Toward a transdiagnostic neurocircuitry-based biomarker model for pro-cognitive effects: challenges, opportunities, and next steps

Petersen, Cecilia S; Miskowiak, Kamilla Woznica

doi:10.1017/s1092852920000061

Cited by 18 publications

(18 citation statements)

References 40 publications

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“…Another explanation could be that the potent placebo response could have masked a possible beneficial effect of exenatide (Figure 3-4). The observed potent placebo response could be due to the standardized cognitive behaviour therapy (CBT) against AUD (38) offered to all participants in the study, but it could also be due to the less severity profile of the AUD patients included, which is typically linked to a higher placebo response (33). Large placebo responses are also reported in other clinical AUD trials and shown to be negatively correlated with the treatment intervention effect sizes (34).…”

Section: Discussionmentioning

confidence: 93%

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial

Klausen¹,

Jensen²,

Møller³

et al. 2022

JCI Insight

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BackgroundAlcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 receptor agonist exenatide reduces alcohol consumption in rodents and nonhuman primates, but its efficacy in patients with AUD is unknown. MethodsIn a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26-weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed fMRI and SPECT brain scans. ResultsA total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared to placebo, it significantly attenuated fMRI alcohol cue-reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, the dopamine transporter availability was lower in the exenatide group compared to the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI>30 kg/m 2 ). Adverse events were mainly gastrointestinal.5 ConclusionsThis first randomized controlled trial (RCT) on the effects of a GLP-1 receptor agonist in AUD patients provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction.

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Section: Discussionmentioning

confidence: 93%

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial

Klausen¹,

Jensen²,

Møller³

et al. 2022

JCI Insight

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“…Abnormal activity within the DMN is classically linked to increased rumination, but is also associated with impaired control of attention ( 54 ). Failing to reduce activation within the DMN whilst actively undertaking a cognitive task appears to directly relate to poor task performance, whereas appropriate “switching off” of the DMN during tasks is linked with improved cognitive performance ( 55 ). In this way, improving appropriate deactivation of the DMN during cognitive tasks has been proposed as a transdiagnostic marker to assess for pro-cognitive effects of interventions ( 55 ).…”

Section: Discussionmentioning

confidence: 99%

“…Failing to reduce activation within the DMN whilst actively undertaking a cognitive task appears to directly relate to poor task performance, whereas appropriate “switching off” of the DMN during tasks is linked with improved cognitive performance ( 55 ). In this way, improving appropriate deactivation of the DMN during cognitive tasks has been proposed as a transdiagnostic marker to assess for pro-cognitive effects of interventions ( 55 ). Therefore, the decreased activation of DMN-related regions during task performance in this fMRI faces task may reflect enhanced attention and cognitive control, which is consistent with the improvement in performance accuracy seen behaviourally.…”

Section: Discussionmentioning

confidence: 99%

The Effect of the 5-HT4 Agonist, Prucalopride, on a Functional Magnetic Resonance Imaging Faces Task in the Healthy Human Brain

et al. 2022

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Depression is a common and often recurrent illness with significant negative impact on a global scale. Current antidepressants are ineffective for up to one third of people with depression, many of whom experience persistent symptomatology. 5-HT4 receptor agonists show promise in both animal models of depression and cognitive deficit. We therefore studied the effect of the 5-HT4 partial agonist prucalopride (1 mg daily for 6 days) on the neural processing of emotional faces in 43 healthy participants using a randomised placebo-controlled design. Participants receiving prucalopride were more accurate at identifying the gender of emotional faces. In whole brain analyses, prucalopride was also associated with reduced activation in a network of regions corresponding to the default mode network. However, there was no evidence that prucalopride treatment produced a positive bias in the neural processing of emotional faces. Our study provides further support for a pro-cognitive effect of 5-HT4 receptor agonism in humans. While our current behavioural and neural investigations do not suggest an antidepressant-like profile of prucalopride in humans, it will be important to study a wider dose range in future studies.

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“…The current study had several limitations to consider. First, although a transdiagnostic sample might be a strength in terms of clinical utility for biomarker discovery, 68,69 it also limits the ability to detect subtle differences between specific anxiety disorders. In addition, our cross-sectional, observational approach did not allow for causal inference.…”

Section: Limitationsmentioning

confidence: 99%

Striatal reactivity during emotion and reward relates to approach–avoidance conflict behaviour and is altered in adults with anxiety or depression

McDermott

Berg

Touthang

et al. 2022

jpn

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Background:We have previously reported activation in reward, salience and executive control regions during functional MRI (fMRI) using an approach-avoidance conflict (AAC) decision-making task with healthy adults. Further investigations into how anxiety and depressive disorders relate to differences in neural responses during AAC can inform their understanding and treatment. We tested the hypothesis that people with anxiety or depression have altered neural activation during AAC. Methods: We compared 118 treatment-seeking adults with anxiety or depression and 58 healthy adults using linear mixed-effects models to examine group-level differences in neural activation (fMRI) during AAC decision-making. Correlational analyses examined relationships between behavioural and neural measures. Results: Adults with anxiety or depression had greater striatal engagement when reacting to affective stimuli (p = 0.008, d = 0.31) regardless of valence, and weaker striatal engagement during reward feedback (p = 0.046, d = −0.27) regardless of the presence of monetary reward. They also had blunted amygdala activity during decision-making (p = 0.023, d = −0.32) regardless of the presence of conflict. Across groups, approach behaviour during conflict decision-making was inversely correlated with striatal activation during affective stimuli (p < 0.001, r = −0.28) and positively related to striatal activation during reward feedback (p < 0.001, r = 0.27). Limitations: Our transdiagnostic approach did not allow for comparisons between specific anxiety disorders, and our cross-sectional approach did not allow for causal inference. Conclusion: Anxiety and depression were associated with altered neural responses to AAC. Findings were consistent with the role of the striatum in action selection and reward responsivity, and they point toward striatal reactivity as a future treatment target. Blunting of amygdala activity in anxiety or depression may indicate a compensatory response to inhibit affective salience and maintain approach.

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Toward a transdiagnostic neurocircuitry-based biomarker model for pro-cognitive effects: challenges, opportunities, and next steps

Cited by 18 publications

References 40 publications

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial

Exenatide once weekly for alcohol use disorder investigated in a randomized, placebo-controlled clinical trial

The Effect of the 5-HT4 Agonist, Prucalopride, on a Functional Magnetic Resonance Imaging Faces Task in the Healthy Human Brain

Striatal reactivity during emotion and reward relates to approach–avoidance conflict behaviour and is altered in adults with anxiety or depression

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