0
Original Article |

Altered Effect of Dopamine Transporter 3′UTR VNTR Genotype on Prefrontal and Striatal Function in Schizophrenia FREE

Diana P. Prata, PhD; Andrea Mechelli, PhD; Marco M. Picchioni, MD; Cynthia H. Y. Fu, MD, PhD; Timothea Toulopoulou, PhD; Elvira Bramon, MD, PhD; Muriel Walshe, PhD; Robin M. Murray, MD, PhD; David A. Collier, PhD; Philip McGuire, MD, PhD
[+] Author Affiliations

Author Affiliations: Division of Psychological Medicine and Psychiatry (all authors), Social, Genetic, and Developmental Psychiatry Centre (Drs Prata and Collier), Department of Psychology (Dr Mechelli), and St Andrew's Academic Centre (Dr Picchioni), Institute of Psychiatry, King's College London, London, England.


Arch Gen Psychiatry. 2009;66(11):1162-1172. doi:10.1001/archgenpsychiatry.2009.147.
Text Size: A A A
Published online

Context  The dopamine transporter plays a key role in the regulation of central dopaminergic transmission, which modulates cognitive processing. Disrupted dopamine function and impaired executive processing are robust features of schizophrenia.

Objective  To examine the effect of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3′ untranslated region) on brain function during executive processing in healthy volunteers and patients with schizophrenia. We hypothesized that this variation would have a different effect on prefrontal and striatal activation in schizophrenia, reflecting altered dopamine function.

Design  Case-control study.

Setting  Psychiatric research center.

Participants  Eighty-five subjects, comprising 44 healthy volunteers (18 who were 9-repeat carriers and 26 who were 10-repeat homozygotes) and 41 patients with DSM-IV schizophrenia (18 who were 9-repeat carriers and 23 who were 10-repeat homozygotes).

Main Outcome Measures  Regional brain activation during word generation relative to repetition in an overt verbal fluency task measured by functional magnetic resonance imaging. Main effects of genotype and diagnosis on activation and their interaction were estimated with analysis of variance in SPM5.

Results  Irrespective of diagnosis, the 10-repeat allele was associated with greater activation than the 9-repeat allele in the left anterior insula and right caudate nucleus. Trends for the same effect in the right insula and for greater deactivation in the rostral anterior cingulate cortex were also detected. There were diagnosis × genotype interactions in the left middle frontal gyrus and left nucleus accumbens, where the 9-repeat allele was associated with greater activation than the 10-repeat allele in patients but not controls.

Conclusions  Insular, cingulate, and striatal function during an executive task is normally modulated by variation in the dopamine transporter gene. Its effect on activation in the dorsolateral prefrontal cortex and ventral striatum is altered in patients with schizophrenia. This may reflect altered dopamine function in these regions in schizophrenia.

Figures in this Article

The dopamine transporter (DAT; SLC6A3 [GenBank DQ307031]) plays a key role in the regulation of central dopaminergic transmission by mediating dopamine reuptake from the synaptic cleft into the presynaptic terminal.1 In the mammalian brain, DAT messenger RNA is localized in cell bodies of dopaminergic neurons.2,3 Its expression is highest in synapses in the striatum, substantia nigra, and ventral tegmentum,46 although it is also abundant in the thalamus and in the insular, motor, posterior parietal, and posterior cingulate cortices.6,7 It is expressed in lower levels in the prefrontal, anterior cingulate, primary sensory, and occipital cortices,68 especially within intrasynaptic as opposed to extrasynaptic extracellular space, and the rate of dopamine uptake in these areas is relatively slow.9 In these brain regions with low levels of DAT, intracellular degradation by catechol O-methyltransferase (COMT) and uptake by nonspecific transporters such as the norepinephrine transporter may play a relatively greater role in the regulation of local dopamine availability. In these regions, DAT is mainly extrasynaptic and may primarily regulate dopamine volume transmission, the spillover of dopamine into the extrasynaptic space.1012

The human DAT gene has a polymorphic 40–base pair (bp) variable number of tandem repeats (VNTR) in the 3′ untranslated region (DAT 3′UTR VNTR). This yields several alleles ranging from 3 to 11 copies of the 40-bp repeats, with 9 and 10 being the most common.13 Although this polymorphism does not affect protein structure,14 it may influence transcription. Four independent studies1518 have found the 10-repeat allele to be associated with higher levels of DAT expression, although there is 1 report of lower expression19 and 1 of no association.20 This DAT 3′UTR VNTR has been previously associated with Parkinson disease,21 alcoholism,22 attention-deficit/hyperactivity disorder,23,24 and Tourette syndrome.25,26

Previous functional neuroimaging studies of memory paradigms in healthy subjects have reported an effect of DAT 3′UTR VNTR on prefrontal activation, and an additive interaction between this effect and that of a functional polymorphism for COMT (Val158Met) in prefrontal cortex.11,2729 Nonlinear interactions between the effects of the DAT and COMT polymorphisms on hippocampal28 and striatal29 activation have also been reported in the context of reward and memory tasks, respectively.

Schizophrenia is associated with alterations in the dopaminergic input to the cerebral cortex3034 and the striatum.3538 The same variation in DAT activity may thus have different effects on brain function in patients with schizophrenia and healthy volunteers. The aims of the present study were to examine the influence of DAT genotype on regional brain function during a verbal fluency task and to assess the extent to which this is altered in schizophrenia. We used functional magnetic resonance imaging to study samples of healthy volunteers and patients large enough to yield subgroups of sufficient size to detect effects of the DAT 3′UTR VNTR genotype on activation. Subjects underwent imaging while they performed a phonologic verbal fluency task, which normally engages the prefrontal, insular, and cingulate cortex; the striatum; and the thalamus3947 and is associated with impaired performance48,49 and altered prefrontal activation44,47,5053 in patients with schizophrenia.54,55 Because they express high levels of DAT47 and are also engaged during verbal fluency tasks,44,46 we predicted that variation in DAT 3′UTR VNTR would modulate activation in the striatum, thalamus, and insula. Our second hypothesis was that variation in the DAT 3′UTR VNTR genotype would have a different effect in patients compared with controls in 2 areas where there is good evidence that dopamine function is perturbed in schizophrenia: the striatum3538 and the dorsolateral prefrontal cortex.3034 Although the prefrontal cortex does not express high levels of DAT, it is connected to the striatum via the corticothalamostriatal loop,11,27 and variation in the DAT 3′UTR VNTR genotype influences activation in the prefrontal cortex as well as the striatum.27,29 In addition, the prefrontal cortex is a robust site of altered activation in schizophrenia during verbal fluency and other cognitive tasks.3034

SUBJECTS

A total of 85 subjects participated. All were native English speakers and gave written informed consent in accordance with protocols approved by the local research ethics committee. Patients who had a diagnosis of schizophrenia from their clinical team and met DSM-IV criteria for schizophrenia (n = 41) were recruited from the South London and Maudsley National Health Service Trust. The DSM-IV diagnosis was made by an experienced psychiatrist (including M.M.P.) using a structured diagnostic interview (Schedules for Clinical Assessment in Neuropsychiatry56 and Schedule for Affective Disorders and Schizophrenia57). When interview data were missing or incomplete, the diagnosis was determined by means of the Operational Criteria Checklist.58 The Schedules for the Assessment of Positive and Negative Symptoms were used to measure psychopathologic symptoms at the time of imaging. All patients were in a stable clinical state and had previously been treated with antipsychotic medication; however, 5 were not taking antipsychotic medication at the time of imaging. The mean duration of antipsychotic treatment was 12 years. Healthy volunteers (n = 44) had no history of mental illness and no first-degree relatives with a psychotic disorder, as assessed by the Family Interview for Genetic Studies. Subjects who met DSM-IV criteria for a substance misuse disorder were excluded.

All subjects were genotyped for DAT at 3′UTR VNTR. This yielded 18 subjects who were 9-repeat carriers (2 of whom were homozygotes) and 26 subjects who were 10-repeat homozygotes in the healthy volunteer group, and 18 who were 9-repeat carriers (2 homozygotes) and 23 who were 10-repeat homozygotes in the patient group. Fisher exact tests or χ2 tests (for categorical variables) and analysis of variance tests (for numeric variables) were calculated with SPSS version 15.0 (SPSS Inc, Chicago, Illinois) to detect demographic differences in relation to genotype, diagnosis, and their interaction. There were no significant differences (P > .05) between the patient and control groups in age, ethnicity, or handedness, but patients had a lower mean IQ, fewer years of education, and a higher proportion of males (Table 1). Within the total sample and within each diagnostic group, there were no significant differences (P > .05) between genotype subgroups in any of the demographic variables. No demographic variables showed a significant genotype × diagnosis interaction, except for sex. Within the patient group, the genotype subgroups did not differ significantly (P > .05) in total scores on the Schedule for the Assessment of Positive Symptoms (mean [SD], 6.6 [6.6]) or Schedule for the Assessment of Negative Symptoms (mean [SD], 7.8 [5.1]) scores, nor in the duration (mean [SD], 12.2 [9.5] years), dose (chlorpromazine equivalents; mean [SD], 598.8 [452.3]), or type (first or second generation) of antipsychotic medication.

Table Graphic Jump LocationTable 1. Demographic Features and VF Error Means in Relation to Diagnosis, DAT 3′UTR VNTR Genotype, and Their Interaction
GENOTYPING

DNA was extracted from blood or cheek swabs by standard methods.64 Amplification of the 3′UTR VNTR region was performed by a polymerase chain reaction using the forward primer 5′TGGCACGCACCTGAGAG3′ (melting temperature, 60.8°C) and the reverse primer 5′GGCATTGGAGGATGGGG3′ (melting temperature, 62.3°C). Its products were then separated under UV light after electrophoresis on a 3.5% agarose gel containing ethidium bromide. Genotyping was successful in 88 subjects (98%). Genotype frequencies were similar to frequencies described in the literature. The patient group was in Hardy-Weinberg equilibrium (P > .99; calculated with GENEPOP65), but the control group showed a minor deviation (P = .03), which was apparently due to the presence by chance of a rare homozygous genotype, a 6/6 repeat, in a single individual. Three subjects carrying genotypes with alleles other than the 9-repeat or the 10-repeat allele (as well as 2 subjects for whom genotype calling was unreliable) were not included in the 85-subject sample further analyzed, to reduce allelic heterogeneity.

