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Synchronised spiking activity underlies phase amplitude coupling in the subthalamic nucleus of Parkinson's disease patients
Both phase-amplitude coupling (PAC) and beta-bursts in the subthalamic nucleus have been significantly linked to symptom severity in Parkinson's disease (PD) in humans and emerged independently as competing biomarkers for closed-loop deep brain stimulation (DBS). However, the underlying nature of subthalamic PAC is poorly understood and its relationship with transient beta burst-events has not been investigated. To address this, we studied macro- and micro electrode recordings of local field potentials (LFPs) and single unit activity from 15 hemispheres in 10 PD patients undergoing DBS surgery. PAC between beta phase and high frequency oscillation (HFO) amplitude was compared to single unit firing rates, spike triggered averages, power spectral densities and phase-spike locking, and was studied in periods of beta-bursting. We found a significant synchronisation of spiking to HFOs and correlation of mean firing rates with HFO-amplitude when the latter was coupled to beta phase (i.e. in the presence of PAC). In the presence of PAC, single unit power spectra displayed peaks in the beta and HFO frequency range and the HFO frequency was correlated with that in the LFP. Finally, PAC significantly increased with beta burst-duration. Our findings offer new insight in the pathology of Parkinson's disease by providing evidence that subthalamic PAC reflects the locking of spiking activity to network beta oscillations and that this coupling progressively increases with beta-burst duration. These findings suggest that beta-bursts capture periods of increased subthalamic input/output synchronisation in the beta frequency range and have important implications for therapeutic closed-loop DBS.
The clinical use of deep brain stimulation (DBS) is among the most important advances in the clinical neurosciences in the past two decades. As a surgical tool, DBS can directly measure pathological brain activity and can deliver adjustable stimulation for therapeutic effect in neurological and psychiatric disorders correlated with dysfunctional circuitry. The development of DBS has opened new opportunities to access and interrogate malfunctioning brain circuits and to test the therapeutic potential of regulating the output of these circuits in a broad range of disorders. Despite the success and rapid adoption of DBS, crucial questions remain, including which brain areas should be targeted and in which patients. This Review considers how DBS has facilitated advances in our understanding of how circuit malfunction can lead to brain disorders and outlines the key unmet challenges and future directions in the DBS field. Determining the next steps in DBS science will help to define the future role of this technology in the development of novel therapeutics for the most challenging disorders affecting the human brain.
Mutations in the nuclear membrane zinc metalloprotease ZMPSTE24 lead to diseases of lamin processing (laminopathies), such as the premature aging disease progeria and metabolic disorders. ZMPSTE24 processes prelamin A, a component of the nuclear lamina intermediate filaments, by cleaving it at two sites. Failure of this processing results in accumulation of farnesylated, membrane-associated prelamin A. The 3.4 angstrom crystal structure of human ZMPSTE24 has a seven transmembrane α-helical barrel structure, surrounding a large, water-filled, intramembrane chamber, capped by a zinc metalloprotease domain with the catalytic site facing into the chamber. The 3.8 angstrom structure of a complex with a CSIM tetrapeptide showed that the mode of binding of the substrate resembles that of an insect metalloprotease inhibitor in thermolysin. Laminopathy-associated mutations predicted to reduce ZMPSTE24 activity map to the zinc metalloprotease peptide - binding site and to the bottom of the chamber.
<jats:sec><jats:title>Background</jats:title><jats:p>MOG-antibody disease has been recently recognized as a demyelinating condition distinct from Multiple Sclerosis. Methods: A single-site study of 106 MOG-antibody positive patients (including a 63-patient incident cohort) describing the clinical phenotype and outcome.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>ON was the most common onset presentation (51%) and was bilateral in about half. From the survival curve analysis in the incident cohort we estimated that 38% of patients relapsed within 18 months. The risk was lower in patients immunosuppressed for >3 months (p=0.013). Permanent motor disability (EDSS ≥6; limited walking distance) and visual acuity ≤6/36 in at least one eye occurred in 3.7% and 13.2% respectively after a median disease duration of 68 months (range 2–484). Permanent bladder dysfunction was present in 23.6% patients and around 2/3 of these had bowel dysfunction. 20% of males had permanent erectile dysfunction (44% of males with TM at onset).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>This is the largest single-centre cohort and the only incident cohort published, and shows that MOG-antibody disease is often relapsing but may be modified with 6–12 months of prednisolone. The prognosis is typically good, better than AQP4-antibody positive disease, but many patients are left with significant sphincter and erectile dysfunction and some with visual impairment.</jats:p></jats:sec>