Neural mechanisms underlying the therapeutic actions of guanfacine treatment in youth with ADHD: A pilot fMRI study

Bédard, Anne-Claude V.; Schulz, Kurt P.; Krone, Beth; Pedraza, Juan D.; Duhoux, Stéphanie; Halperin, Jeffrey M.; Newcorn, Jeffrey H.

doi:10.1016/j.pscychresns.2015.01.012

Cited by 10 publications

(5 citation statements)

References 18 publications

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“…It is also possible that the addition of guanfacine yields more complex effects, for example a mixture of cognitive benefit but also increased sedation, that ultimately cancel out benefits on our cognitive domain score, but that yield reductions in clinical ratings of impulsive and/or inattentive behavior. A related hypothesis is suggested by a recent study showing benefits of guanfacine relative to placebo on clinically observed symptoms, but not cognitive indicators of inhibition; in that study clinical improvements were associated with reduced fMRI signal in the right midcingulate cortex/supplementary motor area and the left posterior cingulate cortex, but not changes in the inferior prefrontal cortex regions often associated with enhanced response inhibition 21 . One interpretation of these results is that the clinical benefits of guanfacine were achieved through dampening of ascending noradrenergic “arousal” from the locus coeruleus (LC), more than an enhancement of the systems involved in inhibitory cognitive control, such as the ventrolateral frontal cortex 22 .…”

Section: Discussionmentioning

confidence: 95%

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder

Bilder

Loo

McGough

et al. 2016

Journal of the American Academy of Child & Adolescent Psych

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Objective Psychostimulants are partially effective in reducing cognitive dysfunction associated with attention-deficit/hyperactivity disorder (ADHD). Cognitive effects of guanfacine, an alternative treatment, are poorly understood. Given its distinct action on α2A receptors, guanfacine may have different or complementary effects relative to stimulants. This study tested stimulant and guanfacine monotherapies relative to combined treatment on cognitive functions important in ADHD. Method Children with ADHD (n = 182; age 7–14 years) completed an eight-week double blind randomized controlled trial with three arms: d-methylphenidate (DMPH), guanfacine (GUAN), or combination treatment with DMPH and GUAN (COMB). A non-clinical comparison group (n = 93) had baseline testing, and a subset was re-tested 8 weeks later (n = 38). Analyses examined treatment effects in four cognitive domains (working memory, response inhibition, reaction time, and reaction time variability) constructed from 20 variables. Results The ADHD group showed impaired working memory relative to the non-clinical comparison group (effect size = −0.53 SD units). The treatments differed in effects on working memory but not other cognitive domains. Combination treatment improved working memory more than GUAN, but was not significantly better than DMPH alone. Treatment did not fully normalize the initial deficit in ADHD relative to the comparison group. Conclusion Combined treatment with DMPH and GUAN yielded greater improvements in working memory than placebo or GUAN alone, but the combined treatment was not superior to DMPH alone, and did not extend to other cognitive domains. Although GUAN may be a useful add-on treatment to psychostimulants, additional strategies appear necessary to achieve normalization of cognitive function in ADHD. Clinical trial registration information Single Versus Combination Medication Treatment for Children With Attention Deficit Hyperactivity Disorder; http://clinicaltrials.gov/; NCT00429273

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Section: Discussionmentioning

confidence: 95%

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder

Bilder

Loo

McGough

et al. 2016

Journal of the American Academy of Child & Adolescent Psych

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“…From baseline to follow-up and compared to placebo-treated patients, 6- to 8-week treatment with guanfacine was not associated with improved accuracy, reaction times, or response inhibition-related brain activity in the fronto-cingulo-parietal network ( 85 ).…”

Section: Resultsmentioning

confidence: 99%

Effect of Pharmacological Interventions on the Fronto-Cingulo-Parietal Cognitive Control Network in Psychiatric Disorders: A Transdiagnostic Systematic Review of fMRI Studies

