The effect of moderate acute psychological stress on working memory-related neural activity is modulated by a genetic variation in catecholaminergic function in humans

“Mood state was assessed using the positive and negative affect scale (PANAS) questionnaire (Watson et al., 1988) at four time points coinciding with the collection of salivary samples.”

“Only men were included to avoid confounds related to gender differences and menstrual cycle-dependent variance in stress responsiveness (Kirschbaum et al., 1999; Kudielka and Kirschbaum, 2005).”

“It is worth noting that our stress induction procedure refers to an emotion focused, moderate acute psychological stressor rather than socially and cognitively oriented stressors such as the Trier social stress test (TSST) and arithmetic calculation with negative evaluation (Kirschbaum et al., 1993; Dickerson and Keme…”

“These effects are believed to result from stress-induced alterations of large-scale brain network functioning including the prefrontal cortex (PFC), through stress-sensitive neuromodulatory systems (GoldmanRakic, 1995; Aston-Jones and Cohen, 2005; Arnsten, 2007, 2009; McEwen, 2007; Sara, 2009; Hermans et al., 2011).”

“…believed to result from stress-induced alterations of large-scale brain network functioning including the prefrontal cortex (PFC), through stress-sensitive neuromodulatory systems (GoldmanRakic, 1995; Aston-Jones and Cohen, 2005; Arnsten, 2007, 2009; McEwen, 2007; Sara, 2009; Hermans et al., 2011).”

“…changes may exert regionally specific effects on PFC functioning (Aston-Jones and Cohen, 2005; Shin et al., 2005; Dolcos and McCarthy, 2006; Etkin and Wager, 2007), but at the same time have their opposite effects on neural processes in limbic regions, particularly the MTL and the amygdala…”

“As evidenced by elevation of both HR and α-amylase, our stress induction procedure succeeded in triggering an increase of sympathetic and noradrenergic activity, and thus resulted in increased central release of stress-sensitive catecholamines (de Kloet et al., 2005; Joels and Baram, 2009; Ulrich-Lai and Herman, 2009)…”

“…believed to result from stress-induced alterations of large-scale brain network functioning including the prefrontal cortex (PFC), through stress-sensitive neuromodulatory systems (GoldmanRakic, 1995; Aston-Jones and Cohen, 2005; Arnsten, 2007, 2009; McEwen, 2007; Sara, 2009; Hermans et al., 2011).”

“…error of mean. an unbiased, anatomically defined, gray matter mask of the PFC covering the entire prefrontal areas, by using non-stationary suprathreshold cluster-size approach based on Monte-Carlo simulations (Forman et al., 1995; Ward, 2000; Nichols and Hayasaka, 2003; Hayasaka et al., 2004).”

“ORIGINAL RESEARCH ARTICLE published: 11 May 2012 doi: 10.3389/fnint.2012.00016 The effect of moderate acute psychological stress on working memory-related neural activity is modulated by a genetic variation in catecholaminergic function in humans”

“…believed to result from stress-induced alterations of large-scale brain network functioning including the prefrontal cortex (PFC), through stress-sensitive neuromodulatory systems (GoldmanRakic, 1995; Aston-Jones and Cohen, 2005; Arnsten, 2007, 2009; McEwen, 2007; Sara, 2009; Hermans et al., 2011).”

“A variation (Val158Met) in the gene encoding Catechol-O-methyltransferase (COMT) is associated with individual differences in basal catecholaminergic availability (Lotta et al., 1995; Mannisto and Kaakkola, 1999) and prefrontal functions (Chen et al., 2004).”

“…alters WM performance with both detrimental (Elzinga and Roelofs, 2005; Oei et al., 2006; Luethi et al., 2008; Schoofs et al., 2008) and enhancing (Lewis et al., 2008; Weerda et al., 2010; Hidalgo et al., 2011) effects, likely through altered efficiency of WM-related processing in dorsolateral…”

“Only men were included to avoid confounds related to gender differences and menstrual cycle-dependent variance in stress responsiveness (Kirschbaum et al., 1999; Kudielka and Kirschbaum, 2005).”

