The nature of immature reward processing and the influence of rewards on basic elements of cognit... more The nature of immature reward processing and the influence of rewards on basic elements of cognitive control during adolescence are currently not well understood. Here, during functional magnetic resonance imaging, healthy adolescents and adults performed a modified antisaccade task in which trial-by-trial reward contingencies were manipulated. The use of a novel fast, event-related design enabled developmental differences in brain function underlying temporally distinct stages of reward processing and response inhibition to be assessed. Reward trials compared with neutral trials resulted in faster correct inhibitory responses across ages and in fewer inhibitory errors in adolescents. During reward trials, the blood oxygen level--dependent signal was attenuated in the ventral striatum in adolescents during cue assessment, then overactive during response preparation, suggesting limitations during adolescence in reward assessment and heightened re-activity in anticipation of reward co...
Of Mice and Men Just how closely must mouse models replicate the known features of human disorder... more Of Mice and Men Just how closely must mouse models replicate the known features of human disorders to be accepted as useful for mechanistic and therapeutic studies? Soliman et al. (p. 863 , published online 14 January) compared mice that vary only in their allelic composition at one position within the gene encoding brain-derived neurotrophic factor (BDNF) with humans exhibiting the same range of allelic variation. Individuals (mice and humans) carrying the allele that codes for a methionine-containing variant of BDNF retained a fearful response to a threatening stimulus even after its removal in comparison to those with the valine variant. Furthermore, in both cases, this linkage was mediated by diminished activity in the ventral-medial region of the prefrontal cortex. This deficit in extinction learning may contribute to differential responses to extinction-based therapies for anxiety disorders.
The ability to exert self-control in the face of appetitive, alluring cues is a critical componen... more The ability to exert self-control in the face of appetitive, alluring cues is a critical component of healthy development. The development of behavioral measures that use disease-relevant stimuli can greatly improve our understanding of cue-specific impairments in self-control. To produce such a tool relevant to the study of eating and weight disorders, we modified the traditional go/no-go task to include food and non-food targets. To confirm that performance on this new task was consistent with other go/no-go tasks, it was given to 147 healthy, normal weight volunteers between the ages of 5 and 30. Highresolution photos of food or toys were used as the target and nontarget stimuli. Consistent with expectations, overall improvements in accuracy were seen from childhood to adulthood. Participants responded more quickly and made more commission errors to food cues compared to nonfood cues (F (1,140)¼ 21.76, P o0.001), although no behavioral differences were seen between low-and high-calorie food cues for this non-obese, healthy developmental sample. This novel food-specific go/no-go task may be used to track the development of self-control in the context of food cues and to evaluate deviations or deficits in the development of this ability in individuals at risk for eating problem behaviors and disorders.
Viral infection triggers a cascade of interferon response genes, but the mechanisms that prime su... more Viral infection triggers a cascade of interferon response genes, but the mechanisms that prime such innate antiviral defenses are poorly understood. Among candidate cellular mediators of the antiviral response are the double-stranded RNA (dsRNA)-binding proteins. Here we show that a C-terminal variant of the ubiquitous dsRNA-binding protein, nuclear factor 90 (NF90ctv), can activate the interferon response genes in the absence of viral infection. NF90ctv-expressing cells were infected with the syncytium-inducing HIV-1 strain NL4-3 and were shown to inhibit viral replication. To gain insight into this mechanism of protection, we analyzed the expression profiles of NF90ctv-positive cells as compared with parental cells transduced with the empty vector. Of the 5600 genes represented on the expression arrays, 90 displayed significant (4-fold or more) changes in mRNA levels in NF90-expressing cells. About 50% are known interferon alpha/beta-stimulated genes. The microarray expression data were confirmed by quantitative reverse transcriptase-polymerase chain reaction analysis of six representative interferon-inducible genes. Electrophoretic mobility shift assays showed that the biological response is mediated by the activation of transcription factors in NF90ctv-expressing cells. Functional significance of the activated transcription complex was evaluated by transfection assays with luciferase reporter constructs driven by the interferon-inducible promoter from the 2'-5'-oligoadenylate synthetase (p69) gene. Resistance to HIV-1, caused by the expression of NF90ctv in the cell culture system, appears to be mediated in part by the induction of interferon response genes. This leads to a hypothesis as to the mechanism of action of NF90 in mediating endogenous antiviral responses.
