Effect of sugammadex on processed EEG parameters in patients undergoing robot-assisted radical prostatectomy.

BACKGROUND: Sugammadex has been associated with increases in the bispectral index (BIS). We evaluated the effects of sugammadex administration on quantitative electroencephalographic (EEG) and electromyographic (EMG) measures. METHODS: We performed a prospective observational study of adult male patients undergoing robot-assisted radical prostatectomy. All patients received a sevoflurane-based general anaesthetic and a continuous infusion of rocuronium, which was reversed with 2 mg kg-1 of sugammadex i.v. BIS, EEG, and EMG measures were captured with the BIS Vista™ monitor. RESULTS: Twenty-five patients were included in this study. Compared with baseline, BIS increased at 4-6 min (ß coefficient: 3.63; 95% confidence interval [CI]: 2.22-5.04; P<0.001), spectral edge frequency 95 (SEF95) increased at 2-4 min (ß coefficient: 0.29; 95% CI: 0.05-0.52; P=0.016) and 4-6 min (ß coefficient: 0.71; 95% CI: 0.47-0.94; P<0.001), and EMG increased at 4-6 min (ß coefficient: 1.91; 95% CI: 1.00-2.81; P<0.001) after sugammadex administration. Compared with baseline, increased beta power was observed at 2-4 min (ß coefficient: 93; 95% CI: 1-185; P=0.046) and 4-6 min (ß coefficient: 208; 95% CI: 116-300; P<0.001), and decreased delta power was observed at 4-6 min (ß coefficient: -526.72; 95% CI: -778 to -276; P<0.001) after sugammadex administration. Neither SEF95 nor frequency band data analysis adjusted for EMG showed substantial differences. None of the patients showed clinical signs of awakening. CONCLUSIONS: After neuromuscular block reversal with 2 mg kg-1 sugammadex, BIS, SEF95, EMG, and beta power showed small but statistically significant increases over time, while delta power decreased.

Brain ventricular enlargement in human and murine acute intermittent porphyria.

The morphological changes that occur in the central nervous system of patients with severe acute intermittent porphyria (AIP) have not yet been clearly established. The aim of this work was to analyze brain involvement in patients with severe AIP without epileptic seizures or clinical posterior reversible encephalopathy syndrome, as well as in a mouse model receiving or not liver-directed gene therapy aimed at correcting the metabolic disorder. We conducted neuroradiologic studies in 8 severely affected patients (6 women) and 16 gender- and age-matched controls. Seven patients showed significant enlargement of the cerebral ventricles and decreased brain perfusion was observed during the acute attack in two patients in whom perfusion imaging data were acquired. AIP mice exhibited reduced cerebral blood flow and developed chronic dilatation of the cerebral ventricles even in the presence of slightly increased porphyrin precursors. While repeated phenobarbital-induced attacks exacerbated ventricular dilation in AIP mice, correction of the metabolic defect using liver-directed gene therapy restored brain perfusion and afforded protection against ventricular enlargement. Histological studies revealed no signs of neuronal loss but a denser neurofilament pattern in the periventricular areas, suggesting compression probably caused by imbalance in cerebrospinal fluid dynamics. In conclusion, severely affected AIP patients exhibit cerebral ventricular enlargement. Liver-directed gene therapy protected against the morphological consequences of the disease seen in the brain of AIP mice. The observational study was registered at Clinicaltrial.gov as NCT02076763.

Effects of dexmedetomidine on subthalamic local field potentials in Parkinson's disease.

