Domoic acid disrupts the activity and connectivity of neuronal networks in organotypic brain slice cultures.

Domoic acid is a neurotoxin produced by algae and is found in seafood during harmful algal blooms. As a glutamate agonist, domoic acid inappropriately stimulates excitatory activity in neurons. At high doses, this leads to seizures and brain lesions, but it is unclear how lower, asymptomatic exposures disrupt neuronal activity. Domoic acid has been detected in an increasing variety of species across a greater geographical range than ever before, making it critical to understand the potential health impacts of low-level exposure on vulnerable marine mammal and human populations. To determine whether prolonged domoic acid exposure altered neuronal activity in hippocampal networks, we used a custom-made 512 multi-electrode array with high spatial and temporal resolution to record extracellular potentials (spikes) in mouse organotypic brain slice cultures. We identified individual neurons based on spike waveform and location, and measured the activity and functional connectivity within the neuronal networks of brain slice cultures. Domoic acid exposure significantly altered neuronal spiking activity patterns, and increased functional connectivity within exposed cultures, in the absence of overt cellular or neuronal toxicity. While the overall spiking activity of neurons in domoic acid-exposed cultures was comparable to controls, exposed neurons spiked significantly more often in bursts. We also identified a subset of neurons that were electrophysiologically silenced in exposed cultures, and putatively identified those neurons as fast-spiking inhibitory neurons. These results provide evidence that domoic acid affects neuronal activity in the absence of cytotoxicity, and suggest that neurodevelopmental exposure to domoic acid may alter neurological function in the absence of clinical symptoms.

The potential impact of biomarker-guided triage decisions for patients with urinary tract infections.

OBJECTIVES: Current guidelines provide limited evidence as to which patients with urinary tract infection (UTI) require hospitalisation. We evaluated the currently used triage routine and tested whether a set of criteria including biomarkers like proadrenomedullin (proADM) and urea have the potential to improve triage decisions. METHODS: Consecutive adults with UTI presenting to our emergency department (ED) were recruited and followed for 30 days. We defined three virtual triage algorithms, which included either guideline-based clinical criteria, optimised admission proADM or urea levels in addition to a set of clinical criteria. We compared actual treatment sites and observed adverse events based on the physician judgment with the proportion of patients assigned to treatment sites according to the three virtual algorithms. Adverse outcome was defined as transfer to the intensive care unit (ICU), death, recurrence of UTI or rehospitalisation for any reason. RESULTS: We recruited 127 patients (age 61.8 ± 20.8 years; 73.2 % females) and analysed the data of 123 patients with a final diagnosis of UTI. Of these 123 patients, 27 (22.0 %) were treated as outpatients. Virtual triage based only on clinical signs would have treated only 22 (17.9 %) patients as outpatients, with higher proportions of outpatients equally in both biomarker groups (29.3 %; p = 0.02). There were no significant differences in adverse events between outpatients according to the clinical (4.5 %), proADM (2.8 %) or urea groups (2.8 %). The mean length of stay was 6.6 days, including 2.2 days after reaching medical stability. CONCLUSIONS: Adding biomarkers to clinical criteria has the potential to improve risk-based triage without impairing safety. Current rates of admission and length of stay could be shortened in patients with UTI.

Dense arrays of micro-needles for recording and electrical stimulation of neural activity in acute brain slices.

OBJECTIVE: This paper describes the design, microfabrication, electrical characterization and biological evaluation of a high-density micro-needle array. The array records from and electrically stimulates individual neurons simultaneously in acute slices of brain tissue. APPROACH: Acute slices, arguably the closest in-vitro model of the brain, have a damaged surface layer. Since electrophysiological recording methods rely heavily on electrode-cell proximity, this layer significantly attenuates the signal amplitude making the use of traditional planar electrodes unsuitable. To penetrate into the tissue, bypassing the tissue surface, and to record and stimulate neural activity in the healthy interior volume of the slice, an array of 61 micro-needles was fabricated. MAIN RESULTS: This device is shown to record extracellular action potentials from individual neurons in acute cortical slices with a signal to noise ratio of up to ∼15:1. Electrical stimulation of individual neurons is achieved with stimulation thresholds of 1.1-2.9 µA. SIGNIFICANCE: The novelty of this system is the combination of close needle spacing (60 µm), needle heights of up to 250 µm and small (5-10 µm diameter) electrodes allowing the recording of single unit activity. The array is coupled to a custom-designed readout system forming a powerful electrophysiological tool that permits two-way electrode-cell communication with populations of neurons in acute brain slices.

