Several lines of evidence support that dopaminergic neurotransmission plays a role in creative thought and behavior. Here, we investigated the relationship between creative ability and dopamine D2 receptor expression in healthy individuals, with a focus on regions where aberrations in dopaminergic function have previously been associated with psychotic symptoms and a genetic liability to schizophrenia. Scores on divergent thinking tests (Inventiveness battery, Berliner Intelligenz Struktur Test) were correlated with regional D2 receptor densities, as measured by Positron Emission Tomography, and the radioligands [11C]raclopride and [11C]FLB 457. The results show a negative correlation between divergent thinking scores and D2 density in the thalamus, also when controlling for age and general cognitive ability. Hence, the results demonstrate that the D2 receptor system, and specifically thalamic function, is important for creative performance, and may be one crucial link between creativity and psychopathology. We suggest that decreased D2 receptor densities in the thalamus lower thalamic gating thresholds, thus increasing thalamocortical information flow. In healthy individuals, who do not suffer from the detrimental effects of psychiatric disease, this may increase performance on divergent thinking tests. In combination with the cognitive functions of higher order cortical networks, this could constitute a basis for the generative and selective processes that underlie real life creativity.
Citation: de Manzano Ö, Cervenka S, Karabanov A, Farde L, Ullén F (2010) Thinking Outside a Less Intact Box: Thalamic Dopamine D2 Receptor Densities Are Negatively Related to Psychometric Creativity in Healthy Individuals. PLoS ONE 5(5): e10670. https://doi.org/10.1371/journal.pone.0010670
Editor: Aldo Rustichini, University of Minnesota, United States of America
Received: February 7, 2010; Accepted: April 11, 2010; Published: May 17, 2010
Copyright: © 2010 de Manzano et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Funding was provided by the Swedish Research Council 2006–4733. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Creativity can be generically defined as the ability to produce work that is at the same time novel and meaningful, as opposed to trivial or bizarre . A main psychometric approach to measuring individual differences in creativity is represented by divergent thinking tests. These tests typically involve generating a multitude of novel and meaningful responses to open-ended questions. For instance, in the classical Guilford's alternate uses test , participants are instructed to propose different uses for certain artifacts, such as a brick, within a limited time.
Scores on divergent thinking tests show positive correlations with involvement in real-life creative activities, self-rated creativity , as well as objective measures of creative achievement, even when controlling for IQ . They are also correlated with several personality traits, such as Openness to Experience, common to individuals with documented creative capacity . In the standard three-stratum model of human cognitive abilities, the Cattell-Horn-Carroll-framework , the main ability captured by divergent thinking tests corresponds to the second-order factor “long-term storage and retrieval” (Glr), which captures individual differences in fluent retrieval of information through association. This factor, thus, predicts creative achievement over and above fluid reasoning (Gf) and crystallized ability (Gc), i.e. beyond traditional measures of “intelligence” and “knowledge”.
Divergent thinking is influenced by dopaminergic function. Reuter  found a correlation between divergent thinking (the Inventiveness battery of the Berliner Intelligenz Struktur Test) and polymorphisms of the dopamine D2 receptor gene–DRD2 TAQ IA. Higher creativity scores were observed in carriers of the A1 allele. This polymorphism is unrelated to general intelligence , , which suggests that it is more specifically related to Glr. This finding is in line with functional imaging research showing the D2 system to be involved in attentional set shifting and response flexibility, which are important components of divergent thinking . Furthermore, the finding indicates that divergent thinking is related to regional differences in D2 densities, since the DRD2 TAQ IA polymorphism has been shown to modulate D2 binding potential (D2BP) in both striatal  and extrastriatal regions .
A clue to where to expect regional D2 density differences related to divergent thinking comes from the link between creativity and psychopathology: In healthy individuals, various creativity-related measures, including divergent thinking, have been associated with the personality traits psychoticism and schizotypy, as well as genetic liability for schizophrenia spectrum and bipolar disorders –. Notably, the networks relevant to divergent thinking, i.e. structures and processes in associative corticostriatal-thalamocortical loops , , overlap to a great extent with regions and networks affected in schizophrenia and bipolar disorder. Furthermore, dopamine is known to influence processing in these networks and alterations in dopaminergic function and activity of D2 receptors have been linked to both positive and negative psychotic symptoms (e.g. –).
Two regions appear to be of particular interest in this context: the thalamus and the striatum. Several studies have shown thalamic D2BP to be reduced in drug-naïve schizophrenia patients –. Moreover, D2BP in subregions of the thalamus was found to be negatively related to total symptoms, general symptoms, positive symptoms, hostility and suspiciousness ,  as well as grandiosity . The direction of this correlation would match with the association between DRD2 TAQ AI and divergent thinking . A metaanalysis by Weinberger and Laurelle  found a significant elevation of striatal D2 receptors in untreated patients with schizophrenia. A later study on twins discordant for schizophrenia shows that this upregulation might be related to a genetic risk for schizophrenia . Two studies have found positive correlations between ventral striatal D2BP and the specific symptoms Disorientation  and Hallucinations .
