The Effectiveness of Neurofeedback and Stimulant Drugs in Treating AD/HD: Part II. Replication

This study replicated T. R. Rossiter and T. J. La Vaque (1995) with a larger sample, expanded age range, and improved statistical analysis. Thirty-one AD/HD patients who chose stimulant drug (MED) treatment were matched with 31 patients who chose a neurofeedback (EEG) treatment program. EEG patients received either office (n = 14) or home (n = 17) neurofeedback. Stimulants for MED patients were titrated using the Test of Variables of Attention (TOVA). EEG (effect size [ES] = 1.01–1.71) and MED (ES = 0.80–1.80) groups showed statistically and clinically significant improvement on TOVA measures of attention, impulse control, processing speed, and variability in attention. The EEG group demonstrated statistically and clinically significant improvement on behavioral measures (Behavior Assessment System for Children, ES = 1.16–1.78, and Brown Attention Deficit Disorder Scales, ES = 1.59). TOVA gain scores for the EEG and MED groups were not significantly different. More importantly, confidence interval and nonequivalence null hypothesis testing confirmed that the neurofeedback program produced patient outcomes equivalent to those obtained with stimulant drugs. An effectiveness research design places some limitations on the conclusions that can be drawn.     

Effect of Biofeedback Training of Sensorimotor and β1EEG Rhythms on Attention Parameters

The effects of the EEG–biofeedback (EEG–BFB) procedure, aimed at increasing the sensorimotor (12–15 Hz) and (15–18 Hz) rhythms on the psychological and electrophysiological parameters of attention, were studied using the methods of scalp recording of evoked potentials in the bistimulus paradigm Go/No–Go and a psychological attention test (Test of Variables of Attention; TOVA). Twenty-five children with attention disorders were included in the study. EEG–BFB sessions significantly improved the attention, behavior, and school study results in 19 (76%) children. In these cases, a significant increase in the amplitude of the inhibitory component in the frontocentral leads and improvement of the TOVA parameters were found.     

Strong genetic influences on measures of behavioral‐regulation among inbred rat strains

A fundamental challenge for any complex nervous system is to regulate behavior in response to environmental challenges. Three measures of behavioral‐regulation were tested in a panel of eight inbred rat strains. These measures were: (1) sensation seeking as assessed by locomotor response to novelty and the sensory reinforcing effects of light onset, (2) attention and impulsivity, as measured by a choice reaction time task and (3) impulsivity as measured by a delay discounting task. Deficient behavioral‐regulation has been linked to a number of psychopathologies, including ADHD, Schizophrenia, Autism, drug abuse and eating disorders. Eight inbred rat strains (August Copenhagen Irish, Brown Norway, Buffalo, Fischer 344, Wistar Kyoto, Spontaneous Hypertensive Rat, Lewis, Dahl Salt Sensitive) were tested. With n = 9 for each strain, we observed robust strain differences for all tasks; heritability was estimated between 0.43 and 0.66. Performance of the eight inbred rat strains on the choice reaction time task was compared to the performance of outbred Sprague Dawley (n = 28) and Heterogeneous strain rats (n = 48). The results indicate a strong genetic influence on complex tasks related to behavioral‐regulation and indicate that some of the measures tap common genetically driven processes. Furthermore, our results establish the potential for future studies aimed at identifying specific alleles that influence variability for these traits. Identification of such alleles could contribute to our understanding of the molecular genetic basis of behavioral‐regulation, which is of fundamental importance and likely contributes to multiple psychiatric disorders .     

Shared Cognitive Impairments and Aetiology in ADHD Symptoms and Reading Difficulties

