Atomoxetine restores the response inhibition network in Parkinson’s disease

Rae, Charlotte L.; Nombela, Cristina; Rodríguez, Patricia Vázquez; Zheng, Yuxiao; Hughes, Laura E.; Jones, P. Simon; Ham, Timothy; Rittman, Timothy; Coyle‐Gilchrist, Ian; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.; Rowe, James B.

doi:10.1093/brain/aww138

Cited by 86 publications

(104 citation statements)

References 88 publications

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“…Dysfunction of the latter circuit in FTLD can cause the failure to self-generate motor patterns, over and above blunted affect or cognitive dysfunction, in keeping with evidence for this circuit in voluntary action selection in health [20,28] and poor signal-to-noise in motor plans arising from the medial frontal cortex [29]. This ‘auto-activation’ deficit can also be formulated as a failure to reach a necessary activation threshold, by leakage, decay or refractoriness in the fronto-parietal neuronal ensembles that represent actions [17].…”

Section: Introductionmentioning

confidence: 70%

The neuroanatomical and neurochemical basis of apathy and impulsivity in frontotemporal lobar degeneration

Passamonti

Lansdall

Rowe

2018

Current Opinion in Behavioral Sciences

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Apathy and impulsivity are common and often coexistent consequences of frontotemporal lobar degeneration (FTLD). They increase patient morbidity and carer distress, but remain under-estimated and poorly treated. Recent trans-diagnostic approaches that span the spectrum of clinical presentations of FTLD and parkinsonism, indicate that apathy and impulsivity can be fractionated into multiple neuroanatomical and pharmacological systems. These include ventral/dorsal fronto-striatal circuits for reward-sensitivity, response-inhibition, and decision-making; moderated by noradrenaline, dopamine, and serotonin. Improved assessment tools, formal models of cognition and behavior, combined with brain imaging and psycho-pharmacology, are creating new therapeutic targets and establishing principles for stratification in future clinical trials.

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Section: Introductionmentioning

confidence: 70%

The neuroanatomical and neurochemical basis of apathy and impulsivity in frontotemporal lobar degeneration

Passamonti

Lansdall

Rowe

2018

Current Opinion in Behavioral Sciences

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“…; Rae et al . ). Direct projections from the LC to the STN might support interactions between the NA, the motor and the executive systems (Parent and Hazrati ).…”

Section: Discussionmentioning

confidence: 97%

“…; Chamberlain and Robbins ; Mather and Harley ; Rae et al . ; Borodovitsyna et al . ; Nahimi et al .…”

mentioning

confidence: 99%

Clonidine modulates the activity of the subthalamic‐supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients

Spay

Albares

Lio

et al. 2018

Journal of Neurochemistry

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Clonidine is an anti-hypertensive medication which acts as an alpha-adrenergic receptor agonist. As the noradrenergic system is likely to support cognitive functions including attention and executive control, other clinical uses of clonidine have recently gained popularity for the treatment of neuropsychiatric disorders like attention-deficit hyperactivity disorder or Tourette syndrome, but the mechanism of action is still unclear. Here, we test the hypothesis that the noradrenergic system regulates the activity of subthalamo-motor cortical loops, and that this influence can be modulated by clonidine. We used pharmacological manipulation of clonidine in a placebo-controlled study in combination with subthalamic nucleus-deep brain stimulation (STN-DBS) in 16 Parkinson's disease patients performing a reaction time task requiring to refrain from reacting (proactive inhibition). We recorded electroencephalographical activity of the whole cortex, and applied spectral analyses directly at the source level after advanced blind source separation. We found only one cortical source localized to the supplementary motor area (SMA) that supported an interaction of pharmacological and subthalamic stimulation. Under placebo, STN-DBS reduced proactive alpha power in the SMA, a marker of local inhibitory activity. This effect was associated with the speeding-up of movement initiation. Clonidine substantially increased proactive alpha power from the SMA source, and canceled out the benefits of STN-DBS on movement initiation. These results provide the first direct neural evidence in humans that the tonic inhibitory activity of the subthalamocortical loops underlying the control of movement initiation is coupled to the noradrenergic system, and that this activity can be targeted by pharmacological agents acting on alpha-adrenergic receptors.

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“…Task-free resting state functional connectivity analysis showed that atomoxetine enhanced connectivity between the RIFG and the dorsal anterior cingulate in Parkinson's disease, hence generally boosting the fronto-striatal circuitry associated with SSRT performance (Borchert et al 2016). More specifically, the fMRI results with Parkinson's disease patients suggest that atomoxetine increases sensitivity of the inferior frontal gyrus to afferent inputs from the pre-supplementary motor cortex; and further that atomoxetine enhances downstream modulation of frontal-subcortical connections for response inhibition (Rae et al 2016). These effects may correspond to the effects of intra-PFC atomoxetine in rats described above and provide a possible explanation of some of the therapeutic effects of the drug in ADHD, as well as Parkinson's disease.…”

Section: Translation From Laboratory To Clinic Of Findings On Impulsimentioning

confidence: 97%

Dissecting Impulsivity: Brain Mechanisms and Neuropsychiatric Implications

Robbins

Dalley

2017

Nebraska Symposium on Motivation

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Atomoxetine restores the response inhibition network in Parkinson’s disease

Cited by 86 publications

References 88 publications

The neuroanatomical and neurochemical basis of apathy and impulsivity in frontotemporal lobar degeneration

The neuroanatomical and neurochemical basis of apathy and impulsivity in frontotemporal lobar degeneration

Clonidine modulates the activity of the subthalamic‐supplementary motor loop: evidence from a pharmacological study combining deep brain stimulation and electroencephalography recordings in Parkinsonian patients

Dissecting Impulsivity: Brain Mechanisms and Neuropsychiatric Implications

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