Adolescent decision-making has been described as impulsive and suboptimal in the presence of ince... more Adolescent decision-making has been described as impulsive and suboptimal in the presence of incentives. In this study we examined the neural substrates of adolescent decision-making using a perceptual discrimination task for which small and large rewards were associated with correctly detecting the direction of motion of a cloud of moving dots. Adults showed a reward bias of faster reaction times on trials for which the direction of motion was associated with a large reward. Adolescents, in contrast, were slower to make decisions on trials associated with large rewards. This behavioral pattern in adolescents was paralleled by greater recruitment of fronto-parietal regions important in representing the accumulation of evidence sufficient for selecting one choice over its alternative and the certainty of that choice. The findings suggest that when large incentives are dependent on performance, adolescents may require more evidence to accumulate prior to responding, to be certain to maximize their gains. Adults, in contrast, appear to be quicker in evaluating the evidence for a decision when primed by rewards. Overall these findings suggest that rather than reacting hastily, adolescents can be incentivized to take more time to make decisions when large rewards are at stake.
Tracking the hemodynamic responses to reward and punishment in the striatum. J Neurophysiol 84: 3... more Tracking the hemodynamic responses to reward and punishment in the striatum. J Neurophysiol 84: 3072-3077, 2000. Research suggests that the basal ganglia complex is a major component of the neural circuitry that mediates reward-related processing. However, human studies have not yet characterized the response of the basal ganglia to an isolated reward, as has been done in animals. We developed an event-related functional magnetic resonance imaging paradigm to identify brain areas that are activated after presentation of a reward. Subjects guessed whether the value of a card was higher or lower than the number 5, with monetary rewards as an incentive for correct guesses. They received reward, punishment, or neutral feedback on different trials. Regions in the dorsal and ventral striatum were activated by the paradigm, showing differential responses to reward and punishment. Activation was sustained following a reward feedback, but decreased below baseline following a punishment feedback.
ity to prepare an action in advance allows us to respond to our environment quickly, accurately, ... more ity to prepare an action in advance allows us to respond to our environment quickly, accurately, and flexibly. Here, we used eventrelated functional MRI to measure human brain activity while subjects maintained an active state of preparedness. At the beginning of each trial, subjects were instructed to prepare a pro-or antisaccade to a visual cue that was continually present during a long and variable preparation interval, but to defer the saccade's execution until a go signal. The deferred saccade task eliminated the mnemonic component inherent in memory-guided saccade tasks and placed the emphasis entirely on advance motor preparation. During the delay while subjects were in an active state of motor preparedness, the blood oxygen level-dependent signal in the frontal cortex showed 1) a sustained elevation throughout the preparation interval; 2) a linear increase with increasing delay length; 3) a bias for contra-rather than ipsiversive movements; 4) greater activity when the specific metrics of the planned saccade were known compared with when they were not; and 5) increased activity when the saccade was directed toward an internal versus an external representation (i.e., anticue location). These findings support the hypothesis that both the human frontal and parietal cortices are involved in the spatial selection and preparation of saccades.
ity to prepare an action in advance allows us to respond to our environment quickly, accurately, ... more ity to prepare an action in advance allows us to respond to our environment quickly, accurately, and flexibly. Here, we used eventrelated functional MRI to measure human brain activity while subjects maintained an active state of preparedness. At the beginning of each trial, subjects were instructed to prepare a pro-or antisaccade to a visual cue that was continually present during a long and variable preparation interval, but to defer the saccade's execution until a go signal. The deferred saccade task eliminated the mnemonic component inherent in memory-guided saccade tasks and placed the emphasis entirely on advance motor preparation. During the delay while subjects were in an active state of motor preparedness, the blood oxygen level-dependent signal in the frontal cortex showed 1) a sustained elevation throughout the preparation interval; 2) a linear increase with increasing delay length; 3) a bias for contra-rather than ipsiversive movements; 4) greater activity when the specific metrics of the planned saccade were known compared with when they were not; and 5) increased activity when the saccade was directed toward an internal versus an external representation (i.e., anticue location). These findings support the hypothesis that both the human frontal and parietal cortices are involved in the spatial selection and preparation of saccades.
