Cognitive processing speed and accuracy are intrinsically different in genetic architecture and brain phenotypes.

Since the birth of cognitive science, researchers have used reaction time and accuracy to measure cognitive ability. Although recognition of these two measures is often based on empirical observations, the underlying consensus is that most cognitive behaviors may be along two fundamental dimensions: cognitive processing speed (CPS) and cognitive processing accuracy (CPA). In this study, we used genomic-wide association studies (GWAS) data from 14 cognitive traits to show the presence of those two factors and revealed the specific neurobiological basis underlying them. We identified that CPS and CPA had distinct brain phenotypes (e.g. white matter microstructure), neurobiological bases (e.g. postsynaptic membrane), and developmental periods (i.e. late infancy). Moreover, those two factors showed differential associations with other health-related traits such as screen exposure and sleep status, and a significant causal relationship with psychiatric disorders such as major depressive disorder and schizophrenia. Utilizing an independent cohort from the Adolescent Brain Cognitive Development (ABCD) study, we also uncovered the distinct contributions of those two factors on the cognitive development of young adolescents. These findings reveal two fundamental factors underlying various cognitive abilities, elucidate the distinct brain structural fingerprint and genetic architecture of CPS and CPA, and hint at the complex interrelationship between cognitive ability, lifestyle, and mental health.

Neural indices of heritable impulsivity: Impact of the COMT Val158Met polymorphism on frontal beta power during early motor preparation.

Studies of COMT Val158Met suggest that the neural circuitry subserving inhibitory control may be modulated by this functional polymorphism altering cortical dopamine availability, thus giving rise to heritable differences in behaviors. Using an anatomically-constrained magnetoencephalography method and stratifying the sample by COMT genotype, from a larger sample of 153 subjects, we examined the spatial and temporal dynamics of beta oscillations during motor execution and inhibition in 21 healthy Met158/Met158 (high dopamine) or 21 Val158/Val158 (low dopamine) genotype individuals during a Go/NoGo paradigm. While task performance was unaffected, Met158 homozygotes demonstrated an overall increase in beta power across regions essential for inhibitory control during early motor preparation (∼100 ms latency), suggestive of a global motor "pause" on behavior. This increase was especially evident on Go trials with slow response speed and was absent during inhibition failures. Such a pause could underlie the tendency of Met158 allele carriers to be more cautious and inhibited. In contrast, Val158 homozygotes exhibited a beta drop during early motor preparation, indicative of high response readiness. This decrease was associated with measures of behavioral disinhibition and consistent with greater extraversion and impulsivity observed in Val homozygotes. These results provide mechanistic insight into genetically-determined interindividual differences of inhibitory control with higher cortical dopamine associated with momentary response hesitation, and lower dopamine leading to motor impulsivity.

Thyroid function variations within the reference range and cognitive function: A two-sample Mendelian randomization study.

BACKGROUND: The causal relationship between thyroid function variations within the reference range and cognitive function remains unknown. We aimed to explore this causal relationship using a Mendelian randomization (MR) approach. METHODS: Summary statistics of a thyroid function genome-wide association study (GWAS) were obtained from the ThyroidOmics consortium, including reference range thyroid stimulating hormone (TSH) (N = 54,288) and reference range free thyroxine (FT4) (N = 49,269). GWAS summary statistics on cognitive function were obtained from the Social Science Genetic Association Consortium (SSGAC) and the UK Biobank, including cognitive performance (N = 257,841), prospective memory (N = 152,605), reaction time (N = 459,523), and fluid intelligence (N = 149,051). The primary method used was inverse-variance weighted (IVW), supplemented with weighted median, Mr-Egger regression, and MR-Pleiotropy Residual Sum and Outlier. Several sensitivity analyses were conducted to identify heterogeneity and pleiotropy. RESULTS: An increase in genetically associated TSH within the reference range was suggestively associated with a decline in cognitive performance (ß = -0.019; 95%CI: -0.034 to -0.003; P = 0.017) and significantly associated with longer reaction time (ß = 0.016; 95 % CI: 0.005 to 0.027; P = 0.004). Genetically associated FT4 levels within the reference range had a significant negative relationship with reaction time (ß = -0.030; 95%CI:-0.044 to -0.015; P = 4.85 × 10-5). These findings remained robust in the sensitivity analyses. CONCLUSIONS: Low thyroid function within the reference range may have a negative effect on cognitive function, but further research is needed to fully understand the nature of this relationship. LIMITATIONS: This study only used GWAS data from individuals of European descent, so the findings may not apply to other ethnic groups.

