Developmental imaging genetics: Linking dopamine function to adolescent behavior

May combine two claims.

Adolescence is often a time when various mental illnesses emerge, including mood disorders, drug abuse disorders, eating disorders, and psychoses.

“adolescence is often a time when various mental illnesses emerge such as mood disorders, drug abuse disorders, eating disorders, and psychoses (Pine 2002; Chambers, Taylor et al. 2003; Sisk and Zehr 2005; Paus, Keshavan et al. 2008)”

• cites Pine 2002 sourceNot checked yet

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• cites Chambers, Taylor et al. 2003 sourceNot checked yet

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• cites Sisk and Zehr 2005 sourceNot checked yet

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Adolescents are capable of mature decision-making, abstract thinking, and often engage in rational behavior.

“adolescents are capable of mature decision-making (Paus 2005), abstract thinking, and often engage rational behavior (Steinberg, Cauffman et al. 2009).”

• cites Paus 2005 sourceNot checked yet

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• cites Steinberg, Cauffman et al. 2009 sourceNot checked yet

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Across species and cultures, adolescence is characterized by peaks in sensation/novelty seeking coupled with diminished harm avoidance, leading to increased risky behaviors.

“Across species and cultures, there are characteristic behaviors during adolescence including peaks in sensation/novelty seeking coupled with diminished levels of harm avoidance, leading to an increase in risky behaviors (Laviola, Macri et al. 2003).”

• cites Laviola, Macri et al. 2003Not checked yet

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Functional connectivity studies suggest that integration and coordination between brain regions, including subcortical to cortical connections, become more refined and efficient over adolescence, leading to reduced task-irrelevant connections, strengthening of connections supporting goal-directed actions, and elimination of redundant connections.

“functional connectivity studies suggest that the integration and coordination between brain regions, including subcortical to cortical connections, become more refined and efficient over adolescence, leading to reduced task-irrelevant connections, strengthening of connections supporting goal-directed actions, and elimination of redundant connections (Durston, Davidson et al. 2006; Liston, Watts et”

• cites Durston, Davidson et al. 2006 sourceNot checked yet

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• cites Liston, Watts et al. 2006 sourceNot checked yet

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• cites Fair, Cohen et al. 2009 sourceNot checked yet

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Adolescents tend to process incentives differently than adults, leading to suboptimal and often risky decision-making.

“Evidence suggests that adolescents tend to both process incentives differently than adults (for reviews see: Geier and Luna (2009; Ernst, Daniele et al. 2011)), leading to suboptimal and often risky decision-making.”

• cites Geier and Luna 2009 sourceNot checked yet

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• cites Ernst, Daniele et al. 2011 sourceNot checked yet

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Neurobiological models of adolescent development suggest that an overactive adolescent incentive system, driven by the striatum, with a still maturing cognitive system, driven by the PFC, may create a functional imbalance in optimal behavioral regulation, thereby enhancing risk taking behavior in adolescence.

“neurobiological models of adolescent development suggest that an over active adolescent incentive system, driven by the striatum, with a still maturing cognitive system, driven by the PFC, may create a functional imbalance in optimal behavioral regulation (i.e. suppressing a potentially rewarding, but inappropriate behavior) thereby enhancing risk taking behavior in adolescence ((Nelson, Leibenlu”

• cites Nelson, Leibenluft et al. 2005 sourceNot checked yet

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• cites Ernst, Pine et al. 2006 sourceNot checked yet

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• cites Casey, Getz et al. 2008 sourceNot checked yet

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Classified as probably not a substantial claim.

Imaging genetics is grounded in the idea that brain function and structure can serve as intermediate phenotypes between genes and behavior, given the relative proximity of brain function to the genotype.

“This approach, known as ‘imaging genetics’, is grounded in the idea that brain function and structure can serve as intermediate phenotypes between genes and behavior, given the relative proximity of brain function to the genotype (Hariri and Weinberger 2003).”

• cites Hariri and Weinberger 2003Not checked yet

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The human striatum is a core node for incentive processing and resulting behaviors, integrating environmental cues and updating behaviors through integration with the PFC.

“The human striatum is recognized as a core node for incentive processing and resulting behaviors, specifically in the ability to synthesize changing environmental cues and appropriately update behaviors through integration with the prefrontal cortex (PFC) by way of overlapping but functionally segregated pathways (Alexander, DeLong et al. 1986; Postuma and Dagher 2006; Di Martino, Scheres et al. 2”

• cites Alexander, DeLong et al. 1986 sourceNot checked yet

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• cites Postuma and Dagher 2006Not checked yet

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• cites Di Martino, Scheres et al. 2008 sourceNot checked yet

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Functional neuroimaging studies of incentive processing demonstrate differential striatal and PFC activation in adolescence relative to adulthood, with the majority reporting increased striatal activation coupled with decreased prefrontal recruitment.

