Electroacupuncture stimulation modulates functional brain connectivity in the treatment of pediatric cerebral palsy: a case report.

Background: Pediatric cerebral palsy (CP) is a non-progressive brain injury syndrome characterized by central motor dysfunction and insufficient brain coordination ability. The etiology of CP is complex and often accompanied by diverse complications such as intellectual disability and language disorders, making clinical treatment difficult. Despite the availability of pharmacological interventions, rehabilitation programs, and spasticity relief surgery as treatment options for CP, their effectiveness is still constrained. Electroacupuncture (EA) stimulation has demonstrated great improvements in motor function, but its comprehensive, objective therapeutic effects on pediatric CP remain to be clarified. Methods: We present a case of a 5-year-old Chinese female child who was diagnosed with CP at the age of 4. The patient exhibited severe impairments in motor, language, social, and cognitive functions. We performed a 3-month period of EA rehabilitation, obtaining resting state functional magnetic resonance imaging (rs-fMRI) of the patient at 0 month, 3 months and 5 months since treatment started, then characterized brain functional connectivity patterns in each phase for comparison. Results: After a 12-month follow-up, notable advancements were observed in the patient's language and social symptoms. Changes of functional connectivity patterns confirmed this therapeutic effect and showed specific benefits for different recovery phase: starting from language functions then modulating social participation and other developmental behaviors. Conclusion: This is a pioneering report demonstrating the longitudinal effect of EA stimulation on functional brain connectivity in CP patients, suggesting EA an effective intervention for developmental disabilities (especially language and social dysfunctions) associated with pediatric CP.

Abnormal brain activity patterns during spatial working memory task in patients with end-stage renal disease on maintenance hemodialysis: a fMRI study.

Hemodialysis (HD) is associated with cognitive impairment in patients with end-stage renal disease (ESRD). However, the neural mechanism of spatial working memory (SWM) impairment in HD-ESRD patients remains unclear. We investigated the abnormal alterations in SWM-associated brain activity patterns in HD-ESRD patients using blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) technique during n-back tasks. Twenty-two HD-ESRD patients and 22 well-matched controls underwent an fMRI scan while undergoing a three-load n-back tasks with different difficulty levels. Cognitive and mental states were assessed using a battery of neuropsychologic tests. The HD-ESRD patients exhibited worse memory abilities than controls. Compared with the control group, the HD-ESRD patient group showed lower accuracy and longer response time under the n-back tasks, especially in the 2-back task. The patterns of brain activation changed under different working memory loads in the HD-ESRD patients, showing decreased activity in the right medial frontal gyrus and inferior frontal gyrus under 0-back and 1-back task, while more decreased activation in the bilateral frontal cortex, parietal lobule, anterior/posterior cingulate cortex and insula cortex under 2-back task. With the increase of task difficulty, the activation degree of the frontal and parietal cortex decreased. More importantly, we found that lower activation in frontal cortex and parietal lobule was associated with worse cognitive function in the HD-ESRD patients. These results demonstrate that the abnormal brain activity patterns of frontal cortex and parietal lobule may reflect the neural mediation of SWM impairment.

Long-term exposure to ephedrine leads to neurotoxicity and neurobehavioral disorders accompanied by up-regulation of CRF in prefrontal cortex and hippocampus in rhesus macaques.

Drug addiction continues to threaten the health and welfare of people worldwide, and ephedrine abuse is a serious drug problem in many areas of the world. Ephedrine toxicity is thought to induce behavioral effects primarily through actions on the central nervous system. The corticotropin-releasing factor (CRF) system plays an important role in regulating behavioral effects induced by addictive drugs, but whether CRF is related to ephedrine toxicity remains unclear. This study seeks to examine whether there is a correlation between the CRF and chronic ephedrine neurotoxicity. To this end, we established a chronic ephedrine (0.4-1.6 mg/kg/d) exposure model in rhesus macaques, assessed its effects on body weight and behavior, examined neuronal changes in the prefrontal cortex and hippocampus, and measured the CRF expression in the prefrontal cortex and hippocampus. After 8-weeks of exposure to ephedrine, the toxic effects of ephedrine included significant weight loss and induction of behavioral changes in rhesus macaques. In particular, in the modeling group, the abnormal behavioral changes mainly manifested as irritability and behavioral sensitization. Meanwhile, the histological abnormalities included neuronal morphological changes, pyknosis and irregular shapes of neurons in the prefrontal cortex and hippocampus. In addition, the expression levels of CRF mRNA and protein were increased in the prefrontal cortex and hippocampus of ephedrine-treated animals. In summary, the finding of this study indicated that ephedrine neurotoxicity can cause neuronal damage in cerebral cortex, which in turn can result in certain neurobehavioral abnormalities, and that CRF expression in prefrontal cortex and hippocampus is elevated in response to ephedrine exposure. These observations suggested that long-term exposure to ephedrine might be causing neurotoxicity and leading to neurobehavioral disorders accompanied by up-regulation of CRF in prefrontal cortex and hippocampus.