Genome-wide association study in 404,302 individuals identifies 7 significant loci for reaction time variability.

Reaction time variability (RTV), reflecting fluctuations in response time on cognitive tasks, has been proposed as an endophenotype for many neuropsychiatric disorders. There have been no large-scale genome-wide association studies (GWAS) of RTV and little is known about its genetic underpinnings. Here, we used data from the UK Biobank to conduct a GWAS of RTV in participants of white British ancestry (n = 404,302) as well as a trans-ancestry GWAS meta-analysis (n = 44,873) to assess replication. We found 161 genome-wide significant single nucleotide polymorphisms (SNPs) distributed across 7 genomic loci in our discovery GWAS. Functional annotation of the variants implicated genes involved in synaptic function and neural development. The SNP-based heritability (h2SNP) estimate for RTV was 3%. We investigated genetic correlations between RTV and selected neuropsychological traits using linkage disequilibrium score regression, and found significant correlations with several traits, including a positive correlation with mean reaction time and schizophrenia. Despite the high genetic correlation between RTV and mean reaction time, we demonstrate distinctions in the genetic underpinnings of these traits. Lastly, we assessed the predictive ability of a polygenic score (PGS) for RTV, calculated using PRSice and PRS-CS, and found that the RTV-PGS significantly predicted RTV in independent cohorts, but that the generalisability to other ancestry groups was poor. These results identify genetic underpinnings of RTV, and support the use of RTV as an endophenotype for neurological and psychiatric disorders.

Effect of Apolipoprotein E4 on the Driving Behavior of Patients with Amnestic Mild Cognitive Impairment or Mild Alzheimer's Disease Dementia.

BACKGROUND: The driving behavior of patients with mild Alzheimer's disease dementia (ADD) and patients with mild cognitive impairment (MCI) is frequently characterized by errors. A genetic factor affecting cognition is apolipoprotein E4 (APOE4), with carriers of APOE4 showing greater episodic memory impairment than non-carriers. However, differences in the driving performance of the two groups have not been investigated. OBJECTIVE: To compare driving performance in APOE4 carriers and matched non-carriers. METHODS: Fourteen APOE4 carriers and 14 non-carriers with amnestic MCI or mild ADD underwent detailed medical and neuropsychological assessment and participated in a driving simulation experiment, involving driving in moderate and high traffic volume in a rural environment. Driving measures were speed, lateral position, headway distance and their SDs, and reaction time. APOE was genotyped through plasma samples. RESULTS: Mixed two-way ANOVAs examining traffic volume and APOE4 status showed a significant effect of traffic volume on all driving variables, but a significant effect of APOE4 on speed variability only. APOE4 carriers were less variable in their speed than non-carriers; this remained significant after a Bonferroni correction. To further examine variability in the driving performance, coefficients of variation (COV) were computed. Larger headway distance COV and smaller lateral position COV were observed in high compared to moderate traffic. APOE4 carriers had smaller speed COV compared to non-carriers. CONCLUSION: The lower speed variability of APOE4 carriers in the absence of neuropsychological test differences indicates reduced speed adaptations, possibly as a compensatory strategy. Simulated driving may be a sensitive method for detecting performance differences in the absence of cognitive differences.

Brain Perfusion Bridges Virtual-Reality Spatial Behavior to TPH2 Genotype for Head Acceleration Events.

