Increasingly memory deficits are recognized in Parkinson's disease (PD). In PD, the dopamine-producing cells of the substantia nigra (SN) are significantly degenerated whereas those in the ventral tegmental area (VTA) are relatively spared. Dopamine-replacement medication improves cognitive processes that implicate the SN-innervated dorsal striatum but is thought to impair those that depend upon the VTA-supplied ventral striatum, limbic and prefrontal cortices. Our aim was to examine memory encoding and retrieval in PD and how they are affected by dopamine replacement. Twenty-nine PD patients performed the Rey Auditory Verbal Learning Test (RAVLT) and a non-verbal analogue, the Aggie Figures Learning Test (AFLT), both on and off dopaminergic medications. Twenty-seven, age-matched controls also performed these memory tests twice and their data were analyzed to correspond to the ON-OFF order of the PD patients to whom they were matched. We contrasted measures that emphasized with those that accentuated retrieval and investigated the effect of PD and dopamine-replacement on these processes separately. For PD patients relative to controls, encoding performance was normal in the off state and was impaired on dopaminergic medication. Retrieval was impaired off medication and improved by dopamine repletion. This pattern of findings suggests that VTA-innervated brain regions such as ventral striatum, limbic and prefrontal cortices are implicated in encoding, whereas the SN-supplied dorsal striatum mediates retrieval. Understanding this pattern of spared functions and deficits in PD, and the effect of dopamine replacement on these distinct memory processes, should prompt closer scrutiny of patients' cognitive complaints to inform titration of dopamine replacement dosages along with motor symptoms.
The main pattern of cognitive impairments seen in early to moderate stages of Parkinson’s disease (PD) includes deficits of executive functions. These nonmotor complications have a significant impact on the quality of life and day-to-day activities of PD patients and are not effectively managed by current therapies, a problem which is almost certainly due to the fact that the disease extends beyond the nigrostriatal system. To investigate the role of extrastriatal dopamine in executive function in PD, PD patients and a control group were studied with positron-emission-tomography using a high-affinity dopamine D2/D3 receptor tracer, [11C]FLB-457. All participants were scanned twice while performing an executive task and a control task. Patients were off medication for at least 12 h. The imaging analysis revealed that parkinsonian patients had lower [11C]FLB-457 binding than control group independently of task conditions across different brain regions. Cognitive assessment measures were positively correlated with [11C]FLB-457 binding in the bilateral dorsolateral prefrontal cortex and anterior cingulate cortex only in control group, but not in PD patients. Within the control group, during the executive task (as compared to control task), there was evidence of reduced [11C]FLB-457 binding (indicative of increased dopamine release) in the right orbitofrontal cortex. In contrast, PD patients did not show any reduction in binding during the executive task (as compared with control task). These findings suggest that PD patients present significant abnormalities in extrastriatal dopamine associated with executive processing. These observations provide important insights on the pathophysiology of cognitive dysfunction in PD.
PMID: 22331665 CAMSID: cams2380
FLB-457; positron emission tomography; set-shifting; cognition; mesocortical dopamine
Patients with idiopathic Parkinson’s disease exhibit impairments in executive processes, including planning and set-shifting, even at the early stages of the disease. We have recently developed a new card-sorting task to study the specific role of the caudate nucleus in such executive processes and have shown, using functional magnetic resonance imaging (fMRI) in young healthy adults, that the caudate nucleus is specifically required when a set-shift must be planned. Here the same fMRI protocol was used to compare the patterns of activation in a group of early-stage Parkinson’s disease patients (seven right-handed patients at Hoehn and Yahr stages 1 and 2; mean age 62 years, range 56–70) and matched control subjects. Increased cortical activation was observed in the patients compared with the control group in the condition not specifically requiring the caudate nucleus. On the other hand, decreased cortical activation was observed in the patient group in the condition significantly involving the caudate nucleus. This event-related fMRI study showed a pattern of cortical activation in Parkinson’s disease characterized by either reduced or increased activation depending on whether the caudate nucleus was involved or not in the task. This activation pattern included not only the prefrontal regions but also posterior cortical areas in the parietal and prestriate cortex. These findings are not in agreement with the traditional model, which proposes that the nigrostriatal dopamine depletion results in decreased cortical activity. These observations provide further evidence in favour of the hypothesis that not only the nigrostriatal and but also the mesocortical dopaminergic substrate may play a significant role in the cognitive deficits observed in Parkinson’s disease.
