Mathematical algorithm-based identification of the functional components and mechanisms in depression treatment: An example of Danggui-Shaoyao-San.

Depression, a complex epidemiological mental disorder, affects around 350 million people worldwide. Despite the availability of antidepressants based on monoamine hypothesis of depression, most patients suffer side effects from these drugs, including psychomotor impairment and dependence liability. Traditional Chinese medicine (TCM) is receiving more and more attention due to the advantages of high therapeutic performance and few side effects in depression treatment. However, complex multicomponents and multi-targets in TCM hinder our ability to identify the functional components and molecular mechanisms of its efficacy. In this study, we designed a novel strategy to capture the functional components and mechanisms of TCM based on a mathematical algorithm. To establish proof of principle, the TCM formula Danggui-Shaoyao-San (DSS), which possesses remarkable antidepressant effect but its functional components and mechanisms are unclear, is used as an example. According to the network motif detection algorithm, key core function motifs (CIM) of DSS in treating depression were captured, followed by a functional analysis and verification. The results demonstrated that 198 pathways were enriched by the target genes of the CIM, and 179 coincided with the enriched pathways of pathogenic genes, accounting for 90.40% of the gene enrichment pathway of the C-T network. Then the functional components group (FCG) comprising 40 components was traced from CIM based on the target coverage accumulation algorithm, after which the pathways enriched by the target genes of FCG were selected to elucidate the potential mechanisms of DSS in treating depression. Finally, the pivotal components in FCG of DSS and the related pathways were selected for experimental validation in vitro and in vivo. Our results indicated good accuracy of the proposed mathematical algorithm in sifting the FCG from the TCM formula, which provided a methodological reference for discovering functional components and interpreting molecular mechanisms of the TCM formula in treating complex diseases.

Limb loss experience evoked by electric cortical stimulation.

Limb loss experience is a type of body illusion characterized by the sensation of a missing limb or body part. We aimed to investigate the brain areas involved in this unusual somatosensory experience evoked by electric cortical stimulation with stereo-electroencephalography electrodes. We retrospectively reviewed the data of patients with medical intractable epilepsy, from October 2015 to December 2020, who underwent stereo-electroencephalography implantation and electric cortical stimulation in order to locate the epileptogenic zone and obtain a functional map. We included patients who reported experiences of limb loss during the process of electric cortical stimulation for functional mapping. Three patients reported experiences of limb loss in the process of electric cortical stimulation. Limb loss experience (including the right hand, right upper limb and right side of the body) occurred when the cortex of the left posterior insula, posterior dorsal cingulate and parietal operculum were stimulated. Limb loss experience can be evoked by electric cortical stimulation of the posterior insula, parietal operculum, and posterior cingulate cortex, and provides additional evidence that these cortices play a role in the integration of body sensory perception.

Establishment of Holistic Quality Control Methods for Nelumbinis Folium Containing Alkaloids and Flavonoids with Simple HPLC Conditions.

In this study, a positive charged C18 column was used to explore its performance in analysis of herbal medicines containing alkaloids and flavonoids with Nelumbinis Folium (NF) as an example. A chromatographic fingerprint analysis method was established by high performance liquid chromatography-diode array detector with commonly used 0.1% formic acid as mobile phase additive and this method could simultaneously detect both alkaloids and flavonoids with good peak shape. It is noted that the HPLC conditions were directly applied in the HPLC-ESI-Orbitrap-MS/MS analysis, and 12 common peaks were identified. In the quantification method of nuciferine, compared with common C18 column, good performance was observed, including sharp and symmetric peak shape of nuciferine, and no obvious retention time shift in chromatogram. The fingerprint method and quantification method of nuciferine and quercetin-3-O-glucuronic acid could be readily utilized as quality control methods for NF and its related preparations.

Comparison of efficiency between VNS and ANT-DBS therapy in drug-resistant epilepsy: A one year follow up study.

