Dopamine transporter genotype predicts behavioural and neural measures of response inhibition

The ability to inhibit unwanted actions is a heritable executive function that may confer risk to disorders such as attention deficit hyperactivity disorder (ADHD). Converging evidence from pharmacology and cognitive neuroscience suggests that response inhibition is instantiated within frontostriatal circuits of the brain with patterns of activity that are modulated by the catecholamines dopamine and noradrenaline. A total of 405 healthy adult participants performed the stop-signal task, a paradigmatic measure of response inhibition that yields an index of the latency of inhibition, termed the stop-signal reaction time (SSRT). Using this phenotype, we tested for genetic association, performing high-density single-nucleotide polymorphism mapping across the full range of autosomal catecholamine genes. Fifty participants also underwent functional magnetic resonance imaging to establish the impact of associated alleles on brain and behaviour. Allelic variation in polymorphisms of the dopamine transporter gene (SLC6A3: rs37020; rs460000) predicted individual differences in SSRT, after corrections for multiple comparisons. Furthermore, activity in frontal regions (anterior frontal, superior frontal and superior medial gyri) and caudate varied additively with the T-allele of rs37020. The influence of genetic variation in SLC6A3 on the development of frontostriatal inhibition networks may represent a key risk mechanism for disorders of behavioural inhibition.     

Serotonin transporter genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults

Recent attempts to understand the biological bases of depression vulnerability have revealed that both the short allele of the serotonin transporter-linked polymorphic region (5-HTTLPR) and activity in the amygdala are associated with depression. Other studies have reported amygdala hyperactivity associated with the 5-HTTLPR short allele, linking the genetic and neuroimaging lines of research and suggesting a mechanism whereby the short allele confers depression risk. However, fewer investigations have examined the associations among depression, 5-HTTLPR variability, and amygdala activation in a single study. The current study thus investigated whether 5-HTTLPR genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults. Regional cerebral blood flow was measured with perfusion fMRI during a task-free scan. We hypothesized differential associations between depressive symptoms and amygdala activity among individuals homozygous for the short allele and individuals homozygous for the long allele. Both whole brain analyses and region-of-interest analyses confirmed this prediction, revealing a significant negative association among the long allele group and a trend of positive association among the short allele group. These results complement existing reports of short allele related amygdala hyperactivity and suggest an additional neurobiological mechanism whereby the 5-HTTLPR is associated with psychiatric outcomes.     

Dopaminergic genotype influences spatial bias in healthy adults

Asymmetries of spatial attention are observed in both clinical and non-clinical populations. While lesions of the right hemisphere frequently result in symptoms of left neglect (right bias), the opposite pattern is often observed in healthy subjects, a phenomenon known as pseudoneglect. Pharmacological and animal studies have suggested a critical role for the catecholamines, in particular dopamine and noradrenaline, in modulating the direction and magnitude of spatial attentional bias. In the present study we investigated the effect of two catecholaminergic genes, DBH and DAT1, on performance in the Landmark task, a perceptual measure of spatial bias. 204 healthy participants performed the Landmark task and were genotyped for the DBH C-1021T and DAT1 3′UTR variants. Homozygosity for the DBH T allele, which is associated with relatively increased dopamine and decreased noradrenaline levels, resulted in a significant increase in rightwards spatial bias relative to the C allele. Similarly, homozygosity for the DAT1 9-repeat allele, which is associated with reduced dopamine transporter density, and consequently increased dopamine availability relative to the 10-repeat allele, was found to result in a greater degree of rightward bias. An additive effect of the two markers was also observed, such that the greatest degree of rightward spatial bias was observed in participants who possessed the ‘high dopamine’ alleles of both genes and the lowest degree in those without these alleles. These results provide the first evidence of genetic modulation of spatial bias in healthy adults.     

