[Intraoral voice recording-towards a new smartphone-based method for vocal rehabilitation. German version]. / Die intraorale Sprachaufnahme ­ die Perspektive einer neuen Smartphone-basierten Methode zur stimmlichen Rehabilitation.

After laryngectomy, a new voice is needed. We present the first steps in the development of a smartphone-based method. A microphone is placed in the mouth to record the pseudo-whispering voice of laryngectomized patients. This recording is analyzed by voice recognition software followed by voice synthesis. Eventually, this will be performed on a smartphone. We placed a microphone at 10 different places inside and outside the mouth (two in front of the mouth (at 2 and 20 cm), five on the palate and three on the lower jaw) and made voice recordings in eight healthy men. These recordings were analyzed by voice recognition software. The text generated by the software was compared with the original text. Over all positions, the correct detection of words recorded in the mouth was 19.3% vs. 75.2% (p = 0.01) outside the mouth. In the mouth, recording taken on the maxilla (22.8%) was much better than on the mandible (13.5%) (p = 0.01). The optimum position for a microphone on the maxilla was at the highest point of the palate with 31.9% correct word identification there (p = 0.028). Further investigations have to be undertaken with forthcoming development of smartphone processing power and with development of a smartphone-based voice recognition application.

Intraoral voice recording-towards a new smartphone-based method for vocal rehabilitation.

After laryngectomy, a new voice is needed. We present the first steps in the development of a smartphone-based method. A microphone is placed in the mouth to record the pseudo-whispering voice of laryngectomized patients. This recording is analyzed by voice recognition software followed by voice synthesis. Eventually, this will be performed on a smartphone. We placed a microphone at 10 different places inside and outside the mouth (two in front of the mouth (at 2 and 20 cm), five on the palate and three on the lower jaw) and made voice recordings in eight healthy men. These recordings were analyzed by voice recognition software. The text generated by the software was compared with the original text. Over all positions, the correct detection of words recorded in the mouth was 19.3% vs. 75.2% (p = 0.01) outside the mouth. In the mouth, recording taken on the maxilla (22.8%) was much better than on the mandible (13.5%) (p = 0.01). The optimum position for a microphone on the maxilla was at the highest point of the palate with 31.9% correct word identification there (p = 0.028). Further investigations have to be undertaken with forthcoming development of smartphone processing power and with development of a smartphone-based voice recognition application.

Positive allosteric modulation of α4ß2 nAChR agonist induced behaviour.

Neuronal cholinergic transmission is a prerequisite for proper CNS function. Consequently, disturbance of this system is associated with a number of pathophysiological conditions such as Parkinson's disease, Alzheimer's disease, schizophrenia and ADHD. Consequently, drug discovery efforts have spurred considerable research endeavours into identifying specific compounds for this system. Nicotinic acetylcholine receptors (nAChR) are ligand gated ion channels involved in cholinergic transmission. nAChRs are homo- or heteromeric pentamers with α4ß2 receptors being the most abundant heteromer. The stoichiometry of α4ß2 receptors can be either (α4)(3)(ß2)(2) or (α4)(2)(ß2)(3) representing channels with low (LS) or high (HS) sensitivity, respectively, to endogenous ligands. In the present study we applied the partial nAChR α4ß2 LS and HS agonist NS3956 and the LS selective positive allosteric modulator NS9283 to investigate the role of α4ß2 in Parkinson and pain models. In 6-OHDA lesioned rats, NS3956 increased rotational behaviour when rats were co-treated with nomifensine. This effect was absent in the presence of mecamylamine. In contrast, co-treatment with NS3956 and NS9283 reduced rotational behaviour in the animals. In a rat formalin pain model NS3956 induced an analgesic response that was strongly potentiated by NS9283. Finally in vitro experiments were applied to determine dopamine release from striatal minces. NS3956 induced a concentration dependent release while NS9283 was unable to potentiate agonist induced release. Together these results emphasize involvement of α4ß2 nAChR in rotational and analgesic responses and confirm striatal α4ß2 receptors to be of the HS form.

Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.