“The lack of a genotype effect on baseline WM performance may be attributed to a lack of sensitivity at a behavioral level (Meyer-Lindenberg and Weinberger, 2006).”

“…error of mean. an unbiased, anatomically defined, gray matter mask of the PFC covering the entire prefrontal areas, by using non-stationary suprathreshold cluster-size approach based on Monte-Carlo simulations (Forman et al., 1995; Ward, 2000; Nichols and Hayasaka, 2003; Hayasaka et al., 2004).”

“…studies have confirmed that acute stress indeed alters WM performance with both detrimental (Elzinga and Roelofs, 2005; Oei et al., 2006; Luethi et al., 2008; Schoofs et al., 2008) and enhancing (Lewis et al., 2008; Weerda et al., 2010; Hidalgo et al., 2011) effects, likely through…”

“Second, exposure to highly aversive films in combination with selfreferencing instruction meets the requirements for the physiological stress response in humans, particularly with activation of the sympatho-adrenomedullary system (SAM) and substantial elevation of epinephrine and norepinephrine levels, as described by…”

“…finding is that stress-sensitive catecholaminergic changes may exert regionally specific effects on PFC functioning (Aston-Jones and Cohen, 2005; Shin et al., 2005; Dolcos and McCarthy, 2006; Etkin and Wager, 2007), but at the same time have their opposite effects on neural processes in limbic…”

“…error of mean. an unbiased, anatomically defined, gray matter mask of the PFC covering the entire prefrontal areas, by using non-stationary suprathreshold cluster-size approach based on Monte-Carlo simulations (Forman et al., 1995; Ward, 2000; Nichols and Hayasaka, 2003; Hayasaka et al., 2004).”

“Such models assume that catecholaminergic activity exhibits an inverted U-shaped relationship with higherorder prefrontal cognitive function, and that optimal performance is reached at moderate levels of catecholamines (Arnsten and Li, 2005; Aston-Jones and Cohen, 2005; Arnsten, 2007, 2009).”

“Human neuroimaging studies consistently show that WMrelated activation of the dorsal frontoparietal “executive” network is accompanied by a reciprocal deactivation in regions comprising the “default mode” network (DMN), including the MTL and amygdala (Selemon and Goldman-Rakic, 1988; Dolcos and McCarthy, 2006; Esposit…”

“…believed to result from stress-induced alterations of large-scale brain network functioning including the prefrontal cortex (PFC), through stress-sensitive neuromodulatory systems (GoldmanRakic, 1995; Aston-Jones and Cohen, 2005; Arnsten, 2007, 2009; McEwen, 2007; Sara, 2009; Hermans et al., 2011).”

“Second, exposure to highly aversive films in combination with selfreferencing instruction meets the requirements for the physiological stress response in humans, particularly with activation of the sympatho-adrenomedullary system (SAM) and substantial elevation of epinephrine and norepinephrine levels, as described by…”

“The function of such a large-scale reallocation of neural resources (Bouret and Sara, 2005; Sara, 2009; Oei et al., 2011) may be to effectuate a hypervigilant brain state promoting rapid behavioral adaptation to adverse conditions at the cost of elaborative executive functions.”

“Moreover, we previously found detrimental effects of acute stress on activity in the dorsolateral PFC across an unselected female sample (Qin et al., 2009), but that study did not implement a crossover design (i.e., repeated testing) and may, therefore, have been slightly more stressful for the…”

“…stress-sensitive catecholaminergic changes may exert regionally specific effects on PFC functioning (Aston-Jones and Cohen, 2005; Shin et al., 2005; Dolcos and McCarthy, 2006; Etkin and Wager, 2007), but at the same time have their opposite effects on neural processes in limbic regions,…”

“After preparation outside the scanner, a numeric N-back WM task was administered twice: in one session it was embedded in a stressful context and the other one in a neutral control condition (see Stress induction for details).”

“The groups (COMT Met-homozygotes and Valcarriers) did not differ significantly regarding age (p > 0.1) and trait anxiety (p > 0.4) (see Table 1).”

