Microglia-dependent excessive synaptic pruning leads to cortical underconnectivity and behavioral abnormality following chronic social defeat stress in mice.

Synapse loss in medial prefrontal cortex (mPFC) has been implicated in stress-related mood disorders, such as depression. However, the exact effect of synapse elimination in the depression and how it is triggered are largely unknown. Through repeated longitudinal imaging of mPFC in the living brain, we found both presynaptic and postsynaptic components were declined, together with the impairment of synapse remodeling and cross-synaptic signal transmission in the mPFC during chronic stress. Meanwhile, chronic stress also induced excessive microglia phagocytosis, leading to engulfment of excitatory synapses. Further investigation revealed that the elevated complement C3 during the stress acted as the tag of synapses to be eliminated by microglia. Besides, chronic stress induced a reduction of the connectivity between the mPFC and neighbor regions. C3 knockout mice displayed significant reduction of synaptic pruning and alleviation of disrupted functional connectivity in mPFC, resulting in more resilience to chronic stress. These results indicate that complement-mediated excessive microglia phagocytosis in adulthood induces synaptic dysfunction and cortical hypo-connectivity, leading to stress-related behavioral abnormality.

Blood-brain barrier and brain structural changes in lung cancer patients with non-brain metastases.

Purpose: To explore the relationship between blood-brain barrier (BBB) leakage and brain structure in non-brain metastasis lung cancer (LC) by magnetic resonance imaging (MRI) as well as to indicate the possibility of brain metastasis (BM) occurrence. Patients and methods: MRI were performed in 75 LC patients and 29 counterpart healthy peoples (HCs). We used the Patlak pharmacokinetic model to calculate the average leakage in each brain region according to the automated anatomical labeling (AAL) atlas. The thickness of the cortex and the volumes of subcortical structures were calculated using the FreeSurfer base on Destrieux atlas. We compared the thickness of the cerebral cortex, the volumes of subcortical structures, and the leakage rates of BBB, and evaluated the relationships between these parameters. Results: Compared with HCs, the leakage rates of seven brain regions were higher in patients with advanced LC (aLC). In contrast to patients with early LC (eLC), the cortical thickness of two regions was decreased in aLCs. The volumes of twelve regions were also reduced in aLCs. Brain regions with increased BBB penetration showed negative correlations with thinner cortices and reduced subcortical structure volumes (P<0.05, R=-0.2 to -0.50). BBB penetration was positively correlated with tumor size and with levels of the tumor marker CYFRA21-1 (P<0.05, R=0.2-0.70). Conclusion: We found an increase in BBB permeability in non-BM aLCs that corresponded to a thinner cortical thickness and smaller subcortical structure volumes. With progression in LC staging, BBB shows higher permeability and may be more likely to develop into BM.

Ferulic Acid Ameliorates Alzheimer's Disease-like Pathology and Repairs Cognitive Decline by Preventing Capillary Hypofunction in APP/PS1 Mice.

Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aß) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aß plaque deposition, the primary pathophysiology of Alzheimer's disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aß plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aß plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aß plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aß plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD.

Long-term acupuncture treatment has a multi-targeting regulation on multiple brain regions in rats with Alzheimer's disease: a positron emission tomography study.

The acute effect of acupuncture on Alzheimer's disease, i.e., on brain activation during treatment, has been reported. However, the effect of long-term acupuncture on brain activation in Alzheimer's disease is unclear. Therefore, in this study, we performed long-term needling at Zusanli (ST36) or a sham point (1.5 mm lateral to ST36) in a rat Alzheimer's disease model, for 30 minutes, once per day, for 30 days. The rats underwent 18F-fluorodeoxyglucose positron emission tomography scanning. Positron emission tomography images were processed with SPM2. The brain areas activated after needling at ST36 included the left hippocampus, the left orbital cortex, the left infralimbic cortex, the left olfactory cortex, the left cerebellum and the left pons. In the sham-point group, the activated regions were similar to those in the ST36 group. However, the ST36 group showed greater activation in the cerebellum and pons than the sham-point group. These findings suggest that long-term acupuncture treatment has targeted regulatory effects on multiple brain regions in rats with Alzheimer's disease.

Diffusion characteristics of the fornix in patients with Alzheimer's disease.