VERBAL FLUENCY TASK

During a “generation” condition, subjects were visually presented with a series of letters and were required to overtly articulate a word beginning with each letter. This was contrasted with a “repetition” condition in which subjects were presented with the word rest and were required to say “rest” out loud. A blocked design was used, with letter and rest cues presented in blocks of 7 events. The demands of the task were manipulated by presenting 2 different sets of letter cues, termed easy and hard.46 These had previously been shown to be associated with a significant difference in behavioral performance in healthy volunteers.46 The easy condition involved the presentation of letters that are normally associated with relatively large numbers of correct responses and relatively few errors (eg, T, B, S), whereas the hard condition involved letters associated with the generation of fewer correct words and relatively more errors (eg, N, E, G). Five blocks of rest trials alternated with 5 blocks of easy letters or hard letters, resulting in a total of 70 generation and 70 repetition trials. Verbal responses were recorded, permitting the identification of “incorrect” trials in which the subject did not generate any response or generated repetitions, derivatives, or grammatical variations of a previous word. Further details are provided in the eMethods section (http://www.archgenpsychiatry.com).44,46,66,67

IMAGE ACQUISITION

T2*-weighted gradient-echo single-shot echo-planar images were acquired on a 1.5-T, neuro-optimized imaging system (IGE LX System; General Electric, Milwaukee, Wisconsin) at the Maudsley Hospital, London, England. Twelve noncontiguous axial planes (7-mm thickness, 1-mm section skip, 3.75 × 3.75-mm voxel size in plane, and 64 × 64-mm matrix size in plane) parallel to the anterior commissure–posterior commissure line were collected during 1100 milliseconds in a “clustered” acquisition (echo time, 40 milliseconds; flip angle, 70°), which permitted articulatory responses to be made when images were not being acquired, minimizing the effects of head movement on the blood oxygen level–dependent signal.46 Immediately after each acquisition, a letter was presented (remaining visible for 750 milliseconds; height, 7 cm; subtending a 0.4° field of view), and a single overt verbal response was made during the silent portion (duration, 2900 milliseconds) of each repetition (repetition time, 4000 milliseconds), with an image acquired during 1100 milliseconds. Head movement was minimized by a forehead strap. To ensure that subjects heard their responses clearly, their speech was amplified by a computer sound card and then relayed back through an acoustic magnetic resonance imaging sound system and noise-insulated headphones. Further details are provided in the eMethods section.

BEHAVIORAL ANALYSIS

The effect of task load, genotype, diagnosis, and their interaction on the level of accuracy of verbal responses (measured by the number of incorrect responses during imaging) was assessed by means of a multivariate 2 × 2 × 2 analysis of variance, with diagnosis and genotype as between-subject factors and task load as a within-subject factor.

IMAGE ANALYSIS

Analysis was performed with SPM5 software (http://www.fil.ion.ucl.ac.uk/spm),68 running under MATLAB 6.5 (MathWorks Inc, Sherbon, Mass). To minimize movement-related artifacts, all volumes from each subject were realigned and unwarped (by means of the first as reference resliced with sinc interpolation), normalized to a standard MNI-305 template, and spatially smoothed with an 8-mm full-width at half-maximum isotropic gaussian kernel. First, the statistical analysis of regional responses was performed in a subject-specific fashion by convolving each onset time with a synthetic hemodynamic response function. To minimize performance confounds, we modeled correct and incorrect trials separately by using an event-related model, yielding 4 experimental conditions: (1) easy generation, (2) hard generation, (3) repetition, and (4) incorrect responses. The last was excluded from the group analysis to control for effects of group differences in task performance. Correct responses among the generation events (35 events in the hard version and 35 in the easy version) were contrasted with 70 repetition events. To remove low-frequency drifts, data were high-pass filtered by using a set of discrete cosine basis functions with a cutoff period of 128 seconds. Parameter estimates were calculated for all brain voxels by means of the general linear model, and contrast images for “easy generation > repetition” and “hard generation > repetition” were computed in a subject-specific fashion. Second, the subject-specific contrast images were entered into a full-factorial 2 × 2 × 2 analysis of variance, with task load as a repeated measurement, to permit inferences at the population level.69 This allowed us to characterize the impact of the experimental task on brain activation in easy and hard conditions separately within each of the 4 experimental groups (9-repeat carrier controls, 10/10-repeat controls, 9-repeat carrier patients, and 10/10-repeat patients) and test for the main effects of diagnostic group and genotype and their interaction. We modeled task load to minimize error variance but report results for the hard and easy conditions combined. Individuals with the 9/9 allele were grouped with heterozygotes to form a group of sufficient size to be included in an analysis of variance. The t-images for each contrast at the second level were transformed into statistical parametric maps of the Z statistic. In regions where there was an a priori hypothesis, we report results that survived family-wise error (FWE) at P < .05 after small-volume correction (SVC). Regions of interest for the main effect of DAT (right and left insula, right and left thalamus, and right and left caudate nucleus) were defined by means of the automated anatomical labeling atlas70 provided in PickAtlas71,72 for SPM5. Regions of interest for the diagnosis × genotype interaction were also defined with PickAtlas, using a 10-mm-radius sphere centered on foci reported in previous studies showing effects of the DAT 3′UTR VNTR genotype (in interaction with the COMT Val158Met genotype) on activation in the left striatum (−15, 9, −9)29 and middle frontal gyrus (−38, 38, 30).27 In the rest of the brain (where we did not have a priori hypotheses), we used FWE correction across the brain at P < .05. Because no effects were detected with this threshold, we report trends evident at P < .001, uncorrected, with a cluster extent of 10 voxels, for completeness. To assess how much of the interindividual (+ error) variance in blood oxygen level–dependent activation was explained by variation in genotype, we used the ηp2 (partial eta squared) measure of effect size in SPSS, after extracting the subjects' beta-measure at the voxel of peak activation.

In regions where there was a significant effect of genotype, we assessed the potentially confounding effects of antipsychotic medication with a linear regression analysis, using duration, type (first or second generation), and dose (in chlorpromazine hydrochloride equivalents) of antipsychotic treatment as covariates. Sex was included as a covariate of no interest in the image analysis because this varied with genotype in the sample. To confirm that other demographic variables did not influence the findings, we repeated the analysis using each as a covariate of no interest.

PERFORMANCE

Expectedly, there was a significant (P < .05) main effect of task demand on the number of incorrect responses (F = 50.36; P < .001), as there was for diagnosis, with patients making more errors than controls (F = 8.72; P = .004). The main effect of genotype was not significant (F = 1.10; P = .30). There was no significant interaction between task demand, diagnosis, and genotype (F = 1.18; P = .28). However, there was a trend for a diagnosis × genotype interaction (F = 3.56; P = .06), irrespective of task load, reflecting poorer performance in 10/10-repeat than 9-repeat carrier patients but the converse in healthy volunteers, especially during the hard version (Table 1).

NEUROIMAGING DATA
Main Effect of Task

In both diagnostic groups, word generation (irrespective of task difficulty or genotype) was associated with activation in a distributed network that included, bilaterally, the inferior frontal, insular, and dorsal anterior cingulate cortex; the caudate and the thalamus; and the left middle frontal, superior temporal, and inferior parietal cortex (FWE P < .05) (Figure 1). Conversely, repetition was associated with greater engagement of the rostral anterior cingulate gyrus, precuneus, and occipital cortex.

Place holder to copy figure label and caption
Figure 1.

Activation common to both groups during verbal fluency (at family-wise error P < .05). In both controls and patients with schizophrenia, there was activation (ie, word generation minus repetition) in the lateral prefrontal cortex, insula, and thalamus and deactivation (ie, word repetition minus generation) in the precuneus and rostral anterior cingulate gyrus.

Graphic Jump Location
Main Effect of Diagnostic Group

Activation in the left inferior frontal gyrus (−44, 18, 30; Z = 3.4), anterior insula (−34, 14, 8; Z = 3.3), and frontal operculum (−36, 14, 12; Z = 3.6) was greater in patients than in healthy volunteers (P < .001, uncorrected). There were no areas more activated in healthy volunteers than in patients, and there were no between-group differences in deactivation.

Main Effect of DAT 3′UTR VNTR Genotype

Within the regions of interest, the 10/10-repeat group showed greater activation than the 9-repeat carrier group in the left insula (ηp2 = 5.6%) and in the right caudate nucleus (ηp2 = 5.4%) (right anterior insula FWE P = .02; left caudate nucleus FWE P = .03, SVC) (Figure 2 and Table 2), irrespective of diagnosis. Inspection of the parameter estimates (plotted in Figure 2A for the left insula) showed that these main effects were driven by relatively strong effects of genotype in the patient group. Also, the focus of maximal significance in the left insula (−30, 6, 16) was close to the focus of the cluster where patients showed greater activation than controls (−34, 14, 8, as noted earlier). None of the regions of interest showed greater activation in 9-repeat carriers than in 10-repeat homozygotes.

Place holder to copy figure label and caption
Figure 2.

Main effect of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3′ untranslated region) on activation during word generation relative to repetition. A, Subjects with the 10/10-repeat genotype showed greater activation in the left insula (plotted), in the right caudate nucleus (family-wise error P < .05 after small-volume correction), and in the right insula (P < .001, uncorrected) during word generation than did carriers of the 9-repeat allele. B, In the anterior cingulate gyrus bilaterally, subjects with the 10/10-repeat genotype showed greater deactivation during word generation than did carriers of the 9-repeat allele (P < .001, uncorrected).

