Multimodal multi-center analysis of electroconvulsive therapy effects in depression: Brainwide gray matter increase without functional changes

BackgroundElectroconvulsive therapy (ECT) is an effective treatment for severe depression and induces gray matter (GM) increases in the brain. Small-scale studies suggest that ECT also leads to changes in brain functioning, but findings are inconsistent. In this study, we investigated the influence of ECT on changes in both brain structure and function and their relation to clinical improvement using multicenter neuroimaging data from the Global ECT-MRI Research Collaboration (GEMRIC).MethodsWe analyzed T1-weighted structural magnetic resonance imaging (MRI) and functional resting-state MRI data of 88 individuals (49 male) with depressive episodes before and within one week after ECT. We performed voxel-based morphometry on the structural data and calculated fractional amplitudes of low-frequency fluctuations, regional homogeneity, degree centrality, functional connectomics, and hippocampus connectivity for the functional data in both unimodal and multimodal analyses. Longitudinal effects in the ECT group were compared to repeated measures of healthy controls (n = 27).ResultsWide-spread increases in GM volume were found in patients following ECT. In contrast, no changes in any of the functional measures were observed, and there were no significant differences in structural or functional changes between ECT responders and non-responders. Multimodal analysis revealed that volume increases in the striatum, supplementary motor area and fusiform gyrus were associated with local changes in brain function.ConclusionThese results confirm wide-spread increases in GM volume, but suggest that this is not accompanied by functional changes or associated with clinical response. Instead, focal changes in brain function appear related to individual differences in brain volume increases.     

Physical exercise prevents motor disorders and striatal oxidative imbalance after cerebral ischemia-reperfusion

Stroke is the third most common cause of death worldwide, and most stroke survivors present some functional impairment. We assessed the striatal oxidative balance and motor alterations resulting from stroke in a rat model to investigate the neuroprotective role of physical exercise. Forty male Wistar rats were assigned to 4 groups: a) control, b) ischemia, c) physical exercise, and d) physical exercise and ischemia. Physical exercise was conducted using a treadmill for 8 weeks. Ischemia-reperfusion surgery involved transient bilateral occlusion of the common carotid arteries for 30 min. Neuromotor performance (open-field and rotarod performance tests) and pain sensitivity were evaluated beginning at 24 h after the surgery. Rats were euthanized and the corpora striata was removed for assay of reactive oxygen species, lipoperoxidation activity, and antioxidant markers. Ischemia-reperfusion caused changes in motor activity. The ischemia-induced alterations observed in the open-field test were fully reversed, and those observed in the rotarod test were partially reversed, by physical exercise. Pain sensitivity was similar among all groups. Levels of reactive oxygen species and lipoperoxidation increased after ischemia; physical exercise decreased reactive oxygen species levels. None of the treatments altered the levels of antioxidant markers. In summary, ischemia-reperfusion resulted in motor impairment and altered striatal oxidative balance in this animal model, but those changes were moderated by physical exercise.     

Methamphetamine induces neuronal death: Evidence from rodent studies

Animal studies have consistently observed neuronal death following methamphetamine (MA) administration, however, these have not been systematically reviewed. This systematic review aims to present the evidence for MA-induced neuronal death in animals (rodents) and identify the regions affected. Locating the brain regions in which neuronal death occurs in animal studies will provide valuable insight into the linkage between MA consumption and the structural alterations observed in the human brain. The data were collected from three databases: Scopus, Ovid, and the Web of Science. Thirty-seven studies met the inclusion criteria and were divided into two sub-groups, i.e. acute and repeated administration. Twenty-six (of 27) acute and ten (of 11) repeated administration studies observed neuronal death. A meta-analysis was not possible due to different variables between studies, i.e. species, treatment regimens, withdrawal periods, methods of quantification, and regions studied. Acute MA treatment induced neuronal death in the frontal cortex, striatum, and substantia nigra, but not in the hippocampus, whereas repeated MA administration led to neuronal loss in the hippocampus, frontal cortex, and striatum. In addition, when animals self-administered the drug, neuronal death was observed at much lower doses than the doses administered by experimenters. There is some overlap in the regions where neuronal death occurred in animals and the identified regions from human studies. For instance, gray matter deficits have been observed in the prefrontal cortex and hippocampus of MA users. The findings presented in this review implicate that not only does MA induce neuronal death in animals, but it also damages the same regions affected in human users. Despite the inter-species differences, animal studies have contributed significantly to addiction research, and are still of great assistance for future research with a more relevant model of compulsive drug use in humans.     

