Clinical features of psychotic disorders and polymorphisms in HT2A, DRD2, DRD4, SLC6A3 (DAT1), and BDNF:a family based association study

Schizophrenia is clinically heterogeneous and multidimensional, but it is not known whether this is due to etiological heterogeneity. Previous studies have not consistently reported association between any specific polymorphisms and clinical features of schizophrenia, and have primarily used case-control designs. We tested for the presence of association between clinical features and polymorphisms in the genes for the serotonin 2A receptor (HT2A), dopamine receptor types 2 and 4, dopamine transporter (SLC6A3), and brain-derived neurotrophic factor (BDNF). Two hundred seventy pedigrees were ascertained on the basis of having two or more members with schizophrenia or poor outcome schizoaffective disorder. Diagnoses were made using a structured interview based on the SCID. All patients were rated on the major symptoms of schizophrenia scale (MSSS), integrating clinical and course features throughout the course of illness. Factor analysis revealed positive, negative, and affective symptom factors. The program QTDT was used to implement a family-based test of association for quantitative traits, controlling for age and sex. We found suggestive evidence of association between the His452Tyr polymorphism in HT2A and affective symptoms (P = 0.02), the 172-bp allele of BDNF and negative symptoms (P = 0.04), and the 480-bp allele in SLC6A3 (= DAT1) and negative symptoms (P = 0.04). As total of 19 alleles were tested, we cannot rule out false positives. However, given prior evidence of involvement of the proteins encoded by these genes in psychopathology, our results suggest that more attention should be focused on the impact of these alleles on clinical features of schizophrenia.

A systematic review and meta-analysis of the ethnic density effect in psychotic disorders

A number of studies have found an ethnic density effect in psychotic disorders, where the incidence for ethnic minorities increases as the neighbourhood proportional ethnic composition decreases [Morgan and Hutchinson, Psychol Med 40:705-709, (2010); Singh, Psychol Med 39:1402-1403, (2009); Schofield et al., Psychol Med 41:1263-1269, (2010)]. However, there is a mixed picture with some studies reporting no effect [Schofield et al., Psychol Med 41:1263-1269, (2010)]. This review aimed to establish the existence of the effect by answering the review question: is there an ethnic density dose effect in the prevalence of psychotic disorders?

Auditory gist: Recognition of very short sounds from timbre cues

Sounds such as the voice or musical instruments can be recognized on the basis of timbre alone. Here, sound recognition was investigated with severely reduced timbre cues. Short snippets of naturally recorded sounds were extracted from a large corpus. Listeners were asked to report a target category (e.g., sung voices) among other sounds (e.g., musical instruments). All sound categories covered the same pitch range, so the task had to be solved on timbre cues alone. The minimum duration for which performance was above chance was found to be short, on the order of a few milliseconds, with the best performance for voice targets. Performance was independent of pitch and was maintained when stimuli contained less than a full waveform cycle. Recognition was not generally better when the sound snippets were time-aligned with the sound onset compared to when they were extracted with a random starting time. Finally, performance did not depend on feedback or training, suggesting that the cues used by listeners in the artificial gating task were similar to those relevant for longer, more familiar sounds. The results show that timbre cues for sound recognition are available at a variety of time scales, including very short ones.

Task-switching deficits and repetitive behaviour in genetic neurodevelopmental disorders: Data from children with Prader-Willi syndrome chromosome 15 q11-q13 deletion and boys with Fragile X syndrome

Prader-Willi syndrome (PWS) and Fragile X syndrome (FraX) are associated with distinctive cognitive and behavioural profiles. We examined whether repetitive behaviours in the two syndromes were associated with deficits in specific executive functions. PWS, FraX, and typically developing (TD) children were assessed for executive functioning using the Test of Everyday Attention for Children and an adapted Simon spatial interference task. Relative to the TD children, children with PWS and FraX showed greater costs of attention switching on the Simon task, but after controlling for intellectual ability, these switching deficits were only significant in the PWS group. Children with PWS and FraX also showed significantly increased preference for routine and differing profiles of other specific types of repetitive behaviours. A measure of switch cost from the Simon task was positively correlated to scores on preference for routine questionnaire items and was strongly associated with scores on other items relating to a preference for predictability. It is proposed that a deficit in attention switching is a component of the endophenotypes of both PWS and FraX and is associated with specific behaviours. This proposal is discussed in the context of neurocognitive pathways between genes and behaviour.

Auditory observation of stepping actions can cue both spatial and temporal components of gait in Parkinson's disease patients

Objectives: A common behavioural symptom of Parkinson’s disease (PD) is reduced step length (SL). Whilst sensory cueing strategies can be effective in increasing SL and reducing gait variability, current cueing strategies conveying spatial or temporal information are generally confined to the use of either visual or auditory cue modalities, respectively. We describe a novel cueing strategy using ecologically-valid ‘action-related’ sounds (footsteps on gravel) that convey both spatial and temporal parameters of a specific action within a single cue.
Methods: The current study used a real-time imitation task to examine whether PD affects the ability to re-enact changes in spatial characteristics of stepping actions, based solely on auditory information. In a second experimental session, these procedures were repeated using synthesized sounds derived from recordings of the kinetic interactions between the foot and walking surface. A third experimental session examined whether adaptations observed when participants walked to action-sounds were preserved when participants imagined either real recorded or synthesized sounds.
Results: Whilst healthy control participants were able to re-enact significant changes in SL in all cue conditions, these adaptations, in conjunction with reduced variability of SL were only observed in the PD group when walking to, or imagining the recorded sounds.
Conclusions: The findings show that while recordings of stepping sounds convey action information to allow PD patients to re-enact and imagine spatial characteristics of gait, synthesis of sounds purely from gait kinetics is insufficient to evoke similar changes in behaviour, perhaps indicating that PD patients have a higher threshold to cue sensorimotor resonant responses.