“, 2008, 2009), particularly when high levels of cortisol and noradrenergic activity occurred concurrently (Elzinga and Roelofs, 2005; Schoofs et al., 2008).”

“Associations have been found in humans between COMT genotype and higher-order PFC functions and emotional processing in both health and disease (Drabant et al., 2006; Meyer-Lindenberg et al., 2006; Bishop et al., 2008).”

“A variation (Val158Met) in the gene encoding Catechol-O-methyltransferase (COMT) is associated with individual differences in basal catecholaminergic availability (Lotta et al., 1995; Mannisto and Kaakkola, 1999) and prefrontal functions (Chen et al., 2004).”

“The lack of a genotype effect on baseline WM performance may be attributed to a lack of sensitivity at a behavioral level (Meyer-Lindenberg and Weinberger, 2006).”

“…2005; Dolcos and McCarthy, 2006; Etkin and Wager, 2007), but at the same time have their opposite effects on neural processes in limbic regions, particularly the MTL and the amygdala (Coull et al., 2001; de Kloet et al., 2005; Chamberlain et al., 2006; Admon et al., 2009; van Marle et al., 2009).”

“…2005; Dolcos and McCarthy, 2006; Etkin and Wager, 2007), but at the same time have their opposite effects on neural processes in limbic regions, particularly the MTL and the amygdala (Coull et al., 2001; de Kloet et al., 2005; Chamberlain et al., 2006; Admon et al., 2009; van Marle et al., 2009).”

“…procedure in which participants saw strongly aversive (vs. neutral control) movie material combined with a self-referencing instruction, which has been shown previously to elicit physiological and psychological stress responses (Henckens et al., 2009; Qin et al., 2009; Hermans et al., 2011).”

“Interestingly, recent evidence from human and rodent studies suggests that COMT genotype may interact with catecholaminergic manipulations altering PFC function (Mattay et al., 2003; Bertolino et al., 2004; Papaleo et al., 2008).”

“…evidence from human behavioral and neuroimaging studies have confirmed that acute stress indeed alters WM performance with both detrimental (Elzinga and Roelofs, 2005; Oei et al., 2006; Luethi et al., 2008; Schoofs et al., 2008) and enhancing (Lewis et al., 2008; Weerda et al., 2010;…”

“…situations (i.e., higher levels of cortisol induced) has been found to result generally in detrimental effects on WM processing (Oei et al., 2006; Schoofs et al., 2008, 2009), particularly when high levels of cortisol and noradrenergic activity occurred concurrently (Elzinga and Roelofs, 2005;…”

“…2005; Dolcos and McCarthy, 2006; Etkin and Wager, 2007), but at the same time have their opposite effects on neural processes in limbic regions, particularly the MTL and the amygdala (Coull et al., 2001; de Kloet et al., 2005; Chamberlain et al., 2006; Admon et al., 2009; van Marle et al., 2009).”

“…activation of the dorsal frontoparietal “executive” network is accompanied by a reciprocal deactivation in regions comprising the “default mode” network (DMN), including the MTL and amygdala (Selemon and Goldman-Rakic, 1988; Dolcos and McCarthy, 2006; Esposito et al., 2006; Arnsten, 2009).”

“Interestingly, recent studies in behaving primates suggest that elevated levels of catecholamines under stress impair prefrontal functioning by excessive cAMP-HCN and phosphatidylinositol-protein kinase C (PKC) intracellular signaling pathways (Arnsten, 2007, 2009).”

“That is, our procedure indeed successfully induced a state characterized by hyperactivation of catecholaminergic systems and negative mood (Arnsten and Goldman-Rakic, 1998; Arnsten, 2009; Hermans et al., 2011; Shackman et al., 2011; Weymar et al., 2011).”

“The function of such a large-scale reallocation of neural resources (Bouret and Sara, 2005; Sara, 2009; Oei et al., 2011) may be to effectuate a hypervigilant brain state promoting rapid behavioral adaptation to adverse conditions at the cost of elaborative executive functions.”