BACKGROUND: Dexmedetomidine is frequently used for sedation during deep brain stimulator implantation in patients with Parkinson's disease, but its effect on subthalamic nucleus activity is not well known. The aim of this study was to quantify the effect of increasing doses of dexmedetomidine in this population. METHODS: Controlled clinical trial assessing changes in subthalamic activity with increasing doses of dexmedetomidine (from 0.2 to 0.6 µg kg-1 h-1) in a non-operating theatre setting. We recorded local field potentials in 12 patients with Parkinson's disease with bilateral deep brain stimulators (24 nuclei) and compared basal activity in the nuclei of each patient and activity recorded with different doses. Plasma levels of dexmedetomidine were obtained and correlated with the dose administered. RESULTS: With dexmedetomidine infusion, patients became clinically sedated, and at higher doses (0.5-0.6 µg kg-1 h-1) a significant decrease in the characteristic Parkinsonian subthalamic activity was observed (P<0.05 in beta activity). All subjects awoke to external stimulus over a median of 1 (range: 0-9) min, showing full restoration of subthalamic activity. Dexmedetomidine dose administered and plasma levels showed a positive correlation (repeated measures correlation coefficient=0.504; P<0.001). CONCLUSIONS: Patients needing some degree of sedation throughout subthalamic deep brain stimulator implantation for Parkinson's disease can probably receive dexmedetomidine up to 0.6 µg kg-1 h-1 without significant alteration of their characteristic subthalamic activity. If patients achieve a 'sedated' state, subthalamic activity decreases, but they can be easily awakened with a non-pharmacological external stimulus and recover baseline subthalamic activity patterns in less than 10 min. CLINICAL TRIAL REGISTRATION: EudraCT 2016-002680-34; NCT-02982512.

Oscillatory activity in the basal ganglia and deep brain stimulation.

Over the past 10 years, research into the neurophysiology of the basal ganglia has provided new insights into the pathophysiology of movement disorders. The presence of pathological oscillations at specific frequencies has been linked to different signs and symptoms in PD and dystonia, suggesting a new model to explain basal ganglia dysfunction. These advances occurred in parallel with improvements in imaging and neurosurgical techniques, both of which having facilitated the more widespread use of DBS to modulate dysfunctional circuits. High-frequency stimulation is thought to disrupt pathological activity in the motor cortex/basal ganglia network; however, it is not easy to explain all of its effects based only on changes in network oscillations. In this viewpoint, we suggest that a return to classic anatomical concepts might help to understand some apparently paradoxical findings. © 2016 International Parkinson and Movement Disorder Society.

Effect of Dexmedetomidine and Propofol on Basal Ganglia Activity in Parkinson Disease: A Controlled Clinical Trial.

BACKGROUND: Deep brain stimulation electrodes can record oscillatory activity from deep brain structures, known as local field potentials. The authors' objective was to evaluate and quantify the effects of dexmedetomidine (0.2 µg·kg·h) on local field potentials in patients with Parkinson disease undergoing deep brain stimulation surgery compared with control recording (primary outcome), as well as the effect of propofol at different estimated peak effect site concentrations (0.5, 1.0, 1.5, 2.0, and 2.5 µg/ml) from control recording. METHODS: A nonrandomized, nonblinded controlled clinical trial was carried out to assess the change in local field potentials activity over time in 10 patients with Parkinson disease who underwent deep brain stimulation placement surgery (18 subthalamic nuclei). The relationship was assessed between the activity in nuclei in the same patient at a given time and repeated measures from the same nucleus over time. RESULTS: No significant difference was observed between the relative beta power of local field potentials in dexmedetomidine and control recordings (-7.7; 95% CI, -18.9 to 7.6). By contrast, there was a significant decline of 12.7% (95% CI, -21.3 to -4.7) in the relative beta power of the local field potentials for each increment in the estimated peak propofol concentrations at the effect site relative to the control recordings. CONCLUSIONS: Dexmedetomidine (0.2 µg·kg·h) did not show effect on local field potentials compared with control recording. A significant deep brain activity decline from control recording was observed with incremental doses of propofol.

Technical flaws in multiple-choice questions in the access exam to medical specialties ("examen MIR") in Spain (2009-2013).

