The neural underpinnings of cognitive flexibility and their disruption in psychotic illness

“…of both activating executive control network (ECN) structures, in the service of goal-directed behavior, and suppressing activity in default mode network (DMN) structures that are most active when the brain is “idling” (Seeley et al., 2007, Sridharan et al., 2008, Menon and Uddin, 2010).”

“The Iowa Gambling Task (Bechara et al., 1994, Bechara et al., 1997) is a reinforcement learning paradigm that was designed to focus on punishment sensitivity, with early studies showing dramatic impairment in individuals with frontal lobe (Bechara et al., 1994) or amygdala (Bechara et al., 1999) lesions.”

“…of both activating executive control network (ECN) structures, in the service of goal-directed behavior, and suppressing activity in default mode network (DMN) structures that are most active when the brain is “idling” (Seeley et al., 2007, Sridharan et al., 2008, Menon and Uddin, 2010).”

“The Iowa Gambling Task (Bechara et al., 1994, Bechara et al., 1997) is a reinforcement learning paradigm that was designed to focus on punishment sensitivity, with early studies showing dramatic impairment in individuals with frontal lobe (Bechara et al., 1994) or amygdala (Bechara et al., 1999)…”

“…of both activating executive control network (ECN) structures, in the service of goal-directed behavior, and suppressing activity in default mode network (DMN) structures that are most active when the brain is “idling” (Seeley et al., 2007, Sridharan et al., 2008, Menon and Uddin, 2010).”

“…impairments in both the formation and overriding of prepotent responses could stem from working memory deficits (Gold et al., 1997, Glahn et al., 2000, Hartman et al., 2003), which are prevalent in schizophrenia (Heinrichs and Zakzanis, 1998, Lee and Park, 2005), but not specific to the condition.”

“In the context of probabilistic reversal learning tasks, individuals can achieve learning in multiple ways: by either integrating reward prediction errors in model-free way, or by inducing a rule in a model-based way (Daw et al., 2005, Chen et al., 2015, Costa et al., 2015).”

“Early studies revealed that patients with frontal lobe lesions frequently exhibited a characteristic behavior on the WCST: they showed particularly difficulty in shifting from one sorting criterion to another, in the face of negative feedback (Milner, 1963, Nelson, 1976, Stuss et al., 2000).”

“Studies of the role of dopamine transmission in reversal learning have focused on three sites: presynaptic dopamine transporters (DATs), post-synaptic dopamine receptors, and the catechol-Omethyltransferase (COMT) enzyme, which acts mainly to metabolize dopamine in the PFC (Egan et al., 2001).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript Barnett JH, Jones PB, Robbins TW, Muller U. Effects of the catechol-O-methyltransferase Val158Met polymorphism on executive function: a meta-analysis of the Wisconsin Card Sort Test in schizophrenia and healthy controls.”

“…Gambling Task (Bechara et al., 1994, Bechara et al., 1997) is a reinforcement learning paradigm that was designed to focus on punishment sensitivity, with early studies showing dramatic impairment in individuals with frontal lobe (Bechara et al., 1994) or amygdala (Bechara et al., 1999) lesions.”

“…strong evidence now linking the short (s) allele of the serotonin transporter gene (SLC6A4; also known as 5-HTT) linked to increased reactivity (especially in the amygdala) to aversive or threatening stimuli, relative to the long (l) form of the allele (Hariri and Holmes, 2006, Caspi et al., 2010).”

“…accumbens (VS/NAcc; Cools et al., 2002) and habenular complex (or epithalamus; Ullsperger and von Cramon, 2003), two areas thought to primarily signal mismatches between expected and obtained outcomes, called reward prediction errors (RPEs; Seymour et al., 2004, Matsumoto and Hikosaka, 2007).”

“Introduction Cognitive flexibility, or the ability to appropriately adjust one's behavior according to a changing environment (Dajani and Uddin, 2015), has long been studied in patients with schizophrenia (SZ), using a variety of measures.”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript behaviors (Soubrie et al., 1986, Deakin and Graeff, 1991).”

“…in other patient samples, with some patient samples (obsessive-compulsive disorder, Parkinson’s disease) being characterized, to some extent, by excessive rigidity in the selection of cognitive and motor plans (Swainson et al., 2000, Cools et al., 2001, Cools et al., 2006, Robbins et al., 2012).”

