Temporal discrimination: Mechanisms and relevance to adult-onset dystonia

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test-retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis

Pdxdc1 modulates prepulse inhibition of acoustic startle in the mouse.

Current antipsychotic medications used to treat schizophrenia all target the dopamine D2 receptor. Although these drugs have serious side effects and limited efficacy, no novel molecular targets for schizophrenia treatment have been successfully translated into new medications. To identify novel potential treatment targets for schizophrenia, we searched for previously unknown molecular modulators of acoustic prepulse inhibition (PPI), a schizophrenia endophenotype, in the mouse. We examined six inbred mouse strains that have a range of PPI, and used microarrays to determine which mRNA levels correlated with PPI across these mouse strains. We examined several brain regions involved in PPI and schizophrenia: hippocampus, striatum, and brainstem, found a number of transcripts that showed good correlation with PPI level, and confirmed this with real-time quantitative PCR. We then selected one candidate gene for further study, Pdxdc1 (pyridoxal-dependent decarboxylase domain containing 1), because it is a putative enzyme that could metabolize catecholamine neurotransmitters, and thus might be a feasible target for new medications. We determined that Pdxdc1 mRNA and protein are both strongly expressed in the hippocampus and levels of Pdxdc1 are inversely correlated with PPI across the six mouse strains. Using shRNA packaged in a lentiviral vector, we suppressed Pdxdc1 protein levels in the hippocampus and increased PPI by 70%. Our results suggest that Pdxdc1 may regulate PPI and could be a good target for further investigation as a potential treatment for schizophrenia

Reduced face identity aftereffects in relatives of children with autism.

Autism is a pervasive developmental condition with complex aetiology. To aid the discovery of genetic mechanisms, researchers have turned towards identifying potential endophenotypes - subtle neurobiological or neurocognitive traits present in individuals with autism and their "unaffected" relatives. Previous research has shown that relatives of individuals with autism exhibit face processing atypicalities, which are similar in nature albeit of lesser degree, to those found in children and adults with autism. Yet very few studies have examined the underlying mechanisms responsible for such atypicalities. Here, we investigated whether atypicalities in adaptive norm-based coding of faces are present in relatives of children with autism, similar to those previously reported in children with autism. To test this possibility, we administered a face identity aftereffect task in which adaptation to a particular face biases perception towards the opposite identity, so that a previously neutral face (i.e., the average face) takes on the computationally opposite identity. Parents and siblings of individuals with autism showed smaller aftereffects compared to parents and siblings of typically developing children, especially so when the adapting stimuli were located further away from the average face. In addition, both groups showed stronger aftereffects for adaptors far from the average than for adaptors closer to the average. These results suggest that, in relatives of children with autism, face-coding mechanism are similar (i.e., norm-based) but less efficient than in relatives of typical children. This finding points towards the possibility that diminished adaptive mechanisms might represent a neurocognitive endophenotype for autism

Seasonal changes in brain serotonin transporter binding in short 5-HTTLPR-allele carriers but not in long-allele homozygotes

Several findings suggest seasonal variations in the serotonin (5-HT) system. We sought evidence for seasonal variation in the serotonin transporter (5-HTT). We found that length of daylight time in minutes correlates negatively with 5-HTT binding in the putamen and the caudate, with a similar tendency in the thalamus, but no such association in the midbrain. In the putamen, an anatomical region with a dense serotonin innervation that is implicated in processing of aversive stimuli, we found a significant gene*daylight effect with a negative correlation between the 5-HTT binding and daylight time in carriers of the short 5-HTTLPR allele, but not in carriers of the long allele. The neurobiological endophenotype identified here directly links activation studies, showing responses on the neural circuit level, with dynamic changes in transporter expression measured in vivo

Self-reported interoceptive deficits in eating disorders: A meta-analysis of studies using the eating disorder inventory