BACKGROUND: The main factor that determines the selection of a medical specialty in Spain after obtaining a medical degree is the MIR ("médico interno residente", internal medical resident) exam. This exam consists of 235 multiple-choice questions with five options, some of which include images provided in a separate booklet. The aim of this study was to analyze the technical quality of the multiple-choice questions included in the MIR exam over the last five years. METHODS: All the questions included in the exams from 2009 to 2013 were analyzed. We studied the proportion of questions including clinical vignettes, the number of items related to an image and the presence of technical flaws in the questions. For the analysis of technical flaws, we adapted the National Board of Medical Examiners (NBME) guidelines. We looked for 18 different issues included in the manual, grouped into two categories: issues related to testwiseness and issues related to irrelevant difficulties. RESULTS: The final number of questions analyzed was 1,143. The percentage of items based on clinical vignettes increased from 50% in 2009 to 56-58% in the following years (2010-2013). The percentage of items based on an image increased progressively from 10% in 2009 to 15% in 2012 and 2013. The percentage of items with at least one technical flaw varied between 68 and 72%. We observed a decrease in the percentage of items with flaws related to testwiseness, from 30% in 2009 to 20% in 2012 and 2013. While most of these issues decreased dramatically or even disappeared (such as the imbalance in the correct option numbers), the presence of non-plausible options remained frequent. With regard to technical flaws related to irrelevant difficulties, no improvement was observed; this is especially true with respect to negative stem questions and "hinged" questions. CONCLUSION: The formal quality of the MIR exam items has improved over the last five years with regard to testwiseness. A more detailed revision of the items submitted, checking systematically for the presence of technical flaws, could improve the validity and discriminatory power of the exam, without increasing its difficulty.

Parkinson's disease, the subthalamic nucleus, inhibition, and impulsivity.

Although Parkinson's disease (PD) is primarily considered a disorder of initiation of actions, patients also have deficits in inhibitory control, both in the motor and cognitive domains. Impulse control disorders, which can develop in association with dopaminergic medication in a small proportion of patients with PD, are the symptoms most commonly considered as representing inhibitory deficits. However, there is now also a body of evidence suggesting a role for the subthalamic nucleus (STN), which is ordinarily hyperactive in PD, in inhibitory control. Here, we review evidence from animal studies, imaging studies, and investigations recording STN activity intra- or perioperatively in patients with PD having surgery for DBS of the STN (STN-DBS). We also highlight relevant hypotheses about the role of the STN and consider evidence from studies that have examined the effect of STN-DBS in patients with PD on performance of experimental tasks requiring inhibition of prepotent or habitual responses or decision making under conflict, as well as the psychiatric side effects of STN-DBS. Though the results are not always consistent, nevertheless, this body of evidence supports the role of the STN in inhibitory and executive control.

Long-term continuous positive airway pressure therapy improves cardiac autonomic tone during sleep in patients with obstructive sleep apnea.

BACKGROUND: Cardiac autonomic tone after long-term continuous positive airway pressure therapy in patients with obstructive sleep apnea remains unexplored. METHODS: Thirty patients with obstructive sleep apnea (14 with moderate and 16 with severe obstructive sleep apnea) were studied during a baseline polysomnographic study, after a full night of acute continuous positive airway pressure treatment, and after long-term (~2 years) chronic continuous positive airway pressure therapy. Twenty age- and gender-matched controls with baseline sleep study were selected for comparison purposes. Cross-spectral analysis and the low-frequency (LF) and high-frequency (HF) components of the heart rate variability were computed separately over 10-min ECG epochs during rapid eye movement sleep, non-rapid eye movement sleep, and wakefulness. RESULTS: During the baseline study, obstructive sleep apnea patients exhibited increased LF, decreased HF, and increased LF/HF ratio during sleep when compared to controls. In a multiple regression model, the mean oxygen saturation explained the increased LF during rapid and non-rapid eye movement sleep in obstructive sleep apnea patients. Acute continuous positive airway pressure therapy decreased the LF modulations and the LF/HF ratio and increased the HF modulations during sleep in patients with severe obstructive sleep apnea. Long-term continuous positive airway pressure therapy decreased LF modulations and LF/HF ratio with increased HF modulations during sleep in patients with moderate and severe obstructive sleep apnea. CONCLUSIONS: Long-term continuous positive airway pressure reduces the sympathovagal imbalance in patients with moderate and severe obstructive sleep apnea, both during rapid and non-rapid eye movement sleep. Continuous positive airway pressure seems to exert its changes in cardiac autonomic modulation by decreasing the burden of nocturnal hypoxia.

