scholarly journals Reduced locus coeruleus integrity linked to response inhibition deficits in parkinsonian disorders

2021 ◽  
Author(s):  
Rong Ye ◽  
Frank Hubert Hezemans ◽  
Claire O'Callaghan ◽  
Kamen A Tsvetanov ◽  
Catarina Rua ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Locus Coeruleus ◽  
Progressive Supranuclear Palsy ◽  
Inhibitory Control ◽  
Response Inhibition ◽  
Stop Signal Task ◽  
Model Parameters ◽  
Noradrenergic System ◽  
Parkinsonian Disorders

Parkinson's disease and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals, and have been linked with worse prognosis and lack of improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus noradrenergic system. Here we test the hypothesis that loss of structural integrity of the locus coeruleus explains response inhibition deficits in progressive supranuclear palsy and Parkinson's disease. This cross-sectional observational study recruited 24 people with idiopathic Parkinson's disease, 14 with PSP-Richardson's syndrome, and 24 age- and sex-matched controls. All participants undertook a stop-signal task and ultrahigh field 7T-magnetic transfer weighted imaging of the locus coeruleus. Hierarchical Bayesian estimation of the parameters of 'race models' of go- versus stop-decisions was used to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between locus coeruleus integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. Progressive supranuclear palsy caused a distinct pattern of abnormalities in inhibitory control, relative to Parkinson's disease and healthy controls, with a paradoxically reduced threshold for go responses, but longer non-decision times, and more lapses of attention. The variation in response inhibition correlated with variation in the integrity of the locus coeruleus, across participants in both clinical groups. Structural imaging of the locus coeruleus, coupled with behavioural modelling in parkinsonian disorders, confirms that locus coeruleus integrity is associated with response inhibition and its degeneration contributes to neurobehavioural changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimisation of noradrenergic treatment is likely to benefit from stratification according to locus coeruleus integrity.

scholarly journals Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson's disease

2020 ◽  
Author(s):  
Claire O'Callaghan ◽  
Frank Hubert Hezemans ◽  
Rong Ye ◽  
Catarina Rua ◽  
P Simon Jones ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Locus Coeruleus ◽  
Response Inhibition ◽  
Therapeutic Potential ◽  
Reaction Times ◽  
Stop Signal ◽  
Stop Signal Task ◽  
Double Blind ◽  
Caudal Portion

Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson's disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomised crossover design, 19 people with Parkinson's disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7T imaging of the locus coeruleus using a neuromelanin-sensitive magnetisation transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in Parkinson's disease patients. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalised treatment approaches.

scholarly journals Prefrontal cortical connectivity mediates locus coeruleus noradrenergic regulation of inhibitory control in older adults

2021 ◽  
Author(s):  
Alessandro Tomassini ◽  
Frank Hubert Hezemans ◽  
Rong Ye ◽  
Kamen Tsvetanov ◽  
Noham Wolpe ◽  
...  
Keyword(s):  
Older Adults ◽  
Locus Coeruleus ◽  
Inhibitory Control ◽  
Response Inhibition ◽  
Magnetization Transfer ◽  
Inferior Frontal Gyrus ◽  
Healthy Adults ◽  
Stop Signal Task ◽  
Adaptive Behaviour ◽  
Noradrenergic System

Response inhibition is a core executive function enabling adaptive behaviour in dynamic environments. Human and animal models indicate that inhibitory control and control networks are modulated by noradrenaline, arising from the locus coeruleus. The integrity (i.e., cellular density) of the locus coeruleus noradrenergic system can be estimated from magnetization transfer sensitive magnetic resonance imaging, in view of neuromelanin present in noradrenergic neurons of older adults. Noradrenergic psychopharmacological studies indicate noradrenergic modulation of prefrontal and frontostriatal stopping-circuits in association with behavioural change. Here we test the noradrenergic hypothesis of inhibitory control, in healthy adults. We predicted that locus coeruleus integrity is associated with age-adjusted variance in response inhibition, mediated by changes in connectivity between frontal inhibitory control regions. In a preregistered analysis, we used magnetization transfer MRI images from N=63 healthy adults aged above 50 years who performed a stop-signal task, with atlas-based measurement of locus coeruleus contrast. We confirm that better response inhibition is correlated with locus coeruleus integrity and stronger connectivity between pre-supplementary motor area and right inferior frontal gyrus, but not volumes of the cortical regions. We confirmed a significant role of prefrontal connectivity in mediating the effect of individual differences in the locus coeruleus on behaviour, whereby this effect was moderated by age, over and above adjustment for the mean effects of age. Our results support the hypothesis that in normal populations, as in clinical settings, the locus coeruleus noradrenergic system regulates inhibitory control.

