Optimal deep brain stimulation sites and networks for stimulation of the fornix in Alzheimer's disease.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer's Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement (R = 0.53, p < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures (R = 0.48, p < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes (R = 0.48, p < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming.

Optimal deep brain stimulation sites and networks for cervical vs. generalized dystonia.

Dystonia is a debilitating disease with few treatment options. One effective option is deep brain stimulation (DBS) to the internal pallidum. While cervical and generalized forms of isolated dystonia have been targeted with a common approach to the posterior third of the nucleus, large-scale investigations regarding optimal stimulation sites and potential network effects have not been carried out. Here, we retrospectively studied clinical results following DBS for cervical and generalized dystonia in a multicenter cohort of 80 patients. We model DBS electrode placement based on pre- and postoperative imaging and introduce an approach to map optimal stimulation sites to anatomical space. Second, we investigate which tracts account for optimal clinical improvements, when modulated. Third, we investigate distributed stimulation effects on a whole-brain functional connectome level. Our results show marked differences of optimal stimulation sites that map to the somatotopic structure of the internal pallidum. While modulation of the striatopallidofugal axis of the basal ganglia accounted for optimal treatment of cervical dystonia, modulation of pallidothalamic bundles did so in generalized dystonia. Finally, we show a common multisynaptic network substrate for both phenotypes in the form of connectivity to the cerebellum and somatomotor cortex. Our results suggest a brief divergence of optimal stimulation networks for cervical vs. generalized dystonia within the pallidothalamic loop that merge again on a thalamo-cortical level and share a common whole-brain network.

Responsive Neurostimulation of the Thalamus Improves Seizure Control in Idiopathic Generalized Epilepsy: A Case Report.

BACKGROUND AND IMPORTANCE: At least 25% of patients with idiopathic generalized epilepsy do not obtain adequate seizure control with medication. This report describes the first use of responsive neurostimulation (RNS), bilaterally targeting the centromedian/ventrolateral (CM/VL) region in a patient with drug-refractory Jeavons syndrome (eyelid myoclonia with absences). CLINICAL PRESENTATION: A patient, diagnosed with eyelid myoclonia with absences (EMA) and refractory to medication, was offered RNS treatment in the CM/VL region of the thalamus. Stimulation was triggered by thalamic neural activity having morphological, spectral, and synchronous features that corresponded to 3- to 5-Hz spike-wave discharges recorded on prior scalp electroencephalography. CONCLUSION: RNS decreased daily absence seizures from a mean of 60 to ≤10 and maintained the patient's level of consciousness during the occurring episodes. This therapy should be evaluated further for its potential to treat patients with pharmaco-refractory generalized epilepsy.

Acupuncture Needling, Electroacupuncture, and Fire Needling Improve Imiquimod-Induced Psoriasis-Like Skin Lesions through Reducing Local Inflammatory Responses.

Psoriasis is a common autoimmune disease. Acupuncture-related techniques have been widely used to treat psoriasis since its ability to engage neuronal function, the immune system, and other systems is well documented. This study aimed to investigate and compare the effects of three common acupuncture-related techniques in psoriasis-like skin inflammatory responses and explore the possible involved mechanisms. Imiquimod (IMQ)-induced psoriasis-like mice were treated with acupuncture needling, electroacupuncture, or fire acupuncture. Methotrexate (MTX) was applied as a positive control. Scoring by the psoriasis area and severity index (PASI) evaluated skin lesion changes. Keratinocyte proliferation and inflammatory cell infiltration were investigated using pathological staining. The secretion levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay. The expression levels of neuropeptides were assessed by Western immunoblotting. We found that acupuncture needling, electroacupuncture, and fire acupuncture all ameliorated skin lesions, reduced epidermal thickness, inhibited keratinocyte proliferation, and reduced CD3+ T cell infiltration. The aforementioned acupuncture techniques also decreased inflammatory cytokine secretion, including IL-1ß, IL-17A, and IL-23p40. Among them, electroacupuncture showed the best curative effects. Additionally, electroacupuncture downregulated the expression levels of Neurokinin A (NKA), which was positively associated with decreased inflammatory cytokine levels in local lesions. In conclusion, acupuncture needling, electroacupuncture, and fire acupuncture alleviated IMQ-induced psoriasis-like lesions. By contrast, electroacupuncture was more beneficial in reducing the inflammatory response, which might be related to locally dampened neuropeptide levels. Observations support the therapeutic effect of acupuncture for psoriasis and indicate a neuromodulatory mechanism in treating psoriasis by electroacupuncture.

