Human mesostriatal response tracks motivational tendencies under naturalistic goal conflict

Gonen, Tal; Soreq, Eyal; Eldar, Eran; Ben-Simon, Eti; Raz, Gal; Hendler, Talma

doi:10.1093/scan/nsw014

Cited by 14 publications

(24 citation statements)

References 53 publications

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“…This pharmacological evidence constitutes the main argument for the translational validity of AAC paradigms as models of human anxiety disorders. Still, the cross-species validity of AAC is not firmly established given that suitable preclinical test beds for humans have only recently been developed in the form of computer games ( 13 , 14 , 15 , 16 , 17 , 18 ). The neural implementation of human anxiety-like behavior thus remains elusive.…”

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confidence: 99%

“…Thus, it appears plausible that benzodiazepines may reduce anxiety-related behavior by inhibiting amygdala neurons in addition to potential effects in the hippocampus. While some functional neuroimaging studies on human AAC have reported involvement of the hippocampus ( 15 , 16 ), others report activity of the amygdala ( 13 , 14 ). Results from a lesion study suggest causal involvement of the human hippocampus in AAC behavior ( 15 ).…”

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confidence: 99%

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Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach–Avoidance Conflict Test

Korn

Vunder

Miró

et al. 2017

Biological Psychiatry

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BackgroundRodent approach–avoidance conflict tests are common preclinical models of human anxiety disorder. Their translational validity mainly rests on the observation that anxiolytic drugs reduce rodent anxiety-like behavior. Here, we capitalized on a recently developed approach–avoidance conflict computer game to investigate the impact of benzodiazepines and of amygdala lesions on putative human anxiety-like behavior. In successive epochs of this game, participants collect monetary tokens on a spatial grid while under threat of virtual predation.MethodsIn a preregistered, randomized, double-blind, placebo-controlled trial, we tested the effect of a single dose (1 mg) of lorazepam (n = 59). We then compared 2 patients with bilateral amygdala lesions due to Urbach-Wiethe syndrome with age- and gender-matched control participants (n = 17). Based on a previous report, the primary outcome measure was the effect of intra-epoch time (i.e., an adaptation to increasing potential loss) on presence in the safe quadrant of the spatial grid. We hypothesized reduced loss adaptation in this measure under lorazepam and in patients with amygdala lesions.ResultsLorazepam and amygdala lesions reduced loss adaptation in the primary outcome measure. We found similar results in several secondary outcome measures. The relative reduction of anxiety-like behavior in patients with amygdala lesions was qualitatively and quantitatively indistinguishable from an impact of anterior hippocampus lesions found in a previous report.ConclusionsOur results establish the translational validity of human approach–avoidance conflict tests in terms of anxiolytic drug action. We identified the amygdala, in addition to the hippocampus, as a critical structure in human anxiety-like behavior.

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confidence: 99%

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confidence: 99%

Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach–Avoidance Conflict Test

Korn

Vunder

Miró

et al. 2017

Biological Psychiatry

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“…Based on previous neuroimaging data, we assumed that the activity of mesocortical structures would be enhanced by our cognitive induction protocol (MPH-Cognitive), which includes inhibitory control ( Luijten et al, 2014 ; Constantinidis and Luna, 2019 ), attention ( Knudsen, 2018 ; Nani et al, 2019 ), working memory ( Emch et al, 2019 ), and abstract reasoning ( Hobeika et al, 2016 ) tasks. To test the specificity of the effect of MPH-Cognitive task, we added a control task induction condition (MPH-Control) in which MPH administration was coupled with a task known to activate mainly mesolimbic areas, and particularly the ventral tegmental area and ventral striatum ( Gonen et al, 2016 ). To control for overall task effects (beyond the drug effect) we added a placebo drug condition for each task (Placebo-Cognitive, Placebo-Control).…”