BackgroundTwin studies indicate that the frequent co-occurrence of attention deficit hyperactivity disorder (ADHD) symptoms and reading difficulties (RD) is largely due to shared genetic influences. Both disorders are associated with multiple cognitive impairments, but it remains unclear which cognitive impairments share the aetiological pathway, underlying the co-occurrence of the symptoms. We address this question using a sample of twins aged 7–10 and a range of cognitive measures previously associated with ADHD symptoms or RD.MethodsWe performed multivariate structural equation modelling analyses on parent and teacher ratings on the ADHD symptom domains of inattention and hyperactivity, parent ratings on RD, and cognitive data on response inhibition (commission errors, CE), reaction time variability (RTV), verbal short-term memory (STM), working memory (WM) and choice impulsivity, from a population sample of 1312 twins aged 7–10 years.ResultsThree cognitive processes showed significant phenotypic and genetic associations with both inattention symptoms and RD: RTV, verbal WM and STM. While STM captured only 11% of the shared genetic risk between inattention and RD, the estimates increased somewhat for WM (21%) and RTV (28%); yet most of the genetic sharing between inattention and RD remained unaccounted for in each case.ConclusionWhile response inhibition and choice impulsivity did not emerge as important cognitive processes underlying the co-occurrence between ADHD symptoms and RD, RTV and verbal memory processes separately showed significant phenotypic and genetic associations with both inattention symptoms and RD. Future studies employing longitudinal designs will be required to investigate the developmental pathways and direction of causality further.     

Oscillatory Activity in the Medial Prefrontal Cortex and Nucleus Accumbens Correlates with Impulsivity and Reward Outcome

Actions expressed prematurely without regard for their consequences are considered impulsive. Such behaviour is governed by a network of brain regions including the prefrontal cortex (PFC) and nucleus accumbens (NAcb) and is prevalent in disorders including attention deficit hyperactivity disorder (ADHD) and drug addiction. However, little is known of the relationship between neural activity in these regions and specific forms of impulsive behaviour. In the present study we investigated local field potential (LFP) oscillations in distinct sub-regions of the PFC and NAcb on a 5-choice serial reaction time task (5-CSRTT), which measures sustained, spatially-divided visual attention and action restraint. The main findings show that power in gamma frequency (50–60 Hz) LFP oscillations transiently increases in the PFC and NAcb during both the anticipation of a cue signalling the spatial location of a nose-poke response and again following correct responses. Gamma oscillations were coupled to low-frequency delta oscillations in both regions; this coupling strengthened specifically when an error response was made. Theta (7–9 Hz) LFP power in the PFC and NAcb increased during the waiting period and was also related to response outcome. Additionally, both gamma and theta power were significantly affected by upcoming premature responses as rats waited for the visual cue to respond. In a subgroup of rats showing persistently high levels of impulsivity we found that impulsivity was associated with increased error signals following a nose-poke response, as well as reduced signals of previous trial outcome during the waiting period. Collectively, these in-vivo neurophysiological findings further implicate the PFC and NAcb in anticipatory impulsive responses and provide evidence that abnormalities in the encoding of rewarding outcomes may underlie trait-like impulsive behaviour.     

Mu and Delta Opioid Receptors Oppositely Regulate Motor Impulsivity in the Signaled Nose Poke Task

Impulsivity is a primary feature of many psychiatric disorders, most notably attention deficit hyperactivity disorder and drug addiction. Impulsivity includes a number of processes such as the inability to delay gratification, the inability to withhold a motor response, or acting before all of the relevant information is available. These processes are mediated by neural systems that include dopamine, serotonin, norepinephrine, glutamate and cannabinoids. We examine, for the first time, the role of opioid systems in impulsivity by testing whether inactivation of the mu- (Oprm1) or delta- (Oprd1) opioid receptor gene alters motor impulsivity in mice. Wild-type and knockout mice were examined on either a pure C57BL6/J (BL6) or a hybrid 50% C57Bl/6J–50% 129Sv/pas (HYB) background. Mice were trained to respond for sucrose in a signaled nose poke task that provides independent measures of associative learning (responses to the reward-paired cue) and motor impulsivity (premature responses). Oprm1 knockout mice displayed a remarkable decrease in motor impulsivity. This was observed on the two genetic backgrounds and did not result from impaired associative learning, as responses to the cue signaling reward did not differ across genotypes. Furthermore, mutant mice were insensitive to the effects of ethanol, which increased disinhibition and decreased conditioned responding in wild-type mice. In sharp contrast, mice lacking the Oprd1 gene were more impulsive than controls. Again, mutant animals showed no deficit in associative learning. Ethanol completely disrupted performance in these animals. Together, our results suggest that mu-opioid receptors enhance, whereas delta-opioid receptors inhibit, motor impulsivity. This reveals an unanticipated contribution of endogenous opioid receptor activity to disinhibition. In a broader context, these data suggest that alterations in mu- or delta-opioid receptor function may contribute to impulse control disorders.     

