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At least 307 records · Page 17Linked to original sources

PubMed2005

Probing the limits of delay intolerance: preliminary young adult data from the Delay Frustration Task (DeFT).

Delay intolerance/aversion is one amongst a number of candidate neuropsychological endophenotypes for ADHD. Pilot data suggest that, because of potential ceiling effects, simple choice measures of delay tolerance used for children are probably not appropriate for adolescents and adults. The Delay Frustration Task (DeFT) is a new measure of delay intolerance, designed to be used in a similar form with adolescents and adults as well as children. In it delay frustration is indexed as the number and duration of responses made on a response key during a series of unpredictable and unsignalled delay periods, which interrupt the completion of a simple computer-based tests. The aim of this study was to provide preliminary data on the applicability of the task in a sample of young adults. The DeFT was administered to 49 male and female undergraduate students selected from a normal population-base. Their mean age was 23.14 (S.D.=1.54). Three measures of delay frustration were recorded across time intervals during the response window; the number of responses, their duration and their combined product (total time button was pressed) was calculated for each second interval bin during the post-response delay period. The AARS and HADS were used as screening questionnaires for ADHD and anxiety behaviour, respectively. The results indicated that young adults with high-ADHD symptoms scores pressed the button more than those with low ADHD scores during the post-response delay condition. While both groups increased responding across time within intervals this was significantly more marked in the high-ADHD symptom group. These effects became more pronounced when anxiety was controlled. Young adults with high-ADHD symptoms appear to be more sensitive to the imposition of unscheduled and unsignalled delay during a simple maths test. DeFT may provide a useful index of delay tolerance in young adults with ADHD. Future research needs to examine DeFT performance in different age groups and in clinical and non-clinical populations.

Adult↗

PubMed2005

Online measurement of motivational processes: introducing the Continuous Delay Aversion Test (ConDAT).

The Continuous Delay Aversion Test (ConDAT), a new computer task for online monitoring and continuously measuring delay aversion (DA), is introduced. DA is a motivational style related to a shortened delay gradient which is proposed as a major endophenotype of attention deficit hyperactivity disorder (ADHD). It is characterised by avoiding or escaping from delay-rich situations despite the prospects of a reward. In each ConDAT trial the rapidly diminishing reward/delay ratio, which tends asymptotically towards zero, is visually presented on the computer screen. The test subject is permanently confronted with the question whether to quit or to continue the trial in the face of the deteriorating reward/time ratio. An elaborated control of stimuli and responses, including the sending of trigger codes to external recording devices, makes the task useful for neurophysiological or brain imaging experiments. Compared to existing tasks, the ConDAT is more flexible and sensitive due to its asymptotic open-ended trials and the interval-scaled output measure. Pilot data give evidence for satisfactory reliability and external validity of the task.

Attention Deficit Disorder with Hyperactivity↗

PubMed2005

Chromosomal fragility, structural rearrangements and mobile element activity may reflect dynamic epigenetic mechanisms of importance in neurobehavioural genetics.

Advances in human genome analyses have not yet allowed identification of specific genetic mechanisms underlying the expression of human neurobehavioural disorders. There is an increasing awareness that several genes may contribute to behavioural phenotypes and these genes appear to interact in as yet undetermined ways. It has been suggested that the problem needs elucidation from an epigenetic, gene expression perspective. Cytogenetic instability manifesting as chromosomal fragile sites, translocations, duplications, deletions and inversions, when co-occurring with neurobehavioural disorders, may offer a doorway to the investigation of such chromatin level, regulatory region, epigenetic processes. Due to earlier indications of non-specificity of chromosomal aberrations, poor phenotype:genotype correlations and a shift to analysing candidate coding regions on high resolution map level, the only utility of chromosomal breakpoints came to be seen as harbouring possible candidate genes of interest when segregating together with particular neurobehavioural disorders. More recent findings of the expression of highly specific subsets of fragile sites in association with Tourette and Rett syndromes need to be extended to other neurobehavioural disorders to ascertain whether observed patterns can be considered representative of 'chromatin endophenotypes' correlating with discrete sets of neurobehavioural symptoms. Environmental/epigenetic factors could affect the chromatin characteristics of the genome arising through DNA strand breakage, mobile element activity and retroinsertion, establishing new architectural features of regulatory control networks very rapidly in comparison to coding region evolution rates. Microarray-based techniques for the genome-wide mapping of in vivo protein-DNA interactions offer increasingly comprehensive views of genetic and epigenetic regulatory networks. It may be informative to include functionally significant chromatin structural variation analyses when considering candidate genes for neurobehavioural disorders.