“functional neuroimaging studies of incentive processing demonstrate differential striatal and PFC activation in adolescence relative to adulthood (Bjork, Knutson et al. 2004; Ernst, Nelson et al. 2005; Galvan, Hare et al. 2006; Bjork, Smith et al. 2010; van Leijenhorst, Moor et al. 2010; Padmanabhan 2011), with the majority of studies reporting an increase in striatal activation, coupled with”

• cites Bjork, Knutson et al. 2004 sourceNot checked yet

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• cites Ernst, Nelson et al. 2005 sourceNot checked yet

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• cites Galvan, Hare et al. 2006 sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

Slow changes in tonic levels of DA may be a preparatory mechanism for an organism to respond to environmental cues associated with reward.

“Slow changes in tonic levels of DA may be a preparatory mechanism for an organism to respond to environmental cues associated with reward (Schultz 1998).”

• cites Schultz 1998 sourceNot checked yet

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These two mechanisms of DA signaling lead to distinct behaviors and are regulated by reuptake and degradation enzymes.

“These two mechanisms of DA signaling have been found to lead to distinct behaviors (Floresco, West et al. 2003) and are regulated by reuptake and degradation enzymes.”

• cites Floresco, West et al. 2003Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Fast phasic DA events occur in response to reward-related events, may serve as teaching signals for error detection, and modulate behavioral changes in response to the environment.

“Fast phasic events occur in response to reward-related events, which may serve as important teaching signals for error detection and modulate behavioral changes in response to the environment (Schultz 1998).”

• cites Schultz 1998 sourceNot checked yet

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Animal and post-mortem human literature suggests an overexpression of receptors for serotonin, dopamine, adrenergic, and endocannabinoids, a peak in density of interneurons, and an increase in levels of GABA during adolescence.

“Animal and post-mortem human literature suggests an overexpression of receptors for serotonin, dopamine, adenergic, and endocannabinoids (Lidow and Rakic 1992), a peak in the density of interneurons (Anderson, Classey et al. 1995; Lewis 1997; Erickson and Lewis 2002), and an increase in levels of GABA (Hedner, Iversen et al. 1984).”

• cites Lidow and Rakic 1992 sourceNot checked yet

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• cites Anderson, Classey et al. 1995Not checked yet

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• cites Lewis 1997 sourceNot checked yet

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DA neurons in the midbrain project to medium spiny neurons in the NAcc as well as pyramidal neurons in the PFC, thereby modulating firing rates and establishing a strong reciprocal relationship between striatum and PFC.

“DA neurons in the midbrain project to medium spiny neurons in the NAcc as well as pyramidal neurons in the PFC, thereby modulating the firing rates of these neurons and establishing a strong reciprocal relationship between striatum and PFC (Grace, Floresco et al. 2007).”

• cites Grace, Floresco et al. 2007 sourceNot checked yet

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DA levels are modulated by two dissociable processes of DA discharge that interact: a constant background tonicity and a burst firing high-amplitude phasic release.

“DA levels are modulated by two dissociable processes of DA discharge that interact, (1) a constant background tonicity regulated by baseline firing of DA neurons and glutamatergic afferents from cortical to striatal regions, and (2) a burst firing high-amplitude phasic release (Grace, Floresco et al. 2007).”

• cites Grace, Floresco et al. 2007 sourceNot checked yet

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Increased myelination in cortical to subcortical axons, changes in axon caliber, pruning of synapses and receptors, cell shrinkage, and glial changes refine the developing brain and strengthen and consolidate highly used connections, while weakening or eliminating redundant or weakly used connections through unique experiences.

“increased myelination in cortical to subcortical axons, changes in axon caliber, pruning of synapses and receptors, cell shrinkage, and glial changes (Yakovlev and Lecours 1967; Rakic, Bourgeois et al. 1986; Benes, Turtle et al. 1994; Andersen 2003) refine the developing brain and strengthen and consolidate highly used connections, while weakening or eliminating redundant or weakly used”

• cites Yakovlev and Lecours 1967Not checked yet

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• cites Rakic, Bourgeois et al. 1986 sourceNot checked yet

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• cites Benes, Turtle et al. 1994Not checked yet

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Research on DA transporters has been inconsistent in the midbrain, suggesting no consistent developmental change, increases over adolescence, and peaks in late childhood.

“Research on DA transporters has been inconsistent in the midbrain suggesting no consistent developmental change (Moll, Mehnert et al. 2000), increases over adolescence (Galineau, Kodas et al. 2004), and peaks in late childhood (Coulter, Happe et al. 1996).”

