The substantia Nigra pars compacta and temporal processing

The basal ganglia and cerebellum are considered to play a role in timing, although their differential roles in timing remain unclear. It has been proposed that the timing of short milliseconds-range intervals involves the cerebellum, whereas longer seconds-range intervals engage the basal ganglia (Ivry, 1996). We tested this hypothesis using positron emission tomography to measure regional cerebral blood flow in eight right-handed males during estimation and reproduction of long and short intervals. Subjects performed three tasks: (1) reproduction of a short 500 ms interval, (2) reproduction of a long 2 s interval, and (3) a control simple reaction time (RT) task. We compared the two time reproduction tasks with the control RT task to investigate activity associated with temporal processing once additional cognitive, motor, or sensory processing was controlled. We found foci in the left substantia nigra and the left lateral premotor cortex to be significantly more activated in the time reproduction tasks than the control RT task. The left caudate nucleus and right cerebellum were more active in the short relative to the long interval, whereas greater activation of the right putamen and right cerebellum occurred in the long rather than the short interval. These results suggest that the basal ganglia and the cerebellum are engaged by reproduction of both long and short intervals but play different roles. The fundamental role of the substantia nigra in temporal processing is discussed in relation to previous animal lesion studies and evidence for the modulating influence of dopamine on temporal processing

The neuropsychology and functional anatomy of timing.

This thesis explores the neural correlates of motor and perceptual timing. Motor timing involves the production of a timed movement (e.g. dancing), whereas perceptual timing requires a perceptual judgement (e.g. deciding which of two events lasted longer). A body of research has investigated this type of timing, concentrating on millisecond- and seconds-range intervals. Patients with Parkinson's disease (PD) and cerebellar pathology exhibit motor and perceptual timing deficits, which has led to the suggestion that both the basal ganglia and cerebellum are involved in this type of temporal processing. The research presented here uses a variety of techniques (functional imaging, transcranial magnetic stimulation (rTMS) and clinical studies on patients) to investigate the contribution of different neural structures to temporal processing. Using positron emission tomography (PET), the basal ganglia and cerebellum were both found to be active during millisecond- and seconds-range timing. However, only the basal ganglia were active when non-temporal aspects of the task were controlled for. At the cortical level, rTMS was used to show that the right dorsolateral prefrontal cortex was essential to the reproduction of seconds-range intervals, possibly due to a role in memory processes. In a further study, the motor and perceptual timing performance of patients with PD was modulated by dopaminergic medication, with medication improving performance. Patients with cerebellar disease displayed increased variability in timing tasks that included a significant motor component, but did not show impaired accuracy. A second PET study, comparing patients with PD and healthy controls, showed that the basal ganglia were active during motor timing for the control group. Compared to their medicated state, the patients showed decreased coupling between the basal ganglia and dorsolateral prefrontal cortex when 'off' medication. These studies support the notion that the basal ganglia, and not the cerebellum, play a fundamental role in motor and perceptual timing

Defining the cognitive phenotype of autism

Although much progress has been made in determining the cognitive profile of strengths and weaknesses that characterise individuals with autism spectrum disorders (ASDs), there remain a number of outstanding questions. These include how universal strengths and deficits are; whether cognitive subgroups exist; and how cognition is associated with core autistic behaviours, as well as associated psychopathology. Several methodological factors have contributed to these limitations in our knowledge, including: small sample sizes, a focus on single domains of cognition, and an absence of comprehensive behavioural phenotypic information. To attempt to overcome some of these limitations, we assessed a wide range of cognitive domains in a large sample (N = 100) of 14- to 16-year-old adolescents with ASDs who had been rigorously behaviourally characterised. In this review, we will use examples of some initial findings in the domains of perceptual processing, emotion processing and memory, both to outline different approaches we have taken to data analysis and to highlight the considerable challenges to better defining the cognitive phenotype(s) of ASDs. Enhanced knowledge of the cognitive phenotype may contribute to our understanding of the complex links between genes, brain and behaviour, as well as inform approaches to remediation