Sex chromosome complement affects multiple aspects of reversal-learning task performance in mice

Determining the mechanisms by which the sex-chromosome complement (SCC) affects learning, attention, and impulsivity has implications for observed sex differences in prevalence, severity, and prognosis of psychiatric/neurodevelopmental disorders and syndromes associated with sex-chromosome aneuploidy. Here, Four Core Genotypes (FCG) mice were evaluated in order to assess the separable and/or interacting effects of gonads (testes vs. ovaries) and their secretions and/or SCC (XX vs. XY) acting via non-gonadal mechanisms on behavior. We tested FCG mice on a reversal-learning task that enables the quantification of aspects of learning, attention and impulsivity. Across testing phases (involving the initial acquisition of a spatial discrimination and subsequent reversal learning), overall error rate was larger in XY compared with XX mice. Although XX and XY groups did not differ in the total number of trials required in order to reach a preset performance criterion, analyses of reversal error types showed more perseverative errors in XY than XX mice, with no difference in regressive errors. Additionally, prepotent-response latencies during the reversal phase were shorter in XY males, as compared with both XX gonadal males and females of either SCC, and failures to sustain the observing response were more frequent in XY mice than XX mice during the acquisition phase. These results indicate that SCC affects the characteristic pattern of response selection during acquisition and reversal performance without affecting the overall learning rate. More broadly, these results show direct effects of the SCC on cognitive processes that are relevant to psychiatric/neurodevelopmental disorders and syndromes associated with sex-chromosome aneuploidies.     

Impaired Decisional Impulsivity in Pathological Videogamers

Background

Pathological gaming is an emerging and poorly understood problem. Impulsivity is commonly impaired in disorders of behavioural and substance addiction, hence we sought to systematically investigate the different subtypes of decisional and motor impulsivity in a well-defined pathological gaming cohort.

Methods

Fifty-two pathological gaming subjects and age-, gender- and IQ-matched healthy volunteers were tested on decisional impulsivity (Information Sampling Task testing reflection impulsivity and delay discounting questionnaire testing impulsive choice), and motor impulsivity (Stop Signal Task testing motor response inhibition, and the premature responding task). We used stringent diagnostic criteria highlighting functional impairment.

Results

In the Information Sampling Task, pathological gaming participants sampled less evidence prior to making a decision and scored fewer points compared with healthy volunteers. Gaming severity was also negatively correlated with evidence gathered and positively correlated with sampling error and points acquired. In the delay discounting task, pathological gamers made more impulsive choices, preferring smaller immediate over larger delayed rewards. Pathological gamers made more premature responses related to comorbid nicotine use. Greater number of hours played also correlated with a Motivational Index. Greater frequency of role playing games was associated with impaired motor response inhibition and strategy games with faster Go reaction time.

Conclusions

We show that pathological gaming is associated with impaired decisional impulsivity with negative consequences in task performance. Decisional impulsivity may be a potential target in therapeutic management.     

Social and biological measures of hyperactivity and inattention: are they describing similar underlying constructs of child behavior?

The relationship between 27 different measures of hyperactive, impulsive, and inattentive behavior, including those considered to be more objective and those considered more influenced by social factors, is examined using a normal sample of 219 Mexican children, ages 6 to 12. Measures were based on activity monitoring by accelerometry, ethological observation of attentional and movements states in the classroom, cognitive testing using the TOVA continuous performance test (CPT), and parents' and teachers' reports on ratings scales and symptom checklists. Factor analysis was used to examine to what degree these different measures are reporting similar underlying constructs (factors) of hyperactivity and inattention. Parent and teacher ratings appear to be describing underlying constructs that are distinct from those described by the other measures, but measures based on CPT, observation, and activity monitoring did not factor together either, nor more highly correlate to each other. Analysis combining all the measures showed that parent and teacher ratings factored together based on who was reporting the behavior, rather than the behavior being reported. The findings underscore that each type of measurement of hyperactivity, impulsivity, and inattention measures a different aspect of a complex behavioral phenomenon, rather than some better measuring than others the same underlying factor.     