Network connectivity predicts language processing in healthy adults

Brain imaging has been used to predict language skills during development and neuropathology but its accuracy in predicting language performance in healthy adults has been poorly investigated. To address this shortcoming, we studied the ability to predict reading accuracy and single‐word comprehension scores from rest‐ and task‐based functional magnetic resonance imaging (fMRI) datasets of 424 healthy adults. Using connectome‐based predictive modeling, we identified functional brain networks with >400 edges that predicted language scores and were reproducible in independent data sets. To simplify these complex models we identified the overlapping edges derived from the three task‐fMRI sessions (language, working memory, and motor tasks), and found 12 edges for reading recognition and 11 edges for vocabulary comprehension that accounted for 20% of the variance of these scores, both in the training sample and in the independent sample. The overlapping edges predominantly emanated from language areas within the frontoparietal and default‐mode networks, with a strong precuneus prominence. These findings identify a small subset of edges that accounted for a significant fraction of the variance in language performance that might serve as neuromarkers for neuromodulation interventions to improve language performance or for presurgical planning to minimize language impairments.     

Subcortical intelligence: Caudate volume predicts IQ in healthy adults

This study examined the association between size of the caudate nuclei and intelligence. Based on the central role of the caudate in learning, as well as neuroimaging studies linking greater caudate volume to better attentional function, verbal ability, and dopamine receptor availability, we hypothesized the existence of a positive association between intelligence and caudate volume in three large independent samples of healthy adults (total N = 517). Regression of IQ onto bilateral caudate volume controlling for age, sex, and total brain volume indicated a significant positive correlation between caudate volume and intelligence, with a comparable magnitude of effect across each of the three samples. No other subcortical structures were independently associated with IQ, suggesting a specific biological link between caudate morphology and intelligence. Hum Brain Mapp 36:1407–1416, 2015. © 2014 Wiley Periodicals, Inc.     

Dopamine transporter genotype conveys familial risk of attention-deficit/hyperactivity disorder through striatal activation

OBJECTIVE: The dopamine transporter (DAT1) gene has been implicated in attention-deficit/hyperactivity disorder (ADHD), although the mechanism by which it exerts its effects remains unknown. The polymorphism associated with ADHD has been shown to affect expression of the transporter in vitro and in vivo. Dopamine transporters are predominantly expressed in the striatum, but also in the cerebellar vermis. Stimulant medication is often effective in ADHD and is believed to exert its effects by blocking dopamine transporters in the striatum. We set out to investigate the effect of the DAT1 genotype in ADHD in a small, preliminary study. We hypothesized that the DAT1 genotype would affect brain activation patterns in a manner similar to that of stimulant medication, with the lesser expressing allele mirroring its effects. METHOD: We investigated DAT1 gene effects on brain activation patterns in an all-male sample of sibling pairs discordant for ADHD (n = 20) and controls (n = 9). All of the subjects participated in a functional magnetic resonance imaging session using a go/no-go paradigm and provided a DNA sample for analysis. RESULTS: DAT1 genotype affected activation in the striatum and cerebellar vermis. The genotype interacted with familial risk of ADHD in the striatum but not the vermis. CONCLUSIONS: These preliminary results suggest that the DAT1 gene effects in the striatum are involved in translating the genetic risk of ADHD into a neurobiological substrate. As such, this study represents a first step in elucidating the neurobiological mechanisms underlying genetic influences in ADHD. Furthermore, these results may contribute to long-term possibilities for the development of new treatments: If the DAT1 genotype has differential effects on striatal activation, then it may be useful as a surrogate endpoint in individualized treatments targeting genotype/functional magnetic resonance imaging activation profiles.     

Dopamine transporter immunoreactivity in rat brain

The dopamine transporter (DAT) is a primary site for the action of cocaine in inducing euphoria. Its action is necessary for the selectivities of dopaminergic neurotoxins that provide the best current experimental models of Parkinson's disease. In the present report, rat ddpamine transporter-like immunoreactivity (iDAT) was assessed by immunohistochemistry using newly developed polyclonal antisera raised against conjugated peptides corresponding to sequences found in the dopainine transporter's carboxy- and amino-termini. Dense iDAT was observed in patterns consistent with neural processes and terminals in the striatum, nucleus accumbens, olfactory tubercle, nigrostriatal bundle, and lateral habenula. Perikarya in the substantia nigra pars compacts, were immunostained with moderate intensity using one of two immunohistochemical methods, while scattered ventral tegmental area perikarya were stained with somewhat less intensity. Immunoreactive neuronal processes with axonal and dendritic morphologies were stained in the substantia nigra and the paranigral and parabrachialis pigmentosus nuclei of the ventral tegmental area, while sparser processes were noted more medially in the ventral tegmental area. Neuronal processes were found in several laminae in the cingulate cortex, with notable fiber densities in the superficial aspects of lamina I and laminae II/III. The intensities of immunoreactivities in striatum and cerebral cortex were dramatically attenuated ipsilateral to nigrostriatal bundle 6-hydroxydopamine lesions. Specificity of immunostaining was supported by agreement of the results using sera directed against two distinct DAT segments, studies with preimmune and preadsorbed sera and studies of the extracted protein. These antisera identify and reveal details of the distribution of DAT immunoreactivity in rat brain and display ivariations in levels of DAT expression of likely functional significance. © 1995 Wiley-Liss, Inc.     