“Acute psychosis has often been associated with excessive striatal dopamine (Laruelle and Abi-Dargham, 1999, Howes et al., 2012), which has, in turn, been associated with reduced sensitivity to punishments (Dodds et al., 2008) and, consequently, reduced cognitive flexibility (lose-shifting; Cools et…”

“…cortex (vlPFC; Brodmann areas 47/12) is an area that has been consistently implicated in set-shifting behavior, both in imaging studies of the WCST and related tasks (Konishi et al., 1999, Monchi et al., 2001), and in imaging studies of probabilistic reversal learning (Cools et al., 2002).”

“…in other patient samples, with some patient samples (obsessive-compulsive disorder, Parkinson’s disease) being characterized, to some extent, by excessive rigidity in the selection of cognitive and motor plans (Swainson et al., 2000, Cools et al., 2001, Cools et al., 2006, Robbins et al., 2012).”

“…flexibility schizophrenia Given that all effective antipsychotic drugs (APDs) occupy dopamine D2-type receptors (almost all being antagonists; Seeman, 1987, Seeman and Tallerico, 1998) and that many also occupy postsynaptic serotonin receptors (Meltzer et al., 2003), it is reasonable to…”

“Theorists (Daw et al., 2002, Boureau and Dayan, 2011) have proposed that dopaminergic and serotoninergic systems interact in systematic and possibly oppositional ways.”

“Finally, given the dependence of rule learning and set-shifting on working memory (Gold et al., 1997, Pantelis et al., 2004), it should come as no surprise that the mid-dorsolateral prefrontal cortex (dlPFC; area 9/46) generally shows increased activity in association with the performance of…”

“Given that all effective antipsychotic drugs (APDs) occupy dopamine D2-type receptors (almost all being antagonists; Seeman, 1987, Seeman and Tallerico, 1998) and that many also occupy postsynaptic serotonin receptors (Meltzer et al., 2003), it is reasonable to think that APDs might modulate reinforcement learning and…”

“…cortex (vlPFC; Brodmann areas 47/12) is an area that has been consistently implicated in set-shifting behavior, both in imaging studies of the WCST and related tasks (Konishi et al., 1999, Monchi et al., 2001), and in imaging studies of probabilistic reversal learning (Cools et al., 2002).”

“…impairments in both the formation and overriding of prepotent responses could stem from working memory deficits (Gold et al., 1997, Glahn et al., 2000, Hartman et al., 2003), which are prevalent in schizophrenia (Heinrichs and Zakzanis, 1998, Lee and Park, 2005), but not specific to the condition.”

“For example, the fact that serotonin depletion appears to increase sensitive to both negative feedback (Evers et al., 2005) and threats (Hariri and Holmes, 2006, Fisher and Hariri, 2013) could have the effect of either increasing impulsive shifting in the face of misleading punishments (Harrison et…”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript et al., 1997, Pohjalainen et al., 1998), most markedly in the ventral striatum.”

“…A uthor M anuscript A second measure commonly used to probe executive function and set-shifting in neuropsychiatric illness is the Intra-dimensional/Extra-dimensional (ID/ED) task from the Cambridge Neuropsychological Test Automated Battery (CANTAB; Downes et al., 1989, Owen et al., 1991).”

“, 2001) and excessive striatal dopamine (Meyer-Lindenberg et al., 2002).”

“These findings have been supported by the results of studies involving the focal depletion of serotonin in the marmoset PFC, using the selective neurotoxin 5,7-dihydroxytryptamine (Clarke et al., 2004, Clarke et al., 2005).”

“…appear to exhibit a more flexible learning rate, and, thus, more rapid updating, in the context of a PRL-like task (Krugel et al., 2009), Val/Val individuals also, by and large, show worse WCST performance than Met/Met carriers (Egan et al., 2001, Malhotra et al., 2002, Barnett et al., 2007).”

“As is the case with dopamine, understanding the role of serotonin in cognitive flexibility requires consideration of multiple kinds of cognitive flexibility, as well as interactions between striatal habit learning systems and frontal systems for goal-directed action selection (Gillan et al., 2011).”

“…accumbens (VS/NAcc; Cools et al., 2002) and habenular complex (or epithalamus; Ullsperger and von Cramon, 2003), two areas thought to primarily signal mismatches between expected and obtained outcomes, called reward prediction errors (RPEs; Seymour et al., 2004, Matsumoto and Hikosaka, 2007).”

“lesion (Hornak et al., 2004) and neuroimaging (Cools et al.”

“These findings come largely from the results of studies using the “Beads” task (Garety et al., 1991, Moritz and Woodward, 2005).”

“Early studies revealed that patients with frontal lobe lesions frequently exhibited a characteristic behavior on the WCST: they showed particularly difficulty in shifting from one sorting criterion to another, in the face of negative feedback (Milner, 1963, Nelson, 1976, Stuss et al., 2000).”

