Anhedonia is not a unitary construct, but instead describes a broad deficit in reward processing,... more Anhedonia is not a unitary construct, but instead describes a broad deficit in reward processing, including, albeit not limited to, the diminished interest or pleasure in typically rewarding stimuli. The presence of these symptoms, be it in clinical or non-clinical samples, have been associated with dysfunctions subsuming the ventral striatum (VS), ventromedial prefrontal cortex (vmPFC) and orbitofrontal cortex (OFC, Der-Avakian and Markou, 2012; Keller et al., 2013). However, due to the complexities of anhedonia, the location and/or direction of frontostriatal abnormalities lacks consensus (see Borsini et al., 2020 for review; Keller et al., 2013; but see, Harvey et al., 2007), perhaps as a consequence, in part, to averaging brain signals across time. An alternative model, arising from the premise that affective states unfold over time (Davidson, 1998), is that anhedonia represents an inability to maintain, rather than instigate, responsiveness to positive information. Accordingly,...
Supplemental material, jop-2018-3438-File002 for Anhedonia and depression severity dissociated by... more Supplemental material, jop-2018-3438-File002 for Anhedonia and depression severity dissociated by dmPFC resting-state functional connectivity in adolescents by Ewelina Rzepa and Ciara McCabe in Journal of Psychopharmacology
Anorexia nervosa (AN) is an eating disorder characterised by severe emaciation due deliberate res... more Anorexia nervosa (AN) is an eating disorder characterised by severe emaciation due deliberate restriction of food intake and an intense fear of gaining weight. Theoretical accounts of AN have to date focused predominately on cognitive elements of the disorder, yet resulting treatments have been inadequate and outcome for AN remains poor. Understanding the processes that maintain the disorder is an important step in developing effective strategies to augment existing treatments. With this in mind, the question arises: what processes drive AN? Novel frameworks for AN suggest that particular information processing configurations or “modes” may underpin many symptoms of AN, such as preoccupation with control of eating, weight and shape. More specifically, it is proposed that a ruminative mode of processing may function as an avoidance strategy in AN, enabling individuals to neglect salient and rewarding stimuli, such as food, and thus uphold restrictive eating practices. Whilst empirical studies have examined processes such as rumination, avoidance and reward in depression, they have seldom been studied in AN. The aim of this thesis is therefore to understand the role of rumination and reward processes in AN. Chapter 1 reviews the literature on AN, rumination and reward processing. Chapter 2 presents data demonstrating to what extent the content of rumination in AN differs from rumination in depression and the effect that rumination may have on ED symptoms. The study conducted in Chapter 3 examines whether individuals with AN can be switched out of rumination around meal times and what effect this has on AN psychopathology. Chapter 4 presents neuroimaging data which elucidates the brain regions involved in processing rewarding and aversive food stimuli after recovery from AN. The study reported in Chapter 5 teases apart hedonic (liking) versus motivational (wanting) aspects of food reward in AN. The final study (Chapter 6) provides further evidence using neuroimaging that rumination may be an important process in AN which may override appetitive responses to rewarding stimuli, such as food. The studies reported support the notion that rumination and aberrant reward processing may be involved in the maintenance of AN.
Background: Anhedonia, a central depression symptom, is associated with impairments in reward pro... more Background: Anhedonia, a central depression symptom, is associated with impairments in reward processing. However how the sub-components of reward processing (anticipation, motivation, consummation and learning) are related to depression symptoms is not well understood. In particular, little is known about how effort cost and reward learning is related to anhedonia.Methods: We recruited young people with high (N=50) and low (N=88) depression symptoms and assessed their learning, consummatory, anticipatory, and motivational responses within an effort and reward learning task. To increase the reward attractiveness, especially for younger people, we included not only money (secondary reward), but also chocolate tastes and puppy images (primary rewards).Results: Across all participants, we found that self-reported willingness to exert effort positively correlated with actual effort exertion and negatively with effort completion times. We also observed higher accuracy for reward learning...