Graphic Jump Location
Table Graphic Jump LocationTable 2. Main Effect of DAT 3′UTR VNTR Genotype on Activation and Diagnosis × DAT 3′UTR VNTR Genotype Interaction After SVC at FWE P < .05 in Regions of Interesta

Whole-brain analysis indicated that, irrespective of diagnosis, subjects in the 10/10-repeat group showed greater activation than those in the 9-repeat carrier group (P < .001, uncorrected) in the left anterior insula (−30, 6, 16; Z = 3.5; ηp2 = 5.6%) and in a right-sided cluster focused at 26, 4, 18 (Z = 3.6; ηp2 = 6.6%) that included the right caudate (reported for the foregoing region of interest analysis) and the adjacent part of the right insula. The plot of the parameter estimates was similar to that of the left anterior insula (described in the previous paragraph; Figure 2A). There was also a trend (P < .001, uncorrected) for a main effect in the rostral part of the anterior cingulate gyrus bilaterally (−2, 40, −2; Z = 3.4; and 2, 40, −2; Z = 3.3; ηp2 = 6.7). Exploration of the parameter estimates (Figure 2B) showed that this reflected deactivation during word generation (ie, more activation during repetition than generation), which was more pronounced in the 10/10-repeat group than in the 9-repeat carrier group.

Group × Genotype Interaction

There was an interaction between the effects of diagnosis and genotype in the left middle frontal gyrus (ηp2 = 6.4%) and in the left nucleus accumbens (ηp2 = 4.8%) (left middle frontal gyrus FWE P = .05; left nucleus accumbens FEW P = .02, SVC) (Figure 3 and Table 2). In the former region, there was no statistically significant difference in activation between the DAT 3′UTR VNTR genotypes in healthy volunteers, but in patients the 9-repeat allele was associated with significantly greater activation (left middle frontal gyrus FWE P = .004, SVC; ηp2 = 21.5%). In the left nucleus accumbens, healthy volunteers with the 10/10-repeat genotype showed more activation than 9-repeat carriers, whereas the opposite applied in the patients. No other brain regions showed a diagnosis × genotype interaction (at P < .001, uncorrected).

Place holder to copy figure label and caption
Figure 3.

Interaction between effect of diagnostic group and of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3′ untranslated region) on activation during word generation relative to repetition in the left middle frontal gyrus (A) and the left ventral striatum (nucleus accumbens) (B). The effect of genotype in controls was significantly different from that in patients with schizophrenia (family-wise error P < .05 after small-volume correction).

Graphic Jump Location
Effects of Potentially Confounding Factors on Activation

Linear regression analysis indicated that activation in the areas where there were significant effects of DAT (either irrespective of or dependent on diagnosis) was not related to the dose, type, or duration of antipsychotic treatment, even at a very liberal statistical threshold (P = .5, uncorrected). Analyses included sex as a covariate of no interest. Repeating these analyses after covarying independently for IQ, years of education, or ethnicity did not alter the location or the Z score of the reported results.

Our hypothesis that the DAT 3′UTR VNTR genotype would influence task-related activation was confirmed in the left insula and caudate nucleus. In both of these regions, the 10-repeat allele was associated with greater activation than the 9-repeat allele in both healthy and schizophrenic subjects. A whole-brain analysis also demonstrated a trend for the same effect of genotype in the part of the right insula homologous to that identified in the region-of-interest analysis. The insula, especially in the left hemisphere, plays a major role in verbal fluency and other language-related tasks44,46,47,51 and expresses high levels of the DAT relative to other cortical areas.7 Greater insular activation in carriers of the 10-repeat allele can be interpreted in terms of the putative effects of dopamine on the “efficiency” of cortical function. According to this model, 10-repeat carriers, who have more DAT than 9-repeat carriers, remove dopamine from synapses more rapidly, reducing dopamine to a level that is suboptimal for the local signal to noise ratio, reducing the efficiency of cortical function, and leading to increased activation.3133 This is, to our knowledge, the first evidence of an effect of the DAT 3′UTR VNTR genotype on function in the insula in humans, previous effects having been reported in the hippocampus (in interaction with COMT genotype) and in the prefrontal cortex.11,2729 The caudate nucleus is, with the putamen, the brain area with the highest expression of DAT7 and is also implicated in verbal fluency and articulation.7376 It is a major termination site of central dopaminergic projections from the brainstem.77 The extent to which the foregoing model of dopaminergic tuning of cortical efficiency is also applicable in the striatum is unclear.

There was a trend for the 10-repeat allele to be associated with greater deactivation during word generation than the 9-repeat allele in the rostral anterior cingulate cortex. The relatively greater engagement of this region during verbal repetition (compared with generation) may be related to its involvement in the “default” network that mediates internally generated processes during low-level baseline conditions.7880 The more marked response in individuals with the 10/10-repeat genotype might reflect an effect of lower dopamine activity on the efficiency of cingulate cortical function during the baseline condition, although the concept of the dopaminergic modulation of efficiency is derived from studies of prefrontal cortex during working memory tasks.7880 The direction of the DAT 3′UTR VNTR's effect on cingulate activation is the same as that of a previous report,11 although this was in a more dorsal part of the gyrus during a working memory task.

Consistent with our hypotheses about genotype × diagnosis interactions, there was an interaction in the left middle frontal gyrus. In this region, there was significantly greater activation in patients carrying the 9-repeat than the 10/10-repeat genotype but a similar response in the 2 genotype subgroups in healthy volunteers. The 9-repeat allele is associated with lower gene expression1518 and hence weaker DAT activity and higher dopamine levels. The fact that this effect of genotype was evident in patients with schizophrenia, accounting for more than one-fifth of the interindividual variance (21.5%), but not controls, raises the possibility that the effect of the 9-repeat allele interacts with other factors contributing to the perturbation of dopamine function in the disorder. In schizophrenia, it is thought that dopamine activity is increased in the striatum but decreased in the cortex.8184 Dopamine transporter is present at relatively low levels in the prefrontal cortex, whereas it is abundant in the striatum,4,6,85 and therefore the effects we observed in the prefrontal cortex may be secondary to effects of the DAT 3′UTR VNTR genotype in the striatum. The striatum receives dopaminergic input from the substantia nigra and the ventral tegmental area. Dopamine transporter removes dopamine from the intrasynaptic space of these terminals, reducing stimulation of dopamine receptors, which, in the striatum, are predominantly D2.8688 Stimulation of these receptors leads to inhibitory effects on the thalamus, which then projects to the prefrontal cortex. A decrease in DAT activity associated with the 9-repeat allele may therefore increase synaptic dopamine levels and, thus, D2 stimulation in the striatum, inhibiting the thalamus and decreasing its excitatory input to the prefrontal cortex, which is thought to be necessary for an optimal signal to noise ratio in the prefrontal cortex. In schizophrenia, increased striatal dopamine activity may be amplified in patients with the 9-repeat allele, further increasing local dopamine levels and inhibition of the thalamus, leading to a marked reduction in the signal to noise ratio in prefrontal pyramidal neurons.89 This could account for the increased prefrontal activation we detected in patients with the 9-repeat allele.

A similar interaction was evident in the left nucleus accumbens. In healthy volunteers, this region was more active during verbal repetition than generation in 9-repeat carriers, but there was no difference between the conditions in subjects with the 10/10-repeat genotype. The converse applied in the patient subgroups (Table 2). As discussed in relation to the interaction in the prefrontal cortex, in schizophrenia, increased dopamine activity in the striatum may alter the impact of variation in DAT genotype on local dopamine levels, producing the opposite effect on activation in patients compared with controls.

Because antipsychotics have an antagonistic effect on central dopamine receptors and because all of our patients were receiving antipsychotic drugs, the potentially confounding effects of medication on our findings in patients with schizophrenia must be considered. Antipsychotics can modulate presynaptic dopamine up take capacity9092 and cortical activation93 and may also affect performance of verbal fluency94,95 and other cognitive tasks,92,96,97 although these findings have not always been replicated.98 Moreover, antipsychotic medication may reduce DAT activity via blockade of D2 receptors.99 Therefore, it is possible that differences in the effect of genotype between patients and controls may have been related to effects of medication rather than an effect of schizophrenia. In view of these concerns, we examined the potential effect of dose, type, and duration of antipsychotic treatment on activation in regions where we found significant effects of genotype. There was no evidence that the effects of genotype we observed were related to effects of medication on activation in these regions. Nevertheless, the possibility that the differences in the effects of genotype in patients compared with controls were related to medication as opposed to schizophrenia cannot be excluded without repetition of the present study in medication-naive patients. However, recruiting and performing imaging in a large sample of this type would be logistically difficult.

The network of areas engaged by the verbal fluency task in the present study is consistent with that reported in several previous studies.44,46,47,51 Patients showed greater activation than healthy volunteers in the left middle frontal gyrus, frontal operculum, and anterior insula. Many previous comparisons of patients with schizophrenia and volunteers have found differences in left frontal activation during verbal fluency, although some have reported decreases and others, increases.44,47,5053,100103 This inconsistency may partly reflect differences in sample sizes and the degree to which the effects of impaired task performance in schizophrenia have been controlled for. The present sample was comparatively large, and the effects of differential task performance were minimized by using a paced paradigm, online monitoring of behavioral performance, and restriction of the analysis to images associated with correct responses. Greater prefrontal activation in schizophrenia during cognitive tasks after controlling for differential performance may reflect impaired prefrontal cortical efficiency.104

The effect of the DAT 3′UTR VNTR genotype on verbal fluency performance has not been investigated before, to our knowledge. Although there was no significant main effect of genotype, there was a trend for a diagnosis × genotype interaction, which reflected poorer performance of the hard condition in 10/10-repeat than in 9-repeat carrier patients but the converse in healthy volunteers. Previous studies in healthy subjects suggest that the DAT 3′UTR VNTR genotype does not influence performance on working memory tasks,11,27 but that the 10-repeat allele is associated with a higher number of commission errors during the Continuous Performance Test and with impaired selective attention and response inhibition.105 The trend for poorer verbal fluency performance in the 10/10-repeat group with schizophrenia might thus reflect an influence of the DAT 3′UTR VNTR genotype (and hence dopamine) on attention and response inhibition, both of which are involved in executing verbal fluency tasks. Because the sample size in the present study was powered to detect differences at the neurophysiologic rather than the neuropsychological level and because the task was paced (reducing task demands), it is possible that more marked effects of DAT genotype on performance would have been evident in a larger sample, using an unpaced version of the paradigm.