Effects of Chronic Ephedrine Toxicity on Functional Connections, Cell Apoptosis, and CREB-Related Proteins in the Prefrontal Cortex of Rhesus Monkeys.

Ephedrine abuse has spread in many parts of the world, severely threatening human health. The mechanism of ephedrine toxicity is still unclear. To explore the possible neural mechanisms of ephedrine toxicity, this study established a non-human primate model of ephedrine exposure, analyzed the functional connectivity changes in its prefrontal cortex through resting state BOLD-fMRI, and then inspected the pathophysiological changes as well as the expression of the cyclic adenosine monophosphate response element-binding protein (CREB), phosphorylated CREB (P-CREB), and CREB target proteins (c-fos and fosB) in the prefrontal cortex. After ephedrine toxicity, we found that the prefrontal cortex of monkeys strengthened its functional connectivity with the brain regions that perform motivation, drive, reward, and learning and memory functions and weakened its functional connectivity with the brain regions that perform cognitive control. These results suggest that ephedrine toxicity causes abnormal neural circuits that lead to the amplification and enhancement of drug-related cues and the weakening and damage of cognitive control function. Histology showed that the neurocytotoxicity of ephedrine can cause neuronal degeneration and apoptosis. Real-time PCR and Western blot showed increased expression of CREB mRNA and CREB/P-CREB/c-fos/fosB protein in the prefrontal cortex after ephedrine toxicity. Collectively, the present study indicates that the enhancement of drug-related cues and the weakening of cognitive control caused by abnormal neural circuits after drug exposure may be a major mechanism of brain function changes caused by ephedrine. These histological and molecular changes may be the pathophysiological basis of brain function changes caused by ephedrine.

Behavioral Changes and Neuronal Damage in Rhesus Monkeys after 10 Weeks of Ketamine Administration Involve Prefrontal Cortex Dopamine D2 Receptor and Dopamine Transporter.

The dopamine D2 receptor (DRD2) and dopamine transporter (DAT) play a regulatory role in dopaminergic neurotransmission and thus play an important role in drug addiction. The prefrontal cortex (PFC), a critical part of the mesencephalic dopaminergic system, is thought to be involved in the development and maintenance of drug addiction. The addiction to ketamine is thought to induce behavioral effects primarily through actions on the central nervous system. However, the neural mechanism underlying the effects of ketamine addiction remains unclear. In this study, we investigate the involvement of PFC DRD2 and DAT in ketamine addiction effects after ketamine administration for 10 weeks in nonhuman primates. To this end, after administering ketamine to rhesus monkeys for 10 weeks, we assessed changes in body weight and behavior. Additionally, neuronal changes in the PFC were examined by hematoxylin and eosin (HE) staining; the DRD2 and DAT mRNA and protein expression levels in the PFC were determined by real-time PCR and Western blot analysis, respectively. After 10-week ketamine administration, the assessment of the manifestations of toxicity in rhesus monkeys revealed significant changes in body weight and behavior, decreased DRD2 and DAT mRNA and protein expression in the PFC, and histological abnormalities including neuronal eosinophilia, pyknosis and disorderly arrangement of neurons in the PFC. These results suggest that the reduced expression of DRD2 and DAT in PFC could be involved in the behavioral and the neurological changes induced by ketamine administration, which may play an important role in the molecular mechanisms of ketamine addiction.

Exploring the neuromechanism of chronic ephedrine addiction in rhesus monkeys: A behavioural and brain resting-state fMRI study.