Neuroimaging demonstrates that athletes of collision sports can suffer significant changes to their brain in the absence of concussion, attributable to head acceleration event (HAE) exposure. In a sample of 24 male Division I collegiate football players, we examine the relationships between tryptophan hydroxylase 2 (TPH2), a gene involved in neurovascular function, regional cerebral blood flow (rCBF) measured by arterial spin labeling, and virtual reality (VR) motor performance, both pre-season and across a single football season. For the pre-season, TPH2 T-carriers showed lower rCBF in two left hemisphere foci (fusiform gyrus/thalamus/hippocampus and cerebellum) in association with higher (better performance) VR Reaction Time, a dynamic measure of sensory-motor reactivity and efficiency of visual-spatial processing. For TPH2 CC homozygotes, higher pre-season rCBF in these foci was associated with better performance on VR Reaction Time. A similar relationship was observed across the season, where TPH2 T-carriers showed improved VR Reaction Time associated with decreases in rCBF in the right hippocampus/amygdala, left middle temporal lobe, and left insula/putamen/pallidum. In contrast, TPH2 CC homozygotes showed improved VR Reaction Time associated with increases in rCBF in the same three clusters. These findings show that TPH2 T-carriers have an abnormal relationship between rCBF and the efficiency of visual-spatial processing that is exacerbated after a season of high-impact sports in the absence of diagnosable concussion. Such gene-environment interactions associated with behavioral changes after exposure to repetitive HAEs have been unrecognized with current clinical analytical tools and warrant further investigation. Our results demonstrate the importance of considering neurovascular factors along with traumatic axonal injury to study long-term effects of repetitive HAEs.

Discovering the shared biology of cognitive traits determined by genetic overlap.

Investigating the contribution of biology to human cognition has assumed a bottom-up causal cascade where genes influence brain systems that activate, communicate, and ultimately drive behavior. Yet few studies have directly tested whether cognitive traits with overlapping genetic underpinnings also rely on overlapping brain systems. Here, we report a step-wise exploratory analysis of genetic and functional imaging overlaps among cognitive traits. We used twin-based genetic analyses in the human connectome project (HCP) dataset (N â€‹= â€‹486), in which we quantified the heritability of measures of cognitive functions, and tested whether they were driven by common genetic factors using pairwise genetic correlations. Subsequently, we derived activation maps associated with cognitive tasks via functional imaging meta-analysis in BrainMap (N â€‹= â€‹4484), and tested whether cognitive traits that shared genetic variation also exhibited overlapping brain activation. Our genetic analysis determined that six cognitive measures (cognitive flexibility, no-go continuous performance, fluid intelligence, processing speed, reading decoding and vocabulary comprehension) were heritable (0.3 â€‹< â€‹h2 â€‹< â€‹0.5), and genetically correlated with at least one other heritable cognitive measure (0.2 â€‹< â€‹ρg â€‹< â€‹0.35). The meta-analysis showed that two genetically-correlated traits, cognitive flexibility and fluid intelligence (ρg â€‹= â€‹0.24), also had a significant brain activation overlap (ρperm â€‹= â€‹0.29). These findings indicate that fluid intelligence and cognitive flexibility rely on overlapping biological features, both at the neural systems level and at the molecular level. The cross-disciplinary approach we introduce provides a concrete framework for data-driven quantification of biological convergence between genetics, brain function, and behavior in health and disease.

The influence of dopaminergic polymorphisms on selective stopping.

Although the genetic influence on global stopping has been extensively investigated, little is known about the genetic contribution to other more complex forms of inhibitory control such as selective stopping. The selectivity of inhibitory control can be assessed by using the stimulus-selective stop-signal task. Notably, recent behavioural and neural evidence indicates that individuals can adopt selective but also non-selective stopping strategies to solve it. This study aimed to investigate for the first time the influence of two relevant dopaminergic polymorphisms (in COMT and DRD2 genes) on stimulus-selective stopping in a sample of 529 adults. Results showed that although none of these polymorphisms (neither individually nor in combination) modulate the latency of the stop process in each strategy (the stop-signal reaction time), the choice of strategy was influenced by their interaction. These results suggest that dopaminergic polymorphisms might influence strategy adoption in selective stopping paradigms, which constitutes a novel finding.

Influence of two functional polymorphisms in NOS1 on baseline cortisol and working memory in healthy subjects.

