Closed-loop optogenetic control of the dynamics of neural activity in non-human primates.

Electrical neurostimulation is effective in the treatment of neurological disorders, but associated recording artefacts generally limit its applications to open-loop stimuli. Real-time and continuous closed-loop control of brain activity can, however, be achieved by pairing concurrent electrical recordings and optogenetics. Here we show that closed-loop optogenetic stimulation with excitatory opsins enables the precise manipulation of neural dynamics in brain slices from transgenic mice and in anaesthetized non-human primates. The approach generates oscillations in quiescent tissue, enhances or suppresses endogenous patterns in active tissue and modulates seizure-like bursts elicited by the convulsant 4-aminopyridine. A nonlinear model of the phase-dependent effects of optical stimulation reproduced the modulation of cycles of local-field potentials associated with seizure oscillations, as evidenced by the systematic changes in the variability and entropy of the phase-space trajectories of seizures, which correlated with changes in their duration and intensity. We also show that closed-loop optogenetic neurostimulation could be delivered using intracortical optrodes incorporating light-emitting diodes. Closed-loop optogenetic approaches may be translatable to therapeutic applications in humans.

Overemphasis of the Autism Diagnostic Observation Schedule (ADOS) Evaluation Subverts a Clinician's Ability to Provide Access to Autism Services.

A concerning trend has emerged in the diagnosis and treatment of autism spectrum disorder (ASD) that has a negative impact on care. Quite often, a clinician's diagnosis of ASD using DSM-5 criteria is no longer sufficient for individuals with ASD to access services. Insurance companies, school districts, and developmental disability agencies commonly require an Autism Diagnostic Observation Schedule (ADOS) to be eligible for services.

Reduced seizure threshold and altered network oscillatory properties in a mouse model of Rett syndrome.

Rett syndrome (RTT) is a disorder with a pronounced neurological phenotype and is caused mainly by mutations in the X-linked gene MECP2. A common feature of RTT is an abnormal electroencephalography and a propensity for seizures. In the current study we aimed to assess brain network excitability and seizure propensity in a mouse model of RTT. Mice in which Mecp2 expression was silenced (Mecp2(stop/y)) showed a higher seizure score (mean=6 ± 0.8 compared to 4±0.2 in wild-type [WT]) and more rapid seizure onset (median onset=10 min in Mecp2(stop/y) and 32 min in WT) when challenged with the convulsant drug kainic acid (25mg/kg). Hippocampal slices from Mecp2(stop/y) brain displayed no spontaneous field potential activities under control conditions but showed higher power gamma frequency field potential oscillations compared to WT in response to kainic acid (400 nM) in vitro. Brain slices challenged with the GABA(A)-receptor antagonist bicuculline (0.1-10 µM) and the potassium channel blocker 4-aminopyridine (1-50 µM) also revealed differences between genotypes with hippocampal circuits from Mecp2(stop/y) mouse slices showing enhanced epileptiform burst duration and frequency. In contrast to these network level findings, single cell analysis of pyramidal cells by whole-cell patch clamp recording revealed no detectable differences in synaptic or biophysical properties between methyl-CpG-binding protein 2 (MeCP2)-containing and MeCP2-deficient neurons. These data support the proposal that loss of MeCP2 alters network level excitability in the brain to promote epileptogenesis.

Synaptic plasticity deficits in an experimental model of rett syndrome: long-term potentiation saturation and its pharmacological reversal.

Rett syndrome (RTT), a disorder caused almost exclusively by mutations in the X-linked gene, MECP2, has a phenotype thought to be primarily of neurological origin. Disruption of Mecp2 in mice results in a prominent RTT-like phenotype. One of the consequences of MeCP2 absence in the brain is altered functional and structural plasticity. We aimed to characterize synaptic effects related to plasticity in the hippocampus further and establish whether plasticity defects are amenable to pharmacological reversal. Using male mice in which Mecp2 expression was prevented by a stop cassette, we assessed synaptic plasticity in area CA1 at different phenotypic stages, scoring the mice weekly for overt RTT-like signs. Strongly symptomatic Mecp2(stop/y) mice displayed reduced long-term potentiation (LTP, 40.2±1.6% of wild-type), post-tetanic potentiation (PTP, 45±18.8% of wild-type) and paired-pulse facilitation (PPF, 78±0.1% of wild type) (all P<0.05), the impairment increasing with symptom severity score. These plasticity impairments were absent in presymptomatic mice. Repeated high frequency stimulation revealed pronounced LTP saturation in symptomatic Mecp2(stop/y) mice, suggesting an LTP 'ceiling' effect. Bath application of the weak NMDA receptor blocker memantine (1 µM) resulted in partial restoration of a short-term plasticity component. These data support that idea that progressive functional synaptic impairment is a key feature in the RTT brain and demonstrate the potential for the pharmacological restoration of plasticity function.