PMID: 17121746 CAMSID: cams3203
executive functions; fMRI; Parkinson’s disease; set-shifting; striatum
Depression in Parkinson's disease (PD) is frequently associated with executive deficits, which can influence nonliteral comprehension and lexical access. This study explores whether depressive symptoms in PD modulate verbal fluency and nonliteral language comprehension. Twelve individuals with PD without depressive symptoms, 13 with PD and depressive symptoms (PDDSs), and 13 healthy controls completed a semantic and phonemic verbal fluency task and an indirect speech acts comprehension task. All groups had the same performance in the phonemic fluency task while the PDDS group was impaired in the semantic task. For the indirect speech act comprehension task, no difference was observed between the groups. However, the PDDS group had difficulty answering direct speech act questions. As some language impairments in PD become apparent when depressive symptoms are associated with the disease, it would appear to be important to take the presence of depressive symptoms into account when evaluating language abilities in PD.
Cognitive abnormalities are a feature of Parkinson's disease (PD). Unlike motor symptoms that are clearly improved by dopaminergic therapy, the effect of dopamine replacement on cognition seems paradoxical. Some cognitive functions are improved whereas others are unaltered or even hindered. Our aim was to understand the effect of dopamine replacement therapy on various aspects of cognition. Whereas dorsal striatum receives dopamine input from the substantia nigra (SN), ventral striatum is innervated by dopamine-producing cells in the ventral tegmental area (VTA). In PD, degeneration of SN is substantially greater than cell loss in VTA and hence dopamine-deficiency is significantly greater in dorsal compared to ventral striatum. We suggest that dopamine supplementation improves functions mediated by dorsal striatum and impairs, or heightens to a pathological degree, operations ascribed to ventral striatum. We consider the extant literature in light of this principle. We also survey the effect of dopamine replacement on functional neuroimaging in PD relating the findings to this framework. This paper highlights the fact that currently, titration of therapy in PD is geared to optimizing dorsal striatum-mediated motor symptoms, at the expense of ventral striatum operations. Increased awareness of contrasting effects of dopamine replacement on dorsal versus ventral striatum functions will lead clinicians to survey a broader range of symptoms in determining optimal therapy, taking into account both those aspects of cognition that will be helped versus those that will be hindered by dopaminergic treatment.
To examine the integrity of the default mode network in patients with Parkinson disease (PD). Previous functional neuroimaging experiments have studied executive deficits in patients with PD with regard to task-related brain activation. However, recent studies suggest that executive performance also relies on the integrity of the default mode network (ie, medial prefrontal cortex, posterior cingulate cortex, precuneus, and lateral parietal and medial temporal cortices), characterized by a deactivation of these cortical areas during the performance of executive tasks.
We used functional magnetic resonance imaging to investigate cortical deactivations during a card-sorting task (retrieval and manipulation of short-term memory contents) compared with a simple sensory-motor matching task. In addition, a functional connectivity analysis was performed.
Tertiary outpatient clinic.
Seven patients with mild to moderate PD (not taking medication) and 7 healthy controls.
Main Outcome Measure
Both groups showed comparable deactivation of the medial prefrontal cortex but different deactivation in the posterior cingulate cortex and the precuneus. Compared with controls, patients with PD not only showed less deactivation of the posterior cingulate cortex and the precuneus, they even demonstrated a reversed pattern of activation and deactivation. Connectivity analysis yielded that in contrast to healthy individuals, medial prefrontal cortex and the rostral ventromedial caudate nucleus were functionally disconnected in PD.
We describe specific malfunctioning of the default mode network during an executive task in PD. This finding is plausibly linked to dopamine depletion and may critically contribute to the understanding of executive deficits in PD.
PMID: 19597090 CAMSID: cams1533
There is clear evidence that the prefrontal cortex is strongly involved in executive processes and that dopamine can influence performance on working memory tasks. Although, some studies have emphasized the role of striatal dopamine in executive functions, the role played by prefrontal dopamine during executive tasks is unknown. In order to investigate cortical dopamine transmission during executive function, we used D2-dopamine receptor ligand [11C]FLB 457 PET in healthy subjects while performing the Montreal Card Sorting Task (MCST). During the retrieval with shift task of the MCST, the subjects had to match each test card to one of the reference cards based on a classification rule (color, shape or number) determined by comparing the previously viewed cue card and the current test card. A reduction in [11C]FLB 457 binding potential in the right dorsal anterior cingulate cortex (ACC) was observed when subjects performed the active task compared to the control task. These findings may suggest that right dorsal ACC dopamine neurotransmission increases significantly during the performance of certain executive processes, e.g., conflict monitoring, in keeping with previous evidence from fMRI studies showing ACC activation during similar tasks. These results may provide some insights on the origin of cognitive deficits underlying certain neurological disorders associated with dopamine dysfunction, such as Parkinson’s disease and schizophrenia.
