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author:("ronchi, Oury")
1.  Asymmetrical Effect of Levodopa on the Neural Activity of Motor Regions in PD 
PLoS ONE  2014;9(11):e111600.
Parkinson's disease (PD) is a neurodegenerative illness often characterized by asymmetrical symptoms. However, the reason for this asymmetry and the cerebral correlates underlying symptom asymmetry are still not well understood. Furthermore, the effects of levodopa on the cerebral correlates of disease asymmetry have not been investigated. In this study, right-handed PD patients performed self-initiated, externally triggered and repetitive control finger movements with both their right and left hands during functional magnetic resonance imaging (fMRI) to investigate asymmetrical effects of levodopa on the hemodynamic correlates of finger movements. Patients completed two experimental sessions OFF and ON medication after a minimum of 12 hours medication withdrawal. We compared the effect of levodopa on the neural activation patterns underlying the execution of both the more affected and less affected hand for self-initiated and externally triggered movements. Our results show that levodopa led to larger differences in cerebral activity for movements of the more affected, left side: there were significant differences in activity after levodopa administration in regions of the motor cortico-striatal network when patients performed self-initiated and externally triggered movements with their left hand. By contrast, when patients used their right hand, levodopa led to differences in cerebellar activity only. As our patients were affected more severely on their left side, we propose that levodopa may help provide additional dopaminergic input, improving movements for the more severely affected side. These results suggest that the impact of reduced dopamine in the cortico-striatal system and the action of levodopa is not symmetrical.
doi:10.1371/journal.pone.0111600
PMCID: PMC4219727  PMID: 25369523
2.  Influence of Depressive Symptoms on Dopaminergic Treatment of Parkinson’s Disease 
Introduction: Depressive symptoms are very common in patients with Parkinson’s disease (PD) and have a significant impact on the quality of life. Dopaminergic medication has been shown to have an influence on the development of depressive symptoms.
Materials and methods: The present study analyzed two groups of non-demented patients with PD, with and without depressive symptoms, and reported the correlations between antiparkinsonian medication [specifically levodopa (l-DOPA) and dopaminergic agonists] with depressive symptoms.
Results: A strong statistically significant positive correlation between l-DOPA dosages and the level of depressive symptoms has been revealed, suggesting that higher l-DOPA dosages correlate with a worsening of depressive status. No significant correlation was found with dopamine agonists.
Discussion: The results of this study show that in patients with PD, higher l-DOPA dosages correlate with worse depressive symptoms. From this point of view, PD patients need to be better diagnosed with respect to depressive symptoms and need additional treatment adjustment when clinical manifestations of depression are present. Clinicians must be aware that dopaminergic drugs are not sufficient to alleviate depressive symptoms.
doi:10.3389/fneur.2014.00188
PMCID: PMC4174860  PMID: 25309508
Parkinson’s disease; l-DOPA; depressive symptoms; dopamine agonists
3.  Striatal and Hippocampal Involvement in Motor Sequence Chunking Depends on the Learning Strategy 
PLoS ONE  2014;9(8):e103885.
Motor sequences can be learned using an incremental approach by starting with a few elements and then adding more as training evolves (e.g., learning a piano piece); conversely, one can use a global approach and practice the whole sequence in every training session (e.g., shifting gears in an automobile). Yet, the neural correlates associated with such learning strategies in motor sequence learning remain largely unexplored to date. Here we used functional magnetic resonance imaging to measure the cerebral activity of individuals executing the same 8-element sequence after they completed a 4-days training regimen (2 sessions each day) following either a global or incremental strategy. A network comprised of striatal and fronto-parietal regions was engaged significantly regardless of the learning strategy, whereas the global training regimen led to additional cerebellar and temporal lobe recruitment. Analysis of chunking/grouping of sequence elements revealed a common prefrontal network in both conditions during the chunk initiation phase, whereas execution of chunk cores led to higher mediotemporal activity (involving the hippocampus) after global than incremental training. The novelty of our results relate to the recruitment of mediotemporal regions conditional of the learning strategy. Thus, the present findings may have clinical implications suggesting that the ability of patients with lesions to the medial temporal lobe to learn and consolidate new motor sequences may benefit from using an incremental strategy.
doi:10.1371/journal.pone.0103885
PMCID: PMC4141721  PMID: 25148078
4.  Differences between Patterns of Brain Activity Associated with Semantics and Those Linked with Phonological Processing Diminish with Age 
PLoS ONE  2014;9(6):e99710.
