Dynamic electrical synapses rewire brain networks for persistent oscillations and epileptogenesis.

One of the very fundamental attributes for telencephalic neural computation in mammals involves network activities oscillating beyond the initial trigger. The continuing and automated processing of transient inputs shall constitute the basis of cognition and intelligence but may lead to neuropsychiatric disorders such as epileptic seizures if carried so far as to engross part of or the whole telencephalic system. From a conventional view of the basic design of the telencephalic local circuitry, the GABAergic interneurons (INs) and glutamatergic pyramidal neurons (PNs) make negative feedback loops which would regulate the neural activities back to the original state. The drive for the most intriguing self-perpetuating telencephalic activities, then, has not been posed and characterized. We found activity-dependent deployment and delineated functional consequences of the electrical synapses directly linking INs and PNs in the amygdala, a prototypical telencephalic circuitry. These electrical synapses endow INs dual (a faster excitatory and a slower inhibitory) actions on PNs, providing a network-intrinsic excitatory drive that fuels the IN-PN interconnected circuitries and enables persistent oscillations with preservation of GABAergic negative feedback. Moreover, the entities of electrical synapses between INs and PNs are engaged in and disengaged from functioning in a highly dynamic way according to neural activities, which then determine the spatiotemporal scale of recruited oscillating networks. This study uncovers a special wide-range and context-dependent plasticity for wiring/rewiring of brain networks. Epileptogenesis or a wide spectrum of clinical disorders may ensue, however, from different scales of pathological extension of this unique form of telencephalic plasticity.

Damage-Free Plasma Source for Atomic-Scale Processing.

As atomic-scale etching and deposition processes become necessary for manufacturing logic and memory devices at the sub-5 nm node, the limitations of conventional plasma technology are becoming evident. For atomic-scale processes, precise critical dimension control at the sub-1 nm scale without plasma-induced damage and high selectivity between layers are required. In this paper, a plasma with very low electron temperature is applied for damage-free processing on the atomic scale. In plasmas with an ultralow electron temperature (ULET, Te < 0.5 eV), ion energies are very low, and the ion energy distribution is narrow. The absence of physical damage in ULET plasma is verified by exposing 2D structural material. In the ULET plasma, charging damage and radiation damage are also expected to be suppressed due to the extremely low Te. This ULET plasma source overcomes the limitations of conventional plasma sources and provides insights to achieve damage-free atomic-scale processes.

Comparative assessment of established and deep learning-based segmentation methods for hippocampal volume estimation in brain magnetic resonance imaging analysis.

In this study, our objective was to assess the performance of two deep learning-based hippocampal segmentation methods, SynthSeg and TigerBx, which are readily available to the public. We contrasted their performance with that of two established techniques, FreeSurfer-Aseg and FSL-FIRST, using three-dimensional T1-weighted MRI scans (n = 1447) procured from public databases. Our evaluation focused on the accuracy and reproducibility of these tools in estimating hippocampal volume. The findings suggest that both SynthSeg and TigerBx are on a par with Aseg and FIRST in terms of segmentation accuracy and reproducibility, but offer a significant advantage in processing speed, generating results in less than 1 min compared with several minutes to hours for the latter tools. In terms of Alzheimer's disease classification based on the hippocampal atrophy rate, SynthSeg and TigerBx exhibited superior performance. In conclusion, we evaluated the capabilities of two deep learning-based segmentation techniques. The results underscore their potential value in clinical and research environments, particularly when investigating neurological conditions associated with hippocampal structures.

Comparison of current relative value unit-based prices and utility between common surgical procedures, including orthopedic surgeries, in South Korea.

BACKGROUND: The medical pricing system strongly influences physicians' job satisfaction and patient health outcomes. This study aimed to investigate the current relative value unit (RVU)-based pricing and utility of patients in commonly performed surgical procedures in South Korea. METHODS: Fifteen common surgical procedures were selected from OECD statistics, and three additional orthopedic procedures were examined. The current pricing of each surgical procedure was retrieved from the Korea National Health Insurance Service, and the corresponding utilities were obtained as quality-adjusted life year (QALY) gains from previous studies. The relationship between the current prices (RVUs) and the patients' utility (incremental QALY gains/year) was analyzed. Subgroup analysis was performed between fatal and non-fatal procedures and between orthopedic and non-orthopedic procedures. RESULTS: A significant negative correlation (r = - 0.558, p < 0.001) was observed between RVU and incremental QALY among all 18 procedures. The fatal subgroup had a significantly higher RVU than the non-fatal subgroup (p < 0.05), while the former had a significantly lower incremental QALY than the latter (p < 0.001). Orthopedic procedures showed higher incremental QALY values than non-orthopedic procedures, but they did not show higher prices (RVU). CONCLUSIONS: This paradoxical relationship between current prices and patient utility is attributed to the higher pricing of surgical procedures for fatal and urgent conditions. Orthopedic surgery has been found to be a cost-effective treatment strategy. These findings could contribute to a better understanding of the potential role of incremental QALY in pursuing value-based purchasing or reasonable modification of the current medical fee schedule.