Changes in physiological properties of rat ganglion cells during retinal degeneration.

Retinitis pigmentosa (RP) is a leading cause of degenerative vision loss, yet its progressive effects on visual signals transmitted from the retina to the brain are not well understood. The transgenic P23H rat is a valuable model of human autosomal dominant RP, exhibiting extensive similarities to the human disease pathology, time course, and electrophysiology. In this study, we examined the physiological effects of degeneration in retinal ganglion cells (RGCs) of P23H rats aged between P37 and P752, and compared them with data from wild-type control animals. The strength and the size of visual receptive fields of RGCs decreased rapidly with age in P23H retinas. Light responses mediated by rod photoreceptors declined earlier (∼ P300) than cone-mediated light responses (∼ P600). Responses of ON and OFF RGCs diminished at a similar rate. However, OFF cells exhibited hyperactivity during degeneration, whereas ON cells showed a decrease in firing rate. The application of synaptic blockers abolished about half of the elevated firing in OFF RGCs, indicating that the remodeled circuitry was not the only source of degeneration-induced hyperactivity. These results advance our understanding of the functional changes associated with retinal degeneration.

Loss of responses to visual but not electrical stimulation in ganglion cells of rats with severe photoreceptor degeneration.

Retinal implants are intended to help patients with degenerative conditions by electrically stimulating surviving cells to produce artificial vision. However, little is known about how individual retinal ganglion cells respond to direct electrical stimulation in degenerating retina. Here we used a transgenic rat model to characterize ganglion cell responses to light and electrical stimulation during photoreceptor degeneration. Retinas from pigmented P23H-1 rats were compared with wild-type retinas between ages P37 and P752. During degeneration, retinal thickness declined by 50%, largely as a consequence of photoreceptor loss. Spontaneous electrical activity in retinal ganglion cells initially increased two- to threefold, but returned to nearly normal levels around P600. A profound decrease in the number of light-responsive ganglion cells was observed during degeneration, culminating in retinas without detectable light responses by P550. Ganglion cells from transgenic and wild-type animals were targeted for focal electrical stimulation using multielectrode arrays with electrode diameters of approximately 10 microns. Ganglion cells were stimulated directly and the success rate of stimulation in both groups was 60-70% at all ages. Surprisingly, thresholds (approximately 0.05 mC/cm(2)) and latencies (approximately 0.25 ms) in P23H rat ganglion cells were comparable to those in wild-type ganglion cells at all ages and showed no change over time. Thus ganglion cells in P23H rats respond normally to direct electrical stimulation despite severe photoreceptor degeneration and complete loss of light responses. These findings suggest that high-resolution epiretinal prosthetic devices may be effective in treating vision loss resulting from photoreceptor degeneration.

[Speach breasing optimization with biofeedback on respiratory arrythmia of heart rate].

Dynamics of physiological and psychological characteristics of healthy volunteers (adolescents and adults), speech professionals (logopedics), and stutter patients (adolescents and adults) in process of adoptive self-regulation with biofeedback on objective physiologic indicator - changes of respiratory arrhythmia of hart rate were investigated. High level of efficacy and practicability of the method application was revealed to study, diagnostics, optimization and correction of breathing, speech and behavior.

Electrical stimulation of mammalian retinal ganglion cells with multielectrode arrays.

Existing epiretinal implants for the blind are designed to electrically stimulate large groups of surviving retinal neurons using a small number of electrodes with diameters of several hundred micrometers. To increase the spatial resolution of artificial sight, electrodes much smaller than those currently in use are desirable. In this study, we stimulated and recorded ganglion cells in isolated pieces of rat, guinea pig, and monkey retina. We used microfabricated hexagonal arrays of 61 platinum disk electrodes with diameters between 6 and 25 microm, spaced 60 microm apart. Charge-balanced current pulses evoked one or two spikes at latencies as short as 0.2 ms, and typically only one or a few recorded ganglion cells were stimulated. Application of several synaptic blockers did not abolish the evoked responses, implying direct activation of ganglion cells. Threshold charge densities were typically <0.1 mC/cm2 for a pulse duration of 100 micros, corresponding to charge thresholds of <100 pC. Stimulation remained effective after several hours and at high frequencies. To show that closely spaced electrodes can elicit independent ganglion cell responses, we used the multielectrode array to stimulate several nearby ganglion cells simultaneously. From these data, we conclude that electrical stimulation of mammalian retina with small-diameter electrode arrays is achievable and can provide high temporal and spatial precision at low charge densities. We review previous epiretinal stimulation studies and discuss our results in the context of 32 other publications, comparing threshold parameters and safety limits.