It is widely believed that language function tends to show little age-related performance decline. Indeed, some older individuals seem to use compensatory mechanisms to maintain a high level of performance when submitted to lexical tasks. However, how these mechanisms affect cortical and subcortical activity during semantic and phonological processing has not been extensively explored. The purpose of this study was to look at the effect of healthy aging on cortico-subcortical routes related to semantic and phonological processing using a lexical analogue of the Wisconsin Cart-Sorting Task. Our results indicate that while young adults tend to show increased activity in the ventrolateral prefrontal cortex, the dorsolateral prefrontal cortex, the fusiform gyrus, the ventral temporal lobe and the caudate nucleus during semantic decisions and in the posterior Broca's area (area 44), the temporal lobe (area 37), the temporoparietal junction (area 40) and the motor cortical regions during phonological decisions, older individuals showed increased activity in the dorsolateral prefrontal cortex and motor cortical regions during both semantic and phonological decisions. Furthermore, when semantic and phonological decisions were contrasted with each other, younger individuals showed significant brain activity differences in several regions while older individuals did not. Therefore, in older individuals, the semantic and phonological routes seem to merge into a single pathway. These findings represent most probably neural reserve/compensation mechanisms, characterized by a decrease in specificity, on which the elderly rely to maintain an adequate level of performance.
doi:10.1371/journal.pone.0099710
PMCID: PMC4074044  PMID: 24972020
5.  Examining dorsal striatum in cognitive effort using Parkinson's disease and fMRI 
Objective
Understanding cognition mediated by the striatum can clarify cognitive deficits in Parkinson's disease (PD). Previously, we claimed that dorsal striatum (DS) mediates cognitive flexibility. To refute the possibility that variation in cognitive effort confounded our observations, we reexamined our data to dissociate cognitive flexibility from effort. PD provides a model for exploring DS-mediated functions. In PD, dopamine-producing cells supplying DS are significantly degenerated. DS-mediated functions are impaired off and improved on dopamine replacement medication. Functional magnetic resonance imaging (fMRI) can confirm striatum-mediated functions.
Methods
Twenty-two PD patients, off-on dopaminergic medication, and 22 healthy age-matched controls performed a number selection task. Numerical distance between number pairs varied systematically. Selecting between two numbers that are closer versus distant in magnitude is more effortful: the symbolic distance effect. However, selecting between closer versus distant number pairs is equivalent in the need to alter attention or response strategies (i.e., cognitive flexibility). In Experiment 2, 28 healthy participants performed the same task with simultaneous measurement of brain activity with fMRI.
Results
The symbolic distance effect was equivalent for PD versus control participants and across medication sessions. Furthermore, symbolic distance did not correlate with DS activation using fMRI. In this dataset, we showed previously that integrating conflicting influences on decision making is (1) impaired in PD and improved by dopaminergic therapy and (2) associated with preferential DS activation using fMRI.
Interpretation
These findings support the notion that DS mediates cognitive flexibility specifically, not merely cognitive effort, accounting for some cognitive deficits in PD and informing treatment.
doi:10.1002/acn3.62
PMCID: PMC4184667  PMID: 25356409
6.  Increased topographical variability of task-related activation in perceptive and motor associative regions in adult autistics 
NeuroImage : Clinical  2014;4:444-453.
Background
An enhanced plasticity is suspected to play a role in various microstructural alterations, as well as in regional cortical reallocations observed in autism. Combined with multiple indications of enhanced perceptual functioning in autism, and indications of atypical motor functioning, enhanced plasticity predicts a superior variability in functional cortical allocation, predominant in perceptual and motor regions.
Method
To test this prediction, we scanned 23 autistics and 22 typical participants matched on age, FSIQ, Raven percentile scores and handedness during a visuo-motor imitation task. For each participant, the coordinates of the strongest task-related activation peak were extracted in the primary (Brodmann area 4) and supplementary (BA 6) motor cortex, the visuomotor superior parietal cortex (BA 7), and the primary (BA 17) and associative (BAs 18 + 19) visual areas. Mean signal changes for each ROI in both hemispheres, and the number of voxels composing the strongest activation cluster were individually extracted to compare intensity and size of the signal between groups. For each ROI, in each hemisphere, and for every participant, the distance from their respective group average was used as a variable of interest to determine group differences in localization variability using repeated measures ANOVAs. Between-group comparison of whole-brain activation was also performed.