White matter degradation is a major part of the pathogenesis of Alzheimer's disease (AD). The fornix is the predominant outflow tract from the hippocampus, and alterations to its microstructure in patients with AD are still being explored. Diffusion tensor imaging (DTI) is an in vivo neuroimaging technique that can provide unique information about alterations in tissue microstructure, which can indicate underlying neurobiological process at the microstructural level. In this prospective study, DTI was used to assess and analyze the microstructural features of the fornix in subjects with AD (n = 17), mild cognitive impairment (MCI; n = 12) and healthy controls (n = 17). DTI was performed using Explore DTI software and the FSL package. Within the fornix, patients with AD showed decreased fractional anisotropy values and length of fiber tracts of the fornix relative to healthy controls, but higher mean diffusivity values. MCI subjects showed a trend towards elevated mean diffusivity values in the fornix. The data suggest that DTI provides supporting information on the microstructural alteration of the fornix in patients with AD, and that these diffusion characteristics of the fornix may be helpful for the clinical diagnosis of AD.

Blood oxygen level-dependent signals via fMRI in the mood-regulating circuit using two animal models of depression are reversed by chronic escitalopram treatment.

BACKGROUND: People exposed to stressful experience are at increased risk of the development of depression. A number of functional imaging studies have found disturbances in the mood-regulating circuit of the stress-exposed depressed patients, although few animal imaging studies have been undertaken addressing the brain functional changes of depression. METHODS: Two rat models of depression: maternal separation (MS) and chronic unpredictable mild stress (CUMS), imitating early life stress and adult stress respectively, were administered with escitalopram. The differences in functional brain changes were determined by blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI). RESULTS: Increased BOLD activation was observed in some brain regions of MS and CUMS animals, such as the bilateral hypothalamus, limbic system, hippocampus and frontal lobe, which were parts of mood-regulating circuit. Furthermore, the MS- and CUMS-induced increases in BOLD activation were partially attenuated by chronic escitalopram treatment. CONCLUSIONS: These results suggested hyperactivation of mood-regulating circuit at baseline in the depressed animals exposed to stressful experience, and escitalopram can at least partially reverse these effects.

An FMRI study of neuronal specificity in acupuncture: the multiacupoint siguan and its sham point.

Clarifying the intrinsic mechanisms of acupuncture's clinical effects has recently been gaining popularity. Here, we choose the Siguan acupoint (a combination of bilateral LI4 and Liv3) and its sham point to evaluate multiacupoint specificity. Thirty-one healthy volunteers were randomly divided into real acupoint (21 subjects) and sham acupoint (10 subjects) groups. Our study used a single block experimental design to avoid the influence of posteffects. Functional magnetic resonance imaging data were acquired during acupuncture stimulation. Results showed extensive increase in neuronal activities with Siguan acupuncture and significant differences between stimulation at real and sham points. Brain regions that were activated more by real acupuncture stimulation than by sham point acupuncture included somatosensory cortex (the superior parietal lobule and postcentral gyrus), limbic-paralimbic system (the calcarine gyrus, precuneus, cingulate cortex, and parahippocampal gyrus), visual-related cortex (the fusiform and occipital gyri), basal ganglia, and the cerebellum. In this way, our study suggests Siguan may elicit specific activities in human brain.

FMRI evidence of acupoints specificity in two adjacent acupoints.

Objectives. Acupoint specificity is the foundation of acupuncture treatment. The aim of this study is to investigate whether the acupoint specificity exists in two adjacent acupoints. Design and Setting. Two adjacent real acupoints, LR3 (Taichong) and ST44 (Neiting), and a nearby nonacupoint were selected. Thirty-three health volunteers were divided into three groups in random order, and each group only received acupuncture at one of the three points. While they received acupuncture, fMRI scan was performed. Results. The common cerebral activated areas responding to LR3 and ST44 included the contralateral primary somatosensory area (SI) and ipsilateral cerebellum. Acupuncture at LR3 specifically activated contralateral middle occipital gyrus, ipsilateral medial frontal gyrus, superior parietal lobe, middle temporal gyrus, rostral anterior cingulate cortex (rACC), lentiform nucleus, insula, and contralateral thalamus. Stimulation at ST44 selectively activated ipsilateral secondary somatosensory area (SII), contralateral middle frontal gyrus, inferior frontal gyrus, lingual gyrus, lentiform nucleus, and bilateral posterior cingulate cortex (PCC). Conclusions. Acupuncture at adjacent acupoints elicits distinct cerebral activation patterns, and those specific patterns might be involved in the mechanism of the specific therapeutic effects of different acupoints.

Abnormalities of cortical-limbic-cerebellar white matter networks may contribute to treatment-resistant depression: a diffusion tensor imaging study.

