Freezing of gait is a debilitating symptom in advanced Parkinson’s disease and responds heterogeneously to treatments such as deep brain stimulation. Recent studies indicated that cortical dysfunction is involved in the development of freezing, while evidence depicting the specific role of the primary motor cortex in the multi-circuit pathology of freezing is lacking. Since abnormal beta-gamma phase-amplitude coupling recorded from the primary motor cortex in patients with Parkinson’s disease indicates parkinsonian state and responses to therapeutic deep brain stimulation, we hypothesized this metric might reveal unique information on understanding and improving therapy on freezing of gait. Here we directly recorded potentials in the primary motor cortex using subdural electrocorticography and synchronously captured gait freezing using optoelectronic motion-tracking systems in 16 freely-walking patients with Parkinson’s disease who received subthalamic nucleus deep brain stimulation surgery. Overall, we recorded 451 timed up-and-go walking trials, and quantified 7,073 s of stable walking and 3,384 s of gait freezing in conditions of ON/OFF-stimulation and with/without dual-tasking. We found that (i) high beta-gamma phase-amplitude coupling in the primary motor cortex was detected in freezing trials (i.e., walking trials that contained freezing), but not nonfreezing trials, and the high coupling in freezing trials was not caused by dual-tasking or the lack of movement; (ii) nonfreezing episodes within freezing trials also demonstrated abnormally high couplings, which predicted freezing severity; (iii) deep brain stimulation of subthalamic nucleus reduced these abnormal couplings and simultaneously improved freezing; and (iv) in trials that were at similar coupling levels, stimulation trials still demonstrated lower freezing severity than no-stimulation trials. These findings suggest that elevated phase-amplitude coupling in the primary motor cortex indicates higher probabilities of freezing. Therapeutic deep brain stimulation alleviates freezing by both decoupling cortical oscillations and enhancing cortical resistance to abnormal coupling. We formalized these findings to a novel “bandwidth model,” which specifies the role of cortical dysfunction, cognitive burden, and therapeutic stimulation on the emergence of freezing. By targeting key elements in the model, we may develop next-generation deep brain stimulation approaches for freezing of gait.

The sox2 expressing (sox2+) progenitors in adult mammalian inner ear lose the capacity to regenerate while progenitors in the zebrafish lateral line are able to proliferate and regenerate damaged HCs throughout lifetime. To mimic the HC damage in mammals, we have established a zebrafish severe injury model to eliminate both progenitors and HCs. The atoh1a expressing (atoh1a+) HC precursors were the main population that survived post severe injury, and gained sox2 expression to initiate progenitor regeneration. In response to severe injury, yap was activated to upregulate lin28a transcription. Severe-injury-induced progenitor regeneration was disabled in lin28a or yap mutants. In contrary, overexpression of lin28a initiated the recovery of sox2+ progenitors. Mechanistically, microRNA let7 acted downstream of lin28a to activate Wnt pathway for promoting regeneration. Our findings that lin28a is necessary and sufficient to regenerate the exhausted sox2+ progenitors shed light on restoration of progenitors to initiate HC regeneration in mammals.

Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting‐therapy efficacy remains unexplored. Here, an L‐phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T‐cell acute lymphoblastic leukemia (T‐ALL) by inhibiting myeloid‐derived suppressor cells (MDSCs) in T‐ALL murine model. Stable‐isotope tracer and in vivo drug distribution experiments show that T‐ALL cells and MDSCs have enhanced cellular uptake of L‐phenylalanine and MRIANs than normal hematopoietic cells and progenitors. Therefore, MRIAN assembled Doxorubicin (MRIAN‐Dox) specifically targets T‐ALL cells and MDSCs but spare normal hematopoietic cells and hematopoietic stem and progenitor cells with enhanced leukemic elimination efficiency. Consequently, MRIAN‐Dox has reduced cardiotoxicity and myeloablation side effects in treating T‐ALL mice. Mechanistically, MRIAN degrades into L‐phenylalanine, which inhibits PKM2 activity and reduces ROS levels in MDSCs to disturb their immunosuppressive function and increase their differentiation toward normal myeloid cells. Overall, a novel amino acid metabolite nanomedicine is invented to treat T‐ALL through the combination of leukemic cell targeting and immunosurveillance stimulation.