We cannot exclude the possibility that the effects of the DAT 3′UTR VNTR genotype were due to other polymorphisms in strong linkage disequilibrium with the 3′UTR VNTR. The latter was selected because it has been shown to have the greatest functional effect on DAT expression.1518 We compared individuals with one or two 9-repeat alleles against those with none (10/10-repeat group) because it was difficult to recruit a sufficient number of individuals homozygous for the 9-repeat allele. This precluded examination of whether the effect of the risk allele is better described by a dominant/recessive or additive model. Although, in most subjects, IQ was assessed by means of the Wechsler Adult Intelligence Scale, different versions of this instrument were used and, in a minority of subjects, IQ was assessed by means of the Quick Test. However, previous studies have shown that the IQ estimates obtained from these scales are highly correlated.5964 Moreover, even if using different instruments had influenced the IQ estimates, it is unlikely to have affected the results because the proportion of subjects assessed with each version was matched across genotype groups. We used an event-related approach in the image analysis, although this is not ideal for data acquired via a block design with fixed interstimulus intervals. Although we modeled correct and incorrect trials separately to minimize the potentially confounding effects of differences in performance accuracy, reaction times were not measured, so the findings could have been influenced by differences in response speed.

Correspondence: Diana P. Prata, PhD, Institute of Psychiatry, King’s College London, PO67, De Crespigny Park, London SE5 8AF, England (d.prata@iop.kcl.ac.uk).

Submitted for Publication: November 15, 2008; final revision received March 16, 2009; accepted April 17, 2009.

Author Contributions: Dr Prata had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Funding/Support: Dr Prata was funded by the Fundacao para a Ciencia e Tecnologia, Lisbon, Portugal. Dr Fu was supported by a Wellcome Travelling Fellowship and Dr Picchioni by a Wellcome Trust Training Fellowship.

Role of the Sponsors: The sponsors had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and the preparation, review, or approval of the manuscript.

Additional Contributions: We thank the reviewers for their useful suggestions. Mitul Mehta, MA, PhD (Institute of Psychiatry, King's College London), provided invaluable comments.

