ADHD related behaviors are associated with brain activation in the reward system

Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) suggest dysfunctional reward processing, with hypo-responsiveness during reward anticipation in the reward system including the nucleus accumbens (NAcc). In this study, we investigated the association between ADHD related behaviors and the reward system using functional magnetic resonance imaging in a non-clinical sample. Participants were 31 healthy, female undergraduate students with varying levels of self-reported ADHD related behaviors measured by the adult ADHD self-report scale. The anticipation of different types of reward was investigated: monetary reward, punishment avoidance, and verbal feedback.All three reward anticipation conditions were found to be associated with increased brain activation in the reward system, with the highest activation in the monetary reward anticipation condition, followed by the punishment avoidance anticipation condition, and the lowest activation in the verbal feedback anticipation condition. Most interestingly, in all three conditions, NAcc activation was negatively correlated with ADHD related behaviors.In conclusion, our results from a non-clinical sample are in accordance with reported deficits in the reward system in ADHD patients: the higher the number and severity of ADHD related behaviors, the lower the neural responses in the dopaminergic driven reward anticipation task. Thus, our data support current aetiological models of ADHD which assume that deficits in the reward system might be responsible for many of the ADHD related behaviors.     

Reduced striatal activation during reward anticipation due to appetite-provoking cues in chronic schizophrenia: a fMRI study

The occurrence of weight gain in schizophrenia (SZ) has profound clinical impact and interacts with antipsychotic medication, life style and disease severity. The functional neuroanatomy underlying altered nutritional behavior is unraveled, but dysregulated reward anticipation might be one of the involved neuronal mechanisms. The striatum, a core region of the reward network and salience attribution, was previously shown to regulate appetite perception and eating behavior. We studied patients suffering from chronic schizophrenia with a stable medication in comparison to age and gender matched healthy adults. Every subject had to undergo a 6h fasting period before a newly developed, appetite-provoking fMRI task was applied. Subjects saw visual stimuli of appetitive food items in a 3Tesla scanner. In healthy controls food images elicited stronger activation in the striatum compared to SZ patients. When adjusting a ROI-based striatal activation for medication and weight, the group difference remained still significant. This points an effect of illness independent of antipsychotic medication. These data underscore the involvement of the striatum into salience attribution, reward anticipation and the neuronal pathways leading to altered eating behavior and weight gain in schizophrenia.     

Common genetic coagulation variants are not associated with ischemic stroke in a case-control study

Abstract

Objective: Abnormalities in the coagulation pathway are often included in the diagnostic work-up of stroke patients, especially in young adults with cryptogenic stroke.

Methods: Three common genetic variants within the coagulation cascade were investigated in 500 control subjects and in 167 patients with ischemic stroke defined by TOAST subclassification. Analysed variants were factor V Leiden, prothrombin 20210G→A and factor XIII Val34Leu.

Results: The factor V Leiden mutation was over-represented in patients with cardioembolic stroke for trend, whereas the prothrombin 20210G→A variant and the factor XIII polymorphism Val34Leu were not associated with stroke of any subtype. The three polymorphisms showed no association with stroke in subgroups of patients defined by age (<40, 40–49, 50–59, ≥60 years).

Discussion: This study suggests that the analysis of prothrombin 20210G→A and factor XIII Val34Leu is not a useful diagnostic procedure in the work-up of ischemic stroke.     

Brain-derived neurotrophic factor variants are associated with childhood-onset mood disorder: confirmation in a Hungarian sample

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. BDNF markers included the (GT)n microsatellite, Val66Met and four other single-nucleotide polymorphisms (SNPs) distributed across the BDNF gene. Family-based association and evolutionary haplotype analysis methods were used. Analysis of linkage disequilibrium (LD) revealed substantial LD among all six polymorphisms. Analyses of the Val66Met polymorphism demonstrated significant overtransmission of the val allele (chi2=7.12, d.f.=1, P=0.0076). Consistent with the pattern of LD, all other SNPs showed significant biased transmission. The (GT)n microsatellite alleles also indicated a trend towards biased transmission (170 bp: Z=2.095, P=0.036). Significant haplotypes involved Val66Met and BDNF2 (P=0.0029). In this Hungarian sample, we found all five BDNF SNPs tested and a haplotype containing the BDNF Val66Met Val allele to be associated with COMD. These results provide evidence that BDNF variants affect liability to juvenile-onset mood disorders, supported by data from two independent samples.     