INTRODUCTION: The neuronal isoform of the nitric oxide synthase (NOS-I) encoded by NOS1 is the main source of nitric oxide (NO) in the brain. Reduced NO signaling in the prefrontal cortex has been linked to schizophrenia and cognitive processes while reduced striatal NOS1 expression has been associated with impulsive behavior. METHODS: To evaluate the effect of two functional polymorphisms in alternative first exons of NOS1, ex1f-VNTR and ex1c-SNP rs41279104, on the HPA stress axis and neurocognitive abilities, 280 healthy subjects were genotyped, had their salivary cortisol levels measured and were assessed in verbal memory, verbal fluency, working memory and verbal IQ by using the California Verbal Learning Test (CVLT), the Regensburger test of verbal fluency (RWT), a n-back task and subscales of the Wechsler Adult Intelligence Scale III (WAIS-III). RESULTS: Schizophrenia risk (A)-allele carriers of NOS1 ex1c-SNP rs41279104 displayed significantly lower baseline cortisol levels (p = 0.004). NOS1 ex1f-VNTR genotype carriers showed differences in working memory performance (p = 0.05) in a gene-dose effect manner, with homozygous carriers of the short impulsivity-risk allele committing most commission errors. Finally, A-allele carriers of the NOS1 ex1c-SNP rs41279104 tended to react faster during the working memory task (p = 0.065). CONCLUSION: For the first time, we demonstrated an influence of the NOS1 ex1c-SNP rs41279104 on salivary cortisol levels and additionally implicate the A-allele in an enhanced reaction time during a working memory task. Regarding the NOS1 ex1f-VNTR our study supports the previously reported influence on impulsivity, lending further support to the hypothesis that this genetic variant underlies impulsive behavior.

Visual-spatial neglect after right-hemisphere stroke: behavioral and electrophysiological evidence.

BACKGROUND: Visual-spatial neglect (VSN) is a neuropsychological syndrome, and right-hemisphere stroke is the most common cause. The pathogenetic mechanism of VSN remains unclear. This study aimed to investigate the behavioral and event-related potential (ERP) changes in patients with or without VSN after right-hemisphere stroke. METHODS: Eleven patients with VSN with right-hemisphere stroke (VSN group) and 11 patients with non-VSN with right-hemisphere stroke (non-VSN group) were recruited along with one control group of 11 age- and gender-matched healthy participants. The visual-spatial function was evaluated using behavioral tests, and ERP examinations were performed. RESULTS: The response times in the VSN and non-VSN groups were both prolonged compared with those of normal controls (P < 0.001). In response to either valid or invalid cues in the left side, the accuracy in the VSN group was lower than that in the non-VSN group (P < 0.001), and the accuracy in the non-VSN group was lower than that in controls (P < 0.05). The P1 latency in the VSN group was significantly longer than that in the control group (F[2, 30] = 5.494, P = 0.009), and the N1 amplitude in the VSN group was significantly lower than that in the control group (F[2, 30] = 4.343, P = 0.022). When responding to right targets, the left-hemisphere P300 amplitude in the VSN group was significantly lower than that in the control group (F[2, 30] = 4.255, P = 0.025). With either left or right stimuli, the bilateral-hemisphere P300 latencies in the VSN and non-VSN groups were both significantly prolonged (all P < 0.05), while the P300 latency did not differ significantly between the VSN and non-VSN groups (all P > 0.05). CONCLUSIONS: Visual-spatial attention function is impaired after right-hemisphere stroke, and clinicians should be aware of the subclinical VSN. Our findings provide neuroelectrophysiological evidence for the lateralization of VSN.

The impact of the COMT genotype and cognitive demands on facets of intra-subject variability.

Intra-Subject Variability (ISV), a potential index of catecholaminergic regulation, is elevated in several disorders linked with altered dopamine function. ISV has typically been defined as reaction time standard deviation. However, the ex-Gaussian and spectral measures capture different aspects and may delineate different underlying sources of ISV; thus reflecting different facets of the construct. We examined the impact of factors associated with dopamine metabolism, namely, Catechol-O-Methyltransferase Val158Met (COMT) genotype and Working Memory (WM) and response-switching on ISV facets in young healthy adults. The Met allele was associated with overall increased variability. The rather exclusive sensitivity of ex-Gaussian tau to frequencies below 0.025 Hz and the quasi-periodic structure of particularly slow responses support the interpretation of tau as low frequency fluctuations of neuronal networks. Sigma, by contrast, may reflect neural noise. Regarding cognitive demands, a WM load-related increase in variability was present for all genotypes and all ISV facets. Contrastingly, ISV facets reacted differently to variations in response-switching as, across genotypes, sigma was elevated for rare target trials whereas tau was elevated for frequent standard trials, particularly for Met homozygotes. Our findings support the significant role of COMT in regulating behavioural ISV with its facetted structure and presumed underlying neural processes.

