Lost in Time: Temporal Monitoring Elicits Clinical Decrements in Sustained Attention Post-Stroke.

OBJECTIVES: Mental fatigue, 'brain fog', and difficulties maintaining engagement are commonly reported issues in a range of neurological and psychiatric conditions. Traditional sustained attention tasks commonly measure this capacity as the ability to detect target stimuli based on sensory features in the auditory or visual domains. However, with this approach, discrete target stimuli may exogenously capture attention to aid detection, thereby masking deficits in the ability to endogenously sustain attention over time. METHODS: To address this, we developed the Continuous Temporal Expectancy Task (CTET) where individuals continuously monitor a stream of patterned stimuli alternating at a fixed temporal interval (690 ms) and detect an infrequently occurring target stimulus defined by a prolonged temporal duration (1020 ms or longer). As such, sensory properties of target and non-target stimuli are perceptually identical and differ only in temporal duration. Using the CTET, we assessed stroke survivors with unilateral right hemisphere damage (N = 14), a cohort in which sustained attention deficits have been extensively reported. RESULTS: Stroke survivors had overall lower target detection accuracy compared with neurologically healthy age-matched older controls (N = 18). Critically, stroke survivors performance was characterised by significantly steeper within-block performance decrements, which occurred within short temporal windows (˜3 ½ min), and were restored by the break periods between blocks. CONCLUSIONS: These findings suggest that continuous temporal monitoring taxes sustained attention processes to capture clinical deficits in this capacity over time, and outline a precise measure of the endogenous processes hypothesised to underpin sustained attention deficits following right hemisphere stroke.

The application of human pluripotent stem cells to model the neuronal and glial components of neurodevelopmental disorders.

Cellular models of neurodevelopmental disorders provide a valuable experimental system to uncover disease mechanisms and novel therapeutic strategies. The ability of induced pluripotent stem cells (iPSCs) to generate diverse brain cell types offers great potential to model several neurodevelopmental disorders. Further patient-derived iPSCs have the unique genetic and molecular signature of the affected individuals, which allows researchers to address limitations of transgenic behavioural models, as well as generate hypothesis-driven models to study disorder-relevant phenotypes at a cellular level. In this article, we review the extant literature that has used iPSC-based modelling to understand the neuronal and glial contributions to neurodevelopmental disorders including autism spectrum disorder (ASD), Rett syndrome, bipolar disorder (BP), and schizophrenia. For instance, several molecular candidates have been shown to influence cellular phenotypes in three-dimensional iPSC-based models of ASD patients. Delays in differentiation of astrocytes and morphological changes of neurons are associated with Rett syndrome. In the case of bipolar disorders and schizophrenia, patient-derived models helped to identify cellular phenotypes associated with neuronal deficits (e.g., excitability) and mutation-specific abnormalities in oligodendrocytes (e.g., CSPG4). Further we provide a critical review of the current limitations of this field and provide methodological suggestions to enhance future modelling efforts of neurodevelopmental disorders. Future developments in experimental design and methodology of disease modelling represent an exciting new avenue relevant to neurodevelopmental disorders.

Rare DNA variants in the brain-derived neurotrophic factor gene increase risk for attention-deficit hyperactivity disorder: a next-generation sequencing study.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent and highly heritable disorder of childhood with negative lifetime outcomes. Although candidate gene and genome-wide association studies have identified promising common variant signals, these explain only a fraction of the heritability of ADHD. The observation that rare structural variants confer substantial risk to psychiatric disorders suggests that rare variants might explain a portion of the missing heritability for ADHD. Here we believe we performed the first large-scale next-generation targeted sequencing study of ADHD in 152 child and adolescent cases and 188 controls across an a priori set of 117 genes. A multi-marker gene-level analysis of rare (<1% frequency) single-nucleotide variants (SNVs) revealed that the gene encoding brain-derived neurotrophic factor (BDNF) was associated with ADHD at Bonferroni corrected levels. Sanger sequencing confirmed the existence of all novel rare BDNF variants. Our results implicate BDNF as a genetic risk factor for ADHD, potentially by virtue of its critical role in neurodevelopment and synaptic plasticity.

Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.

The molecular genetic architecture of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common childhood behavioral condition which affects 2-10% of school age children worldwide. Although the underlying molecular mechanism for the disorder is poorly understood, familial, twin and adoption studies suggest a strong genetic component. Here we provide a state-of-the-art review of the molecular genetics of ADHD incorporating evidence from candidate gene and linkage designs, as well as genome-wide association (GWA) studies of common single-nucleotide polymorphisms (SNPs) and rare copy number variations (CNVs). Bioinformatic methods such as functional enrichment analysis and protein-protein network analysis are used to highlight biological processes of likely relevance to the aetiology of ADHD. Candidate gene associations of minor effect size have been replicated across a number of genes including SLC6A3, DRD5, DRD4, SLC6A4, LPHN3, SNAP-25, HTR1B, NOS1 and GIT1. Although case-control SNP-GWAS have had limited success in identifying common genetic variants for ADHD that surpass critical significance thresholds, quantitative trait designs suggest promising associations with Cadherin13 and glucose-fructose oxidoreductase domain 1 genes. Further, CNVs mapped to glutamate receptor genes (GRM1, GRM5, GRM7 and GRM8) have been implicated in the aetiology of the disorder and overlap with bioinformatic predictions based on ADHD GWAS SNP data regarding enriched pathways. Although increases in sample size across multi-center cohorts will likely yield important new results, we advocate that this must occur in parallel with a shift away from categorical case-control approaches that view ADHD as a unitary construct, towards dimensional approaches that incorporate endophenotypes and statistical classification methods.

Alpha-2A adrenergic receptor gene variants are associated with increased intra-individual variability in response time.

Intra-individual variability in response time has been proposed as an important endophenotype for attention deficit hyperactivity disorder (ADHD). Here we asked whether intra-individual variability is predicted by common variation in catecholamine genes and whether it mediates the relationship between these gene variants and self-reported ADHD symptoms. A total of 402 non-clinical Australian adults of European descent completed a battery of five cognitive tasks and the Conners' Adult ADHD Rating Scale. Exclusion criteria included the presence of major psychiatric or neurologic illnesses and substance dependency. A total of 21 subjects were excluded due to incomplete data or poor quality cognitive or genotyping data. The final sample comprised 381 subjects (201 males; mean age=21.2 years, s.d.=5.1 years). Principal components analysis on variability measures yielded two factors (response selection variability vs selective attention variability). Association of these factors with catecholamine gene variants was tested using single-step linear regressions, with multiple comparisons controlled using permutation analysis. The response selection variability factor was associated with two ADRA2A single-nucleotide polymorphisms (SNPs) (rs1800544, rs602618), p corrected=0.004, 0.012, respectively, whereas the selective attention variability factor was associated with a TH SNP (rs3842727), p corrected=0.024. A bootstrapping analysis indicated that the response selection variability factor mediated the relationship between the ADRA2A SNP rs1800544 and self-reported ADHD symptoms. Thus this study finds evidence that DNA variation in the ADRA2A gene may be causally related to ADHD-like behaviors, in part through its influence on intra-individual variability. Evidence was also found for a novel association between a TH gene variant and intra-individual variability.

Neurodevelopmental and neuropsychiatric disorders represent an interconnected molecular system.

Many putative genetic factors that confer risk to neurodevelopmental disorders such as autism spectrum disorders (ASDs) and X-linked intellectual disability (XLID), and to neuropsychiatric disorders including attention deficit hyperactivity disorder (ADHD) and schizophrenia (SZ) have been identified in individuals from diverse human populations. Although there is significant aetiological heterogeneity within and between these conditions, recent data show that genetic factors contribute to their comorbidity. Many studies have identified candidate gene associations for these mental health disorders, albeit this is often done in a piecemeal fashion with little regard to the inherent molecular complexity. Here, we sought to abstract relationships from our knowledge of systems level biology to help understand the unique and common genetic drivers of these conditions. We undertook a global and systematic approach to build and integrate available data in gene networks associated with ASDs, XLID, ADHD and SZ. Complex network concepts and computational methods were used to investigate whether candidate genes associated with these conditions were related through mechanisms of gene regulation, functional protein-protein interactions, transcription factor (TF) and microRNA (miRNA) binding sites. Although our analyses show that genetic variations associated with the four disorders can occur in the same molecular pathways and functional domains, including synaptic transmission, there are patterns of variation that define significant differences between disorders. Of particular interest is DNA variations located in intergenic regions that comprise regulatory sites for TFs or miRNA. Our approach provides a hypothetical framework, which will help discovery and analysis of candidate genes associated with neurodevelopmental and neuropsychiatric disorders.