Factors Associated with Tremor Changes during Sedation with Dexmedetomidine in Parkinson's Disease Surgery.

INTRODUCTION: Dexmedetomidine is an α2-agonist recently proposed as a potentially ideal drug for sedation during the surgical treatment of Parkinson's disease (PD). This report documents the incidence of changes in motor symptoms (especially tremor) in PD patients sedated with dexmedetomidine for deep brain stimulation or ablation procedures. METHODS: We reviewed a retrospective cohort of 22 patients who underwent surgery for PD with dexmedetomidine sedation at a single institution from 2010 to 2014. A logistic regression analysis was performed to analyze possible confounding factors. RESULTS: 14 cases of tremor reduction or suppression were recorded (cumulative incidence: 63.6%; 95% CI: 40.7-82.8). No association could be identified between loading dose, ß-blocker use and preoperative total Unified Parkinson's Disease Rating Scale III, with tremor changes. The maintenance dose of dexmedetomidine was higher in patients who did not experience changes [median and range for patients with and without tremor alteration 0.75 (0.2-1.0) and 1.0 µg × kg(-1) × h(-1) (0.7-1.4), respectively; p = 0.021]. CONCLUSION: Dexmedetomidine provides adequate sedation during surgery for PD, but it might affect motor signs making intraoperative testing difficult or even impossible. Dosage appears not to be the determining factor in motor changes, whose cause remains unclear.

High beta activity in the subthalamic nucleus and freezing of gait in Parkinson's disease.

OBJECTIVE: Oscillatory activity in the beta band is increased in the subthalamic nucleus (STN) of Parkinson's disease (PD) patients. Rigidity and bradykinesia are associated with the low-beta component (13-20Hz) but the neurophysiological correlate of freezing of gait in PD has not been ascertained. METHODS: We evaluated the power and coherence of the low- and high-beta bands in the STN and cortex (EEG) of PD patients with (p-FOG) (n=14) or without freezing of gait (n-FOG) (n=8) in whom electrodes for chronic stimulation in the STN had been implanted for treatment with deep brain stimulation. RESULTS: p-FOG patients showed higher power in the high-beta band (F=11.6, p=0.002) that was significantly reduced after l-dopa administration along with suppression of FOG (F=4.6, p=0.042). High-beta cortico-STN coherence was maximal for midline cortical EEG electrodes, whereas the low-beta band was maximal for lateral electrodes (χ(2)=20.60, p<0.0001). CONCLUSIONS: The association between freezing of gait, high-beta STN oscillations and cortico-STN coherence suggests that this oscillatory activity might interfere in the frontal cortex-basal ganglia networks, thereby participating in the pathophysiology of FOG in PD.

Basal cardiac autonomic tone is normal in patients with periodic leg movements during sleep.

The relationship between the autonomic nervous system and periodic leg movements during sleep (PLMS) is not completely understood. We aimed to determine whether patients with PLMS exhibit any changes in their basal heart rate variability (HRV), excluding episodes of leg movements and arousals. To investigate this, we conducted a cross-sectional study including 13 patients with PLMS (PLMS ≥ 20) and 13 matched controls, free of cardiovascular diseases and medications. Time-and frequency-domain HRV measures [mean R-R interval, low frequency (LF), high frequency (HF), LF/HF] were calculated across all sleep stages as well during wakefulness just before and after sleep during one-night polysomnography. We only took ECG segments of sleep without arousals and excluded periods of 30 s before and after the leg movements. No statistical differences between PLMS and control subjects were found in any of the time- or frequency-domain HRV measures across sleep stages. Basal cardiac autonomic modulation in patients with PLMS is similar to that of control subjects. Our results argue against a role for a basal disturbance of the cardiac autonomic nervous system in the pathogenesis of PLMS.

Subthalamic activity during diphasic dyskinesias in Parkinson's disease.