Region- and time-dependent gene regulation in the amygdala and anterior cingulate cortex of a PTSD-like mouse model.

Posttraumatic stress disorder is developed by exposure to a threatening and/or a horrifying event and characterized by the presence of anxiety, hyperarousal, avoidance, and sleep abnormality for a prolonged period of time. To elucidate the potential molecular mechanisms, we constructed a mouse model by electric foot shock followed by situational reminders and performed transcriptome analysis in brain tissues. The stressed mice acquired anxiety-like behavior after 2 weeks and exaggerated startle response after 4 weeks. Avoidance latency and freezing behavior were sustained up to 5 weeks post stress and abnormal static behavior was observed during the sleep period. RNA sequencing was performed in two of the emotional regulatory regions, anterior cingulate cortex and amygdala, at 2 and 5 weeks post stress. More than 1000 differentially expressed genes were identified at 2 weeks in both regions. The number of the regulated genes remained constant in amygdala at 5 weeks post stress, whereas those in anterior cingulate cortex were plummeted. Although synaptic remodeling and endocrine system were the most enriched signaling pathways in both anterior cingulate cortex and amygdala, the individual gene expression profile was regulated in a region- and time-dependent manner. In addition, several genes associated with PTSD involved in Hypothalamic-Pituitary-Adrenal axis were differentially regulated. These findings suggested that global gene expression profile was dynamically regulated in accordance with the disease development stage, and therefore targeting the distinct signaling molecules in different region and development stage might be critical for effective treatment to PTSD.

Lack of ß-amyloid cleaving enzyme-1 (BACE1) impairs long-term synaptic plasticity but enhances granule cell excitability and oscillatory activity in the dentate gyrus in vivo.

BACE1 is a ß-secretase involved in the cleavage of amyloid precursor protein and the pathogenesis of Alzheimer's disease (AD). The entorhinal cortex and the dentate gyrus are important for learning and memory, which are affected in the early stages of AD. Since BACE1 is a potential target for AD therapy, it is crucial to understand its physiological role in these brain regions. Here, we examined the function of BACE1 in the dentate gyrus. We show that loss of BACE1 in the dentate gyrus leads to increased granule cell excitability, indicated by enhanced efficiency of synaptic potentials to generate granule cell spikes. The increase in granule cell excitability was accompanied by prolonged paired-pulse inhibition, altered network gamma oscillations, and impaired synaptic plasticity at entorhinal-dentate synapses of the perforant path. In summary, this is the first detailed electrophysiological study of BACE1 deletion at the network level in vivo. The results suggest that BACE1 is important for normal dentate gyrus network function. This has implications for the use of BACE1 inhibitors as therapeutics for AD therapy, since BACE1 inhibition could similarly disrupt synaptic plasticity and excitability in the entorhinal-dentate circuitry.

Aggression in BALB/cJ mice is differentially predicted by the volumes of anterior and midcingulate cortex.

