Diagnostic Utility of Specific Frailty Questionnaire: The Kihon Checklist for Hippocampal Atrophy in COPD.

Background/Objectives: COPD patients who are frail have been reported to develop brain atrophy, but no non-invasive diagnostic tool has been developed to detect this condition. Our study aimed to explore the diagnostic utility of the Kihon Checklist (KCL), a frailty questionnaire, in assessing hippocampal volume loss in patients with COPD. Methods: We recruited 40 COPD patients and 20 healthy individuals using the KCL to assess frailty across seven structural domains. Hippocampal volumes were obtained from T1-weighted MRI images, and ROC analysis was performed to detect hippocampal atrophy. Results: Our results showed that patients with COPD had significantly greater atrophic left hippocampal volumes than healthy subjects (p < 0.05). The univariate correlation coefficient between the left hippocampal volume and KCL (1-20), which pertains to instrumental and social activities of daily living, was the largest (ρ = -0.54, p < 0.0005) among the KCL subdomains. Additionally, both KCL (1-25) and KCL (1-20) demonstrated useful diagnostic potential (93% specificity and 90% sensitivity, respectively) for identifying individuals in the lowest 25% of the left hippocampal volume (AUC = 0.82). Conclusions: Our study suggests that frailty questionnaires focusing on daily vulnerability, such as the KCL, can effectively detect hippocampal atrophy in COPD patients.

Correlation between frailty and reduction in cortical thickness in patients with chronic obstructive pulmonary disease.

Physical inactivity and cognitive impairment in patients with chronic obstructive pulmonary disease (COPD) can lead to frailty and poor prognoses. However, little is known regarding the association between frailty and the human brain. We hypothesized that the brain structure could change according to frailty in patients with COPD and focused on cortical thickness. Cortical thickness measured by magnetic resonance imaging and frailty scores using the Kihon Checklist (KCL) were assessed in 40 patients with stable COPD and 20 healthy controls. Among the 34 regions assessed, multiple regions were thinner in patients with COPD than in healthy individuals (p < 0.05). We found significant negative correlations between the eight regions and the KCL scores only in patients with COPD. After adjusting for age and cognitive impairment, the association between the left and six right regions remained statistically significant. The correlation coefficient was the strongest in the bilateral superior frontal gyrus (left: ρ = - 0.5319, p = 0.0006) (right: ρ = - 0.5361, p = 0.0005). Interestingly, among the KCL scores, the daily activity domain showed the strongest correlation (sensitivity, 90%; specificity, 73%) with the bottom quartile of the reduction in the superior frontal gyrus. Frailty in patients with COPD is associated with a thickness reduction in the cortical regions, reflecting social vulnerability.

Impact of Frailty on Hippocampal Volume in Patients with Chronic Obstructive Pulmonary Disease.

Brain frailty may be related to the pathophysiology of poor clinical outcomes in chronic obstructive pulmonary disease (COPD). This study examines the relationship between hippocampal subfield volumes and frailty and depressive symptoms, and their combined association with quality of life (QOL) in patients with COPD. The study involved 40 patients with COPD. Frailty, depressive symptoms and QOL were assessed using Kihon Checklist (KCL), Hospital Anxiety and Depression Scale (HADS), and World Health Organization Quality of Life Assessment (WHO/QOL-26). Anatomical MRI data were acquired, and volumes of the hippocampal subfields were obtained using FreeSurfer (version 6.0). Statistically, HADS score had significant association with WHO/QOL-26 and KCL scores. KCL scores were significantly associated with volumes of left and right whole hippocampi, presubiculum and subiculum, but HADS score had no significant association with whole hippocampi or hippocampal subfield volumes. Meanwhile, WHO/QOL-26 score was significantly associated with volume of the left CA1. There was a significant association between frailty, depression, and QOL. Hippocampal pathology was related to frailty and, to some extent, with QOL in patients with COPD. Our results suggest the impact of frailty on hippocampal volume and their combined associations with poor QOL in COPD.