Recent evidence has shown that individuals with acute anorexia nervosa and those recovered have a... more Recent evidence has shown that individuals with acute anorexia nervosa and those recovered have aberrant physiological responses to rewarding stimuli. We hypothesized that women recovered from anorexia nervosa would show aberrant neural responses to both rewarding and aversive disorder-relevant stimuli. Using functional magnetic resonance imaging (fMRI), the neural response to the sight and flavor of chocolate, and their combination, in 15 women recovered from restricting-type anorexia nervosa and 16 healthy control subjects matched for age and body mass index was investigated. The neural response to a control aversive condition, consisting of the sight of moldy strawberries and a corresponding unpleasant taste, was also measured. Participants simultaneously recorded subjective ratings of "pleasantness," "intensity," and "wanting." Despite no differences between the groups in subjective ratings, individuals recovered from anorexia nervosa showed increased neural response to the pleasant chocolate taste in the ventral striatum and pleasant chocolate sight in the occipital cortex. The recovered participants also showed increased neural response to the aversive strawberry taste in the insula and putamen and to the aversive strawberry sight in the anterior cingulate cortex and caudate. Individuals recovered from anorexia nervosa have increased neural responses to both rewarding and aversive food stimuli. These findings suggest that even after recovery, women with anorexia nervosa have increased salience attribution to food stimuli. These results aid our neurobiological understanding and support the view that the neural response to reward may constitute a neural biomarker for anorexia nervosa.
Several recent studies have shown that reducing gamma-aminobutyric acid (GABA)-mediated neurotran... more Several recent studies have shown that reducing gamma-aminobutyric acid (GABA)-mediated neurotransmission retards extinction of aversive conditioning. However, relatively little is known about the effect of GABA on extinction of appetitively motivated tasks. We examined the effect of chlordiazepoxide (CDP), a classical benzodiazepine (BZ) and two novel subtype-selective BZs when administered to male C57Bl/6 mice during extinction following training on a discrete-trial fixed-ratio 5 (FR5) food reinforced lever-press procedure. Initially CDP had no effect, but after several extinction sessions CDP significantly facilitated extinction, i.e. slowed responding, compared with vehicle-treated mice. This effect was not due to drug accumulation because mice switched from vehicle treatment to CDP late in extinction showed facilitation immediately. Likewise, this effect could not be attributed to sedation because the dose of CDP used (15 mg/kg i.p.) did not suppress locomotor activity. The two novel subtype-selective BZ partial agonists, L-838417 and TP13, selectively facilitated extinction in similar fashion to CDP. The non-GABAergic anxiolytic buspirone was also tested and found to have similar effects when administered at a non-sedating dose. These studies demonstrate that GABA-mediated processes are important during extinction of an appetitively motivated task, but only after the animals have experienced several extinction sessions.
Drugs that alter brain serotonin (5-HT) function can modulate the behavioral effects of cocaine, ... more Drugs that alter brain serotonin (5-HT) function can modulate the behavioral effects of cocaine, but the underlying receptor mechanisms are poorly understood. The present study examined the effects of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.01-0.1 mg/kg, i.v.) on cocaine self-administration in the context of a choice procedure. Five adult male cynomolgus monkeys self-administered cocaine (saline, 0.003-0.03 mg/kg per injection) under a concurrent fixed-ratio 50 schedule of food (1-g banana-flavored pellets) and cocaine presentation. Allocation of responses to the cocaine-associated lever (cocaine choice) increased in a dose-related manner from < or =20% of total responses when saline or 0.003 mg/kg per injection cocaine was the alternative to food to > or =75% when 0.03 mg/kg per injection cocaine was available. In four of five monkeys, when choice was between a low cocaine dose and food, 0.01 mg/kg 8-OH-DPAT increased injection-lever responding. At cocaine doses which occasioned > or =75% cocaine choice, 8-OH-DPAT did not alter response allocation. In the fifth monkey, 8-OH-DPAT only decreased injection-lever responding. When choice was between saline and food, 8-OH-DPAT did not reliably shift responding to the injection lever, except at doses that disrupted operant performance. These results suggest that a 5-HT1A receptor agonist can increase the reinforcing strength of a low cocaine dose relative to a concurrently available non-drug reinforcer.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 25, 2014
Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as... more Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders. We previously showed that the cannabis receptor subtype (CB1) inverse agonist rimonabant, an antiobesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses (Horder et al., 2010). Unlike rimonabant, tetrahydrocannabivarin is a neutral CB1 receptor antagonist (Pertwee, 2005) and may therefore produce different modulations of the neural reward system. We hypothesized that tetrahydrocannabivarin would, unlike rimonabant, leave intact neural reward responses but augment aversive responses. We used a within-subject, double-blind design. Twenty healthy volunteers received a single dose of tetrahydrocannabivarin (10mg) and placebo in randomized order on 2 separate occasions. We measured the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (picture of moldy strawbe...