Dopamine transporter (DAT) genotype (VNTR) and phenotype in extrapyramidal symptoms induced by antipsychotics

INTRODUCTION: Impaired dopamine transporter (DAT) function may be involved in antipsychotic (AP)-induced extrapyramidal symptoms (EPS). A polymorphism involving a variable number of tandem repeats (VNTR) has been described in the DAT gene (SLC6A3). OBJECTIVE: We studied whether the SLC6A3 VNTR polymorphism is a risk or protection factor for AP-induced EPS. We also investigated the relationship between the polymorphism and DAT availability in the schizophrenic patient's brain. METHODS: Sixty-one patients receiving AP therapy participated in the EPS study. Of these, thirty-two cases presented EPS (Simpson-Angus >3) and twenty-nine without EPS (Simpson-Angus < or =3). The DAT expression was studied in fifteen AP-naive patients by [(123)I] FP-CIT SPECT. RESULTS: No significant differences were observed for the more common alleles ((*)9R and (*)10R) or for genotype frequencies between patients with EPS and those without EPS. The frequency of the (*)9R and (*)10R alleles was similar to that described in other European populations. There were no significant differences in striatal DAT binding among the three major VNTR genotype groups. CONCLUSIONS: Our results suggest that the VNTR polymorphism did not influence AP-induced EPS and did not affect DAT gene expression or protein function.     

Dopamine transporter binding in Wilson's disease

INTRODUCTION: In Wilson's disease (WD), brain magnetic resonance images (MRI) show increased signal intensity in T2 weighted images in the lenticular nuclei, thalamus and brainstem, including the substantia nigra. A poor therapeutic response to levodopa in WD suggests the mechanism of a postsynaptic abnormality. However positron emission tomography studies show an involvement of the nigrostriatal presynaptic dopaminergic pathway. CASE REPORT: We report the clinical manifestations in a case of WD with akinetic-rigid syndrome and initial hesitation. The brain MRI showed an increased signal intensity lesion in the substantia nigra region, in addition to basal ganglion and thalamic lesions. However, dopamine transporter (DAT) imaging with 99mTc-TRODAT-1 revealed a nonsignificantly increased DAT uptake, suggesting a normal presynaptic nigrostriatal dopaminergic terminal. CONCLUSION: We suggest that significant heterogeneity can be found in WD patients and a normal presynaptic dopaminergic pathway may occur in some patients, even those with typical akinetic-rigid syndrome and evidence of substantia nigra involvement in the brain on MRI.     

Association of schizotypy with striatocortical functional connectivity and its asymmetry in healthy adults

Altered striatocortical functional connectivity has been suggested to be a trait marker of schizophrenia spectrum disorders, including schizotypal personality. In the present study, we examined the association between schizotypal personality traits and striatocortical functional connectivity in a sample of healthy adults. The German version of the Schizotypal Personality Questionnaire was obtained from N = 111 participants recruited from the general public. Resting‐state functional magnetic resonance imaging scans were acquired at 3T. Six striatal seed regions in each hemisphere were defined and striatocortical resting‐state functional connectivity (rsFC) as well as its lateralization indices was calculated. Regression analysis showed that schizotypy scores, especially from the positive dimension, were positively correlated with rsFC between ventral striatum and frontal cortex and negatively associated with rsFC between dorsal striatum and posterior cingulate. No significant associations were found between negative dimension schizotypy and striatocortical rsFC. We also found positive correlations between schizotypy total scores and lateralization index of right dorsal caudate and right rostral putamen. In conclusion, the present study extends previous evidence of altered striatocortical rsFC in the schizophrenia spectrum. The observed associations resemble in part the alterations observed in psychotic patients and their relatives, providing support for dimensionality from schizotypal personality to the clinical disorder. Hum Brain Mapp 39:288–299, 2018. © 2017 Wiley Periodicals, Inc.     

