Intraindividual variability (IIV) in an animal model of ADHD - the Spontaneously Hypertensive Rat

Attention-deficit/hyperactivity disorder (ADHD) is characterized by numerous behaviors including inattention, hyperactivity and impulsiveness. ADHD-affected individuals also have high intra-individual variability (IIV) in reaction time. The genetic control of IIV is not well understood. The single study of the genetics of this phenomenon in humans detected only marginal associations between genotypes at two candidate genes for ADHD and variability in response time. The Spontaneously Hypertensive Rat (SHR/NCrl) is an animal model of ADHD, expressing high activity, inattention and impulsive behavior during operant and task tests. The SHR might be useful for identifying genes for variability, but it is not known whether it also expresses high IIV, as is symptomatic of ADHD. We therefore conducted an investigation of IIV in the SHR. We used 16 SHR/NCrl rats and 15 Wistar-Kyoto (WKY/Nico) controls applying a reinforcement schedule used in the validation of the SHR as an animal model of ADHD. We represented IIV as the average absolute deviation of individual behavior within the five 18-min segments of each experimental session from the average behavioral trait value within that session ('individual phenotypic dispersion', PDi). PDi for hyperactivity, impulsiveness and inattention in the SHR and WKY rats was analyzed using nonparametric ranking by experimental session. SHR/NCrl rats had higher PDi than WKY/Nico controls for impulsiveness and inattention. There was a significant upward trend for PDi over experimental segments within sessions for attention in SHR rats, but not in WKY. PDi for hyperactivity was correlated with PDi for impulsiveness and we therefore excluded observations associated with short IRTs (< 0.67s); dispersion in hyperactivity outside this interval was also significantly higher in SHR rats than in WKY rats. Some studies indicate the sharing of symptoms of hyperactivity and impulsiveness in SHR and ADHD-affected humans; high IIV in operant behavioral metrics suggests that the SHR may be useful in elucidating the genetic basis for IIV in humans

COMT Val158Met polymorphism, cognitive stability and cognitive flexibility: an experimental examination

<p>Abstract</p> <p>Background</p> <p>Dopamine in prefrontal cortex (PFC) modulates core cognitive processes, notably working memory and executive control. Dopamine regulating genes and polymorphisms affecting PFC - including Catechol-O-Methyltransferase (COMT) Val158Met - are crucial to understanding the molecular genetics of cognitive function and dysfunction. A mechanistic account of the COMT Val158Met effect associates the Met allele with increased tonic dopamine transmission underlying maintenance of relevant information, and the Val allele with increased phasic dopamine transmission underlying the flexibility of updating new information. Thus, consistent with some earlier work, we predicted that Val carriers would display poorer performance when the maintenance component was taxed, while Met carriers would be less efficient when rapid updating was required.</p> <p>Methods</p> <p>Using a Stroop task that manipulated level of required cognitive stability and flexibility, we examined reaction time performance of patients with schizophrenia (n = 67) and healthy controls (n = 186) genotyped for the Val/Met variation.</p> <p>Results</p> <p>In both groups we found a Met advantage for tasks requiring cognitive stability, but no COMT effect when a moderate level of cognitive flexibility was required, or when a conflict cost measure was calculated.</p> <p>Conclusions</p> <p>Our results do not support a simple stability/flexibility model of dopamine COMT Val/Met effects and suggest a somewhat different conceptualization and experimental operationalization of these cognitive components.</p

No association of COMT with insight problem solving in Chinese college students

Genes involved in dopamine (DA) neurotransmission, such as the catechol-O-methyltransferase gene (COMT), have been suggested as key genetic candidates that might underlie the genetic basis of insight. In a sample of Chinese college students, this study examined whether COMT was associated with individual differences in the ability to solve classic insight problems. The results demonstrated that COMT was not associated with insight problem solving and there was no gender-dependent effect. This study, together with previous studies, raises the possibility of a complex relationship between COMT and insight problem solving

Genetic Contributions to Age-Related Decline in Executive Function: A 10-Year Longitudinal Study of COMT and BDNF Polymorphisms

Genetic variability in the dopaminergic and neurotrophic systems could contribute to age-related impairments in executive control and memory function. In this study we examined whether genetic polymorphisms for catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) were related to the trajectory of cognitive decline occurring over a 10-year period in older adults. A single nucleotide polymorphism in the COMT (Val158/108Met) gene affects the concentration of dopamine in the prefrontal cortex. In addition, a Val/Met substitution in the pro-domain for BDNF (Val66Met) affects the regulated secretion and trafficking of BDNF with Met carriers showing reduced secretion and poorer cognitive function. We found that impairments over the 10-year span on a task-switching paradigm did not vary as a function of the COMT polymorphism. However, for the BDNF polymorphism the Met carriers performed worse than Val homozygotes at the first testing session but only the Val homozygotes demonstrated a significant reduction in performance over the 10-year span. Our results argue that the COMT polymorphism does not affect the trajectory of age-related executive control decline, whereas the Val/Val polymorphism for BDNF may promote faster rates of cognitive decay in old age. These results are discussed in relation to the role of BDNF in senescence and the transforming impact of the Met allele on cognitive function in old age