Biofeedback-induced relaxation training as an alternative for the elementary school learning-disabled child

This study examined the effects of biofeedback-induced relaxation training on attention to task, impulsivity, and locus of control among 32 learning-disabled children between the ages of 8 and 11 years. Attention to task and impulsivity were measured by the Matching Familiar Figures Test and locus of control was measured by the Nowicki-Strickland Scale. Participants were randomly assigned to experimental (N=16) and control (N=16) groups. The study spanned a total of 8 weeks, with the experimental treatment consisting of three sessions spaced approximately 2 weeks apart. The treatment included EMG biofeedback training used with relaxation tapes. Univariate F values and discriminant analysis procedures revealed that the attention to task and impulsivity measures proved to be valid discriminators, respectively beyond the .01 and .05 levels of significance. Experimental group subjects had significantly fewer number of errors on the attention to task measure and significantly lower impulsivity scores. It was concluded that the biofeedback-induced relaxation training affords promise in assisting learning-disabled children in reaching their education potentials. It was recommended that future research examine the long-term efficacy and the transfer to school-related tasks of this intervention.     

Biofeedback-induced relaxation training as an alternative for the elementary school learning-disabled child

This study examined the effects of biofeedback-induced relaxation training on attention to task, impulsivity, and locus of control among 32 learning-disabled children between the ages of 8 and 11 years. Attention to task and impulsivity were measured by the Matching Familiar Figures Test and locus of control was measured by the Nowicki-Strickland Scale. Participants were randomly assigned to experimental (N = 16) and control (N = 16) groups. The study spanned a total of 8 weeks, with the experimental treatment consisting of three sessions spaced approximately 2 weeks apart. The treatment included EMG biofeedback training used with relaxation tapes. Univariate F values and discriminant analysis procedures revealed that the attention to task and impulsivity measures proved to be valid discriminators, respectively beyond the .01 and .05 levels of significance. Experimental group subjects had significantly fewer number of errors on the attention to task measure and significantly lower impulsivity scores. It was concluded that the biofeedback-induced relaxation training affords promise in assisting learning-disabled children in reaching their education potentials. It was recommended that future research examine the long-term efficacy and the transfer to school-related tasks of this intervention.     

Multiple Modes of Impulsivity in Parkinson's Disease

Cognitive problems are a major factor determining quality of life of patients with Parkinson''s disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinson''s disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinson''s disease patients (Hoehn and Yahr stage I–III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinson''s disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinson''s disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinson''s disease will support more evidence-based and effective strategies to treat impulsivity.     

Heritable variation in locomotion,reward sensitivity and impulsive behaviors in a genetically diverse inbred mouse panel

Drugs of abuse, including alcohol and stimulants like cocaine, produce effects that are subject to individual variability, and genetic variation accounts for at least a portion of those differences. Notably, research in both animal models and human subjects point toward reward sensitivity and impulsivity as being trait characteristics that predict relatively greater positive subjective responses to stimulant drugs. Here we describe use of the eight collaborative cross (CC) founder strains and 38 (reversal learning) or 10 (all other tests) CC strains to examine the heritability of reward sensitivity and impulsivity traits, as well as genetic correlations between these measures and existing addiction-related phenotypes. Strains were all tested for activity in an open field and reward sensitivity (intake of chocolate BOOST®). Mice were then divided into two counterbalanced groups and underwent reversal learning (impulsive action and waiting impulsivity) or delay discounting (impulsive choice). CC and founder mice show significant heritability for impulsive action, impulsive choice, waiting impulsivity, locomotor activity, and reward sensitivity, with each impulsive phenotype determined to be non-correlating, independent traits. This research was conducted within the broader, inter-laboratory effort of the Center for Systems Neurogenetics of Addiction (CSNA) to characterize CC and DO mice for multiple, cocaine abuse related traits. These data will facilitate the discovery of genetic correlations between predictive traits, which will then guide discovery of genes and genetic variants that contribute to addictive behaviors.     