Cell Cycle↗

PubMed2006

Therapeutic possibilities of cysteamine in the treatment of schizophrenia.

Schizophrenia has complicated pathogeneses that is not able to be explained by any one supposed hypothesis, although alterations in dopamine neurotransmission have been widely accepted as the most plausible mechanism. A transition from traditional typical antipsychotics to contemporary atypical antipsychotics which have significantly improved tolerability and enhanced specific efficacy has been also made based on this dopamine hypothesis. Cysteamine is a natural product of mammalian cells and found to be useful pharmacological alternative. A number of evidence suggests that cysteamine may control directly or indirectly dopamine neurotransmission in nucleus accumbens and other schizophrenia-related brain regions. Systemic cysteamine injection mitigated the apomorphine-induced stereotypy as well as decreasing motor stimulant effects of amphetamine, which favor cysteamine over animal models of schizophrenia relative to hyperactivity of dopaminergic pathway. In addition, cysteamine showed neuroprotective effects by way of enhancing central and serum brain derived neurotrophic factor (BDNF) that has been proved to be altered in patients with schizophrenia. Antipsychotic drugs exert their effect partly by modifying the synthesis and distribution of BDNF in selected brain region. Cysteamine was effective to reverse a disruption in prepulse inhibition, an endophenotypic marker of schizophrenia. Cysteamine can also stimulate the release of cortical dopamine, which is interesting in that decreased dopaminergic function in the cerebral cortex has been repeatedly demonstrated in patients with schizophrenia and associated with prominent depressive and negative symptoms. Cysteamine can also increase an important antioxidant, glutathione. Finally, cysteamine treatment was found to decrease weight gain, cataleptic behavior, and serum prolactin levels, which are the major beneficial properties of contemporary atypical antipsychotics. Hence, further explorations of therapeutic implication of cysteamine for schizophrenia in preclinical studies should be warranted in future.

Brain↗

PubMed2004

Meta-analysis and the science of schizophrenia: variant evidence or evidence of variants?

Quantification (meta-analysis) of the neuroscience evidence on schizophrenia shows very modest average differences between patient and control distributions across a great variety of measures and literatures. The strongest findings involve cognitive and psychophysiological measures. Several possible explanations for this situation are reviewed including technical immaturity, methodological variability, dimensional and multiple illness models and the nature of cognitive measurement. An argument is developed that biological subtypes and endophenotypes within the broad diagnostic category of schizophrenia underpin the meta-analytic evidence. Considerations in the use of this evidence to identify illness variants are described and four candidate subtypes are proposed. Schizophrenia is a disease that will resist biological definition until its variants are isolated and extracted from the generic patient population.

Case-Control Studies↗

PubMed2004

Anxiety and panic: from human studies to animal research and back.

The role of learning and conditioning varies across human anxiety disorders, and distinguishing between fear and panic is important to guide investigation in panic disorder. By reminding that some psychological and psychobiological theories view panic attacks as false alarms of unconditioned biological origin, we suggest that employing endophenotypes of biological and evolutionary relevance--such as the respiratory responses to suffocative stimuli--can be fruitful for both human research and animal models of panic, and can help keeping unconditioned components of the clinical picture separate from the conditioned components in the experimental setting. We present a review of a model of panic disorder by which idiosyncratic environmental adverse events can promote unconditioned and unexpected spells of physical alarm. Along the proposed causal pathway the alternative splicing expression of polymorphic genes of the cholinergic system play an important role. The overproduction of the Acetylcholinesterase readthrough splice variant after minor stress can promote passive avoidance and learning through action at the level of the corticolimbic circuitries, as well as heightened sensitivity to suffocative stimuli by action upon the cholinergic components of chemoception. When a component of anticipatory anxiety complicates the clinical picture of recurrent panic attacks, and the HPA becomes activated, the glucocorticoid response element 17 kb upstream of the Acetylcholinesterase gene transcription initiation site may sustain sensitivity to suffocative stimuli for prolonged time. Finally, we review how animal models of human panic based on unconditioned provocation of alarm reactions by the same respiratory panicogens that are employed in man are viable and promising.

Acetylcholinesterase↗

PubMed2004

Molecular genetic aspects of attention-deficit/hyperactivity disorder.