Genetic contributions to female gout and hyperuricaemia using genome-wide association study and polygenic risk score analyses.

OBJECTIVES: To identify genetic variants and polygenic risk score (PRS) relating to female gout and asymptomatic hyperuricaemia (AH) in a genome-wide association study (GWAS). METHODS: Gout, AH and normouricemia controls were included from Taiwan biobank and China Medical University Hospital. All participants were divided into discovery and replication cohorts for GWAS. PRS was estimated according to whether the variant exhibited a protective effect on the phenotypes or not. Each cohort was separated into two groups by the age of 50 years old. RESULTS: A total of 59 472 females were enrolled, and gout and AH occupied 1.60% and 19.59%, respectively. Six variants located in genes SLC2A9, C5orf22, CNTNAP2 and GLRX5 were significantly predictors of female gout in those aged ≥50. For those aged <50 years old, only the variant rs147750368 (SPANXN1) on chromosome X was found. Most variants located in genes SLC2A9, ZNF518B, PKD2 and ABCG2 were found to be significantly related to AH in both age groups. The PRS could explain ∼0.59% to 0.89% of variance of gout in variants with protective effects, which showed 6.2 times of mean PRS in the risk variants, but only 1.2 times in the AH phenotype. Moreover, the PRS also revealed a dose-response trend between AH rates and quartile scores. CONCLUSION: The variants in gene SLC2A9 are the major genetic factors for females associated with gout in those aged ≥50. PRS can provide a more robust prediction of the gout/AH under a homogeneous selection of variants that show effects on the traits.

SUMO Protease SMT7 Modulates Ribosomal Protein L30 and Regulates Cell-Size Checkpoint Function.

Proliferating cells actively coordinate growth and cell division to ensure cell-size homeostasis; however, the underlying mechanism through which size is controlled is poorly understood. Defect in a SUMO protease protein, suppressor of mat3 7 (SMT7), has been shown to reduce cell division number and increase cell size of the small-size mutant mating type locus 3-4 (mat3-4), which contains a defective retinoblastoma tumor suppressor-related protein of Chlamydomonas (Chlamydomonas reinhardtii). Here we describe development of an in vitro SUMOylation system using Chlamydomonas components and use it to provide evidence that SMT7 is a bona fide SUMO protease. We further demonstrate that the SUMO protease activity is required for supernumerous mitotic divisions of the mat3-4 cells. In addition, we identified RIBOSOMAL PROTEIN L30 (RPL30) as a prime SMT7 target and demonstrated that its SUMOylation is an important modulator of cell division in mat3-4 cells. Loss of SMT7 caused elevated SUMOylated RPL30 levels. Importantly, overexpression of the translational fusion version of RPL30-SUMO4, which mimics elevation of the SUMOylated RPL30 protein in mat3-4, caused a decrease in mitotic division and recapitulated the size-increasing phenotype of the smt7-1 mat3-4 cells. In summary, our study reveals a novel mechanism through which a SUMO protease regulates cell division in the mat3-4 mutant of Chlamydomonas and provides yet another important example of the role that protein SUMOylation can play in regulating key cellular processes, including cell division.

When to Combine Acetabular Osteotomy in Patients With Proximal Femoral Deformity Causing Residual Hip Dysplasia/Subluxation After Reduction of Developmental Dysplasia of the Hip.

