Status of Noninvasive Brain Stimulation in the Therapy of Alzheimer's Disease

Alzheimer's disease (AD),characterized by progressive memory impairment and dementia leading to severe deterioration of daily living,has been a public health crisis that currently lacks effective treatments.The reported prevalence of AD was 3.21% in people aged ≥65 years,More than 7 million people live with AD in China today and the number continues to increase.AD imposes a heavy financial burden on the society and it is becoming worse.The total socioeconomic costs of Chinese patients with AD was estimated to be US $167.74 billion in 2015 and is predicted to reach US $1.89 trillion by 2050.

Stimulation of Anterior Thalamic Nuclei Protects Against Seizures and Neuronal Apoptosis in Hippocampal CA3 Region of Kainic Acid-induced Epileptic Rats

Background：The antiepileptic effect of the anterior thalamic nuclei （ANT） stimulation has been demonstrated;however,its underlying mechanism remains unclear.The aim of this study was to investigate the effect of chronic ANT stimulation on hippocampal neuron loss and apoptosis.Methods：Sixty-four rats were divided into four groups：The control group,the kainic acid （KA） group,the sham-deep brain stimulation （DBS） group,and the DBS group.KA was used to induce epilepsy.Seizure count and latency to the first spontaneous seizures were calculated.Nissl staining was used to analyze hippocampal neuronal loss.Polymerase chain reaction and Western blotting were conducted to assess the expression of caspase-3 （Casp3）,B-cell lymphoma-2 （Bcl2）,and Bcl2-associated X protein （Box） in the hippocampal CA3 region.One-way analysis of variance was used to determine the differences between the four groups.Results：The latency to the first spontaneous seizures in the DBS group was significantly longer than that in the KA group （27.50 ± 8.05 vs.16.38 ± 7.25 days,P =0.0005）.The total seizure number in the DBS group was also significantly reduced （DBS vs.KA group：11.75 ± 6.80 vs.23.25 ± 7.72,P =0.0002）.Chronic ANT-DBS reduced neuronal loss in the hippocampal CA3 region （DBS vs.KA group：23.58 ± 6.34 vs.13.13 ± 4.00,P =0.0012）.After chronic DBS,the relative mRNA expression level of Casp3 was decreased （DBS vs.KA group：1.18 ± 0.37 vs.2.09 ± 0.46,P =0.0003）,and the relative mRNA expression level of Bcl2 was increased （DBS vs.KA group：0.92 ± 0.21 vs.0.48 ± 0.16,P =0.0004）.The protein expression levels of CASP3 （DBS vs.KA group：1.25 ± 0.26 vs.2.49 ± 0.38,P 〈 0.0001） and BAX （DBS vs.KA group：1.57 ± 0.49 vs.2.80 ± 0.63,P =0.0012） both declined in the DBS group whereas the protein expression level of BCL2 （DBS vs.KA group：0.78 ± 0.32 vs.0.36 ± 0.17,P =0.0086） increased in the DBS group.Conclusions：This study demonstrated that chronic ANT stimulation could exert a neuroprotective effect on hippocampal neurons.This neuroprotective effect is likely to be mediated by the inhibition of apoptosis in the epileptic hippocampus.

Repetitive Transcranial Magnetic Stimulation for the Treatment of Restless Legs Syndrome

