Weak extracellular electric fields can influence spike timing in neural networks. Approaches to noninvasively impose these fields on the brain have high therapeutic potential in neurology and psychiatry. Transcranial alternating current stimulation (TACS) is hypothesized to affect spike timing and cause neural entrainment. However, the conditions under which these effects occur in vivo are unknown. Here, we recorded single-unit activity in the neocortex in awake nonhuman primates during TACS and found dose-dependent neural entrainment to the stimulation waveform. Cluster analysis of changes in interspike intervals identified two main types of neural responses to TACS—increased burstiness and phase entrainment. Our results uncover key mechanisms of TACS and show that the stimulation affects spike timing in the awake primate brain at intensities feasible in humans. Thus, novel TACS protocols tailored to ongoing brain activity may be a tool to normalize spike timing in maladaptive brain networks and neurological disease.
Results of this trial demonstrate that treatment of periodontitis with subgingivally delivered doxycycline in a biodegradable polymer is equally effective as scaling and root planing and superior in effect to placebo control and oral hygiene in reducing the clinical signs of adult periodontitis over a 9-month period. This represents positive changes resulting from the use of subgingivally applied doxycycline as scaling and root planing was not limited regarding time of the procedure or use of local anesthesia.
Background
Incorporating feedback controls based on real-time measures of pathological brain activity may improve deep brain stimulation (DBS) approaches for the treatment of Parkinson’s disease (PD). Excessive beta oscillations in subthalamic nucleus (STN) local field potentials (LFP) have been proposed as a potential biomarker for closed-loop DBS (CL-DBS).
Objective
In a non-human primate PD model we compared CL-DBS, which delivered stimulation only when STN LFP beta activity was elevated, to traditional continuous DBS (tDBS).
Methods
Therapeutic effects of CL-DBS and tDBS relative to the Off-DBS condition were evaluated via a clinical rating scale and objective measures of movement speed during a cued reaching task.
Results
CL-DBS was comparable to tDBS at reducing rigidity, while reducing the amount of time DBS was on by ≈ 50%; however, only tDBS improved bradykinesia during the reaching behavior. This was likely due to reach-related reductions in beta amplitude that influence the timing and duration of stimulation in the CL-DBS condition.
Conclusion
These results illustrate the potential utility of closed-loop DBS devices for PD based on STN beta LFP levels. They also point to possible consequences in behavioral tasks when restricting real-time sensing to a single LFP frequency that itself is modulated during performance of such tasks. The present study provides data that suggest alternate algorithms or more than one physiological biomarker or may be required to optimize the performance of behavioral tasks and demonstrates the value of using multiple objective measures when evaluating the efficacy of closed-loop DBS systems.
The primary goal of this study was to characterize the release profile of doxycycline hyclate (8.5% w/w) from a biodegradable controlled-release delivery system (DH) placed in periodontal pockets. Pharmacokinetic data were obtained from gingival crevicular fluid (GCF), saliva, and serum of adult periodontitis patients. These results were compared to those obtained from individuals who received standard oral doses of doxycycline hyclate (200 mg on day 0, then 100 mg/day for 7 days). All participants presented with multiple pockets > or = 5 mm that bled upon probing. At the baseline visit patients receiving local drug delivery had all pockets > or = 5 mm that bled upon probing on one side of the mouth filled with DH. Drug retention was enhanced with 1 of 2 periodontal dressings (non-eugenol [NE] or 2-octyl cyanoacrylate [2-octyl]). Doxycycline concentrations were analyzed with the aid of reverse phase high performance liquid chromatography. GCF saliva, and serum samples were obtained just prior to drug delivery and then at hours 2, 4, 6, 8, 18, 24 and days 2, 3, 5, 7, and 8. GCF and saliva samples were also obtained at days 10, 14, 21, and 28. Thirty two subjects participated in the study; 13 in the NE group, 13 in the 2-octyl group, and 6 in the group taking oral doxycycline. The release of doxycycline in the GCF peaked at 2 hours (1473 microg/ml in the NE group, and 1986 microg/ml in the 2-octyl group). The mean concentration at day 7 was 309 microg/ml for the NE group and 148 microg/ml for the 2-octyl group. Minimal levels of drug were detected in the GCF of the oral doxycycline group with a peak concentration of 2.53 microg/ml at 12 hours. Salivary concentrations for both local delivery groups peaked at hour 2 (4.05 microg/ml for the NE group and 8.78 microg/ml for the 2-octyl group); by the end of day 1 levels were < or = 2 microg/ml. For subjects who took the oral doxycycline, salivary concentrations never exceeded 0.11 microg/ml. Serum concentrations of doxycycline for individuals receiving the local drug delivery never exceeded 0.1 microg/ml. For the oral doxycycline group serum concentrations ranged from 0.91 to 2.26 microg/ml over the 8 days data were collected. The high concentration of drug available at the treated sites coupled with the relatively low levels in the saliva and almost non-existent levels in the serum indicate that this biodegradable controlled-release delivery system displays an appropriate pharmacokinetic profile for the delivery of doxycycline into periodontal pockets.
In this largely male study population, the fractal dimension was found to be a good discriminator of low BMD in both men and women. The MCW did not perform as well in men.
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