8
Pharmacological Effects on Creativity
In the pursuit of understanding of how creative processes are carried out in the brain, it is particularly important to understand how these processes are affected by the major neurotransmitter systems. Not only does this allow a greater understanding of the mechanism, but as will be discussed below, it allows a greater opportunity for clinical intervention than more anatomical approaches. Most research has focused on the catecholaminergic systems—the dopaminergic system and the noradrenergic system—but evidence is beginning to be explored for other systems as well. A greater volume of literature exists for the pharmacological effects on other executive functions highly interrelated with creativity, such as set-shifting and working memory. These will be discussed as relevant for creativity, but the distinctions between creativity and these other executive functions may also be quite critical, as some evidence already suggests. Studies on the effects of pharmacology on creativity have generally focused on creativity in problem-solving (convergent) tasks and creativity in divergent tasks.
The Dopaminergic System
Early suggestions as to the potential role of the dopaminergic system in creativity came from the effects on the semantic network as observed in priming studies, since the ability to search within the semantic network is a critical component of both semantic priming and verbal creativity tasks. In 1996, Kischka et al. demonstrated in a priming experiment in healthy individuals that word recognition occurs more rapidly when presented 700 milliseconds after exposure to another directly related or indirectly related word. However, after administration of L-dopa, the precursor for dopamine, only words presented after directly related words are recognized quickly. Kischka et al. proposed a role of the dopaminergic system in restriction of the semantic network in priming. Spreading activation of either a directly or indirectly related word facilitated word recognition without L-dopa, but only the directly related word facilitated word recognition with L-dopa. This effect appears to be sensitive to the time between the initial and target stimuli, likely a reflection of the effects of the timing of spreading activation. Subsequent research by Angwin et al. (2004) demonstrated that L-dopa affected both direct and indirect priming with an interstimulus interval of 500 milliseconds, but had no affect at 250 milliseconds. This would seem consistent with what might be expected with an effect on a widely distributed network. However, since L-dopa is a dopamine precursor, it remained unclear as to which specific dopamine receptors might be responsible for the priming effect. Studies in healthy volunteers (Roesch-Ely et al., 2006), in addition to studies in patients with Parkinson’s disease (Pederzolli et al., 2008), suggest that the priming effect is mediated by action on the D1 receptor.
In order to begin to examine how dopaminergic agents might affect semantic networks, researchers looked at the effect of L-dopa on functional connectivity during functional magnetic resonance imaging (fcMRI) using a nonpriming language task: a word categorization task. An isolated increase in connectivity was observed with L-dopa between the left fusiform and the receptive language areas, with no other region pairs affected (Tivarus et al., 2008). Since the left fusiform is considered the visual word form receptive area (Beversdorf et al., 1997), this would appear to fit with the effects on priming, as the interaction between this fusiform area (critical for visual word form recognition) and Wernicke’s area (critical for processing word meaning) would be essential for priming effects. However, since the predominant target among cortical areas for dopaminergic projecting fibers is the frontal lobe (Hall et al., 1994; Lidow et al., 1991) (figure 8.1), such an effect of L-dopa on these posterior regions seems unexpected. Subsequent evidence using independent component analysis of functional magnetic resonance imaging (fMRI) data during language tasks suggests that the posterior effects of L-dopa may be mediated indirectly by the frontothalamic connections from the areas containing the frontal projections of the dopaminergic fibers (Kim et al., 2010). A recent fMRI study examining the effect of L-dopa during priming revealed changes in region-of-interest (ROI) activation with drug in the dorsal prefrontal cortex, anterior cingulate, left rolandic operculum, and left middle temporal gyrus (Copland et al., 2009), which also may suggest an indirect frontal-posterior interaction.