Amelsvoort

Hernaus

2016

Front. Psychiatry

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Executive function deficits, such as working memory, decision-making, and attention problems, are a common feature of several psychiatric disorders for which no satisfactory treatment exists. Here, we transdiagnostically investigate the effects of pharmacological interventions (other than methylphenidate) on the fronto-cingulo-parietal cognitive control network, in order to identify functional brain markers for future procognitive pharmacological interventions. Twenty-nine manuscripts investigated the effect of pharmacological treatment on executive function-related brain correlates in psychotic disorders (n = 11), depression (n = 4), bipolar disorder (n = 4), ADHD (n = 4), OCD (n = 2), smoking dependence (n = 2), alcohol dependence (n = 1), and pathological gambling (n = 1). In terms of impact on the fronto-cingulo-parietal network, the preliminary evidence for catechol-O-methyl-transferase inhibitors, nicotinic receptor agonists, and atomoxetine was relatively consistent, the data for atypical antipsychotics and anticonvulsants moderate, and interpretation of the data for antidepressants was hampered by the employed study designs. Increased activity in task-relevant areas and decreased activity in task-irrelevant areas were the most common transdiagnostic effects of pharmacological treatment. These markers showed good positive and moderate negative predictive value. It is concluded that fronto-cingulo-parietal activity changes can serve as a marker for future procognitive interventions. Future recommendations include the use of randomized double-blind designs and selective cholinergic and glutamatergic compounds.

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“…However, there were no significant changes in the differences between before and after GXR oral administration and before and after placebo oral administration. Bédard et al (2015) performed fMRI measurement during a go/no-go task after 6-8 weeks of continuous oral administration of GXR and placebo on the pediatric ADHD patients (aged 8-15) (Bédard et al, 2015), which is the only reported fMRI study of the ADHD patients. However, their study observed neither activation in the prefrontal area nor in any other brain regions, including the angular gyrus.…”

Section: Fnirs Examination Of Go/no-go Task and Gxr Effectsmentioning

confidence: 99%

“…Previous neuroimaging studies have shown that GXR activates the frontal cortex in animals (Avery et al, 2000 ) and in healthy young adult persons (Clerkin et al, 2009 ; Schulz et al, 2013 ). To our knowledge, only one fMRI study has revealed pharmacological neuromodulation by GXR on inhibition function in human ADHD subjects (Bédard et al, 2015 ) but provided negative evidence for activation in the PFC. Thus, the present study aims to reveal the neuropharmacological effects of GXR monotherapy on ADHD children, using fNIRS in a randomized, double-blind, crossover, placebo-controlled design.…”

Section: Introductionmentioning

confidence: 99%

Visualizing Neuropharmacological Effects of Guanfacine Extended Release in Attention Deficit Hyperactivity Disorder Using Functional Near-Infrared Spectroscopy

Ikeda

Inoue

Tanaka

et al. 2021

Front. Neuroergonomics

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Objective: In the current study, we explored the neural substrate for acute effects of guanfacine extended release (GXR) on inhibitory control in school-aged children with attention deficit hyperactivity disorder (ADHD), using functional near-infrared spectroscopy (fNIRS).Methods: Following a GXR washout period, 12 AD HD children (6–10 years old) performed a go/no-go task before and 3 h after GXR or placebo administration, in a randomized, double-blind, placebo-controlled, crossover design study. In the primary analysis, fNIRS was used to monitor the right prefrontal cortical hemodynamics of the participants, where our former studies showed consistent dysfunction and osmotic release oral system-methylphenidate (OROS-MPH) and atomoxetine hydrochloride (ATX) elicited recovery. We examined the inter-medication contrast, comparing the effect of GXR against the placebo. In the exploratory analysis, we explored neural responses in regions other than the right prefrontal cortex (PFC).Results: In the primary analysis, we observed no significant main effects or interactions of medication type and age in month (two-way mixed ANCOVA, Fs < 0.20, all ps > .05). However, in the post-hoc analysis, we observed significant change in the oxy-Hb signal in the right angular gyrus (AG) for inter-medication (one sample t-test, p < 0.05, uncorrected, Cohen's d = 0.71).Conclusions: These results are different from the neuropharmacological effects of OROS-MPH and ATX, which, in an upregulated manner, reduced right PFC function in ADHD children during inhibitory tasks. This analysis, while limited by its secondary nature, suggested that the improved cognitive performance was associated with activation in the right AG, which might serve as a biological marker to monitor the effect of GXR in the ADHD children.

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Neural mechanisms underlying the therapeutic actions of guanfacine treatment in youth with ADHD: A pilot fMRI study

Cited by 10 publications

References 18 publications

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder

Cognitive Effects of Stimulant, Guanfacine, and Combined Treatment in Child and Adolescent Attention-Deficit/Hyperactivity Disorder

Effect of Pharmacological Interventions on the Fronto-Cingulo-Parietal Cognitive Control Network in Psychiatric Disorders: A Transdiagnostic Systematic Review of fMRI Studies

Visualizing Neuropharmacological Effects of Guanfacine Extended Release in Attention Deficit Hyperactivity Disorder Using Functional Near-Infrared Spectroscopy

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