Deep brain stimulation induced normalization of the human functional connectome in Parkinson's disease.

Neuroimaging has seen a paradigm shift away from a formal description of local activity patterns towards studying distributed brain networks. The recently defined framework of the 'human connectome' enables global analysis of parts of the brain and their interconnections. Deep brain stimulation (DBS) is an invasive therapy for patients with severe movement disorders aiming to retune abnormal brain network activity by local high frequency stimulation of the basal ganglia. Beyond clinical utility, DBS represents a powerful research platform to study functional connectomics and the modulation of distributed brain networks in the human brain. We acquired resting-state functional MRI in 20 patients with Parkinson's disease with subthalamic DBS switched on and off. An age-matched control cohort of 15 subjects was acquired from an open data repository. DBS lead placement in the subthalamic nucleus was localized using a state-of-the art pipeline that involved brain shift correction, multispectral image registration and use of a precise subcortical atlas. Based on a realistic 3D model of the electrode and surrounding anatomy, the amount of local impact of DBS was estimated using a finite element method approach. On a global level, average connectivity increases and decreases throughout the brain were estimated by contrasting on and off DBS scans on a voxel-wise graph comprising eight thousand nodes. Local impact of DBS on the motor subthalamic nucleus explained half the variance in global connectivity increases within the motor network (R = 0.711, P < 0.001). Moreover, local impact of DBS on the motor subthalamic nucleus could explain the degree to how much voxel-wise average brain connectivity normalized towards healthy controls (R = 0.713, P < 0.001). Finally, a network-based statistics analysis revealed that DBS attenuated specific couplings known to be pathological in Parkinson's disease. Namely, coupling between motor thalamus and motor cortex was increased while striatal coupling with cerebellum, external pallidum and subthalamic nucleus was decreased by DBS. Our results show that resting state functional MRI may be acquired in DBS on and off conditions on clinical MRI hardware and that data are useful to gain additional insight into how DBS modulates the functional connectome of the human brain. We demonstrate that effective DBS increases overall connectivity in the motor network, normalizes the network profile towards healthy controls and specifically strengthens thalamo-cortical connectivity while reducing striatal control over basal ganglia and cerebellar structures.

Matrine alleviates imiquimod-induced psoriasiform dermatitis in BALB/c mice via dendritic cell regulation.

Matrine, is a bioactive compound isolated from Sophora flavescens (Ku shen), an herb used in Chinese traditional medicine that possesses wide-reaching pharmacological action. Psoriasis is a chronic relapsing inflammatory disorder with an incompletely understood pathophysiology, and dendritic cells (DCs) play a central role in the disease. This study aimed to explore DCs related potential mechanisms based on the effect of matrine on imiquimod (IMQ)-induced psoriasiform dermatitis in BALB/c mice and DCs simulated by resiquimod. Mice with IMQ-induced psoriasiform cutaneous lesions were treated with matrine [12.5, 25 or 50 mg/(kg·d), for 6 days]. Morphology, histological changes, keratinocyte proliferation and differentiation, inflammatory cell infiltration, protein expression levels of myeloid differentiation factor 88 (MyD88), and mRNA expression levels of inflammatory factors [interleukin (IL)-12, IL-23, and IL-1ß] in lesional skin were assessed. The application of matrine decreased the proliferation of IMQ-induced keratinocytes. The treatment attenuated the infiltration of PCNA+ and CD3+ cells in the lesions. Matrine reduced the expression of the MyD88 protein and the inflammatory factors' mRNA in lesional skin, but also in BMDCs (bone marrow derived dendritic cells). These results indicated that matrine suppressed expression of the inflammatory factors by decreasing the expression of the MyD88 protein on the surface of BMDCs, finally alleviating psoriasiform skin lesions. Therefore, the findings suggest that matrine might be a potential candidate for treating psoriasis.

Qingchang Wenzhong Decoction Attenuates DSS-Induced Colitis in Rats by Reducing Inflammation and Improving Intestinal Barrier Function via Upregulating the MSP/RON Signalling Pathway.