BACKGROUND: White matter abnormalities can cause network dysfunction that underlies major depressive disorder (MDD). Diffusion tensor imaging (DTI) is used to examine the neural connectivity and integrity of the white matter. Previous studies have implicated frontolimbic neural networks in the pathophysiology of MDD. Approximately 30% of MDD patients demonstrate treatment-resistant depression (TRD). However, the neurobiology of TRD remains unclear. METHODS: We used a voxel-based analysis method to analyze DTI data in young patients with TRD (n = 30; 19 males, 11 females) compared with right-handed, age- and sex-matched healthy volunteers (n = 25; 14 males, 11 females). RESULTS: We found a significant decrease in fractional anisotropy (FA) (corrected, cluster size >50) in the left middle frontal gyrus (peak coordinates [-18 46-14]), left limbic lobe uncus (peak coordinates [-18 2-22]), and right cerebellum posterior lobe (peak coordinates [26-34 -40]). There was no increase in FA in any brain region in patients. We also found a significant negative correlation between mean regional FA values in the three areas and Beck Depression Inventory symptom scores. CONCLUSIONS: We found significant differences in white matter FA in the frontal lobe, limbic lobe and cerebellum between TRD patients and controls. These data suggest that abnormalities of cortical-limbic-cerebellar white matter networks may contribute to TRD in young patients.

[Characteristics of PET cerebral functional imaging during "Deqi" of acupuncture in healthy volunteers].

OBJECTIVE: To observe the characteristics of needling sensation of "Deqi" (feelings of soreness, numbness, distending and heaviness, SNDH) by using positron emission tomography (PET) based on changes of glucose metabolism in different functional brain areas. METHODS: Eighteen normal volunteers [9 men and 9 women, mean age (23.23-1- 3. 32) years] were randomly divided into control, Waiguan (SJ 5) and non-acupoint groups (n=6 in each group). SJ 5 and non-acupoint (the midpoint between SJ 5 and the running course of the Small Intestine Meridian on the right forearm) were punctured by using a sterilized filiform needle. PET scan of the brain began 40 min after intravenous 18 F-fluorodeoxyglucose (FDG) injection (0. 11 mCi/kg body weight, left opisthenar vein). Needling sensations including "Deqi"(n= 5), tingling (n 5) and no-apparently-specific-feeling (NASF) were acquired by acupuncture stimulation and grouped. The needling sensations were evaluated by using Visual Analog Scale(VAS). The acquired image data of different needling-sensation groups were analyzed using SPM 2. 0 software in the Matlab Platform. RESULTS: After receiving acupuncture stimulation of SJ 5, 5 volunteers in the Waiguan (SJ 5) group experienced fee- lings of SNDH, with the mean VAS score being 4.23 +/- 1. 50, and 5 volunteers of the non-acupoint group had a tingling feeling, with the mean VAS score being 5.73 2.40. The VAS score of the tingling group was significantly higher than that of SNDH group (P<0. 05). Compared with the NASF control group, the activated cerebral areas were Brodmann area (BA) 7, 13, 20, 22, 39, 42 and BA 45 in the SNDH group, mainly involving the left temporal lobe, superior temporal gyrus, etc. and being obviously different to those of the control group (P<0. 001,k>10 voxels). The activated cerebral areas in the tingling group were BA 18, 19, 22, 24, 25, 32, 36, 40 and BA 45, predominantly involving the left limbic lobe, hippocampal gyrus, etc. and being apparently different to those of the control group (P<0. 001,k> 10 voxels). CONCLUSION: Acupuncture of Waiguan (SJ 5) mainly produces feelings of soreness, numbness, distending and heaviness, and the activated cerebral areas mainly involve the left temporal lobe, superior temporal gyrus, etc. ; while acupuncture of its neighboring non-acupoint chiefly induces a feeling of tingling in the healthy subjects, and the activated regions predominately involve the left limbic lobe, hippocampal gyrus, etc.

Hippocampal neurochemistry is involved in the behavioural effects of neonatal maternal separation and their reversal by post-weaning environmental enrichment: a magnetic resonance study.

Exposure to early life stress results in behavioural changes, and these dysfunctions may persist throughout adulthood. In this study, we investigated whether hippocampus volume and neurochemical changes were involved in the appearance of these effects in the maternal separation (MS) animal model using the noninvasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Sprague-Dawley rats exposed to MS for 180 min from postnatal days (PND) 2-14 demonstrated decreased sucrose preference, increased immobility in the forced swimming test (FST), and impaired memory in the Morris water maze in adulthood. Environmental enrichment (EE) (PND 21-60) could ameliorate the effects of MS on sucrose preference and learning and memory but not on immobility in the FST. In addition, EE significantly increased N-acetylaspartate (NAA) of MS animals. However, we did not find an effect of MS or EE on hippocampal volume. These results indicate the involvement of hippocampal neurochemistry in the behavioural changes that result from early stressful life events and their modification by post-weaning EE. Thus changes in NAA, as a measure of neuronal integrity, appear to be a sensitive correlate of these behavioural effects.