“Short allele carriers also demonstrated enhanced loss aversion in the context of a common decision making task called the Balloon Analog Risk Task (BART; Lejuez et al., 2003), in which a virtual balloon pops after a random number of presses.”

“While the Val/Val type of the COMT gene may increase the tendency to reverse (in the context of a PRL task) by increasing sensitivity to (and/or boosting learning rates associated with) losses, the Met/Met genotype is associated with enhanced working memory performance (Goldberg et al., 2003).”

“Major depressive disorder (MDD) is another example of a condition where cognitive flexibility has been a focus of study (Eshel and Roiser, 2010).”

“Chamberlain et al. (2006) specifically found that an acute low dose of citalopram, which most likely reduces 5-HT function, enhanced sensitivity to negative feedback in human subjects.”

“More recent analyses (Maia and McClelland, 2004) have emphasized the complexity of the task, noting that the need to integrate both punishments and rewards to estimate the values of decks, as well as the need to rapidly update estimates of value based on fluctuations in the magnitudes of…”

“The 10- repeat (10R) allele of this gene has been associated with increased gene expression and presumably lower levels of synaptic dopamine in the striatum, relative to the 9-repeat (9R) allele (Heinz et al., 2000, Fuke et al., 2001, Mill et al., 2002).”

“…A uthor M anuscript A second measure commonly used to probe executive function and set-shifting in neuropsychiatric illness is the Intra-dimensional/Extra-dimensional (ID/ED) task from the Cambridge Neuropsychological Test Automated Battery (CANTAB; Downes et al., 1989, Owen et al., 1991).”

“…in other patient samples, with some patient samples (obsessive-compulsive disorder, Parkinson’s disease) being characterized, to some extent, by excessive rigidity in the selection of cognitive and motor plans (Swainson et al., 2000, Cools et al., 2001, Cools et al., 2006, Robbins et al., 2012).”

“Acute psychosis has often been associated with excessive striatal dopamine (Laruelle and Abi-Dargham, 1999, Howes et al., 2012), which has, in turn, been associated with reduced sensitivity to punishments (Dodds et al., 2008) and, consequently, reduced cognitive flexibility (lose-shifting; Cools et…”

“Theorists (Daw et al., 2002, Boureau and Dayan, 2011) have proposed that dopaminergic and serotoninergic systems interact in systematic and possibly oppositional ways.”

“…and Holmes, 2006, Fisher and Hariri, 2013) could have the effect of either increasing impulsive shifting in the face of misleading punishments (Harrison et al., 1997, Chamberlain et al., 2006) or indirectly driving compulsive behavior by increasing anxiety (Deakin, 1998, Stein and Stahl,…”

“Furthermore, while frontostriatal dysfunction is common among individuals with psychotic illness, it is also prevalent in numerous other psychiatric and neurological conditions (Clark et al., 2009, Klanker et al., 2013).”

“The 10- repeat (10R) allele of this gene has been associated with increased gene expression and presumably lower levels of synaptic dopamine in the striatum, relative to the 9-repeat (9R) allele (Heinz et al., 2000, Fuke et al., 2001, Mill et al., 2002).”

“Variants of the dopamine transporter (DAT) gene have been observed to predict reward-related activity in the ventral striatum (Forbes et al., 2009), with 9R carriers showing stronger responses to reward predicting cues than 10R homozygotes (Dreher et al., 2009).”

“…with considerable evidence indicating that SZ patients make a significantly higher number of perseverative responses than do normal control subjects and patients with other psychiatric disorders (Bellini et al., 1991, Braff et al., 1991, Abbruzzese et al., 1995, Cavallaro et al., 2003).”

“Considerable early evidence from studies of SZ pointed to the presence of deficits in cognitive executive functions, such as attentional set-shifting and task switching (Kehagia et al., 2010), similar to those observed individuals with frontal lobe lesions (Elliott et al.”

“The habenula has been identified as a potential hub of said opposition (Luo et al., 2015), in that its stimulation has been associated with both the stimulation of 5HT cells in the midbrain Raphe (Morris et al., 1999, Amat et al., 2001, Pobbe and Zangrossi, 2010) and the cessation of dopamine cell firing in the SN/VTA…”

“Variants of the dopamine transporter (DAT) gene have been observed to predict reward-related activity in the ventral striatum (Forbes et al., 2009), with 9R carriers showing stronger responses to reward predicting cues than 10R homozygotes (Dreher et al., 2009).”

“…learning Evidence that dopamine system function modulates behavior and neural signals associated with reversal learning comes from studies in both human and nonhuman subjects (Dodds et al., 2008, Boulougouris et al., 2009, Clatworthy et al., 2009, Cools et al., 2009, Rutledge et al., 2009).”