“The analysis (Cousijn et al., 2010; Strahler et al., 2010) was carried out at the Biopsychology Department in Dresden, where samples were prepared for biochemical analysis by centrifuging at 1500 × g for 5 min, which resulted in a clear supernatant of low viscosity.”

“, 2011) effects, likely through altered efficiency of WM-related processing in dorsolateral PFC (Porcelli et al., 2008; Qin et al., 2009; Weerda et al., 2010).”

“Nevertheless, converging evidence from multiple elegant readout measurements in the present study as well as our previous studies, including increase in hear rate and cortisol, changes in pupil dilation responses (Henckens et al., 2009; Qin et al., 2012) and increase in α-amylase and amygdala perfusion (Cousijn et al.”

“That is, our procedure indeed successfully induced a state characterized by hyperactivation of catecholaminergic systems and negative mood (Arnsten and Goldman-Rakic, 1998; Arnsten, 2009; Hermans et al., 2011; Shackman et al., 2011; Weymar et al., 2011).”

“…including increase in hear rate and cortisol, changes in pupil dilation responses (Henckens et al., 2009; Qin et al., 2012) and increase in α-amylase and amygdala perfusion (Cousijn et al., 2010, 2012), firmly promote the conclusion that our emotion focused stress induction procedure was effective.”

“…alters WM performance with both detrimental (Elzinga and Roelofs, 2005; Oei et al., 2006; Luethi et al., 2008; Schoofs et al., 2008) and enhancing (Lewis et al., 2008; Weerda et al., 2010; Hidalgo et al., 2011) effects, likely through altered efficiency of WM-related processing in dorsolateral…”

“…(Elzinga and Roelofs, 2005; Oei et al., 2006; Luethi et al., 2008; Schoofs et al., 2008) and enhancing (Lewis et al., 2008; Weerda et al., 2010; Hidalgo et al., 2011) effects, likely through altered efficiency of WM-related processing in dorsolateral PFC (Porcelli et al., 2008; Qin et al.,…”

“That is, our procedure indeed successfully induced a state characterized by hyperactivation of catecholaminergic systems and negative mood (Arnsten and Goldman-Rakic, 1998; Arnsten, 2009; Hermans et al., 2011; Shackman et al., 2011; Weymar et al., 2011).”

“acute stress, Met homozygotes show impairments in working memory performance and reduced PFC activation, while Val carriers show the opposite effects (101; 102).”

“, oxytocin and testosterone [79]), and genetic variants influencing catecholaminergic and executive function [80].”

“, during stress, impairing dlPFC functions [256].”

“Also, combined behavioral-genetics (e.g., Jasinska et al., 2012a) and imaging-genetics investigations (Bishop et al., 2006; Morey et al., 2011; Qin et al., 2012) have highlighted the role of genetic differences in the response to emotional challenge.”

“The subjects with met/met genotype had impaired performance on a numerical N-back working memory task and reduced fMRI BOLD response in dlPFC after exposure to upsetting imagery, consistent with high levels of DA suppressing dlPFC neuronal firing during stress (Qin et al., 2012).”

“…Dodson, 1908) in that impairments in executive control and decreased responsiveness within executive control network regions occur at suboptimal and supraoptimal arousal levels, such as mental fatigue (Ishii et al., 2015) and stress (Qin et al., 2009; 2012; McMenamin et al., 2014), respectively.”

“stressful situations (Qin et al., 2012).”

“This state-change of brain processing has previously been attributed to the actions of catecholamines on brain function (Arnsten and Li, 2005; Hermans et al., 2011; Qin et al., 2012).”

“For example, exposure to violent images impairs performance of a working memory task and reduces the activity of the dlPFC in humans [83], and the degree of impairment is related to COMT genotype, with greater catecholamines associated with greater dlPFC dysfunction [84].”

“, 2004) and humans (Qin et al., 2012), which may help to explain the greater prevalence of PTSD and depression in”

“that is related to elevated catecholamines (Qin et al., 2012).”