PMID: 19264140 CAMSID: cams1532
FLB 457; Positron emission tomography; Executive function; Anterior cingulate cortex; Dopamine; Conflict monitoring
The prefrontostriatal network is considered to play a key role in executive functions. Previous neuroimaging studies have shown that executive processes tested with card-sorting tasks requiring planning and set-shifting [e.g. Montreal-card-sorting-task (MCST)] may engage the dorsolateral prefrontal cortex (DLPFC) while inducing dopamine release in the striatum. However, functional imaging studies can only provide neuronal correlates of cognitive performance and cannot establish a causal relation between observed brain activity and task performance. In order to investigate the contribution of the DLPFC during set-shifting and its effect on the striatal dopaminergic system, we applied continuous theta burst stimulation (cTBS) to left and right DLPFC. Our aim was to transiently disrupt its function and to measure MCST performance and striatal dopamine release during [11C]raclopride PET. A significant hemispheric asymmetry was observed. cTBS of the left DLPFC impaired MCST performance and dopamine release in the ipsilateral caudate–anterior putamen and contralateral caudate nucleus, as compared to cTBS of the vertex (control). These effects appeared to be limited only to left DLPFC stimulation while right DLPFC stimulation did not influence task performance or [11C]raclopride binding potential in the striatum. This is the first study showing that cTBS, by disrupting left prefrontal function, may indirectly affect striatal dopamine neurotransmission during performance of executive tasks. This cTBS-induced regional prefrontal effect and modulation of the frontostriatal network may be important for understanding the contribution of hemisphere laterality and its neural bases with regard to executive functions, as well as for revealing the neurochemical substrate underlying cognitive deficits.
PMID: 19046396 CAMSID: cams1540
basal ganglia; executive function; positron emission tomography; transcranial magnetic stimulation
Repetitive transcranial magnetic stimulation (rTMS) is a valuable probe of brain function. Ever since its adoption as a research tool, there has been great interest regarding its potential clinical role. Presently, it is unclear whether rTMS will have some role as an alternative treatment for neuropsychiatric and neurological disorders such as Parkinson’s disease (PD). To date, studies addressing the contribution of placebo during rTMS are missing. The placebo effect has been shown to be associated either with release of dopamine in the striatum or with changes in brain glucose metabolism. The main objective of this study was to test whether, in patients with PD, the expectation of therapeutic benefit from rTMS, which actually was delivered only as sham rTMS (placebo-rTMS) induced changes in striatal [11C] raclopride binding potentials (BP) as measured with positron emission tomography (PET). Placebo-rTMS induced a significant bilateral reduction in [11C] raclopride BP in dorsal and ventral striatum as compared to the baseline condition. This reduction BP is indicative of an increase in dopamine neurotransmission. The changes in [11C] raclopride binding were more evident in the hemisphere contralateral to the more affected side supporting the hypothesis that the more severe the symptoms, the greater the drive for symptom relief, and therefore the placebo response. This is the first study addressing the placebo contribution during rTMS. While our results seem to confirm earlier evidence that expectation induces dopaminergic placebo effects, they also suggest the importance of placebo-controlled studies for future clinical trials involving brain stimulation techniques.
PMID: 16545582 CAMSID: cams1537
Positron emission tomography; Transcranial magnetic stimulation; Parkinson’s disease; Dopamine; Placebo; Expectation
Several animal studies have shown that striatal dopamine can be released under direct control of glutamatergic corticostriatal efferents. In Parkinson’s disease (PD), abnormalities in corticostriatal interactions are believed to play an important role in the pathophysiology of the disease. Previously, we have reported that, in healthy subjects, repetitive transcranial magnetic stimulation (rTMS) of motor cortex (MC) induces focal dopamine release in the ipsilateral putamen. In the present study, using [11C]raclopride PET, we sought to investigate early PD patients with evidence of unilateral motor symptoms. We measured in the putamen changes in extracellular dopamine concentration following rTMS (intensity, 90% of the resting motor threshold; frequency, 10 Hz) of the left and right MC. The main objective was to identify potential differences in corticostriatal dopamine release between the hemisphere associated with clear contralateral motor symptoms (symptomatic hemisphere) and the presymptomatic stage of the other hemisphere (asymptomatic hemisphere). Repetitive TMS of MC caused a binding reduction in the ipsilateral putamen of both hemispheres. In the symptomatic hemisphere, while the amount of TMS-induced dopamine release was, as expected, smaller, the size of the significant cluster of change in [11C]raclopride binding was, instead, 61.4% greater than in the asymptomatic hemisphere. This finding of a spatially enlarged area of dopamine release, following cortical stimulation, may represent a possible in vivo expression of a loss of functional segregation of cortical information to the striatum and an indirect evidence of abnormal corticostriatal transmission in early PD. This has potential implications for models of basal ganglia function in PD.