Although the density of D2 receptors in cortical regions is very low  and thus difficult to estimate using PET due to low signal-to noise ratio, a few studies have found correlations between positive symptoms in schizophrenia and D2BP in cortical regions , , . However, the results across studies are not consistent and more experimental data are required in order to determine their significance to cognition . Hence, it is difficult to state a clear hypothesis about the relation between cortical D2 receptor density and divergent thinking.
Based on these findings, our main hypotheses were that higher scores on divergent thinking would be associated with lower D2BP in the thalamus and/or higher D2BP in the striatum. Since the frontal cortex has been implicated in creative ability from other lines of research (see e.g. ), this region was also included in the analysis. For exploratory purposes, we performed an additional analysis of striatal functional subregions.
Descriptive statistics of all variables of interest are summarized in Table 1. Table 2 shows partial correlations between regional D2BP and divergent thinking controlling for age. These correlations are also illustrated in Figure 1. There was a significant negative correlation between D2BP and divergent thinking in the thalamus (Fig. 1A; r = −.64, p = .013; Bonferroni corrected α = .017), confirming our hypothesis with regard to this region. This correlation remained significant when simultaneously controlling for age and Raven scores. There was no significant correlation between divergent thinking and D2BP in the striatum (Fig. 1B; r = .10, p = .37) nor in the frontal cortex (Fig. 1C; r = −.23, p = .46), or in any striatal subregion (associative striatum: r = .05, p = .44; ventral striatum: r = .35, p = .13; sensorimotor striatum: r = .07, p = .37). Raven scores were not associated with any other measure.
(A) Correlation between thalamic D2 binding potential (D2BP) and divergent thinking (BIS score). (B) Correlation between D2BP and BIS score in the striatum. (C) Correlation between D2BP and BIS score in the frontal cortex.
The main finding in the present study is a negative correlation between divergent thinking and D2BP in the thalamus, thus confirming our hypothesis for this region. There was no significant correlation between divergent thinking and D2BP in the striatum or in the frontal cortex. Furthermore, there were no relations between Raven scores and BIS scores, or between Raven scores and D2BP, which is in line with previous findings showing that divergent thinking is essentially separate from measures of intelligence.
Two methodological issues should be considered. Firstly, the time between the PET-examination and the administration of the divergent thinking test was quite extended (approximately eighteen months). However, in thalamus - where significant results were found - the age effect on D2BP is less pronounced: In a sample of 35 participants, age range 16–50, Talvik  found a 6% decline in the right thalamus per decade, and no significant decrease at all in the left thalamus. Secondly, since D2BP is a function of both receptor density and apparent affinity, these parameters cannot be dissociated based on a single PET measurement . Among the factors influencing apparent affinity, endogenous dopamine levels have been shown to affect [11C]FLB 457 binding , , . However, other studies have been negative ,  and using scatchard approaches where Kd and Bmax can be separated is has been shown that Bmax accounts for most of the variance in BP . This suggests that the low D2BP measurements in individuals with high creativity scores demonstrated in the present study are related primarily to a reduced density of dopamine D2 receptors, rather than an increased level of endogenous dopamine.
Divergent thinking and thalamic D2BP
In the past, several different measures of divergent test performance have been used, e.g. Fluency–the number of valid responses; Originality–how frequent the participant's responses were among the responses of the rest of the sample; Flexibility–the number of semantic categories produced; Switching–the number of shifts between semantic categories; and Elaboration–how extensive each response is (if the task involves producing more than single words). Importantly however, all these measures have been found highly intercorrelated: Someone who has high fluency is also more likely to show more flexibility of thought and provide more elaborate and uncommon solutions. One simple explanation to this was given by Campbell  who reformulated an original idea by Guilford  into a theory of “blind variation and selective attention”. In brief, if idea generation is based on a more or less random process of free association, and you are able to come up with many ideas, the probability for being flexible and original is consequently increased.
Based on the current findings, we suggest that a lower D2BP in the thalamus may be one factor that facilitates performance on divergent thinking tasks. The thalamus contains the highest levels of dopamine D2 receptors out of all extrastriatal brain regions , . Decreased D2BP in the thalamus has been suggested, firstly, to lower thalamic gating thresholds, resulting in decreased filtering and autoregulation of information flow  and, secondly, to increase excitation of cortical regions through decreased inhibition of prefrontal pyramidal neurons , , . The decreased prefrontal signal-to-noise ratio may place networks of cortical neurons in a more labile state, allowing them to more easily switch between representations and process multiple stimuli across a wider association range . This state, which we hereforth will refer to as the “creative bias”, could benefit performance on tasks that involve continuous generation and (re-)combination of mental representations and switching between mind-sets. The creative bias could also explain why the different measures of divergent task performance correlate: A decreased signal-to-noise ratio in thalamus would decrease information gating and possibly increase fluency; decreased signal-to-noise ratio in cortical regions should better enable flexibility and switching between representations; similarly, the associative range should be widened and selectivity should be decreased which might spur originality and elaboration.