Ephedrine is thought to exert behavioural effects primarily through actions on the central nervous system. However, the neuromechanism underlying the effects of ephedrine addiction still remains unclear. Our study aimed to establish chronic ephedrine addiction models in rhesus monkeys and to investigate the neuromechanism of chronic ephedrine addiction using the behavioural methods combined with resting-state blood oxygenation level dependent-functional magnetic resonance imaging (BOLD-fMRI). Monkeys in the ephedrine addiction group (n = 6) received intramuscular injections of ephedrine using a dose escalation method, with a chronic model established in 8 weeks, while in the control group (n = 4), monkeys received a pure 0.9% saline injection. The weight and behaviors of the monkeys were observed throughout the treatment. All monkeys underwent the brain MR scans for two times (before treatment and after treatment had been discontinued). After molding, the weight of the ephedrine group was significantly reduced, while the weight of the control group increased significantly. Compared with the control group, the ephedrine addicted monkeys showed more abnormal behaviors related to addiction. In fMRI study, the ephedrine addicted monkeys showed more increased brain activation than that of the control group, mainly including the prefrontal cortex(PFC) and anterior cingulate cortex (ACC), the left ventral tegmental area(VTA), right insula, right amygdala, hippocampus, left thalamus, and left cerebellum.We hypothesize that the principal neuromechanism underlying chronic ephedrine addiction involves multiple abnormal brain neuron circuits, mainly in the PFC and the limbic system, and is closely related to addictive behaviors.

Impaired decision-making and functional neuronal network activity in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is associated with cognitive deficit but the exact neural mechanisms remain unclear. PURPOSE: To explore sequential brain activities using functional magnetic resonance imaging (fMRI) during the performance of a decision-making task, and to determine whether serum or clinical markers can reflect the involvement of the brain in SLE. SUBJECTS: Sixteen female SLE patients without overt clinical neuropsychiatric symptoms and 16 healthy controls were included. FIELD STRENGTH/SEQUENCE: 1.5T, T1 -weighted anatomic images, gradient-echo echo-planar imaging sequence, and 3D images. ASSESSMENT: The computer-based Iowa Gambling Task (IGT) for assessing decision-making was performed by SLE patients and 16 matched controls; brain activity was recorded via blood oxygen level-dependent (BOLD) fMRI. The amplitudes of the average BOLD responses were calculated for each individual subject, and activation data from fMRI experiments were compared between the two groups. STATISTICAL TESTS: Two-sample t-test; repeated-measures analysis of variance (ANOVA); linear regression analyses. RESULTS: Imaging revealed activity in a distributed network of brain regions in both groups, including the ventromedial prefrontal cortex (vmPFC), the orbitofrontal cortex (OFC), the dorsolateral prefrontal cortex (dlPFC), the anterior cingulate cortex (ACC), the posterior cingulate cortex (PCC), and the striatum, as well as the insular, parietal, and occipital cortices. Compared to controls, SLE patients showed lower activation in a convergence zone and the limbic system, namely, the OFC, vmPFC, ACC, and PCC, but greater activation in memory, emotion, and behavior systems involving the dlPFC, the insular cortex and the striatum. Furthermore, brain activation in the vmPFC was positively correlated with IGT scores (r = 0.63, P < 0.001), but inversely related to disease activity (r = -0.57, P < 0.01). DATA CONCLUSION: The dynamics among the aforementioned neural systems (some hyperfunctioning, others hypofunctioning) may shed some light on the pathologic mechanisms underlying SLE without overt clinical neuropsychiatric symptoms. In addition, disease activity may potentially be used as an effective biomarker reflecting cerebral involvement in SLE. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;48:1508-1517.

cAMP Response Element Binding Protein Expression in the Hippocampus of Rhesus Macaques with Chronic Ephedrine Addiction.

BACKGROUND: Drug addiction is classified as a chronic relapse nature brain disease with complicated neurobiology mechanisms. There are an increasing number of researchers that are investigating the possible mechanisms for solving the thorny problem. METHODS: The model of chronic addiction of rhesus monkey ephedrine was established, where changes in body weight and behavior were monitored. The expression of cAMP response element binding protein (CREB) in the hippocampus of rhesus monkeys was identified by real-time PCR and Western blot. RESULTS: We were successful in establishing the chronic ephedrine addiction model in the rhesus macaques. They exhibited changes in body weight and behavior. Immunofluorescence showed that CREB was expressed in the nucleus of the hippocampus, and the expression of CREB mRNA and protein in the hippocampus were increased by real-time PCR and Western blot. The CREB positive expression in the hippocampus of the modeling group was significantly higher than in the control group. CONCLUSIONS: The changes of body weight and behavior of the rhesus monkeys after ephedrine chronic addiction were significant. The changes of CREB in the hippocampus of rhesus macaques with ephedrine chronic addiction are important molecular mechanisms, and the upregulation of CREB may be involved in the physiological pathology and behavior process in individuals with chronic ephedrine addiction.

Decision-making in primary onset middle-age type 2 diabetes mellitus: a BOLD-fMRI study.