Background： Repetitive transcranial magnetic stimulation （rTMS） is a noninvasive technique used to alter cortex excitability that has been proposed as an efficient method for treating brain hyperexcitability or hypoexcitability disorders. Tile aim of this study was to investigate whether high-fi-equency rTMS could have any beneficial effects in restless legs syndrome （RLS）. Methods： Fourteen patients with RLS were given high-frequency rTMS （15 Hz, 100% motor threshold） to tile leg representation motor cortex area of the frontal lobe for 14 sessions over 18 days. Patients were diagnosed according to the international criteria proposed by the International Restless Legs Syndrome Study Group in 2003. The International RLS Rating Scale （1RLS-RS）, Pittsburgh Sleep Quality Index （PSQI）, Hamilton Anxiety Scale （llAMA） and Hamilton Depression Scale were used to evaluate the severity of RLS, sleep quality, anxiety and depression, respectively. The scale scores were evaluated at four-time points （baseline, end of the 14th session, and at 1- and 2-month posttreatrnent）. One-way analysis of variance was used to compare scale scores at different time points. Results： There was significant improvement in the 1RLS-RS （from 23.86 ± 5.88 to 11.21 ± 7.23, P 〈 0.05）, PSQ1 （frorn 15.00 ± 4.88 to 9.29 ± 3.91, P 〈 0.05）, and HAMA （from 17.93 ± 7.11 to 10.36 ± 7.13, P 〈 0.05） scale scores at the end of 14th session, with ongoing effects lasting for at least 2 months. Conclusions： High-17equency rTMS can markedly alleviate the motor system symptoms, sleep disturbances, and anxiety in RLS patients. These restllts suggest that rTMS might be an option for treating RLS.

Comparison Study of Polysomnographic Features in Multiple System Atrophy-cerebellar Types Combined with and without Rapid Eye Movement Sleep Behavior Disorder

Background： The brain stem is found to be impaired in multiple system atrophy-ccrcbellar types （MSA-C）. Rapid eye movement （REM） sleep behavior disorder （RBD） is reported as a marker of progressive brain stem dysfunction. Few systematic studies about the sleep disturbances in MSA-C patients combined with or without RBD were reported. This study aimed to explore the polysomnographic （PSG） features of sleep disturbances between MSA-C patients with and without RBD. Methods： Totally, 46 MSA-C patients （23 with RBD, and 23 without RBD） were enrolled in this study. All patients underwent a structured interview for their demographic data, history of sleep pattern, and movement disorders; and then, overnight video-PSG was performed in each patient. All the records were evaluated by specialists at the Sleep Medicine Clinic for RBD and the Movement Disorder Clinic for MSA-C. The Student＇s t-test, Mann-Whitney U-test for continuous variables, and the Chi-square test for categorical variables were used in this study. Results： MSA-C patients with RBD had younger visiting age （52.6 ± 7.4 vs. 56.7 ± 6.0 years, P = 0.046） and shorter duration of the disease （12.0 [12.0, 24.0] vs. 24.0 [14.0, 36.0] months, P 0.009） than MSA-C patients without RBD. MSA-C with RBD had shorter REM sleep latency （111.7 ± 48.2 vs. 157.0 ± 68.8 rain, P = 0.042）, higher percentage of REM sleep （14.9% ±4.0% vs. 10.0% ± 3.2%, P = 0.019）, and lower Stage 1 （9.5% ±7.2% vs. 15.9% ±8.0%, P= 0.027） than MSA-C without RBD. Moreover, MSA-C patients with RBD had more decreased sleep efficiency （52.4% ±12.6% vs. 65.8% ±15.9%, P = 0.029） than that without RBD. Conclusions： In addition to the RBD, MSA-C patients with RBD had other more severe sleep disturbances than those without RBD. The sleep disorders of MSA patients might be associated with the progress of the disease.

Protocol on transcranial alternating current stimulation for the treatment of major depressive disorder:a randomized controlled trial