Effect of a novel penetration enhancer on the ungual permeation of two antifungal agents

The definitive version can be found at: http://www3.interscience.wiley.com/ Copyright Royal Pharmaceutical Society of Great Britain.Objectives The aim of this study was to demonstrate the effect of a novel permeation enhancer system using two existing marketed nail lacquers and the delivery of terbinafine through human nail samples in vitro. Methods Initially a modified Franz cell was used, where sections of human nail serve as the barrier through which drug penetrates into an agar-filled chamber infected with dermatophytes. A second study was performed using a novel infected nail model where dermatophytes are incubated with and grow into human nail and ATP levels are used as biological marker for antimicrobial activity. Key findings The novel permeation enhancing system increased the permeation of both existing drugs formulated in nail lacquers and terbinafine through human nail sections mounted in a modified Franz cell. Furthermore the ATP assay confirmed that the system also enhanced the permeation of terbinafine through infected cadaver nail resulting in a decrease in ATP levels equivalent to those of uninfected negative control samples. Conclusions This study has clearly demonstrated that the use of a novel permeation enhancing system, which fundamentally alters the chemical structure of the nail, not only enhances the efficacy of the existing topical formulations but also enables the delivery and efficacy of terbinafine when applied ungually. Such a topically applied system has the possibility of overcoming the systemic side effects when terbinafine is delivered orally.Peer reviewe

Overcoming the nail barrier : A systematic investigation of ungual chemical penetration enhancement

Original article can be found at: http://www.sciencedirect.com/science/journal/03785173 Copyright Elsevier B.V. DOI: 10.1016/j.ijpharm.2008.11.009This study investigated the in vitro nail permeability of penetrants of varying lipophilicity—caffeine (CF, log P −0.07), methylparaben (MP, log P 1.96) and terbinafine (TBF, log P 3.3) and the effect of 2 novel penetration enhancers (PEs), thioglycolic acid (TA) and urea hydrogen peroxide (urea H2O2) on their permeation. Studies were conducted using full thickness human nail clippings and ChubTur® diffusion cells and penetrants were applied as saturated solutions. The rank order of steady-state penetrant flux throughnails without PE application(MP > CF > TBF) suggesteda greater sensitivity to penetrant molecular weight rather than log P. TA increased the flux of CF and MP ∼4- and ∼2-fold, respectively, whilst urea H2O2 proved ineffective at enhancing permeability. The sequential application of TA followed by urea H2O2 increased TBF and CF flux (∼19- and ∼4-fold, respectively) but reversing the application order of the PEs was only mildly effective at increasing just MP flux (∼2-fold). Both nail PEs are likely to function via disruption of keratin disulphide bonds and the associated formation of pores that provide more ‘open’ drug transport channels. Effects of the PEs were penetrant specific, but the use of a reducing agent (TA) followed by an oxidising agent (urea H2O2) dramatically improved human nail penetration.Peer reviewe

Alexithymia in Adolescents with Autism Spectrum Disorder: Its Relationship to Internalising Difficulties, Sensory Modulation and Social Cognition

Alexithymia is a personality trait frequently found in adults with autism spectrum disorder (ASD), and has been linked to impairments in emotion recognition and empathy. The presentation of alexithymia within ASD at younger ages remains unexplored, and was examined in the present study. Alexithymia rates were significantly elevated in ASD (55 %; 31/56 scoring above cut-off) versus non-ASD adolescents (16 %; 5/32 scoring above cut-off). Within individuals with ASD, alexithymia was associated with increased self-reported anxiety, parent-reported emotional difficulties, self-reported sensory processing atypicalities, and poorer emotion recognition, but was not associated with theory of mind ability. Overall, our results suggest that alexithymia is highly prevalent, and has selective cognitive correlates in young people with ASD