Locus coeruleus integrity correlates with inhibitory functions of the fronto-subthalamic ‘hyperdirect’ pathway in Parkinson’s disease

Degeneration of the noradrenergic system is now considered a pathological hallmark of Parkinson’s disease but little is known about its consequences in terms of parkinsonian manifestations. Here, we evaluate two aspects of the noradrenergic system using multimodal in vivo imaging in patients with Parkinson’s disease and healthy controls: the pigmented cell bodies of the locus coeruleus with neuromelanin sensitive MRI and the density of α2-adrenergic receptors (ARs) with PET using [11C]yohimbine. Thirty patients with Parkinson’s disease and thirty age- and sex-matched healthy control subjects were included. Patient’s symptoms characteristics were assessed using the MDS-UPDRS scale. Patients showed reduced neuromelanin signal intensity in the locus coeruleus compared to controls, and diminished [11C]yohimbine binding in widespread cortical regions including the motor cortex as well as in the insula, the thalamus and the putamen. Clinically, locus coeruleus neuronal loss was correlated with motor (bradykinesia, motor fluctuations, tremor) and non-motor (fatigue, apathy, constipation) symptoms. A reduction of α2-ARs availability in the thalamus was associated with tremor, while a reduction in the putamen, the insula and the superior temporal gyrus was associated with anxiety. These findings highlight a multifaceted alteration of the noradrenergic system in Parkinson’s disease since locus coeruleus and α2-ARs degenerations were found to be partly uncoupled. These findings raise important issues about noradrenergic dysfunctions that may encourage the search for new drugs targeting this system, including α2-ARs, for the treatment of Parkinson’s disease.

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Charting the brain networks of impulsivity: Meta-analytic synthesis, functional connectivity modelling, and neurotransmitter associations

Gell,

Langner,

Küppers

et al. 2024

Imaging Neuroscience

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Impulsivity is a multi-dimensional construct that plays a crucial role in human behaviour and is believed to be a transdiagnostic marker of several psychiatric disorders. However, given its multi-faceted nature, investigations of its neural correlates are challenging and systematic comparisons across dimensions are lacking. In this study, we used a comprehensive multi-modal approach to investigate the functional network organisation of two dimensions in which impulsivity manifests: decision-making and response inhibition. Activation likelihood estimation (ALE) meta-analyses of task-based fMRI studies within each dimension identified two distinct and non-overlapping functional systems. One located in the default-mode network, associated with value-based judgements and goal-directed decision-making, and the other distributed across higher-order networks associated with cognitive control. Resting-state functional connectivity revealed the two systems were organised into four specialised communities of default-mode, cingulo-insular, fronto-parietal, and temporal regions. Finally, given the widespread use of neurotransmitter-acting medication to treat conditions with impulsive symptoms, we investigated the association between this organisation and neurochemistry and found that integration across communities was associated with PET-derived serotonin receptor density. Our findings reinforce insights from previous behavioural research and provide substantial evidence for the multi-dimensional nature of impulsivity on the neural level. This highlights the necessity for a comprehensive dimensional ontology on all levels of investigation to address impulsivity in a transdiagnostic manner.

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Locus coeruleus integrity correlates with inhibitory functions of the fronto-subthalamic ‘hyperdirect’ pathway in Parkinson’s disease

Cited by 3 publications

References 48 publications

Subjective time dilation in abstinent patients with alcohol use disorder

Subjective time dilation in abstinent patients with alcohol use disorder

Noradrenergic alterations in Parkinson’s disease: a combined 11C-yohimbine PET/neuromelanin MRI study

Charting the brain networks of impulsivity: Meta-analytic synthesis, functional connectivity modelling, and neurotransmitter associations

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