Drug therapies for attentional disorders alter the signal-to-noise ratio in the superior colliculus

Despite high levels of use, the mechanism of action of effective pharmacotherapies in attention deficit hyperactivity disorder (ADHD) is unknown. It has recently been hypothesized that one site of therapeutic action is the midbrain superior colliculus, a structure traditionally associated with visual processing, but also strongly implicated in distractibility, a core symptom of ADHD. We used male juvenile Wistar rats to examine the effects of therapeutically relevant doses of methylphenidate and d-amphetamine on collicular activity in vitro. Here we report a novel shared mechanism of the two drugs whereby they enhance the signal-to-noise ratio in the superior colliculus. The effects on the signal-to-noise ratio were mediated by serotonin (5-HT) via a pre-synaptic mechanism. This modulatory action would bias the system towards salient events and lead to an overall decrease in distractibility

On the action potential as a propagating density pulse and the role of anesthetics

The Hodgkin-Huxley model of nerve pulse propagation relies on ion currents through specific resistors called ion channels. We discuss a number of classical thermodynamic findings on nerves that are not contained in this classical theory. Particularly striking is the finding of reversible heat changes, thickness and phase changes of the membrane during the action potential. Data on various nerves rather suggest that a reversible density pulse accompanies the action potential of nerves. Here, we attempted to explain these phenomena by propagating solitons that depend on the presence of cooperative phase transitions in the nerve membrane. These transitions are, however, strongly influenced by the presence of anesthetics. Therefore, the thermodynamic theory of nerve pulses suggests a explanation for the famous Meyer-Overton rule that states that the critical anesthetic dose is linearly related to the solubility of the drug in the membranes.Comment: 13 pages, 8 figure

Attention-deficit hyperactivity disorder-like traits and distractibility in the visual periphery

We examined the performance of non-clinical subjects with high and low levels of self-reported ADHD-like traits in a novel distractibility paradigm with far peripheral visual distractors, the likely origin of many distractors in everyday life. Subjects were tested on a Sustained Attention to Response Task with distractors appearing before some of the target/non-target stimuli. When the distractors appeared 80 ms before the targets/non-targets, participants with high levels of ADHD-like traits were less affected in their reaction times than those with lower levels. Reducing the distractor-target/non-target interval to 10 ms removed the reaction time advantage for the high group. We suggest that at 80 ms the distractors were cueing the arrival of the target/non-target and that those with high levels of ADHD-like traits were more sensitive to the cues. Increased sensitivity to stimuli in the visual periphery is consistent with hyper-responsiveness at the level of the superior colliculus

Altered visual processing in a rodent model of Attention-Deficit Hyperactivity Disorder

A central component of Attention-Deficit Hyperactivity Disorder (ADHD) is increased distractibility, which is linked to the superior colliculus (SC) in a range of species, including humans. Furthermore, there is now mounting evidence of altered collicular functioning in ADHD and it is proposed that a hyper-responsive SC could mediate the main symptoms of ADHD, including distractibility. In the present study we have provided a systematic characterization of the SC in the most commonly used and well-validated animal model of ADHD, the spontaneously hypertensive rat (SHR). We examined collicular-dependent orienting behavior, local field potential (LFP) and multiunit responses to visual stimuli in the anesthetized rat and morphological measures in the SHR in comparison to the Wistar Kyoto (WKY) and Wistar (WIS). We found that SHRs remain responsive to a repeated visual stimulus for more presentations than control strains and have a longer response duration. In addition, LFP and multiunit activity within the visually responsive superficial layers of the SC showed the SHR to have a hyper-responsive SC relative to control strains, which could not be explained by altered functioning of the retinocollicular pathway. Finally, examination of collicular volume, neuron and glia densities and glia:neuron ratio revealed that the SHR had a reduced ratio relative to the WKY which could explain the increased responsiveness. In conclusion, this study demonstrates strain-specific changes in the functioning and structure of the SC in the SHR, providing convergent evidence that the SC might be dysfunctional in ADHD

Increased microsaccade rate in individuals with ADHD traits

Microsaccades are involuntary, small, jerk-like eye-movements with high-velocity that are observed during fixation. Abnormal microsaccade rates and characteristics have been observed in a number of psychiatric and developmental disorders. In this study, we examine microsaccade differences in 43 non-clinical participants with high and low levels of ADHD-like traits, assessed with the Adult ADHD Self-Report Scale (ASRS, Kessler, Adler, et al., 2005). A simple sustained attention paradigm, which has been previously shown to elicit microsaccades, was employed. A positive correlation was found between ADHD-like traits and binocular and monocular microsaccade rates. No other differences in microsaccade properties were observed. The relationship between ADHD traits and microsaccades suggests that abnormal oculomotor behaviour is a core deficit in ADHD and could potentially lead to the development of a biomarker for the disorder

The design and performance of an improved target for MICE

The linear motor driving the target for the Muon Ionisation Cooling Experiment has been redesigned to improve its reliability and performance. A new coil-winding technique is described which produces better magnetic alignment and improves heat transport out of the windings. Improved field-mapping has allowed the more precise construction to be demonstrated, and an enhanced controller exploits the full features of the hardware, enabling increased acceleration and precision. The new user interface is described and analysis of performance data to monitor friction is shown to allow quality control of bearings and a measure of the ageing of targets during use

A Self-Consistent Model for Positronium Formation from Helium Atoms

The differential and total cross sections for electron capture by positrons from helium atoms are calculated using a first-order distorted wave theory satisfying the Coulomb boundary conditions. In this formalism a parametric potential is used to describe the electron screening in a consistent and realistic manner. The present procedure is self consistent because (i) it satisfies the correct boundary conditions and post-prior symmetry, and (ii) the potential and the electron binding energies appearing in the transition amplitude are consistent with the wave functions describing the collision system. The results are compared with the other theories and with the available experimental measurements. At the considered range of collision energies, the results agree reasonably well with recent experiments and theories. [Note: This paper will be published on volume 42 of the Brazilian Journal of Physics

Azi-isoflurane, a Photolabel Analog of the Commonly Used Inhaled General Anesthetic Isoflurane

Volatility and low-affinity hamper an ability to define molecular targets of the inhaled anesthetics. Photolabels have proven to be a useful approach in this regard, although none have closely mimicked contemporary drugs. We report here the synthesis and validation of azi-isoflurane, a compound constructed by adding a diazirinyl moiety to the methyl carbon of the commonly used general anesthetic isoflurane. Azi-isoflurane is slightly more hydrophobic than isoflurane, and more potent in tadpoles. This novel compound inhibits Shaw2 K(+) channel currents similarly to isoflurane and binds to apoferritin with enhanced affinity. Finally, when irradiated at 300 nm, azi-isoflurane adducts to residues known to line isoflurane-binding sites in apoferritin and integrin LFA-1, the only proteins with isoflurane binding sites defined by crystallography. This reagent should allow rapid discovery of isoflurane molecular targets and binding sites within those targets