In the 1960s, Mischel and colleagues developed a simple marshmallow test to measure preschoolers ... more In the 1960s, Mischel and colleagues developed a simple marshmallow test to measure preschoolers ability to delay gratification. In numerous follow-up studies over 40 years, this test proved to have surprisingly significant predictive validity for consequential social, cognitive and mental health outcomes over the life course. In this article, we review key findings from the longitudinal work and from earlier delay-of-gratification experiments examining the cognitive appraisal and attention control strategies that underlie this ability. Further, we outline a set of hypotheses that emerge from the intersection of these findings with research on cognitive control mechanisms and their neural bases. We discuss implications of these hypotheses for decomposing the phenomena of willpower and the lifelong individual differences in self-regulatory ability that were identified in the earlier research and that are currently being pursued.
Proceedings of the National Academy of Sciences, 2011
We examined the neural basis of self-regulation in individuals from a cohort of preschoolers who ... more We examined the neural basis of self-regulation in individuals from a cohort of preschoolers who performed the delay-ofgratification task 4 decades ago. Nearly 60 individuals, now in their mid-forties, were tested on "hot" and "cool" versions of a go/ nogo task to assess whether delay of gratification in childhood predicts impulse control abilities and sensitivity to alluring cues (happy faces). Individuals who were less able to delay gratification in preschool and consistently showed low self-control abilities in their twenties and thirties performed more poorly than did high delayers when having to suppress a response to a happy face but not to a neutral or fearful face. This finding suggests that sensitivity to environmental hot cues plays a significant role in individuals' ability to suppress actions toward such stimuli. A subset of these participants (n = 26) underwent functional imaging for the first time to test for biased recruitment of frontostriatal circuitry when required to suppress responses to alluring cues. Whereas the prefrontal cortex differentiated between nogo and go trials to a greater extent in high delayers, the ventral striatum showed exaggerated recruitment in low delayers. Thus, resistance to temptation as measured originally by the delay-of-gratification task is a relatively stable individual difference that predicts reliable biases in frontostriatal circuitries that integrate motivational and control processes.
The nature of immature reward processing and the influence of rewards on basic elements of cognit... more The nature of immature reward processing and the influence of rewards on basic elements of cognitive control during adolescence are currently not well understood. Here, during functional magnetic resonance imaging, healthy adolescents and adults performed a modified antisaccade task in which trial-by-trial reward contingencies were manipulated. The use of a novel fast, eventrelated design enabled developmental differences in brain function underlying temporally distinct stages of reward processing and response inhibition to be assessed. Reward trials compared with neutral trials resulted in faster correct inhibitory responses across ages and in fewer inhibitory errors in adolescents. During reward trials, the blood oxygen level--dependent signal was attenuated in the ventral striatum in adolescents during cue assessment, then overactive during response preparation, suggesting limitations during adolescence in reward assessment and heightened reactivity in anticipation of reward compared with adults. Importantly, heightened activity in the frontal cortex along the precentral sulcus was also observed in adolescents during reward-trial response preparation, suggesting reward modulation of oculomotor control regions supporting correct inhibitory responding. Collectively, this work characterizes specific immaturities in adolescent brain systems that support reward processing and describes the influence of reward on inhibitory control. In sum, our findings suggest mechanisms that may underlie adolescents' vulnerability to poor decision-making and risk-taking behavior.
identical MIS 5e/5a relative sea-level histories of tectonically stable Bermuda and Mallorca. The... more identical MIS 5e/5a relative sea-level histories of tectonically stable Bermuda and Mallorca. The very rapid onset and relatively brief nature of the MIS 5a highstand may have plausibly generated lags between the timing of sea-level changes and the timing of coral reef growth, and may provide a partial explanation as to why reefs on Barbados and New Guinea do not record a comparable eustatic height for this event. This and other factors that could be part of the apparent discrepancy are discussed in (9).