Fidelity of the ensemble code for visual motion in primate retina.

Sensory experience typically depends on the ensemble activity of hundreds or thousands of neurons, but little is known about how populations of neurons faithfully encode behaviorally important sensory information. We examined how precisely speed of movement is encoded in the population activity of magnocellular-projecting parasol retinal ganglion cells (RGCs) in macaque monkey retina. Multi-electrode recordings were used to measure the activity of approximately 100 parasol RGCs simultaneously in isolated retinas stimulated with moving bars. To examine how faithfully the retina signals motion, stimulus speed was estimated directly from recorded RGC responses using an optimized algorithm that resembles models of motion sensing in the brain. RGC population activity encoded speed with a precision of approximately 1%. The elementary motion signal was conveyed in approximately 10 ms, comparable to the interspike interval. Temporal structure in spike trains provided more precise speed estimates than time-varying firing rates. Correlated activity between RGCs had little effect on speed estimates. The spatial dispersion of RGC receptive fields along the axis of motion influenced speed estimates more strongly than along the orthogonal direction, as predicted by a simple model based on RGC response time variability and optimal pooling. on and off cells encoded speed with similar and statistically independent variability. Simulation of downstream speed estimation using populations of speed-tuned units showed that peak (winner take all) readout provided more precise speed estimates than centroid (vector average) readout. These findings reveal how faithfully the retinal population code conveys information about stimulus speed and the consequences for motion sensing in the brain.

A low noise multichannel integrated circuit for recording neuronal signals using microelectrode arrays.

This paper reports on the development of a fully integrated 32-channel integrated circuit (IC) for recording neuronal signals in neurophysiological experiments using microelectrode arrays. The IC consists of 32 channels of low-noise preamplifiers and bandpass filters, and an output analog multiplexer. The continuous-time RC active filters have a typical passband of 20-2000 Hz; the low and the high cut-off frequencies can be separately controlled by external reference currents. This chip provides a satisfactory signal-to-noise ratio for neuronal signals with amplitudes greater than 50 microV. For the nominal passband setting, an equivalent input noise of 3 microV rms has been achieved. A single channel occupies 0.35 mm(2) of silicon area and dissipates 1.7 mW of power. The chip was fabricated in a 0.7 microm CMOS process.

Amplitude of visual P3 event-related potential as a phenotypic marker for a predisposition to alcoholism: preliminary results from the COGA Project. Collaborative Study on the Genetics of Alcoholism.

Recent data collected at six identical electrophysiological laboratories from the large national multisite Collaborative Study on the Genetics of Alcoholism provide evidence for considering the P3 amplitude of the event-related potential as a phenotypic marker for the risk of alcoholism. The distribution of P3 amplitude to target stimuli at the Pz electrode in individuals 16 years of age and over from 163 randomly ascertained control families (n = 687) was compared with those from 219 densely affected alcoholic families (n = 1276) in which three directly interviewed first-degree relatives met both DSM-III-R and Feighner criteria at the definite level for alcohol dependence (stage II). The control sample did not exclude individuals with psychiatric illness or alcoholism to obtain incidence rates of psychiatric disorders similar to those of the general population. P3 amplitude data from control families was converted to Z-scores, and a P3 amplitude beyond 2 SD's below the mean was considered an "abnormal trait." When age- and sex-matched distributions of P3 amplitude were compared, members of densely affected stage II families were more likely to manifest low P3 amplitudes (2 SD below the mean) than members of control families, comparing affected and unaffected offspring, and all individuals; all comparisons of these distributions between groups were significant (p < 0.00001). P3 amplitude means were also significantly lower in stage II family members, compared with control family members for all comparisons, namely probands, affected and unaffected individuals (p < 0.0001), and offspring (p < 0.01). Furthermore, affected individuals from stage II families, but not control families, had significantly lower P3 amplitudes than unaffected individuals (p < 0.001). Affected males from stage II families had significantly lower P3 amplitudes than affected females (p < 0.001). Recent linkage analyses indicate that visual P3 amplitude provides a biological phenotypic marker that has genetic underpinnings.

Reflection of working memory: ERP mnemonic effects.