BACKGROUND AND PURPOSE: Positive allosteric modulation of α4ß2 nicotinic acetylcholine (nACh) receptors could add a new dimension to the pharmacology and therapeutic approach to these receptors. The novel modulator NS9283 was therefore tested extensively. EXPERIMENTAL APPROACH: Effects of NS9283 were evaluated in vitro using fluorescence-based Ca(2+) imaging and electrophysiological voltage clamp experiments in Xenopus oocytes, mammalian cells and thalamocortical neurons. In vivo the compound was tested in models covering a range of cognitive domains in mice and rats. KEY RESULTS: NS9283 was shown to increase agonist-evoked response amplitude of (α4)(3) (ß2)(2) nACh receptors in electrophysiology paradigms. (α2)(3) (ß2)(2) , (α2)(3) (ß4)(2) and (α4)(3) (ß4)(2) were modulated to comparable extents, but no effects were detected at α3-containing or any 2α : 3ß stoichiometry nACh receptors. Native nACh receptors in thalamocortical neurons similarly displayed DHßE-sensitive currents that were receptive to modulation. NS9283 had favourable effects on sensory information processing, as shown by reversal of PCP-disrupted pre-pulse inhibition. NS9283 further improved performance in a rat model of episodic memory (social recognition), a rat model of sustained attention (five-choice serial reaction time task) and a rat model of reference memory (Morris water maze). Importantly, the effects in the Morris water maze could be fully reversed with mecamylamine, a blocker of nACh receptors. CONCLUSIONS AND IMPLICATIONS: These results provide compelling evidence that positive allosteric modulators acting at the (α4)(3) (ß2)(2) nACh receptors can augment activity across a broad range of cognitive domains, and that α4ß2 nACh receptor allosteric modulation therefore constitutes a promising therapeutic approach to symptomatic treatment of cognitive impairment.

The selective alpha7 nicotinic acetylcholine receptor agonist A-582941 activates immediate early genes in limbic regions of the forebrain: Differential effects in the juvenile and adult rat.

Due to the cognitive-enhancing properties of alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists, they have attracted interest for the treatment of cognitive disturbances in schizophrenia. Schizophrenia typically presents in late adolescence or early adulthood. It is therefore important to study whether alpha7 nAChR stimulation activates brain regions involved in cognition in juvenile as well as adult individuals. Here, we compared the effects of the novel and selective alpha7 nAChR agonist 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) in the juvenile and adult rat forebrain using two markers, activity-regulated cytoskeleton-associated protein (Arc) and c-Fos, to map neuronal activity. Acute administration of A-582941 (1, 3, 10 mg/kg) induced a dose-dependent increase in Arc mRNA expression in the medial prefrontal cortex (mPFC) and the ventral/lateral orbitofrontal (VO/LO) cortex of juvenile, but not adult rats. This effect was mitigated by the alpha7 nAChR antagonist methyllycaconitine. A-582941 also increased c-Fos mRNA expression in the mPFC of juvenile, but not adult rats. Furthermore, A-582941 increased the number of Arc and c-Fos immunopositive cells in the mPFC, VO/LO, and shell of the nucleus accumbens, in both juvenile and adult rats. The A-582941-induced c-Fos protein expression was significantly greater in the mPFC and VO/LO of juvenile compared with adult rats. These data indicate that A-582941-induced alpha7 nAChR stimulation activates brain regions critically involved in working memory and attention. Furthermore, this effect is more pronounced in juvenile than adult rats, indicating that the juvenile forebrain is more responsive to alpha7 nAChR stimulation. This observation may be relevant in the treatment of juvenile-onset schizophrenia.