Dopamine transporter binding in chronic manganese intoxication

Abstract. Chronic exposure to manganese may induce parkinsonism similar to idiopathic Parkinsons disease (PD). However, clinical manifestations of manganism also have some features different from PD. The mechanisms of manganese-induced parkinsonism remain not fully understood. ^99mTc-TRODAT-1 is a cocaine analogue that can bind to the dopamine transporter (DAT) site reflecting the function of presynaptic dopaminergic terminals. The purpose of this study was to evaluate DAT function using ^99mTc-TRODAT-1 to investigate the integrity of the presynaptic dopaminergic terminals in manganese-induced parkinsonism. Brain ^99mTc-TRODAT-1 single photon emission computed tomography was performed in 4 patients with chronic manganese intoxication in a ferromanganese smelting plant in Taiwan. Twelve PD patients and 12 healthy volunteers served as abnormal and normal controls, respectively. Clinically, all manganism patients had a bradykinetic-rigid syndrome. The scores of the Unified Parkinsons Disease Rating Scale ranged between 19 and 64. The uptake values of the ^99mTc-TRODAT-1 were 0.868±0.136 in the right corpus striatum and 0.865±0.118 in the left, as compared with 0.951±0.059 and 0.956±0.058, respectively for the normal controls. The data were significantly higher than 0.250±0.070 and 0.317±0.066 respectively for the PD patients. Interestingly, there was a mild decrease in the uptake of ^99mTc-TRODAT-1 in the putamen and the ratio of putamen and caudate when compared with the normal controls. Although the DAT shows a slight decrease in the putamen of manganism patients as compared with that of the normal controls, the data indicate that the presynaptic dopaminergic terminals are not the main target of chronic manganese intoxication. In addition ^99mTc-TRODAT-1 SPECT can provide a useful, convenient and inexpensive tool for differentiation between chronic manganism and PD.     

Dopamine transporter PET in normal aging: Dopamine transporter decline and its possible role in preservation of motor function

Objectives : To determine the impact of age‐related decline in dopamine transporter (DAT) expression on motor function in the elderly. Methods : About 33 normal individuals of a wide age range were scanned with PET employing d‐threo‐[¹¹C]‐methylphenidate (MP, a marker of DAT) and [¹¹C]‐dihydrotetrabenazine (DTBZ, that binds to the vesicular monoamine transporter Type 2). Motor function was assessed using the Purdue Pegboard Test (PPB). We analyzed the relationship between [¹¹C]‐MP and motor performance. Results : Age ranged from 27‐ to 77‐year old (mean ± SD, 54.75 ± 14.14). There was no age‐related decline in binding potentials (BP) for [¹¹C]‐DTBZ. In contrast, [¹¹C]‐MP BP was inversely related to age in all striatal regions analyzed (caudate: reduction of 11.2% per decade, P < 0.0001, r = ?0.86; putamen: reduction of 10.5% per decade, P < 0.0001, r = ?0.80). A differential effect of [¹¹C]‐MP on PPB could be observed according to age group. There was a positive relation between the PPB and [¹¹C]‐MP in young individuals (coefficient = 13.56), whereas in individuals greater than 57 years this relationship was negative (coefficient = ?19.53, P = 0.031). Conclusions : Our findings confirm prior observations of age‐related DAT decline and suggest that this phenomenon is independent of changes in VMAT2. After the fifth decade of life, this reduction in DAT binding is associated with a motor performance comparable to mid‐adult life. These findings imply that biochemical processes associated with healthy aging may offset the naturaldecline in motor function observed in the elderly. Synapse 64:146–151, 2010. © 2009 Wiley‐Liss, Inc.     