BACKGROUND: Diphasic dyskinesias are a subtype of levodopa-induced dyskinesias that appear typically at the onset and end of levodopa antiparkinsonian action. The pathophysiology of diphasic dyskinesias is not well understood. METHODS: We analyzed local field potentials recorded from the subthalamic nucleus in 7 Parkinson's disease (PD) patients who showed typical diphasic dyskinesias during postoperative recordings through a deep brain stimulation electrode. The evolution of the different oscillatory activities related to the onset and end of diphasic dyskinesias was studied by windowed fast Fourier transforms. RESULTS: Typical "off"-state beta activity disappeared with the onset of diphasic dyskinesias, whereas gamma activity was absent or minimal until their end. Theta activity during diphasic dyskinesias was similar to that observed during peak-dose dyskinesias. CONCLUSIONS: From a neurophysiological viewpoint, patients exhibited oscillatory activity typical of the "on" medication state during diphasic dyskinesias. The minimal presence of gamma activity during diphasic dyskinesias, however, suggests that this "on" state might be incomplete or limited to dopaminergic mechanisms affecting the lower limbs.

Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson's disease.

Behavioural abnormalities such as impulse control disorders may develop when patients with Parkinson's disease receive dopaminergic therapy, although they can be controlled by deep brain stimulation of the subthalamic nucleus. We have recorded local field potentials in the subthalamic nucleus of 28 patients with surgically implanted subthalamic electrodes. According to the predominant clinical features of each patient, their Parkinson's disease was associated with impulse control disorders (n = 10), dyskinesias (n = 9) or no dopaminergic mediated motor or behavioural complications (n = 9). Recordings were obtained during the OFF and ON dopaminergic states and the power spectrum of the subthalamic activity as well as the subthalamocortical coherence were analysed using Fourier transform-based techniques. The position of each electrode contact was determined in the postoperative magnetic resonance image to define the topography of the oscillatory activity recorded in each patient. In the OFF state, the three groups of patients had similar oscillatory activity. By contrast, in the ON state, the patients with impulse control disorders displayed theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that was generated 2-8 mm below the intercommissural line. Similarly, the patients with dyskinesia showed theta-alpha activity that peaked at a higher frequency (mean: 8.38 Hz) and was generated 0-2 mm below the intercommissural line. No such activity was detected in patients that displayed no dopaminergic side effects. Cortico-subthalamic coherence was more frequent in the impulsive patients in the 4-7.5 Hz range in scalp electrodes placed on the frontal regions anterior to the primary motor cortex, while in patients with dyskinesia it was in the 7.5-10 Hz range in the leads overlying the primary motor and supplementary motor area. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations. These findings suggest that the activity recorded in parkinsonian patients with impulse control disorders stems from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Conversely, in patients with l-dopa-induced dyskinesias such activity is recorded in the motor area (dorsal subthalamic area) and it is coherent with cortical motor activity. Consequently, the subthalamic nucleus appears to be implicated in the motor and behavioural complications associated with dopaminergic drugs in Parkinson's disease, specifically engaging different anatomo-functional territories.

Sustained enzymatic correction by rAAV-mediated liver gene therapy protects against induced motor neuropathy in acute porphyria mice.

Acute intermittent porphyria (AIP) is characterized by a hereditary deficiency of hepatic porphobilinogen deaminase (PBGD) activity. Clinical features are acute neurovisceral attacks accompanied by overproduction of porphyrin precursors in the liver. Recurrent life-threatening attacks can be cured only by liver transplantation. We developed recombinant adeno-associated virus (rAAV) vectors expressing human PBGD protein driven by a liver-specific promoter to provide sustained protection against induced attacks in a predictive model for AIP. Phenobarbital injections in AIP mice induced porphyrin precursor accumulation, functional block of nerve conduction, and progressive loss of large-caliber axons in the sciatic nerve. Hepatocyte transduction showed no gender variation after rAAV2/8 injection, while rAAV2/5 showed lower transduction efficiency in females than males. Full protection against induced phenobarbital-attacks was achieved in animals showing over 10% of hepatocytes expressing high amounts of PBGD. More importantly, sustained hepatic expression of hPBGD protected against loss of large-caliber axons in the sciatic nerve and disturbances in nerve conduction velocity as induced by recurrent phenobarbital administrations. These data show for the first time that porphyrin precursors generated in the liver interfere with motor function. rAAV2/5-hPBGD vector can be produced in sufficient quantity for an intended gene therapy trial in patients with recurrent life-threatening porphyria attacks.