The study of working memory often utilizes a delayed matching to sample paradigm (DMS). Typically in the matching condition, the test and sample stimuli are identical, raising the possible confound of retinotopic projections for the matching stimuli in contrast to the non-matching stimuli. In the present study, 65 healthy subjects performed a modified delayed matching to sample task while monitoring their ERP waveforms. The stimuli consisted of 60 different sample stimuli (S1) and 60 different test stimuli (S2). Half of the S2s were complementary to the sample stimuli (Fit), the other half of the S2s were not complementary (Nonfit). After S2, the subjects pressed one of the buttons to indicate whether the test stimulus fits the sample stimulus. Our statistical results indicated that the ERPs to sample stimuli differed from the ERPs to test stimuli from 200 ms poststimulus to the end of the recording epoch. The ERPs to fitting stimuli were significantly different from those to non-fitting stimuli from 200 to 400 ms poststimulus. The ERP patterns in the present study may reflect ERP mnemonic effect for working memory. Our results ruled out the retinotopic confound as a potential mediator variable, and are in agreement with other animal or human neurophysiological studies on memory.

Visual object priming differs from visual word priming: an ERP study.

Implicit memory is inferred from repetition priming effects in tasks such as word identification, word fragment completion, and perceptual recognition with masking or brief exposures. In this experiment, we explored whether the visual word and object repetition priming effects can be reflected by features of ERP and whether visual word repetition priming differs from visual object repetition priming. We have observed that (1) pre-exposure to recognizable stimuli (both word and object picture) shortened the response time in identifying their repetitions; (2) repetition of unrecognized scrambles of words or object pictures did not show any effects on ERP patterns; (3) ERPs distinguished recognizable from unrecognizable stimuli; and, (4) repetitions of both words and pictures strongly influenced the patterns of ERPs, though the ERPs to word stimuli differed from the ERPs to picture stimuli.

Electrophysiological evidence of memory impairment in alcoholic patients.

In a series of event-related potential (ERP) studies, we have consistently demonstrated an ERP component correlate of visual short-term memory. There have been frequent reports on the deficits of information encoding, retention, and retrieval in chronic alcoholics. In the present study, we investigated that the ERP mnemonic effects could be influenced by long-term alcohol abuse. ERP data were recorded from 48 controls and 77 alcoholics while the subjects performed a modified delayed matching to sample paradigm using a series of object pictures as stimuli. The alcoholics completed the task with more errors and longer response times than the controls. The major differences in the evoked potentials between the two groups are found at the temporo-occipital and frontal regions in the sample and nonmatching trials, and mostly prominent in the right hemisphere. The current study indicates that the ERP technique can be a useful tool to index short-term memory. The ERP mnemonic effect difference between the two groups may be a reflection of a working memory deficit caused by long-term alcohol abuse. Our data also suggest right hemisphere dysfunction in alcoholics, with deficits in information encoding.

A simple auditory oddball task in young adult males at high risk for alcoholism.

The reduction in the amplitude of the auditory P300 in young adult males at high risk for alcoholism has not been as consistently replicated as has been the reduction in the visual P300 amplitude in the same group. The easier nature of the auditory task was thought to be responsible for the inconsistency. We examined the auditory P300 amplitude in a group that has not yet been studied, young adult sons of alcoholics (mean age = 24.9 years, n = 48), and compared them with age and sex-matched controls (mean age = 27.8 years, n = 23). We found the auditory P300 amplitude to be reduced in the high-risk group and this reduction to be the greatest over the posterior centroparietal and occipital areas when individual leads were examined. We further analyzed the data using current source density, a mathematical transformation that circumvents some of the errors inherent in measuring scalp-evoked potentials, and found reduced current source density in the high-risk group in the posterior central and parietal areas. Thus, we found that a simple auditory oddball task was effective in eliciting P300 differences in groups at high and low risk for alcoholism. The clinical significance of the P300 is discussed, as well as the relevance of task difficulty in eliciting auditory P300 differences in young males at high risk for alcoholism.

Event related potentials during object recognition tasks.

In our previous studies, we have demonstrated an ERP correlate of visual memory with a modified delayed matching-to-sample paradigm using a series of nonsense line drawings or faces as stimuli. In this experiment, we employed pictures of objects to determine whether the ERP can reflect the object recognition process and whether visual stimuli with a verbal label would result in a different topographic distribution from past topography obtained with visual stimuli without a verbal label. The results of this study suggest that the amplitude of the ERP component (c247) to repeated (primed) pictures of common objects was significantly decreased as compared to the unrepeated (unprimed) pictures; the latency for the peak of c247 was decreased for the repeated compared to the unrepeated, and the response time was also significantly shorter to the repeated picture stimuli than to the unrepeated; the topographical distribution of c247 was mainly located in the occipitotemporal areas of the brain. However, the source energy density map showed that the topographic involvement of the brain regions to the c247 was different in the matching and nonmatching trials.