Ulcerative colitis (UC) is a chronic, nonspecific, inflammatory disease for which an effective treatment is lacking. Our previous study found that Qingchang Wenzhong Decoction (QCWZD) can significantly improve the clinical symptoms of UC and ameliorate dextran sulphate sodium- (DSS-) induced ulcerative colitis in rats by downregulating the IP10/CXCR3 axis-mediated inflammatory response. The purpose of the present study was to further explore the mechanism of QCWZD for UC in rats models, which were established by 7-day administration of 4.5% dextran sulphate sodium solution. QCWZD was administered daily for 7 days; then we determined the serum macrophage-stimulating protein concentration (MSP) and recepteur d'origine nantais (RON) expression and its downstream proteins (protein kinase B [Akt], phosphorylated [p] Akt, occludin, zona occluden- [ZO-] 1, and claudin-2) in colon tissue using Western blotting and quantitative polymerase chain reaction. In DSS-induced UC, QCWZD significantly alleviated colitis-associated inflammation, upregulated serum MSP expression and RON expression in the colon, reduced the pAkt levels, promoted colonic occluding and ZO-1 expression, and depressed claudin-2 expression. In conclusion, the MSP/RON signalling pathway plays an important role in the pathogenesis of UC by involving the inflammatory response and improving intestinal barrier function. QCWZD appears to attenuate DSS-induced UC in rats by upregulating the MSP/RON signalling pathway.

Paeonol ameliorates imiquimod-induced psoriasis-like skin lesions in BALB/c mice by inhibiting the maturation and activation of dendritic cells.

Paeonol, an active component derived from the traditional Chinese medicine Cortex Moutan, possesses anti-inflammatory, analgesic, antioxidant and anti-allergic properties. Psoriasis is a chronic, recurrent, inflammatory dermatosis accompanied by excessive activation of Toll­like receptors (TLRs) in dendritic cells (DCs), which are primarily responsible for initiating an immune response. We investigated the effect of paeonol on inflammation in an imiquimod (IMQ)-induced psoriasis-like mouse model and murine bone marrow-derived dendritic cells (BMDCs) stimulated by R848. Mice were intragastrically administered 100 mg/kg (high), 50 mg/kg (medium) and 25 mg/kg (low) paeonol, respectively. We evaluated inflammation of psori-asis­like lesions based on histological changes, protein levels of myeloid differentiation factor 88 (MyD88) and TLR8 in skin lesions by western blotting, and levels of CD11c+ DCs in skin by immunoassay and in spleens by flow cytometry. Inflammatory cytokines [interleukin (IL)-23, IL-12 and IL-1ß] in skin lesions and BMDCs were also assessed by RT-PCR and ELISA. Application of paeonol decreased IMQ-induced keratinocyte proliferation, and infiltration of CD3+ cells, while the treatment ameliorated CD11c+ cells in the spleen and skin, and reduced MyD88 and TLR8 proteins in skin lesions. Paeonol inhibited IMQ-induced mRNA expression of IL-23, but not IL-12 and IL-1ß in BMDCs, along with significantly lower levels of DCs expressing MHCⅡ, CD80 and CD86 in vitro. These results indicate that paeonol suppresses the maturation and activation of DCs by decreasing MyD88 and TLR8 proteins in the TLR7/8 signaling pathway which finally alleviates psoriasis­like skin lesions. The TLR7/8 signaling pathway in DCs provides an important insight into the mechanism of psoriasis, and paeonol may be a potent therapeutic drug for psoriasis.

Gender Differences in Internalizing Symptoms and Suicide Risk Among Men and Women Seeking Treatment for Cannabis Use Disorder from Late Adolescence to Middle Adulthood.

Cannabis continues to rise in popularity as the perception of its harmfulness decreases and evidence of its deleterious developmental effect increases. While internalizing distress and suicide risk have been linked with cannabis use problems [DSM-5 cannabis use disorder (CUD); DSM-IV cannabis abuse and dependence] it remains unclear how this association varies over the course of development in treatment-seeking men and women. The current study utilized the National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) to conduct a cross-sectional comparison of internalizing distress and suicide risk among men (n=437) and women (n=163) spanning ages 18-50 who met DSM-5 criteria for CUD. Interactions between gender and developmental stage (i.e., late adolescence, early adulthood, and middle adulthood) were observed for suicide risk and anxiety but not depression problems. Specifically, women seeking CUD treatment in late adolescence and middle adulthood exhibited significantly higher rates of anxiety and suicide risk compared to men seeking treatment during the same developmental stages. Internalizing distress and suicide risk did not differ between treatment-seeking men and women in the early adult stage. Overall, results suggest that the structure of risk for CUD may differ in men and women across the lifespan and that women presenting for CUD treatment during late adolescence and middle adulthood may uniquely benefit from intervention designed to address these elevations in anxiety and suicide risk.