Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knock-out mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

The Effect of Dietary Tartrazine on Brain Dopamine and the Behavioral Symptoms of Attention Deficit Hyperactivity Disorder

Attention Deficit Hyperactivity Disorder is a neurodevelopmental disorder correlated with a decrease in brain dopamine and an increase in behavioral symptoms of hyperactivity and impulsivity. This experiment explored how tartrazine (Yellow #5) impacts these symptoms. After tartrazine administration to Spontaneously Hypertensive Rats (SHR), dopamine concentrations in regions of brain tissue were measured using Enzyme-Linked Immunosorbent Assay analysis. Behavioral testing with a T-maze and open field test measured impulsivity and hyperactivity, respectively. Results indicate that dietary tartrazine increases hyperactive behaviors in the SHR. However, results do not indicate a relationship between dietary tartrazine and brain dopamine. No conclusions regarding the relationship between dietary tartrazine and impulsivity were drawn.

Limiting glutamate transmission in a Vglut2-expressing subpopulation of the subthalamic nucleus is sufficient to cause hyperlocomotion

The subthalamic nucleus (STN) is a key area of the basal ganglia circuitry regulating movement. We identified a subpopulation of neurons within this structure that coexpresses Vglut2 and Pitx2, and by conditional targeting of this subpopulation we reduced Vglut2 expression levels in the STN by 40%, leaving Pitx2 expression intact. This reduction diminished, yet did not eliminate, glutamatergic transmission in the substantia nigra pars reticulata and entopeduncular nucleus, two major targets of the STN. The knock-out mice displayed hyperlocomotion and decreased latency in the initiation of movement while preserving normal gait and balance. Spatial cognition, social function, and level of impulsive choice also remained undisturbed. Furthermore, these mice showed reduced dopamine transporter binding and slower dopamine clearance in vivo, suggesting that Vglut2-expressing cells in the STN regulate dopaminergic transmission. Our results demonstrate that altering the contribution of a limited population within the STN is sufficient to achieve results similar to STN lesions and high-frequency stimulation, but with fewer side effects.

Effects of efficient fronto-temporal circuitry on lexical ambiguity resolution: converging evidence from cross-age comparisons in eye-tracking and ERP data

Eye-tracking was used to examine how younger and older adults use syntactic and semantic information to disambiguate noun/verb (NV) homographs (e.g., park). We find that young adults exhibit inflated first fixations to NV-homographs when only syntactic cues are available for disambiguation (i.e., in syntactic prose). This effect is eliminated with the addition of disambiguating semantic information. Older adults (60+) as a group fail to show the first fixation effect in syntactic prose; they instead reread NV homographs longer. This pattern mirrors that in prior event-related potential work (Lee & Federmeier, 2009, 2011), which reported a sustained frontal negativity to NV-homographs in syntactic prose for young adults, which was eliminated by semantic constraints. The frontal negativity was not observed in older adults as a group, although older adults with high verbal fluency showed the young-like pattern. Analyses of individual differences in eye-tracking patterns revealed a similar effect of verbal fluency in both young and older adults: high verbal fluency groups of both ages show larger first fixation effects, while low verbal fluency groups show larger downstream costs (rereading and/or refixating NV homographs). Jointly, the eye-tracking and ERP data suggest that effortful meaning selection recruits frontal brain areas important for suppressing contextually inappropriate meanings, which also slows eye movements. Efficacy of fronto-temporal circuitry, as captured by verbal fluency, predicts the success of engaging these mechanisms in both young and older adults. Failure to recruit these processes requires compensatory rereading or leads to comprehension failures (Lee & Federmeier, in press).

Asymmetrical processing of olfactory input in the piriform cortex mediates "activation" of the avian navigation circuitry

The role of odors in the long-distance navigation of birds has elicited intense debate for more than half a century. Failure to resolve many of the issues fueling this debate is due at least in part to the absence of controls for a variety of non-specific effects that odors have on the navigational process. The present experiments were carried out to investigate whether the olfactory inputs are involved only in “activation” of neuronal circuitry involved in navigation or are also playing a role in providing directional information. Experienced adult pigeons were exposed to controlled olfactory stimuli during different segments of the journey (release site vs. displacement + release site). Protein levels of IEGs (immediate early genes used to mark synaptic activity) were analyzed in areas within the olfactory/navigation avian circuitry. The results indicate that 1) exposure to natural odors at the release site (and not before) elicit greater activation across brain regions than exposure to filtered air, artificial odors, and natural odors along the entire outward journey (from home to the release site, inclusive); 2) activation of the piriform cortex in terms of odor discrimination is lateralized; 3) activation of the navigation circuitry is achieved by means of lateralized activation of piriform cortex neurons. Altogether, the findings provide the first direct evidence that activation of the avian navigation circuitry is mediated by asymmetrical processing of olfactory input occurring in the right piriform cortex.