Reduced P3 amplitudes are associated with both a family history of alcoholism and antisocial personality disorder

1. 1. Previous research has demonstrated that the amplitude of the P3 component of the event-related electroencephalographic potential (ERP) is influenced by the presence/absence of a family history of alcoholism (FHA). The present study extended this line of research by examining the P3 effects of both FHA and antisocial personality disorder (ASP) in a 2 × 2 factorial design.

2. 2. The task required subjects to judge the orientation of an infrequently-occurring outline drawing, representing an aerial view of a human head.

3. 3. Analyses of P3 amplitudes elicited by this drawing revealed reductions attributable to the effects of both FHA and ASP, but not their interaction. These effects were most apparent at frontal electrode sites. Analyses of P3 latency revealed no consistent pattern of findings. However, the interval between P3 and manual reaction time was shorter in the ASP+ group relative to the ASP- group.

Differential patterns of nucleus accumbens activation during anticipation of monetary and social reward in young and older adults

Recent studies have reported inconsistent results regarding the loss of reward sensitivity in the aging brain. Although such an age effect might be due to a decline of physiological processes, it may also be a consequence of age-related changes in motivational preference for different rewards. Here, we examined whether the age effects on neural correlates of reward anticipation are modulated by the type of expected reward. Functional magnetic resonance images were acquired in 24 older (60–78 years) and 24 young participants (20–28 years) while they performed an incentive delay task offering monetary or social rewards. Anticipation of either reward type recruited brain structures associated with reward, including the nucleus accumbens (NAcc). Region of interest analysis revealed an interaction effect of reward type and age group in the right NAcc: enhanced activation to cues of social reward was detected in the older subsample while enhanced activation to cues of monetary reward was detected in the younger subsample. Our results suggest that neural sensitivity to reward-predicting cues does not generally decrease with age. Rather, neural responses in the NAcc appear to be modulated by the type of reward, presumably reflecting age-related changes in motivational value attributed to different types of reward.     

Ventral striatal activation during attribution of stimulus saliency and reward anticipation is correlated in unmedicated first episode schizophrenia patients

Patients with schizophrenia show deficits in motivation, reward anticipation and salience attribution. Several functional magnetic resonance imaging (fMRI) investigations revealed neurobiological correlates of these deficits, raising the hypothesis of a common basis in midbrain dopaminergic signaling. However, investigations of drug-na?ve first-episode patients with comprehensive fMRI tasks are still missing. We recruited unmedicated schizophrenia spectrum patients (N=27) and healthy control subjects (N=27) matched for sex, age and educational levels. An established monetary reward anticipation task in combination with a novel task aiming at implicit salience attribution without the confound of monetary incentive was applied. Patients showed reduced right ventral striatal activation during reward anticipation. Furthermore, patients with a more pronounced hypoactivation attributed more salience to neutral stimuli, had more positive symptoms and better executive functioning. In the patient group, a more differentially active striatum during reward anticipation was correlated positively to differential ventral striatal activation in the implicit salience attribution task. In conclusion, a deficit in ventral striatal activation during reward anticipation can already be seen in drug-na?ve, first episode schizophrenia patients. The data suggest that rather a deficit in differential ventral striatal activation than a generally reduced activation underlies motivational deficits in schizophrenia and that this deficit is related to the aberrant salience attribution.     

PEN2 is not a genetic risk factor for Alzheimer's disease in a large family sample

PEN2 is a reasonable Alzheimer's disease (AD) candidate gene because it is a necessary component of the gamma-secretase complex that generates beta-amyloid peptide. Moreover, its gene (PEN2) maps to a highly significant linkage region on chromosome 19q13. Four common polymorphisms in PEN2 were tested for genetic association with AD in a large and carefully ascertained AD family sample (789 subjects from 202 nuclear families) using single-locus and haplotype-based analyses. These results do not suggest PEN2 to be a major AD risk factor.     