Although type 2 diabetes mellitus (T2DM) is a well-recognized risk factor for dementia, the neural mechanisms that underlying cognitive impairment in T2DM remain unclear. We used functional magnetic resonance imaging (fMRI) during a computerized version of the Iowa Gambling Task to investigate the neural basis of decision making at the initial onset stage of T2DM. Eighteen newly diagnosed middle-aged T2DM patients, with no previous diabetic treatment history, and 18 matched controls were recruited. Results indicated that T2DM patients made more disadvantageous decisions than controls. Compared to healthy subjects, T2DM patients showed decreased activation in the ventral medial prefrontal cortex (VMPFC), orbitofrontal cortex (OFC) and anterior cingulate cortex, and increased activity in the dorsolateral prefrontal cortex, posterior cingulate cortex, insula and occipital lobes. IGT performance positively correlated with changes in brain activation in the VMPFC and OFC in both groups. Moreover, poor glycemic control was associated with decision-making function both in behavioral and brain activity in the VMPFC and OFC in patients. Conclusively, T2DM patients may suffer from weaknesses in their prefrontal cortex functions that lead to poorer decision-making under ambiguity, at least as assessed by the IGT.

Diagnosis and treatment of pediatric benign pneumoperitoneum: A case report series of 9 patients.

INTRODUCTION: Benign pneumoperitoneum (BPPT) is defined as asymptomatic free intraabdominal air or as pneumoperitoneum without peritonitis. Symptomatic free air requires surgical anagement, but management of asymptomatic pneumoperitoneum is controversial. In this study, we investigate the diagnosis and treatment of BPPT in children. CLINICAL FINDINGS: The clinical data of 9 pediatric patients with BPPT who were admitted to our hospital from January 2000 to January 2015 were retrospectively analyzed to summarize the diagnosis and treatment. Overall, 9 cases were included with 8 males and 1 female, aged from 4 days to 4 years. Among them there were 6 newborns (including 1 premature infant). Patients were all admitted to hospital with the major clinical symptom of abdominal distension, including 2 cases accompanied by tachypnea, 2 cases with vomiting, 1 case with diarrhea, and 2 cases with fever. No previous constipation or obstructive defecation existed. Six newborns had meconium defecation within 24 hours after birth. Physical examination revealed all patients with relaxed abdominal wall except 1 patient with abdominal distension had slight muscle stiffness and hyperactive bowel sounds. Abdominal X-ray suggested free air under the diaphragm in all cases. INTERVENTIONS/OUTCOMES: All patients except for one case of laparotomy were conservatively treated and cured with fasting, infection prevention, rehydration, abdominocentesis, and close observation. Nine cases of patients were all discharged with no death occurrence. After discharge follow-up of 7 months to 6 years was conducted. There was no recurrence of similar symptoms, and children were in good growth and development. CONCLUSION: The diagnosis of BPPT mainly relies on clinical symptoms in patient, careful abdominal examination, abdominal X-ray combined with abdominocentesis, and the exclusion of gastrointestinal perforation for confirmation. Conservative treatment can cure the disease. Attention should be paid to distinguish with surgical pneumoperitoneum to avoid unnecessary surgical exploration.

Spatial Working Memory Impairment in Patients with Non-neuropsychiatric Systemic Lupus Erythematosus: A Blood-oxygen-level Dependent Functional Magnetic Resonance Imaging Study.

OBJECTIVE: Using ethology and functional magnetic resonance imaging (fMRI) to explore mild cognitive dysfunction and spatial working memory (WM) impairment in patients with systemic lupus erythematosus (SLE) without overt neuropsychiatric symptoms (non-NPSLE) and to study whether any clinical biomarkers could serve as predictors of brain dysfunction in this disease. METHODS: Eighteen non-NPSLE patients and 18 matched subjects were all tested using the Montreal cognitive assessment scale test and scanned using blood-oxygen-level dependent fMRI while performing the n-back task to investigate the activation intensity of some cognition-related areas. RESULTS: Ethology results showed that non-NPSLE patients had mild cognitive dysfunction and memory dysfunction (p < 0.05). The fMRI scan confirmed a neural network consisting of bilateral dorsolateral prefrontal cortex (DLPFC), premotor area, parietal lobe, and supplementary motor area (SMA)/anterior cingulate cortex (ACC) that was activated during the n-back task, with right hemisphere dominance. However, only the right SMA/ACC showed a load effect in the non-NPSLE group; the activation intensity of most WM-related brain areas for the non-NPSLE group was lower than for the control group under 3 memory loads. Further, we found that the activation intensity of some cognition-related areas, including the bilateral caudate nucleus/insula and hippocampus/parahippocampal gyrus were lower than the control group under the memory loads. An inverse correlation existed between individual activation intensity and disease duration. CONCLUSION: Non-NPSLE-related brain damage with right DLPFC-posterior parietal lobe and parahippocampal gyrus default network causes impairment of spatial WM and mild cognitive dysfunction. Patients with longer disease duration would be expected to exhibit increased central nervous system damage.