Regional abnormality of functional connectivity is associated with clinical manifestations in individuals with intractable focal epilepsy.

We explored regional functional connectivity alterations in intractable focal epilepsy brains using resting-state functional MRI. Distributions of the network parameters (corresponding to degree and eigenvector centrality) measured at each brain region for all 25 patients were significantly different from age- and sex-matched control data that were estimated by a healthy control dataset (n = 582, 18-84 years old). The number of abnormal regions whose parameters exceeded the mean + 2 SD of age- and sex-matched data for each patient were associated with various clinical parameters such as the duration of illness and seizure severity. Furthermore, abnormal regions for each patient tended to have functional connections with each other (mean ± SD = 58.6 ± 20.2%), the magnitude of which was negatively related to the quality of life. The abnormal regions distributed within the default mode network with significantly higher probability (p < 0.05) in 7 of 25 patients. We consider that the detection of abnormal regions by functional connectivity analysis using a large number of control datasets is useful for the numerical assessment of each patient's clinical conditions, although further study is necessary to elucidate etiology-specific abnormalities.

Detection of gastric slow oscillatory contraction using parasagittal cine MR images: Comparison with simultaneously measured electrogastrogram.

PURPOSE: To determine if parasagittal gastric cine magnetic resonance imaging (MRI) is able to measure gastric oscillatory contractions around 0.05 Hz and to determine its relationship with electrical activity as measured by electrogastrography (EGG). METHODS: Assessment of the gastric motility is important for the research of the enteric nervous system and for the diagnosis of functional gastric disorders. Electrogastrography is a non-invasive method that can measure gastric oscillatory electrical activity around 0.05 Hz (slow wave) using electrodes on the abdominal skin, but its sensitivity and specificity of the slow wave detection is limited. We used parasagittal gastric cine MRI around the angular incisure to measure gastric oscillatory contraction around 0.05 Hz in 24 healthy volunteers. Cine MRI was acquired with time resolution of 1 s for 10 min while freely breathing participants were lying on the bed. The gastric area of the cross section was measured for each MR image and assessed its change over time. The results were compared with those for simultaneously recorded EGG. RESULTS: The main frequency of the gastric area change for each participant ranged from 0.041 to 0.059 Hz (mean ± S.D. = 0.049 ± 0.004), which corresponds to the gastric slow wave frequency (mean ± S.D. = 0.049 ± 0.004) as measured by EGG (p = 7.9585 × 10 -8, Kendall 's tau test). Cross correlation analysis showed that 22 of 24 participants' gastric area changes were significantly (p < 0.05) related to the EGG waveforms. Displacement of the stomach due to respiration did not affect gastric area measurements. CONCLUSIONS: Parasagittal cine MRI is correlated with EGG recordings and able to detect and quantifying gastric motility abnormalities.

A Novel Role of Growth Differentiation Factor (GDF)-15 in Overlap with Sedentary Lifestyle and Cognitive Risk in COPD.

Sedentary behavior and cognitive impairment have a direct impact on patients' outcomes. An energy metabolic disorder may be involved in the overlap of these comorbid conditions (motoric cognitive risk (MCR)) in patients with chronic obstructive pulmonary disease (COPD). We aimed to explore the linkage between a proapoptotic protein, growth differentiation factor (GDF)-15, and MCR. Physical activity (PA), cognitive function (Japanese version of the Montreal Cognitive Assessment: MOCA-J), and the serum GDF-15 levels were assessed in healthy subjects (n = 14), asthmatics (n = 22), and COPD patients (n = 28). In the entire cohort, serum GDF-15 had negative correlations with exercise (Ex) (ρ = -0.43, p < 0.001) and MoCA-J (ρ = -0.44, p < 0.001), and Ex and MOCA-J showed a positive correlation (ρ = 0.52, p < 0.0001). Compared to healthy subjects and asthmatics, COPD patients showed the highest serum GDF-15 levels and had a significantly higher proportion of subjects with MCR (both sedentary lifestyle (EX < 1.5) and cognitive risk (MoCA-J ≤ 25)). Also, we found that serum GDF-15 has a screening potential (100% sensitivity) greater than aging (67% sensitivity) for detecting MCR in COPD patients. In conclusion, higher serum GDF-15 had interrelationships with a sedentary lifestyle and cognitive risk. This protein was not disease-specific but could be a screening biomarker to detect MCR related to poor health outcomes of COPD patients.