Vagus nerve stimulation (VNS) and anterior thalamic deep brain stimulation (ANT-DBS) have both been used for treatments of drug-resistant epilepsy (DRE). However, there is no comparative study on the effectiveness of two methods from one single center. 17 patients with DRE who underwent VNS therapy and 18 patients who underwent DBS were enrolled. A retrospective study was performed starting from baseline before operation extending to 12 months after operation. The seizure types, duration of epilepsy, age at implantation, failed numbers of antiepileptic drugs (AEDs) before operation, history of craniotomy, stimulation parameters and response rate were described. The analysis of liner regression on the age of onset, duration of epilepsy, numbers of AEDs, and the seizure reduction at 12 months after operation was applied. The mean seizure reduction in patients with DBS at 3, 6, 9 and 12 months after the operation was 57.22%, 61.61%, 63.94% and 65.28%, and that in cases with VNS was 36.06%, 39.94%, 45.24% and 48.35%, respectively. At 1 year after the operation, the patients with older operation age, focal seizures and older age of onset responded better to VNS; and those older operation age, focal generalized seizures, history of craniotomy and longer duration of disease responded better to DBS. The efficiency of ANT-DBS was higher than that of VNS at each follow up time point. Patients can choose the appropriate treatment according to the individual clinical characteristics.

The thalamus-precentral gyrus functional connectivity changes in epilepsy patients following vagal nerve stimulation.

Vagal nerve stimulation (VNS) is an effective treatment for patients with drug-resistant epilepsy who are unsuitable for surgical epilepsy treatment. However, the mechanism of action of VNS remains unclear, and the efficacy of VNS treatment regarding seizure frequency reduction cannot be assessed before surgery. This study measured changes in functional connectivity between thalamus and precentral gyrus which are activated as vital targets of deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS) using resting-state functional MRI to evaluate the effects of VNS. 16 epilepsy patients who underwent VNS were collected and scanned by resting-state functional MRI before and after operation. The functional connections (regions of interest: thalamus, precentral gyrus) were examined. After three months of stimulation, there were eight responders (≥50 % seizure reduction) and eight non-responders to VNS. No significant difference in thalamus-precentral gyrus functional connectivity was found between responders and nonresponders before operation. Enhanced functional connections were observed between bilateral thalamus and bilateral precentral gyrus in responders, which decreased in nonresponders, while functional connections between bilateral thalamus decreased in both responders and nonresponders. Short-term stimulation may cause thalamus-precentral gyrus functional connectivity changes in DRE patients, and control seizures by enhancing functional connections between bilateral thalamus and bilateral precentral gyrus.

Functional characteristics of the human primary somatosensory cortex: An electrostimulation study.

The common knowledge of the functional organization of the human primary somatosensory cortex (S1) had been primarily established by Penfield who electrically stimulated the exposed surface [referred as Brodmann area (BA)1] of S1 under neurosurgical conditions. Nevertheless, the functional information regarding the deep surface (BA 2 and 3) of S1 is poorly understood. We retrospectively analyzed all the clinical manifestations induced by extra-operative cortical electrical stimulation (ES) in 33 patients with medically intractable epilepsy who underwent stereo-electroencephalography (SEEG) monitoring for presurgical assessment. Demographic and clinical data were gathered and evaluated to delineate the determinants of the occurrence of positive responses, types of responses, and size of body regions involved. The stimulation of 244 sites in S1 yielded 198 positive sites (81.1%), most of which were located in the sulcal cortex. In multivariable analyses, no clinical or demographic factors predicted the occurrence of responses or their threshold levels. The size of body region involved in the responses had ordinal association with the stimulated BA sites (p < 0.001). Various types of responses elicited from the S1 were documented and classified, and the predictors of those responses were also assessed. Our analysis revealed the functional characteristics of the entire S1 and proved the multiplicity of functions of S1.

The effect of vagal nerve stimulation on hippocampal-thalamic functional connectivity in epilepsy patients.