Startle response related genes

The startle reaction (also known as the startle response, the startle reflex, or the alarm reaction) is the psychological and physiological response to a sudden unexpected stimulus, such as a flash of light, a loud noise (acoustic startle reflex), or a quick movement near the face. Abnormalities of startle response have been observed in many stress-related mental disorders, such as schizophrenia and post-traumatic stress disorder (PTSD). However, the molecular mechanisms of startle in stress-associated conditions – for example, whether the startle reaction is associated with any gene variance – is still unknown. In this paper, we will carry out a systematic review by retrieving, assessing, and combining, when applicable, individual studies investigating association of the molecular variation of candidate gene with the startle response. The systematic review is based on the search for numerous publications using the keywords ‘‘startle gene’’ on September 15, 2010 using PubMed, which comprises more than 20 million citations for biomedical literature from MEDLINE and life science journals. A total of 486 publications regarding genes associated with startle have been obtained and reviewed here. There are fewer than 20 publications associating genes with the startle response between 1979, when the first valuable paper was published, and 1999. However, publications have dramatically increase from 2001 and reaches over 70 in 2009. We have characterized them into three categories: startle-associated gene studies in humans, in animals, as well as in both human and animals. This review of research strategy may provide the information for identifying a biomarker for startle response, with the objective of translating research into clinical utility: diagnosis and treatment of stress-induced mental disorders

Parkinson's disease and dopaminergic therapy—differential effects on movement, reward and cognition

Cognitive deficits are very common in Parkinson's disease particularly for ‘executive functions’ associated with frontal cortico-striatal networks. Previous work has identified deficits in tasks that require attentional control like task-switching, and reward-based tasks like gambling or reversal learning. However, there is a complex relationship between the specific cognitive problems faced by an individual patient, their stage of disease and dopaminergic treatment. We used a bimodality continuous performance task during fMRI to examine how patients with Parkinson's disease represent the prospect of reward and switch between competing task rules accordingly. The task-switch was not separately cued but was based on the implicit reward relevance of spatial and verbal dimensions of successive compound stimuli. Nineteen patients were studied in relative ‘on’ and ‘off’ states, induced by dopaminergic medication withdrawal (Hoehn and Yahr stages 1–4). Patients were able to successfully complete the task and establish a bias to one or other dimension in order to gain reward. However the lateral prefrontal cortex and caudate nucleus showed a non-linear U-shape relationship between motor disease severity and regional brain activation. Dopaminergic treatment led to a shift in this U-shape function, supporting the hypothesis of differential neurodegeneration in separate motor and cognitive cortico–striato–thalamo–cortical circuits. In addition, anterior cingulate activation associated with reward expectation declined with more severe disease, whereas activation following actual rewards increased with more severe disease. This may facilitate a change in goal-directed behaviours from deferred predicted rewards to immediate actual rewards, particularly when on dopaminergic treatment. We discuss the implications for investigation and optimal treatment of this common condition at different stages of disease

Physiological Signal Variability in hMT+ Reflects Performance on a Direction Discrimination Task

Our ability to perceive visual motion is critically dependent on the human motion complex (hMT+) in the dorsal visual stream. Extensive electrophysiological research in the monkey equivalent of this region has demonstrated how neuronal populations code for properties such as speed and direction, and that neurometric functions relate to psychometric functions within the individual monkey. In humans, the physiological correlates of inter-individual perceptual differences are still largely unknown. To address this question, we used functional magnetic resonance imaging (fMRI) while participants viewed translational motion in different directions, and we measured thresholds for direction discrimination of moving stimuli in a separate psychophysics experiment. After determining hMT+ in each participant with a functional localizer, we were able to decode the different directions of visual motion from it using pattern classification (PC). We also characterized the variability of fMRI signal in hMT+ during stimulus and rest periods with a generative model. Relating perceptual performance to physiology, individual direction discrimination thresholds were significantly correlated with the variability measure in hMT+, but not with PC accuracies. Individual differences in PC accuracy were driven by non-physiological noise like head-movement, which makes this method a poor tool to investigate inter-individual differences. In contrast, variability analysis of the fMRI signal was robust to non-physiological noise, and variability characteristics in hMT+ correlated with psychophysical thresholds in the individual participants. Higher levels of fMRI signal variability compared to rest correlated with lower discrimination thresholds. This result is in line with theories on stochastic resonance in the context of neuronal populations, which suggest that endogenous or exogenous noise can increase the sensitivity of neuronal populations to incoming signals