Histamine-4 receptor antagonist ameliorates Parkinson-like pathology in the striatum

Growing evidence indicates that microglia activation and a neuroinflammatory trigger contribute to dopaminergic cell loss in Parkinson’s disease (PD). Furthermore, increased density of histaminergic fibers and enhanced histamine levels have been observed in the substantia nigra of PD-postmortem brains. Histamine-induced microglial activation is mediated by the histamine-4 receptor (H₄R). In the current study, gene set enrichment and pathway analyses of a PD basal ganglia RNA-sequencing dataset revealed that upregulation of H₄R was in the top functional category for PD treatment targets. Interestingly, the H₄R antagonist JNJ7777120 normalized the number of nigrostriatal dopaminergic fibers and striatal dopamine levels in a rotenone-induced PD rat model. These improvements were accompanied by a reduction of α-synuclein-positive inclusions in the striatum. In addition, intracerebroventricular infusion of JNJ7777120 alleviated the morphological changes in Iba-1-positive microglia and resulted in a lower tumor necrosis factor-α release from this brain region, as well as in ameliorated apomorphine-induced rotation behaviour. Finally, JNJ7777120 also restored basal ganglia function by decreasing the levels of γ-aminobutyric acid (GABA) and the 5-hydroxyindoleactic acid to serotonin (5-HIAA/5-HT) concentration ratios in the striatum of the PD model. Our results highlight H₄R inhibition in microglia as a promising and specific therapeutic target to reduce or prevent neuroinflammation, and as such the development of PD pathology.     

Striatal structure and its association with N-Acetylaspartate and glutamate in autism spectrum disorder and obsessive compulsive disorder

Autism spectrum disorders (ASD) and obsessive compulsive disorder (OCD) are often comorbid and are associated with changes in striatal volumes and N-Acetylaspartate (NAA) and glutamate levels. Here, we investigated the relation between dorsal striatal volume and NAA and glutamate levels. We additionally compared striatal volume and shape between ASD, OCD and controls. T1-weighted magnetic resonance (MR) images, proton spectra (1H-MRS) in the left striatum, and phenotypic information were collected from 54 children with ASD, 32 with OCD, and 56 controls (aged 8–13 years) in a four-site study. Dorsal striatal volume and shape were determined using the FMRIB integrated registration and segmentation tool (FIRST). Spectra were processed with Linear Combination Model. The relationship of left striatal volume with NAA and glutamate was investigated, and group comparisons were performed for NAA levels and for bilateral striatal volume and shape. NAA levels were lower in subjects with ASD compared with controls (t=2.86, p=0.005) and were associated with striatal volume (β=0.37, t=2.78, p=0.008). Glutamate levels were also associated with volume in the ASD group (β=0.38, t=2.46, p=0.018). No group differences were found for striatal volume or shape, but a post-hoc diagnosis-by-hemisphere interaction (F_(2,129)=3.86, p=0.024) revealed greater asymmetry (right>left) in striatal volume for the disorder-groups compared with controls. Our findings show involvement of NAA and glutamate in striatal volume in ASD and suggest greater asymmetry in paediatric ASD and OCD compared with controls, pointing to overlapping subcortical abnormalities. The lower NAA in ASD reflects reduced neuronal integrity or impaired neuronal functioning.     

Dynamic of neurochemical alterations in striatum,hippocampus and cortex after the 6-OHDA mesostriatal lesion