Two genome wide scans, one of which was subsequently extended, have led to the identification of different chromosomal regions assumed to harbour genes underlying attention-deficit/hyperactivity disorder (ADHD). Some of these regions were also identified in patients with autism and/or dyslexia. The only region for which both studies detected a LOD score >1 was on chr 5p13 which is in the vicinity of the location of the candidate gene DAT1. The candidate gene approach has revealed the most robust and replicated findings for DRD4, DRD5, and DAT1 polymorphisms. Meanwhile interesting endophenotype studies have also been conducted suggesting a genetic basis for different diagnostic and therapeutic criteria. Animal studies for ADHD have investigated especially hyperactivity and have focused mainly on knockout and QTL designs. In knockout mice models the most promising results were obtained for genes of the dopaminergic pathway. QTL results in rodents suggest multiple loci underlying different forms of natural and induced hyperactivity. The molecular results mentioned above are presented and discussed in detail, thus providing both clinicians and geneticists with an overview of the current research status of this important child and adolescent psychiatric disorder.

Animals↗

PubMed2004

Neurobiology of emotion and high risk for schizophrenia: role of the amygdala and the X-chromosome.

Abnormalities in emotion processing and in structure of the amygdala have consistently been documented in schizophrenia. A major question is whether amygdala abnormalities reflect a genetic vulnerability for the disease. In the present paper, we reviewed Magnetic Resonance Imaging (MRI) studies that reported amygdala measures in several high-risk populations: subjects from the general population with subclinical schizophrenia symptoms and relatives of schizophrenia patients. In addition, we reviewed the evidence regarding Klinefelter syndrome (characterised by an additional X-chromosome), which has also been related to an increased risk for schizophrenia. Overall, the evidence points to structural abnormalities of the amygdala in individuals at increased risk for schizophrenia. Although the genetic basis of amygdala deficits remains unclear, abnormalities (of genes) on the X-chromosome might play a role as suggested by the evidence from individuals with sex chromosome aneuploidies. We propose that amygdala abnormalities are an endophenotype in schizophrenia and may account for subtle emotional processing deficits that have been described in these high-risk groups.

Amygdala↗

PubMed2005

Mutant mouse models of depression: candidate genes and current mouse lines.

Depression is a multifactorial and multigenetic disease. At present, three main theories try to conceptualize its molecular and biochemical mechanisms, namely the monoamine-, the hypothalamus-pituitary-adrenal- (HPA-) system- and the neurotrophin-hypotheses. One way to explore, validate or falsify these hypotheses is to alter the expression of genes that are involved in these systems and study their respective role in animal behavior and neuroendocrinological parameters. Following an introduction in which we briefly describe each hypothesis, we review here the different mouse lines generated to study the respective molecular pathways. Among the many mutant lines generated, only a few can be regarded as genetic depression models or as models of predisposition for a depressive syndrome after stress exposure. However, this is likely to reflect the human situation where depressive syndromes are complex, can vary to a great extent with respect to their symptomatology, and may be influenced by a variety of environmental factors. Mice with mutations of candidate genes showing depression-like features on behavioral or neurochemical levels may help to define a complex molecular framework underlying depressive syndromes. Because it is conceivable that manipulation of one single genetic function may be necessary but not sufficient to cause complex behavioral alterations, strategies for improving genetic modeling of depression-like syndromes in animals possibly require a simultaneous targeted dysregulation of several genes involved in the pathogenesis of depression. This approach would correspond to the new concept of 'endophenotypes' in human depression research trying to identify behavioral traits which are thought to be encoded by a limited set of genes.

Animals↗

PubMed2006

The genetic background to PTSD.

Although extensive research has already been done on the genetic bases of psychiatric disorders, little is known about polygenetic influences in posttraumatic stress disorder (PTSD). This article reviews molecular genetic studies relating to PTSD that were found in a literature search in Medline, Embase and Web of Science. Association studies have investigated 8 major genotypes in connection with PTSD. They have tested hypotheses involving key candidate genes in the serotonin (5-HTT), dopamine (DRD2, DAT), glucocorticoid (GR), GABA (GABRB), apolipoprotein systems (APOE2), brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY). The studies have produced inconsistent results, many of which may be attributable to methodological shortcomings and insufficient statistical power. The complex aetiology of PTSD, for which experiencing a traumatic event forms a necessary condition, makes it difficult to identify specific genes that substantially contribute to the disorder. Gene-finding strategies are difficult to apply. Interactions between different genes and between them and the environment probably make certain people vulnerable to developing PTSD. Gene-environmental studies are needed that focus more narrowly on specific, distinct endophenotypes and on influences from environmental factors.