BACKGROUND: Vagal nerve stimulation (VNS) is widely used as an auxiliary treatment for patients with intractable epilepsy. Up to now, the therapeutic mechanisms remain elusive, and no surgical prediction criteria has been proposed. METHODS: In this study, the resting-state functional magnetic resonance imaging (rs-fMRI) was chosen to explore aberrant intrinsic brain activity and functional connections in 14 epilepsy patients with VNS stimulators between March 2019 and April 2019. Seven patients who ≥ 50 % seizure reduction was defined as responders, and seven non-responders. All patients had got rs-fMRI scan before and after operation. The hippocampal - thalamic connections (hippocampal and thalamus as regions of interest) were detected to evaluate the diversity in all 14 patients and seven responders with stimulation at 0, 0.5, 1.0, and 1.5 mA. The hippocampal-thalamic connections before operation were also examined between responders and non-responders. RESULTS: The preoperative left hippocampal - left thalamic connections and left hippocampal - right thalamic connections in responders were lower than those in non-responders (p < 0.05). While, there was no significant difference in hippocampal - thalamic connections in all epilepsy patients or responders with different current intensities (p > 0.05). CONCLUSIONS: VNS may be more suitable for patients with lower left hippocampal - left thalamic connections and/or left hippocampal - right thalamic connections. The current intensity ≤ 1.5 mA and stimulation time ≤ 3 months may not cause significant changes in hippocampal-thalamic functional connectivity.

[Quality evaluation methods for standard decoction of Nelumbinis Folium].

The quality evaluation method for standard decoction of Chinese herbal slices is the basis for the quality evaluation of granules and preparations of classical formula(decoction)of traditional Chinese medicine. This study aimed to establish a method for the determination of quercetin-3-O-glucuronic acid in Nelumbinis Folium(NF)and its standard decoction, so as to provide reference for the quality control of NF and its standard decoction. Fifteen batches of representative NF were collected to prepare standard decoction, and the parameters of dry extract rate, transfer rate of index component, and pH value were calculated. HPLC was used to establish the content determination method for quercetin-3-O-glucuronic acid in NF and its standard decoction. The concentration range of quercetin-3-O-glucuronic acid in the standard decoction of NF was 1.09-3.06 g·L~(-1), while the concentration range of nuciferine was 0.01-0.17 g·L~(-1). The average extraction rate of NF standard decoction was(14.4±2.6)%, the average transfer rate of quercetin-3-O-glucuronic acid was(70.7±18.6)%, and the average transfer rate of nuciferine was(9.6±5.4)%. Compared with Nuciferine, quercetin-3-O-glucuronic acid had a high content and stable transfer rate in standard decoction, and was recommended to be the quality control marker for NF and its standard decoction. This paper establishes a quality evaluation method for NF standard decoction, and can provide reference for the quality control of all preparations derived from NF and its decoction.

High-frequency stimulation of anterior nucleus of thalamus desynchronizes epileptic network in humans.

Epilepsy has been classically seen as a brain disorder resulting from abnormally enhanced neuronal excitability and synchronization. Although it has been described since antiquity, there are still significant challenges achieving the therapeutic goal of seizure freedom. Deep brain stimulation of the anterior nucleus of the thalamus has emerged as a promising therapy for focal drug-resistant epilepsy; the basic mechanism of action, however, remains unclear. Here, we show that desynchronization is a potential mechanism of deep brain stimulation of the anterior nucleus of the thalamus by studying local field potentials recordings from the cortex during high-frequency stimulation (130 Hz) of the anterior nucleus of the thalamus in nine patients with drug-resistant focal epilepsy. We demonstrate that high-frequency stimulation applied to the anterior nucleus of the thalamus desynchronizes ipsilateral hippocampal background electrical activity over a broad frequency range, and reduces pathological epileptic discharges including interictal spikes and high-frequency oscillations. Furthermore, high-frequency stimulation of the anterior nucleus of the thalamus is capable of decoupling large-scale neural activity involving the hippocampus and distributed cortical areas. We found that stimulation frequencies ranging from 15 to 45 Hz were associated with synchronization of hippocampal local field potentials, whereas higher frequencies (>45 Hz) promoted desynchronization of ipsilateral hippocampal activity. Moreover, reciprocal effective connectivity between the anterior nucleus of the thalamus and the hippocampus was demonstrated by hippocampal-thalamic evoked potentials and thalamic-hippocampal evoked potentials. In summary, high-frequency stimulation of the anterior nucleus of the thalamus is shown to desynchronize focal and large-scale epileptic networks, and here is proposed as the mechanism for reducing seizure generation and propagation. Our data also demonstrate position-specific correlation between deep brain stimulation applied to the anterior nucleus of the thalamus and patients with temporal lobe epilepsy and seizure onset zone within the Papaz circuit or limbic system. Our observation may prove useful for guiding electrode implantation to increase clinical efficacy.