“These findings come largely from the results of studies using the “Beads” task (Garety et al., 1991, Moritz and Woodward, 2005).”

“These findings have been supported by the results of studies involving the focal depletion of serotonin in the marmoset PFC, using the selective neurotoxin 5,7-dihydroxytryptamine (Clarke et al., 2004, Clarke et al., 2005).”

“As with the WCST, the performance of SZ patients is not characterized exclusively by perseveration; rather, many patients show difficulty in acquiring stages of the task not involving reversals (Pantelis et al., 1999).”

“The 10- repeat (10R) allele of this gene has been associated with increased gene expression and presumably lower levels of synaptic dopamine in the striatum, relative to the 9-repeat (9R) allele (Heinz et al., 2000, Fuke et al., 2001, Mill et al., 2002).”

“While it was clear that patients with schizophrenia achieved fewer reversals than healthy volunteers (Waltz and Gold, 2007), it was not clear why.”

“…schizophrenia Given that all effective antipsychotic drugs (APDs) occupy dopamine D2-type receptors (almost all being antagonists; Seeman, 1987, Seeman and Tallerico, 1998) and that many also occupy postsynaptic serotonin receptors (Meltzer et al., 2003), it is reasonable to think that APDs…”

“…M anuscript A uthor M anuscript that “excessive” cognitive flexibility, as quantified by the tendency to shift prematurely following probabilistic negative feedback, has also been observed in individuals diagnosed with MDD (Murphy et al., 2003, Dombrovski et al., 2013, Dombrovski et al., 2015).”

“Pharmacological studies of reversal learning in human subjects—What these studies have tended to reveal is that PD patients on DA-enhancing medication (L-dopa, DAreceptor agonists) exhibited impaired reversal learning relative to patients off medication, chiefly because they were less sensitive to unexpected punishmen…”

“…the effects of ATD on set-shifting and reinforcement learning (Rogers et al., 1999, 2003) appeared to point to a detrimental effect of ATD on set-shifting behavior, with ATD leading to deficits in reversal learning (Rogers et al., 1999) and the processing of reward magnitude (Rogers et al., 2003).”

“…M anuscript A uthor M anuscript that “excessive” cognitive flexibility, as quantified by the tendency to shift prematurely following probabilistic negative feedback, has also been observed in individuals diagnosed with MDD (Murphy et al., 2003, Dombrovski et al., 2013, Dombrovski et al., 2015).”

“…hub of said opposition (Luo et al., 2015), in that its stimulation has been associated with both the stimulation of 5HT cells in the midbrain Raphe (Morris et al., 1999, Amat et al., 2001, Pobbe and Zangrossi, 2010) and the cessation of dopamine cell firing in the SN/VTA (Ji and Shepard, 2007,…”

“…the effects of ATD on set-shifting and reinforcement learning (Rogers et al., 1999, 2003) appeared to point to a detrimental effect of ATD on set-shifting behavior, with ATD leading to deficits in reversal learning (Rogers et al., 1999) and the processing of reward magnitude (Rogers et al., 2003).”

“…appear to exhibit a more flexible learning rate, and, thus, more rapid updating, in the context of a PRL-like task (Krugel et al., 2009), Val/Val individuals also, by and large, show worse WCST performance than Met/Met carriers (Egan et al., 2001, Malhotra et al., 2002, Barnett et al., 2007).”

“Second, ATD in healthy volunteers had the effect of reducing punishment-induced inhibition of responding (Crockett et al., 2009).”

“Considerable early evidence from studies of SZ pointed to the presence of deficits in cognitive executive functions, such as attentional set-shifting and task switching (Kehagia et al., 2010), similar to those observed individuals with frontal lobe lesions (Elliott et al., 1995).”

“It is likely this benefit to the ability to manipulate information in working memory that contributes to the superior WCST performance often exhibited by Met/Met carriers (Bruder et al., 2005).”

“…theories have been proposed, including: 1) serotonin provides an anticipatory signal for both rewarding and punishing motivational outcomes (Miyazaki et al., 2011); and 2) that the nature of the behavioral deficit may depend on what use is made of the anticipatory signal: for example, to…”

“For example, reduced metabolic activity in prefrontal cortex is often seen as a hallmark of schizophrenia (Weinberger, 1988).”

“…learning Evidence that dopamine system function modulates behavior and neural signals associated with reversal learning comes from studies in both human and nonhuman subjects (Dodds et al., 2008, Boulougouris et al., 2009, Clatworthy et al., 2009, Cools et al., 2009, Rutledge et al., 2009).”