Results
Both groups displayed a higher mean variability in the localization of activations in the associative areas compared to the primary visual or motor areas. However, despite this shared increased variability in associative cortices, a direct between-group comparison of the individual variability in localization of the activation revealed a significantly greater variability in the autistic group than in the typical group in the left visuo-motor superior parietal cortex (BA 7) and in the left associative visual areas (BAs 18 + 19).
Conclusion
Different and possibly unique strategies are used by each autistic individual. That enhanced variability in localization of activations in the autistic group is found in regions typically more variable in non-autistics raises the possibility that autism involves an enhancement and/or an alteration of typical plasticity mechanisms. The current study also highlights the necessity to verify, in fMRI studies involving autistic people, that hypoactivation at the group level does not result from each individual successfully completing a task using a unique brain allocation, even by comparison to his own group.
Highlights
•Functional activation in associative regions are more variable in autistics than in typicals.•Autistics showed enhanced variability in regions that are typically more variable in typicals.•Enhanced variability follows the same rule in perceptive and motor-related regions.
doi:10.1016/j.nicl.2014.02.008
PMCID: PMC4116759  PMID: 25101235
Autism; fMRI; Plasticity; Primary areas; Associative areas
7.  Function of basal ganglia in bridging cognitive and motor modules to perform an action 
The basal ganglia (BG) are thought to be involved in the integration of multiple sources of information, and their dysfunction can lead to disorders such as Parkinson's disease (PD). PD patients show motor and cognitive dysfunction with specific impairments in the internal generation of motor actions and executive deficits, respectively. The role of the BG, then, would be to integrate information from several sources in order to make a decision on a resulting action adequate for the required task. Reanalyzing the data set from our previous study (Martinu et al., 2012), we investigated this hypothesis by applying a graph theory method to a series of fMRI data during the performance of self-initiated (SI) finger movement tasks obtained in healthy volunteers (HV) and early stage PD patients. Dorsally, connectivity strength between the medial prefrontal areas (mPFC) and cortical regions including the primary motor area (M1), the extrastriate visual cortex, and the associative cortex, was reduced in the PD patients. The connectivity strengths were positively correlated to activity in the striatum in both groups. Ventrally, all connectivity between the striatum, the thalamus, and the extrastriate visual cortex decreased in strength in the PD, as did the connectivity between the striatum and the ventrolateral PFC (VLPFC). Individual response time (RT) was negatively correlated to connectivity strength between the dorsolateral PFC (DLPFC) and the striatum and positively correlated to connectivity between the VLPFC and the striatum in the HV. These results indicate that the BG, with the mPFC and thalamus, are involved in integrating multiple sources of information from areas such as DLPFC, and VLPFC, connecting to M1, thereby determining a network that leads to the adequate decision and performance of the resulting action.
doi:10.3389/fnins.2014.00187
PMCID: PMC4086202  PMID: 25071432
basal ganglia; dopamine; fMRI; cross-network synchrony; Parkinson's disease
8.  Differential Effects of Parkinson's Disease and Dopamine Replacement on Memory Encoding and Retrieval 
PLoS ONE  2013;8(9):e74044.
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.
doi:10.1371/journal.pone.0074044
PMCID: PMC3784427  PMID: 24086309
9.  Prefrontal Dopaminergic Receptor Abnormalities and Executive Functions in Parkinson’s Disease 
Human brain mapping  2012;34(7):1591-1604.
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.
doi:10.1002/hbm.22006
PMCID: PMC3542387  PMID: 22331665 CAMSID: cams2380
FLB-457; positron emission tomography; set-shifting; cognition; mesocortical dopamine
10.  Cortical activity in Parkinson’s disease during executive processing depends on striatal involvement 
Brain : a journal of neurology  2006;130(0 1):233-244.
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.
doi:10.1093/brain/awl326
PMCID: PMC3714298  PMID: 17121746 CAMSID: cams3203
executive functions; fMRI; Parkinson’s disease; set-shifting; striatum
11.  Are Verbal Fluency and Nonliteral Language Comprehension Deficits Related to Depressive Symptoms in Parkinson's Disease? 
Parkinson's Disease  2012;2012:308501.