• cites Moll, Mehnert et al. 2000 sourceNot checked yet

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• cites Galineau, Kodas et al. 2004Not checked yet

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• cites Coulter, Happe et al. 1996Not checked yet

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A peak in activity of midbrain DA neurons has been documented in the rat model, suggesting an overall increase in DA levels.

“A peak in activity of midbrain DA neurons has been documented in the rat model (McCutcheon, White et al. 2009), suggesting an overall increase in DA levels.”

• cites McCutcheon, White et al. 2009Not checked yet

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Tonic DA activity regulates phasic signaling in an inhibitory fashion and phasic DA enhances tonic activity.

“These systems also interact as tonic DA activity regulates phasic signaling in an inhibitory fashion and phasic DA has been shown to enhance tonic activity (Niv, Daw et al. 2007).”

• cites Niv, Daw et al. 2007 sourceNot checked yet

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Other studies have noted a peak in tonic DA concentrations in late adolescence with a subsequent decline in adulthood.

“Other studies have noted a peak in tonic DA concentrations in late adolescence with a subsequent decline in adulthood ((Badanich, Adler et al. 2006; Philpot, Wecker et al. 2009).”

• cites Badanich, Adler et al. 2006 sourceNot checked yet

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• cites Philpot, Wecker et al. 2009Not checked yet

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Dopaminergic innervation to the PFC peaks in adolescence, with the largest increase in cortical layer III.

“Dopaminergic innervation to the PFC peaks in adolescence (Rosenberg and Lewis 1995; Benes, Taylor et al. 2000), with the largest increase being in cortical layer III, a region that that is highly implicated in cognitive processing (Lewis and Gonzalez-Burgos 2000).”

• cites Rosenberg and Lewis 1995 sourceNot checked yet

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• cites Benes, Taylor et al. 2000Not checked yet

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• cites Lewis and Gonzalez-Burgos 2000Not checked yet

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In the striatum, peaks in both D1 and D2 receptors occur in childhood and begin to decline in adolescence, evident in both animal and human work.

“In the striatum, peaks in both D1 and D2 receptors occur in childhood and begin to decline in adolescence, evident in both animal and human work (Seeman, Bzowej et al. 1987; Lidow and Rakic 1992; Montague, Lawler et al. 1999; Andersen, Thompson et al. 2002).”

• cites Seeman, Bzowej et al. 1987 sourceNot checked yet

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• cites Lidow and Rakic 1992 sourceNot checked yet

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• cites Montague, Lawler et al. 1999Not checked yet

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Non-human primate research suggests that the density of D1 and D2 receptors in PFC increase at different rates, with D1 receptor density demonstrating earlier peaks than D2, which peaks in late-adolescence/early adulthood.

“non-human primate research suggests that the density of D1 and D2 receptors in PFC increase at different rates, with D1 receptor density demonstrating earlier peaks than D2, which peaks in late-adolescence/early adulthood (Tseng and O'Donnell 2007).”

• cites Tseng and O'Donnell 2007Not checked yet

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Probably not a substantial claim: may not pass S4 (based).

Abnormalities in DA signaling are implicated in the pathophysiology of neuropsychiatric disorders that often emerge in adolescence (e.g. schizophrenia, drug abuse).

“abnormalities in DA signaling are implicated in the pathophysiology of neuropsychiatric disorders that often emerge in adolescence (e.g. schizophrenia, drug abuse).”

• AssumptionRests on an assumption: The risk factors for mental illnesses that emerge in adolescence are not fully characterized.

May combine two claims.

Adolescents show decreased aversive response to substances of abuse (i.e. milder withdrawal responses, reduced psychomotor effects) and increased sensitivity to DA receptor antagonists.

“Adolescents also show decreased aversive response to substances of abuse (i.e. milder withdrawal responses, reduced psychomotor effects) (Spear 2002; Doremus, Brunell et al. 2003; Levin, Rezvani et al. 2003) and increased sensitivity to DA receptor antagonists (Spear, Shalaby et al. 1980; Spear and Brake 1983; Teicher, Barber et al. 1993).”

• cites Spear 2002Not checked yet

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• cites Doremus, Brunell et al. 2003Not checked yet

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• cites Levin, Rezvani et al. 2003 sourceNot checked yet

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DA signaling in adolescence may also influence and be influenced by differences in rates of maturation of subcortical systems relative to cortical, and a functional imbalance in the adolescent brain that is driven by striatal signaling with immaturities in PFC-driven regulation.