scholarly journals Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders

Brain ◽  
2017 ◽  
Vol 140 (9) ◽  
pp. 2460-2474 ◽  
Author(s):  
Junchao Tong ◽  
Gausiha Rathitharan ◽  
Jeffrey H Meyer ◽  
Yoshiaki Furukawa ◽  
Lee-Cyn Ang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Monoamine Oxidase ◽  
Multiple System Atrophy ◽  
Frontal Cortex ◽  
Progressive Supranuclear Palsy ◽  
Dopamine Neurons ◽  
Astroglial Cells ◽  
Parkinsonian Disorders

Abstract See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article.  The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson’s disease. Inhibitors of MAOB are used clinically in Parkinson’s disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson’s disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson’s disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson’s disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is ‘substantially’ localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson’s disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the enzyme in the parkinsonian substantia nigra; instead, increased nigral levels of a MAOA fragment and ‘turnover’ of the enzyme were observed in the conditions. Our findings provide support that MAOB might serve as a biochemical imaging marker, albeit not entirely specific, for astrocyte activation in human brain. The observation that MAOB protein concentration is generally increased in degenerating brain areas in multiple system atrophy (especially putamen) and in progressive supranuclear palsy, but not in the nigra in Parkinson’s disease, also distinguishes astrocyte behaviour in Parkinson’s disease from that in the two ‘Parkinson-plus’ conditions. The question remains whether suppression of either MAOB in astrocytes or MAOA in dopamine neurons might influence progression of the parkinsonian disorders.

scholarly journals Continuous force measurements reveal no inhibitory control deficits in Parkinson’s disease

2019 ◽  
Author(s):  
Jade S. Pickering ◽  
Jennifer McBride ◽  
Iracema Leroi ◽  
Ellen Poliakoff
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inhibitory Control ◽  
Response Inhibition ◽  
Force Measurement ◽  
Button Press ◽  
Continuous Measure ◽  
Response Force ◽  
Link Type ◽  
And Control

AbstractSuppression of unwanted motor responses can be disrupted by Parkinson’s disease. People with Parkinson’s (PwP) can show maladaptive reward-driven behaviours in the form of impulse control behaviours, which are associated with use of the dopaminergic treatments used to alleviate the motor symptoms of the disease. However, the effects of Parkinson’s itself on impulsive behaviour and control are unclear – empirical studies have yielded mixed findings, and some imaging studies have shown a functional deficit in the absence of a measurable change in behaviour. Here, we investigated the effects of Parkinson’s on response activation and control by studying the dynamics of response in standard inhibitory control tasks – the Stop Signal and Simon tasks – using a continuous measure of response force. Our results are largely in favour of the conclusion that response inhibition appears to be intact in PwP, even when using a more sensitive measure of behavioural control relative to traditional button-press measures. Our findings provide some clarity as to the effects of Parkinson’s on response inhibition and show continuous response force measurement can provide a sensitive means of detecting erroneous response activity in PwP, which could also be generalised to studying related processes in other populations.Open dataData and analysis can be found on the Open Science Framework (osf.io/kx6h3/)Pre-print templateWiernik, B.M. (2019, October 11). Preprint templates. osf.io/hsv6a/

scholarly journals Continuous force measurements reveal no inhibitory control deficits in Parkinson’s disease

2020 ◽  
Vol 238 (5) ◽  
pp. 1119-1132
Author(s):  
Jade S. Pickering ◽  
Iracema Leroi ◽  
Jennifer McBride ◽  
Ellen Poliakoff
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inhibitory Control ◽  
Response Inhibition ◽  
Force Measurement ◽  
Empirical Studies ◽  
Button Press ◽  
Continuous Measure ◽  
Response Force ◽  
And Control