Variants in the 1q21 risk region are associated with a visual endophenotype of autism and schizophrenia

Deficits in sensitivity to visual stimuli of low spatial frequency and high temporal frequency (so-called frequency-doubled gratings) have been demonstrated both in schizophrenia and in autism spectrum disorder (ASD). Such basic perceptual functions are ideal candidates for molecular genetic study, because the underlying neural mechanisms are well characterized; but they have sometimes been overlooked in favor of cognitive and neurophysiological endophenotypes, for which neural substrates are often unknown. Here, we report a genome-wide association study of a basic visual endophenotype associated with psychological disorder. Sensitivity to frequency-doubled gratings was measured in 1060 healthy young adults, and analyzed for association with genotype using linear regression at 642758 single nucleotide polymorphism (SNP) markers. A significant association (P=7.9×10) was found with the SNP marker rs1797052, situated in the 5′-untranslated region of PDZK1; each additional copy of the minor allele was associated with an increase in sensitivity equivalent to more than half a standard deviation. A permutation procedure, which accounts for multiple testing, showed that the association was significant at the α=0.005 level. The region on chromosome 1q21.1 surrounding PDZK1 is an established susceptibility locus both for schizophrenia and for ASD, mirroring the common association of the visual endophenotype with the two disorders. PDZK1 interacts with N-methyl-d-aspartate receptors and neuroligins, which have been implicated in the etiologies of schizophrenia and ASD. These findings suggest that perceptual abnormalities observed in two different disorders may be linked by common genetic elements. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Processing of short auditory stimuli:The rapid audio sequential presentation paradigm (RASP)

Human listeners seem to be remarkably able to recognise acoustic sound sources based on timbre cues. Here we describe a psychophysical paradigm to estimate the time it takes to recognise a set of complex sounds differing only in timbre cues: both in terms of the minimum duration of the sounds and the inferred neural processing time. Listeners had to respond to the human voice while ignoring a set of distractors. All sounds were recorded from natural sources over the same pitch range and equalised to the same duration and power. In a first experiment, stimuli were gated in time with a raised-cosine window of variable duration and random onset time. A voice/non-voice (yes/no) task was used. Performance, as measured by d', remained above chance for the shortest sounds tested (2 ms); d's above 1 were observed for durations longer than or equal to 8 ms. Then, we constructed sequences of short sounds presented in rapid succession. Listeners were asked to report the presence of a single voice token that could occur at a random position within the sequence. This method is analogous to the "rapid sequential visual presentation" paradigm (RSVP), which has been used to evaluate neural processing time for images. For 500-ms sequences made of 32-ms and 16-ms sounds, d' remained above chance for presentation rates of up to 30 sounds per second. There was no effect of the pitch relation between successive sounds: identical for all sounds in the sequence or random for each sound. This implies that the task was not determined by streaming or forward masking, as both phenomena would predict better performance for the random pitch condition. Overall, the recognition of familiar sound categories such as the voice seems to be surprisingly fast, both in terms of the acoustic duration required and of the underlying neural time constants.

Representations of specific acoustic patterns in the auditory cortex and hippocampus

Previous behavioural studies have shown that repeated presentation of a randomly chosen acoustic pattern leads to the unsupervised learning of some of its specific acoustic features. The objective of our study was to determine the neural substrate for the representation of freshly learnt acoustic patterns. Subjects first performed a behavioural task that resulted in the incidental learning of three different noise-like acoustic patterns. During subsequent high-resolution functional magnetic resonance imaging scanning, subjects were then exposed again to these three learnt patterns and to others that had not been learned. Multi-voxel pattern analysis was used to test if the learnt acoustic patterns could be 'decoded' from the patterns of activity in the auditory cortex and medial temporal lobe. We found that activity in planum temporale and the hippocampus reliably distinguished between the learnt acoustic patterns. Our results demonstrate that these structures are involved in the neural representation of specific acoustic patterns after they have been learnt.

Evidence-based management and intervention for autism spectrum disorders

Autism Spectrum Disorder (ASD) is diagnosed along a continuum of behavioural variants in social communication and repetitive behaviours [96]. Most individuals on the autism spectrum also experience differences in sensory perception. Some individuals on the spectrum are ‘high-functioning’ and able to cope in every day environments, while others are severely affected, non-verbal, and may have co-occurring diagnoses, such as intellectual disability, epilepsy, and/or obsessional, conduct, or mental health disorders. These individuals require substantial support, caring and careful management, and evidence-based, effective interventions.