Background:Transcranial alternating current stimulation(tACS)offers a new approach for adult patients with major depressive disorder(MDD).The study is to evaluate the efficacy and safety of tACS treating MDD.Methods:This is an 8-week,double-blind,randomized,placebo-controlled study.Ninety-two drug-naive patients with MDD aged 18 to 65 years will receive 20 daily 40-min,77.5-Hz,15-mA sessions of active or sham tACS targeting the forehead and both mastoid areas on weekdays for 4 consecutive weeks(week 4),following a 4-week observation period(week 8).The primary outcome is the remission rate defined as the 17-item Hamilton depression rating scale(HDRS-17)score≤7 at week 8.Secondary outcomes are the rates of response at weeks 4 and 8 and rate of remission at week 4 based on HDRS-17,the proportion of participants having improvement in the clinical global impression-improvement,the change in HDRS-17 score(range,0-52,with higher scores indicating more depression)over the study,and variations of brain imaging and neurocognition from baseline to week 4.Safety will be assessed by vital signs at weeks 4 and 8,and adverse events will be collected during the entire study.Discussion:The tACS applied in this trial may have treatment effects on MDD with minimal side effects.Trial registration:Chinese Clinical Trial Registry,ChiCTR1800016479;http://www.chictr.org.cn/showproj.aspx?proj=22048.

Hippocampus chronic deep brain stimulation induces reversible transcript changes in a macaque model of mesial temporal lobe epilepsy

Background:Deep brain stimulation(DBS)has seizure-suppressing effects but the molecular mechanisms underlying its therapeutic action remain unclear.This study aimed to systematically elucidate the mechanisms underlying DBS-induced seizure suppression at a molecular level.Methods:We established a macaque model of mesial temporal lobe epilepsy(mTLE),and continuous high-frequency hippocampus DBS(hip-DBS)was applied for 3 months.The effects of hip-DBS on hippocampus gene expression were examined using high-throughput microarray analysis followed by bioinformatics analysis.Moreover,the microarray results were validated using quantitative real-time polymerase chain reaction(qRT-PCR)and Western blot analyses.Results:The results showed that chronic hip-DBS modulated the hippocampal gene expression.We identified 4119 differentially expressed genes and assigned these genes to 16 model profiles.Series test of cluster analysis showed that profiles 5,3,and 2 were the predominant expression profiles.Moreover,profile 5 was mainly involved in focal adhesion and extracellular matrix-receptor interaction pathway.Nine dysregulated genes(Arhgap5,Colla2,Itgbl^Pik3rl,Lama4,Fnl,Col3al,Itga9,and Shc4)and three genes(Colla2,Itgbl,and Flna)in these two pathways were further validated by qRT-PCR and Western blot analyses,respectively,which showed a concordance.Conclusion:Our findings suggest that hip-DBS could markedly reverse mTLE-induced abnormal gene expression.Findings from this study establish the basis for further investigation of the underlying regulatory mechanisms of DBS for mTLE.

Expert consensus on clinical applications of high-frequency oscillations in epilepsy

Studies in animal models of epilepsy and pre-surgical patients have unanimously found a strong correlation between high-frequency oscillations(HFOs,>80 Hz)and the epileptogenic zone,suggesting that HFOs can be a potential biomarker of epileptogenicity and epileptogenesis.This consensus includes the definition and standard detection techniques of HFOs,the localizing value of pathological HFOs for epileptic foci,and different ways to distinguish physiological from epileptic HFOs.The latest clinical applications of HFOs in epilepsy and the related findings are also discussed.HFOs will advance our understanding of the pathophysiology of epilepsy.

Long-term Effects of Subthalamic Nucleus Deep Brain Stimulation in Tardive Dystonia

To the Editor： Tardive dystonia （TD） is a specific type of secondary dystonia caused primarily by the chronic application of dopamine receptors antagonists.Deep brain stimulation （DBS） has been becoming a promising therapy to treat dystonia. Here, we report the long-term effect of subthalamic nucleus （STN） stimulation for a TD patient after a 12-year follow-up.