Abstract Suppression of unwanted motor responses can be disrupted by Parkinson’s disease. People with Parkinson’s (PwP) can show maladaptive reward-driven behaviours in the form of impulse control behaviours, which are associated with the use of the dopaminergic treatments used to alleviate the motor symptoms of the disease. However, the effects of Parkinson’s itself on impulsive behaviour and control are unclear—empirical studies have yielded mixed findings, and some imaging studies have shown a functional deficit in the absence of a measurable change in behaviour. Here, we investigated the effects of Parkinson’s on response activation and control by studying the dynamics of response in standard inhibitory control tasks—the Stop Signal and Simon tasks—using a continuous measure of response force. Our results are largely in favour of the conclusion that response inhibition appears to be intact in PwP, even when using a more sensitive measure of behavioural control relative to traditional button-press measures. Our findings provide some clarity as to the effects of Parkinson’s on response inhibition and show continuous response force measurement can provide a sensitive means of detecting erroneous response activity in PwP, which could also be generalised to studying related processes in other populations.

scholarly journals Inhibitory control dysfunction in parkinsonian impulse control disorders

Brain ◽  
2020 ◽  
Author(s):  
Garance M Meyer ◽  
Charlotte Spay ◽  
Alina Beliakova ◽  
Gabriel Gaugain ◽  
Gianni Pezzoli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inhibitory Control ◽  
Response Inhibition ◽  
Impulse Control ◽  
Supplementary Motor Area ◽  
Impulse Control Disorders ◽  
Motor Area ◽  
Beta Activity ◽  
Visuomotor Task

Abstract Impulse control disorders (ICDs) in Parkinson’s disease have been associated with dysfunctions in the control of value- or reward-based responding (choice impulsivity) and abnormalities in mesocorticolimbic circuits. The hypothesis that dysfunctions in the control of response inhibition (action impulsivity) also play a role in Parkinson’s disease ICDs has recently been raised, but the underlying neural mechanisms have not been probed directly. We used high-resolution EEG recordings from 41 patients with Parkinson’s disease with and without ICDs to track the spectral and dynamical signatures of different mechanisms involved in inhibitory control in a simple visuomotor task involving no selection between competing responses and no reward to avoid potential confounds with reward-based decision. Behaviourally, patients with Parkinson’s disease with ICDs proved to be more impulsive than those without ICDs. This was associated with decreased beta activity in the precuneus and in a region of the medial frontal cortex centred on the supplementary motor area. The underlying dynamical patterns pinpointed dysfunction of proactive inhibitory control, an executive mechanism intended to gate motor responses in anticipation of stimulation in uncertain contexts. The alteration of the cortical drive of proactive response inhibition in Parkinson’s disease ICDs pinpoints the neglected role the precuneus might play in higher order executive functions in coordination with the supplementary motor area, specifically for switching between executive settings. Clinical perspectives are discussed in the light of the non-dopaminergic basis of this function.

scholarly journals Different decision deficits impair response inhibition in progressive supranuclear palsy and Parkinson’s disease

Brain ◽  
2015 ◽  
Vol 139 (1) ◽  
pp. 161-173 ◽  
Author(s):  
Jiaxiang Zhang ◽  
Timothy Rittman ◽  
Cristina Nombela ◽  
Alessandro Fois ◽  
Ian Coyle-Gilchrist ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Progressive Supranuclear Palsy ◽  
Response Inhibition

scholarly journals Stimulation of the Subthalamic Region Facilitates the Selection and Inhibition of Motor Responses in Parkinson's Disease

2006 ◽  
Vol 18 (4) ◽  
pp. 626-636 ◽  
Author(s):  
Wery P. M. van den Wildenberg ◽  
Geert J. M. van Boxtel ◽  
Maurits W. van der Molen ◽  
D. Andries Bosch ◽  
Johannes D. Speelman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Basal Ganglia ◽  
Response Inhibition ◽  
Response Selection ◽  
Stop Signal ◽  
Stop Signal Task ◽  
Motor Responses ◽  
Two Samples ◽  
Ventral Intermediate Nucleus