多巴胺转运体基因与精神分裂症

目的 探讨精神分裂症及其亚型与多巴胺转运体（ＤＡＴ１）基因间的关系。方法 采用Ａｍｐ－ＦＬＰ技术,对上海地区汉族人群中精神分裂症与ＤＡＴ１基因小卫星多态性进行遗传关联分析。结果 ⑴观察到ＤＡＴ１基因中５种等基因（３６０ｂｐ、４００ｂｐ、４４０ｂｐ、４８０ｂｐ、５２０ｂｐ）,最常见是４８０ｂｐ。⑵精神分裂症和健康对照组在ＤＡＴ１的等位基因、基因型的分布上无显著性差异（Ｚ值小于１．９６,Ｐ〉０．０５）     

Visual attentional capture predicts belief in a meaningful world

Here we show that the automatic, involuntary process of attentional capture is predictive of beliefs that are typically considered as much more complex and higher-level. Whereas some beliefs are well supported by evidence, others, such as the belief that coincidences occur for a reason, are not. We argue that the tendency to assign meaning to coincidences is a byproduct of an adaptive system that creates and maintains cognitive schemata, and automatically directs attention to violations of a currently active schema. Earlier studies have shown that, within subjects, attentional capture increases with schema strength. Yet, between-subjects effects could exist too: whereas each of us has schemata of various strengths, most likely different individuals are differently inclined to maintain strong or weak ones. Since schemata can be interpreted as beliefs, we predict more attentional capture for subjects with stronger beliefs than for subjects with weaker ones. We measured visual attentional capture in a reaction time experiment, and correlated it with scores on questionnaires about religious and other beliefs and about meaningfulness and surprisingness of coincidences. We found that visual attentional capture predicts a belief in meaningfulness of coincidences, and that this belief mediates a relationship between visual attentional capture and religiosity. Remarkably, strong believers were more disturbed by schema violations than weak believers, and yet appeared less aware of the disrupting events. We conclude that (a) religious people have a stronger belief in meaningfulness of coincidences, indicative of a more general tendency to maintain strong schemata, and that (b) this belief leads them to suppress, ignore, or forget information that has demonstrably captured their attention, but happens to be inconsistent with their schemata.     

Noradrenergic genotype predicts lapses in sustained attention

Sustained attention is modulated by the neurotransmitter noradrenaline. The balance of dopamine and noradrenaline in the cortex is controlled by the DBH gene. The principal variant in this gene is a C/T change at position −1021, and the T allele at this locus is hypothesised to result in a slower rate of dopamine to noradrenaline conversion than the C allele.Two hundred participants who were genotyped for the DBH C−1021T marker performed the Sustained Attention to Response Task (SART). DBH genotype was found to significantly predict performance; participants with more copies of the T allele made more errors of commission, indicative of lapses in sustained attention. A significant negative correlation was also observed for all participants between errors of commission and mean reaction time.The decrease in noradrenaline occasioned by the T allele may impair sustained attention by reducing participants’ ability to remain alert throughout the task and by increasing their susceptibility to distractors.     

Loneliness in healthy young adults predicts inflammatory responsiveness to a mild immune challenge in vivo

The established link between loneliness and poor health outcomes may stem from aberrant inflammatory regulation. The present study tested whether loneliness predicted the inflammatory response to a standardised in vivo immune challenge. Using a within-subjects double blind placebo-controlled design, 40 healthy men (mean age = 25, SD = 5) received a Salmonella Typhi vaccination (0.025 mg; Typhim Vi, Sanofi Pasteur, UK) and placebo (saline) on two separate occasions. Loneliness was assessed using the R-UCLA loneliness scale. Regression analyses showed that those that reported feeling more lonely exhibited an elevated interleukin-6 response (β = 0.564, 95% confidence interval [0.003, 0.042], p < .05). This association withstood adjustment for potentially confounding variables, including age, sleep quality, socio-emotional factors, and health factors. The present findings are in line with evidence that loneliness may shift immune system responsivity, suggesting a potential biobehavioural pathway linking loneliness to impaired health.     

Dopamine transporter binding in depressed patients with anhedonia

Central dopaminergic dysfunction has been widely proposed as a common neurobiological correlate of the psychopathological expression of anhedonia. The dopamine transporter (DAT) is a predominantly presynaptic receptor that may play a critical role in the pathophysiology of dopaminergic transmission. The aim of our study was to evaluate DAT binding in a population of depressed patients with anhedonia. Single photon emission computed tomography (SPECT) with the radiotracer DATSCAN was used to evaluate DAT binding in 11 depressed patients with anhedonia and 9 healthy comparison subjects. Compared with healthy subjects, patients showed significantly lower DAT binding. No significant correlation was found between DAT binding ratios and scores on administered psychometric tests. These findings suggest an alteration in DAT density in depressed patients with anhedonia that may be a primary susceptibility factor or a secondary phenomenon to reduced dopamine concentration in the synaptic cleft.