“Finally, a small number of studies (Waltz and Gold, 2007, Waltz et al., 2013, Schlagenhauf et al., 2014, Culbreth et al., 2015, Reddy et al., In press) have examined probabilistic reversal learning (PRL) in patients with schizophrenia, in order to probe set-shifting.”

“While studies using this paradigm have produced mixed results in individuals with schizophrenia (Wilder et al. 1998; Ritter et al. 2004; Shurman et al. 2005; Sevy et al. 2007), findings are relatively clear that, while some SZ patients show performance impairments on the task, they rarely exhibit the stark insensitivi…”

“…example, is of particular interest, from the standpoint of schizophrenia research, due to the suspected involvement of these neurochemicals (especially dopamine) in the positive and negative symptoms of the disorder (Laruelle and Abi-Dargham, 1999, Abi-Dargham, 2007, Toda and Abi-Dargham, 2007).”

“Results in MDD have been mixed, as well (Chen et al., 2015), but it is interesting to note Waltz Page 17”

“…enhanced tendency to switch in response to negative feedback, even when it might be invalid, is consistent with evidence of either an oversensitivity to punishment in MDD, or impaired control over negative feedback, behaviorally and/or neurally (Taylor Tavares et al., 2008, Mueller et al., 2015).”

“In a study involving the performance of a probabilistic RL task in conjunction with event-related MRI, Krugel et al. (2009) found that the Val/Val genotype of the Val158Met polymorphism was associated with a higher and more flexible learning rate.”

“In a study combining pharmacological challenge and molecular imaging, Clatworthy et al. (2009) administered therapeutic doses of oral methylphenidate to young healthy subjects, measuring D2/D3 receptor availability using [(11)C]-raclopride radioligand PET imaging.”

“…2008), there is still tremendous variation among individuals with psychotic illness, and associations of specific genotypes with diagnoses may be mediated by associations with intermediate phenotypes (such as deficits in reinforcement learning or cognitive flexibility; e.g., Nolan et al., 2004).”

“…receptor antagonists has also been shown to increase sensitivity to aversive outcomes, at the expense of rewarding ones, leading to a reduction in the number of perseverative errors during the performance of a reversal learning paradigm (Boulougouris et al., 2008, Boulougouris and Robbins, 2010).”

“Additional data, however, point to the stability of ID/ED performance over the first six years of illness (Leeson et al., 2009).”

“…misleading punishments (Harrison et al., 1997, Chamberlain et al., 2006) or indirectly driving compulsive behavior by increasing anxiety (Deakin, 1998, Stein and Stahl, 2000, Maron et al., 2012) and/or interacting with other neuromodulatory pathways, such as dopamine systems (Perani et al., 2008).”

“Furthermore, while frontostriatal dysfunction is common among individuals with psychotic illness, it is also prevalent in numerous other psychiatric and neurological conditions (Clark et al., 2009, Klanker et al., 2013).”

“For example, the fact that serotonin depletion appears to increase sensitive to both negative feedback (Evers et al., 2005) and threats (Hariri and Holmes, 2006, Fisher and Hariri, 2013) could have the effect of either increasing impulsive shifting in the face of misleading punishments (Harrison et al.”

“A limited number of studies have examined the role of 5-HTT genotypes in reinforcement learning and decision making, and these studies (Crisan et al., 2009, Roiser et al., 2009) tend to support the idea that the short allele of the 5-HTT gene is associated with increased loss aversion.”

“…cortex (vlPFC; Brodmann areas 47/12) is an area that has been consistently implicated in set-shifting behavior, both in imaging studies of the WCST and related tasks (Konishi et al., 1999, Monchi et al., 2001), and in imaging studies of probabilistic reversal learning (Cools et al., 2002).”

“By contrast, SSRIs may reduce compulsivity by reducing threat sensitivity (Fisher and Hariri, 2013, Williams et al., 2015) and/or stress-related dopamine release (Vaessen et al., 2015).”

“While studies using this paradigm have produced mixed results in individuals with schizophrenia (Wilder et al. 1998; Ritter et al. 2004; Shurman et al. 2005; Sevy et al. 2007), findings are relatively clear that, while some SZ patients show performance impairments on the task, they rarely exhibit the stark insensitivi…”

“…(Luo et al., 2015), in that its stimulation has been associated with both the stimulation of 5HT cells in the midbrain Raphe (Morris et al., 1999, Amat et al., 2001, Pobbe and Zangrossi, 2010) and the cessation of dopamine cell firing in the SN/VTA (Ji and Shepard, 2007, Matsumoto and Hikosaka,…”

“Specifically, Jocham et al. (2009) investigated the effects of variations in the DRD2/ANKK1-Taqla polymorphism on reversal learning.”