BACKGROUND: After the successful reduction of developmental dysplasia of the hip, residual hip dysplasia may persist and lead to early osteoarthritis. Femoral and/or acetabular osteotomy has been used to address this problem. The purpose of this study is to determine the indication of femoral versus combined femoral-acetabular osteotomy in the management of residual hip dysplasia. METHODS: Fifty-five patients with unilateral dislocated-type dysplasia of the hip, who had residual hip dysplasia after reduction, underwent femoral osteotomy with or without acetabular osteotomy before 8 years of age, and were followed for more than 2 years and over 8 years of age, were the subjects of this retrospective study. Twenty-eight patients underwent femoral osteotomy only at a median age of 34 months (group F), and 27 underwent combined femoral-Dega osteotomy at a median age of 49 months (group C). Seventeen patients in group F and 4 in group C had an additional osteotomy due to persistent hip dysplasia. Acetabular index (AI), lateral center-edge angle, and center-head distance difference were measured on serial radiographs. The z-value of AI (Z AI ) was calculated. At the latest follow-up, patients in group F with Severin I/II who did not have an additional osteotomy were considered satisfactory, and patients with Severin III/IV or those who had an additional osteotomy were considered unsatisfactory. Preoperative variables were tested for the difference between satisfactory and unsatisfactory cases. Receiver operating characteristic analysis was performed to delineate a cutoff value of a significant parameter dividing the outcome. RESULTS: AI and Z AI before index osteotomy were significant parameters predicting a satisfactory outcome in group F. Receiver operating characteristic analysis returned a cutoff value of Z AI 2.6 (Area Under the Curve=0.86, P =0.001). Eight of 12 cases (66.7%) with Z AI <2.6 in group F achieved a satisfactory outcome, whereas only 2 of 14 cases with Z AI ≥2.6 in group F did ( P =0.02). CONCLUSION: Z AI 2.6 may serve as a threshold to combine acetabular osteotomy with femoral osteotomy in the management of residual hip dysplasia before 8 years of age. LEVEL OF EVIDENCE: Therapeutic III.

Identification of 13 Novel Loci in a Genome-Wide Association Study on Taiwanese with Hepatocellular Carcinoma.

Liver cancer is caused by complex interactions among genetic factors, viral infection, alcohol abuse, and metabolic diseases. We conducted a genome-wide association study and polygenic risk score (PRS) model in Taiwan, employing a nonspecific etiology approach, to identify genetic risk factors for hepatocellular carcinoma (HCC). Our analysis of 2836 HCC cases and 134,549 controls revealed 13 novel associated loci such as the FAM66C gene, noncoding genes, liver-fibrosis-related genes, metabolism-related genes, and HCC-related pathway genes. We incorporated the results from the UK Biobank and Japanese database into our study for meta-analysis to validate our findings. We also identified specific subtypes of the major histocompatibility complex that influence both viral infection and HCC progression. Using this data, we developed a PRS to predict HCC risk in the general population, patients with HCC, and HCC-affected families. The PRS demonstrated higher risk scores in families with multiple HCCs and other cancer cases. This study presents a novel approach to HCC risk analysis, identifies seven new genes associated with HCC development, and introduces a reproducible PRS model for risk assessment.

Hamsters Protected from SARS-CoV-2 Delta Variant Challenge after Two Doses of Adjuvanted SARS-CoV-2 Recombinant Spike Protein (S-2P) and One Dose of Beta S-2P.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern negatively impact the effectiveness of vaccines. In this study, we challenge hamsters with the delta variant after 2- or 3-dose inoculations with SARS-CoV-2 vaccines constructed from stabilized prefusion spike proteins (S-2P) of Wuhan (W) and beta (B) variants. Compared to 3 doses of W S-2P, 2 doses of W S-2P followed by a third dose of B S-2P induced the highest neutralizing antibody titer against live SARS-CoV-2 virus and enhanced neutralization of omicron variant pseudovirus. Reduced lung live virus titer and pathology suggested that all vaccination regimens protect hamsters from SARS-CoV-2 delta variant challenge.

Emerging role of protein modification by UFM1 in cancer.

Ubiquitin-fold modifier 1 (UFM1) is a newly identified ubiquitin-like protein. Like ubiquitin, UFM1 is conjugated to its target proteins through a three-step enzyme system: UBA5 (E1), UFC1 (E2), and UFL1 (E3), but with an additional essential component, UFBP1. This protein modification by UFM1 (ufmylation) can be reversed by UFM1-specific proteases (UFSPs). So far only a handful of target proteins for ufmylation have been identified, and they are mostly associated with either promotion or suppression of tumorigenesis. Here, we summarize the recent progress in the knowledge of tumor-suppressive and tumorigenic functions of ufmylation as well as in the development of therapeutic drugs against ufmylation-associated cancer.