“DA signaling in adolescence may also influence and be influenced by differences in rates of maturation of subcortical systems relative to cortical, and an functional imbalance in the adolescent brain that is driven by striatal signaling with immaturities in PFC-driven regulation (Chambers, Taylor et al. 2003; Ernst, Pine et al. 2006).”

• cites Chambers, Taylor et al. 2003 sourceNot checked yet

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• cites Ernst, Pine et al. 2006 sourceNot checked yet

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The adult literature suggests that increasing DA signaling through administration of DA or DA agonists increases novelty-seeking and exploration behaviors, whereas reducing DA signaling with antagonists halts such behaviors.

“The adult literature suggests that increasing DA signaling through administration of DA or DA agonists increases novelty-seeking and exploration behaviors, whereas reducing DA signaling with antagonists halts such behaviors (Pijnenburg, Honig et al. 1976; Fouriezos, Hansson et al. 1978; Le Moal and Simon 1991).”

• cites Pijnenburg, Honig et al. 1976Not checked yet

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• cites Fouriezos, Hansson et al. 1978Not checked yet

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• cites Le Moal and Simon 1991Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In the striatum, DA transporter levels increase into late childhood and remain stable through adolescence.

“Other research has suggested that in the striatum, DA transporter levels increase into late childhood and remain stable through adolescence (Coulter, Happe et al. 1996; Tarazi, Tomasini et al. 1998; Galineau, Kodas et al. 2004).”

• cites Coulter, Happe et al. 1996Not checked yet

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• cites Tarazi, Tomasini et al. 1998Not checked yet

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• cites Galineau, Kodas et al. 2004Not checked yet

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The DA system is at a functional ceiling in adolescence relative to childhood or adulthood, due to peaks in midbrain DA cell firing, overall tonic levels, innervation, as well as increased receptor densities.

“It is posited that the DA system is at a “functional ceiling” in adolescence relative to childhood or adulthood (Chambers, Taylor et al. 2003), due to peaks in midbrain DA cell firing, overall tonic levels, innervation, as well as increased receptor densities.”

• cites Chambers, Taylor et al. 2003 sourceNot checked yet

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Classified as probably not a substantial claim. May combine two claims.

Maturational changes in DA function have not been mapped directly onto behaviors in adolescence, suggesting that a comprehensive examination of the interaction of various aspects of the DA system and their direct effects on behavior is warranted.

“Adding to this complexity, maturational changes in DA function have not been mapped directly onto behaviors in adolescence suggesting that a comprehensive examination of the interaction of various aspects of the DA system (e.g. receptors, clearance, innervation) and their direct effects on behavior is warranted (Spear 2011; Luciana, Wahlstrom et al. 2012).”

• cites Spear 2011 sourceNot checked yet

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• cites Luciana, Wahlstrom et al. 2012Not checked yet

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Overall heightened DA signaling in adolescence leads to heightened motivation, or approach-like behaviors, due to increased activation of the direct pathway and inhibition of the indirect pathway.

“These early findings point to a hypothesized model of adolescent DA function whereby overall heightened DA signaling leads to heightened motivation, or approach-like behaviors-due to increased activation of the direct pathway and inhibition of the indirect pathway.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The elevation of tonic DA during adolescence may impact regulation of the phasic response in response to salient or rewarding information, but this has not been empirically tested.

“For example, the elevation of tonic DA during adolescence may impact regulation of the phasic response in response to salient or rewarding information (for review see (Luciana, Wahlstrom et al. 2012)), but this has not been empirically tested.”

• cites Luciana, Wahlstrom et al. 2012Not checked yet

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Increases in both D1 and D2 receptors, as seen in adolescence, may have an overall excitatory effect on the brain, which could result in an increase in behaviors that are DA dependent (such as reward and novelty seeking).

“Increases in both D1 and D2 receptors, as seen in adolescence thus may have an overall excitatory effect on the brain, which could result in an increase in behaviors that are DA dependent (such as reward and novelty seeking).”

• AssumptionRests on an assumption: D1 receptors are more abundant in the direct pathway, exciting GABAergic neurons in response to preferred behaviors, and D2 in the indirect pathway, which inhibit GABAergic neurons and reduce the inhibitory effect of the indirect pathway.

May combine two claims.

Increasing DA levels in individuals who have high baseline DA levels impairs cognitive performance, whereas improvements are noted in individuals with lower baseline levels.

“For example, increasing DA levels in individuals who have high baseline DA levels impairs cognitive performance, (perhaps pushing them over the peak of the inverted U curve) whereas improvements are noted in individuals with lower baseline levels (pushing them closer to the apex of the curve) (Mattay, Goldberg et al. 2003; Apud, Mattay et al. 2007; Cools, Frank et al. 2009).”