Masson  JRiad  MChaudhry  FDarmon  MAïdouni  ZConrath  MGiros  BHamon  MStorm-Mathisen  JDescarries  LEl Mestikawy  S Unexpected localization of the Na+/Cl-dependent-like orphan transporter, Rxt1, on synaptic vesicles in the rat central nervous system. Eur J Neurosci 1999;11 (4) 1349- 1361
PubMed
Lorang  DAmara  SGSimerly  RB Cell-type-specific expression of catecholamine transporters in the rat brain. J Neurosci 1994;14 (8) 4903- 4914
PubMed
Nirenberg  MJVaughan  RAUhl  GRKuhar  MJPickel  VM The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons. J Neurosci 1996;16 (2) 436- 447
PubMed
Ciliax  BJHeilman  CDemchyshyn  LLPristupa  ZBInce  EHersch  SMNiznik  HBLevey  AI The dopamine transporter: immunochemical characterization and localization in brain. J Neurosci 1995;15 (3 pt 1) 1714- 1723
PubMed
Sesack  SRCarr  DB Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol Behav 2002;77 (4-5) 513- 517
PubMed
Lewis  DAMelchitzky  DSSesack  SRWhitehead  REAuh  SSampson  A Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 2001;432 (1) 119- 136
PubMed
Wang  GJVolkow  NDFowler  JSDing  YSLogan  JGatley  SJMacGregor  RRWolf  AP Comparison of two PET radioligands for imaging extrastriatal dopamine transporters in human brain. Life Sci 1995;57 (14) PL187- PL191
PubMed
Sesack  SRHawrylak  VAGuido  MALevey  AI Cellular and subcellular localization of the dopamine transporter in rat cortex. Adv Pharmacol 1998;42171- 174
PubMed
Wayment  HKSchenk  JOSorg  BA Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. J Neurosci 2001;21 (1) 35- 44
PubMed
Cragg  SJRice  ME DAncing past the DAT at a DA synapse. Trends Neurosci 2004;27 (5) 270- 277
PubMed
Bertolino  ABlasi  GLatorre  VRubino  VRampino  ASinibaldi  LCaforio  GPetruzzella  VPizzuti  AScarabino  TNardini  MWeinberger  DRDallapiccola  B Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain. J Neurosci 2006;26 (15) 3918- 3922
PubMed
Tunbridge  EMHarrison  PJWeinberger  DR Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 2006;60 (2) 141- 151
PubMed
Vandenbergh  DJPersico  AMHawkins  ALGriffin  CALi  XJabs  EWUhl  GR Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 1992;14 (4) 1104- 1106
PubMed
Vandenbergh  DJThompson  MDCook  EHBendahhou  ENguyen  TKrasowski  MDZarrabian  DComings  DSellers  EMTyndale  RFGeorge  SRO’Dowd  BFUhl  GR Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations. Mol Psychiatry 2000;5 (3) 283- 292
PubMed
Fuke  SSuo  STakahashi  NKoike  HSasagawa  NIshiura  S The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression. Pharmacogenomics J 2001;1 (2) 152- 156
PubMed
Mill  JAsherson  PBrowes  CD’Souza  UCraig  I Expression of the dopamine transporter gene is regulated by the 3′UTR VNTR: evidence from brain and lymphocytes using quantitative RT-PCR. Am J Med Genet 2002;114 (8) 975- 979
PubMed
Heinz  AGoldman  DJones  DWPalmour  RHommer  DGorey  JGLee  KSLinnoila  MWeinberger  DR Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 2000;22 (2) 133- 139
PubMed
VanNess  SHOwens  MJKilts  CD The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genet 2005;655
PubMed10.1186/1471-2156-6-55
van Dyck  CHMalison  RTJacobsen  LKSeibyl  JPStaley  JKLaruelle  MBaldwin  RMInnis  RBGelernter  J Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. J Nucl Med 2005;46 (5) 745- 751
PubMed
Martinez  DGelernter  JAbi-Dargham  Avan Dyck  CHKegeles  LInnis  RBLaruelle  M The variable number of tandem repeats polymorphism of the dopamine transporter gene is not associated with significant change in dopamine transporter phenotype in humans. Neuropsychopharmacology 2001;24 (5) 553- 560
PubMed
Le Couteur  DGLeighton  PW McCann  SJPond  S Association of a polymorphism in the dopamine-transporter gene with Parkinson's disease. Mov Disord 1997;12 (5) 760- 763
PubMed
Muramatsu  THiguchi  S Dopamine transporter gene polymorphism and alcoholism. Biochem Biophys Res Commun 1995;211 (1) 28- 32
PubMed
Gill  MDaly  GHeron  SHawi  ZFitzgerald  M Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. Mol Psychiatry 1997;2 (4) 311- 313
PubMed
Faraone  SVPerlis  RHDoyle  AESmoller  JWGoralnick  JJHolmgren  MASklar  P Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;57 (11) 1313- 1323
PubMed
Díaz-Anzaldúa  AJoober  RRiviere  JBDion  YLespérance  PRicher  FChouinard  SRouleau  GAMontreal Tourette Syndrome Study Group, Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population. Mol Psychiatry 2004;9 (3) 272- 277
PubMed
Comings  DEWu  SChiu  CRing  RHGade  RAhn  CMacMurray  JPDietz  GMuhleman  D Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: the additive and subtractive effect of the three dopaminergic genes—DRD2, D beta H, and DAT1. Am J Med Genet 1996;67 (3) 264- 288
PubMed
Caldú  XVendrell  PBartres-Faz  DClemente  IBargalló  NJurado  MASerra-Grabulosa  JMJunqué  C Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects. Neuroimage 2007;37 (4) 1437- 1444
PubMed
Bertolino  ADi Giorgio  ABlasi  GSambataro  FCaforio  GSinibaldi  LLatorre  VRampino  ATaurisano  PFazio  LRomano  RDouzgou  SPopolizio  TKolachana  BNardini  MWeinberger  DRDallapiccola  B Epistasis between dopamine regulating genes identifies a nonlinear response of the human hippocampus during memory tasks. Biol Psychiatry 2008;64 (3) 226- 234
PubMed
Yacubian  JSommer  TSchroeder  KGläscher  JKalisch  RLeuenberger  BBraus  DFBüchel  C Gene-gene interaction associated with neural reward sensitivity. Proc Natl Acad Sci U S A 2007;104 (19) 8125- 8130
PubMed
Akil  MKolachana  BSRothmond  DAHyde  TMWeinberger  DRKleinman  JE Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 2003;23 (6) 2008- 2013
PubMed
Weinberger  DRBerman  KFChase  TN Mesocortical dopaminergic function and human cognition. Ann N Y Acad Sci 1988;537330- 338
PubMed
Weinberger  DREgan  MFBertolino  ACallicott  JHMattay  VSLipska  BKBerman  KFGoldberg  TE Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001;50 (11) 825- 844
PubMed
Abi-Dargham  AMawlawi  OLombardo  IGil  RMartinez  DHuang  YHwang  DRKeilp  JKochan  LVan Heertum  RGorman  JMLaruelle  M Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002;22 (9) 3708- 3719
PubMed
Akil  MPierri  JNWhitehead  REEdgar  CLMohila  CSampson  ARLewis  DA Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry 1999;156 (10) 1580- 1589
PubMed
Meyer-Lindenberg  AMiletich  RSKohn  PDEsposito  GCarson  REQuarantelli  MWeinberger  DRBerman  KF Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002;5 (3) 267- 271
PubMed
Bertolino  ABreier  ACallicott  JHAdler  CMattay  VSShapiro  MFrank  JAPickar  DWeinberger  DR The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology 2000;22 (2) 125- 132
PubMed
Grace  AA Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Brain Res Rev 2000;31 (2-3) 330- 341
PubMed
Laruelle  M The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev 2000;31 (2-3) 371- 384
PubMed
Yetkin  FZHammeke  TASwanson  SJMorris  GLMueller  WM McAuliffe  TLHaughton  VM A comparison of functional MR activation patterns during silent and audible language tasks. AJNR Am J Neuroradiol 1995;16 (5) 1087- 1092
PubMed
Lurito  JTKareken  DALowe  MJChen  SHMathews  VP Comparison of rhyming and word generation with FMRI. Hum Brain Mapp 2000;10 (3) 99- 106
PubMed
Hutchinson  MSchiffer  WJoseffer  SLiu  ASchlosser  RDikshit  SGoldberg  EBrodie  JD Task-specific deactivation patterns in functional magnetic resonance imaging. Magn Reson Imaging 1999;17 (10) 1427- 1436
PubMed
Friedman  LKenny  JTWise  ALWu  DStuve  TAMiller  DAJesberger  JALewin  JS Brain activation during silent word generation evaluated with functional MRI. Brain Lang 1998;64 (2) 231- 256
PubMed
Schlösser  RHutchinson  MJoseffer  SRusinek  HSaarimaki  AStevenson  JDewey  SLBrodie  JD Functional magnetic resonance imaging of human brain activity in a verbal fluency task. J Neurol Neurosurg Psychiatry 1998;64 (4) 492- 498
PubMed
Curtis  VABullmore  ETBrammer  MJWright  ICWilliams  SCMorris  RGSharma  TSMurray  RM McGuire  PK Attenuated frontal activation during a verbal fluency task in patients with schizophrenia. Am J Psychiatry 1998;155 (8) 1056- 1063
PubMed
Phelps  EAHyder  FBlamire  AMShulman  RG FMRI of the prefrontal cortex during overt verbal fluency. Neuroreport 1997;8 (2) 561- 565
PubMed
Fu  CHMorgan  KSuckling  JWilliams  SCAndrew  CVythelingum  GN McGuire  PK A functional magnetic resonance imaging study of overt letter verbal fluency using a clustered acquisition sequence: greater anterior cingulate activation with increased task demand. Neuroimage 2002;17 (2) 871- 879
PubMed
Yurgelun-Todd  DAWaternaux  CMCohen  BMGruber  SAEnglish  CDRenshaw  PF Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production. Am J Psychiatry 1996;153 (2) 200- 205
PubMed
Allen  HALiddle  PFFrith  CD Negative features, retrieval processes and verbal fluency in schizophrenia. Br J Psychiatry 1993;163769- 775
PubMed
Howanitz  ECicalese  CHarvey  PD Verbal fluency and psychiatric symptoms in geriatric schizophrenia. Schizophr Res 2000;42 (3) 167- 169
PubMed
Frith  CDFriston  KJHerold  SSilbersweig  DFletcher  PCahill  CDolan  RJFrackowiak  RSLiddle  PF Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br J Psychiatry 1995;167 (3) 343- 349
PubMed
Fletcher  PCFrith  CDGrasby  PMFriston  KJDolan  RJ Local and distributed effects of apomorphine on fronto-temporal function in acute unmedicated schizophrenia. J Neurosci 1996;16 (21) 7055- 7062
PubMed
Fu  CHSuckling  JWilliams  SCAndrew  CMVythelingum  GN McGuire  PK Effects of psychotic state and task demand on prefrontal function in schizophrenia: an fMRI study of overt verbal fluency. Am J Psychiatry 2005;162 (3) 485- 494
PubMed
Artiges  EMartinot  JLVerdys  MAttar-Levy  DMazoyer  BTzourio  NGiraud  MJPaillère-Martinot  ML Altered hemispheric functional dominance during word generation in negative schizophrenia. Schizophr Bull 2000;26 (3) 709- 721
PubMed
Broome  MRMatthiasson  PFusar-Poli  PWoolley  JBJohns  LCTabraham  PBramon  EValmaggia  LWilliams  SCBrammer  MJChitnis  X McGuire  PK Neural correlates of executive function and working memory in the “at-risk mental state.” Br J Psychiatry 2009;194 (1) 25- 33
PubMed
Gur  REKeshavan  MSLawrie  SM Deconstructing psychosis with human brain imaging. Schizophr Bull 2007;33 (4) 921- 931
PubMed
Wing  JKBabor  TBrugha  TBurke  JCooper  JEGiel  RJablenski  ARegier  DSartorius  N SCAN: Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990;47 (6) 589- 593