How Can an Na+ Channel Inhibitor Ameliorate Seizures in Lennox-Gastaut Syndrome?

OBJECTIVE: Lennox-Gastaut syndrome (LGS) is an epileptic encephalopathy frequently associated with multiple types of seizures. The classical Na+ channel inhibitors are in general ineffective against the seizures in LGS. Rufinamide is a new Na+ channel inhibitor, but approved for the treatment of LGS. This is not consistent with a choice of antiseizure drugs (ASDs) according to simplistic categorical grouping. METHODS: The effect of rufinamide on the Na+ channel, cellular discharges, and seizure behaviors was quantitatively characterized in native neurons and mammalian models of epilepsy, and compared with the other Na+ channel inhibitors. RESULTS: With a much faster binding rate to the inactivated Na+ channel than phenytoin, rufinamide is distinctively effective if the seizure discharges chiefly involve short bursts interspersed with hyperpolarized interburst intervals, exemplified by spike and wave discharges (SWDs) on electroencephalograms. Consistently, rufinamide, but not phenytoin, suppresses SWD-associated seizures in pentylenetetrazol or AY-9944 models, which recapitulate the major electrophysiological and behavioral manifestations in typical and atypical absence seizures, including LGS. INTERPRETATION: Na+ channel inhibitors shall have sufficiently fast binding to exert an action during the short bursts and then suppress SWDs, in which cases rufinamide is superior. For the epileptiform discharges where the interburst intervals are not so hyperpolarized, phenytoin could be better because of the higher affinity. Na+ channel inhibitors with different binding kinetics and affinity to the inactivated channels may have different antiseizure scope. A rational choice of ASDs according to in-depth molecular pharmacology and the attributes of ictal discharges is advisable. ANN NEUROL 2021;89:1099-1113.

Characteristics of pre-cluster symptoms in cluster headache: A cross-sectional multicentre study.

BACKGROUND: Contrary to pre-attack symptoms before an individual cluster headache attack, little is known about the pre-cluster symptoms before the onset of cluster bouts. We previously described pre-attack symptoms before cluster headache attacks. The aim of this study was to investigate characteristics of pre-cluster symptoms in patients with episodic cluster headache. METHODS: In this multicentre study, 184 patients with episodic cluster headache were recruited between October 2018 and December 2020. They were interviewed by investigators and completed a structured questionnaire. To investigate pre-cluster and pre-attack symptoms, we assessed 20 symptoms and signs using the questionnaire. RESULTS: The upcoming cluster bout was predictable in 35.3% (n = 65/184) of the patients. When present, pre-cluster symptoms occurred at a median duration of 7 days (interquartile range, 2.3-14 days) before the onset of the cluster bout. Patients with pre-cluster symptoms showed a higher proportion of women, prevalence of pre-attack symptoms and seasonal rhythmicity, frequency of cluster headache attacks per day, and total number of cluster bouts compared to patients without pre-cluster symptoms. In univariable and multivariable logistic regression analyses, female sex was associated with the predictability of pre-cluster symptoms (odds ratio = 2.297, p = 0.016). CONCLUSIONS: The upcoming cluster bout was predicted in approximately 35% of patients with episodic cluster headache, which may allow for an earlier preventive treatment and help understand the pathophysiology.

Guidelines of the International Headache Society for Controlled Clinical Trials in Cluster Headache.

In 1995, a committee of the International Headache Society developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Cluster Headache. These have not been revised. With the emergence of new medications, neuromodulation devices and trial designs, an updated version of the International Headache Society Guidelines for Controlled Clinical Trials in Cluster Headache is warranted. Given the scarcity of evidence-based data for cluster headache therapies, the update is largely consensus-based, but takes into account lessons learned from recent trials and demands by patients. It is intended to apply to both drug and neuromodulation treatments, with specific proposals for the latter when needed. The primary objective is to propose a template for designing high quality, state-of-the-art, controlled clinical trials of acute and preventive treatments in episodic and chronic cluster headache. The recommendations should not be regarded as dogma and alternative solutions to particular methodological problems should be explored in the future and scientifically validated.

Effect of caffeine and caffeine cessation on cerebrovascular reactivity in patients with migraine.