Figure 8.1
Noradrenergic (blue) and dopaminergic (green) pathways. In blue: The locus coeruleus (LC) projects posteriorly to the cerebellum and up to the thalamus (thal) and amygdala (amyg), as well as throughout the neocortex along a pericingular tract, also terminating posteriorly at the hippocampus (Heimer, 1995). The descending fibers to the spinal cord are also shown. Not shown is the lateral tegmental noradrenergic system which also projects to the amygdala and down to the spinal cord. In green: Projections from the substantia nigra (SN) to the striatum are demonstrated, as are projections from the ventral tegmental area (VTA) to the amygdala (amyg), ventral striatum, and frontal cortex (Heimer, 1995). Not shown are the tuberoinfundibular and posterior hypothalamic dopaminergic systems.
This literature surrounding the relationship between the catecholaminergic systems and semantic priming has led to a proposal of its role in verbal creativity as well as potentially in nonverbal forms of creativity (Heilman et al., 2003). However, in consideration of the research based on administration of L-dopa, it must be noted that L-dopa is also a precursor to norepinephrine. Further study has been initiated in hopes of disentangling the potential effects of the dopaminergic and noradrenergic systems on priming and creativity in problem solving, both of which are known to be sensitive to the action of catecholaminergic agents (dopamine and norepinephrine) on semantic networks (Campbell et al., 2008; Kischka et al., 1996). Dopaminergic agonists were found to have no effect on creativity in verbal problem solving (Smyth & Beversdorf, 2007), and noradrenergic agents did not appear to affect priming in the manner observed with dopaminergic agents (Cios et al., 2009). This appears to suggest a role for the dopaminergic system (but not the noradrenergic system) in effects on automatic searches of the semantic network as with word recognition (Cios et al., 2009; Kischka et al., 1996), and a role for the noradrenergic system (but not the dopaminergic system) in effects on controlled searches of the semantic network as with verbal problem solving (Campbell et al., 2008; Smyth & Beversdorf, 2007). The relationship between the noradrenergic system and creativity will be discussed subsequently. However, despite these findings, other recent research has suggested a more direct relationship between the dopaminergic system and creativity. Studies examining rate of eyeblink, proposed as a marker of dopaminergic activity, demonstrated an inverted U-shaped relationship between eyeblink rate and creativity as assessed by an alternate uses task (AUT) and the remote associates task (RAT) (Chermahini & Hommel, 2010). Genetic studies demonstrate a relationship between D2 receptor polymorphisms and a composite creativity score as well as performance on verbal creativity, as assessed by object use fluency and sentence fluency from three words (Reuter et al., 2006). A positive association has been found in the relationship between gray matter volume in dopaminergic subcortical regions as well as the right dorsolateral prefrontal cortex and divergent thinking (fluency for unusual uses and unimaginable things) with voxel-based morphometry on MRI (Takeuchi et al., 2010), and a negative association in the relationship between thalamic D2 receptor densities and performance on verbal, figural, and numerical fluency tasks with receptor binding studies using positron emission tomography (de Manzano et al., 2010). A case study describing changes in artistic behavior with dopaminergic agonists in Parkinson’s disease has also been proposed as evidence for a relationship between the dopaminergic system and creativity (Kulisevsky et al., 2009), but the effects on interest in (as well as obsession with) artistic output and effects on style in such cases are hard to disentangle from other aspects of creativity (Chatterjee et al., 2006). While this array of indirect supportive data for a role for the dopaminergic system in creativity is of interest, the distinction between the roles of the noradrenergic and dopaminergic systems in creativity is in need of further study.