Increased large-scale inter-network connectivity in relation to impulsivity in Parkinson's disease.

Impulsivity is a neuropsychiatric feature of Parkinson's disease (PD). We investigated the pathophysiology of impulsivity in PD using resting-state functional magnetic resonance imaging (rs-fMRI). We investigated 45 patients with idiopathic PD and 21 healthy controls. Based on Barratt Impulsiveness Scale (BIS-11) score, PD patients were classified as higher (PD-HI) or lower impulsivity (PD-LI). Functional connectivity (FC) between various large-scale brain networks were analysed using the CONN toolbox. FC between the right frontoparietal network (FPN) and medial visual network (MVN) was significantly higher in PD-HI patients than PD-LI patients (false discovery rate [FDR]-adjusted p = 0.0315). FC between the right FPN and MVN had a significant positive correlation with total BIS-11 score (FDR-adjusted p = 0.010) and the attentional impulsivity (FDR-adjusted p = 0.046) and non-planning impulsivity subscale scores (FDR-adjusted p = 0.018). On the other hand, motor impulsivity subscale score had a significant negative correlation with the FC between the default-mode and salience networks (right supramarginal gyrus, FDR-adjusted p = 0.018; anterior cingulate cortex, FDR-adjusted p = 0.027); this trend was observed in healthy controls. The attentional and non-planning impulsivity, regarded as 'cognitive' impulsivity, may be associated with dysfunction in integration of perceptual information and flexible cognitive control in PD.

Hippocampal functional organization: A microstructure of the place cell network encoding space.

A clue to hippocampal function has been the discovery of place cells, leading to the 'spatial map' theory. Although the firing attributes of place cells are well documented, little is known about the organization of the spatial map. Unit recording studies, thus far, have reported a low coherence between neighboring cells and geometric space, leading to the prevalent view that the spatial map is not topographically organized. However, the number of simultaneously recorded units is severely limited, rendering construction of the spatial map nearly impossible. To visualize the functional organization of place cells, we used the activity-dependent immediate-early gene Zif268 in combination with behavioral, pharmacological and electrophysiological methods, in mice and rats exploring an environment. Here, we show that in animals confined to a small part of a maze, principal cells in the CA1/CA3 subfields of the dorsal hippocampus immunoreactive (IR) for Zif268 adhere to a 'cluster-type' organization. Unit recordings confirmed that the Zif268 IR clusters correspond to active place cells, while blockade of NMDAR (which alters place fields) disrupted the Zif268 IR clusters. Contrary to the prevalent view that the spatial map consists of a non-topographic neural network, our results provide evidence for a 'cluster-type' functional organization of hippocampal neurons encoding for space.

Effects of perinatal blood pressure on maternal brain functional connectivity.

Perinatal hypertensive disorder including pre-eclampsia is a systemic syndrome that occurs in 3-5% of pregnant women. It can result in various degrees of brain damage. A recent study suggested that even gestational hypertension without proteinuria can cause cardiovascular or cognitive impairments later in life. We hypothesized that perinatal hypertension affects the brain functional connectivity (FC) regardless of the clinical manifestation of brain functional impairment. In the present study, we analyzed regional global connectivity (rGC) strength (mean cross-correlation coefficient between a brain region and all other regions) using resting-state functional magnetic resonance imaging to clarify brain FC changes associated with perinatal blood pressure using data from 16 women with a normal pregnancy and 21 pregnant women with pre-eclampsia. The rGC values in the bilateral orbitofrontal gyri were negatively correlated with diastolic blood pressure (dBP), which could not be explained by other pre-eclampsia symptoms. The strength of FC seeding at the left orbitofrontal gyrus was negatively correlated with dBP in the anterior cingulate gyri and right middle frontal gyrus. These results suggest that dBP elevation during pregnancy can affect the brain FC. Since FC is known to be associated with various brain functions and diseases, our findings are important for elucidating the neural correlate of cognitive impairments related to hypertension in pregnancy.