Divergent thinking and psychopathology
Besides carrying benefits related to fluency and switching, the decreased signal-to-noise ratio associated with the creative bias should be disadvantageous in relation to tasks that require high levels of selective attention. Some support for this prediction can be taken from Dorfman  who showed that the greater a person's divergent thinking scores, the slower his or her reaction times were on a negative priming task requiring the inhibition of interfering information. Furthermore, the creative bias may also bring a risk of excessive excitatory signals from the thalamus overwhelming cortical neurotransmission, with ensuing cognitive disorganization and positive symptoms . It is thus tempting to suggest that dopaminergic modulation of neurotransmission mediated through dopamine D2-receptors could be one of the mechanisms which associate creativity with positive psychotic symptoms. Interestingly, positive symptoms are not necessarily related to problems in executive function, at least not to the same extent as negative symptoms , which indicates that in the creative individual “blind variation” might be affected without a concomitant decline in “selective retention”. It can be speculated that aberrant thalamic function may promote unusual associations, as well as improved performance on divergent thinking tests in healthy individuals, in the absence of the detrimental effects typically associated with psychiatric disorders. In other words, thinking outside the box might be facilitated by having a somewhat less intact box.
Materials and Methods
All participants gave verbal and written informed consent and the study was approved by the Ethics and Radiation Safety committees of Karolinska Institutet (Dnr. 2007/704-31/4, 02-431, 2007/1611-32).
The participants in the present study had previously served as control subjects in a clinical study . Fourteen participants (6 male, 8 female) with at least nine years of basic education were included in the study (age: 41–65, M = 56±8 years). The participants had no history of neurological or psychiatric illness, as determined by clinical interview, MRI examination, blood and urine tests, and ECG. None of the subjects were nicotine users, and the use of caffeine or alcohol was not allowed during the days of PET examinations. All women were menopausal. One participant was excluded from analysis because of an extremely low Raven score, giving a total of thirteen participants.
The psychological tests were administered individually. The personality questionnaires were administered in connection with the PET-experiments. Divergent thinking and general cognitive ability was assessed approximately eighteen months after the original PET-examination.
Divergent thinking was assessed using three timed subtests from the “inventiveness” test battery of the “Berliner Intelligenz Struktur Test” (BIS) . The tests measured performance within the figural, verbal, and numeric domains and were chosen based on their having the highest factor loadings on the total inventiveness-score. In the figural test, a simple line drawing should be completed in various ways in order to create pictures of as many possible real objects as possible. In the verbal test, the participant was instructed to produce as many alternate uses for a given object as possible. In the numeric test the participant had to generate as many logical number sequences as possible, while trying to vary the rule of construction. Raw scores from each subtest were transformed into Z scores , which were subsequently summed and used as a composite measure of divergent thinking.
MR and PET experimental procedure
Magnetic resonance (MR) and head fixation system.
T1 weighted MR-images were acquired using a 1.5 T GE Signa system (Milwaukee, WI) To allow for the same head position in all measurements and to minimize head movement, a plaster helmet was made for each participant individually and used during both MRI and PET examinations .
Positron emission tomography (PET) examinations.
PET studies were performed on an ECAT Exact HR system (CTI Siemens, Knoxville, TN) [11C]raclopride and [11C]FLB 457 were prepared from [11C]methyl triflate as described previously , . The radioligands were given intravenously as a rapid bolus and the cannula was flushed with saline. Radioactivity in the brain was measured during 51 min for [11C]raclopride and 87 min for [11C]FLB 457,
Image processing and analysis.
The MR-images were realigned to the AC–PC plane using the SPM2 software and PET images were coregistered to the MR image using the normalized mutual information method implemented in SPM2 (Wellcome Department of Imaging Neuroscience, London, UK). For determination of regional radioligand binding, regions of interest (ROIs) were manually delineated on each individual MR-image using the Human Brain Atlas software.
In the present study, the selection of ROIs was limited to the thalamus and frontal cortex for [11C]FLB 457 examinations, and to the striatum for [11C]raclopride examinations. In an extended anatomical analysis of the striatum, ROIs for striatal subregions were defined according to a method described in the literature ,  in which striatum is divided into ventral, associative and sensorimotor subregions based on the differential connectivity of the striatum . ROIs for the thalamus were defined using a modified version of a procedure described previously , , . Finally, a ROI for cerebellum was drawn below the petrosal bone using five slices, corresponding to a thickness of 10 mm. For an example of ROI delineation, see Figure 2.
(A) Sagittal image of regional radioactivity after intravenous injection of [11C]FLB 457 in one subject. Thalamic ROI. (B) Coronal image of regional radioactivity after intravenous injection of [11C]raclopride. Striatal ROI.