The nature of immature reward processing and the influence of rewards on basic elements of cognit... more The nature of immature reward processing and the influence of rewards on basic elements of cognitive control during adolescence are currently not well understood. Here, during functional magnetic resonance imaging, healthy adolescents and adults performed a modified antisaccade task in which trial-by-trial reward contingencies were manipulated. The use of a novel fast, event-related design enabled developmental differences in brain function underlying temporally distinct stages of reward processing and response inhibition to be assessed. Reward trials compared with neutral trials resulted in faster correct inhibitory responses across ages and in fewer inhibitory errors in adolescents. During reward trials, the blood oxygen level--dependent signal was attenuated in the ventral striatum in adolescents during cue assessment, then overactive during response preparation, suggesting limitations during adolescence in reward assessment and heightened re-activity in anticipation of reward co...
Of Mice and Men Just how closely must mouse models replicate the known features of human disorder... more Of Mice and Men Just how closely must mouse models replicate the known features of human disorders to be accepted as useful for mechanistic and therapeutic studies? Soliman et al. (p. 863 , published online 14 January) compared mice that vary only in their allelic composition at one position within the gene encoding brain-derived neurotrophic factor (BDNF) with humans exhibiting the same range of allelic variation. Individuals (mice and humans) carrying the allele that codes for a methionine-containing variant of BDNF retained a fearful response to a threatening stimulus even after its removal in comparison to those with the valine variant. Furthermore, in both cases, this linkage was mediated by diminished activity in the ventral-medial region of the prefrontal cortex. This deficit in extinction learning may contribute to differential responses to extinction-based therapies for anxiety disorders.
The ability to exert self-control in the face of appetitive, alluring cues is a critical componen... more The ability to exert self-control in the face of appetitive, alluring cues is a critical component of healthy development. The development of behavioral measures that use disease-relevant stimuli can greatly improve our understanding of cue-specific impairments in self-control. To produce such a tool relevant to the study of eating and weight disorders, we modified the traditional go/no-go task to include food and non-food targets. To confirm that performance on this new task was consistent with other go/no-go tasks, it was given to 147 healthy, normal weight volunteers between the ages of 5 and 30. Highresolution photos of food or toys were used as the target and nontarget stimuli. Consistent with expectations, overall improvements in accuracy were seen from childhood to adulthood. Participants responded more quickly and made more commission errors to food cues compared to nonfood cues (F (1,140)¼ 21.76, P o0.001), although no behavioral differences were seen between low-and high-calorie food cues for this non-obese, healthy developmental sample. This novel food-specific go/no-go task may be used to track the development of self-control in the context of food cues and to evaluate deviations or deficits in the development of this ability in individuals at risk for eating problem behaviors and disorders.
Viral infection triggers a cascade of interferon response genes, but the mechanisms that prime su... more Viral infection triggers a cascade of interferon response genes, but the mechanisms that prime such innate antiviral defenses are poorly understood. Among candidate cellular mediators of the antiviral response are the double-stranded RNA (dsRNA)-binding proteins. Here we show that a C-terminal variant of the ubiquitous dsRNA-binding protein, nuclear factor 90 (NF90ctv), can activate the interferon response genes in the absence of viral infection. NF90ctv-expressing cells were infected with the syncytium-inducing HIV-1 strain NL4-3 and were shown to inhibit viral replication. To gain insight into this mechanism of protection, we analyzed the expression profiles of NF90ctv-positive cells as compared with parental cells transduced with the empty vector. Of the 5600 genes represented on the expression arrays, 90 displayed significant (4-fold or more) changes in mRNA levels in NF90-expressing cells. About 50% are known interferon alpha/beta-stimulated genes. The microarray expression data were confirmed by quantitative reverse transcriptase-polymerase chain reaction analysis of six representative interferon-inducible genes. Electrophoretic mobility shift assays showed that the biological response is mediated by the activation of transcription factors in NF90ctv-expressing cells. Functional significance of the activated transcription complex was evaluated by transfection assays with luciferase reporter constructs driven by the interferon-inducible promoter from the 2'-5'-oligoadenylate synthetase (p69) gene. Resistance to HIV-1, caused by the expression of NF90ctv in the cell culture system, appears to be mediated in part by the induction of interferon response genes. This leads to a hypothesis as to the mechanism of action of NF90 in mediating endogenous antiviral responses.