The aim of the present study was to specify the involvement of the basal ganglia in motor response selection and response inhibition. Two samples were studied. The first sample consisted of patients diagnosed with Parkinson's disease (PD) who received deep-brain stimulation (DBS) of the subthalamic nucleus (STN). The second sample consisted of patients who received DBS for the treatment of PD or essential tremor (ET) in the ventral intermediate nucleus of the thalamus (Vim). Stop-signal task and go/no-go task performances were studied in both groups. Both groups performed these tasks with (on stimulation) and without (off stimulation) DBS to address the question of whether stimulation is effective in improving choice reaction time (RT) and stop-signal RT. The results show that DBS of the STN was associated with significantly enhanced inhibitory control, as indicated by shorter stop-signal RTs. An additional finding is that DBS of the STN led to significantly shorter choice RT. The effects of DBS on responding and response inhibition were functionally independent. Although DBS of the Vim did not systematically affect task performance in patients with ET, a subgroup of Vim-stimulated PD patients showed enhanced stop-signal RTs in on stimulation versus off stimulation. This result suggests that the change in performance to stop signals may not be directly related to STN function, but rather results from a change in PD function due to DBS in general. The findings are discussed in terms of current functional and neurobiological models that relate basal ganglia function to the selection and inhibition of motor responses.

scholarly journals Locus Coeruleus Integrity from 7T MRI Relates to Apathy and Cognition in Parkinson’s Disease and Progressive Supranuclear Palsy

2021 ◽  
Author(s):  
Rong Ye ◽  
Claire O’Callaghan ◽  
Catarina Rua ◽  
Frank H. Hezemans ◽  
Negin Holland ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Spatial Pattern ◽  
Locus Coeruleus ◽  
Progressive Supranuclear Palsy ◽  
Neuropsychiatric Symptoms ◽  
Test Group ◽  
Cross Sectional ◽  
Richardson’S Syndrome

AbstractBackground and ObjectivesThe loss of noradrenergic neurons in the locus coeruleus (LC) contributes to various cognitive and neuropsychiatric symptoms in Parkinson’s disease (PD) and progressive supranuclear palsy (PSP). The spatial precision of in vivo LC imaging is improved using a magnetisation transfer sequence combined with ultra-high field 7T MRI. This study aimed to test the sensitivity of LC imaging in PD and PSP, to characterise the spatial pattern of LC atrophy in patients, and its relationship to cognition and apathy.MethodsThis cross-sectional observational study recruited patients with idiopathic PD, probable PSP-Richardson’s syndrome and age-matched healthy controls (HC) via specialist clinics and volunteer registries. All participants underwent clinical assessments for cognition and apathy, and high-resolution (0.08 mm3) LC scans. To quantify LC integrity, the contrast-to-noise ratio (CNR) relative to a pons reference region was calculated and extracted using a probabilistic atlas. Subregional mean CNRs were summarised to test group differences and to correlate LC integrity with apathy and cognition scores. LC clusters were identified to confirm the spatial pattern of the effect (threshold free cluster enhancement, 10000 permutations, p<0.05, corrected for family-wise error).ResultsTwenty-five patients with PD, 14 with PSP and 24 controls with completed dataset were included in the study. Patients with PSP were more impaired on global cognition and apathy scores, compared to controls and PD. Clusters with reduced contrast were observed in the caudal LC for both PD and PSP patients relative to controls (HC>PD, right caudal LC, 37 voxels; HC>PSP, bilateral caudal LC, 206 voxels). PSP and PD patients showed similar levels of LC degeneration, but this was more extensive in PSP. Across both disease groups, LC integrity was associated with cognitive performance (MoCA: F(1,37)=5.339, p=0.027, bilateral LC, 200 voxels; ACE-R: F(1,37)=4.297, p=0.045, left LC, 70 voxels) and apathy (Apathy Scale: F(1,37)=4.335, p=0.044, left LC, 99 voxels).DiscussionWe confirm the sensitivity of 7T LC imaging to detect sub-regional LC changes in PD and PSP. The relationship between LC integrity and non-motor symptoms highlights the potential for noradrenergic therapeutic strategies to ameliorate cognitive and behavioural features of PD and PSP.

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