The ROIs were transferred to the series of PET images to generate time–activity curves (procedure described elsewhere ). D2 receptor binding potential (BP) values were calculated using the simplified reference tissue model with the cerebellum as reference region. In this context, BP refers to BPND, which represents the ratio at equilibrium of specifically bound radioligand to that of nondisplaceable radioligand in tissue . The SRTM has previously been validated for both [11C]raclopride and [11C]FLB 457  and .
Data was analyzed using Statistica 8.0 (StatSoft). A partial correlation between regional thalamic D2BP, striatal D2BP, intelligence and divergent thinking was then performed, keeping participant age constant. For the thalamus and the striatum, one-tailed significance tests were used, since we predicted negative and positive directions of the correlations, respectively. Significance levels were Bonferroni corrected (n = 3; thalamus/striatum/frontal cortex). Striatal subregions were analyzed separately in an extended analysis, also using one-tailed significance tests.
Conceived and designed the experiments: OdM SC LF FU. Performed the experiments: OdM SC AK. Analyzed the data: OdM. Contributed reagents/materials/analysis tools: OdM SC. Wrote the paper: OdM FU. Interpretation of data: SC AK LF FU. Revision of paper: SC AK LF.
- 1. Sternberg RJ, Lubart TI (2002) The Concept of Creativity: Prospects and Paradigms. In: Sternberg RJ, editor. Handbook of Creativity. New York: Cambridge University Press. 3 p.RJ SternbergTI Lubart2002The Concept of Creativity: Prospects and Paradigms.RJ SternbergHandbook of CreativityNew YorkCambridge University Press3
- 2. Christensen PR, Guilford JP, Merrifield PR, Wilson RC (1960) Alternate Uses. Beverley Hills, CA: Sheridan Psychological Services. PR ChristensenJP GuilfordPR MerrifieldRC Wilson1960Alternate Uses.Beverley Hills, CASheridan Psychological Services
- 3. Furnham A, Bachtiar V (2008) Personality and intelligence as predictors of creativity. Personality and Individual Differences 45: A. FurnhamV. Bachtiar2008Personality and intelligence as predictors of creativity.Personality and Individual Differences45
- 4. Carson SH, Peterson JB, Higgins DM (2003) Decreased Latent Inhibition Is Associated With Increased Creative Achievement in High-Functioning Individuals. Journal of Personality and Social Psychology 85: 499–506.SH CarsonJB PetersonDM Higgins2003Decreased Latent Inhibition Is Associated With Increased Creative Achievement in High-Functioning Individuals.Journal of Personality and Social Psychology85499506
- 5. McGrew KS (2009) CHC theory and the human cognitive abilities project: Standing on the shoulders of the giants of psychometric intelligence research. Jan 2009. Intelligence 37: KS McGrew2009CHC theory and the human cognitive abilities project: Standing on the shoulders of the giants of psychometric intelligence research. Jan 2009.Intelligence37
- 6. Reuter M, Roth S, Holve K, Hennig J (2006) Identification of first candidate genes for creativity: A pilot study. Jan 2006. Brain Research 1069: M. ReuterS. RothK. HolveJ. Hennig2006Identification of first candidate genes for creativity: A pilot study. Jan 2006.Brain Research1069
- 7. Moises HW, Frieboes RM, Spelzhaus P, Yang L, Kohnke M, et al. (2001) No association between dopamine D2 receptor gene (DRD2) and human intelligence. J Neural Transm 108: 115–121.HW MoisesRM FrieboesP. SpelzhausL. YangM. Kohnke2001No association between dopamine D2 receptor gene (DRD2) and human intelligence.J Neural Transm108115121
- 8. Ball D, Hill L, Eley TC, Chorney MJ, Chorney K, et al. (1998) Dopamine markers and general cognitive ability. Neuroreport 9: 347–349.D. BallL. HillTC EleyMJ ChorneyK. Chorney1998Dopamine markers and general cognitive ability.Neuroreport9347349
- 9. Durstewitz D, Seamans JK (2008) The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-o-methyltransferase genotypes and schizophrenia. Biol Psychiatry 64: 739–749.D. DurstewitzJK Seamans2008The dual-state theory of prefrontal cortex dopamine function with relevance to catechol-o-methyltransferase genotypes and schizophrenia.Biol Psychiatry64739749
- 10. Ritchie T, Noble EP (2003) Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics. Neurochem Res 28: 73–82.T. RitchieEP Noble2003Association of seven polymorphisms of the D2 dopamine receptor gene with brain receptor-binding characteristics.Neurochem Res287382