Anterior cingulate cortex (ACC) and midcingulate cortex (MCC) have been implicated in the regulation of aggressive behaviour. For instance, patients with conduct disorder (CD) show increased levels of aggression accompanied by changes in ACC and MCC volume. However, accounts of ACC/MCC changes in CD patients have been conflicting, likely due to the heterogeneity of the studied populations. Here, we address these discrepancies by studying volumetric changes of ACC/MCC in the BALB/cJ mouse, a model of aggression, compared to an age- and gender-matched control group of BALB/cByJ mice. We quantified aggression in BALB/cJ and BALB/cByJ mice using the resident-intruder test, and related this to volumetric measures of ACC/MCC based on Nissl-stained coronal brain slices of the same animals. We demonstrate that BALB/cJ behave consistently more aggressively (shorter attack latencies, more frequent attacks, anti-social biting) than the control group, while at the same time showing an increased volume of ACC and a decreased volume of MCC. Differences in ACC and MCC volume jointly predicted a high amount of variance in aggressive behaviour, while regression with only one predictor had a poor fit. This suggests that, beyond their individual contributions, the relationship between ACC and MCC plays an important role in regulating aggressive behaviour. Finally, we show the importance of switching from the classical rodent anatomical definition of ACC as cingulate area 2 and 1 to a definition that includes the MCC and is directly homologous to higher mammalian species: clear behaviour-related differences in ACC/MCC anatomy were only observed using the homologous definition.

Responses to executive demand in young adulthood differ by APOE genotype.

Despite evidence of a relationship between Apolipoprotein E (APOE) ε4+ and later-life cognitive decline, the lifespan effects of carrying an ε4+ allele on cognitive ageing are not well understood. Evidence of ε4+ advantages in early-life are inconsistent, but not inconsiderable. We explored the proposal that APOE ε4+ cognitive advantages arise only in response to complex and sensitive tasks targeting specific executive functions. We systematically manipulated executive demand within verbal fluency, decision-making, prospective memory, and sustained attention tasks. Participants aged 18-25 years (21 ε4+, 63 ε33) also completed a measure of subjective effort. Under low executive demand, ε4+ made fewer verbal fluency word repeats compared to ε33 carriers. Under high executive demand, ε4+ showed lower costs associated with performing concurrent tasks, greater switching errors, and more verbal fluency root repetition errors. Overall, ε4+ appeared to be showing working memory updating advantages under conditions of low executive demand, more effective resource allocation under elevated levels of executive demand, and errors indicating different strategy use compared to ε33 carriers, including speed-accuracy trade-offs.

Symptoms of ADHD Affect Intrasubject Variability in Youths with Autism Spectrum Disorder: An Ex-Gaussian Analysis.

Increased intrasubject variability in reaction times (RT-ISV) is frequently found in individuals with autism spectrum disorder (ASD). However, how dimensional attention deficit/hyperactivity disorder (ADHD) symptoms impact RT-ISV in individuals with ASD remains elusive. We assessed 97 high-functioning youths with co-occurring ASD and ADHD (ASD+ADHD), 124 high-functioning youths with ASD only, 98 youths with ADHD only, and 249 typically developing youths, 8-18 years of age, using the Conners Continuous Performance Test (CCPT). We compared the conventional CCPT parameters (omission errors, commission errors, mean RT and RT standard error (RTSE) as well as the ex-Gaussian parameters of RT (mu, sigma, and tau) across the four groups. We also conducted regression analyses to assess the relationships between RT indices and symptoms of ADHD and ASD in the ASD group (i.e., the ASD+ADHD and ASD-only groups). The ASD+ADHD and ADHD-only groups had higher RT-ISV than the other two groups. RT-ISV, specifically RTSE and tau, was significantly associated with ADHD symptoms rather than autistic traits in the ASD group. Regression models also revealed that sex partly accounted for RT-ISV variance in the ASD group. A post hoc analysis showed girls with ASD had higher tau and RTSE values than their male counterparts. Our results suggest that RT-ISV is primarily associated with co-occurring ADHD symptoms/diagnosis in children and adolescents with ASD. These results do not support the hypothesis of response variability as a transdiagnostic phenotype for ASD and ADHD and warrant further validation at a neural level.

A preliminary investigation of reaction time variability in relation to social functioning in children evaluated for ADHD.