Apolipoproteins↗

PubMed2003

Genetic influences on prepulse inhibition of startle reflex in humans.

Prepulse inhibition (PPI) is a suppression of the startle reflex that occurs when an intense startling stimulus is preceded by a weaker 'prepulse' stimulus. PPI deficits have been implicated in the biological bases of schizophrenia and some other neuropsychiatric disorders and proposed as a possible biological marker (endophenotype) for genetic studies. However, little is known about the genetic determination of PPI in humans. We examined acoustic eye-blink startle reflex and PPI in 142 young female twins (40 monozygotic and 31 dizygotic pairs) and conducted a biometrical genetic analysis using structural equation modeling. PPI showed significant heritability suggesting that over 50% of PPI variance in this sample can be attributed to genetic factors. Baseline startle magnitude showed higher heritability (about 70%).

Acoustic Stimulation↗

PubMed2004

A single nucleotide polymorphism in glycogen synthase kinase 3-beta promoter gene influences onset of illness in patients affected by bipolar disorder.

Genetic studies in medicine exploited age of onset as a criterion to delineate subgroups of illness. Bipolar patients stratified with this criterion were shown to share clinical characteristics and patterns of inheritance of illness. The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50 T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been identified. GSK3-beta codes for an enzyme which is a target for the action of lithium and which is also known to regulate circadian rhythms in Drosophila. We studied the effect of this polymorphism on the age at onset of bipolar disorder type I. A homogeneous sample of 185 Italian patients affected by bipolar disorder was genotyped. Age at onset was retrospectively ascertained with best estimation procedures. No association was detected between GSK3-beta -50 T/C SNP and the presence of bipolar illness. Homozygotes for the wild variant (T/T) showed an earlier age at onset than carriers of the mutant allele (F=5.53, d.f.=2,182, P=0.0047). Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited.

Adolescent↗

PubMed2004

A glycogen synthase kinase 3-beta promoter gene single nucleotide polymorphism is associated with age at onset and response to total sleep deprivation in bipolar depression.

The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been linked with different age at onset of bipolar illness. GSK3-beta codes for an enzyme which is a target for the action of lithium and valproic acid, and the inhibition of which causes antidepressant-like behaviors in a preclinical model. We studied the effect of this polymorphism on the acute response to total sleep deprivation of 60 depressed bipolar type I inpatients. Homozygotes for the mutant allele of GSK3-beta promoter (-50T/C) SNP showed a later onset of bipolar illness, and better acute effects of TSD treatment on perceived mood (as rated on VAS). Overall, these observations suggest a protective role for this genotype in respect to bipolar illness. Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, and for GSK3-beta as a target of a new class of antidepressant drugs, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited because of the low frequency of the GSK3-beta*C/C genotype in the studied populations.

Adult↗

PubMed2004

Genetics, prefrontal cortex, and cognitive control: a twin study of event-related brain potentials in a response inhibition task.

Inhibition of prepotent responses plays a key role in cognitive executive control of goal-directed behavior. Response inhibition in Go/No-Go tasks elicits a distinct midfrontal ERP component, the N2, localized in previous studies to the anterior cingulate cortex. We assessed heritability of the No-Go N2 and the succeeding positive P3 component in 194 young female twins (52 monozygotic and 45 dizygotic pairs) who completed a cued version of the Continuous Performance Test. Genetic model-fitting analysis showed that about 60% of the variance in N2 and P3 amplitudes can be attributed to genetic factors, suggesting that frontal No-Go N2 and P3 components may index genetically transmitted individual differences in brain activity related to conflict processing and can potentially serve as endophenotypes for genetic studies of disorders characterized by neurobehavioral disinhibition.

Adolescent↗

PubMed2004

Long-term response to lithium salts in bipolar illness is influenced by the glycogen synthase kinase 3-beta -50 T/C SNP.

The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50 T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been linked with different age at onset of bipolar illness and with different antidepressant effects of total sleep deprivation. GSK3-beta codes for an enzyme which is a target for the action of lithium and possibly of valproic acid. We studied the effect of this polymorphism on the therapeutic response to lithium salts of 88 bipolar type I patients. Data about recurrence rate of mood episodes were collected for at least 2 years before lithium and 2 years on lithium. Results showed that homozygotes for the wild variant did not change their recurrence index while carriers of the mutant allele improved, thus supporting the hypothesis that GSK is a target for the therapeutic action of lithium. Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited because of the low frequency of the GSK3-beta*C/C genotype in the studied populations.