Vagus Nerve Stimulation for Pediatric and Adult Patients with Pharmaco-resistant Epilepsy

Background：Over past two decades,vagus nerve stimulation （VNS） has been widely used and reported to alleviate seizure frequency worldwide,however,so far,only hundreds of patients with pharmaco-resistant epilepsy （PRE） have been treated with VNS in China's Mainland.The study aimed to evaluate the effectiveness of VNS for Chinese patients with PRE and compare its relationship with age cohort and gender.Methods：We retrospectively assessed the clinical outcome of 94 patients with PRE,who were treated with VNS at Beijing Fengtai Hospital and Beij ing Tiantan Hospital between November 2008 and April 2014 from our database of 106 consecutive patients.The clinical data analysis was retrospectively examined.Results：Seizure frequency significantly decreased with VNS therapy after intermittent stimulation of the vagus nerve.At last follow-up,we found McHugh classifications of Class Ⅰ in 33 patients （35.1％）,Class Ⅱ in 27 patients （28.7％）,Class Ⅲ in 20 patients （21.3％）,Class Ⅳ in 3 patients （3.2％）,and Class Ⅴ in 11 patients （l 1.7％）.Notably,8 （8.5％） patients were seizure-free while ≥50％ seizure frequency reduction occurred in as many as 60 patients （63.8％）.Furthermore,with regard to the modified Engel classification,12 patients （12.8％） were classified as Class Ⅰ,l l patients （11.7％） were classified as Class Ⅱ,37 patients （39.4％） were classified as Class Ⅲ,34 patients （36.2％） were classified as Class Ⅳ.We also found that the factors of gender or age are not associated with clinical outcome.Conclusions：This comparative study confirmed that VNS is a safe,well-tolerated,and effective treatment for Chinese PRE patients.VNS reduced the seizure frequency regardless of age or gender of studied patients.

Brain stimulation for epilepsy

Anumber of therapies have been developed in the past decades.About two thirds of patients can be seizure free with antiepileptic drugs.1 Other patients are drug resistant,some of whom are good candidates for epileptic focus resection and become seizure free after surgery.2 The treatment for drug-resistant patients who are not eligible for resection is still challenging.Traditionally,these patients can receive palliative surgery such as callosotomy and multiple subpial transection,3,4 but the long-term outcomes of these procedures are not satisfactory.5-7 In the past decades,neuromodulation techniques have been applied in the treatment of epilepsy.Much evidence has been accumulated about the therapeutic effects of vagus nerve stimulation for epilepsy.In contrast to peripheral nerve stimulation,brain stimulation techniques have also been developed for patients with epilepsy recently.

Antibody prevalence and immunotherapy response in Chinese patients with epilepsy and encephalopathy scores for patients with different neuronal surface antibodies

Background:The scale assessment was helpful in predicting the presence of antibodies to autoimmune encephalitis.This study aimed to evaluate the application of antibody prevalence in Chinese patients with epilepsy and encephalopathy(APE2-CHN)and response to immunotherapy in Chinese patients with epilepsy and encephalopathy(RITE2-CHN)for patients with different neuronal surface antibodies.Methods:A total of 1365 patients with epileptic seizures as the prominent feature in Xuanwu Hospital,Capital Medical University,from June 2016 to June 2020 were enrolled in our study.Of these,915 patients with epilepsy of unknown etiology whose serum and/or cerebrospinal fluid samples were examined for autoimmune antibodies were selected.All patients were scored with antibody prevalence in patients with epilepsy and encephalopathy(APE2),response to immunotherapy with epilepsy and encephalopathy(RITE2),APE2-CHN,and RITE2-CHN scores.Results:Of the 915 patients,191 patients were positive for neural-surface specific antibodies(115 N-methyl-D-aspartate receptor(NMDAR)Ab,47 leucine-rich glioma-inactivated protein 1(LGI1)Ab,8 contactin-associated protein 2(CASPR2)Ab,4 AMPA2RAb,and 11 GABAR-B-Ab;3 CASPR2-Ab and LGI1-Ab,2 NMDAR-Ab and CASPR2-Ab,and 1 NMDAR-Ab and myelinoligodendrocyte glycoprotein[MOG]Ab).The sensitivity and specificity of APE2≥4 in predicting the presence of neural-surface specific antibodies in our study were 74.35%and 81.77%,respectively,and the sensitivity and specificity of APE2-CHN≥4 were 75.92%and 84.53%,respectively.Eight cases had an APE2 score<4 and APE2-CHN score≥5;all these patients had memory decline as the prominent manifestation.We divided the patients into six groups according to the different antibodies.APE2-CHN scores showed higher sensitivity for the prediction of NMDAR-Ab,but lower sensitivity for LGI1-Ab.A total of 187/191(97.91%)patients received immunotherapy and 142/191(74.35%)patients benefited from the treatments.The patients who were positive for LGI1-Ab with RITE2-CHN≥8 responded well to immunotherapy.Conclusions:APE2-CHN had the highest value for predicting the positivity of NMDAR-Ab and RITE2-CHN evaluated the response of immunotherapy for anti-LGI1 encephalitis appropriately.However,RITE2 and RITE2-CHN do not appear to be good predictors of immunotherapy outcomes for patients with specific neuronal-surface antibodies and high APE2-CHN scores are often indicative of a poor response to immunotherapy.