The dopaminergic system has a range of other cognitive effects, including other aspects of executive function closely related to creativity, in addition to the well-known effects on the motor system. Research in animal models has demonstrated varying effects of dopaminergic agents on set-shifting tasks, differing according to which receptor subtype each agent impacts (Floresco et al., 2005). Among set-shifting tasks, this effect appears to be specific to intradimensional set shifting (Robbins, 2007). Whereas agonists for both D1 and D2 receptors did not affect set shifting, D2 antagonists impaired set shifting in rodents (Floresco et al., 2006; Stefani & Moghaddam, 2005), an effect also observed in humans (Mehta et al., 2004). In further support of a role of the dopaminergic system in executive function, ability to maintain and flexibly alter cognitive representations in response to environmental demands is known to be impaired in Parkinson’s disease (Cools, 2006). Computational models propose that phasic stimulation of D2 receptors in the striatum drives flexible adaptation of cognitive representations that are maintained by the prefrontal cortex (Cohen et al., 2002), which contrasts with the effect on priming, which appears to be mediated by D1 receptors (Roesch-Ely et al., 2006; Pederzolli et al., 2008). Receptor specificity of effects on creativity is not known. It should be noted, regarding the effect of dopamine on executive function in patient populations, that the interaction between dopaminergic agonists and Parkinson’s disease and their effect on cognition is complex for set shifting as well as working memory. Early in Parkinson’s disease, greater dopaminergic depletion in the dorsal striatum leads to impaired adaptation in responses and updating in working memory, which is improved by L-dopa, while maintenance of working memory is less affected. However, L-dopa also can excessively enhance reward biases due to effects on the relatively intact ventral striatum (Cools, 2006). These other cognitive effects of the dopaminergic system are discussed further below.
Regarding these dopaminergic effects on other closely related executive functions, in healthy subjects, individuals with lower working memory capacity tend to be the ones who benefit from increased prefrontal function with dopaminergic stimulation (Gibbs & D’Esposito, 2005; Kimberg et al., 1997). This is likely related to the fact that dopamine synthesis capacity in the striatum is related to working memory capacity, such that those with the least working memory capacity also have less dopamine, and therefore benefit from dopaminegic stimulation (Cools, Gibbs et al., 2008), again suggesting an inverted U-shaped relationship between performance and dopaminergic function. In animal models, this effect on working memory appears to be mediated by action at the D1 receptor (Arnsten et al., 1994; Sawaguchi & Goldman-Rakic, 1991; Williams and Goldman-Rakic, 1995). Dopamine also appears to be critical for a range of other aspects of cognition involving frontal-subcortical circuits, including the temporal coupling of deliberation and execution during decision making, as dopamine replacement reverses the delay specific to decision-related hesitations, independent of motor slowing, in situations requiring decision making in uncertainty in patients with Parkinson’s disease (Pessiglione et al., 2005).
Whereas working memory, set shifting (“constrained cognitive flexibility”), and creativity involved in problem solving and divergent thinking tasks (both considered as “unconstrained cognitive flexibility”) are highly interrelated, significant further work is necessary to disentangle the roles of the various neurotransmitter systems on each domain. This becomes particularly critical for the effects of the noradrenergic system, as is discussed below.
Another critical role of dopamine has recently become apparent with the development of pathological gambling in the setting of treatment with dopaminergic agonists (Dodd et al., 2005; Gallagher et al., 2007). This has contributed to a greater understanding of the roles of dopamine in decision making, revealing that dopamine neurons encode the difference between expected and received rewards, and interact with other neurotransmitter systems to regulate such decision making (Nakamura et al., 2008). The relationship between this effect of dopamine and creativity is also in need of further exploration.
The Noradrenergic System
The effects of performance anxiety and test anxiety have been associated with activation of the noradrenergic system, leading to the development of treatment limiting the adrenergic activating effects of stress. Propranolol, a centrally acting β-adrenergic antagonist, has long been used for stress-induced impairment in performance on tasks including public speaking in anxiety-prone individuals (Lader, 1988; Laverdue & Boulenger, 1991). This has led to further exploration of the role of the noradrenergic system in the impact of stress on cognitive performance. Furthermore, research involving healthy adolescents with a history of stress-induced cognitive impairment during exams has demonstrated that treatment with the beta-adrenergic antagonist propranolol significantly improved scores on the Scholastic Aptitude Test (SAT) (Faigel, 1991). The effects of stress and the noradrenergic system on cognition are not limited to patients with known stress-induced cognitive impairment. Stress has long been known to impair performance on tasks requiring creativity in healthy individuals (Martindale & Greenough, 1973), and stress is also known to increase activity of the noradrenergic system (Kvetnansky et al., 1998; Ward et al., 1983). In more recent work beginning to examine the effects of stress in individuals without any history of anxiety-related disorders, administration of a well-characterized social stressor characterized by public speaking and mental arithmetic (Kirschbaum et al., 1993) resulted in impaired performance on creative verbal problem solving requiring flexibility of access to lexical, semantic, and associative networks, and the impairment was reversed by propranolol (Alexander et al., 2007). Therefore, the pharmacological and stress effects on cognition in this setting appear to represent a fundamental aspect of the brain-behavior relationship, not requiring the presence of an anxiety-related disorder or a dysregulated noradrenergic system. However, it should be noted that the effect of propranolol in this study does not exclusively implicate the noradrenergic system, since propranolol has also been shown to block the corticosterone-induced impairment of working memory (Roozendaal et al., 2004).