Brain volume alteration and the correlations with the clinical characteristics in drug-naïve first-episode MDD patients: a voxel-based morphometry study.

Structural brain abnormalities have been widely reported in major depressive disorder (MDD). However, many previous results cannot exclude the interferences of medication or multiple recurrent episodes. In this study, we examined structural brain abnormalities by comparing 68 drug-naïve first-episode adult-onset MDD and 68 healthy controls (HCs). Structural magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) methods were used. The mean values of grey matter volume/white matter volume (GMV/WMV) were calculated, then the differences between MDD and HCs were analyzed, and the associations of the differences with clinical characteristics of depression were discussed. The whole brain GMV/WMV did not differ between MDD patients and HCs; however, the regional GMV of the right pre-supplementary motor area (pre-SMA) was smaller in MDD patients. The GMV of both hippocampi was positively correlated with symptom severity and lower in patients with long durations. These results indicate the GMV reduction of the pre-SMA at an early stage of depression, whereas the GMV of the hippocampus is associated with depressive characteristics. Moreover, the whole brain GMV/WMV was negatively related to the duration of depression, supporting that volume loss could become progressive during the development of disease. These results may suggest the importance of identifying and intervening depression at an early stage, especially the first year after onset, to prevent volume loss in the brain.

Abnormal grey matter in victims of rape with PTSD in Mainland China: a voxel-based morphometry study.

UNLABELLED: Sui SG, Wu MX, King ME, Zhang Y, Ling L, Xu JM, Weng XC, Duan L, Shan BC, Li LJ. Abnormal grey matter in victims of rape with PTSD in Mainland China: a voxel-based morphometry study. OBJECTIVE: This study examined changes in brain grey matter in victims of rape (VoR) with and without post-traumatic stress disorder (PTSD). Previous research has focused on PTSD caused by various traumatic events, such as war and disaster, among others. Although considerable research has focused on rape-related PTSD, limited studies have been carried out in the context of Mainland China. METHODS: The study included 11 VoR with PTSD, 8 VoR without PTSD and 12 healthy comparison (HC) subjects. We used voxel-based morphometry to explore changes in brain grey-matter density (GMD) by applying statistical parametric mapping to high-resolution magnetic resonance images. RESULTS: Compared with HC, VoR with PTSD showed significant GMD reductions in the bilateral medial frontal cortex, left middle frontal cortex, middle temporal gyrus and fusiform cortex and significant GMD increases in the right posterior cingulate cortex, postcentral cortex, bilateral precentral cortex and inferior parietal lobule. Compared to VoR without PTSD, VoR with PTSD showed significant GMD reductions in the right uncus, left middle temporal gyrus, and the fusiform cortex, and increases in the left precentral cortex, inferior parietal lobule and right post-central cortex. CONCLUSION: The findings of abnormal GMD in VoR with PTSD support the hypothesis that PTSD is associated with widespread anatomical changes in the brain. The medial frontal cortex, precentral cortex, posterior cingulate cortex, post-central cortex and inferior parietal lobule may play important roles in the neuropathology of PTSD.

Brain areas involved in acupuncture treatment on functional dyspepsia patients: a PET-CT study.

Neuroimaging studies on brain responses to acupuncture stimulations have received considerable attention recently. The majority of these studies are centered on healthy controls (HC) and neuropathy, while little work has addressed other disorders. This study aimed to investigate the influence of acupuncture stimulations on brain activities in functional dyspepsia (FD) patients. Eight FD patients and eight healthy controls (HC) were involved in this study. Each HC received an 18F-FDG PET-CT scan at baseline, while each patient received scans at baseline and after acupuncture stimulations. Manual acupuncture stimulations were performed at ST34 (Liangqiu), ST36 (Zusanli), ST40 (Fenglong) and ST42 (Chongyang) in FD patients. The images were analyzed with the Statistical Parametric Mapping software 2.0. Compared to HC, the FD patients showed a lower glycometabolism in the right orbital gyrus, the left caudate tail and the cingulate gyrus, and a higher glycometabolism in the left inferior temporal gyrus (p<0.005). After acupuncture stimulations, the FD patients showed a glycometabolism decrease in the postcentral gyrus and the cerebella, and an increase in the visual-related cortices(p<0.005). The results suggest that the anterior cingulate cortex, the prefrontal cortices and the caudate tail involve in processing gastric perceptions in FD patients and that the deactivation of the primary somatosensory area and the cerebella is contributable to acupuncture stimulation, while activation of the visual-related cortex is a response to pain or acupoint actions.