igh-frequency Oscillations and the Seizure Onset Zones in Neocortical Epilepsy

Background： To study the characters of high-frequency oscillations （HFOs） in the seizure onset zones （SOZ） and the nonseizure onset zones （NSOZ） in the electrocorticography （ECoG） of patients with neocortical epilepsy. Methods： Only patients with neocortical epilepsy who were seizure-free after surgery as determined with ECoG were included. We selected patients with normal magnetic resonance imaging before surgery in order to avoid the influence of HFOs by other lesions. Three minutes preictal and 1 0 rain interictal ECoG as recorded in 39 channels in the SOZ and 256 channels in the NSOZ were analyzed. Ripples and fast ripples （FRs） were analyzed by Advanced Source Analysis soltware （ASA, The Netherlands）. Average duration of HFOs was analyzed in SOZ and NSOZ separately. Results： For ripples, the permillage time occupied by HFOs was 0.83 in NSOZ and 1.17 in SOZ during the interictal period. During preictal period, they were 2.02 in NSOZ and 7.93 in SOZ. For FRs, the permillage time occupied by HFOs was 0.02 in NSOZ and 0.42 in SOZ during the interictal period. During preictal period, they were 0.03 in NSOZ and 2 in SOZ. Conclusions： High-frequency oscillations are linked to SOZ in neocortical epilepsy. Our study demonstrates the prevalent occurrence of HFOs in SOZ. More and more burst of HFOs, especially FRs, means the onset of seizures.

Internal Pallidum and Subthalamic Nucleus Deep Brain Stimulation for Oromandibular Dystonia

Dystonia is a neurologic disorder characterized by sustained involuntary movements or abnormal posture. Oromandibular dystonia is a form of focal dystonia that is characterized by forceful contractions of face, jaw, or tongue.

High-frequency oscillations detected by electroencephalography as biomarkers to evaluate treatment outcome,mirror pathological severity and predict susceptibility to epilepsy

High-frequency oscillations(HFOs)in the electroencephalography(EEG)have been extensively investigated as a potential biomarker of epileptogenic zones.The understanding of the role of HFOs in epilepsy has been advanced considerably over the past decade,and the use of scalp EEG facilitates recordings of HFOs.HFOs were initially applied in large scale in epilepsy surgery and are now being utilized in other applications.In this review,we summarize applications of HFOs in 3 subtopics:(1)HFOs as biomarkers to evaluate epilepsy treatment outcome;(2)HFOs as biomarkers to measure seizure propensity;(3)HFOs as biomarkers to reflect the pathological severity of epilepsy.Nevertheless,knowledge regarding the above clinical applications of HFOs remains limited at present.Further validation through prospective studies is required for its reliable application in the clinical management of individual epileptic patients.