“First, ATD has been shown to enhance prediction of punishment (Cools et al., 2008).”

“In a similar study, Crisan et al. (2009) also found that short allele carriers showed an exaggerated framing effect, in that they showed a greater tendency to gamble in loss frames than long allele homozygotes.”

“In the context of probabilistic reversal learning tasks, individuals can achieve learning in multiple ways: by either integrating reward prediction errors in model-free way, or by inducing a rule in a model-based way (Daw et al., 2005, Chen et al., 2015, Costa et al., 2015).”

“The fact that antipsychotics vary in their affinity for D2 and 5HT receptors (Kusumi et al., 2015) has led to possible differences between subgroups of SZ patients on different antipsychotic medications, as I describe below.”

“While studies using this paradigm have produced mixed results in individuals with schizophrenia (Wilder et al. 1998; Ritter et al. 2004; Shurman et al. 2005; Sevy et al. 2007), findings are relatively clear that, while some SZ patients show performance impairments on the task, they rarely exhibit the stark insensitivi…”

“…with considerable evidence indicating that SZ patients make a significantly higher number of perseverative responses than do normal control subjects and patients with other psychiatric disorders (Bellini et al., 1991, Braff et al., 1991, Abbruzzese et al., 1995, Cavallaro et al., 2003).”

“Data on the effects of illness course are mixed, as set-shifting deficits have been found to be present at initial psychotic episodes (Joyce et al., 2002, Murray et al., 2008), and the severity of these deficits has been found to correlate with illness duration (Pantelis et al., 2004).”

“…with striatal hyperdopaminergia, then one would expect acutely psychotic individuals to show increased reward sensitivity, reduced punishment sensitivity, and reduced cognitive flexibility, as people with more 9R alleles of the DAT1 gene appear to (Aarts et al., 2010, den Ouden et al., 2013).”

“Data on the effects of illness course are mixed, as set-shifting deficits have been found to be present at initial psychotic episodes (Joyce et al., 2002, Murray et al., 2008), and the severity of these deficits has been found to correlate with illness duration (Pantelis et al., 2004).”

“While there is evidence that some genes that code for aspects of dopamine system function may be schizophrenia risk genes (Talkowski et al., 2008), there is still tremendous variation among individuals with psychotic illness, and associations of specific genotypes with diagnoses may be mediated by associations with in…”

“2011); and 2) that the nature of the behavioral deficit may depend on what use is made of the anticipatory signal: for example, to inhibit responding (conditioned suppression), to maintain a particular choice (ignoring misleading feedback, as in the probabilistic discrimination task), or to increase response vigor as…”

“While studies using this paradigm have produced mixed results in individuals with schizophrenia (Wilder et al. 1998; Ritter et al. 2004; Shurman et al. 2005; Sevy et al. 2007), findings are relatively clear that, while some SZ patients show performance impairments on the task, they rarely exhibit the stark insensitivi…”

“…with considerable evidence indicating that SZ patients make a significantly higher number of perseverative responses than do normal control subjects and patients with other psychiatric disorders (Bellini et al., 1991, Braff et al., 1991, Abbruzzese et al., 1995, Cavallaro et al., 2003).”

“…receptor antagonists has also been shown to increase sensitivity to aversive outcomes, at the expense of rewarding ones, leading to a reduction in the number of perseverative errors during the performance of a reversal learning paradigm (Boulougouris et al., 2008, Boulougouris and Robbins, 2010).”

“…to indicate that impairments in both the formation and overriding of prepotent responses could stem from working memory deficits (Gold et al., 1997, Glahn et al., 2000, Hartman et al., 2003), which are prevalent in schizophrenia (Heinrichs and Zakzanis, 1998, Lee and Park, 2005), but not specific…”

“In conjunction with loseshifting behavior (essential for achieving reversal), SZ patients have exhibited abnormal signals in frontal, striatal, and parietal regions (Waltz et al., 2013, Culbreth et al., 2015).”

“At least one study (Beninger et al., 2003) has found that the administration of second-generation antipsychotics is associated with impaired performance on the Iowa Gambling Task, which is thought to depend heavily on sensitivity to the frequency and magnitude of monetary losses (Bechara et al.”