- 11. Hirvonen MM, Lumme V, Hirvonen J, Pesonen U, Nagren K, et al. (2009) C957T polymorphism of the human dopamine D2 receptor gene predicts extrastriatal dopamine receptor availability in vivo. Prog Neuropsychopharmacol Biol Psychiatry 33: 630–636.MM HirvonenV. LummeJ. HirvonenU. PesonenK. Nagren2009C957T polymorphism of the human dopamine D2 receptor gene predicts extrastriatal dopamine receptor availability in vivo.Prog Neuropsychopharmacol Biol Psychiatry33630636
- 12. Andreasen NC (1987) Creativity and mental illness: prevalence rates in writers and their first-degree relatives. Am J Psychiatry 144: 1288–1292.NC Andreasen1987Creativity and mental illness: prevalence rates in writers and their first-degree relatives.Am J Psychiatry14412881292
- 13. Batey M, Furnham A (2008) The relationship between measures of creativity and schizotypy. Personality and Individual Differences 45: 816–821.M. BateyA. Furnham2008The relationship between measures of creativity and schizotypy.Personality and Individual Differences45816821
- 14. Burch GSJ, Hemsley DR, Pavelis C, Corr PJ (2006) Personality, Creativity and Latent Inhibition. European Journal of Personality 20: 107–122.GSJ BurchDR HemsleyC. PavelisPJ Corr2006Personality, Creativity and Latent Inhibition.European Journal of Personality20107122
- 15. Eysenck H (1995) Genius: The natural history of creativity. Cambridge: Cambridge University Press. H. Eysenck1995Genius: The natural history of creativity.CambridgeCambridge University Press
- 16. Folley BS, Park S (2005) Verbal creativity and schizotypal personality in relation to prefrontal hemispheric laterality: a behavioral and near-infrared optical imaging study. Schizophr Res 80: 271–282.BS FolleyS. Park2005Verbal creativity and schizotypal personality in relation to prefrontal hemispheric laterality: a behavioral and near-infrared optical imaging study.Schizophr Res80271282
- 17. Karlsson JL (1970) Genetic association of giftedness and creativity with schizophrenia. Hereditas 66: 177–182.JL Karlsson1970Genetic association of giftedness and creativity with schizophrenia.Hereditas66177182
- 18. Kinney DK, Richards R, Lowing PA, LeBlanc D, Zimbalist ME, et al. (2001) Creativity in Offspring of Schizophrenic and Control Parents: An Adoption Study. Creativity Research Journal 13: 17–25.DK KinneyR. RichardsPA LowingD. LeBlancME Zimbalist2001Creativity in Offspring of Schizophrenic and Control Parents: An Adoption Study.Creativity Research Journal131725
- 19. Post F (1994) Creativity and psychopathology. A study of 291 world-famous men. Br J Psychiatry 165: 22–34.F. Post1994Creativity and psychopathology. A study of 291 world-famous men.Br J Psychiatry1652234
- 20. Post F (1996) Verbal creativity, depression and alcoholism. An investigation of one hundred American and British writers. Br J Psychiatry 168: 545–555.F. Post1996Verbal creativity, depression and alcoholism. An investigation of one hundred American and British writers.Br J Psychiatry168545555
- 21. Richards R, Kinney DK, Lunde I, Benet M, Merzel AP (1988) Creativity in manic-depressives, cyclothymes, their normal relatives, and control subjects. J Abnorm Psychol 97: 281–288.R. RichardsDK KinneyI. LundeM. BenetAP Merzel1988Creativity in manic-depressives, cyclothymes, their normal relatives, and control subjects.J Abnorm Psychol97281288
- 22. Chavez-Eakle RA, Graff-Guerrero A, Garcia-Reyna JC, Vaugier V, Cruz-Fuentes C (2007) Cerebral blood flow associated with creative performance: a comparative study. Neuroimage 38: 519–528.RA Chavez-EakleA. Graff-GuerreroJC Garcia-ReynaV. VaugierC. Cruz-Fuentes2007Cerebral blood flow associated with creative performance: a comparative study.Neuroimage38519528
- 23. Fink A, Grabner RH, Benedek M, Reishofer G, Hauswirth V, et al. (2009) The creative brain: investigation of brain activity during creative problem solving by means of EEG and FMRI. Hum Brain Mapp 30: 734–748.A. FinkRH GrabnerM. BenedekG. ReishoferV. Hauswirth2009The creative brain: investigation of brain activity during creative problem solving by means of EEG and FMRI.Hum Brain Mapp30734748
- 24. Guillin O, Abi-Dargham A, Laruelle M (2007) Neurobiology of dopamine in schizophrenia. Int Rev Neurobiol 78: 1–39.O. GuillinA. Abi-DarghamM. Laruelle2007Neurobiology of dopamine in schizophrenia.Int Rev Neurobiol78139
- 25. Cousins DA, Butts K, Young AH (2009) The role of dopamine in bipolar disorder. Bipolar Disord 11: 787–806.DA CousinsK. ButtsAH Young2009The role of dopamine in bipolar disorder.Bipolar Disord11787806