Adolescent decision-making has been described as impulsive and suboptimal in the presence of ince... more Adolescent decision-making has been described as impulsive and suboptimal in the presence of incentives. In this study we examined the neural substrates of adolescent decision-making using a perceptual discrimination task for which small and large rewards were associated with correctly detecting the direction of motion of a cloud of moving dots. Adults showed a reward bias of faster reaction times on trials for which the direction of motion was associated with a large reward. Adolescents, in contrast, were slower to make decisions on trials associated with large rewards. This behavioral pattern in adolescents was paralleled by greater recruitment of fronto-parietal regions important in representing the accumulation of evidence sufficient for selecting one choice over its alternative and the certainty of that choice. The findings suggest that when large incentives are dependent on performance, adolescents may require more evidence to accumulate prior to responding, to be certain to maximize their gains. Adults, in contrast, appear to be quicker in evaluating the evidence for a decision when primed by rewards. Overall these findings suggest that rather than reacting hastily, adolescents can be incentivized to take more time to make decisions when large rewards are at stake.
Tracking the hemodynamic responses to reward and punishment in the striatum. J Neurophysiol 84: 3... more Tracking the hemodynamic responses to reward and punishment in the striatum. J Neurophysiol 84: 3072-3077, 2000. Research suggests that the basal ganglia complex is a major component of the neural circuitry that mediates reward-related processing. However, human studies have not yet characterized the response of the basal ganglia to an isolated reward, as has been done in animals. We developed an event-related functional magnetic resonance imaging paradigm to identify brain areas that are activated after presentation of a reward. Subjects guessed whether the value of a card was higher or lower than the number 5, with monetary rewards as an incentive for correct guesses. They received reward, punishment, or neutral feedback on different trials. Regions in the dorsal and ventral striatum were activated by the paradigm, showing differential responses to reward and punishment. Activation was sustained following a reward feedback, but decreased below baseline following a punishment feedback.
ity to prepare an action in advance allows us to respond to our environment quickly, accurately, ... more ity to prepare an action in advance allows us to respond to our environment quickly, accurately, and flexibly. Here, we used eventrelated functional MRI to measure human brain activity while subjects maintained an active state of preparedness. At the beginning of each trial, subjects were instructed to prepare a pro-or antisaccade to a visual cue that was continually present during a long and variable preparation interval, but to defer the saccade's execution until a go signal. The deferred saccade task eliminated the mnemonic component inherent in memory-guided saccade tasks and placed the emphasis entirely on advance motor preparation. During the delay while subjects were in an active state of motor preparedness, the blood oxygen level-dependent signal in the frontal cortex showed 1) a sustained elevation throughout the preparation interval; 2) a linear increase with increasing delay length; 3) a bias for contra-rather than ipsiversive movements; 4) greater activity when the specific metrics of the planned saccade were known compared with when they were not; and 5) increased activity when the saccade was directed toward an internal versus an external representation (i.e., anticue location). These findings support the hypothesis that both the human frontal and parietal cortices are involved in the spatial selection and preparation of saccades.
ity to prepare an action in advance allows us to respond to our environment quickly, accurately, ... more ity to prepare an action in advance allows us to respond to our environment quickly, accurately, and flexibly. Here, we used eventrelated functional MRI to measure human brain activity while subjects maintained an active state of preparedness. At the beginning of each trial, subjects were instructed to prepare a pro-or antisaccade to a visual cue that was continually present during a long and variable preparation interval, but to defer the saccade's execution until a go signal. The deferred saccade task eliminated the mnemonic component inherent in memory-guided saccade tasks and placed the emphasis entirely on advance motor preparation. During the delay while subjects were in an active state of motor preparedness, the blood oxygen level-dependent signal in the frontal cortex showed 1) a sustained elevation throughout the preparation interval; 2) a linear increase with increasing delay length; 3) a bias for contra-rather than ipsiversive movements; 4) greater activity when the specific metrics of the planned saccade were known compared with when they were not; and 5) increased activity when the saccade was directed toward an internal versus an external representation (i.e., anticue location). These findings support the hypothesis that both the human frontal and parietal cortices are involved in the spatial selection and preparation of saccades.