Anhedonia is not a unitary construct, but instead describes a broad deficit in reward processing,... more Anhedonia is not a unitary construct, but instead describes a broad deficit in reward processing, including, albeit not limited to, the diminished interest or pleasure in typically rewarding stimuli. The presence of these symptoms, be it in clinical or non-clinical samples, have been associated with dysfunctions subsuming the ventral striatum (VS), ventromedial prefrontal cortex (vmPFC) and orbitofrontal cortex (OFC, Der-Avakian and Markou, 2012; Keller et al., 2013). However, due to the complexities of anhedonia, the location and/or direction of frontostriatal abnormalities lacks consensus (see Borsini et al., 2020 for review; Keller et al., 2013; but see, Harvey et al., 2007), perhaps as a consequence, in part, to averaging brain signals across time. An alternative model, arising from the premise that affective states unfold over time (Davidson, 1998), is that anhedonia represents an inability to maintain, rather than instigate, responsiveness to positive information. Accordingly,...
Supplemental material, jop-2018-3438-File002 for Anhedonia and depression severity dissociated by... more Supplemental material, jop-2018-3438-File002 for Anhedonia and depression severity dissociated by dmPFC resting-state functional connectivity in adolescents by Ewelina Rzepa and Ciara McCabe in Journal of Psychopharmacology
Anorexia nervosa (AN) is an eating disorder characterised by severe emaciation due deliberate res... more Anorexia nervosa (AN) is an eating disorder characterised by severe emaciation due deliberate restriction of food intake and an intense fear of gaining weight. Theoretical accounts of AN have to date focused predominately on cognitive elements of the disorder, yet resulting treatments have been inadequate and outcome for AN remains poor. Understanding the processes that maintain the disorder is an important step in developing effective strategies to augment existing treatments. With this in mind, the question arises: what processes drive AN? Novel frameworks for AN suggest that particular information processing configurations or “modes” may underpin many symptoms of AN, such as preoccupation with control of eating, weight and shape. More specifically, it is proposed that a ruminative mode of processing may function as an avoidance strategy in AN, enabling individuals to neglect salient and rewarding stimuli, such as food, and thus uphold restrictive eating practices. Whilst empirical studies have examined processes such as rumination, avoidance and reward in depression, they have seldom been studied in AN. The aim of this thesis is therefore to understand the role of rumination and reward processes in AN. Chapter 1 reviews the literature on AN, rumination and reward processing. Chapter 2 presents data demonstrating to what extent the content of rumination in AN differs from rumination in depression and the effect that rumination may have on ED symptoms. The study conducted in Chapter 3 examines whether individuals with AN can be switched out of rumination around meal times and what effect this has on AN psychopathology. Chapter 4 presents neuroimaging data which elucidates the brain regions involved in processing rewarding and aversive food stimuli after recovery from AN. The study reported in Chapter 5 teases apart hedonic (liking) versus motivational (wanting) aspects of food reward in AN. The final study (Chapter 6) provides further evidence using neuroimaging that rumination may be an important process in AN which may override appetitive responses to rewarding stimuli, such as food. The studies reported support the notion that rumination and aberrant reward processing may be involved in the maintenance of AN.
Background: Anhedonia, a central depression symptom, is associated with impairments in reward pro... more Background: Anhedonia, a central depression symptom, is associated with impairments in reward processing. However how the sub-components of reward processing (anticipation, motivation, consummation and learning) are related to depression symptoms is not well understood. In particular, little is known about how effort cost and reward learning is related to anhedonia.Methods: We recruited young people with high (N=50) and low (N=88) depression symptoms and assessed their learning, consummatory, anticipatory, and motivational responses within an effort and reward learning task. To increase the reward attractiveness, especially for younger people, we included not only money (secondary reward), but also chocolate tastes and puppy images (primary rewards).Results: Across all participants, we found that self-reported willingness to exert effort positively correlated with actual effort exertion and negatively with effort completion times. We also observed higher accuracy for reward learning...