PubMed
Endicott  JSpitzer  RL A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 1978;35 (7) 837- 844
PubMed
McGuffin  PFarmer  AHarvey  I A polydiagnostic application of operational criteria in studies of psychotic illness: development and reliability of the OPCRIT system. Arch Gen Psychiatry 1991;48 (8) 764- 770
PubMed
Wechsler  D Wechsler Adult Intelligence Scale—Third Edition Manual.  San Antonio, TX Psychological Corp1997;
Wechsler  D Manual for the Wechsler Intelligence ScaleRevised.  San Antonio, TX Psychological Corp1981;
Wechsler  D Wechsler Abbreviated Scale of Intelligence.  San Antonio, TX Psychological Corp1999;
Ammons  RBAmmons  CH Quick Test.  Missoula, MT Psychological Test Specialists1962;
Frith  CDLeary  JCahill  CJohnstone  EC Performance on psychological tests: demographic and clinical correlates of the results of these tests. Br J Psychiatry Suppl 1991; (13) 26- 29, 44-46
PubMed
Freeman  BSmith  NCurtis  CHuckett  LMill  JCraig  IW DNA from buccal swabs recruited by mail: evaluation of storage effects on long-term stability and suitability for multiplex polymerase chain reaction genotyping. Behav Genet 2003;33 (1) 67- 72
PubMed
Raymond  MRousset  F GENEPOP (version 1.2): population genetics software for exact tests and ecumenicism. J Hered 1995;86 (3) 248- 249
Benton  ALHamsher  KD Multilingual Aphasia Examination.  New York, NY Oxford University Press1994;
Lezak  MD Neuropsychological Assessment. 3rd ed. New York, NY Oxford University Press1995;
Friston  KJ Introduction: experimental design and statistical parametric mapping. Frackowiak  RSFriston  KJFrith  CDDolan  RJPrice  CJZeki  SHuman Brain Function. 2nd ed. New York, NY Academic Press2003;
Penny  WDHolmes  APFriston  KJ Random effects analysis. Frackowiak  RSFriston  KJFrith  CDDolan  RJPrice  CJZeki  SHuman Brain Function. 2nd ed. New York, NY Academic Press2003;
Tzourio-Mazoyer  NLandeau  BPapathanassiou  DCrivello  FEtard  ODelcroix  NMazoyer  BJoliot  M Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15 (1) 273- 289
PubMed
Maldjian  JALaurienti  PJKraft  RABurdette  JH An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003;19 (3) 1233- 1239
PubMed
Maldjian  JALaurienti  PJBurdette  JH Precentral gyrus discrepancy in electronic versions of the Talairach atlas. Neuroimage 2004;21 (1) 450- 455
PubMed
Pickett  ERKuniholm  EProtopapas  AFriedman  JLieberman  P Selective speech motor, syntax and cognitive deficits associated with bilateral damage to the putamen and the head of the caudate nucleus: a case study. Neuropsychologia 1998;36 (2) 173- 188
PubMed
Murphy  KCorfield  DRGuz  AFink  GRWise  RJHarrison  JAdams  L Cerebral areas associated with motor control of speech in humans. J Appl Physiol 1997;83 (5) 1438- 1447
PubMed
Fabbro  FClarici  ABava  A Effects of left basal ganglia lesions on language production. Percept Mot Skills 1996;82 (3 pt 2) 1291- 1298
PubMed
Speedie  LJWertman  ETa’ir  JHeilman  KM Disruption of automatic speech following a right basal ganglia lesion. Neurology 1993;43 (9) 1768- 1774
PubMed
Lindvall  OBjorklund  A Anatomy of the dopaminergic neuron systems in the rat brain. Adv Biochem Psychopharmacol 1978;191- 23
PubMed
Binder  JRFrost  JAHammeke  TABellgowan  PSRao  SMCox  RW Conceptual processing during the conscious resting state: a functional MRI study. J Cogn Neurosci 1999;11 (1) 80- 95
PubMed
McKiernan  KAKaufman  JNKucera-Thompson  JBinder  JR A parametric manipulation of factors affecting task-induced deactivation in functional neuroimaging. J Cogn Neurosci 2003;15 (3) 394- 408
PubMed
McKiernan  KAD’Angelo  BRKaufman  JNBinder  JR Interrupting the “stream of consciousness”: an fMRI investigation. Neuroimage 2006;29 (4) 1185- 1191
PubMed
Breier  ASu  TPSaunders  RCarson  REKolachana  BSde Bartolomeis  AWeinberger  DRWeisenfeld  NMalhotra  AKEckelman  WCPickar  D Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 1997;94 (6) 2569- 2574
PubMed
Abi-Dargham  AGil  RKrystal  JBaldwin  RMSeibyl  JPBowers  Mvan Dyck  CHCharney  DSInnis  RBLaruelle  M Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998;155 (6) 761- 767
PubMed
Laruelle  MAbi-Dargham  A Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol 1999;13 (4) 358- 371
PubMed
Laruelle  MAbi-Dargham  AGil  RKegeles  LInnis  R Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999;46 (1) 56- 72
PubMed
Sesack  SRPickel  VM Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol 1992;320 (2) 145- 160
PubMed
Weiner  DMLevey  AISunahara  RKNiznik  HBO’Dowd  BFSeeman  PBrann  MR D1 and D2 dopamine receptor mRNA in rat brain. Proc Natl Acad Sci U S A 1991;88 (5) 1859- 1863
PubMed
Camps  MCortes  RGueye  BProbst  APalacios  JM Dopamine receptors in human brain: autoradiographic distribution of D2 sites. Neuroscience 1989;28 (2) 275- 290
PubMed
Cortés  RGueye  BPazos  AProbst  APalacios  JM Dopamine receptors in human brain: autoradiographic distribution of D1 sites. Neuroscience 1989;28 (2) 263- 273
PubMed
Tanaka  S Dopaminergic control of working memory and its relevance to schizophrenia: a circuit dynamics perspective. Neuroscience 2006;139 (1) 153- 171
PubMed
Gründer  GVernaleken  IMüller  MJDavids  EHeydari  NBuchholz  HGBartenstein  PMunk  OLStoeter  PWong  DFGjedde  ACumming  P Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo. Neuropsychopharmacology 2003;28 (4) 787- 794
PubMed
Vernaleken  IKumakura  YCumming  PBuchholz  HGSiessmeier  TStoeter  PMüller  MJBartenstein  PGründer  G Modulation of [18F]fluorodopa (FDOPA) kinetics in the brain of healthy volunteers after acute haloperidol challenge. Neuroimage 2006;30 (4) 1332- 1339
PubMed
Vernaleken  IKumakura  YBuchholz  HGSiessmeier  THilgers  RDBartenstein  PCumming  PGründer  G Baseline [18F]-FDOPA kinetics are predictive of haloperidol-induced changes in dopamine turnover and cognitive performance: a positron emission tomography study in healthy subjects. Neuroimage 2008;40 (3) 1222- 1231
PubMed
Honey  GDBullmore  ETSoni  WVaratheesan  MWilliams  SCSharma  T Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci U S A 1999;96 (23) 13432- 13437
PubMed
Lee  MAJayathilake  KMeltzer  HY A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia. Schizophr Res 1999;37 (1) 1- 11
PubMed
Hagger  CBuckley  PKenny  JTFriedman  LUbogy  DMeltzer  HY Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biol Psychiatry 1993;34 (10) 702- 712
PubMed
Lee  MAThompson  PAMeltzer  HY Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry 1994;55 ((suppl B)) 82- 87
PubMed
Vernaleken  IBuchholz  HGKumakura  YSiessmeier  TStoeter  PBartenstein  PCumming  PGründer  G “Prefrontal” cognitive performance of healthy subjects positively correlates with cerebral FDOPA influx: an exploratory [18F]-fluoro-L-DOPA-PET investigation. Hum Brain Mapp 2007;28 (10) 931- 939
PubMed
Meltzer  HY McGurk  SR The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 1999;25 (2) 233- 255
PubMed
Kimmel  HLJoyce  ARCarroll  FIKuhar  MJ Dopamine D1 and D2 receptors influence dopamine transporter synthesis and degradation in the rat. J Pharmacol Exp Ther 2001;298 (1) 129- 140
PubMed
Stevens  AAGoldman-Rakic  PSGore  JCFulbright  RKWexler  BE Cortical dysfunction in schizophrenia during auditory word and tone working memory demonstrated by functional magnetic resonance imaging. Arch Gen Psychiatry 1998;55 (12) 1097- 1103
PubMed
Crespo-Facorro  BParadiso  SAndreasen  NCO’Leary  DSWatkins  GLBoles Ponto  LLHichwa  RD Recalling word lists reveals “cognitive dysmetria” in schizophrenia: a positron emission tomography study. Am J Psychiatry 1999;156 (3) 386- 392
PubMed
Lewis  DAHayes  TLLund  JSOeth  KM Dopamine and the neural circuitry of primate prefrontal cortex: implications for schizophrenia research. Neuropsychopharmacology 1992;6 (2) 127- 134
PubMed
Spence  SALiddle  PFStefan  MDHellewell  JSSharma  TFriston  KJHirsch  SRFrith  CDMurray  RMDeakin  JFGrasby  PM Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk: focal dysfunction and distributed disconnectivity reappraised. Br J Psychiatry 2000;17652- 60
PubMed
Winterer  GWeinberger  DR Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 2004;27 (11) 683- 690
PubMed
Cornish  KMManly  TSavage  RSwanson  JMorisano  DButler  NGrant  CCross  GBentley  LHollis  CP Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample. Mol Psychiatry 2005;10 (7) 686- 698
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Activation common to both groups during verbal fluency (at family-wise error P < .05). In both controls and patients with schizophrenia, there was activation (ie, word generation minus repetition) in the lateral prefrontal cortex, insula, and thalamus and deactivation (ie, word repetition minus generation) in the precuneus and rostral anterior cingulate gyrus.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Main effect of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3′ untranslated region) on activation during word generation relative to repetition. A, Subjects with the 10/10-repeat genotype showed greater activation in the left insula (plotted), in the right caudate nucleus (family-wise error P < .05 after small-volume correction), and in the right insula (P < .001, uncorrected) during word generation than did carriers of the 9-repeat allele. B, In the anterior cingulate gyrus bilaterally, subjects with the 10/10-repeat genotype showed greater deactivation during word generation than did carriers of the 9-repeat allele (P < .001, uncorrected).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Interaction between effect of diagnostic group and of a polymorphism in the dopamine transporter gene (the variable number of tandem repeats in the 3′ untranslated region) on activation during word generation relative to repetition in the left middle frontal gyrus (A) and the left ventral striatum (nucleus accumbens) (B). The effect of genotype in controls was significantly different from that in patients with schizophrenia (family-wise error P < .05 after small-volume correction).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic Features and VF Error Means in Relation to Diagnosis, DAT 3′UTR VNTR Genotype, and Their Interaction
Table Graphic Jump LocationTable 2. Main Effect of DAT 3′UTR VNTR Genotype on Activation and Diagnosis × DAT 3′UTR VNTR Genotype Interaction After SVC at FWE P < .05 in Regions of Interesta