In the 1960s, Mischel and colleagues developed a simple marshmallow test to measure preschoolers ... more In the 1960s, Mischel and colleagues developed a simple marshmallow test to measure preschoolers ability to delay gratification. In numerous follow-up studies over 40 years, this test proved to have surprisingly significant predictive validity for consequential social, cognitive and mental health outcomes over the life course. In this article, we review key findings from the longitudinal work and from earlier delay-of-gratification experiments examining the cognitive appraisal and attention control strategies that underlie this ability. Further, we outline a set of hypotheses that emerge from the intersection of these findings with research on cognitive control mechanisms and their neural bases. We discuss implications of these hypotheses for decomposing the phenomena of willpower and the lifelong individual differences in self-regulatory ability that were identified in the earlier research and that are currently being pursued.
Proceedings of the National Academy of Sciences, 2011
We examined the neural basis of self-regulation in individuals from a cohort of preschoolers who ... more We examined the neural basis of self-regulation in individuals from a cohort of preschoolers who performed the delay-ofgratification task 4 decades ago. Nearly 60 individuals, now in their mid-forties, were tested on "hot" and "cool" versions of a go/ nogo task to assess whether delay of gratification in childhood predicts impulse control abilities and sensitivity to alluring cues (happy faces). Individuals who were less able to delay gratification in preschool and consistently showed low self-control abilities in their twenties and thirties performed more poorly than did high delayers when having to suppress a response to a happy face but not to a neutral or fearful face. This finding suggests that sensitivity to environmental hot cues plays a significant role in individuals' ability to suppress actions toward such stimuli. A subset of these participants (n = 26) underwent functional imaging for the first time to test for biased recruitment of frontostriatal circuitry when required to suppress responses to alluring cues. Whereas the prefrontal cortex differentiated between nogo and go trials to a greater extent in high delayers, the ventral striatum showed exaggerated recruitment in low delayers. Thus, resistance to temptation as measured originally by the delay-of-gratification task is a relatively stable individual difference that predicts reliable biases in frontostriatal circuitries that integrate motivational and control processes.
The nature of immature reward processing and the influence of rewards on basic elements of cognit... more The nature of immature reward processing and the influence of rewards on basic elements of cognitive control during adolescence are currently not well understood. Here, during functional magnetic resonance imaging, healthy adolescents and adults performed a modified antisaccade task in which trial-by-trial reward contingencies were manipulated. The use of a novel fast, eventrelated design enabled developmental differences in brain function underlying temporally distinct stages of reward processing and response inhibition to be assessed. Reward trials compared with neutral trials resulted in faster correct inhibitory responses across ages and in fewer inhibitory errors in adolescents. During reward trials, the blood oxygen level--dependent signal was attenuated in the ventral striatum in adolescents during cue assessment, then overactive during response preparation, suggesting limitations during adolescence in reward assessment and heightened reactivity in anticipation of reward compared with adults. Importantly, heightened activity in the frontal cortex along the precentral sulcus was also observed in adolescents during reward-trial response preparation, suggesting reward modulation of oculomotor control regions supporting correct inhibitory responding. Collectively, this work characterizes specific immaturities in adolescent brain systems that support reward processing and describes the influence of reward on inhibitory control. In sum, our findings suggest mechanisms that may underlie adolescents' vulnerability to poor decision-making and risk-taking behavior.
identical MIS 5e/5a relative sea-level histories of tectonically stable Bermuda and Mallorca. The... more identical MIS 5e/5a relative sea-level histories of tectonically stable Bermuda and Mallorca. The very rapid onset and relatively brief nature of the MIS 5a highstand may have plausibly generated lags between the timing of sea-level changes and the timing of coral reef growth, and may provide a partial explanation as to why reefs on Barbados and New Guinea do not record a comparable eustatic height for this event. This and other factors that could be part of the apparent discrepancy are discussed in (9).
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Papers by T. Teslovich