Routine assessment of patient-reported outcomes in behavioral health: room for improvement.

Outcomes assessment has become an important tool in assessing the quality of health care. To date, most quality initiatives have focused on adverse events, clinical processes, and/or cost variables. Considerably less attention has been paid to indices of clinical improvement, especially from a patient's perspective and in behavioral health settings. The relative inattention given to clinical improvement is attributable to a number of reasons, including (but not limited to) a lack of consensus regarding measures of improvement, few simple methods for data collection and analysis, and an inability to provide timely feedback. In this article, the authors describe a Web-based system designed to routinely collect quality-of-life ratings from patients in outpatient behavioral health clinics, allowing for real-time feedback at the patient levels regarding clinical improvement. The system also allows for administrative evaluation of overall clinic performance. The costs and benefits of this system are discussed.

Human in-vitro fertilisation, in-vivo sperm penetration of cervical mucus, and unexplained infertility.

Oocytes were recovered at routine diagnostic laparoscopy for infertility after stimulation with clomiphene and human chorionic gonadotropin. The results of in-vitro fertilisation (IVF) with the husband's semen were compared in 3 distinct groups of fully investigated infertile couples. Those with bilateral tubal occlusion (36) were combined with fertile controls undergoing sterilisation (6) to form a "tubal" group for normal reference. In this tubal group 48/88 (55%) oocytes were fertilised, at least one oocyte being fertilised in each of 33/42 couples (79%). In couples with a negative or poor postcoital test (PCT), despite mostly normal semen analysis, 8/50 (16%) oocytes were fertilised in 6/21 (29%) couples. In couples with unexplained infertility and a positive PCT, 22/61 (36%) oocytes were fertilised in 17/25 (68%) couples. The results show that spermatozoa unable to penetrate preovulatory cervical mucus are generally also unable to fertilise the human oocyte. They emphasise the biological and prognostic importance of the PCT, and the hidden frequency of defective sperm function as a cause of unexplained infertility. Human IVF is likely to be a more helpful diagnostic investigation than hamster egg penetration testing because it is specific for individual couples. If IVF is to offer therapeutic hope to couples with impaired sperm/mucus penetration the fertilisation rates and the numbers of mature oocytes stimulated for recovery will both have to be high.

Monoamniotic twins with an unusual cord complication. Case report.

During the birth of monoamniotic twins the second twin's cord was divided after the birth of the first twin's head. Both infants survived. Division of a cord around the neck of a first twin should be avoided wherever possible.

Ruptured renal artery aneurysm in pregnancy. Case report.

A patient who survived rupture of a renal artery aneurysm in pregnancy is described. The aneurysm was caused by fibromuscular dysplasia of the renal artery.

The pulsed Doppler ultrasound flowmeter: experimental evaluation of velocity accuracy and range resolution.

Accurate quantitation of blood flow patterns, particularly in the physiological state, is important to the successful study of several problems in biomedical research. The pulsed Doppler ultrasonic flowmeter offers promise of overcoming some of the difficulties present in other methods. This flowmeter can be either implantable or noninvasive. Although a number of papers describe important design criteria, the design or selection of a Doppler system for a given task remains a complex matter involving many compromises based on theoretical considerations and very limited data. Experimental data from well-defined flows are needed to help identify those areas in which ultrasonic flowmeters can be most useful. This paper defines and evaluates two important parameters for the pulsed Doppler ultrasonic flowmeter by comparing experimental results with those predicted theorectically. The first parameter is velocity accuracy; the second parameter is range resolution. Findings show that centerline flow velocities in circular tubes can be estimated to within a few percent of the correct value, and that a 1.5-mm range resolution can be realized with the system tested.