Happy for Us not Them: Differences in neural activation in a vicarious reward task between family and strangers during adolescent development

During adolescence social-interactions with other people become more relevant. One key aspect of these interactions is cooperative behavior. Cooperation relies on a set of cognitive and affective mechanisms. In this study, we focused on the mental ability to feel happy for another person’s positive experience, called vicarious joy. We investigated the neural mechanisms of this ability using a false-choice vicarious reward fMRI task. Participants played a game where they could win monetary rewards for themselves, their mother, their father, and a stranger. A region-of-interest (ROI) analysis of the Nucleus Accumbens revealed robust activation in this region for personal reward as well as vicarious rewards for both parents. Vicarious reward for a stranger was not associated with activation within the Nucleus Accumbens. ROI activation was associated with self-reported vicarious joy for mother and father. A Prisoner’s Dilemma game outside the scanner showed an increase in cooperative behavior until age 14 for parents and strangers, followed by a decline for the stranger but not for the parents. Together, these findings demonstrate that adolescence is an important time for developing ingroup-outgroup relations.     

Genetic variants of FOXP2 and KIAA0319/TTRAP/THEM2 locus are associated with altered brain activation in distinct language-related regions

Recent advances have been made in the genetics of two human communication skills: speaking and reading. Mutations of the FOXP2 gene cause a severe form of language impairment and orofacial dyspraxia, while single-nucleotide polymorphisms (SNPs) located within a KIAA0319/TTRAP/THEM2 gene cluster and affecting the KIAA0319 gene expression are associated with reading disability. Neuroimaging studies of clinical populations point to partially distinct cerebral bases for language and reading impairments. However, alteration of FOXP2 and KIAA0319/TTRAP/THEM2 polymorphisms on typically developed language networks has never been explored. Here, we genotyped and scanned 94 healthy subjects using fMRI during a reading task. We studied the correlation of genetic polymorphisms with interindividual variability in brain activation and functional asymmetry in frontal and temporal cortices. In FOXP2, SNPs rs6980093 and rs7799109 were associated with variations of activation in the left frontal cortex. In the KIAA0319/TTRAP/THEM2 locus, rs17243157 was associated with asymmetry in functional activation of the superior temporal sulcus (STS). Interestingly, healthy subjects bearing the KIAA0319/TTRAP/THEM2 variants previously identified as enhancing the risk of dyslexia showed a reduced left-hemispheric asymmetry of the STS. Our results confirm that both FOXP2 and KIAA0319/TTRAP/THEM2 genes play an important role in human language development, but probably through different cerebral pathways. The observed cortical effects mirror previous fMRI results in developmental language and reading disorders, and suggest that a continuum may exist between these pathologies and normal interindividual variability.     

Alcohol dehydrogenase 2 genotype and allelic variants are not associated with the risk for essential tremor

OBJECTIVE: To investigate the possible association between alcohol dehydrogenase 1B, beta-polypeptide (ADH2) genotype and allelic variants and the risk for developing essential tremor (ET). METHODS: Leukocytary DNA from 204 ET patients and 200 healthy controls was studied for the genotype ADH2 and the occurrence of ADH2 allelic variants using allele-specific polymerase chain reaction amplification and MslI-restriction fragment length polymorphism's analyses. RESULTS: The frequencies of the ADH2*1/ADH2*2 genotype and of the allelic variant ADH2*2 did not differ significantly in ET patients when compared with those of the controls. The mean age at onset of ET did not differ significantly between patients with genotypes ADH2*1/ADH2*2 and ADH2*1/ADH2*1. The frequencies of the genotype ADH2*1/ADH2*2 and of the allelic variant ADH2*2 in patients with voice, tongue, and chin tremors did not differ from those of the controls, whereas patients with voice tremor showed lower frequencies of mutated genotypes and ADH2*2 alleles. The frequencies of ADH2 genotypes and ADH2 alleles did not differ significantly between patients who did not drink ethanol and those who reported improvement, no improvement, or unknown response of tremor to ethanol. CONCLUSIONS: These results suggest that ADH2 genotype and allelic variants are not associated with the risk for ET in white Spanish people.     