Physiological Effects of Alcohol on Crayfish Escape Circuitry

Alcohol is one of the oldest and most widely used drugs on the planet, but the cellular mechanisms by which it affects neural function are still poorly understood. Unlike other drugs of abuse, alcohol has no specific receptor in the nervous system, but is believed to operate through GABAergic and serotonergic neurotransmitter systems. Invertebrate models offer circuits of reduced numerical complexity and involve the same cell types and neurotransmitter systems as vertebrate circuits. The well-understood neural circuits controlling crayfish escape behavior offer neurons that are modulated by GABAergic inhibition, thus making tail-flip circuitry an effective circuit model to study the cellular mechanisms of acute alcohol exposure. Crayfish are capable of two stereotyped, reflexive escape behaviors known as tail-flips that are controlled by two different pairs of giant interneurons, the lateral giants (LG) and the medial giants (MG). The LG circuit has been an established model in the neuroscience field for more than 60 years and is almost completely mapped out. In contrast, the MG is still poorly understood, but has important behavioral implications in social behavior and value-based decision making. In this dissertation, I show that both crayfish tail-flip circuitry are physiologically sensitive to relevant alcohol concentrations and that this sensitivity is observable on the single cell level. I also show that this ethyl alcohol (EtOH) sensitivity in the LG can be changed by altering the crayfish’s recent social experience and by removing descending inputs to the LG. While the MG exhibits similar physiological sensitivity, its inhibitory properties have never been studied before this research. Through the use of electrophysiological and pharmacological techniques, I show that the MG exhibits many similar inhibitory properties as the LG that appear to be the result of GABA-mediated chloride currents. Finally, I present evidence that the EtOH-induced changes in the MG are blocked through pre-treatment of the potent GABAA receptor agonist, muscimol, which underlines the role of GABA in EtOH’s effects on crayfish tail-flip circuitry. The work presented here opens the way for crayfish tail-flip circuitry to be used as an effective model for EtOH’s acute effects on aggression and value-based decision making.

Integrating hardware and software information flow analyses

Security-critical communications devices must be evaluated to the highest possible standards before they can be deployed. This process includes tracing potential information flow through the device's electronic circuitry, for each of the device's operating modes. Increasingly, however, security functionality is being entrusted to embedded software running on microprocessors within such devices, so new strategies are needed for integrating information flow analyses of embedded program code with hardware analyses. Here we show how standard compiler principles can augment high-integrity security evaluations to allow seamless tracing of information flow through both the hardware and software of embedded systems. This is done by unifying input/output statements in embedded program execution paths with the hardware pins they access, and by associating significant software states with corresponding operating modes of the surrounding electronic circuitry.

Self-commutated current source converter with multi-level current reinjection

The multi-level current reinjection concept described in literature is well-known to produce high quality AC current waveforms in high power and high voltage self-commutating current source converters. This paper proposes a novel reinjection circuitry which is capable of producing a 7-level reinjection current. It is shown that this reinjection current effectively increases the pulse number of the converter to 72. The use of PSCAD/EMTDC simulation validates the functionality of the proposed concept illustrating its effectiveness on both AC and DC sides of the converter.

Apparatus for monitoring load bearing rehabilitation exercises of a transfemoral amputee fitted with an osseointegrated fixation : a proof-of-concept study

The purpose of this proof-of-concept study was to determine the relevance of direct measurements to monitor the load applied on the osseointegrated fixation of transfemoral amputees during static load bearing exercises. The objectives were (A) to introduce an apparatus using a three-dimensional load transducer, (B) to present a range of derived information relevant to clinicians, (C) to report on the outcomes of a pilot study and (D) to compare the measurements from the transducer with those from the current method using a weighing scale. One transfemoral amputee fitted with an osseointegrated implant was asked to apply 10 kg, 20 kg, 40 kg and 80 kg on the fixation, using self-monitoring with the weighing scale. The loading was directly measured with a portable kinetic system including a six-channel transducer, external interface circuitry and a laptop. As the load prescribed increased from 10 kg to 80 kg, the forces and moments applied on and around the antero-posterior axis increased by 4 fold anteriorly and 14 fold medially, respectively. The forces and moments applied on and around the medio-lateral axis increased by 9 fold laterally and 16 fold from anterior to posterior, respectively. The long axis of the fixation was overloaded and underloaded in 17 % and 83 % of the trials, respectively, by up to ±10 %. This proof-of-concept study presents an apparatus that can be used by clinicians facing the challenge of improving basic knowledge on osseointegration, for the design of equipment for load bearing exercises and for rehabilitation programs.