“…has often been associated with excessive striatal dopamine (Laruelle and Abi-Dargham, 1999, Howes et al., 2012), which has, in turn, been associated with reduced sensitivity to punishments (Dodds et al., 2008) and, consequently, reduced cognitive flexibility (lose-shifting; Cools et al., 2006).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript subjects points to increased cognitive flexibility, in the form of improved performance on the Stroop color word task and an antisaccade task, e.g. (Chaudhry et al., 2002; but see Hensman et al., 1991).”

“…the clinical picture suggests that increasing available serotonin (through SSRI administration), can be used to successfully reduce compulsivity (Goddard et al., 2008), whereas reducing 5HT transmission, with 5HT receptor antagonists, can induce compulsivity (Schirmbeck et al., 2013, Fonseka et…”

“…learning Evidence that dopamine system function modulates behavior and neural signals associated with reversal learning comes from studies in both human and nonhuman subjects (Dodds et al., 2008, Boulougouris et al., 2009, Clatworthy et al., 2009, Cools et al., 2009, Rutledge et al., 2009).”

“Interestingly, set-shifting deficits do not appear to be highly heritable (Ceaser et al., 2008), suggesting that set-shifting deficits in SZ may be closely-related to illness state, Neuroscience.”

“…example, is of particular interest, from the standpoint of schizophrenia research, due to the suspected involvement of these neurochemicals (especially dopamine) in the positive and negative symptoms of the disorder (Laruelle and Abi-Dargham, 1999, Abi-Dargham, 2007, Toda and Abi-Dargham, 2007).”

“…picture suggests that increasing available serotonin (through SSRI administration), can be used to successfully reduce compulsivity (Goddard et al., 2008), whereas reducing 5HT transmission, with 5HT receptor antagonists, can induce compulsivity (Schirmbeck et al., 2013, Fonseka et al., 2014).”

“Importantly, many SZ patients achieve no categories at all, on the WCST (Prentice et al., 2008), a fact suggestive of a more general problem of reinforcement learning, not limited to set-shifting.”

“In conjunction with loseshifting behavior (essential for achieving reversal), SZ patients have exhibited abnormal signals in frontal, striatal, and parietal regions (Waltz et al., 2013, Culbreth et al., 2015).”

“, 2015) and/or stress-related dopamine release (Vaessen et al., 2015).”

“…face of misleading punishments (Harrison et al., 1997, Chamberlain et al., 2006) or indirectly driving compulsive behavior by increasing anxiety (Deakin, 1998, Stein and Stahl, 2000, Maron et al., 2012) and/or interacting with other neuromodulatory pathways, such as dopamine systems (Perani et…”

“In fact, there have been several reports of improvements in cognitive flexibility associated with APD administration to schizophrenia patients, such as improvements in WCST performance (Sumiyoshi et al., 2003) and performance on an antisaccade task (Harris et al., 2006).”

“A number of other studies, however, report that APD administration has either no effect on cognitive flexibility in schizophrenia (Verdoux et al., 1995, Purdon et al., 2001), or no effect independent of that due to symptom amelioration (Borkowska et al., 2002, Daban et al., 2005).”

“…misleading punishments (Harrison et al., 1997, Chamberlain et al., 2006) or indirectly driving compulsive behavior by increasing anxiety (Deakin, 1998, Stein and Stahl, 2000, Maron et al., 2012) and/or interacting with other neuromodulatory pathways, such as dopamine systems (Perani et al., 2008).”

“…enhanced tendency to switch in response to negative feedback, even when it might be invalid, is consistent with evidence of either an oversensitivity to punishment in MDD, or impaired control over negative feedback, behaviorally and/or neurally (Taylor Tavares et al., 2008, Mueller et al., 2015).”

“Rather, poor performance in SZ patients appears to stem from a more general difficulty in integrating the frequency and magnitudes of gains and losses over time, in order to estimate the values of choices (Brown et al., 2015).”

“…differences in the activation of anterior cingulate, dlPFC, and areas of parietal cortex, our group (Waltz et al., 2013) found that patients failed to deactivate right vmPFC in response to surprising negative feedback, a signal shown to contribute to response inhibition, by Greening et al. (2011).”

“Data on the effects of illness course are mixed, as set-shifting deficits have been found to be present at initial psychotic episodes (Joyce et al., 2002, Murray et al., 2008), and the severity of these deficits has been found to correlate with illness duration (Pantelis et al., 2004).”

“…impairments in both the formation and overriding of prepotent responses could stem from working memory deficits (Gold et al., 1997, Glahn et al., 2000, Hartman et al., 2003), which are prevalent in schizophrenia (Heinrichs and Zakzanis, 1998, Lee and Park, 2005), but not specific to the condition.”