The locus coeruleus contains the majority of neurons in the central nervous system, sending efferents throughout the brain (Barnes & Pompeiano, 1991), without the degree of selectivity of projection to the frontal lobe as is observed with dopamine (figure 8.1). Therefore, an effect of the noradrenergic system on such a distributed function such as creativity might be expected. However, the effects of the noradrenergic system outside the setting of stress are more dependent on the situation. In our previous work, performance on the anagram task was better after administration of the centrally and peripherally acting beta-adrenergic antagonist propranolol than after the noradrenergic agonist ephedrine (Beversdorf et al., 1999; Heilman et al., 2003). Performance on the anagram task was also better after administration of propranolol than after the peripheral-only beta-adrenergic antagonist nadolol (Beversdorf et al., 2002), suggesting that the effect of propranolol on this aspect of cognition is mediated centrally rather than as a result of peripheral feedback. A central mechanism would be predicted by the effect of norepinephrine on the signal-to-noise ratio of neuronal activity within the cerebral cortex (Hasselmo et al., 1997) as well as the correlation between the electronic coupling of noradrenergic neurons in the monkey cortex and proportions of goal-directed versus exploratory behavior (Usher et al., 1999). However, in each of the anagram studies, whereas performance on propranolol was better than on ephedrine or nadolol, it did not significantly differ from placebo (Beversdorf et al., 1999, 2002). In order to better understand the effect of propranolol, subsequent research examined how task difficulty might relate to the drug’s effect, since a drug proposed to benefit a broad search of a network due to signal-to-noise effects might be expected to yield a greater beneficial effect when problems are more challenging. Consistent with this, propranolol was found to be beneficial for a range of verbal problem-solving tasks requiring network flexibility when the subject was struggling, and did not confer benefit and in some cases impaired performance when the subject was solving problems with ease (Campbell et al., 2008). The benefit was seen both for the subjects who had the greatest difficulty solving the problems, and for the most difficult problems across all subjects (Campbell et al., 2008). However, propranolol can benefit performance on such language tasks for the easiest problems in situations where there is up-regulated activity of the noradrenergic system due to cocaine withdrawal (Kelley et al., 2005, 2007) and psychosocial stress (Alexander et al., 2007), or where there is anatomic rigidity of the language network (Beversdorf et al., 2007a) due to conditions such as autism (convergent task effects—Beversdorf et al., 2008; divergent task effects—Beversdorf et al., 2011) and Broca’s aphasia due to stroke (Beversdorf et al., 2007b).
This variability in effect of noradrenergic drugs between patient groups, as observed in cocaine withdrawal, autism, and aphasia, may also be important for attention deficit disorder. As with the dopaminergic system, early theories proposed that arousal and optimal performance might be related on an inverted U-shaped curve (Yerkes & Dodson, 1908), suggesting such a relationship for the noradrenergic system. Therefore, whereas markedly increased arousal or noradrenergic tone might result in hyper-arousal and inability to perform a task in most individuals, a person with attention deficit disorder might be at baseline at a suboptimal point on the inverted U-shaped curve and require stimulants to perform optimally. Animal data suggest that there is an optimal point of tonic activity of the locus coeruleus that tends to support the emergence of phasic activity, which is associated with focused or selective attention (Aston-Jones et al., 1999; Aston-Jones & Cohen, 2005). Noradrenergic transmission is known to be genetically weaker in some patients with attention deficit disorder (Arnsten, 2007). The effects of drugs on creativity in this population warrant further study. However, preliminary evidence suggests that the effect of stimulants on creativity is limited (Farah et al., 2009).