• cites Mattay, Goldberg et al. 2003Not checked yet

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• cites Apud, Mattay et al. 2007 sourceNot checked yet

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• cites Cools, Frank et al. 2009Not checked yet

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D1 receptor stimulation allows for maintenance of information online and stabilization of functional states, and D2 receptor binding is involved in flexible updating of information and allowing for the transition between functional states.

“D1 receptors stimulation allows for maintenance of information online and stabilization of functional states, and D2 receptor binding is involved in flexible updating of information and allowing for the transition between functional states (Seamans, Durstewitz et al. 2001; Durstewitz and Seamans 2002; Seamans and Yang 2004).”

• cites Seamans, Durstewitz et al. 2001Not checked yet

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• cites Durstewitz and Seamans 2002Not checked yet

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• cites Seamans and Yang 2004 sourceNot checked yet

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Classified as probably not a substantial claim.

The study of the influence of genetic polymorphisms on brain function or imaging genetics has already provided considerable insight on the influence of genetically driven variability on brain physiology.

“Indeed, the study of the influence of genetic polymorphisms on brain function or “imaging genetics” has already provided considerable insight on the influence of genetically driven variability on brain physiology (e.g. (Hariri and Weinberger 2003; Brown and Hariri 2006; Drabant, Hariri et al. 2006; Hariri and Lewis 2006)).”

• cites Hariri and Weinberger 2003Not checked yet

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• cites Brown and Hariri 2006Not checked yet

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• cites Drabant, Hariri et al. 2006Not checked yet

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Probably not a substantial claim: may not pass S4 (based).

Baseline inter-individual differences in adolescence may be unique relative to differences in adulthood due to maturation in the DA system.

“Following this model, it is possible that baseline inter-individual differences in adolescence would be unique relative to differences in adulthood due to maturation in the DA system.”

May combine two claims.

Despite an overall peak in DA signaling and general maturational processes that occur in adolescence, there is considerable individual variability both in DA signaling, as well as DA-influenced behaviors, likely due to a combination of genetic and environmental factors.

“Despite an overall peak in DA signaling and general maturational processes that occur in adolescence, there is considerable individual variability both in DA signaling, as well as DA-influenced behaviors, likely due to a combination of genetic and environmental factors (Depue and Collins 1999; Frank and Hutchison 2009).”

• cites Depue and Collins 1999 sourceNot checked yet

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• cites Frank and Hutchison 2009Not checked yet

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AG heterozygotes, who have increased D1 receptors, showed increased recruitment of DLPFC relative to AA homozygotes, who engaged a more widely distributed set of brain regions.

“AG heterozygotes, who have increased D1 receptors, showed increased recruitment of DLPFC relative to AA homozygotes, who engaged a more widely distributed set of brain regions.”

• cites Tura, Turner et al. 2008Not checked yet

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The D2 receptor is expressed more abundantly in striatum than in PFC and exerts a strong influence on frontostriatal connectivity through inhibition of excitatory and disinhibition of inhibitory pathways.

“The D2 receptor, which is expressed more abundantly in striatum relative to PFC, exerts a strong influence on frontostriatal connectivity through both inhibition of excitatory and disinhib tion of inhibitory pathways (Cepeda and Levine 1998; Goto and Grace 2005).”

• cites Cepeda and Levine 1998Not checked yet

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• cites Goto and Grace 2005Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

These findings are in line with other work suggesting that increased prefrontal DA tone results in improved cognitive performance and more efficient prefrontal signaling.

“These findings are in line with other work suggesting that increased prefrontal DA tone results in improved cognitive performance and more efficient prefrontal signaling (e.g. (Egan, Goldberg et al. 2001; Mattay, Goldberg et al. 2003)).”

• cites Egan, Goldberg et al. 2001Not checked yet

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• cites Mattay, Goldberg et al. 2003Not checked yet

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D1 receptor activation on local GABAergic (inhibitory) interneurons serves to inhibit irrelevant glutamatergic inputs.

“Simultaneously, D1 receptor activation on local GABAergic (inhibitory) interneurons serves to inhibit irrelevant glutamatergic inputs (Durstewitz, Seamans et al. 2000).”

• cites Durstewitz, Seamans et al. 2000Not checked yet

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Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

In adolescence, when D2 receptor density is higher, the relationship between brain activation and D2 receptor availability might parallel previous findings using pharmacological interventions targeting D2 receptors, suggesting an age by genotype interaction that is yet to be empirically tested.

“In adolescence, when there is a higher density of D2 receptors, the relationship between brain activation and D2 receptor availability might parallel previous findings using pharmacological interventions that target D2 receptors (Kirsch, Reuter et al. 2006; van der Schaaf, van Schouwenburg et al. 2012), suggesting an age by genotype interaction that is yet to be empirically tested.”