Effects of gender, digit ratio, and menstrual cycle on intrinsic brain functional connectivity: A whole-brain, voxel-wise exploratory study using simultaneous local and global functional connectivity mapping.

Introduction: Gender and sex hormones influence brain function, but their effects on functional network organization within the brain are not yet understood. Methods: We investigated the influence of gender, prenatal sex hormones (estimated by the 2D:4D digit ratio), and the menstrual cycle on the intrinsic functional network organization of the brain (as measured by 3T resting-state functional MRI (rs-fMRI)) using right-handed, age-matched university students (100 males and 100 females). The mean (±SD) age was 20.9 ± 1.5 (range: 18-24) years and 20.8 ± 1.3 (range: 18-24) years for males and females, respectively. Using two parameters derived from the normalized alpha centrality analysis (one for local and another for global connectivity strength), we created mean functional connectivity strength maps. Results: There was a significant difference between the male mean map and female mean map in the distributions of network properties in almost all cortical regions and the basal ganglia but not in the medial parietal, limbic, and temporal regions and the thalamus. A comparison between the mean map for the low 2D:4D digit ratio group (indicative of high exposure to testosterone during the prenatal period) and that for the high 2D:4D digit ratio group revealed a significant difference in the network properties of the medial parietal region for males and in the temporal region for females. The menstrual cycle affected network organization in the brain, which varied with the 2D:4D digit ratio. Most of these findings were reproduced with our other datasets created with different preprocessing steps. Conclusions: The results suggest that differences in gender, prenatal sex hormone exposure, and the menstrual cycle are useful for understanding the normal brain and investigating the mechanisms underlying the variable prevalence and symptoms of neurological and psychiatric diseases.

Severity of Premenstrual Symptoms Predicted by Second to Fourth Digit Ratio.

Women of reproductive age often experience a variety of unpleasant symptoms prior to the onset of menstruation. While genetics may influence the variability of these symptoms and their severity among women, the exact causes remain unknown. We hypothesized that symptom variability originates from differences in the embryonic environment and thus development caused by variation in exposure to sex hormones. We measured the second to fourth digit ratios (2D:4D) in 402 young women and investigated the potential relationships of this ratio premenstrual symptoms using a generalized linear model. We found that two models (one with two predictors such as both hands' digit ratios and the other with the difference between the two digit ratios, Dr-l) were significantly different from the constant model as assessed by chi-square test. The right digit ratio and Dr-l were negatively related to the symptom scores, and the left digit ratio was related to the scores. When premenstrual symptoms were classified into eight categories, five categories, including pain, concentration, autonomic reaction, negative affect, and control were associated with the digit ratios and Dr-l. Behavioral changes and water retention were not predicted by them. Arousal was predicted by Dr-l. The right 2D:4D is thought to be determined by the balance of testosterone and estrogen levels during early embryogenesis and is not affected by postpartum levels of sex hormones, while the left 2D:4D might be affected by the other prenatal environmental factors. We conclude that the embryonic environment, including the relative concentration of sex hormones an embryo is exposed to, is associated with the severity of premenstrual symptoms once menarche is reached.

Interhemispheric disconnectivity in the sensorimotor network in bipolar disorder revealed by functional connectivity and diffusion tensor imaging analysis.