Section: Study 1: Neurobehavioral Effects Of Mph Functional-pharmacolmentioning

confidence: 99%

Inducing a Functional-Pharmacological Coupling in the Human Brain to Achieve Improved Drug Effect

et al. 2020

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Neuropharmacotherapy is substantially hindered by poor drug targeting, resulting in low specificity and efficacy. It is known that different behavioral tasks increase functional activity and cerebral blood flow (CBF), two key parameters controlling drug delivery and efficacy. Here, we tested a novel, non-invasive drug targeting approach (termed functional-pharmacological coupling), which couples drug administration with a task that is known to specifically activate the drug’s sites-of-action in the brain. In two studies we administered Methylphenidate (MPH) to neurotypical adults and to subjects with attention deficit hyperactivity disorder (ADHD). In study 1 we employed a within-subject factorial design and found that only following MPH administration, subjects that performed better in the cognitive induction task showed greater improvements in N-back performance. Moreover, only under MPH-Cognitive induction condition, this improvement correlated with concurrent N-Back rDLPFC activation. In Study 2, subjects with ADHD performed better on sustained attention when MPH administration was followed by a cognitive challenge rather than a control task. Again, those who were more attentive to the cognitive challenge scored higher. Our results provide preliminary support for the feasibility of functional-pharmacological coupling concept, hence opening a new horizon for patient-tailored, context-driven drug therapy.

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“…We therefore set out to examine whether the coupling of MPH administration with a cognitive task (Cognitive-MPH) would result in increased drug effect on cognitive performance that is known to involve prefrontal cortex activation. To test the specificity of the effect of Cognitive-MPH, we added a control task induction condition in which MPH administration was coupled with a task known to activate mesolimbic areas (Control-MPH) [16]. To control for overall task effects (beyond the drug effect) we added a placebo drug condition for each task (Cognitive-Placebo, Control-Placebo).…”

Section: Introductionmentioning

confidence: 99%

“…As the control state induction, we employed two paradigms known to probe reward processing and mesolimbic activation. One is a 25 minute competitive computer game developed in our lab as a paradigm to assess goal directed behavior with regard to reward and punishment [16], and the other is a 20 minute passive listening excerpt using emotional music extracted from the Pachelbel's Canon, previously used in our lab to induce positive emotions [25].…”

Section: Introductionmentioning

confidence: 99%

Context of Psychotropic Drug Delivery Modulates its Neurobehavioral Effects: the Case of Methylphenidate

Sar-el¹,

Raz²,

Lubianiker³

et al. 2017

Preprint

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Pharmacotherapy is substantially hindered by poor drug targeting, resulting in low specificity and efficacy. Here, we tested a novel, non-invasive targeting approach (termed functional-pharmacology), which couples drug administration with a task that activates the drug's sites-of-action in the brain, thus possibly improving absorption and efficacy. Methylphenidate (MPH) or Placebo were administered to healthy subjects, which then performed a cognitive induction or a control task. N-Back fMRI before and after drug-task coupling measured therapeutic effects. Only following MPH, subjects that performed better in the cognitive induction task showed greater improvements in N-back performance. Moreover, only under MPH-Cognitive induction condition, there existed a significant correlation between improved recruitment of N-Back rDLPFC activation, and a concurrent improvement in task performance. Importantly, mediation analysis suggested a causal role of rDLPFC activation in these coupling effects. Our results support the functional-pharmacology concept feasibility and efficacy, hence opening a new horizon for patient-tailored, context-driven drug therapy.not peer-reviewed)

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Human mesostriatal response tracks motivational tendencies under naturalistic goal conflict

Cited by 14 publications

References 53 publications

Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach–Avoidance Conflict Test

Amygdala Lesions Reduce Anxiety-like Behavior in a Human Benzodiazepine-Sensitive Approach–Avoidance Conflict Test

Inducing a Functional-Pharmacological Coupling in the Human Brain to Achieve Improved Drug Effect

Context of Psychotropic Drug Delivery Modulates its Neurobehavioral Effects: the Case of Methylphenidate

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