Research reportDopaminergic modulation of cognitive interference after pharmacological washout in Parkinson's disease
Introduction
It is recognized that patients with Parkinson's disease (PD) show executive dysfunction [17], [34], [22], which may predict incident dementia [43]. Functional imaging studies invocated a role for disruption of both nigro-striatal [31], [10] and mesocortical dopaminergic pathways [28]. Although levodopa can improve high-level cognition [23], [15], [38], it can also have no effects, or sometimes selectively exacerbate cognitive deficits [37]. This does not depend on neuropsychological specificity of the drug, disease duration or severity. A high variability across cognitive tasks suggests that the magnitude and the direction of the effects of levodopa depend on cognitive demand [8], but they also reflect the amount of dopamine (DA) depletion and the level of DA receptors stimulation in the prefrontal cortex (PFC). The relationship between dopaminergic function and cognitive performance follows an “Inverted-U” shaped curve [1], suggesting the need to be in an optimal DA range. Thus, the manipulation of the DA system will be profoundly influenced by baseline individual DA levels in the PFC.
Functional MRI (fMRI) demonstrated that after administrating dextroamphetamine, healthy subjects show an “Inverted-U” shaped relationship between PFC function and working-memory. Dextroamphetamine induced a right shift of DA function in the PFC, as suggested by improved accuracy (optimal stimulation) in poor performers at baseline, but supraoptimal (detrimental) stimulation in good performers [26].
PD offers the opportunity to investigate the pharmacological manipulation of the DA system in humans. Neuroimaging studies evaluated the cognitive effects of a controlled levodopa withdrawal in PD patients, by using ON–OFF approaches [28], [9]. The administration of levodopa induced task-related changes in the PFC response, associated with better performance on specific executive tasks. A limitation of these studies is that they were based on a single overnight withdrawal procedure and therefore they did not account for the long duration response (LDR) to levodopa, a sustained motor benefit that builds up over days and likewise decreases over days after withdrawal [33]. Stable PD patients under chronic treatment are likely close to their maximal therapeutic gain, as they benefit from the LDR. The relatively hypodopaminergic state induced by an overnight drug withdrawal may partly mask the effects of levodopa on the DA system, because of the high variability in terms of medication status and disease progression [45]. Conservative protocols, designed to abolish the LDR, will target the suboptimal-optimal range of the “Inverted-U” curve and might be more sensitive in picking up differences between “ON” and “OFF” states.
Here we used blood oxygenation level dependent (BOLD) fMRI to test whether: (i) levodopa-induced changes in cognitive performance of PD patients in a complete baseline condition correlate with changes in the BOLD response; (ii) drug effects are still described by an “Inverted-U” curve within the task-related brain network.
The functional response was assessed with the Stroop task. This task relies on the interference of word reading upon color naming, when a color name is displayed using a different color, semantically incongruent. Several investigators using different versions of this task found activations in the anterior cingulate/paracingulate cortices (ACC/pre-supplementary motor area, pre-SMA), parietal cortex and lateral PFC [2], [6], [32], [40]. Conflict resolution is a cognitively demanding condition and is strongly expected to expose impairment in PD patients undergoing a pharmacological washout.
Section snippets
Subjects
Before fMRI testing, patients underwent a full clinical assessment including Hoehn–Yahr (H–Y) staging [20], the Unified PD rating scale (UPDRS) [12] and a general neuropsychological battery that included MMSE [13], verbal fluency [3], Token test [11] and Hamilton's depression rating scale (HRS) [18]. Patients were screened for medical conditions or medication use which could affect the cerebral blood flow. All of them had been in an MR scanner at least once, as part of previous studies and all
Behavioral data
As expected a drug-related motor improvement was found in all PD patients, with a significant decrease in UPDRS-III scores after the pharmacological peak (p < 0.001) (Table 1).
The mean task accuracy was not significantly different in both the “Neutral” and the “Sensorimotor” control conditions when comparing the “OFF” versus the “ON” state. On the other hand, a significant drug-related improvement in accuracy was evident in the “Incongruent” condition (p < 0.03), even if the drug × task interaction
Discussion
This study was designed to induce a truly hypodopaminergic state in a group of mild to moderate idiopathic PD patients. A high-level cognitive task was used (Stroop task) to assess with fMRI the levodopa-induced changes in information processing associated to the task.
A relative drug-related attenuation of the BOLD response was observed during both “Incongruent” and “Neutral” conditions of the Stroop task relative to the “Sensorimotor control” condition. However, when contrasting the
References (45)
- et al.
Investigations of the functional anatomy of attention using the Stroop test
Neuropsychologia
(1993) - et al.
l-DOPA metabolism in cortical and striatal tissues in an animal model of parkinsonism
Brain Res. Bull.
(1995) - et al.
Interference and facilitation effects during selective attention: an H215O PET study of Stroop task performance
Neuroimage
(1995) - et al.
“Mini Mental State”. A practical method for grading the cognitive state of patients for the clinician
J. Psychiatr. Res.
(1975) - et al.
Common and distinct neural substrates of attentional control in an integrated Simon and spatial Stroop task as assessed by event-related fMRI
Neuroimage
(2004) - et al.
Effects of dextroamphetamine on cognitive performance and cortical activation
Neuroimage
(2000) - et al.
Attentional control in the aging brain: insight from an fMRI study of the Stroop task
Brain Cognit.
(2002) - et al.
Cognitive- and motor-related regions in Parkinson's disease: FDOPA and FDG PET studies
Neuroimage
(2004) - et al.
An fMRI study of the Stroop color-word interference: evidence for cingulate subregions subserving multiple distributed attentional system
Biol. Psychiatr.
(1999) - et al.
Reduction of cortical dopamine, noradrenalin, serotonin and their metabolites in Parkinson's disease
Brain Res.
(1983)
The role of dopamine in cognitive sequence learning: evidence from Parkinson's disease
Behav. Brain Res.
Isolation of specific interference processing in the Stroop task: PET activation studies
Neuroimage
Frontal–subcortical neuronal circuits and clinical neuropsychiatry: an update
J. Psychosom. Res.
Practice effects on cognitive tasks: a major problem?
Lancet Neurol.
Catecholamine modulation of prefrontal cortical cognitive function
Trends Cognit. Sci.
Differential behavioural effects of frontal lobe disease
Neuropsychologia
Conflict monitoring and cognitive control
Psychol. Rev.
Anterior cingulate and prefrontal cortex: who's in control?
Nat. Neurosci.
Enhanced or impaired cognitive function in Parkinson's disease as a function of dopaminergic medication and task demands
Cereb. Cortex
Dopaminergic modulation of high-level cognition in Parkinson's disease: the role of the prefrontal cortex revealed by PET
Brain
The role of the striatum and hippocampus in planning: a PET activation study in Parkinson's disease
Brain
The Token test: a sensitive test to detect receptive disturbances in aphasia
Brain
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