BACKGROUND: Little is known regarding interhemispheric functional connectivity (FC) abnormalities via the corpus callosum in subjects with bipolar disorder (BD), which might be a key pathophysiological basis of emotional processing alterations in BD. METHODS: We performed tract-based spatial statistics (TBSS) using diffusion tensor imaging (DTI) in 24 healthy control (HC) and 22 BD subjects. Next, we analyzed the neural networks with independent component analysis (ICA) in 32HC and 25 BD subjects using resting-state functional magnetic resonance imaging. RESULTS: In TBSS analysis, we found reduced fractional anisotropy (FA) in the corpus callosum of BD subjects. In ICA, functional within-connectivity was reduced in two clusters in the sensorimotor network (SMN) (right and left primary somatosensory areas) of BD subjects compared with HCs. FC between the two clusters and FA values in the corpus callosum of BD subjects was significantly correlated. Further, the functional within-connectivity was related to Young Mania Rating Scale (YMRS) total scores in the right premotor area in the SMN of BD subjects. LIMITATIONS: Almost all of our BD subjects were taking several medications which could be a confounding factor. CONCLUSIONS: Our findings suggest that interhemispheric FC dysfunction in the SMN is associated with the impaired nerve fibers in the corpus callosum, which could be one of pathophysiological bases of emotion processing dysregulation in BD patients.

Elucidating the aberrant brain regions in bipolar disorder using T1-weighted/T2-weighted magnetic resonance ratio images.

Although diffusion tensor imaging (DTI) have revealed brain abnormalities in bipolar disorder (BD) subjects, DTI methods might not detect disease-related abnormalities in the white matter (WM) where nerve fibers are crossing. We investigated BD myelin-related abnormal brain regions in both gray matter and WM for 29 BD and 33 healthy control (HC) participants using T1-weighted (T1w)/T2-weighted (T2w) ratio images that increase myelin-related contrast irrespective of nerve fiber orientation. To check effect of the brain volume, the results were compared with those of voxel-based morphometry (VBM). We found significantly lower T1w/T2w signal intensity in broad WM regions in BD subjects, including the corpus callosum, corona radiata, internal capsule, middle cerebellar peduncle and cerebellum. Regional volume reduction was found in the WM bilateral posterior thalami and retrolenticular part of the internal capsules of BD subjects. We also performed tract-based spatial statistics (TBSS) in 25 BD and 24 HC participants and compared those for the T1w/T2w ratio images. Both methods detected the BD corpus callosum abnormality. Further, the ratio images detected the corona radiata and the cerebellar abnormality in BD. These results suggest that T1w/T2w ratio image analysis could take a complementary role with the DTI method in elucidating myelin-related abnormalities in BD.

Use of T1-weighted/T2-weighted magnetic resonance ratio images to elucidate changes in the schizophrenic brain.

INTRODUCTION: One leading hypothesis suggests that schizophrenia (SZ) is a neurodevelopmental disorder caused by genetic defects in association with environmental risk factors that affect synapse and myelin formation. Recent magnetic resonance imaging (MRI) studies of SZ brain showed both gray matter (GM) reduction and white matter (WM) fractional anisotropy reduction. In this study, we used T1-weighted (T1w)/T2-weighted (T2w) MRI ratio images, which increase myelin-related signal contrast and reduce receiver-coil bias. METHODS: We measured T1w/T2w ratio image signal intensity in 29 patients with SZ and 33 healthy controls (HCs), and then compared them against bias-corrected T1w images. RESULTS: Mean T1w/T2w ratio signal intensity values across all SZ GM and WM voxels were significantly lower than those for the HC values (analysis of covariance with age, gender, handedness, and premorbid intelligence quotient as nuisance covariates). SZ mean WM T1w/T2w ratio values were related to Global Assessment of Functioning (GAF) scores and were inversely related to the positive psychotic symptoms of the Positive and Negative Syndrome Scale. Voxel-based analysis revealed significantly lower T1w/T2w ratio image signal intensity values in the right ventral putamen in SZ GM. T1w image intensities did not differ between the SZ and HC groups. CONCLUSIONS: T1-weighted/T2-weighted ratio imaging increased the detectability of SZ pathological changes. Reduced SZ brain signal intensity is likely due to diminished myelin content; therefore, mapping myelin-related SZ brain changes using T1w/T2w ratio images may be useful for studies of SZ brain abnormalities.