References

Masson  JRiad  MChaudhry  FDarmon  MAïdouni  ZConrath  MGiros  BHamon  MStorm-Mathisen  JDescarries  LEl Mestikawy  S Unexpected localization of the Na+/Cl-dependent-like orphan transporter, Rxt1, on synaptic vesicles in the rat central nervous system. Eur J Neurosci 1999;11 (4) 1349- 1361
PubMed
Lorang  DAmara  SGSimerly  RB Cell-type-specific expression of catecholamine transporters in the rat brain. J Neurosci 1994;14 (8) 4903- 4914
PubMed
Nirenberg  MJVaughan  RAUhl  GRKuhar  MJPickel  VM The dopamine transporter is localized to dendritic and axonal plasma membranes of nigrostriatal dopaminergic neurons. J Neurosci 1996;16 (2) 436- 447
PubMed
Ciliax  BJHeilman  CDemchyshyn  LLPristupa  ZBInce  EHersch  SMNiznik  HBLevey  AI The dopamine transporter: immunochemical characterization and localization in brain. J Neurosci 1995;15 (3 pt 1) 1714- 1723
PubMed
Sesack  SRCarr  DB Selective prefrontal cortex inputs to dopamine cells: implications for schizophrenia. Physiol Behav 2002;77 (4-5) 513- 517
PubMed
Lewis  DAMelchitzky  DSSesack  SRWhitehead  REAuh  SSampson  A Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 2001;432 (1) 119- 136
PubMed
Wang  GJVolkow  NDFowler  JSDing  YSLogan  JGatley  SJMacGregor  RRWolf  AP Comparison of two PET radioligands for imaging extrastriatal dopamine transporters in human brain. Life Sci 1995;57 (14) PL187- PL191
PubMed
Sesack  SRHawrylak  VAGuido  MALevey  AI Cellular and subcellular localization of the dopamine transporter in rat cortex. Adv Pharmacol 1998;42171- 174
PubMed
Wayment  HKSchenk  JOSorg  BA Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. J Neurosci 2001;21 (1) 35- 44
PubMed
Cragg  SJRice  ME DAncing past the DAT at a DA synapse. Trends Neurosci 2004;27 (5) 270- 277
PubMed
Bertolino  ABlasi  GLatorre  VRubino  VRampino  ASinibaldi  LCaforio  GPetruzzella  VPizzuti  AScarabino  TNardini  MWeinberger  DRDallapiccola  B Additive effects of genetic variation in dopamine regulating genes on working memory cortical activity in human brain. J Neurosci 2006;26 (15) 3918- 3922
PubMed
Tunbridge  EMHarrison  PJWeinberger  DR Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biol Psychiatry 2006;60 (2) 141- 151
PubMed
Vandenbergh  DJPersico  AMHawkins  ALGriffin  CALi  XJabs  EWUhl  GR Human dopamine transporter gene (DAT1) maps to chromosome 5p15.3 and displays a VNTR. Genomics 1992;14 (4) 1104- 1106
PubMed
Vandenbergh  DJThompson  MDCook  EHBendahhou  ENguyen  TKrasowski  MDZarrabian  DComings  DSellers  EMTyndale  RFGeorge  SRO’Dowd  BFUhl  GR Human dopamine transporter gene: coding region conservation among normal, Tourette's disorder, alcohol dependence and attention-deficit hyperactivity disorder populations. Mol Psychiatry 2000;5 (3) 283- 292
PubMed
Fuke  SSuo  STakahashi  NKoike  HSasagawa  NIshiura  S The VNTR polymorphism of the human dopamine transporter (DAT1) gene affects gene expression. Pharmacogenomics J 2001;1 (2) 152- 156
PubMed
Mill  JAsherson  PBrowes  CD’Souza  UCraig  I Expression of the dopamine transporter gene is regulated by the 3′UTR VNTR: evidence from brain and lymphocytes using quantitative RT-PCR. Am J Med Genet 2002;114 (8) 975- 979
PubMed
Heinz  AGoldman  DJones  DWPalmour  RHommer  DGorey  JGLee  KSLinnoila  MWeinberger  DR Genotype influences in vivo dopamine transporter availability in human striatum. Neuropsychopharmacology 2000;22 (2) 133- 139
PubMed
VanNess  SHOwens  MJKilts  CD The variable number of tandem repeats element in DAT1 regulates in vitro dopamine transporter density. BMC Genet 2005;655
PubMed10.1186/1471-2156-6-55
van Dyck  CHMalison  RTJacobsen  LKSeibyl  JPStaley  JKLaruelle  MBaldwin  RMInnis  RBGelernter  J Increased dopamine transporter availability associated with the 9-repeat allele of the SLC6A3 gene. J Nucl Med 2005;46 (5) 745- 751
PubMed
Martinez  DGelernter  JAbi-Dargham  Avan Dyck  CHKegeles  LInnis  RBLaruelle  M The variable number of tandem repeats polymorphism of the dopamine transporter gene is not associated with significant change in dopamine transporter phenotype in humans. Neuropsychopharmacology 2001;24 (5) 553- 560
PubMed
Le Couteur  DGLeighton  PW McCann  SJPond  S Association of a polymorphism in the dopamine-transporter gene with Parkinson's disease. Mov Disord 1997;12 (5) 760- 763
PubMed
Muramatsu  THiguchi  S Dopamine transporter gene polymorphism and alcoholism. Biochem Biophys Res Commun 1995;211 (1) 28- 32
PubMed
Gill  MDaly  GHeron  SHawi  ZFitzgerald  M Confirmation of association between attention deficit hyperactivity disorder and a dopamine transporter polymorphism. Mol Psychiatry 1997;2 (4) 311- 313
PubMed
Faraone  SVPerlis  RHDoyle  AESmoller  JWGoralnick  JJHolmgren  MASklar  P Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry 2005;57 (11) 1313- 1323
PubMed
Díaz-Anzaldúa  AJoober  RRiviere  JBDion  YLespérance  PRicher  FChouinard  SRouleau  GAMontreal Tourette Syndrome Study Group, Tourette syndrome and dopaminergic genes: a family-based association study in the French Canadian founder population. Mol Psychiatry 2004;9 (3) 272- 277
PubMed
Comings  DEWu  SChiu  CRing  RHGade  RAhn  CMacMurray  JPDietz  GMuhleman  D Polygenic inheritance of Tourette syndrome, stuttering, attention deficit hyperactivity, conduct, and oppositional defiant disorder: the additive and subtractive effect of the three dopaminergic genes—DRD2, D beta H, and DAT1. Am J Med Genet 1996;67 (3) 264- 288
PubMed
Caldú  XVendrell  PBartres-Faz  DClemente  IBargalló  NJurado  MASerra-Grabulosa  JMJunqué  C Impact of the COMT Val108/158 Met and DAT genotypes on prefrontal function in healthy subjects. Neuroimage 2007;37 (4) 1437- 1444
PubMed
Bertolino  ADi Giorgio  ABlasi  GSambataro  FCaforio  GSinibaldi  LLatorre  VRampino  ATaurisano  PFazio  LRomano  RDouzgou  SPopolizio  TKolachana  BNardini  MWeinberger  DRDallapiccola  B Epistasis between dopamine regulating genes identifies a nonlinear response of the human hippocampus during memory tasks. Biol Psychiatry 2008;64 (3) 226- 234
PubMed
Yacubian  JSommer  TSchroeder  KGläscher  JKalisch  RLeuenberger  BBraus  DFBüchel  C Gene-gene interaction associated with neural reward sensitivity. Proc Natl Acad Sci U S A 2007;104 (19) 8125- 8130
PubMed
Akil  MKolachana  BSRothmond  DAHyde  TMWeinberger  DRKleinman  JE Catechol-O-methyltransferase genotype and dopamine regulation in the human brain. J Neurosci 2003;23 (6) 2008- 2013
PubMed
Weinberger  DRBerman  KFChase  TN Mesocortical dopaminergic function and human cognition. Ann N Y Acad Sci 1988;537330- 338
PubMed
Weinberger  DREgan  MFBertolino  ACallicott  JHMattay  VSLipska  BKBerman  KFGoldberg  TE Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001;50 (11) 825- 844
PubMed
Abi-Dargham  AMawlawi  OLombardo  IGil  RMartinez  DHuang  YHwang  DRKeilp  JKochan  LVan Heertum  RGorman  JMLaruelle  M Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 2002;22 (9) 3708- 3719
PubMed
Akil  MPierri  JNWhitehead  REEdgar  CLMohila  CSampson  ARLewis  DA Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects. Am J Psychiatry 1999;156 (10) 1580- 1589
PubMed
Meyer-Lindenberg  AMiletich  RSKohn  PDEsposito  GCarson  REQuarantelli  MWeinberger  DRBerman  KF Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 2002;5 (3) 267- 271
PubMed
Bertolino  ABreier  ACallicott  JHAdler  CMattay  VSShapiro  MFrank  JAPickar  DWeinberger  DR The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology 2000;22 (2) 125- 132
PubMed
Grace  AA Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res Brain Res Rev 2000;31 (2-3) 330- 341
PubMed
Laruelle  M The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev 2000;31 (2-3) 371- 384
PubMed
Yetkin  FZHammeke  TASwanson  SJMorris  GLMueller  WM McAuliffe  TLHaughton  VM A comparison of functional MR activation patterns during silent and audible language tasks. AJNR Am J Neuroradiol 1995;16 (5) 1087- 1092
PubMed
Lurito  JTKareken  DALowe  MJChen  SHMathews  VP Comparison of rhyming and word generation with FMRI. Hum Brain Mapp 2000;10 (3) 99- 106
PubMed
Hutchinson  MSchiffer  WJoseffer  SLiu  ASchlosser  RDikshit  SGoldberg  EBrodie  JD Task-specific deactivation patterns in functional magnetic resonance imaging. Magn Reson Imaging 1999;17 (10) 1427- 1436
PubMed
Friedman  LKenny  JTWise  ALWu  DStuve  TAMiller  DAJesberger  JALewin  JS Brain activation during silent word generation evaluated with functional MRI. Brain Lang 1998;64 (2) 231- 256
PubMed
Schlösser  RHutchinson  MJoseffer  SRusinek  HSaarimaki  AStevenson  JDewey  SLBrodie  JD Functional magnetic resonance imaging of human brain activity in a verbal fluency task. J Neurol Neurosurg Psychiatry 1998;64 (4) 492- 498
PubMed
Curtis  VABullmore  ETBrammer  MJWright  ICWilliams  SCMorris  RGSharma  TSMurray  RM McGuire  PK Attenuated frontal activation during a verbal fluency task in patients with schizophrenia. Am J Psychiatry 1998;155 (8) 1056- 1063
PubMed
Phelps  EAHyder  FBlamire  AMShulman  RG FMRI of the prefrontal cortex during overt verbal fluency. Neuroreport 1997;8 (2) 561- 565
PubMed
Fu  CHMorgan  KSuckling  JWilliams  SCAndrew  CVythelingum  GN McGuire  PK A functional magnetic resonance imaging study of overt letter verbal fluency using a clustered acquisition sequence: greater anterior cingulate activation with increased task demand. Neuroimage 2002;17 (2) 871- 879
PubMed
Yurgelun-Todd  DAWaternaux  CMCohen  BMGruber  SAEnglish  CDRenshaw  PF Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production. Am J Psychiatry 1996;153 (2) 200- 205
PubMed
Allen  HALiddle  PFFrith  CD Negative features, retrieval processes and verbal fluency in schizophrenia. Br J Psychiatry 1993;163769- 775
PubMed
Howanitz  ECicalese  CHarvey  PD Verbal fluency and psychiatric symptoms in geriatric schizophrenia. Schizophr Res 2000;42 (3) 167- 169
PubMed
Frith  CDFriston  KJHerold  SSilbersweig  DFletcher  PCahill  CDolan  RJFrackowiak  RSLiddle  PF Regional brain activity in chronic schizophrenic patients during the performance of a verbal fluency task. Br J Psychiatry 1995;167 (3) 343- 349
