Relating Response Inhibition, Brain Connectivity, and Freezing of Gait in People with Parkinson’s Disease

ABSTRACT Objective: Freezing of gait (FoG) in Parkinson’s disease (PD) has been associated with response inhibition. However, the relationship between response inhibition, neural dysfunction, and PD remains unclear. We assessed response inhibition and microstructural integrity of brain regions involved in response inhibition [right hemisphere inferior frontal cortex (IFC), bilateral pre-supplementary motor areas (preSMA), and subthalamic nuclei (STN)] in PD subjects with and without FoG and elderly controls. Method: Twenty-one people with PD and FoG (PD-FoG), 18 without FoG (PD-noFoG), and 19 age-matched controls (HC) completed a Stop-Signal Task (SST) and MRI scan. Probabilistic fiber tractography assessed structural integrity (fractional anisotropy, FA) among IFC, preSMA, and STN regions. Results: Stop-signal performance did not differ between PD and HC, nor between PD-FoG and PD-noFoG. Differences in white matter integrity were observed across groups (.001 < p < .064), but were restricted to PD versus HC groups; no differences in FA were observed between PD-FoG and PD-noFoG (p > .096). Interestingly, worse FoG was associated with higher (better) mean FA in the r-preSMA, (β = .547, p = .015). Microstructural integrity of the r-IFC, r-preSMA, and r-STN tracts correlated with stop-signal performance in HC (p ≤ .019), but not people with PD. Conclusion: These results do not support inefficient response inhibition in PD-FoG. Those with PD exhibited white matter loss in the response inhibition network, but this was not associated with FoG, nor with response inhibition deficits, suggesting FoG-specific neural changes may occur outside the response inhibition network. As shown previously, white matter loss was associated with response inhibition in elderly controls, suggesting PD may disturb this relationship.

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

10.1101/2020.09.03.20176800 ◽

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.

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

Journal of Cognitive Neuroscience ◽

10.1162/jocn.2006.18.4.626 ◽

2006 ◽

Vol 18 (4) ◽

pp. 626-636 ◽

Cited By ~ 164

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.

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White matter hyperintensities as a predictor of freezing of gait in Parkinson's disease

Parkinsonism & Related Disorders ◽

10.1016/j.parkreldis.2019.07.019 ◽

2019 ◽

Vol 66 ◽

pp. 105-109 ◽

Cited By ~ 6

Author(s):

Seok Jong Chung ◽

Yang Hyun Lee ◽

Han Soo Yoo ◽

Jungsu S. Oh ◽

Jae Seung Kim ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

White Matter ◽

White Matter Hyperintensities ◽

Freezing Of Gait

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Levodopa medication does not influence motor inhibition or conflict resolution in a conditional stop-signal task in Parkinson’s disease

Experimental Brain Research ◽

10.1007/s00221-011-2793-x ◽

2011 ◽

Vol 213 (4) ◽

pp. 435-445 ◽

Cited By ~ 47

Author(s):

Ignacio Obeso ◽

Leonora Wilkinson ◽

Marjan Jahanshahi

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Conflict Resolution ◽

Stop Signal ◽

Stop Signal Task ◽

Motor Inhibition

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The motor inhibitory network in patients with asymmetrical Parkinson’s disease: An fMRI study

Brain Imaging and Behavior ◽

10.1007/s11682-021-00587-5 ◽

2022 ◽

Author(s):

Francis R. Loayza ◽

Ignacio Obeso ◽

Rafael González Redondo ◽

Federico Villagra ◽

Elkin Luis ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Subthalamic Nucleus ◽

Inferior Frontal Gyrus ◽

Stop Signal ◽

Stop Signal Task ◽

Healthy Controls ◽

Inhibitory Network ◽

Fmri Study ◽

The Right

AbstractRecent imaging studies with the stop-signal task in healthy individuals indicate that the subthalamic nucleus, the pre-supplementary motor area and the inferior frontal gyrus are key components of the right hemisphere “inhibitory network”. Limited information is available regarding neural substrates of inhibitory processing in patients with asymmetric Parkinson’s disease. The aim of the current fMRI study was to identify the neural changes underlying deficient inhibitory processing on the stop-signal task in patients with predominantly left-sided Parkinson’s disease. Fourteen patients and 23 healthy controls performed a stop-signal task with the left and right hands. Behaviorally, patients showed delayed response inhibition with either hand compared to controls. We found small imaging differences for the right hand, however for the more affected left hand when behavior was successfully inhibited we found reduced activation of the inferior frontal gyrus bilaterally and the insula. Using the stop-signal delay as regressor, contralateral underactivation in the right dorsolateral prefrontal cortex, inferior frontal and anterior putamen were found in patients. This finding indicates dysfunction of the right inhibitory network in left-sided Parkinson’s disease. Functional connectivity analysis of the left subthalamic nucleus showed a significant increase of connectivity with bilateral insula. In contrast, the right subthalamic nucleus showed increased connectivity with visuomotor and sensorimotor regions of the cerebellum. We conclude that altered inhibitory control in left-sided Parkinson’s disease is associated with reduced activation in regions dedicated to inhibition in healthy controls, which requires engagement of additional regions, not observed in controls, to successfully stop ongoing actions.

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