Immediate neurochemical alterations produced by 6-OHDA could explain the general toxic pattern in the central nervous system. However, no evidences describe the effects of 6-OHDA on early changes of neurotransmitters in rats’ striatum, cortex and hippocampus. In our study, unilateral 6-OHDA injection into medial forebrain bundle (MFB) was used in rats, then five neurotransmitters were analyzed at 3, 6, 12, 24, 48 and 72 h, respectively. Results showed that 6-OHDA injection caused a sharp decline of striatal dopamine (DA) levels in the first 12 h followed by a further reduction between 12 and 48 h. However, striatal levels of homovanillic acid (HVA) were stable in the first 12 h and showed a marked reduction between 12 and 24 h. Striatal levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) decreased linearly for 72 h, whereas levels of norepinephrine (NE) showed a slight reduction in the first 48 h, and returned back to normal afterwards. Striatal HVA/DA ratio increased significantly in the first 12 h, but 5-HIAA/5-HT ratio showed a sharp increase between 12 and 72 h. Besides, neurochemical alterations were also found in hippocampus and cortex, and the correlations of neurotransmitters were analyzed. Our study indicated that NE system had little influence in the early phase of 6-OHDA injection, moreover, early neurochemical alterations were involved with striatum, hippocampus and cortex.     

ER stress and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity in the rat striatum in vivo

Manganese (Mn) is an essential trace element found in many enzymes, however, excessive Mn-exposure can result in manganism which is similar to Parkinson's movement disorder. The mechanisms of manganism are not well-known. The present in vivo study was carried out to determine whether endoplasmic reticulum stress (ER stress) and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity. Sixty-four SD rats were randomly divided into four groups and were administered intraperitoneally with normal saline (NS, as control) or MnCl₂ (7.5, 15 and 30 mg/kg body weight, respectively) for 4 weeks. We found that MnCl₂ dose-dependently accumulate in striatal. HE staining and TUNEL assay results indicated that MnCl₂ induced striatal neurocytes apoptosis in both male and female rats. The alterations of ultrastructures showed that MnCl₂ resulted in chromatin condensation, mitochondria and ER tumefaction in rat striatal neurocytes. Furthermore, MnCl₂ increased the expressions of p-IRE-1, ATF-6α, PERK, GRP78, Sigma-1R, CHOP, Bim, Bax, caspase-12 and caspase-3, and decreased the expression of Bcl-2 in rat striatal neurocytes. In conclusion, MnCl₂ could induce ER stress and ER stress-mediated apoptosis in rat striatal neurocytes, which might be one of the important mechanisms of Mn-induced neurotoxicity.     

Toward sophisticated basal ganglia neuromodulation: Review on basal ganglia deep brain stimulation

This review presents state-of-the-art knowledge about the roles of the basal ganglia (BG) in action-selection, cognition, and motivation, and how this knowledge has been used to improve deep brain stimulation (DBS) treatment of neurological and psychiatric disorders. Such pathological conditions include Parkinson's disease, Huntington's disease, Tourette syndrome, depression, and obsessive-compulsive disorder. The first section presents evidence supporting current hypotheses of how the cortico-BG circuitry works to select motor and emotional actions, and how defects in this circuitry can cause symptoms of the BG diseases. Emphasis is given to the role of striatal dopamine on motor performance, motivated behaviors and learning of procedural memories. Next, the use of cutting-edge electrochemical techniques in animal and human studies of BG functioning under normal and disease conditions is discussed. Finally, functional neuroimaging studies are reviewed; these works have shown the relationship between cortico-BG structures activated during DBS and improvement of disease symptoms.     

电针对帕金森病大鼠纹状体缝隙连接蛋白43的表达及谷氨酸含量的影响

目的:观察电针对帕金森病(PD)大鼠纹状体缝隙连接蛋白(Cx)43及谷氨酸(Glu)的影响,探讨电针治疗PD的作用机制。方法:雄性SD大鼠,随机分为正常组、假手术组、模型组、电针组,每组10只。用立体定向微量注射法向大鼠右侧纹状体注射6-羟基多巴胺制备偏侧PD大鼠旋转模型。电针组电针"风府""太冲"穴,每次30min,每日1次,7d为1个疗程,共治疗2个疗程。行为学测试观察PD大鼠旋转行为的改变,运用HPLC荧光法检测纹状体Glu含量,采用Western blot法检测纹状体Cx 43蛋白活性表达的变化。结果:电针组大鼠治疗后旋转行为较治疗前及模型组改善明显(P0.01,P0.05)。模型组大鼠Cx43表达较正常组和假手术组显著升高(P0.01),Glu含量显著升高(P0.01)。电针组大鼠Cx 43表达较模型组显著降低(P0.01),Glu含量降低(P0.05)。结论:电针防治帕金森病的机制可能与针刺能够抑制纹状体Cx 43的表达,减少星形胶质细胞释放Glu有关。