• cites Kirsch, Reuter et al. 2006Not checked yet

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• cites van der Schaaf, van Schouwenburg et al. 2012Not checked yet

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D2 receptors have two isoforms: D2-S acts mainly as a presynaptic autoreceptor inhibiting DA release, whereas D2-L primarily inhibits the postsynaptic cell.

“D2 receptors have two distinct isoforms, the short isoform (D2-S) acts mainly as a presynaptic autoreceptor, inhibiting DA release, whereas the long isoform (D2-L) primarily functions to inhibit the post synaptic cell (Centonze, Grande et al. 2003).”

• cites Centonze, Grande et al. 2003Not checked yet

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Decreased D2 autoreceptor function increases DA release, and individuals with decreased D2-S show increased novelty-seeking and reward reactivity.

“Decreased D2 autoreceptor function increases DA release and individuals with decreased D2-S demonstrate increased novelty-seeking and reward reactivity (Zald, Cowan et al. 2008; Pecina, Mickey et al. 2012).”

• cites Zald, Cowan et al. 2008Not checked yet

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• cites Pecina, Mickey et al. 2012Not checked yet

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Inter-individual differences are expressed differentially as a function of relative DA across development based on genotype, such that the val allele may confer a relative advantage for cognitive function earlier in development when DA levels are higher than in adulthood.

“It is thus possible that inter-individual differences are expressed differentially as a function of relative DA across development based on genotype (e.g. the val allele may confer a relative advantage for cognitive function earlier in development, when DA levels are higher than in adulthood).”

May combine two claims.

Increasing DA levels interacts with the COMT val158met SNP consistent with the inverted U model, with met individuals demonstrating diminished cortical efficiency during cognitive control and val individuals demonstrating improvements.

“Furthermore, increasing DA levels interacts with the COMT val158met SNP consistent with the putative inverted U model with met individuals demonstrating diminished cortical efficiency during tasks of cognitive control and val individuals demonstrating improvements (Mattay, Goldberg et al. 2003; Apud, Mattay et al. 2007).”

• cites Mattay, Goldberg et al. 2003Not checked yet

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• cites Apud, Mattay et al. 2007 sourceNot checked yet

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Adolescents carrying the met allele may surpass optimal thresholds, which could result in less efficient cortical function relative to val.

“This is adolescents carrying the met allele may surpass optimal thresholds, which could result in less efficient cortical function, relative to val (Wahlstrom, Collins et al. 2010; Wahlstrom, White et al. 2010).”

• cites Wahlstrom, Collins et al. 2010Not checked yet

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• cites Wahlstrom, White et al. 2010Not checked yet

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The DA transporter (DAT) is mainly expressed in the striatum and is responsible for DA reuptake, clearing DA from the extracellular space after release.

“The DA transporter (DAT) is mainly expressed in the striatum and is responsible for DA reuptake, clearing DA from the extracellular space after release (Jaber, Bloch et al. 1998).”

• cites Jaber, Bloch et al. 1998Not checked yet

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DAT binding site density is significantly less for the 9-repeat allele than the 10-repeat allele, linking the 9-repeat allele with reduced DAT expression and greater striatal synaptic DA, although some studies suggest the opposite.

“The DAT binding site density for the most common repeat alleles (9-repeat and 10-repeat) is significantly less for the 9-repeat allele than the 10-repeat allele, linking the 9-repeat allele with reduced DAT expression and greater striatal synaptic DA (Fuke, Suo et al. 2001; Mill, Asherson et al. 2002; VanNess, Owens et al. 2005), although some studies have suggested the opposite (Mill, Asherson et”

• cites Fuke, Suo et al. 2001Not checked yet

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• cites Mill, Asherson et al. 2002 sourceNot checked yet

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• cites VanNess, Owens et al. 2005Not checked yet

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Probably not a substantial claim: may not pass S4 (based).

No studies to date have examined the influence of these polymorphisms across development.

“However, no studies to date have examined the influence of these polymorphisms across development.”

May combine two claims.

The COMT val allele is associated with high enzymatic activity and low synaptic dopamine, whereas the COMT met allele results in approximately one third less enzyme activity and high synaptic dopamine.

“The COMT val allele is associated with high enzymatic activity and consequently low synaptic dopamine levels, whereas the COMT met allele results in approximately one third less enzyme activity and consequently high synaptic dopamine (Chen, Lipska et al. 2004).”

• cites Chen, Lipska et al. 2004 sourceNot checked yet

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During a visuo-spatial working memory task in individuals aged 6 to 20, activation in frontal and parietal regions increased across development in val/val homozygotes but not met carriers, suggesting delayed development of cognitive function in individuals with the val allele.