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.
doi:10.1155/2012/308501
PMCID: PMC3306925  PMID: 22496988
12.  Differential Effects of Dopaminergic Therapies on Dorsal and Ventral Striatum in Parkinson's Disease: Implications for Cognitive Function 
Parkinson's Disease  2011;2011:572743.
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.
doi:10.4061/2011/572743
PMCID: PMC3062097  PMID: 21437185
13.  Dysfunction of the Default Mode Network in Parkinson Disease 
Archives of neurology  2009;66(7):877-883.
Objective
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.
Design
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.
Setting
Tertiary outpatient clinic.
Participants
Seven patients with mild to moderate PD (not taking medication) and 7 healthy controls.
Main Outcome Measure
Cortical deactivations.
Results
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.
Conclusions
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.
doi:10.1001/archneurol.2009.97
PMCID: PMC2972248  PMID: 19597090 CAMSID: cams1533
14.  Increased dopamine release in the right anterior cingulate cortex during the performance of a sorting task: A [11C]FLB 457 PET study 
NeuroImage  2009;46(2):516-521.
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.
doi:10.1016/j.neuroimage.2009.02.031
PMCID: PMC2972252  PMID: 19264140 CAMSID: cams1532
FLB 457; Positron emission tomography; Executive function; Anterior cingulate cortex; Dopamine; Conflict monitoring
15.  Theta burst stimulation-induced inhibition of dorsolateral prefrontal cortex reveals hemispheric asymmetry in striatal dopamine release during a set-shifting task – a TMS–[11C]raclopride PET study 
The European journal of neuroscience  2008;28(10):2147-2155.
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.
doi:10.1111/j.1460-9568.2008.06501.x
PMCID: PMC2967524  PMID: 19046396 CAMSID: cams1540
basal ganglia; executive function; positron emission tomography; transcranial magnetic stimulation
16.  Therapeutic application of transcranial magnetic stimulation in Parkinson’s disease: The contribution of expectation 
NeuroImage  2006;31(4):1666-1672.
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.
doi:10.1016/j.neuroimage.2006.02.005
PMCID: PMC2967525  PMID: 16545582 CAMSID: cams1537
Positron emission tomography; Transcranial magnetic stimulation; Parkinson’s disease; Dopamine; Placebo; Expectation
17.  Corticostriatal functional interactions in Parkinson’s disease: a rTMS/[11C]raclopride PET study 
The European journal of neuroscience  2005;22(11):2946-2952.
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.
doi:10.1111/j.1460-9568.2005.04476.x
PMCID: PMC2967526  PMID: 16324129 CAMSID: cams1536
Parkinson’s disease; positron emission tomography; raclopride; motor cortex stimulation; transcranial magnetic stimulation
18.  Striatal dopamine release during performance of executive functions: A [11C] raclopride PET study 
NeuroImage  2006;33(3):907-912.
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.
doi:10.1016/j.neuroimage.2006.06.058
PMCID: PMC2967527  PMID: 16982202 CAMSID: cams1538
Positron emission tomography; Functional imaging; Raclopride; Dopamine; Basal ganglia; Executive functions; Cognition
19.  Regional Brain Stem Atrophy in Idiopathic Parkinson's Disease Detected by Anatomical MRI 
PLoS ONE  2009;4(12):e8247.
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.
doi:10.1371/journal.pone.0008247
PMCID: PMC2784293  PMID: 20011063
20.  L-Dopa Medication in Parkinson's Disease Restores Activity in the Motor Cortico-Striatal Loop but Does Not Modify the Cognitive Network 
PLoS ONE  2009;4(7):e6154.
Background
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.
Methodology/Principal Findings
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.
Conclusions/Significance
These studies provide explanation at the neural level regarding the relatively poor effects of L-Dopa on the cognitive deficits observed in PD.
doi:10.1371/journal.pone.0006154
PMCID: PMC2702753  PMID: 19584921
21.  Repetitive Transcranial Magnetic Stimulation of Dorsolateral Prefrontal Cortex Affects Performance of the Wisconsin Card Sorting Task during Provision of Feedback 
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.
doi:10.1155/2008/143238
PMCID: PMC2266810  PMID: 18350118
22.  Recent Advances in Neuroimaging Methods 
doi:10.1155/2008/218582
PMCID: PMC2376048  PMID: 18483610

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