- 26. Talvik M, Nordstrom AL, Okubo Y, Olsson H, Borg J, et al. (2006) Dopamine D2 receptor binding in drug-naive patients with schizophrenia examined with raclopride-C11 and positron emission tomography. Psychiatry Res 148: 165–173.M. TalvikAL NordstromY. OkuboH. OlssonJ. Borg2006Dopamine D2 receptor binding in drug-naive patients with schizophrenia examined with raclopride-C11 and positron emission tomography.Psychiatry Res148165173
- 27. Weinberger D, Laruelle M (2001) Neurochemical and neuropharmachological imaging in schizophrenia. In: Davis KL, Charney DS, Coyle JT, Nemeroff C, editors. Neuropsychopharmacology: The Fifth Generation of Progress. New York: Lippincott, Williams & Wilkins. pp. 833–856.D. WeinbergerM. Laruelle2001Neurochemical and neuropharmachological imaging in schizophrenia.KL DavisDS CharneyJT CoyleC. NemeroffNeuropsychopharmacology: The Fifth Generation of ProgressNew YorkLippincott, Williams & Wilkins833856
- 28. Buchsbaum MS, Christian BT, Lehrer DS, Narayanan TK, Shi B, et al. (2006) D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia. Schizophr Res 85: 232–244.MS BuchsbaumBT ChristianDS LehrerTK NarayananB. Shi2006D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia.Schizophr Res85232244
- 29. Kessler RM, Woodward ND, Riccardi P, Li R, Ansari MS, et al. (2009) Dopamine D2 receptor levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects. Biol Psychiatry 65: 1024–1031.RM KesslerND WoodwardP. RiccardiR. LiMS Ansari2009Dopamine D2 receptor levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects.Biol Psychiatry6510241031
- 30. Takahashi H, Higuchi M, Suhara T (2006) The role of extrastriatal dopamine D2 receptors in schizophrenia. Biol Psychiatry 59: 919–928.H. TakahashiM. HiguchiT. Suhara2006The role of extrastriatal dopamine D2 receptors in schizophrenia.Biol Psychiatry59919928
- 31. Yasuno F, Suhara T, Okubo Y, Sudo Y, Inoue M, et al. (2004) Low dopamine d(2) receptor binding in subregions of the thalamus in schizophrenia. Am J Psychiatry 161: 1016–1022.F. YasunoT. SuharaY. OkuboY. SudoM. Inoue2004Low dopamine d(2) receptor binding in subregions of the thalamus in schizophrenia.Am J Psychiatry16110161022
- 32. Hirvonen J, van Erp TG, Huttunen J, Aalto S, Nagren K, et al. (2005) Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia. Arch Gen Psychiatry 62: 371–378.J. HirvonenTG van ErpJ. HuttunenS. AaltoK. Nagren2005Increased caudate dopamine D2 receptor availability as a genetic marker for schizophrenia.Arch Gen Psychiatry62371378
- 33. Kessler RM, Whetsell WO, Ansari MS, Votaw JR, de Paulis T, et al. (1993) Identification of extrastriatal dopamine D2 receptors in post mortem human brain with [125I]epidepride. Brain Res 609: 237–243.RM KesslerWO WhetsellMS AnsariJR VotawT. de Paulis1993Identification of extrastriatal dopamine D2 receptors in post mortem human brain with [125I]epidepride.Brain Res609237243
- 34. Suhara T, Okubo Y, Yasuno F, Sudo Y, Inoue M, et al. (2002) Decreased dopamine D2 receptor binding in the anterior cingulate cortex in schizophrenia. Arch Gen Psychiatry 59: 25–30.T. SuharaY. OkuboF. YasunoY. SudoM. Inoue2002Decreased dopamine D2 receptor binding in the anterior cingulate cortex in schizophrenia.Arch Gen Psychiatry592530
- 35. Glenthoj BY, Mackeprang T, Svarer C, Rasmussen H, Pinborg LH, et al. (2006) Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender. Biol Psychiatry 60: 621–629.BY GlenthojT. MackeprangC. SvarerH. RasmussenLH Pinborg2006Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender.Biol Psychiatry60621629
- 36. Mintun MA, Raichle ME, Kilbourn MR, Wooten GF, Welch MJ (1984) A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 15: 217–227.MA MintunME RaichleMR KilbournGF WootenMJ Welch1984A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography.Ann Neurol15217227
- 37. Aalto S, Bruck A, Laine M, Nagren K, Rinne JO (2005) Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: a positron emission tomography study using the high-affinity dopamine D2 receptor ligand [11C]FLB 457. J Neurosci 25: 2471–2477.S. AaltoA. BruckM. LaineK. NagrenJO Rinne2005Frontal and temporal dopamine release during working memory and attention tasks in healthy humans: a positron emission tomography study using the high-affinity dopamine D2 receptor ligand [11C]FLB 457.J Neurosci2524712477
- 38. Montgomery AJ, Asselin MC, Farde L, Grasby PM (2007) Measurement of methylphenidate-induced change in extrastriatal dopamine concentration using [11C]FLB 457 PET. J Cereb Blood Flow Metab 27: 369–377.AJ MontgomeryMC AsselinL. FardePM Grasby2007Measurement of methylphenidate-induced change in extrastriatal dopamine concentration using [11C]FLB 457 PET.J Cereb Blood Flow Metab27369377