Variation in the effects of noradrenergic drugs is not limited to differences between patient groups. Variation in response can also be observed in unaffected subjects due to exposure to specific environmental conditions. Performance on creative verbal problem-solving tasks is affected by alterations in noradrenergic tone due to changes in posture (Lipnicki & Byrne, 2005), sleep phase (Stickgold et al., 2001), and vagal nerve stimulation (Ghacibeh et al., 2006). These effects appear to be specific to the noradrenergic system and not due to general anxiolytic effects, since such cognitive effects do not appear to occur with non-adrenergic anxiolytics (Silver et al., 2004).
Data are only beginning to emerge regarding how propranolol might affect network performance. Evidence from models derived from data from activity in brain-slice preparations support an effect of norepinephrine on the signal-to-noise ratio of neuronal activity within the cerebral cortex (Hasselmo et al., 1997). Presumably, propranolol increases access to “noise” which in this case would be represented by increased associational input that might be adaptive for solving more difficult problems, where the most immediate response is not optimal (Alexander et al., 2007). In one population characterized by decreased flexibility of network access (Beversdorf et al., 2007a), a potential imaging marker is observed. Decreased functional connectivity on fMRI (fcMRI), or a decrease in the synchrony of activation between activated brain regions, is observed in autism (Just et al., 2004, 2007), believed to be related to the underconnectivity between distant cortical regions in autism (Belmonte et al., 2004). Recent evidence suggests that propranolol increases functional connectivity on fMRI in autism, lending some support to the proposed mechanism of action of propranolol on network access (Narayanan et al., 2010). It is not clear whether the noradrenergic system is dysregulated in autism (Martchek et al., 2006; Minderaa et al., 1994). However, some have proposed that the behavioral effects of fever in autism (Curran et al., 2007) may be related to normalization of a developmentally dysregulated noradrenergic system in autism (Mehler & Purpura, 2009). Regardless of the ambient activity of the noradrenergic system in autism, network rigidity in autism (Beversdorf et al., 2007a) and the suggested effect or propranolol on network access (Campbell et al., 2008) suggest a potential for benefit from noradrenergic agents in autism. Furthermore, case series have suggested a benefit in both social and language domains in autism with beta-adrenergic antagonists (Ratey et al., 1987). The effect of propranolol on task performance has not yet been assessed in imaging studies, as the previous imaging study assessed fcMRI during a task where all subjects perform at ceiling (Narayanan et al., 2010). Decreased functional connectivity has also been observed in patients in acute cocaine withdrawal (Narayanan et al., 2012).
The role of the noradrenergic system in behavior is, of course, not limited to effects on network access and creativity as is detailed above. The noradrenergic system is critical in arousal (Coull et al., 1997, 2004; Smith & Nutt, 1996). Furthermore, the prefrontal cortex, important in a range of types of cognitive flexibility (Duncan et al., 1995; Eslinger & Grattan, 1993; Karnath & Wallesch, 1992; Robbins, 2007; Vilkki, 1992), has afferent projections TO the locus coeruleus in primates (Arnsten & Goldman-Rakic, 1984), containing the majority of noradrenergic neurons in the central nervous system and sending the previously described efferents throughout the brain (Barnes & Pompeiano, 1991). The cognitive flexibility as assessed by verbal problem-solving tasks, such as anagrams and the compound remote associates task (Bowden & Jung-Beeman, 2003), involves a search through a wide network in order to identify a solution (“unconstrained flexibility”), and appears to be modulated by the noradrenergic system as described above, where performance generally improves with decreased noradrenergic activity. Other cognitive flexibility tasks such as the Wisconsin Card Sort Test (Heaton, 1981) involve set shifting between a limited range of options (“constrained flexibility”), which may not be modulated by the noradrenergic system in the same manner, and may even benefit from increased noradrenergic activity (Aston-Jones & Cohen, 2005; Usher et al., 1999). Evidence suggests that decreased noradrenergic activity appears to benefit tasks such as anagrams when subjects are struggling or challenged by stressors (Alexander et al., 2007; Campbell et al., 2008), whereas increased set switching on a two alternative forced choice task is associated with increased noradrenergic tone in primate studies (Aston-Jones & Cohen, 2005; Usher et al., 1999). “Constrained” flexibility can be further subdivided into intradimensional and extradimensional set shifting (Robbins, 2007). The dopaminergic system appears to affect intradimensional set shifting (Robbins, 2007), while the noradrenergic system, specifically by action on the alpha-1 receptor, appears to modulate performance on extradimensional set shifting (Lapiz & Morilak, 2006; Robbins, 2007). The beta-adrenergic receptors in the noradrenergic system, though, appear to modulate the “unconstrained” flexibility (Alexander et al., 2007; Beversdorf et al., 1999, 2002). As discussed with the dopaminergic system, a systematic exploration of the effects of the noradrenergic system on intradimensional and extradimensional set shifting as well as creative problem solving and divergent tasks with “unconstrained cognitive flexibility” is warranted. Noradrenergic agents are also known to have a range of other cognitive effects, including effects on motor learning (Foster et al., 2006), response inhibition (Chamberlain et al., 2006b), working memory, and emotional memory (Chamberlain et al., 2006a).
The role of the noradrenergic system in emotional memory deserves particular comment, due to a potentially important clinical role. Centrally acting beta-adrenergic receptor antagonists are known to reduce the enhancement of memory resulting from emotional arousal (Cahill et al., 1994; van Stegeren et al., 1998). This may contribute to the development of intrusive memories in clinical conditions such as posttraumatic stress disorder (Ehlers et al., 2002, 2004; Smith & Beversdorf, 2008). Evidence is beginning to suggest a secondary preventative role of propranolol in the development of posttraumatic stress disorder, by interfering with reconsolidation (Pitman et al., 2002; Vaiva et al., 2003). Alpha-1 antagonists have similarly revealed benefit in patients with posttraumatic stress disorder (Arnsten, 2007). The relationship between creativity and the emotional effects of the noradrenergic system is in need of further exploration.
In the periphery, alpha-2 adrenergic agonists inhibit release of norepinephrine presynaptically, which might make one consider that they would have a similar effect as the postsynaptic beta-adrenergic antagonists. However, alpha-2 agonists have distinct cognitive effects. High-dose clonidine, an alpha-2 agonist, has been shown to improve immediate spatial memory in aged monkeys (Arnsten et al., 1988; Arnsten & Leslie, 1991), an effect also found in younger monkeys (Franowicz & Arnsten, 1999), believed to be mediated by action at the prefrontal cortex (Li et al., 1999). Lower doses of clonidine, those that are typically utilized clinically in humans, demonstrate varying results at varying doses, including impaired visual working memory, impulsive responses on planning tasks, and varying effects on spatial working memory (Coull et al., 1995; Jäkälä et al., 1999). Pharmacological stimulation of postsynaptic alpha-2A subtype of adrenoreceptors decreases noise and results in beneficial effects for attention deficit disorder patients (Brennan & Arnsten, 2008). However, alpha-2 agonists do not appear to have the effect on creative verbal problem solving that beta-adrenergic antagonists have (Choi et al., 2006).
Less is known about the specific cognitive effects of beta-1 and beta-2 adrenergic receptors. However, in one animal study, endogenous beta-1 selective activation impaired working memory (Ramos et al., 2005). A subsequent study demonstrated that beta-2 selective agonists enhance working memory in aging animals (Ramos et al., 2008), suggesting opposing effects between beta-1 and beta-2 receptors on working memory, and explaining the lack of effect of the nonspecific beta-antagonist propranolol on working memory in previous research (Arnsten & Goldman-Rakic, 1985; Li & Mei, 1994). Further research will be necessary to better understand the specific cognitive effects due to action at selective subtypes of beta (beta-1 and beta-2) receptors.