Alterations of Regional Cerebral Blood Flow in Tinnitus Patients as Assessed Using Single-Photon Emission Computed Tomography.

Tinnitus is the perception of phantom sound without an external auditory stimulus. Using neuroimaging techniques, such as positron emission tomography, electroencephalography, magnetoencephalography, and functional magnetic resonance imaging (fMRI), many studies have demonstrated that abnormal functions of the central nervous system are closely associated with tinnitus. In our previous research, we reported using resting-state fMRI that several brain regions, including the rectus gyrus, cingulate gyrus, thalamus, hippocampus, caudate, inferior temporal gyrus, cerebellar hemisphere, and medial superior frontal gyrus, were associated with tinnitus distress and loudness. To reconfirm these results and probe target regions for repetitive transcranial magnetic stimulation (rTMS), we investigated the regional cerebral blood flow (rCBF) between younger tinnitus patients (<60 years old) and the age-matched controls using single-photon emission computed tomography and easy Z-score imaging system. Compared with that of controls, the rCBF of tinnitus patients was significantly lower in the bilateral medial superior frontal gyri, left middle occipital gyrus and significantly higher in the bilateral cerebellar hemispheres and vermis, bilateral middle temporal gyri, right fusiform gyrus. No clear differences were observed between tinnitus patients with normal and impaired hearing. Regardless of the assessment modality, similar brain regions were identified as characteristic in tinnitus patients. These regions are potentially involved in the pathophysiology of chronic subjective tinnitus.

Brain regions responsible for tinnitus distress and loudness: a resting-state FMRI study.

Subjective tinnitus is characterized by the perception of phantom sound without an external auditory stimulus. We hypothesized that abnormal functionally connected regions in the central nervous system might underlie the pathophysiology of chronic subjective tinnitus. Statistical significance of functional connectivity (FC) strength is affected by the regional autocorrelation coefficient (AC). In this study, we used resting-state functional MRI (fMRI) and measured regional mean FC strength (mean cross-correlation coefficient between a region and all other regions without taking into account the effect of AC (rGC) and with taking into account the effect of AC (rGCa) to elucidate brain regions related to tinnitus symptoms such as distress, depression and loudness. Consistent with previous studies, tinnitus loudness was not related to tinnitus-related distress and depressive state. Although both rGC and rGCa revealed similar brain regions where the values showed a statistically significant relationship with tinnitus-related symptoms, the regions for rGCa were more localized and more clearly delineated the regions related specifically to each symptom. The rGCa values in the bilateral rectus gyri were positively correlated and those in the bilateral anterior and middle cingulate gyri were negatively correlated with distress and depressive state. The rGCa values in the bilateral thalamus, the bilateral hippocampus, and the left caudate were positively correlated and those in the left medial superior frontal gyrus and the left posterior cingulate gyrus were negatively correlated with tinnitus loudness. These results suggest that distinct brain regions are responsible for tinnitus symptoms. The regions for distress and depressive state are known to be related to depression, while the regions for tinnitus loudness are known to be related to the default mode network and integration of multi-sensory information.

Variance and autocorrelation of the spontaneous slow brain activity.

Slow (<0.1 Hz) oscillatory activity in the human brain, as measured by functional magnetic imaging, has been used to identify neural networks and their dysfunction in specific brain diseases. Its intrinsic properties may also be useful to investigate brain functions. We investigated the two functional maps: variance and first order autocorrelation coefficient (r(1)). These two maps had distinct spatial distributions and the values were significantly different among the subdivisions of the precuneus and posterior cingulate cortex that were identified in functional connectivity (FC) studies. The results reinforce the functional segregation of these subdivisions and indicate that the intrinsic properties of the slow brain activity have physiological relevance. Further, we propose a sample size (degree of freedom) correction when assessing the statistical significance of FC strength with r(1) values, which enables a better understanding of the network changes related to various brain diseases.