Dopamine transporter genotype predicts behavioural and neural measures of response inhibition.

The ability to inhibit unwanted actions is a heritable executive function that may confer risk to disorders such as attention deficit hyperactivity disorder (ADHD). Converging evidence from pharmacology and cognitive neuroscience suggests that response inhibition is instantiated within frontostriatal circuits of the brain with patterns of activity that are modulated by the catecholamines dopamine and noradrenaline. A total of 405 healthy adult participants performed the stop-signal task, a paradigmatic measure of response inhibition that yields an index of the latency of inhibition, termed the stop-signal reaction time (SSRT). Using this phenotype, we tested for genetic association, performing high-density single-nucleotide polymorphism mapping across the full range of autosomal catecholamine genes. Fifty participants also underwent functional magnetic resonance imaging to establish the impact of associated alleles on brain and behaviour. Allelic variation in polymorphisms of the dopamine transporter gene (SLC6A3: rs37020; rs460000) predicted individual differences in SSRT, after corrections for multiple comparisons. Furthermore, activity in frontal regions (anterior frontal, superior frontal and superior medial gyri) and caudate varied additively with the T-allele of rs37020. The influence of genetic variation in SLC6A3 on the development of frontostriatal inhibition networks may represent a key risk mechanism for disorders of behavioural inhibition.

Loss of insight in frontotemporal dementia, corticobasal degeneration and progressive supranuclear palsy.

Loss of insight is one of the core features of frontal/behavioural variant frontotemporal dementia (FTD). FTD shares many clinical and pathological features with corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP). The aim of this study was to investigate awareness of cognitive deficits in FTD, CBD and PSP using a multidimensional approach to assessment, which examines metacognitive knowledge of the disorders, online monitoring of errors (emergent awareness) and ability to accurately predict performance on future tasks (anticipatory awareness). Thirty-five patients (14 FTD, 11 CBD and 10 PSP) and 20 controls were recruited. Results indicated that loss of insight was a feature of each of the three patient groups. FTD patients were most impaired on online monitoring of errors compared to the other two patient groups. Linear regression analysis demonstrated that different patterns of neuropsychological performance and behavioural rating scores predicted insight deficits across the three putative awareness categories. Furthermore, higher levels of depression were associated with poor anticipatory awareness, reduced empathy was related to impaired metacognitive awareness and impaired recognition of emotional expression in faces was associated with both metacognitive and anticipatory awareness deficits. The results are discussed in terms of neurocognitive models of awareness and different patterns of neurobiological decline in the separate patient groups.

Visuospatial memory deficits in adolescent onset schizophrenia.

Visuospatial memory encoding deficits have been reported in adults with schizophrenia, while adolescents with schizophrenia have not been specifically investigated with visuospatial memory encoding and retrieval paradigms. A cross sectional study of delayed matching-to-sample performance in 19 right handed, male, anti-psychotic medication naïve adolescents with undifferentiated schizophrenia and 28 age, gender, IQ and handedness matched healthy participants was completed. The adolescent-onset schizophrenia group demonstrated significant impairment in visuospatial memory, independent of the degree of delay, consistent with an encoding impairment. The impaired encoding phase of visuospatial memory in the adolescent-onset schizophrenia group is consistent with findings in adult onset schizophrenia samples, suggesting a developmental stage-independent deficit.

Visuospatial working memory deficits in adolescent onset schizophrenia.