Other Systems
Neurons in the nucleus basalis, medial septal nucleus, and the diagonal band of Broca in the basal forebrain are the main sources of cholinergic projection throughout the neocortex and hippocampus (Selden et al., 1998). The cholinergic system is another neurotransmitter system involved in modulating the signal-to-noise ratio within the cortex by suppressing background intrinsic cortical activity (Hasselmo & Bower, 1992), thus modulating efficiency of cortical processing of sensory or associational information (Sarter & Bruno, 1997). Acetylcholine is particularly important for attentional performance (Sarter & Bruno, 2001). Studies in rodents demonstrate that acetylcholine is critical for both top-down and bottom-up processing of stimuli, mediated by action on the prefrontal cortex (Gill et al., 2000; Newman & McGaughy, 2008). Cholinergic dysfunction has been used as a model for Alzheimer’s disease (Whitehouse et al., 1982), due to the significant degeneration of the cholinergic neurons in these patients. Among the two main subtypes of acetylcholine receptors, muscarinic receptors have been clearly demonstrated to interfere with encoding of new information with less of an effect on previously stored information (Hasselmo & Wyble, 1997). Blockade of nicotinic receptors has also revealed significant effects on memory in an age-dependent manner (Newhouse et al., 1992, 1994). However, despite clear effects on signal-to-noise ratio in the cortex as well as memory effects, neither muscarinic nor nicotinic blockade resulted in effects on the type of unconstrained cognitive flexibility modulated by the noradrenergic system (Smyth & Beversdorf, in preparation).
Our understanding of the role of individual neurotransmitter systems in cognition has significantly progressed over the past twenty years. However, these systems do not act in isolation. Complex interactions occur between them, which are only beginning to be understood. For example, action at D2 dopaminergic receptors and at NMDA receptors appear to interact in their effects on set shifting (Floresco et al., 2005, 2006; Stefani & Moghaddam, 2005). Also, as described above, the dopaminergic system appears to affect intradimensional set shifting (Robbins, 2007), while the noradrenergic system, specifically by action on the alpha-1 adrenergic receptor, appears to modulate performance on extradimensional set shifting (Lapiz & Morilak, 2006; Robbins, 2007). Noradrenergic innervation of dopaminergic neurons, by action on alpha-1 adrenergic receptors, is known to directly inhibit the activity of the dopaminergic neurons (Paladini & Williams, 2004). In addition, the effects of drugs on cognition also depend on location of action when isolated brain regions are studied (Cools & Robbins, 2004). Also, the mechanism by which the regulatory neurotransmitters act is beginning to be more fully understood, with potential treatment options targeting these second messenger systems (Arnsten, 2007, 2009). These factors will all need to be accounted for in future studies of creativity.
The serotonergic system, with neurons in the dorsal raphe nucleus projecting throughout the forebrain and neocortex, has long been known for its effects on mood and other psychiatric issues. However, recent research is revealing that the serotonergic system and its interaction with other neurotransmitter systems serve important cognitive roles as well. Recent evidence suggests that the balance between the serotonergic and dopaminergic systems appears to be critical for processing of reward and punishment (Krantz et al., 2010). The firing of midbrain dopamine neurons shows a firing pattern that reflects the magnitude and probability of rewards (Roesch et al., 2007; Schultz, 2007). While tryptophan depletion enhances punishment prediction but does not affect reward prediction (Cools, Robinson, & Sahakian, 2008), serotonergic neurons appear to signal reward value (Nakamura et al., 2008). Furthermore, prefrontal serotonin depletion affects reversal learning, but not set shifting (Clarke et al., 2005). A potential role in creativity is also suggested for the serotonergic system. Performance on figural and numeric creativity tasks has been associated with polymorphisms of the tryptophan hydroxide gene TPH1 (Reuter et al., 2006), and both the number solved and the prevalence of use of insight on the compound remote associates task was positively associated with high positive mood (Subramaniam et al., 2008), also suggesting a role of the serotonergic system.
Continued understanding of the roles of neurotransmitter interactions, localized effects, and other types of neurotransmitters and neuropeptides will be needed to fully understand how cognitive processes such as creativity are carried out in the brain. This will have a high potential to result in clinical benefits for patients with a wide variety of clinical syndromes as well.
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