Adult↗

PubMed2006

The T393C polymorphism of the GNAS1 gene is associated with deficit schizophrenia in an Italian population sample.

Programmed cell death and alterations in intracellular G-protein signaling may be involved in the pathophysiology of schizophrenia. The Galphas subunit of heterotrimeric G-proteins, encoded by the gene GNAS1, may play a role in both of these processes. Additionally, transgenic mice expressing a constitutively active form of Galphas provide a reliable model of certain endophenotypes of schizophrenia. To investigate whether the functional single nucleotide polymorphism T393C in GNAS1 gene could affect risk of schizophrenia, we examined its distribution in Italian subjects with (n=383) and without (n=400) schizophrenia. We also evaluated whether a specific association could exist between the deficit (n=108) and nondeficit (n=275) forms of the disorder. The alleles and genotypes frequency in the entire cohort of schizophrenic patients did not differ from that of controls. However, the frequency of the homozygous 393TT genotype was significantly higher in deficit schizophrenic patients (37.1%) compared to both nondeficit schizophrenic (22.5%, p=0.011) and controls (22.8%, p=0.015). This association with deficit schizophrenia persisted even after allowance for potential confounders [adjusted odds ratio (OR) for deficit schizophrenia: 2.06 (95% confidence interval (CI): 1.21-3.47), p=0.007]. Altogether, our data suggest that the GNAS1 T393C status could influence susceptibility for deficit schizophrenia in Italian subjects.

Adult↗

PubMed2006

Linkage disequilibrium analysis of the CHRNA7 gene and its partially duplicated region in schizophrenia.

Several previous studies have reported a significant linkage between markers in the alpha 7 nicotinic cholinergic receptor subunit (CHRNA7) gene and either schizophrenia or the P50 sensory gating deficit, a schizophrenia endophenotype. However, CHRFAM7A, a partially duplicated gene 1.6Mb upstream of the CHRNA7 gene, has complicated further genetic analysis. We genotyped 14 polymorphic markers throughout the full-length CHRNA7 gene and the duplicated region in 188 unrelated Han Chinese patients with schizophrenia and 188 controls. The duplicated regions were assessed by genotyping up- and down-stream polymorphic markers in the vicinity of each region and analyzing the linkage disequilibrium (LD) between each pair of markers. No evidence of risk variants for schizophrenia in either the CHRNA7 gene or the partially duplicated region was found in the LD analysis. A significant deviation from the Hardy-Weinberg equilibrium (HWE) was found only in the genotypic distribution of SNP9 (IVS4-1912) in patients (p=0.00829), but not in controls. In conclusion, our LD analysis did not reveal any association between schizophrenia in our Han Chinese population and the CHRNA7 gene or its partially duplicated region. However, we could not exclude the possibility of a weak genetic effect due to the small sample size. Analyses of larger samples and higher-density markers, particularly around SNP9 (IVS4-1912), are still needed.

Asian People↗

PubMed2006

Gray and white matter density changes in monozygotic and same-sex dizygotic twins discordant for schizophrenia using voxel-based morphometry.

Global gray matter brain tissue volume decreases in schizophrenia have been associated to disease-related (possibly nongenetic) factors. Global white matter brain tissue volume decreases were related to genetic risk factors for the disease. However, which focal gray and white matter brain regions best reflect the genetic and environmental risk factors in the brains of patients with schizophrenia remains unresolved. 1.5-T MRI brain scans of 11 monozygotic and 11 same-sex dizygotic twin-pairs discordant for schizophrenia were compared to 11 monozygotic and 11 same-sex dizygotic healthy control twin-pairs using voxel-based morphometry. Linear regression analysis was done in each voxel for the average and difference in gray and white matter density separately, in each twin-pair, with group (discordant, healthy) and zygosity (monozygotic, dizygotic) as between subject variables, and age, sex and handedness as covariates. The t-maps (critical threshold value mid R:tmid R: > 6.0, P < 0.05) revealed a focal decrease in gray matter density accompanied by a focal increase in white matter density in the left medial orbitofrontal gyrus and a focal decrease in white matter density in the left sensory motor gyrus in twin-pairs discordant for schizophrenia as compared to healthy twin-pairs. Focal changes in left medial (orbito)frontal and left sensory motor gyri may reflect the increased genetic risk to develop schizophrenia. Focal changes in the left anterior hemisphere may therefore be particularly relevant as endophenotype in genetic studies of schizophrenia.

Brain↗