Association of Impulsivity and Polymorphic MicroRNA-641 Target Sites in the SNAP-25 Gene

Impulsivity is a personality trait of high impact and is connected with several types of maladaptive behavior and psychiatric diseases, such as attention deficit hyperactivity disorder, alcohol and drug abuse, as well as pathological gambling and mood disorders. Polymorphic variants of the SNAP-25 gene emerged as putative genetic components of impulsivity, as SNAP-25 protein plays an important role in the central nervous system, and its SNPs are associated with several psychiatric disorders. In this study we aimed to investigate if polymorphisms in the regulatory regions of the SNAP-25 gene are in association with normal variability of impulsivity. Genotypes and haplotypes of two polymorphisms in the promoter (rs6077690 and rs6039769) and two SNPs in the 3′ UTR (rs3746544 and rs1051312) of the SNAP-25 gene were determined in a healthy Hungarian population (N = 901) using PCR–RFLP or real-time PCR in combination with sequence specific probes. Significant association was found between the T–T 3′ UTR haplotype and impulsivity, whereas no association could be detected with genotypes or haplotypes of the promoter loci. According to sequence alignment, the polymorphisms in the 3′ UTR of the gene alter the binding site of microRNA-641, which was analyzed by luciferase reporter system. It was observed that haplotypes altering one or two nucleotides in the binding site of the seed region of microRNA-641 significantly increased the amount of generated protein in vitro. These findings support the role of polymorphic SNAP-25 variants both at psychogenetic and molecular biological levels.     

Impulsivity and Concussion in Juvenile Rats: Examining Molecular and Structural Aspects of the Frontostriatal Pathway

Impulsivity and poor executive control have been implicated in the pathogenesis of many developmental and neuropsychiatric disorders. Similarly, concussions/mild traumatic brain injuries (mTBI) have been associated with increased risk for neuropsychiatric disorders and the development of impulsivity and inattention. Researchers and epidemiologists have therefore considered whether or not concussions induce symptoms of attention-deficit/hyperactivity disorder (ADHD), or merely unmask impulsive tendencies that were already present. The purpose of this study was to determine if a single concussion in adolescence could induce ADHD-like impulsivity and impaired response inhibition, and subsequently determine if inherent impulsivity prior to a pediatric mTBI would exacerbate post-concussion symptomology with a specific emphasis on impulsive and inattentive behaviours. As these behaviours are believed to be associated with the frontostriatal circuit involving the nucleus accumbens (NAc) and the prefrontal cortex (PFC), the expression patterns of 8 genes (Comt, Drd2, Drd3, Drd4, Maoa, Sert, Tph1, and Tph2) from these two regions were examined. In addition, Golgi-Cox staining of medium spiny neurons in the NAc provided a neuroanatomical examination of mTBI-induced structural changes. The study found that a single early brain injury could induce impulsivity and impairments in response inhibition that were more pronounced in males. Interestingly, when animals with inherent impulsivity experienced mTBI, injury-related deficits were exacerbated in female animals. The single concussion increased dendritic branching, but reduced synaptic density in the NAc, and these changes were likely associated with the increase in impulsivity. Finally, mTBI-induced impulsivity was associated with modifications to gene expression that differed dramatically from the gene expression pattern associated with inherent impulsivity, despite very similar behavioural phenotypes. Our findings suggest the need to tailor treatment strategies for mTBI in light of an individual’s premorbid characteristics, given significant differences in molecular profiles of the frontostriatal circuits that depend upon sex and the etiology of the behavioural phenotype.     

Genetic Influence on Slope Variability in a Childhood Reflexive Attention Task

Individuals are not perfectly consistent, and interindividual variability is a common feature in all varieties of human behavior. Some individuals respond more variably than others, however, and this difference may be important to understanding how the brain works. In this paper, we explore genetic contributions to response time (RT) slope variability on a reflexive attention task. We are interested in such variability because we believe it is an important part of the overall picture of attention that, if understood, has the potential to improve intervention for those with attentional deficits. Genetic association studies are valuable in discovering biological pathways of variability and several studies have found such associations with a sustained attention task. Here, we expand our knowledge to include a reflexive attention task. We ask whether specific candidate genes are associated with interindividual variability on a childhood reflexive attention task in 9–16 year olds. The genetic makers considered are on 11 genes: APOE, BDNF, CHRNA4, COMT, DRD4, HTR4, IGF2, MAOA, SLC5A7, SLC6A3, and SNAP25. We find significant associations with variability with markers on nine and we discuss the results in terms of neurotransmitters associated with each gene and the characteristics of the associated measures from the reflexive attention task.     