PMID: 16324129 CAMSID: cams1536
Parkinson’s disease; positron emission tomography; raclopride; motor cortex stimulation; transcranial magnetic stimulation
To date, while the contribution of the striatum in executive processes is well documented, the role played by striatal dopamine during tasks requiring executive functions is still unknown. We used D2-dopamine receptor ligand [11C] raclopride PET in healthy subjects while performing the Montreal Card Sorting Task (MCST). We observed a striatal reduction in [11C] raclopride binding potential during planning of a set-shift when compared with matching according to an ongoing rule. These findings suggest that striatal dopamine neurotransmission increases significantly during the performance of specific executive processes confirming previous evidence of striatal activation during fMRI studies. The present observation may provide some insights on the origin of cognitive deficits underlying certain neurological disorders associated with dopamine dysfunction, such as Parkinson’s disease.
PMID: 16982202 CAMSID: cams1538
Positron emission tomography; Functional imaging; Raclopride; Dopamine; Basal ganglia; Executive functions; Cognition
Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder characterized by the dysfunction of dopaminergic dependent cortico-basal ganglia loops and diagnosed on the basis of motor symptoms (tremors and/or rigidity and bradykinesia). Post-mortem studies tend to show that the destruction of dopaminergic neurons in the substantia nigra constitutes an intermediate step in a broader neurodegenerative process rather than a unique feature of Parkinson's disease, as a consistent pattern of progression would exist, originating from the medulla oblongata/pontine tegmentum. To date, neuroimaging techniques have been unable to characterize the pre-symptomatic stages of PD. However, if such a regular neurodegenerative pattern were to exist, consistent damages would be found in the brain stem, even at early stages of the disease. We recruited 23 PD patients at Hoenn and Yahr stages I to II of the disease and 18 healthy controls (HC) matched for age. T1-weighted anatomical scans were acquired (MPRAGE, 1 mm3 resolution) and analyzed using an optimized VBM protocol to detect white and grey matter volume reduction without spatial a priori. When the HC group was compared to the PD group, a single cluster exhibited statistical difference (p<0.05 corrected for false detection rate, 4287 mm3) in the brain stem, between the pons and the medulla oblongata. The present study provides in-vivo evidence that brain stem damage may be the first identifiable stage of PD neuropathology, and that the identification of this consistent damage along with other factors could help with earlier diagnosis in the future. This damage could also explain some non-motor symptoms in PD that often precede diagnosis, such as autonomic dysfunction and sleep disorders.
The goal of this study was to evaluate the effects of L-Dopa medication in Parkinson's disease (PD) on brain activation during the performance of a set-shifting task. Using fMRI, we have previously studied the patterns of activity observed in patients with PD after overnight removal of dopaminergic medication compared with control participants during the performance of different stages of the Wisconsin Card Sorting Task (WCST). The results revealed decreased cortical activity in the PD group compared to controls in the conditions that significantly required striatum, while increased cortical activity was observed when striatum was not involved. However, the effect of dopaminergic medication in PD patients on those patterns of activity has not yet been studied.
Here, eleven PD patients at early stage of the disease taking L-Dopa medication were recruited and underwent two fMRI sessions while performing the WCST: one session while taking their normal dose of medication and the other following overnight dopaminergic medication withdrawal. We found that L-dopa medication helped restoring a normal pattern of activity when matching and not planning was required, by increasing cortical activity in the premotor cortex. This effect was even stronger in the motor loop, i.e. when the putamen was required for controls, when matching following negative feedback. However, the medication did not change the pattern of activity in conditions relying primarily on a cognitive loop, i.e. when the caudate nucleus was required.
These studies provide explanation at the neural level regarding the relatively poor effects of L-Dopa on the cognitive deficits observed in PD.
Early functional neuroimaging studies of tasks evaluating executive processes, such as the Wisconsin card sorting task (WCST), only assessed trials in blocks that may contain a large amount of different cognitive processes. More recently, we showed using event-related fMRI that the dorsolateral prefrontal cortex (DL-PFC) significantly increased activity during feedback but not matching periods of the WCST, consistent with its proposed role in the monitoring of information in working memory. Repetitive transcranial magnetic stimulation (rTMS) is a method that allows to disrupt processing within a given cortical region and to affect task performance for which this region is significantly solicited. Here we applied rTMS to test the hypothesis that the DL-PFC stimulation influences monitoring of working memory without interfering with other executive functions. We applied rTMS to the right DL-PFC and the vertex (control site) in different time points of the WCST. When rTMS was applied to the DL-PFC specifically during the period when subjects were receiving feedback regarding their previous response, WCST performance deteriorated, while rTMS did not affect performance during matching either when maintaining set or during set-shifting. This selective impairment of the DL-PFC is consistent with its proposed role in monitoring of events in working memory.