The human brain response to acupuncture on same-meridian acupoints: evidence from an fMRI study.

OBJECTIVES: Stimulation of acupuncture points (acupoints) located on meridians has been proven to activate specific areas of the human brain, as evidenced by functional imaging studies. To date, the specificity of acupoints located on different meridians has been investigated with functional magnetic resonance image (fMRI). The present fMRI study explored the effects of stimulating 4 acupoints on 2 different meridians for the purpose of researching the characteristic response of acupoints on the same meridian. MATERIALS AND METHODS: The acupoints studied were LR3 (Taichong) and LR6 (Zhongdu), which belong to the Liver meridian of Foot-Jueyin; ST36 (Zusanli) and ST43 (Xiangu), which belong to the Stomach meridian of Foot-Yangming; and 2 nearby sham acupoints. Fifty-three (53) healthy right-handed subjects were divided randomly into 6 groups. Each group only received acupuncture at one acupoint. All the acupoints in this study were stimulated only on the right side of the subject's body. Through analysis of fMRI data from all subjects, we obtained the activation patterns in the central nervous system (CNS) evoked by acupuncture. RESULTS: In contrast to the CNS activation by sham acupoint, the results showed that all 4 real acupoints under consideration had the common effect of activating 2 specific areas of the brain: the bilateral primary somatosensory area and the ipsilateral cerebellum. Acupuncture stimulation of both acupoints LR3 and LR6 evoked activation at the ipsilateral superior parietal lobe (BA7). Acupuncture stimulation of both acupoints ST36 and ST43 evoked activation at the ipsilateral middle frontal gyrus (BA10). CONCLUSIONS: These results suggest that different acupoints on the same meridian may activate certain similar areas of the brain. In addition, acupoints that are commonly used in clinical practice might modulate a greater extent of cortical areas than uncommonly used acupoints.

Improved temporal clustering analysis method applied to whole-brain data in acupuncture fMRI study.

Temporal clustering analysis (TCA) has been proposed as a method for detecting the brain responses of a functional magnetic resonance imaging (fMRI) time series when the time and location of activation are completely unknown. But TCA is not suitable for treating the time series of the whole brain due to the existence of many inactive pixels. In theory, active pixels are located only in gray matter (GM). In this study, SPM2 was used to segment functional images into GM, white matter and cerebrospinal fluid, and only the pixels in GM were considered. Thus, most of inactive pixels are deleted, so that the sensitivity of TCA is greatly improved in the analysis of the whole brain. The same set of acupuncture fMRI data was treated using both conventional TCA and modified TCA (MTCA) for comparing their analytical ability. The results clearly show a significant improvement in the sensitivity achieved by MTCA.

An improved temporal clustering analysis method applied to whole-brain data in fMRI study.

Temporal clustering analysis (TCA) has been proposed as a method to detect the brain responses of an fMRI time series when the time and location of the activation are completely unknown. But TCA is still incompetent in dealing with the time series of the whole brain due to the existence of many inactive pixels. If only active pixels are considered, the sensitivity of TCA will be improved greatly and it could be applied to the whole brain. In this study, some modifications were made to TCA to remove inactive pixels, and the applicability of the modified TCA to the whole brain was validated with a set of visual fMRI data. Based on the time series of the modified TCA, activations of the whole brain corresponding to the visual stimulation were detected. Compared with the previous TCA, the modified TCA method shows a significant improvement in the sensitivity to detect activation peaks of the whole brain.

Improved temporal clustering analysis method for detecting multiple response peaks in fMRI.

PURPOSE: To develop an improved temporal clustering analysis (TCA) method for detecting multiple active peaks by running the method once. MATERIALS AND METHODS: Two cases of simulation data and a set of actual fMRI data from nine subjects were used to compare the traditional TCA method with the new method, termed extremum TCA (ETCA). The first case of simulation data simulated event-related activation and block activation in one cerebral area, and the second case simulated event-related activation and block activation in two cerebral areas. An in vivo visual stimulating experiment was performed on a 1.5T MR scanner. All imaging data were processed using both traditional TCA and the new method. RESULTS: The results of both the simulated and actual fMRI data show that the new method is more sensitive and exact than traditional TCA in detecting multiple response peaks. CONCLUSION: The new method is effective in detecting multiple activations even when the timing and location of the brain activation are completely unknown.