Mechanisms of change in negative thinking and urinary monoamines in depressed patients during acute treatment with group cognitive behavior therapy and antidepressant medication

This naturalistic study investigated the mechanisms of change in measures of negative thinking and in 24-h urinary metabolites of noradrenaline (norepinephrine), dopamine and serotonin in a sample of 43 depressed hospital patients attending an eight-session group cognitive behavior therapy program. Most participants (91%) were taking antidepressant medication throughout the therapy period according to their treating Psychiatrists' prescriptions. The sample was divided into outcome categories (19 Responders and 24 Non-responders) on the basis of a clinically reliable change index [Jacobson, N.S., & Truax, P., 1991. Clinical significance: a statistical approach to defining meaningful change in psychotherapy research. Journal of Consulting and Clinical Psychology, 59, 12–19.] applied to the Beck Depression Inventory scores at the end of the therapy. Results of repeated measures analysis of variance [ANOVA] analyses of variance indicated that all measures of negative thinking improved significantly during therapy, and significantly more so in the Responders as expected. The treatment had a significant impact on urinary adrenaline and metadrenaline excretion however, these changes occurred in both Responders and Non-responders. Acute treatment did not significantly influence the six other monoamine metabolites. In summary, changes in urinary monoamine levels during combined treatment for depression were not associated with self-reported changes in mood symptoms.

A preliminary investigation of the role of the Phenylalynine: Tyrosine Ratio in children with early and continuously treated phenylketonuria : toward identification of “safe” levels

Children with early and continuously treated phenylketonuria (ECT-PKU) remain at risk of developing executive function (EF) deficits. There is some evidence that a high phenylalanine to tyrosine ratio (phe:tyr) is more strongly associated with impaired EF development than high phenylalanine alone. This study examined EF in a sample of 11 adolescents against concurrent and historical levels of phenylalanine, phe:tyr, and tyrosine. Lifetime measures of phe:tyr were more strongly associated with EF than phenylalanine-only measures. Children with a lifetime phe:tyr less than 6 demonstrated normal EF, whereas children who had a lifetime phe:tyr above 6, on average, demonstrated clinically impaired EF.

Artful determination : "state of the art" and PCME Ltd v. Goyen COntrols Co. UK Ltd

In a recent decision by Mr Justice Laddie, a patent was held anticipated by, inter alia, prior use of a device which fell within the claims of the patent in suit, even though its circuitry was enclosed in resin. The anticipating invention had been "made available to the public" within the terms of section 2 (2) of the Patents Act 1977 because its essential integers would have been revealed by an interesting character, the "skilled forensic engineer".

Design and evaluation of a prototype tracking system

In this paper, we present the design and construction of a prototype target tracking system. The experimental set up consists of three main modules for moving the object, detecting the motion of the object and its tracking. The mechanism for moving the object includes an object and two stepper motors and their driving and control circuitry. The detection of the object’s motion is realized by photo switch array. The tracking mechanism consists of a laser beam and two DC servomotors and their associated circuitry. The control algorithm is a standard fuzzy logic controller. The system is designed to operate in two modes in such a way that the role of target and tracker can be interchanged. Experimental results indicate that the fuzzy controller is capable of controlling the system in both modes.

Tyrosine monitoring in children with early and continuously treated phenylketonuria: Results of an international practice survey

Investigations into the biochemical markers associated with executive function (EF) impairment in children with early and continuously treated phenylketonuria (ECT-PKU) remain largely phenylalanine-only focused, despite experimental data showing that a high phenylalanine:tyrosine (phe:tyr) ratio is more strongly associated with EF deficit than phe alone. A high phe:tyr ratio is hypothesized to lead to a reduction in dopamine synthesis within the brain, which in turn results in the development of EF impairment. This paper provides a snapshot of current practice in the monitoring and/or treatment of tyrosine levels in children with PKU, across 12 countries from Australasia, North America and Europe. Tyrosine monitoring in this population has increased over the last 5 years, with over 80% of clinics surveyed reporting routine monitoring of tyrosine levels in infancy alongside phe levels. Twenty-five percent of clinics surveyed reported actively treating/managing tyrosine levels (with supplemental tyrosine above that contained in PKU formulas) to ensure tyrosine levels remain within normal ranges. Anecdotally, supplemental tyrosine has been reported to ameliorate symptoms of both attention deficit hyperactivity disorder and depression in this population. EF assessment of children with ECT-PKU was likewise highly variable, with 50% of clinics surveyed reporting routine assessments of intellectual function. However when function was assessed, test instruments chosen tended towards global measures of IQ prior to school entry, rather than specific assessment of EF development. Further investigation of the role of tyrosine and its relationship with phe and EF development is needed to establish whether routine tyrosine monitoring and increased supplementation is recommended.

A DRD2 polymorphism predicts PANSS score variability in schizophrenia patients treated with antipsychotics

Antipsychotic medications act as either antagonists or partial agonists of the dopamine D2 receptor (DRD2) and antipsychotic drugs vary widely in their binding affinity for the D2 receptor (Kapur and Seeman, 2000). The DRD2 957CNT (rs6277) polymorphism has previously been associated with schizophrenia (Lawford et al., 2005) and the T-allele of the 957CNT polymorphism is associated with reduced mRNA stability and synthesis of the dopamine D2 receptor (Duan et al., 2003). The aim of the study was to determine if the rs6277 polymorphism predicts some of the variability of positive and negative symptoms observed in schizophrenia patients being treated with antipsychotic medication.