OBJECTIVE: To investigate the effect of chronic caffeine use and caffeine cessation on vasodilatory function in the posterior circulation in patients with migraine. BACKGROUND: Studies regarding cerebrovascular reactivity (CVR) using vasodilatory stimuli in patients with migraine have yielded conflicting results. We postulated that CVR may not be static, and caffeine might negatively affect vasodilatory function via its vasoconstrictive effect. METHODS: In this prospective longitudinal observation study, we recruited patients with episodic migraine who were 18-50 years of age and free of vascular risk factors at the Samsung Medical Center between August 2015 and March 2020. Patients were classified into caffeine users and non-users at baseline, and caffeine users were instructed to discontinue caffeine intake. We measured the mean breath-holding index (BHI) of bilateral posterior cerebral arteries (PCA) using transcranial Doppler in all the included patients at baseline and followed up after 3 months. We compared breath-holding indices cross-sectionally between caffeine users and non-users and analyzed BHI changes according to caffeine cessation. RESULTS: In total, 84 patients completed the study protocol. Cross-sectional analysis showed that the baseline BHI of PCA was lower in caffeine users (n = 56, 1.1 [interquartile range (IQR) 0.8-1.3]) than that in nonusers (n = 28, 1.3 [IQR 1.0-1.5], p = 0.030). In the longitudinal analysis, caffeine quitters showed a significant improvement in BHI in PCA (baseline 1.1 [IQR 0.8-1.2], follow-up 1.3 [IQR 1.0-1.4], p = 0.034), whereas continuous users and non-users did not. Multivariable analysis showed an independent effect of caffeine cessation on the changes in BHI of PCA (unstandardized ß = 0.27, 95% confidence interval 0.01-0.53, p = 0.044). CONCLUSION: In patients with migraine, caffeine use is associated with reduced CVR in the posterior circulation, and caffeine cessation might be beneficial in improving CVR.

Modification of PCNA by ISG15 plays a crucial role in termination of error-prone translesion DNA synthesis.

In response to DNA damage, PCNA is mono-ubiquitinated and triggers translesion DNA synthesis (TLS) by recruiting polymerase-η. However, it remained unknown how error-prone TLS is turned off after DNA lesion bypass to prevent mutagenesis. Here we showed that ISG15 modification (ISGylation) of PCNA plays a key role in TLS termination. Upon UV irradiation, EFP, an ISG15 E3 ligase, bound to mono-ubiquitinated PCNA and promoted its ISGylation. ISGylated PCNA then tethered USP10 for deubiquitination and in turn the release of polymerase-η from PCNA. Eventually, PCNA was deISGylated by UBP43 for reloading of replicative DNA polymerases and resuming normal DNA replication. However, ISGylation-defective Lys-to-Arg mutations in PCNA or knockdown of any of ISG15, EFP, or USP10 led to persistent recruitment of mono-ubiquitinated PCNA and polymerase-η to nuclear foci, causing an increase in mutation frequency. These findings establish a crucial role of PCNA ISGylation in termination of error-prone TLS for preventing excessive mutagenesis.

Modification of ASC1 by UFM1 is crucial for ERα transactivation and breast cancer development.

Biological roles for UFM1, a ubiquitin-like protein, are largely unknown, and therefore we screened for targets of ufmylation. Here we show that ufmylation of the nuclear receptor coactivator ASC1 is a key step for ERα transactivation in response to 17ß-estradiol (E2). In the absence of E2, the UFM1-specific protease UfSP2 was bound to ASC1, which maintains ASC1 in a nonufmylated state. In the presence of E2, ERα bound ASC1 and displaced UfSP2, leading to ASC1 ufmylation. Polyufmylation of ASC1 enhanced association of p300, SRC1, and ASC1 at promoters of ERα target genes. ASC1 overexpression or UfSP2 knockdown promoted ERα-mediated tumor formation in vivo, which could be abrogated by treatment with the anti-breast cancer drug tamoxifen. In contrast, expression of ufmylation-deficient ASC1 mutant or knockdown of the UFM1-activating E1 enzyme UBA5 prevented tumor growth. These findings establish a role for ASC1 ufmylation in breast cancer development by promoting ERα transactivation.

Intrasubject Radiographic Progression of Hallux Valgus Deformity in Patients With and Without Metatarsus Adductus: Bilateral Asymmetric Hallux Valgus Deformity.