Recent evidence has shown that individuals with acute anorexia nervosa and those recovered have a... more Recent evidence has shown that individuals with acute anorexia nervosa and those recovered have aberrant physiological responses to rewarding stimuli. We hypothesized that women recovered from anorexia nervosa would show aberrant neural responses to both rewarding and aversive disorder-relevant stimuli. Using functional magnetic resonance imaging (fMRI), the neural response to the sight and flavor of chocolate, and their combination, in 15 women recovered from restricting-type anorexia nervosa and 16 healthy control subjects matched for age and body mass index was investigated. The neural response to a control aversive condition, consisting of the sight of moldy strawberries and a corresponding unpleasant taste, was also measured. Participants simultaneously recorded subjective ratings of "pleasantness," "intensity," and "wanting." Despite no differences between the groups in subjective ratings, individuals recovered from anorexia nervosa showed increased neural response to the pleasant chocolate taste in the ventral striatum and pleasant chocolate sight in the occipital cortex. The recovered participants also showed increased neural response to the aversive strawberry taste in the insula and putamen and to the aversive strawberry sight in the anterior cingulate cortex and caudate. Individuals recovered from anorexia nervosa have increased neural responses to both rewarding and aversive food stimuli. These findings suggest that even after recovery, women with anorexia nervosa have increased salience attribution to food stimuli. These results aid our neurobiological understanding and support the view that the neural response to reward may constitute a neural biomarker for anorexia nervosa.
Several recent studies have shown that reducing gamma-aminobutyric acid (GABA)-mediated neurotran... more Several recent studies have shown that reducing gamma-aminobutyric acid (GABA)-mediated neurotransmission retards extinction of aversive conditioning. However, relatively little is known about the effect of GABA on extinction of appetitively motivated tasks. We examined the effect of chlordiazepoxide (CDP), a classical benzodiazepine (BZ) and two novel subtype-selective BZs when administered to male C57Bl/6 mice during extinction following training on a discrete-trial fixed-ratio 5 (FR5) food reinforced lever-press procedure. Initially CDP had no effect, but after several extinction sessions CDP significantly facilitated extinction, i.e. slowed responding, compared with vehicle-treated mice. This effect was not due to drug accumulation because mice switched from vehicle treatment to CDP late in extinction showed facilitation immediately. Likewise, this effect could not be attributed to sedation because the dose of CDP used (15 mg/kg i.p.) did not suppress locomotor activity. The two novel subtype-selective BZ partial agonists, L-838417 and TP13, selectively facilitated extinction in similar fashion to CDP. The non-GABAergic anxiolytic buspirone was also tested and found to have similar effects when administered at a non-sedating dose. These studies demonstrate that GABA-mediated processes are important during extinction of an appetitively motivated task, but only after the animals have experienced several extinction sessions.
Drugs that alter brain serotonin (5-HT) function can modulate the behavioral effects of cocaine, ... more Drugs that alter brain serotonin (5-HT) function can modulate the behavioral effects of cocaine, but the underlying receptor mechanisms are poorly understood. The present study examined the effects of the selective 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 0.01-0.1 mg/kg, i.v.) on cocaine self-administration in the context of a choice procedure. Five adult male cynomolgus monkeys self-administered cocaine (saline, 0.003-0.03 mg/kg per injection) under a concurrent fixed-ratio 50 schedule of food (1-g banana-flavored pellets) and cocaine presentation. Allocation of responses to the cocaine-associated lever (cocaine choice) increased in a dose-related manner from < or =20% of total responses when saline or 0.003 mg/kg per injection cocaine was the alternative to food to > or =75% when 0.03 mg/kg per injection cocaine was available. In four of five monkeys, when choice was between a low cocaine dose and food, 0.01 mg/kg 8-OH-DPAT increased injection-lever responding. At cocaine doses which occasioned > or =75% cocaine choice, 8-OH-DPAT did not alter response allocation. In the fifth monkey, 8-OH-DPAT only decreased injection-lever responding. When choice was between saline and food, 8-OH-DPAT did not reliably shift responding to the injection lever, except at doses that disrupted operant performance. These results suggest that a 5-HT1A receptor agonist can increase the reinforcing strength of a low cocaine dose relative to a concurrently available non-drug reinforcer.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), Jan 25, 2014
Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as... more Disturbances in the regulation of reward and aversion in the brain may underlie disorders such as obesity and eating disorders. We previously showed that the cannabis receptor subtype (CB1) inverse agonist rimonabant, an antiobesity drug withdrawn due to depressogenic side effects, diminished neural reward responses yet increased aversive responses (Horder et al., 2010). Unlike rimonabant, tetrahydrocannabivarin is a neutral CB1 receptor antagonist (Pertwee, 2005) and may therefore produce different modulations of the neural reward system. We hypothesized that tetrahydrocannabivarin would, unlike rimonabant, leave intact neural reward responses but augment aversive responses. We used a within-subject, double-blind design. Twenty healthy volunteers received a single dose of tetrahydrocannabivarin (10mg) and placebo in randomized order on 2 separate occasions. We measured the neural response to rewarding (sight and/or flavor of chocolate) and aversive stimuli (picture of moldy strawbe...
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