Diethylstilbestrol Regulates the Expression of LGR8 in Mouse Gubernaculum Testis Cells.

BACKGROUND Hormonal effects on the gubernaculum can affect testicular descent. Diethylstilbestrol (DES) is a nonsteroidal synthetic estrogen that disrupts the outgrowth of gubernaculums, leading to testis maldescent. However, the underlying mechanisms remain elusive. MATERIAL AND METHODS The gubernaculum were removed from 3-day-old mice and cultured. The subcultured cells were randomly divided into a normal control group and experimental groups. The DES groups were administered 10 µg/ml, 1 µg/ml, 0.1 µg/ml, 0.01 µg/ml of diethylstilbestrol dissolved in dimethyl sulfoxide (DMSO) respectively. The cell morphology was observed under an inverted microscope, and leucine-rich repeat-containing G protein-coupled receptor 8 (LGR8) was localized by immunofluorescence. The expressions of LGR8 gene and protein in gubernaculum cells were quantified by RT-PCR and Flow Cytometer respectively. RESULTS DES treatment converted cells from a normal fibroblast-like morphology into a more refractile, spindle-shaped morphology or irregular elliptical shapes along with cytoplasmic shrinkage. LGR8 was expressed in the cytoplasmic membrane, DES dose-dependently downregulated LGR8 expression at low doses (≤1.0 µg/ml), but upregulated LGR8 at high doses (10 µg/ml) at both the mRNA and protein levels. CONCLUSIONS These results suggest that DES causes testicular maldescent by altering the LGR8 pathway in mouse gubernaculum testis cells.

Spatial working memory impairment in primary onset middle-age type 2 diabetes mellitus: An ethology and BOLD-fMRI study.

PURPOSE: To explore mild cognitive dysfunction and/or spatial working memory impairment in patients with primary onset middle-age type 2 diabetes mellitus (T2DM] using ethology (behavior tests) and blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI). MATERIALS AND METHODS: Eighteen primary onset T2DM patients and 18 matched subjects with normal blood glucose levels were all tested using the Montreal cognitive assessment scale test, the Wechsler Memory Scale Chinese-revised test, and scanned using BOLD-fMRI (1.5T, EPI sequence) while performing the n-back task to find the activation intensity of some cognition-related areas. RESULTS: The ethology results showed that T2DM patients had a mild cognitive impairment and memory dysfunction (P < 0.05). The fMRI scan identified a neural network consisting of bilateral dorsolateral prefrontal cortex (DLPFC), bilateral premotor area (PreMA), bilateral parietal lobe (PA), and anterior cingulate cortex (ACC) / supplementary motor area (SMA) that was activated during the n-back task, with right hemisphere dominance. However, only the right PA and ACC/SMA showed a load effect via quantitative analysis in the T2DM group; the activation intensity of most working memory-related brain areas for the T2DM group were lower than for the control group under three memory loads. Furthermore, we found that the activation intensity of some cognition-related areas, including the right insular lobe, left caudate nucleus, and bilateral hippocampus/parahippocampal gyrus were lower than the control group under the memory loads. CONCLUSION: Diabetes-related brain damage of primary onset middle-age T2DM patients with right DLPFC-posterior parietal lobe and parahippocampal gyrus default network causes impairment of spatial working memory and mild cognitive dysfunction.

An insight into insulin-like factor 3 regulate its receptor RXFP2 in mouse gubernaculum testis cells.

The etiology of testicular dysgenesis syndrome is multifactorial and involves abnormalities in the anatomical structures and endocrine factors. Several studies have shown that the abnormal development of the gubernaculum may affect testicular descent, and the insulin-like factor 3 (INSL3) appears to play an important role in development of the gubernaculum have been proved. INSL3 binds its specific receptor (Relaxin family peptide 2, RXFP2), which was highly expressed in gubernaculum, to produce a crucial effect in the first transabdominal descent stage, but its mechanism still remain unclear. In this study, in order to explore how does INSL3 regulate its receptor RXFP2, we cultured mouse gubernaculum testis cells in vitro, which was treated by INSL3, and examined the expression of RXFP2 in mouse gubernaculum testis cells. The results displayed that INSL3 changed RXFP2 expression, and we found that low dose INSL3 can increase RXFP2 expression, the mechanism of above-mentioned might be related with the hormesis of INSL3.