Intraindividual Variability in Inhibitory Function in Adults with ADHD – An Ex-Gaussian Approach

Objective

Attention deficit disorder (ADHD) is commonly associated with inhibitory dysfunction contributing to typical behavioral symptoms like impulsivity or hyperactivity. However, some studies analyzing intraindividual variability (IIV) of reaction times in children with ADHD (cADHD) question a predominance of inhibitory deficits. IIV is a measure of the stability of information processing and provides evidence that longer reaction times (RT) in inhibitory tasks in cADHD are due to only a few prolonged responses which may indicate deficits in sustained attention rather than inhibitory dysfunction. We wanted to find out, whether a slowing in inhibitory functioning in adults with ADHD (aADHD) is due to isolated slow responses.

Methods

Computing classical RT measures (mean RT, SD), ex-Gaussian parameters of IIV (which allow a better separation of reaction time (mu), variability (sigma) and abnormally slow responses (tau) than classical measures) as well as errors of omission and commission, we examined response inhibition in a well-established GoNogo task in a sample of aADHD subjects without medication and healthy controls matched for age, gender and education.

Results

We did not find higher numbers of commission errors in aADHD, while the number of omissions was significantly increased compared with controls. In contrast to increased mean RT, the distributional parameter mu did not document a significant slowing in aADHD. However, subjects with aADHD were characterized by increased IIV throughout the entire RT distribution as indicated by the parameters sigma and tau as well as the SD of reaction time. Moreover, we found a significant correlation between tau and the number of omission errors.

Conclusions

Our findings question a primacy of inhibitory deficits in aADHD and provide evidence for attentional dysfunction. The present findings may have theoretical implications for etiological models of ADHD as well as more practical implications for neuropsychological testing in aADHD.     

Enhanced interannual precipitation variability increases plant functional diversity that in turn ameliorates negative impact on productivity

Although precipitation interannual variability is projected to increase due to climate change, effects of changes in precipitation variance have received considerable less attention than effects of changes in the mean state of climate. Interannual precipitation variability effects on functional diversity and its consequences for ecosystem functioning are assessed here using a 6‐year rainfall manipulation experiment. Five precipitation treatments were switched annually resulting in increased levels of precipitation variability while maintaining average precipitation constant. Functional diversity showed a positive response to increased variability due to increased evenness. Dominant grasses decreased and rare plant functional types increased in abundance because grasses showed a hump‐shaped response to precipitation with a maximum around modal precipitation, whereas rare species peaked at high precipitation values. Increased functional diversity ameliorated negative effects of precipitation variability on primary production. Rare species buffered the effect of precipitation variability on the variability in total productivity because their variance decreases with increasing precipitation variance.     

Cognitive assessment of mice strains heterozygous for cell-adhesion genes reveals strain-specific alterations in timing

We used a fully automated system for the behavioural measurement of physiologically meaningful properties of basic mechanisms of cognition to test two strains of heterozygous mutant mice, Bfc (batface) and L1, and their wild-type littermate controls. Both of the target genes are involved in the establishment and maintenance of synapses. We find that the Bfc heterozygotes show reduced precision in their representation of interval duration, whereas the L1 heterozygotes show increased precision. These effects are functionally specific, because many other measures made on the same mice are unaffected, namely: the accuracy of matching temporal investment ratios to income ratios in a matching protocol, the rate of instrumental and classical conditioning, the latency to initiate a cued instrumental response, the trials on task and the impulsivity in a switch paradigm, the accuracy with which mice adjust timed switches to changes in the temporal constraints, the days to acquisition, and mean onset time and onset variability in the circadian anticipation of food availability.