Role of GluR2 expression in AMPA-induced toxicity in cultured murine cerebral cortical neurons.

alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R)-mediated neurotoxicity was studied in relation to subunit expression and the presence of Ca(2+)-permeable receptor channels. AMPA-mediated toxicity had two components: 1) a direct AMPA-R-mediated component, which was not due to Ca(2+) influx through voltage-gated Ca(2+) channels, reversal of the Na(+)/Ca(2+) exchanger or release of calcium from dantrolene-sensitive intracellular Ca(2+) stores, and 2) a minor, indirect component involving activation of NMDA receptor channels, because of glutamate release and removal of the Mg(2+) block of the NMDA receptor on AMPA-R stimulation. The involvement of Ca(2+) influx through AMPA-R was also examined. The number of neurons possessing Ca(2+)-permeable AMPA-R increased during culture development, concurrently with an increasing susceptibility for AMPA-induced toxicity during development. GluR2(R) levels also increased during development, and channel blockers of Ca(2+)-permeable AMPA-R lacking the GluR2(R) subunit (spermine and philanthotoxin) failed to prevent neurotoxicity or increases in [Ca(2+)](i). Thus, the direct AMPA-R-mediated toxicity may be explained by initiation of cell death by Ca(2+) fluxing through AMPA-R containing GluR2(R). The components of direct AMPA-R-mediated toxicity are proposed to be 1) toxicity mediated by GluR2(R)-lacking AMPA-R and 2) toxicity mediated by low-Ca(2+)-permeability AMPA-R containing GluR2(R).

Localization and pharmacological characterization of voltage dependent calcium channels in cultured neocortical neurons.

The physiological significance and subcellular distribution of voltage dependent calcium channels was defined using calcium channel blockers to inhibit potassium induced rises in cytosolic calcium concentration in cultured mouse neocortical neurons. The cytosolic calcium concentration was measured using the fluorescent calcium chelator fura-2. The types of calcium channels present at the synaptic terminal were determined by the inhibitory action of calcium channel blockers on potassium-induced [3H]GABA release in the same cell preparation. L-, N-, P-, Q- and R-/T-type voltage dependent calcium channels were differentially distributed in somata, neurites and nerve terminals. omega-conotoxin MVIIC (omega-CgTx MVIIC) inhibited approximately 40% of the Ca(2+)-rise in both somata and neurites and 60% of the potassium induced [3H]GABA release, indicating that the Q-type channel is the quantitatively most important voltage dependent calcium channel in all parts of the neuron. After treatment with thapsigargin the increase in cytosolic calcium was halved, indicating that calcium release from thapsigargin sensitive intracellular calcium stores is an important component of the potassium induced rise in cytosolic calcium concentration. The results of this investigation demonstrate that pharmacologically distinct types of voltage dependent calcium channels are differentially localized in cell bodies, neurites and nerve terminals of mouse cortical neurons but that the Q-type calcium channel appears to predominate in all compartments.

Effects of 20-min audio-visual stimulation (AVS) at dominant alpha frequency and twice dominant alpha frequency on the cortical EEG.

The effects of audio-visual stimulation at the dominant alpha frequency and twice dominant alpha frequency on the EEG were investigated. An eyes-closed baseline EEG determined each subject's dominant alpha frequency. Subjects were stimulated at their dominant alpha frequency and at twice dominant alpha frequency for 20 min on two occasions. A 30-min post-session eyes-closed EEG was recorded after each session. Power data were analyzed for 19 locations in six bandpasses using repeated-measures ANOVAs and appropriate post-hoc tests. Alpha stimulation significantly increased power over baseline levels in the delta 1, delta 2, theta, beta 1 and beta 2, with significant effects remaining 30 min later in beta 1. Twice alpha stimulation significantly increased theta, beta 1 and beta 2 power over baseline levels, with significant effects remaining 30 min later in theta, alpha, beta 1 and beta 2.

Methylphenidate effects on EEG, behavior, and performance in boys with ADHD.

The psychophysiologic and behavioral effects of methylphenidate were assessed in boys with attention deficit hyperactivity disorder between the ages of 9 and 11 years. The effects of methylphenidate on the EEG during baseline and cognitive tasks were evaluated using spectral analysis. Both subjective (rating scales) and objective (continuous performance) measures were administered and analyzed in conjunction with the electrophysiologic data. Although methylphenidate induced regional changes in the EEG under certain task-specific conditions, it had no global effects. Behavioral and performance measures improved with methylphenidate.