“During a visuo-spatial working memory task in individuals between the ages of 6 and 20,Dumontheil et al. (2011), demonstrated that activation in frontal and parietal regions increased across development in individuals homozygous for the val allele, but not met carriers, suggesting delayed development of cognitive function in individuals with the val allele.”

• cites Dumontheil et al. (2011) sourceNot checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

Following the inverted U model, increased D1 and D2 receptor availability may result in increased competition between the direct and indirect pathways, which may be more exacerbated in adolescents with higher receptor availability at baseline, leading to a generally more disorganized processing system.

“Following the inverted U model, increased D1 and D2 receptor availability may result in increased competition between the direct and indirect pathways which may be more exacerbated in adolescents with higher receptor availability at baseline, leading to a generally more disorganized processing system.”

• AssumptionRests on an assumption: D1 and D2 receptor densities peak in late childhood, so receptor density is higher in adolescence than in adulthood.

Classified as probably not a substantial claim.

Adolescents, who have increased DA levels relative to adults, may follow a similar pattern as a function of COMT genotype as the pharmacological studies in adults.

“Based on this evidence, it is posited that adolescents, who have increased DA levels relative to adults, may follow a similar pattern as a function of COMT genotype as the pharmacological studies in adults.”

May combine two claims.

A SNP in DRD4 (rs6277, −521 SNP) results in a 40% reduction in RNA transcription for the T-allele relative to the C-allele, although another study found no differences.

“A SNP in the DRD4 gene (rs6277, −521 SNP) results in a 40% reduction in RNA transcription for the T-allele relative to the C-allele (Okuyama, Ishiguro et al. 1999), although another study found no differences (Kereszturi, Kiraly et al. 2006).”

• cites Okuyama, Ishiguro et al. 1999Not checked yet

  Not checked in the free run.

• cites Kereszturi, Kiraly et al. 2006Not checked yet

  Not checked in the free run.

May combine two claims.

Lower DAT expression reduces synaptic DA clearance, thereby increasing DA levels.

“Lower DAT expression reduces synaptic DA clearance thereby increasing DA levels (Cagniard, Balsam et al. 2006; Cagniard, Beeler et al. 2006).”

• cites Cagniard, Balsam et al. 2006Not checked yet

  Not checked in the free run.

• cites Cagniard, Beeler et al. 2006Not checked yet

  Not checked in the free run.

May combine two claims.

Typically developing adolescents with the 9-repeat allele demonstrate reduced activation of prefrontal and striatal regions during inhibitory control and reward prediction.

“Developmental studies using the DAT1 polymorphism suggest that typically developing adolescents with the 9-repeat allele demonstrate reduced activation of prefrontal and striatal regions during inhibitory control (Braet, Johnson et al. 2011), and reward prediction (Paloyelis, Mehta et al. 2012).”

• cites Braet, Johnson et al. 2011Not checked yet

  Not checked in the free run.

• cites Paloyelis, Mehta et al. 2012Not checked yet

  Not checked in the free run.

May combine two claims.

Prior studies have shown additive effects of the COMT val158met SNP and the DAT1 3'VNTR during reward anticipation and outcome stages of reward processing in both PFC and striatum, reporting increased activation associated with genotypes that have increased DA availability.

“For example, prior studies have shown additive effects of the COMT val158met SNP and the DAT1 3’VNTR during the reward anticipation and outcome stages of reward processing in both PFC and striatum, reporting increased activation associated with genotypes that have increased DA availability (Yacubian, Sommer et al. 2007; Dreher, Kohn et al. 2009).”

• cites Yacubian, Sommer et al. 2007 sourceNot checked yet

  Not checked in the free run.

• cites Dreher, Kohn et al. 2009Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

Meta-analyses tend to be biased, as studies with null findings are generally not published.

“However, it is also important to keep in mind that meta-analyses tend to be biased, as studies with null findings are generally not published.”

Classified as probably not a substantial claim.

Munafo et al. (2008) conducted a meta-analysis of studies reporting associations between a VNTR polymorphism in the serotonin transporter gene (5-HTTLPR) and amygdala activation and suggested that an imaging genetics study would require a total sample of about 70 participants to achieve .8 power for an alpha power of .05.

“For example,Munafo et al. (2008) conducted a meta-analysis of studies that have reported associations between a VNTR polymorphism in the serotonin transporter gene (5-HTTLPR) and amygdala activation and suggested that an imaging genetics study would require a total sample of about 70 participants to achieve .8 power for an alpha power of .05.”

• cites Munafo et al. (2008) sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S4 (based).