This study determines that visuospatial working memory (VSWM) deficits are evident in adolescent-onset schizophrenia, while the spatial strategy and spatial span components of VSWM are spared. These findings imply that frontal-striatal-parietal neural networks are dysfunctional in adolescent-onset schizophrenia, while mid-dorsolateral and ventrolateral PFC functions remain intact: the current conceptualisation of schizophrenia as a progressive neurodevelopmental disorder is consistent with these results.

Response programming in dementia of the Alzheimer type: a kinematic analysis.

Although planning is important for the functioning of patients with dementia of the Alzheimer Type (DAT), little is known about response programming in DAT. This study used a cueing paradigm coupled with quantitative kinematic analysis to document the preparation and execution of movements made by a group of 12 DAT patients and their age and sex matched controls. Participants connected a series of targets placed upon a WACOM SD420 graphics tablet, in response to the pattern of illumination of a set of light emitting diodes (LEDs). In one condition, participants could programme the upcoming movement, whilst in another they were forced to reprogramme this movement on-line (i.e. they were not provided with advance information about the location of the upcoming target). DAT patients were found to have programming deficits, taking longer to initiate movements, particularly in the absence of cues. While problems spontaneously programming a movement might cause a greater reliance upon on-line guidance, when both groups were required to guide the movement on-line, DAT patients continued to show slower and less efficient movements implying declining sensori-motor function; these differences were not simply due to strategy or medication status.

Response (re-)programming in aging: a kinematic analysis.

BACKGROUND: Age-related motor slowing may reflect either motor programming deficits, poorer movement execution, or mere strategic preferences for online guidance of movement. We controlled such preferences, limiting the extent to which movements could be programmed. METHODS: Twenty-four young and 24 older adults performed a line drawing task that allowed movements to be prepared in advance in one case (i.e., cue initially available indicating target location) and not in another (i.e., no cue initially available as to target location). Participants connected large or small targets illuminated by light-emitting diodes upon a graphics tablet that sampled pen tip position at 200 Hz. RESULTS: Older adults had a disproportionate difficulty initiating movement when prevented from programming in advance. Older adults produced slower, less efficient movements, particularly when prevented from programming under greater precision requirements. CONCLUSIONS: The slower movements of older adults do not simply reflect a preference for online control, as older adults have less efficient movements when forced to reprogram their movements. Age-related motor slowing kinematically resembles that seen in patients with cerebellar dysfunction.

Human amygdala volume is predicted by common DNA variation in the stathmin and serotonin transporter genes.

Despite the relevance of changes in amygdala volume to psychiatric illnesses and its heritability in both health and disease, the influence of common genetic variation on amygdala morphology remains largely unexplored. In the present study, we investigated the influence of a number of novel genetic variants on amygdala volume in 139 neurologically healthy individuals of European descent. Amygdala volume was significantly associated with allelic variation in the stathmin (STMN1) and serotonin transporter (SLC6A4) genes, which have been linked to healthy and disordered affective processing. These results were replicated across both manual and automated methods of amygdala parcellation, although manual tracing showed stronger effects, providing a cautionary note to studies relying on automated parcellation methods. Future studies will need to determine whether amygdala volume mediates the impact of stathmin and serotonin transporter gene variants on normal and dysfunctional emotion processing.

Right parietal dysfunction in children with attention deficit hyperactivity disorder, combined type: a functional MRI study.

Attention deficit hyperactivity disorder, combined type (ADHD-CT) is associated with spatial working memory deficits. These deficits are known to be subserved by dysfunction of neural circuits involving right prefrontal, striatal and parietal brain regions. This study determines whether decreased right prefrontal, striatal and parietal activation with a mental rotation task shown in adolescents with ADHD-CT is also evident in children with ADHD-CT. A cross-sectional study of 12 pre-pubertal, right-handed, 8-12-year-old boys with ADHD-CT and 12 pre-pubertal, right-handed, performance IQ-matched, 8-12-year-old healthy boys, recruited from local primary schools, was completed. Participants underwent functional magnetic resonance imaging while performing a mental rotation task that requires spatial working memory. The two groups did not differ in their accuracy or response times for the mental rotation task. The ADHD-CT group showed significantly less activation in right parieto-occipital areas (cuneus and precuneus, BA 19), the right inferior parietal lobe (BA 40) and the right caudate nucleus. Our findings with a child cohort confirm previous reports of right striatal-parietal dysfunction in adolescents with ADHD-CT. This dysfunction suggests a widespread maturational deficit that may be developmental stage independent.