Reaction time variability (RTV) is a ubiquitous phenomenon in Attention-Deficit/Hyperactivity Disorder (ADHD). Few studies have examined RTV in relation to functional outcomes such as social impairment in children with ADHD. In this exploratory study, we investigated whether RTV is associated with social functioning in children at risk for ADHD. Specifically, we explored the association between RTV (tau derived from correct go trials of a Stop-Signal task) and social functioning in 198 children ages 7-12 years referred for an ADHD evaluation. Social functioning measures included child and/or parent ratings of social competence, aggression, social problems, and impairment in relationships. In regression analyses that also included Oppositional Defiant Disorder symptoms and sex, higher RTV was significantly associated with lower ratings of social competence, and higher proactive/reactive aggression ratings on the child self-report measures. RTV was not significantly associated with parent report of social functioning or relationship impairment. This study provides preliminary evidence that RTV may be associated with social functioning in children at risk for ADHD. We propose that lapses of attention affecting cognitive control may also negatively impact social information processing thereby affecting social functioning. Replication is warranted and longitudinal studies are needed to investigate whether RTV predicts social dysfunction in ADHD.

Latency to startle is increased in the 5xFAD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that results in cognitive decline and a number of other neuropsychiatric symptoms. One area that is often affected by neuropsychiatric disease is the response to sudden, loud noises, as measured by the acoustic startle response (ASR), and prepulse inhibition (PPI), which indicates sensory-gating abilities. Evidence suggests AD patients, even early in the disease, show alteration in ASR. Studies have also shown changes in this measure in transgenic mouse models of AD. To assess the homology of 5xFAD mice to AD patients, the current study analyzed several aspects of the startle response in these mice using a protocol with fewer trials than previous studies. It was found that the 5xFAD mice had a delayed startle response, similar to what has been observed in AD sufferers. These results suggest the ASR may be a useful tool in assessing the efficacy of potential therapeutics, and that a simplified protocol may be more sensitive to between-groups differences for this task.

Effects of galanin receptor 2 and receptor 3 knockout in mouse models of acute seizures.

There exists solid evidence that endogenous galanin and galanin agonists exert anticonvulsive actions mediated both by galanin 1 receptor (GAL1-R) and galanin 2 receptor (GAL2-R). We have now investigated whether depletion of the recently identified third galanin receptor, GAL3-R, and that of GAL2-R, alters the threshold to the systemically applied γ-aminobutyric acid (GABA) antagonist pentylenetetrazole (PTZ) or to intrahippocampally administered kainic acid (KA). In neither model, GAL3-KO mice differed in their latency to the first seizure, mean seizure duration, total number of seizures, or time spent in seizures compared to wild-type controls. In addition, consistent with previous data, the response to PTZ was not altered in GAL2-KO mice. In contrast, intrahippocampal KA resulted in a significantly increased number of seizures and time spent in seizures in GAL2-KO mice, although the latency to the first seizure and the duration of individual seizures was not altered. These results are consistent with the previous data showing that GAL2-R knockdown does not affect the number of perforant path stimulations required for initiating status epilepticus but significantly increases the seizure severity during the ongoing status. In conclusion, our data support a specific role of GAL2-R but not of GAL3-R in mediating the anticonvulsive actions of endogenous galanin.

"Like parent, like child": Attention deficit hyperactivity disorder-like characteristics in parents of ADHD cases.

The objective of this study was to characterize an attention deficit hyperactivity disorder (ADHD) endophenotype in non-affected parents of adolescents with a history of ADHD, based on the relationship between performance on a sustained attention test (continuous performance task, or CPT) and polymorphisms of the DRD4 gene. In a sample of 25 non-affected parents of adolescents with ADHD history obtained from a longitudinal study of a nonclinical population, and 25 non-affected parents of adolescents with no ADHD history, four groups were evaluated with respect to the presence or absence of the long allele polymorphism of the DRD4 gene (i.e., over seven repeats). Comparisons of CPT performance among the four study groups included the number of commission errors, the number of omission errors, mean reaction time on correct responses (MRT), and reaction time (RT) variability (mean standard deviation of RT in each block [SDRT, as variability], and the sigma and tau components of the ex-Gaussian approach). The group of non-affected parents of adolescents with ADHD history and at least one long allele of the DRD4 gene showed greater RT variability (measured by SDRT), which is best explained by the greater frequency of abnormally slow responses (measured by tau). An association between the presence of the long allele of the DRD4 gene polymorphism and ADHD-like failure in CPT performance was evident in the non-affected parents of adolescents with ADHD in childhood. These findings suggest that certain traits of CPT performance could be considered an ADHD endophenotype.