This study aims to investigate how the frequency settings of deep brain stimulation (DBS) targeting the subthalamic nucleus (STN) influence the motor symptoms of Parkinson’s disease (PD). Stimulation with frequencies less than 100 Hz (mostly 60 or 80 Hz) is considered low-frequency stimulation (LFS) and with frequencies greater than 100 Hz (mostly 130 or 150 Hz) is considered high-frequency stimulation (HFS). We conducted a comprehensive literature review and meta-analysis with a random-effect model. Ten studies with 132 patients were included in our analysis. The pooled results showed no significant difference in the total Unified Parkinson Disease Rating Scale part III (UPDRS-III) scores (mean effect, −1.50; p = 0.19) or the rigidity subscore between HFS and LFS. Compared to LFS, HFS induced greater reduction in the tremor subscore within the medication-off condition (mean effect, 1.01; p = 0.002), while no significance was shown within the medication-on condition (mean effect, 0.01; p = 0.92). LFS induced greater reduction in akinesia subscore (mean effect, −1.68, p = 0.003), the time to complete the stand-walk-sit (SWS) test (mean effect, −4.84; p < 0.00001), and the number of freezing of gait (FOG) (mean effect, −1.71; p = 0.03). These results suggest that two types of frequency settings may have different effects, that is, HFS induces better responses for tremor and LFS induces greater response for akinesia, gait, and FOG, respectively, which are worthwhile to be confirmed in future study, and will ultimately inform the clinical practice in the management of PD using STN-DBS.

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Aims Deep brain stimulation of the anterior nuclei of the thalamus (ANT‐DBS) is effective in temporal lobe epilepsy (TLE). Previous studies have shown that the basal ganglia are involved in seizure propagation in TLE, but the effects of ANT‐DBS on the basal ganglia have not been clarified. Methods ANT‐DBS was applied to monkeys with kainic acid–induced TLE using a robot‐assisted system. Behavior was monitored continuously. Immunofluorescence analysis and Western blotting were used to estimate protein expression levels in the basal ganglia and the effects of ANT stimulation. Results The seizure frequency decreased after ANT‐DBS. D1 and D2 receptor levels in the putamen and caudate were significantly higher in the ANT‐DBS group than in the epilepsy (EP) model. Neuronal loss and apoptosis were less severe in the ANT‐DBS group. Glutamate receptor 1 (GluR1) in the nucleus accumbens (NAc) shell and globus pallidus internus (GPi) increased in the EP group but decreased after ANT‐DBS. γ‐Aminobutyric acid receptor A (GABAA‐R) decreased and glutamate decarboxylase 67 (GAD67) increased in the GPi of the EP group, whereas the reverse tendencies were observed after ANT‐DBS. Conclusion ANT‐DBS exerts neuroprotective effects on the caudate and putamen, enhances D1 and D2 receptor expression, and downregulates GPi overactivation, which enhanced the antiepileptic function of the basal ganglia.

Subthalamic nuclei deep brain stimulation (STN-DBS) is a well-established treatment for Parkinson's disease (PD). Some studies have confirmed the long-term efficacy is associated with brain connectivity; however, whether the initial outcome is associated with brain connectivity and efficacy of prediction based on these factors has not been well investigated. In the present study, a total of 98 patients were divided into a training set (n = 78) and a test set (n = 20). The stimulation and medication responses were calculated based on the motor performance. The functional and structural connectomes were established based on a public database and used to measure the association between stimulation response and brain connectivity. The prediction of initial outcome was achieved via a machine learning algorithm-support vector machine based on the model established with the training set. It was found that the initial outcome of STN-DBS was associated with functional/ structural connectivities between the volume of tissue activated and multiple brain regions, including the supplementary motor area, precentral and frontal areas, cingulum, temporal cortex, and striatum. These factors could be used to predict the initial outcome, with an r value of 0.4978 (P = 0.0255). Our study demonstrates a correlation between a specific connectivity pattern and initial outcome of STN-DBS, which could be used to predict the initial outcome of DBS.