Dopaminergic genotype biases spatial attention in healthy children.

In everyday life, our sensory system is bombarded with visual input and we rely upon attention to select only those inputs that are relevant to behavioural goals. Typically, humans can shift their attention from one visual field to the other with little cost to perception. In cases of 'unilateral neglect', however, there is a persistent bias of spatial attention towards the same side as the damaged cerebral hemisphere. We used a visual orienting task to examine the influence of functional polymorphisms of the dopamine transporter gene (DAT1) on individual differences in spatial attention in normally developing children. DAT1 genotype significantly influenced spatial bias. Healthy children who were homozygous for alleles that influence the expression of dopamine transporters in the brain displayed inattention for left-sided stimuli, whereas heterozygotes did not. Our data provide the first evidence in healthy individuals of a genetically mediated bias in spatial attention that is related to dopamine signalling.

Response selection deficits in melancholic but not nonmelancholic unipolar major depression.

One consistent functional imaging finding from patients with major depression has been abnormality of the anterior cingulate cortex (ACC). Hypoperfusion has been most commonly reported, but some studies suggest relative hyperperfusion is associated with response to somatic treatments. Despite these indications of the possible importance of the ACC in depression there have been relatively few cognitive studies ACC function in patients with major depression. The present study employed a series of reaction time (RT) tasks involving selection with melancholic and nonmelancholic depressed patients, as well as age-matched controls. Fifteen patients with unipolar major depression (7 melancholic, 8 nonmelancholic) and 8 healthy age-matched controls performed a series of response selection tasks (choice RT, spatial Stroop, spatial stimulus-response compatibility (SRC), and a combined Stroop + SRC condition). Reaction time and error data were collected. Melancholic patients were significantly slower than controls on all tasks but were slower than nonmelancholic patients only on the Stroop and Stroop + SRC conditions. Nonmelancholic patients did not differ from the control group on any task. The Stroop task seems crucial in differentiating the two depressive groups, they did not differ on the choice RT or SRC tasks. This may reflect differential task demands, the SRC involved symbolic manipulation that might engage the dorsal ACC and dorsolateral prefrontal cortex (DLPFC) to a greater extent than the, primarily inhibitory, Stroop task which may engage the ventral ACC and orbitofrontal cortex (OFC). This might suggest the melancholic group showed a greater ventral ACC-OFC deficit than the nonmelancholic group, while both groups showed similar dorsal ACC-DLPFC deficit.

Bimanual coordination in chronic schizophrenia.

Anomalies of movement are observed both clinically and experimentally in schizophrenia. While the basal ganglia have been implicated in its pathogenesis, the nature of such involvement is equivocal. The basal ganglia may be involved in bimanual coordination through their input to the supplementary motor area (SMA). While a neglected area of study in schizophrenia, a bimanual movement task may provide a means of assessing the functional integrity of the motor circuit. Twelve patients with chronic schizophrenia and 12 matched control participants performed a bimanual movement task on a set of vertically mounted cranks at different speeds (1 and 2 Hz) and phase relationships. Participants performed in-phase movements (hands separated by 0 degrees ) and out-of-phase movements (hands separated by 180 degrees ) at both speeds with an external cue on or off. All participants performed the in-phase movements well, irrespective of speed or cueing conditions. Patients with schizophrenia were unable to perform the out-of-phase movements, particularly at the faster speed, reverting instead to the in-phase movement. There was no effect of external cueing on any of the movement conditions. These results suggest a specific problem of bimanual coordination indicative of SMA dysfunction per se and/or faulty callosal integration. A disturbance in the ability to switch attention during the out-of-phase task may also be involved.