic interventions for CPSP.

Background The nucleus basalis magnocellularis/Meynert (NBM) has been explored as a new target for deep brain stimulation for neurological disorders. Although anatomical studies suggest the existence of cholinergic topographical projections of the NBM, it is still unknown whether NBM subregions differentially activate the frontal cortex. Objective To investigate the topography between the NBM and frontal cortex. Methods Electrical stimulation was applied to the anterior and posterior sites of the NBM in rats, and the evoked frontal activity was investigated using voltage-sensitive dye (VSD) imaging. Results VSD imaging revealed the functional topography of the NBM and frontal cortex: the anteroposterior axis of the NBM corresponded to the mediolateral axis of the dorsal frontal cortex. Conclusion The present results suggest site-specific control of frontal neuronal activity by the NBM. These findings have practical implications, as the anterior and posterior parts of the NBM could be targeted to improve cognitive and motor function, respectively.

Central post-stroke pain (CPSP) can occur after stroke in the somatosensory pathway that includes the posterolateral region of the thalamus. Tactile allodynia, in which innocuous tactile stimuli are perceived as painful, is common in patients with CPSP. Previous brain imaging studies have reported plastic changes in brain activity in patients with tactile allodynia after stroke, but a causal relationship between such changes and the symptoms has not been established. We recently developed a non-human primate (macaque) model of CPSP based on thalamic lesions, in which the animals show behavioral changes consistent with the occurrence of tactile allodynia. Here we performed functional magnetic resonance imaging under propofol anesthesia to investigate the changes in brain activation associated with the allodynia in this CPSP model. Before the lesion, innocuous tactile stimuli significantly activated the contralateral sensorimotor cortex. When behavioral changes were observed after the thalamic lesion, equivalent stimuli significantly activated pain-related brain areas, including the posterior insular cortex (PIC), secondary somatosensory cortex (SII), anterior cingulate cortex (ACC), and amygdala. Moreover, when either PIC/SII or ACC was pharmacologically inactivated, the signs of tactile allodynia were dampened. Our results show that increased cortical activity plays a role in CPSP-induced allodynia.

We used the immunotoxin 192 immunoglobulin G-saporin to produce a selective cholinergic lesion in the nucleus basalis of Meynert (NBM) of rats and investigated whether the NBM lesion led to tactile hypersensitivity in the forepaw. The paw mechanical threshold test showed that the lesioned rats had a decreased threshold compared to the control. Surprisingly, there was a significant positive correlation between mechanical threshold and survival rate of NBM cholinergic neurons. Furthermore, using local field potential (LFP) recordings and voltage-sensitive dye (VSD) imaging, we found that the forepaw-evoked response in the primary somatosensory cortex (S1) was significantly enhanced in both amplitude and spatial extent in the NBM-lesioned rats. The neurophysiological measures of S1 response, such as LFP amplitude and maximal activated cortical area depicted by VSD, were also correlated with withdrawal behavior. Additional pharmacological experiments demonstrated that forepaw-evoked responses were increased in naive rats by blocking S1 cholinergic receptors with mecamylamine and scopolamine, while the response decreased in NBM-lesioned rats with the cholinergic agonist carbachol. In addition, NBM burst stimulation, which facilitates acetylcholine release in the S1, suppressed subsequent sensory responses to forepaw stimulation. Taken together, these results suggest that neuronal loss in the NBM diminishes acetylcholine actions in the S1, thereby enhancing the cortical representation of sensory stimuli, which may in turn lead to behavioral hypersensitivity.

Noisy galvanic vestibular stimulation (nGVS) enhances the vestibular system. The center of pressure (COP) sway has been shown to decrease during nGVS, but the after-effect of nGVS remains unclear. The aim of this study is to elucidate the after-effect of nGVS on COP sway. We randomly assigned 26 participants to either control (sham stimulation) or nGVS groups. All participants were measured for COP sway while standing with open eyes at baseline, during stimulation, and after stimulation. In the nGVS group, sway path length, mediolateral mean velocity, and anteroposterior mean velocity decreased both during stimulation and after stimulation compared with baseline. Conversely, no significant difference in COP sway was detected in the control group. There was a correlation between the stimulation effect and the after-effect in the nGVS group, indicating that nGVS is effective for people with high baseline COP sway.

Lesion and inactivation methods have played important roles in neuroscience studies. However, traditional techniques for creating a brain lesion are highly invasive, and control of lesion size and shape using these techniques is not easy. Here, we developed a novel method for creating a lesion on the cortical surface via 365 nm ultraviolet (UV) irradiation without breaking the dura mater. We demonstrated that 2.0 mWh UV irradiation, but not the same amount of non-UV light irradiation, induced an inverted bell-shaped lesion with neuronal loss and accumulation of glial cells. Moreover, the volume of the UV irradiation-induced lesion depended on the UV light exposure amount. We further succeeded in visualizing the lesioned site in a living animal using magnetic resonance imaging (MRI). Importantly, we also observed using an optical imaging technique that the spread of neural activation evoked by adjacent cortical stimulation disappeared only at the UV-irradiated site. In summary, UV irradiation can induce a focal brain lesion with a stable shape and size in a less invasive manner than traditional lesioning methods. This method is applicable to not only neuroscientific lesion experiments but also studies of the focal brain injury recovery process.

The antineoplastic agent oxaliplatin induces a painful peripheral neuropathy characterized by an acute cold hypersensitivity. There is a lack of effective treatments to manage oxaliplatin-induced cold hypersensitivity which is due, in part, to a lack of understanding of the pathophysiology of oxaliplatin-induced cold hypersensitivity. Thus, brain activity in oxaliplatin-treated macaques was examined using functional magnetic resonance imaging (fMRI). Oxaliplatin treatment reduced tail withdrawal latency to a cold (10 °C) stimulus, indicating cold hypersensitivity and increased activation in the secondary somatosensory cortex (SII) and the anterior insular cortex (Ins) was observed. By contrast, no activation was observed in these areas following cold stimulation in untreated macaques. Systemic treatment with an antinociceptive dose of the serotonergic-noradrenergic reuptake inhibitor duloxetine decreased SII and Ins activity. Pharmacological inactivation of SII and Ins activity by microinjection of the GABAA receptor agonist muscimol increased tail withdrawal latency. The current findings indicate that SII/Ins activity is a potential mediator of oxaliplatin-induced cold hypersensitivity.