- 39. Narendran R, Frankle WG, Mason NS, Rabiner EA, Gunn RN, et al. (2009) Positron emission tomography imaging of amphetamine-induced dopamine release in the human cortex: a comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride. Synapse 63: 447–461.R. NarendranWG FrankleNS MasonEA RabinerRN Gunn2009Positron emission tomography imaging of amphetamine-induced dopamine release in the human cortex: a comparative evaluation of the high affinity dopamine D2/3 radiotracers [11C]FLB 457 and [11C]fallypride.Synapse63447461
- 40. Aalto S, Hirvonen J, Kaasinen V, Hagelberg N, Kajander J, et al. (2009) The effects of d-amphetamine on extrastriatal dopamine D2/D3 receptors: a randomized, double-blind, placebo-controlled PET study with [11C]FLB 457 in healthy subjects. Eur J Nucl Med Mol Imaging 36: 475–483.S. AaltoJ. HirvonenV. KaasinenN. HagelbergJ. Kajander2009The effects of d-amphetamine on extrastriatal dopamine D2/D3 receptors: a randomized, double-blind, placebo-controlled PET study with [11C]FLB 457 in healthy subjects.Eur J Nucl Med Mol Imaging36475483
- 41. Okauchi T, Suhara T, Maeda J, Kawabe K, Obayashi S, et al. (2001) Effect of endogenous dopamine on endogenous dopamine on extrastriated [(11)C]FLB 457 binding measured by PET. Synapse 41: 87–95.T. OkauchiT. SuharaJ. MaedaK. KawabeS. Obayashi2001Effect of endogenous dopamine on endogenous dopamine on extrastriated [(11)C]FLB 457 binding measured by PET.Synapse418795
- 42. Olsson H, Halldin C, Farde L (2004) Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. Neuroimage 22: 794–803.H. OlssonC. HalldinL. Farde2004Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET.Neuroimage22794803
- 43. Campbell DT (1960) Blind variation and selective retention in creative thought as in other knowledge processes. Psychol Rev 67: 380–400.DT Campbell1960Blind variation and selective retention in creative thought as in other knowledge processes.Psychol Rev67380400
- 44. Guilford JP (1950) Creativity. Am Psychol 5: 444–454.JP Guilford1950Creativity.Am Psychol5444454
- 45. Hall H, Farde L, Halldin C, Hurd YL, Pauli S, et al. (1996) Autoradiographic localization of extrastriatal D2-dopamine receptors in the human brain using [125I]epidepride. Synapse 23: 115–123.H. HallL. FardeC. HalldinYL HurdS. Pauli1996Autoradiographic localization of extrastriatal D2-dopamine receptors in the human brain using [125I]epidepride.Synapse23115123
- 46. Seamans JK, Gorelova N, Durstewitz D, Yang CR (2001) Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons. J Neurosci 21: 3628–3638.JK SeamansN. GorelovaD. DurstewitzCR Yang2001Bidirectional dopamine modulation of GABAergic inhibition in prefrontal cortical pyramidal neurons.J Neurosci2136283638
- 47. Seamans JK, Yang CR (2004) The principal features and mechanisms of dopamine modulation in the prefrontal cortex. Prog Neurobiol 74: 1–58.JK SeamansCR Yang2004The principal features and mechanisms of dopamine modulation in the prefrontal cortex.Prog Neurobiol74158
- 48. Trantham-Davidson H, Neely LC, Lavin A, Seamans JK (2004) Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex. J Neurosci 24: 10652–10659.H. Trantham-DavidsonLC NeelyA. LavinJK Seamans2004Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex.J Neurosci241065210659
- 49. Floresco SB, Magyar O (2006) Mesocortical dopamine modulation of executive functions: beyond working memory. Psychopharmacology (Berl) 188: 567–585.SB FlorescoO. Magyar2006Mesocortical dopamine modulation of executive functions: beyond working memory.Psychopharmacology (Berl)188567585
- 50. Dorfman L, Martindale C, Gassimova V, Vartanian O (2007) Creativity and speed of information processing: A double dissociation involving elementary versus inhibitory cognitive tasks. Personality and Individual Differences 44: 1382–1390.L. DorfmanC. MartindaleV. GassimovaO. Vartanian2007Creativity and speed of information processing: A double dissociation involving elementary versus inhibitory cognitive tasks.Personality and Individual Differences4413821390
- 51. Dibben CR, Rice C, Laws K, McKenna PJ (2009) Is executive impairment associated with schizophrenic syndromes? A meta-analysis. Psychol Med 39: 381–392.CR DibbenC. RiceK. LawsPJ McKenna2009Is executive impairment associated with schizophrenic syndromes? A meta-analysis.Psychol Med39381392