This document is the Accepted Manuscript version of the following article: Paul M. Jenkinson, Lauren Taylor, Keith R. Laws, ‘Self-reported interoceptive deficits in eating disorders: A meta-analysis of studies using the eating disorder inventory’, Journal of Psychosomatic Research, Vol. 110: 38-45, July 2018, under embargo until 19 April 2019. The Version of Record is available online at DOI: https://doi.org/10.1016/j.jpsychores.2018.04.005Objective: An impairment of the ability to sense the physiological condition of the body – interoception – has long been proposed as central to the onset and maintenance of eating disorders. More recent attention to this topic has generally indicated the presence of interoceptive deficits in individuals with an eating disorder diagnosis; however, possible links with specific diagnosis, BMI, age, illness duration, depression, and alexithymia remain unclear from individual studies. This meta-analysis aimed to provide a necessary quantitative overview of self-reported interoceptive deficits in eating disorder populations, and the relationship between these deficits and the previously mentioned factors. Methods: Using a random effects model, our meta-analysis assessed the magnitude of differences in interoceptive abilities as measured using the Eating Disorder Inventory in 41 samples comparing people with eating disorders (n=4308) and healthy controls (n=3459). Follow-up and moderator analysis was conducted, using group comparisons and meta-regressions. Results: We report a large pooled effect size of 1.62 for eating disorders with some variation between diagnostic groups. Further moderator analysis showed that BMI, age and alexithymia were significant predictors of overall effect size. Conclusion: This meta-analysis is the first to confirm that large interoceptive deficits occur in a variety of eating disorders and crucially, in those who have recovered. These deficits may be useful in identifying and distinguishing eating disorders. Future research needs to consider both objective and subjective measures of interoception across different types of eating disorders and may fruitfully examine interoception as a possible endophenotype and target for treatment.Peer reviewe

Integrating cognitive (neuro)science using mechanisms

In this paper, an account of theoretical integration in cognitive (neuro)science from the mechanistic perspective is defended. It is argued that mechanistic patterns of integration can be better understood in terms of constraints on representations of mechanisms, not just on the space of possible mechanisms, as previous accounts of integration had it. This way, integration can be analyzed in more detail with the help of constraintsatisfaction account of coherence between scientific representations. In particular, the account has resources to talk of idealizations and research heuristics employed by researchers to combine separate results and theoretical frameworks. The account is subsequently applied to an example of successful integration in the research on hippocampus and memory, and to a failure of integration in the research on mirror neurons as purportedly explanatory of sexual orientation

Assessment of Metabolic Parameters For Autism Spectrum Disorders

Autism is a brain development disorder that first appears during infancy or childhood, and generally follows a steady course without remission. Impairments result from maturation-related changes in various systems of the brain. Autism is one of the five pervasive developmental disorders (PDD), which are characterized by widespread abnormalities of social interactions and communication, and severely restricted interests and highly repetitive behavior. The reported incidence of autism spectrum disorders (ASDs) has increased markedly over the past decade. The Centre for Disease Control and Prevention has recently estimated the prevalence of ASDs in the United States at approximately 5.6 per 1000 (1 of 155 to 1 of 160) children. Several metabolic defects, such as phenylketonuria, are associated with autistic symptoms. In deciding upon the appropriate evaluation scheme a clinician must consider a host of different factors. The guidelines in this article have been developed to assist the clinician in the consideration of these factors

Transcriptome-Wide Association Supplements Genome-Wide Association in Zea mays.

Modern improvement of complex traits in agricultural species relies on successful associations of heritable molecular variation with observable phenotypes. Historically, this pursuit has primarily been based on easily measurable genetic markers. The recent advent of new technologies allows assaying and quantifying biological intermediates (hereafter endophenotypes) which are now readily measurable at a large scale across diverse individuals. The usefulness of endophenotypes for delineating the regulatory landscape of the genome and genetic dissection of complex trait variation remains underexplored in plants. The work presented here illustrated the utility of a large-scale (299-genotype and seven-tissue) gene expression resource to dissect traits across multiple levels of biological organization. Using single-tissue- and multi-tissue-based transcriptome-wide association studies (TWAS), we revealed that about half of the functional variation acts through altered transcript abundance for maize kernel traits, including 30 grain carotenoid abundance traits, 20 grain tocochromanol abundance traits, and 22 field-measured agronomic traits. Comparing the efficacy of TWAS with genome-wide association studies (GWAS) and an ensemble approach that combines both GWAS and TWAS, we demonstrated that results of TWAS in combination with GWAS increase the power to detect known genes and aid in prioritizing likely causal genes. Using a variance partitioning approach in the largely independent maize Nested Association Mapping (NAM) population, we also showed that the most strongly associated genes identified by combining GWAS and TWAS explain more heritable variance for a majority of traits than the heritability captured by the random genes and the genes identified by GWAS or TWAS alone. This not only improves the ability to link genes to phenotypes, but also highlights the phenotypic consequences of regulatory variation in plants