This study was to analyze intrasubject radiographic progression of the hallux valgus deformity by comparing the mildly and severely affected sides in patients with bilateral asymmetric hallux valgus in the whole group as well as the metatarsus adductus and the nonmetatarsus adductus subgroups. A total of 186 patients with bilateral asymmetrical hallux valgus deformity with a difference of 5° or greater in the hallux valgus angle were included, and 11 radiographic measurements were analyzed. The radiographic differences between the mildly and severely affected sides were compared. Correlation between the changes in the hallux valgus angle and those in other measurements was analyzed, and multiple regression analyses were performed. The anteroposterior talo-second metatarsal angle showed no significant difference between the mildly and severely affected sides. Changes in the intermetatarsal angle and sesamoid rotation angle were significantly associated with the progression of hallux valgus angle in the whole group as well as the nonmetatarsus adductus subgroup. Change in the intermetatarsal angle (p = .006) was the significant factor associated with the progression of hallux valgus angle in the metatarsus adductus subgroup. The anteroposterior talo-second metatarsal angle might be useful in evaluating the overall foot shape in the hallux valgus deformity. Progression of the hallux valgus deformity might be pathophysiologically different between those with and without metatarsus adductus.

Glutamate transmission rather than cellular pacemaking propels excitatory-inhibitory resonance for ictogenesis in amygdala.

Epileptic seizures are automatic, excessive, and synchronized neuronal activities originating from many brain regions especially the amygdala, the allocortices and neocortices. This may reflect a shared principle for network organization and signaling in these telencephalic structures. In theory, the automaticity of epileptic discharges may stem from spontaneously active "oscillator" neurons equipped with intrinsic pacemaking conductances, or from a group of synaptically-connected collaborating "resonator" neurons. In the basolateral amygdalar (BLA) network of pyramidal-inhibitory (PN-IN) neuronal resonators, we demonstrated that rhythmogenic currents are provided by glutamatergic rather than the classic intrinsic or cellular pacemaking conductances (namely the h currents). The excitatory output of glutamatergic neurons such as PNs presumably propels a novel network-based "relay burst mode" of discharges especially in INs, which precondition PNs into a state prone to burst discharges and thus further glutamate release. Also, selective activation of unilateral PNs, but never INs, readily drives bilateral BLA networks into reverberating discharges which are fully synchronized with the behavioral manifestations of seizures (e.g. muscle contractions). Seizures originating in BLA and/or the other structures with similar PN-IN networks thus could be viewed as glutamate-triggered erroneous network oscillations that are normally responsible for information relay.

An electrophysiological perspective on Parkinson's disease: symptomatic pathogenesis and therapeutic approaches.

Parkinson's disease (PD), or paralysis agitans, is a common neurodegenerative disease characterized by dopaminergic deprivation in the basal ganglia because of neuronal loss in the substantia nigra pars compacta. Clinically, PD apparently involves both hypokinetic (e.g. akinetic rigidity) and hyperkinetic (e.g. tremor/propulsion) symptoms. The symptomatic pathogenesis, however, has remained elusive. The recent success of deep brain stimulation (DBS) therapy applied to the subthalamic nucleus (STN) or the globus pallidus pars internus indicates that there are essential electrophysiological abnormalities in PD. Consistently, dopamine-deprived STN shows excessive burst discharges. This proves to be a central pathophysiological element causally linked to the locomotor deficits in PD, as maneuvers (such as DBS of different polarities) decreasing and increasing STN burst discharges would decrease and increase the locomotor deficits, respectively. STN bursts are not so autonomous but show a "relay" feature, requiring glutamatergic synaptic inputs from the motor cortex (MC) to develop. In PD, there is an increase in overall MC activities and the corticosubthalamic input is enhanced and contributory to excessive burst discharges in STN. The increase in MC activities may be relevant to the enhanced beta power in local field potentials (LFP) as well as the deranged motor programming at the cortical level in PD. Moreover, MC could not only drive erroneous STN bursts, but also be driven by STN discharges at specific LFP frequencies (~ 4 to 6 Hz) to produce coherent tremulous muscle contractions. In essence, PD may be viewed as a disorder with deranged rhythms in the cortico-subcortical re-entrant loops, manifestly including STN, the major component of the oscillating core, and MC, the origin of the final common descending motor pathways. The configurations of the deranged rhythms may play a determinant role in the symptomatic pathogenesis of PD, and provide insight into the mechanism underlying normal motor control. Therapeutic brain stimulation for PD and relevant disorders should be adaptively exercised with in-depth pathophysiological considerations for each individual patient, and aim at a final normalization of cortical discharge patterns for the best ameliorating effect on the locomotor and even non-motor symptoms.