Brain oscillations and Parkinson disease.

Brain oscillations have been associated with Parkinson's disease (PD) for a long time mainly due to the fundamental oscillatory nature of parkinsonian rest tremor. Over the years, this association has been extended to frequencies well above that of tremor, largely owing to the opportunities offered by deep brain stimulation (DBS) to record electrical activity directly from the patients' basal ganglia. This chapter reviews the results of research on brain oscillations in PD focusing on theta (4-7Hz), beta (13-35Hz), gamma (70-80Hz) and high-frequency oscillations (200-400Hz). For each of these oscillations, we describe localization and interaction with brain structures and between frequencies, changes due to dopamine intake, task-related modulation, and clinical relevance. The study of brain oscillations will also help to dissect the mechanisms of action of DBS. Overall, the chapter tentatively depicts PD in terms of "oscillopathy."

Static magnetic stimulation of human auditory cortex: a feasibility study.

There is a growing interest about the effects of static transcranial magnetic stimulation (tSMS) over different cortical areas, being the motor cortex the most widely studied region. Previous experiments have shown that noninvasive magnetic static stimulation of the human brain may change its excitability in a reversible way for a period that outlasts the time of application of the magnetic field. However, evidence about the effects over the auditory cortex are poor and this is the purpose of the present study. Twelve voluntary subjects were studied in two different sessions, immediately before and 20 min after the placement of a magnet or a sham over the left primary auditory cortex, for 30 min. No significant effects of the magnet were observed on auditory responses, including onset and offset potentials and oscillatory responses to stimulus frequency modulation. A reduction in the amplitude of the cortical onset and offset potentials was observed after the two sessions, both with the magnet and with the false magnet (sham). No effects of unilateral static magnetic stimulation on cortical auditory responses have been observed. However, we probe the feasibility and tolerability of the protocol performed and suggest the use of different stimulation protocols.

Quality of Life Impact of Hypoglossal Nerve Stimulation with Inspire® Device in Patients with Obstructive Sleep Apnea Intolerant to Continuous Positive Airway Pressure Therapy.

Patients with obstructive sleep apnea (OSA) that do not tolerate/accept continuous positive airway pressure (CPAP) are candidates for surgical alternatives. Hypoglossal nerve stimulation (HNS) through the implantation of the Inspire® device constitutes a minimally invasive operative option. The main objective of this study is to estimate, under real-world clinical practice conditions, the 3-month impact on the quality of life (IQoL) of the HNS in patients with moderate/severe OSA who do not tolerate or accept CPAP, compared to patients who did not receive HNS. As a baseline, the unadjusted EuroQol utility index was 0.764 (SD:0.190) in the intervention group (IGr) and 0.733 (SD:0.205) in the control group (CGr); three months later, the indexes were 0.935 (SD: 0.101) and 0.727 (SD:0.200), respectively. The positive impact on quality of life was estimated to be +0.177 (95% CI: 0.044−0.310; p = 0.010). All dimensions in the IGr improved compared to CGr, especially for usual activities (p < 0.001) and anxiety/depression (p > 0.001). At the end of the follow-up, there was no significant difference in the quality of life between the general Spanish population and the IGr (difference: 0.012; CI95%: −0.03 to −0.057; p = 0.0578) for the same age range; however, there was a difference concerning the CGr (difference: −0.196; CI95%: −0.257 to −0.135; p < 0.001). In conclusion, patients with moderate/severe OSA implanted with the Inspire® device showed a positive IQoL.

Simple and Autonomous Sleep Signal Processing System for the Detection of Obstructive Sleep Apneas.