“Importantly, Alsiö et al. (2015) have shown that the 5-HT2C antagonist, SB 242084, improved early performance on a 3-stimulus reversal task, ostensibly through reducing the tendency to perseverate, but failed to improved overall performance, due to a detrimental effect on new learning later in…”

“Studies with 5HT receptor agonists and antagonists have been more rare, but there is some evidence that buspirone, a partial agonist at the 5HT1 receptor, reduces sensitivity to aversive stimuli in conditioning paradigms (Hellewell et al., 1999, Bond et al., 2003).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript behaviors (Soubrie et al., 1986, Deakin and Graeff, 1991).”

“…picture suggests that increasing available serotonin (through SSRI administration), can be used to successfully reduce compulsivity (Goddard et al., 2008), whereas reducing 5HT transmission, with 5HT receptor antagonists, can induce compulsivity (Schirmbeck et al., 2013, Fonseka et al., 2014).”

“A number of other studies, however, report that APD administration has either no effect on cognitive flexibility in schizophrenia (Verdoux et al., 1995, Purdon et al., 2001), or no effect independent of that due to symptom amelioration (Borkowska et al., 2002, Daban et al., 2005).”

“In order to do this analysis, my colleagues and I divided patients into subgroups by performing a median-split on average scores from psychosis/reality distortion items from the Brief Psychiatric Rating Scale (after McMahon et al., 2002; median average score = 2.25).”

“The habenula has been identified as a potential hub of said opposition (Luo et al., 2015), in that its stimulation has been associated with both the stimulation of 5HT cells in the midbrain Raphe (Morris et al.”

“…M anuscript A uthor M anuscript that “excessive” cognitive flexibility, as quantified by the tendency to shift prematurely following probabilistic negative feedback, has also been observed in individuals diagnosed with MDD (Murphy et al., 2003, Dombrovski et al., 2013, Dombrovski et al., 2015).”

“In fact, there have been several reports of improvements in cognitive flexibility associated with APD administration to schizophrenia patients, such as improvements in WCST performance (Sumiyoshi et al., 2003) and performance on an antisaccade task (Harris et al., 2006).”

“…misleading punishments (Harrison et al., 1997, Chamberlain et al., 2006) or indirectly driving compulsive behavior by increasing anxiety (Deakin, 1998, Stein and Stahl, 2000, Maron et al., 2012) and/or interacting with other neuromodulatory pathways, such as dopamine systems (Perani et al., 2008).”

“…the fact that serotonin depletion appears to increase sensitive to both negative feedback (Evers et al., 2005) and threats (Hariri and Holmes, 2006, Fisher and Hariri, 2013) could have the effect of either increasing impulsive shifting in the face of misleading punishments (Harrison et al., 1997,…”

“…above indicate that limiting dopamine transmission at D2 receptors, either through D2 receptor blockade or acute tyrosine and phenylalanine depletion (Robinson et al., 2010b, Janssen et al., 2015), improves punishment processing at the expense of reward processing in healthy human subjects.”

“Finally, performance on the WCST, among patients with schizophrenia, may vary with symptom profile, with paranoid patients making a higher number of perseverative errors than nonparanoid patients (Abbruzzese et al., 1996).”

“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript subjects points to increased cognitive flexibility, in the form of improved performance on the Stroop color word task and an antisaccade task, e.g. (Chaudhry et al., 2002; but see Hensman et al., 1991).”

“A number of other studies, however, report that APD administration has either no effect on cognitive flexibility in schizophrenia (Verdoux et al., 1995, Purdon et al., 2001), or no effect independent of that due to symptom amelioration (Borkowska et al., 2002, Daban et al., 2005).”

“Studies with 5HT receptor agonists and antagonists have been more rare, but there is some evidence that buspirone, a partial agonist at the 5HT1 receptor, reduces sensitivity to aversive stimuli in conditioning paradigms (Hellewell et al., 1999, Bond et al., 2003).”

“…with considerable evidence indicating that SZ patients make a significantly higher number of perseverative responses than do normal control subjects and patients with other psychiatric disorders (Bellini et al., 1991, Braff et al., 1991, Abbruzzese et al., 1995, Cavallaro et al., 2003).”

“By contrast, SGAs do not appear to impact performance on more procedural/BG-dependent learning tasks (Beninger et al., 2003, Kumari et al., 2015).”

“circuits originating in the PFC [141, 142], and ayahuasca and psilocybin have been shown to promote certain aspects of cognitive flexibility [143–147].”

“group (10 models; Two-way RM ANOVA test, F(1,18) = 25.”

“A prior study in people with schizophrenia described excessive win-switch behavior that correlated with the severity of delusional beliefs and hallucinations (Waltz, 2017).”