- 52. Cervenka S, Palhagen SE, Comley RA, Panagiotidis G, Cselenyi Z, et al. (2006) Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding. Brain 129: 2017–2028.S. CervenkaSE PalhagenRA ComleyG. PanagiotidisZ. Cselenyi2006Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding.Brain12920172028
- 53. Jäger AO, Süß HM, Beauducel A (1997) Berliner Intelligenzstruktur-Test (BIS-Test): Form 4. Göttingen: Hogrefe. AO JägerHM SüßA. Beauducel1997Berliner Intelligenzstruktur-Test (BIS-Test): Form 4.GöttingenHogrefe
- 54. Raven JC, Styles I, Raven MA (1998) Raven's Progressive Matrices: SPM plus test booklet. Oxford: Oxford Psychologists Press. JC RavenI. StylesMA Raven1998Raven's Progressive Matrices: SPM plus test booklet.OxfordOxford Psychologists Press
- 55. Gustafsson J-E (1984) A Unifying Model for the Structure of Intellectual Abilities. Intelligence 8: 179–203.J-E Gustafsson1984A Unifying Model for the Structure of Intellectual Abilities.Intelligence8179203
- 56. Bergstrom M, Boethius J, Eriksson L, Greitz T, Ribbe T, et al. (1981) Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr 5: 136–141.M. BergstromJ. BoethiusL. ErikssonT. GreitzT. Ribbe1981Head fixation device for reproducible position alignment in transmission CT and positron emission tomography.J Comput Assist Tomogr5136141
- 57. Langer O, Någren K, Dolle F, Lundkvist C, Sandell J, et al. (1999) Precursor synthesis and radiolabelling of the dopamine D2 receptor ligand [11C]raclopride from [11C]methyl triflate. Journal of Labelled Compounds and Radiopharmaceuticals 42: 1183–1193.O. LangerK. NågrenF. DolleC. LundkvistJ. Sandell1999Precursor synthesis and radiolabelling of the dopamine D2 receptor ligand [11C]raclopride from [11C]methyl triflate.Journal of Labelled Compounds and Radiopharmaceuticals4211831193
- 58. Sandell J, Langer O, Larsen P, Dolle F, Vaufrey F, et al. (2000) Improved specific radioactivity of the PET radioligand [11C]FLB 457 by use of the GE Medical Systems PETtrace MeI MicroLab. Journal of Labelled Compounds & Radiopharmaceuticals 43: J. SandellO. LangerP. LarsenF. DolleF. Vaufrey2000Improved specific radioactivity of the PET radioligand [11C]FLB 457 by use of the GE Medical Systems PETtrace MeI MicroLab.Journal of Labelled Compounds & Radiopharmaceuticals43
- 59. Mawlawi O, Martinez D, Slifstein M, Broft A, Chatterjee R, et al. (2001) Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum. J Cereb Blood Flow Metab 21: 1034–1057.O. MawlawiD. MartinezM. SlifsteinA. BroftR. Chatterjee2001Imaging human mesolimbic dopamine transmission with positron emission tomography: I. Accuracy and precision of D(2) receptor parameter measurements in ventral striatum.J Cereb Blood Flow Metab2110341057
- 60. Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, et al. (2003) Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab 23: 285–300.D. MartinezM. SlifsteinA. BroftO. MawlawiDR Hwang2003Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum.J Cereb Blood Flow Metab23285300
- 61. Joel D, Weiner I (2000) The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Neuroscience 96: 451–474.D. JoelI. Weiner2000The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum.Neuroscience96451474
- 62. Buchsbaum MS, Someya T, Teng CY, Abel L, Chin S, et al. (1996) PET and MRI of the thalamus in never-medicated patients with schizophrenia. Am J Psychiatry 153: 191–199.MS BuchsbaumT. SomeyaCY TengL. AbelS. Chin1996PET and MRI of the thalamus in never-medicated patients with schizophrenia.Am J Psychiatry153191199
- 63. Gilbert AR, Rosenberg DR, Harenski K, Spencer S, Sweeney JA, et al. (2001) Thalamic volumes in patients with first-episode schizophrenia. Am J Psychiatry 158: 618–624.AR GilbertDR RosenbergK. HarenskiS. SpencerJA Sweeney2001Thalamic volumes in patients with first-episode schizophrenia.Am J Psychiatry158618624
- 64. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, et al. (2007) Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab 27: 1533–1539.RB InnisVJ CunninghamJ. DelforgeM. FujitaA. Gjedde2007Consensus nomenclature for in vivo imaging of reversibly binding radioligands.J Cereb Blood Flow Metab2715331539
- 65. Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4: 153–158.AA LammertsmaSP Hume1996Simplified reference tissue model for PET receptor studies.Neuroimage4153158
- 66. Olsson H, Halldin C, Swahn CG, Farde L (1999) Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain. J Cereb Blood Flow Metab 19: 1164–1173.H. OlssonC. HalldinCG SwahnL. Farde1999Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain.J Cereb Blood Flow Metab1911641173