Short-term cognition deficits during early alcohol withdrawal are associated with elevated plasma homocysteine levels in patients with alcoholism

Summary. Higher plasma homocysteine levels have been found in actively drinking alcoholics as well as in early abstinent patients. Furthermore, elevated homocysteine levels are associated with cognitive decline in dementia and in healthy elderly people. The aim of this prospective study was to investigate a possible association between homocysteine serum levels and clinically well known cognitive deficits during alcohol withdrawal. We examined 89 patients (67 men, 22 women) during early withdrawal treatment. Cognitive function was assessed using the c.I.-Test. Patients with cognitive deficits showed significantly higher homocysteine serum levels (Mann-Whitney-U, p = 0.004) than patients without cognitive deficits, while the difference in blood alcohol concentration was not significant. Using logistic regression analysis, cognitive deficits were best predicted by high homocysteine serum levels (Wald χ² = 4.071, OR = 1.043, 95% CI 1.001–1.086, p<0.05), which was confirmed by Receiver Operating Curves (AUC = 0.68, 95% CI = 0.57–0.79, p = 0.004). The present results show first evidence of an association between elevated plasma homocysteine levels in alcoholics and cognition deficits in patients undergoing alcohol withdrawal.     

LINGO1 and LINGO2 variants are associated with essential tremor and Parkinson disease

Genetic variation in the leucine-rich repeat and Ig domain containing 1 gene (LINGO1) was recently associated with an increased risk of developing essential tremor (ET) and Parkinson disease (PD). Herein, we performed a comprehensive study of LINGO1 and its paralog LINGO2 in ET and PD by sequencing both genes in patients (ET, n?=?95; PD, n?=?96) and by examining haplotype-tagging single-nucleotide polymorphisms (tSNPs) in a multicenter North American series of patients (ET, n?=?1,247; PD, n?=?633) and controls (n?=?642). The sequencing study identified six novel coding variants in LINGO1 (p.S4C, p.V107M, p.A277T, p.R423R, p.G537A, p.D610D) and three in LINGO2 (p.D135D, p.P217P, p.V565V), however segregation analysis did not support pathogenicity. The association study employed 16 tSNPs at the LINGO1 locus and 21 at the LINGO2 locus. One variant in LINGO1 (rs9652490) displayed evidence of an association with ET (odds ratio (OR)?=?0.63; P?=?0.026) and PD (OR?=?0.54; P?=?0.016). Additionally, four other tSNPs in LINGO1 and one in LINGO2 were associated with ET and one tSNP in LINGO2 associated with PD (P?<?0.05). Further analysis identified one tSNP in LINGO1 and two in LINGO2 which influenced age at onset of ET and two tSNPs in LINGO1 which altered age at onset of PD (P?<?0.05). Our results support a role for LINGO1 and LINGO2 in determining risk for and perhaps age at onset of ET and PD. Further studies are warranted to confirm these findings and to determine the pathogenic mechanisms involved.     

Anomalous self-experiences are strongly associated with negative symptoms in a clinical high-risk for psychosis sample

ObjectiveAnomalous self-experiences (ASE) are considered as central features of the schizophrenia spectrum disorders and prodromal schizophrenia. We investigated total and single-item prevalence of these phenomena in a clinical high-risk (CHR) for psychosis sample, and associations with conventional psychosis-risk symptoms, present and childhood global/psychosocial functioning, and childhood trauma.MethodsThe sample (n = 38) included 31 CHR, according to ultra-high risk or cognitive basic symptoms (COGDIS) criteria, and seven with non-progressive attenuated positive symptoms. Psychopathological evaluations included the Examination of Anomalous Self-Experience (EASE), Structured Clinical Interview for Prodromal Syndromes (SIPS), Schizophrenia Proneness Instrument – Adult (SPI-A) (only the COGDIS-criteria), a diagnostic interview (SCID-I), Global Assessment of Functioning – Split version (S-GAF), Premorbid Adjustment Scale (PAS) and Childhood Trauma Questionnaire (CTQ).ResultsThe mean total EASE score was in line with reports from other CHR samples, and was particularly enhanced in schizotypal personality disorder and in subjects fulfilling COGDIS-criteria. The four most frequent EASE-items were present in two-thirds or more of the participants. EASE total was significantly associated with negative and disorganization symptoms. A multiple regression analysis revealed that the level of negative symptoms explained most of the variance in EASE total.ConclusionsThese results corroborates other findings that anomalous self-experiences are frequent and important features in CHR conditions and in the schizophrenia spectrum. The strong associations with negative symptoms and cognitive disturbances (COGDIS) should be investigated in longitudinal studies to address causality, psychopathological pathways and schizophrenia spectrum specificity. The weaker correlation between EASE total and positive symptoms may partly be related to a restricted range of positive symptoms.