PubMed
Fletcher  PCFrith  CDGrasby  PMFriston  KJDolan  RJ Local and distributed effects of apomorphine on fronto-temporal function in acute unmedicated schizophrenia. J Neurosci 1996;16 (21) 7055- 7062
PubMed
Fu  CHSuckling  JWilliams  SCAndrew  CMVythelingum  GN McGuire  PK Effects of psychotic state and task demand on prefrontal function in schizophrenia: an fMRI study of overt verbal fluency. Am J Psychiatry 2005;162 (3) 485- 494
PubMed
Artiges  EMartinot  JLVerdys  MAttar-Levy  DMazoyer  BTzourio  NGiraud  MJPaillère-Martinot  ML Altered hemispheric functional dominance during word generation in negative schizophrenia. Schizophr Bull 2000;26 (3) 709- 721
PubMed
Broome  MRMatthiasson  PFusar-Poli  PWoolley  JBJohns  LCTabraham  PBramon  EValmaggia  LWilliams  SCBrammer  MJChitnis  X McGuire  PK Neural correlates of executive function and working memory in the “at-risk mental state.” Br J Psychiatry 2009;194 (1) 25- 33
PubMed
Gur  REKeshavan  MSLawrie  SM Deconstructing psychosis with human brain imaging. Schizophr Bull 2007;33 (4) 921- 931
PubMed
Wing  JKBabor  TBrugha  TBurke  JCooper  JEGiel  RJablenski  ARegier  DSartorius  N SCAN: Schedules for Clinical Assessment in Neuropsychiatry. Arch Gen Psychiatry 1990;47 (6) 589- 593
PubMed
Endicott  JSpitzer  RL A diagnostic interview: the Schedule for Affective Disorders and Schizophrenia. Arch Gen Psychiatry 1978;35 (7) 837- 844
PubMed
McGuffin  PFarmer  AHarvey  I A polydiagnostic application of operational criteria in studies of psychotic illness: development and reliability of the OPCRIT system. Arch Gen Psychiatry 1991;48 (8) 764- 770
PubMed
Wechsler  D Wechsler Adult Intelligence Scale—Third Edition Manual.  San Antonio, TX Psychological Corp1997;
Wechsler  D Manual for the Wechsler Intelligence ScaleRevised.  San Antonio, TX Psychological Corp1981;
Wechsler  D Wechsler Abbreviated Scale of Intelligence.  San Antonio, TX Psychological Corp1999;
Ammons  RBAmmons  CH Quick Test.  Missoula, MT Psychological Test Specialists1962;
Frith  CDLeary  JCahill  CJohnstone  EC Performance on psychological tests: demographic and clinical correlates of the results of these tests. Br J Psychiatry Suppl 1991; (13) 26- 29, 44-46
PubMed
Freeman  BSmith  NCurtis  CHuckett  LMill  JCraig  IW DNA from buccal swabs recruited by mail: evaluation of storage effects on long-term stability and suitability for multiplex polymerase chain reaction genotyping. Behav Genet 2003;33 (1) 67- 72
PubMed
Raymond  MRousset  F GENEPOP (version 1.2): population genetics software for exact tests and ecumenicism. J Hered 1995;86 (3) 248- 249
Benton  ALHamsher  KD Multilingual Aphasia Examination.  New York, NY Oxford University Press1994;
Lezak  MD Neuropsychological Assessment. 3rd ed. New York, NY Oxford University Press1995;
Friston  KJ Introduction: experimental design and statistical parametric mapping. Frackowiak  RSFriston  KJFrith  CDDolan  RJPrice  CJZeki  SHuman Brain Function. 2nd ed. New York, NY Academic Press2003;
Penny  WDHolmes  APFriston  KJ Random effects analysis. Frackowiak  RSFriston  KJFrith  CDDolan  RJPrice  CJZeki  SHuman Brain Function. 2nd ed. New York, NY Academic Press2003;
Tzourio-Mazoyer  NLandeau  BPapathanassiou  DCrivello  FEtard  ODelcroix  NMazoyer  BJoliot  M Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain. Neuroimage 2002;15 (1) 273- 289
PubMed
Maldjian  JALaurienti  PJKraft  RABurdette  JH An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 2003;19 (3) 1233- 1239
PubMed
Maldjian  JALaurienti  PJBurdette  JH Precentral gyrus discrepancy in electronic versions of the Talairach atlas. Neuroimage 2004;21 (1) 450- 455
PubMed
Pickett  ERKuniholm  EProtopapas  AFriedman  JLieberman  P Selective speech motor, syntax and cognitive deficits associated with bilateral damage to the putamen and the head of the caudate nucleus: a case study. Neuropsychologia 1998;36 (2) 173- 188
PubMed
Murphy  KCorfield  DRGuz  AFink  GRWise  RJHarrison  JAdams  L Cerebral areas associated with motor control of speech in humans. J Appl Physiol 1997;83 (5) 1438- 1447
PubMed
Fabbro  FClarici  ABava  A Effects of left basal ganglia lesions on language production. Percept Mot Skills 1996;82 (3 pt 2) 1291- 1298
PubMed
Speedie  LJWertman  ETa’ir  JHeilman  KM Disruption of automatic speech following a right basal ganglia lesion. Neurology 1993;43 (9) 1768- 1774
PubMed
Lindvall  OBjorklund  A Anatomy of the dopaminergic neuron systems in the rat brain. Adv Biochem Psychopharmacol 1978;191- 23
PubMed
Binder  JRFrost  JAHammeke  TABellgowan  PSRao  SMCox  RW Conceptual processing during the conscious resting state: a functional MRI study. J Cogn Neurosci 1999;11 (1) 80- 95
PubMed
McKiernan  KAKaufman  JNKucera-Thompson  JBinder  JR A parametric manipulation of factors affecting task-induced deactivation in functional neuroimaging. J Cogn Neurosci 2003;15 (3) 394- 408
PubMed
McKiernan  KAD’Angelo  BRKaufman  JNBinder  JR Interrupting the “stream of consciousness”: an fMRI investigation. Neuroimage 2006;29 (4) 1185- 1191
PubMed
Breier  ASu  TPSaunders  RCarson  REKolachana  BSde Bartolomeis  AWeinberger  DRWeisenfeld  NMalhotra  AKEckelman  WCPickar  D Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 1997;94 (6) 2569- 2574
PubMed
Abi-Dargham  AGil  RKrystal  JBaldwin  RMSeibyl  JPBowers  Mvan Dyck  CHCharney  DSInnis  RBLaruelle  M Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 1998;155 (6) 761- 767
PubMed
Laruelle  MAbi-Dargham  A Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol 1999;13 (4) 358- 371
PubMed
Laruelle  MAbi-Dargham  AGil  RKegeles  LInnis  R Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999;46 (1) 56- 72
PubMed
Sesack  SRPickel  VM Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area. J Comp Neurol 1992;320 (2) 145- 160
PubMed
Weiner  DMLevey  AISunahara  RKNiznik  HBO’Dowd  BFSeeman  PBrann  MR D1 and D2 dopamine receptor mRNA in rat brain. Proc Natl Acad Sci U S A 1991;88 (5) 1859- 1863
PubMed
Camps  MCortes  RGueye  BProbst  APalacios  JM Dopamine receptors in human brain: autoradiographic distribution of D2 sites. Neuroscience 1989;28 (2) 275- 290
PubMed
Cortés  RGueye  BPazos  AProbst  APalacios  JM Dopamine receptors in human brain: autoradiographic distribution of D1 sites. Neuroscience 1989;28 (2) 263- 273
PubMed
Tanaka  S Dopaminergic control of working memory and its relevance to schizophrenia: a circuit dynamics perspective. Neuroscience 2006;139 (1) 153- 171
PubMed
Gründer  GVernaleken  IMüller  MJDavids  EHeydari  NBuchholz  HGBartenstein  PMunk  OLStoeter  PWong  DFGjedde  ACumming  P Subchronic haloperidol downregulates dopamine synthesis capacity in the brain of schizophrenic patients in vivo. Neuropsychopharmacology 2003;28 (4) 787- 794
PubMed
Vernaleken  IKumakura  YCumming  PBuchholz  HGSiessmeier  TStoeter  PMüller  MJBartenstein  PGründer  G Modulation of [18F]fluorodopa (FDOPA) kinetics in the brain of healthy volunteers after acute haloperidol challenge. Neuroimage 2006;30 (4) 1332- 1339
PubMed
Vernaleken  IKumakura  YBuchholz  HGSiessmeier  THilgers  RDBartenstein  PCumming  PGründer  G Baseline [18F]-FDOPA kinetics are predictive of haloperidol-induced changes in dopamine turnover and cognitive performance: a positron emission tomography study in healthy subjects. Neuroimage 2008;40 (3) 1222- 1231
PubMed
Honey  GDBullmore  ETSoni  WVaratheesan  MWilliams  SCSharma  T Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci U S A 1999;96 (23) 13432- 13437
PubMed
Lee  MAJayathilake  KMeltzer  HY A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia. Schizophr Res 1999;37 (1) 1- 11
PubMed
Hagger  CBuckley  PKenny  JTFriedman  LUbogy  DMeltzer  HY Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biol Psychiatry 1993;34 (10) 702- 712
PubMed
Lee  MAThompson  PAMeltzer  HY Effects of clozapine on cognitive function in schizophrenia. J Clin Psychiatry 1994;55 ((suppl B)) 82- 87
PubMed
Vernaleken  IBuchholz  HGKumakura  YSiessmeier  TStoeter  PBartenstein  PCumming  PGründer  G “Prefrontal” cognitive performance of healthy subjects positively correlates with cerebral FDOPA influx: an exploratory [18F]-fluoro-L-DOPA-PET investigation. Hum Brain Mapp 2007;28 (10) 931- 939
PubMed
Meltzer  HY McGurk  SR The effects of clozapine, risperidone, and olanzapine on cognitive function in schizophrenia. Schizophr Bull 1999;25 (2) 233- 255
PubMed
Kimmel  HLJoyce  ARCarroll  FIKuhar  MJ Dopamine D1 and D2 receptors influence dopamine transporter synthesis and degradation in the rat. J Pharmacol Exp Ther 2001;298 (1) 129- 140
PubMed
Stevens  AAGoldman-Rakic  PSGore  JCFulbright  RKWexler  BE Cortical dysfunction in schizophrenia during auditory word and tone working memory demonstrated by functional magnetic resonance imaging. Arch Gen Psychiatry 1998;55 (12) 1097- 1103
PubMed
Crespo-Facorro  BParadiso  SAndreasen  NCO’Leary  DSWatkins  GLBoles Ponto  LLHichwa  RD Recalling word lists reveals “cognitive dysmetria” in schizophrenia: a positron emission tomography study. Am J Psychiatry 1999;156 (3) 386- 392
PubMed
Lewis  DAHayes  TLLund  JSOeth  KM Dopamine and the neural circuitry of primate prefrontal cortex: implications for schizophrenia research. Neuropsychopharmacology 1992;6 (2) 127- 134
PubMed
Spence  SALiddle  PFStefan  MDHellewell  JSSharma  TFriston  KJHirsch  SRFrith  CDMurray  RMDeakin  JFGrasby  PM Functional anatomy of verbal fluency in people with schizophrenia and those at genetic risk: focal dysfunction and distributed disconnectivity reappraised. Br J Psychiatry 2000;17652- 60
PubMed
Winterer  GWeinberger  DR Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 2004;27 (11) 683- 690
PubMed
Cornish  KMManly  TSavage  RSwanson  JMorisano  DButler  NGrant  CCross  GBentley  LHollis  CP Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample. Mol Psychiatry 2005;10 (7) 686- 698
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
JAMAevidence.com


Genotype