Disrupted working memory circuitry and psychotic symptoms in 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11DS) is a recurrent genetic mutation that is highly penetrant for psychosis. Behavioral research suggests that 22q11DS patients exhibit a characteristic neurocognitive phenotype that includes differential impairment in spatial working memory (WM). Notably, spatial WM has also been proposed as an endophenotype for idiopathic psychotic disorder, yet little is known about the neurobiological substrates of WM in 22q11DS. In order to investigate the neural systems engaged during spatial WM in 22q11DS patients, we collected functional magnetic resonance imaging (fMRI) data while 41 participants (16 22q11DS patients, 25 demographically matched controls) performed a spatial capacity WM task that included manipulations of delay length and load level. Relative to controls, 22q11DS patients showed reduced neural activation during task performance in the intraparietal sulcus (IPS) and superior frontal sulcus (SFS). In addition, the typical increases in neural activity within spatial WM-relevant regions with greater memory load were not observed in 22q11DS. We further investigated whether neural dysfunction during WM was associated with behavioral WM performance, assessed via the University of Maryland letter-number sequencing (LNS) task, and positive psychotic symptoms, assessed via the Structured Interview for Prodromal Syndromes (SIPS), in 22q11DS patients. WM load activity within IPS and SFS was positively correlated with LNS task performance; moreover, WM load activity within IPS was inversely correlated with the severity of unusual thought content and delusional ideas, indicating that decreased recruitment of working memory-associated neural circuitry is associated with more severe positive symptoms. These results suggest that 22q11DS patients show reduced neural recruitment of brain regions critical for spatial WM function, which may be related to characteristic behavioral manifestations of the disorder

Error-related brain activity as a transdiagnostic endophenotype for obsessive-compulsive disorder, anxiety and substance use disorder

Background Increased neural error-signals have been observed in obsessive-compulsive disorder (OCD), anxiety disorders, and inconsistently in depression. Reduced neural error-signals have been observed in substance use disorders (SUD). Thus, alterations in error-monitoring are proposed as a transdiagnostic endophenotype. To strengthen this notion, data from unaffected individuals with a family history for the respective disorders are needed. Methods The error-related negativity (ERN) as a neural indicator of error-monitoring was measured during a flanker task from 117 OCD patients, 50 unaffected first-degree relatives of OCD patients, and 130 healthy comparison participants. Family history information indicated, that 76 healthy controls were free of a family history for psychopathology, whereas the remaining had first-degree relatives with depression (n = 28), anxiety (n = 27), and/or SUD (n = 27). Results Increased ERN amplitudes were found in OCD patients and unaffected first-degree relatives of OCD patients. In addition, unaffected first-degree relatives of individuals with anxiety disorders were also characterized by increased ERN amplitudes, whereas relatives of individuals with SUD showed reduced amplitudes. Conclusions Alterations in neural error-signals in unaffected first-degree relatives with a family history of OCD, anxiety, or SUD support the utility of the ERN as a transdiagnostic endophenotype. Reduced neural error-signals may indicate vulnerability for under-controlled behavior and risk for substance use, whereas a harm- or error-avoidant response style and vulnerability for OCD and anxiety appears to be associated with increased ERN. This adds to findings suggesting a common neurobiological substrate across psychiatric disorders involving the anterior cingulate cortex and deficits in cognitive control