“…PFC activation during N-back Val carriers show blunted activation during control and elevated activation following stress 41 (within subject design) Qin et al, 2012 NPSR1 rs324981 Acute psychosocial stress and urban upbringing Amygdala and ACC activation during stress T/T: positive association…”

“This design has been proved effective and robust by previous studies (Egan et al., 2003; Hur et al., 2017; Owen et al., 2005; Qin et al., 2012, 2009), which allows us to further test the proactive effects of the CAR on prefrontal and hippocampal functional organization during WM task.”

“…recent evidence suggested that a stress-related increase in prefrontal dopamine exerted differential effects on prefrontal functioning depending on the genetically determined baseline dopamine level in the prefrontal cortex (Buckert, Kudielka, Reuter, & Fiebach, 2012; Qin et al., 2012).”

“…studies using stressors such as aversive videos produce lower cortisol elevations (i.e., milder stress responses) than other validated laboratory stressors (i.e., TSST, MAST; e.g., Qin et al., 2012), if they produce a cortisol response at all (e.g., Peterson et al., 2014; Wittling & Pflüger, 1990).”

“, 2009) as well as (to a more limited extent) with humans (Mattay, Goldberg, Fera, Hariri, Tessitore, Egan, & Weinberger, 2003; Lupien, Gillin, & Hauger, 1999; Qin et al., 2012) indicates that moderate, time-limited increase in catecholamines, norepinephrine and dopamine, and in the glucocorticoid hormone cortisol is…”

“The modulation pattern of the COMT genotype on stress-induced activation was found to be an inverted U-shape in the dorsolateral PFC but U-shaped modulation was observed in the medial temporal lobe during working memory processing [49].”

“…stress was associated with less middle temporal lobe deactivation in one study e where there was also poorer performance in the stressed group (Qin et al., 2012), but the other study reported decreased middle temporal lobe activity, but only during the maintenance phase e with no relationship…”

“More severe mild stress has been found to impair COMT-Mets and help no one (COMT-Vals showed no benefit from stress; Buckert et al. 2012; Qin et al. 2012).”

“Specifically, studies demonstrate that increased catecholamine availability, as with the presence of the Met allele in Val158Met, is associated with greater executive cognitive ability when resting catecholamine levels are low, but with reduced executive cognitive ability when pretask levels are high (Mattay et al., 2…”

“stress on working memory-related activity were identified (MNI coordinates: x1⁄4 30, y1⁄4 30, z1⁄4 42) (Qin et al., 2012).”

“It has been reported that Brodmann’s area 46 as well as in insula controls higher brain functions including the stresssensitive neuromodulatory systems, which, in turn, control sympathoadrenal and hypothalamic-pituitary-adrenal activity [24-26].”

“Consistent with the nonlinear relationship between the dopamine levels and neuronal activity (Bertolino et al., 2009; Qin et al., 2012; Seamans & Yang, 2004; Williams & Goldman-Rakic, 1995), the effect of dopamine levels on structure and function of the brain has been commonly described as an…”

“…consistent with those of human experiments indicating that the impairing effects of stress induction on working memory are usually observed within a time window in which both glucocorticoid and noradrenergic activity are elevated (Elzinga and Roelofs, 2005; Schoofs et al., 2008; Qin et al., 2012).”

“pattern (Williams and Goldman-Rakic 1995; Goldman-Rakic 1998), in which both the lowest and the highest dopamine levels may impair behavioral performance (Giakoumaki et al. 2008; Qin et al. 2012; Fallon et al. 2013).”

“The clip content of the present study closely resembled that used in previous research (G ¨ artner et al., 2014; Qin et al., 2012).”

“Dysfunctional higher-order functions following acute stress [8, 68] weaken error monitoring and impair post-error adjustment.”

“23,24 Healthy individuals with a less active COMT variant (permitting more DA signaling) perform worse on WM tests in response to stressful situations compared with individuals with a highly active COMT variant (that more rapidly clears DA).”

“Accumulating evidence suggests that PFC activity is altered following exposure to stress and both reduced PFC activity (Vijayraghavan et al., 2007; Qin et al., 2009; Qin et al., 2012) and enhanced PFC activity (Grimm et al.”