Obstructive sleep apnea (OSA) is a common sleep disorder characterized by repetitive upper airway obstruction, intermittent hypoxemia, and recurrent awakenings during sleep. The most used treatment for this syndrome is a device that generates a positive airway pressure­Continuous Positive Airway Pressure (CPAP), but it works continuously, whether or not there is apnea. An alternative consists on systems that detect apnea episodes and produce a stimulus that eliminates them. Article focuses on the development of a simple and autonomous processing system for the detection of obstructive sleep apneas, using polysomnography (PSG) signals: electroencephalography (EEG), electromyography (EMG), respiratory effort (RE), respiratory flow (RF), and oxygen saturation (SO2). The system is evaluated using, as a gold standard, 20 PSG tests labeled by sleep experts and it performs two analyses. A first analysis detects awake/sleep stages and is based on the accumulated amplitude in a channel-dependent frequency range, according to the criteria of the American Academy of Sleep Medicine (AASM). The second analysis detects hypopneas and apneas, based on analysis of the breathing cycle and oxygen saturation. The results show a good estimation of sleep events, where for 75% of the cases of patients analyzed it is possible to determine the awake/asleep states with an effectiveness of >92% and apneas and hypopneas with an effectiveness of >55%, through a simple processing system that could be implemented in an electronic device to be used in possible OSA treatments.

Recombinant porphobilinogen deaminase targeted to the liver corrects enzymopenia in a mouse model of acute intermittent porphyria.

Correction of enzymatic deficits in hepatocytes by systemic administration of a recombinant protein is a desired therapeutic goal for hepatic enzymopenic disorders such as acute intermittent porphyria (AIP), an inherited porphobilinogen deaminase (PBGD) deficiency. Apolipoprotein A-I (ApoAI) is internalized into hepatocytes during the centripetal transport of cholesterol. Here, we generated a recombinant protein formed by linking ApoAI to the amino terminus of human PBGD (rhApoAI-PBGD) in an attempt to transfer PBGD into liver cells. In vivo experiments showed that, after intravenous injection, rhApoAI-PBGD circulates in blood incorporated into high-density lipoprotein (HDL), penetrates into hepatocytes, and crosses the blood-brain barrier, increasing PBGD activity in both the liver and brain. Consistently, the intravenous administration of rhApoAI-PBGD or the hyperfunctional rApoAI-PBGD-I129M/N340S (rApoAI-PBGDms) variant efficiently prevented and abrogated phenobarbital-induced acute attacks in a mouse model of AIP. One month after a single intravenous dose of rApoAI-PBGDms, the protein was still detectable in the liver, and hepatic PBGD activity remained increased above control values. A long-lasting therapeutic effect of rApoAI-PBGDms was observed after either intravenous or subcutaneous administration. These data describe a method to deliver PBGD to hepatocytes with resulting enhanced hepatic enzymatic activity and protection against AIP attacks in rodent models, suggesting that the approach might be an effective therapy for AIP.

Coupling between beta and high-frequency activity in the human subthalamic nucleus may be a pathophysiological mechanism in Parkinson's disease.

In Parkinson's disease (PD), the oscillatory activity recorded from the basal ganglia shows dopamine-dependent changes. In the "off" parkinsonian motor state, there is prominent activity in the beta band (12-30 Hz) that is mostly attenuated after dopaminergic therapy ("on" medication state). The on state is also characterized by activity in the gamma (60-80 Hz) and high-frequency (300 Hz) bands that is modulated by movement. We recorded local field potentials from a group of 15 PD patients (three females) treated with bilateral deep brain stimulation of the subthalamic nucleus, using a high sampling rate (2 kHz) and filters suitable to study high-frequency activity (0.3-1000 Hz). We observed high-frequency oscillations (HFOs) in both the off and on motor states. In the off state, the amplitude of the HFOs was coupled to the phase of the abnormal beta activity. The beta-coupled HFOs showed little or even negative movement-related changes in amplitude. Moreover, the degree of movement-related modulation of the HFOs correlated negatively with the rigidity/bradykinesia scores. In the on motor state, the HFOs were liberated from this beta coupling, and they displayed marked movement-related amplitude modulation. Cross-frequency interactions between the phase of slow activities and the amplitude of fast frequencies have been attributed an important role in information processing in cortical structures. Our findings suggest that nonlinear coupling between frequencies may not only be a physiological mechanism (as shown previously) but also that it may participate in the pathophysiology of parkinsonism.