Auditory thalamic reticular nucleus of the rat: anatomical nodes for modulation of auditory and cross-modal sensory processing in the loop connectivity between the cortex and thalamus.

The auditory sector of the thalamic reticular nucleus (TRN) plays a pivotal role in gain and/or gate control of auditory input relayed from the thalamus to cortex. The TRN is also likely involved in cross-modal sensory processing for attentional gating function. In the present study, we anatomically examined how cortical and thalamic afferents intersect in the auditory TRN with regard to these two functional pathways. Iontophoretic injections of biocytin into subregions of the auditory TRN, which were made with the guidance of electrophysiological recording of auditory response, resulted in retrograde labeling of cortical and thalamic cells, indicating the sources of afferents to the TRN. Cortical afferents from area Te1 (temporal cortex, area 1), which contains the primary and anterior auditory fields, topographically intersected thalamic afferents from the ventral division of the medial geniculate nucleus at the subregions of the auditory TRN, suggesting tonotopically organized convergence of afferents, although they innervated a given small part of the TRN from large parts. In the caudodorsal and rostroventral parts of the auditory TRN, cortical afferents from nonprimary visual and somatosensory areas intersected thalamic afferents from auditory, visual, and somatosensory nuclei. Furthermore, afferents from the caudal insular cortex and the parvicellular part of the ventral posterior thalamic nucleus, which are associated with visceral processing, converged to the rostroventral end of the auditory TRN. The results suggest that the auditory TRN consists of anatomical nodes that mediate tonotopic and/or cross-modal modulation of auditory and other sensory processing in the loop connectivity between the cortex and thalamus.

Activation of mitogen-activated protein kinase in descending pain modulatory system.

The descending pain modulatory system is thought to undergo plastic changes following peripheral tissue injury and exerts bidirectional (facilitatory and inhibitory) influence on spinal nociceptive transmission. The mitogen-activated protein kinases (MAPKs) superfamily consists of four main members: the extracellular signal-regulated protein kinase1/2 (ERK1/2), the c-Jun N-terminal kinases (JNKs), the p38 MAPKs, and the ERK5. MAPKs not only regulate cell proliferation and survival but also play important roles in synaptic plasticity and memory formation. Recently, many studies have demonstrated that noxious stimuli activate MAPKs in several brain regions that are components of descending pain modulatory system. They are involved in pain perception and pain-related emotional responses. In addition, psychophysical stress also activates MAPKs in these brain structures. Greater appreciation of the convergence of mechanisms between noxious stimuli- and psychological stress-induced neuroplasticity is likely to lead to the identification of novel targets for a variety of pain syndromes.

Involvement of descending facilitation from the rostral ventromedial medulla in the enhancement of formalin-evoked nocifensive behavior following repeated forced swim stress.

In the present study we examined whether the descending facilitation from the rostral ventromedial medulla (RVM) is required for the enhancement of formalin-evoked nocifensive behavior following repeated forced swim stress. Rats were subjected to forced or sham swim stress for 3days. Withdrawal latency to noxious thermal stimuli and mechanical withdrawal threshold to von Frey filaments did not change significantly in both groups at 24h after the last stress session. The forced swim stress showed significantly enhanced nocifensive behavior to the subcutaneous administration of formalin at 2days after the last stress session (1330.1+/-62.8s), compared to the sham swim (1076+/-102.4s, p<0.05) and naive groups (825.9+/-83.2s, p<0.01). The destruction of the RVM with ibotenic acid led to prevent the enhancement of formalin-evoked nocifensive behavior in the forced swim group. These findings suggest that the descending facilitation from the RVM may be involved in the enhancement of formalin-evoked nocifensive behavior following the forced swim stress.