Evidence points to a protracted development of brain systems including PFC and striatum throughout childhood and adolescence.

“Evidence points to a protracted development of brain systems including PFC and the striatum throughout childhood and adolescence.”

Probably not a substantial claim: may not pass S4 (based). May combine two claims.

The majority of imaging genetics research to date has focused on differences between genotypes in adulthood or within discrete age groups, despite growing evidence that brain systems continue to reorganize across the lifespan and that gene effects likely manifest differently at different stages.

“The majority of imaging genetics research to date has focused on differences between genotypes in adulthood or within discrete age groups, despite growing evidence that brain systems continue to reorganize across the lifespan and that gene effects likely manifest differently at different stages.”

Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing). May combine two claims.

It is likely that sample sizes will have to be increased in order to replicate previous findings and to generate accurate assessments of the effect sizes of different polymorphisms.

“It is likely that sample sizes will have to be increased in order to replicate previous findings and to generate accurate assessments of the effect sizes of different polymorphisms.”

May combine two claims.

DAT1 genotype may influence the system differentially in adolescence, with the 9-repeat allele resulting in decreased striatal and cortical reactivity than in adulthood, when the 9-repeat allele has been associated with increased activation.

“These results suggest that DAT1 genotype may influence the system differentially in adolescence – with the 9-repeat allele resulting in decreased striatal and cortical reactivity-than in adulthood – when the 9-repeat allele has been associated with increased activation.”

Classified as probably not a substantial claim. May combine two claims.

In adolescence, when excess DA levels are present, individuals carrying the 9-repeat allele may have an overabundance of synaptic DA availability, which may have opposite effects on brain function than in adulthood.

“It is possible that in adolescence, when excess DA levels are present, individuals carrying the 9-repeat allele have an overabundance of synaptic DA availability, which may have opposite effects on brain function than in adulthood.”

May combine two claims.

Exaggerated DA levels in both striatum and PFC in adolescence may result in an increased sensitivity to rewards coupled with poor executive regulation of impulse-driven behaviors, thereby increasing vulnerability for risk-taking behaviors.

“However, exaggerated DA levels in both striatum and PFC in adolescence may result in an increased sensitivity to rewards coupled with poor executive regulation of impulse driven behaviors, thereby increasing vulnerability for risk-taking behaviors.”

May combine two claims.

The inability to consistently control behavior concurrent with increased sensation seeking persists in adolescence, leading to increases in risk-taking behaviors.

“The inability to consistently control behavior concurrent with increased sensation seeking persists in adolescence, leading to increases in risk taking behaviors.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Others have suggested that sample sizes of over 25 subjects in each group are necessary for general fMRI studies in order to have adequate reliability.

“Similarly, others have suggested that sample sizes of over 25 subjects in each group are necessary for general fMRI studies in order to have adequate reliability (Thirion, Pinel et al. 2007).”

• cites Thirion, Pinel et al. 2007 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Given evidence that various aspects of the DA system are heightened or changed in adolescence and that single gene effects may manifest differently in the adolescent brain, gene interactions may differ in the adolescent brain compared with the adult brain.

“Given evidence that various aspects of the DA system are heightened or changed in adolescence and that single gene effects may manifest differently in the adolescent brain, it is also possible that gene interactions differ in the adolescent brain than in the adult brain.”

May combine two claims.

DA availability and signaling is heightened during the adolescent period and may promote novelty seeking in an adaptive fashion in order to gain skills that support adult survival.

“DA availability and signaling is heightened during the adolescent period and may promote novelty seeking in an adaptive fashion in order to gain skills that support adult survival.”

Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

Gene expression is one of the primary sources of variability, acting through cellular and system-level neural processes to produce complex phenomena that manifest in behavioral function and dysfunction.

“Gene expression is one of the primary sources of variability, acting through cellular and system-level neural processes to produce complex phenomena that manifest in behavioral function and dysfunction.”

May combine two claims.

fMRI is one of the most common and reliable methods of measuring brain function at decent spatial and temporal resolutions, but because it is an indirect measure of brain activity, interpretation of gene effects is limited.

“fMRI is one the most common and reliable methods of measuring brain function at decent spatial and temporal resolutions, but given that it is an indirect measure of brain activity, reflecting a paradigm related change in metabolic consumption (Logothetis, Pauls et al. 2001), interpretation of gene effects is limited.”

• cites Logothetis, Pauls et al. 2001 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Assuming a relatively even distribution of the alleles, a total sample of about 70 participants would result in approximately 30-35 participants per group.

“Assuming a relatively even distribution of the alleles, this would result in approximately 30–35 participants per group.”

• AssumptionThe authors state this as an assumption: The alleles are relatively evenly distributed.