Aging and risk taking: toward an integration of cognitive, emotional, and neurobiological perspectives

In this article, we characterize the relationship between natural aging and risky decision making through an integration of cognitive, emotional, and neurobiological theories on the effects of natural aging. Based on the existing evidence, we propose that the positivity emotional bias in elderly adults steers them away from taking high risks and toward more conservative approaches during decision making as part of their positive emotional regulatory strategies. However, aging is also associated with marked declines in cognitive functioning, such as attention and working memory, as well as impaired reinforcement-based associative learning, which arises from anatomical and functional declines in the dopaminergic transmission systems and in distinct brain regions such as the dorsolateral prefrontal cortex and hippocampus. In consequence, elderly adults may deviate from their usual conservative stance and toward more risk-taking tendencies, as observed in a subset of studies, if the demands of the risk-taking task exceed their cognitive and learning capacities. More empirical investigations are needed to determine the key factors that influence elderly individuals' decision making and behavior in risky situations. Research in this field is likely to have important practical implications for the financial and medical decision making of elderly adults, as well as promoting designated help targeting the elderly population in making important life decisions.published_or_final_versio

Understanding space by moving through it: neural networks of motion- and space processing in humans

Humans explore the world by moving in it, whether moving their whole body as during walking or driving a car, or moving their arm to explore the immediate environment. During movement, self-motion cues arise from the sensorimotor system comprising vestibular, proprioceptive, visual and motor cues, which provide information about direction and speed of the movement. Such cues allow the body to keep track of its location while it moves through space. Sensorimotor signals providing self-motion information can therefore serve as a source for spatial processing in the brain. This thesis is an inquiry into human brain systems of movement and motion processing in a number of different sensory and motor modalities using functional magnetic resonance imaging (fMRI). By characterizing connections between these systems and the spatial representation system in the brain, this thesis investigated how humans understand space by moving through it. In the first study of this thesis, the recollection networks of whole-body movement were explored. Brain activation was measured during the retrieval of active and passive self-motion and retrieval of observing another person performing these tasks. Primary sensorimotor areas dominated the recollection network of active movement, while higher association areas in parietal and mid-occipital cortex were recruited during the recollection of passive transport. Common to both self-motion conditions were bilateral activations in the posterior medial temporal lobe (MTL). No MTL activations were observed during recollection of movement observation. Considering that on a behavioral level, both active and passive self-motion provide sufficient information for spatial estimations, the common activation in MTL might represent the common physiological substrate for such estimations. The second study investigated processing in the 'parahippocampal place area' (PPA), a region in the posterior MTL, during haptic exploration of spatial layout. The PPA in known to respond strongly to visuo-spatial layout. The study explored if this region is processing visuo-spatial layout specifically or spatial layout in general, independent from the encoding sensory modality. In both a cohort of sighted and blind participants, activation patterns in PPA were measured while participants haptically explored the spatial layout of model scenes or the shape of information-matched objects. Both in sighted and blind individuals, PPA activity was greater during layout exploration than during object-shape exploration. While PPA activity in the sighted could also be caused by a transformation of haptic information into a mental visual image of the layout, two points speak against this: Firstly, no increase in connectivity between the visual cortex and the PPA were observed, which would be expected if visual imagery took place. Secondly, blind participates, who cannot resort to visual imagery, showed the same pattern of PPA activity. Together, these results suggest that the PPA processes spatial layout information independent from the encoding modality. The third and last study addressed error accumulation in motion processing on different levels of the visual system. Using novel analysis methods of fMRI data, possible links between physiological properties in hMT+ and V1 and inter-individual differences in perceptual performance were explored. A correlation between noise characteristics and performance score was found in hMT+ but not V1. Better performance correlated with greater signal variability in hMT+. Though neurophysiological variability is traditionally seen as detrimental for behavioral accuracy, the results of this thesis contribute to the increasing evidence which suggests the opposite: that more efficient processing under certain circumstances can be related to more noise in neurophysiological signals. In summary, the results of this doctoral thesis contribute to our current understanding of motion and movement processing in the brain and its interface with spatial processing networks. The posterior MTL appears to be a key region for both self-motion and spatial processing. The results further indicate that physiological characteristics on the level of category-specific processing but not primary encoding reflect behavioral judgments on motion. This thesis also makes methodological contributions to the field of neuroimaging: it was found that the analysis of signal variability is a good gauge for analysing inter-individual physiological differences, while superior head-movement correction techniques have to be developed before pattern classification can be used to this end