We used a network approach to assess systems-level abnormalities in motor activation in humans with Parkinson’s disease (PD). This was done by measuring the expression of the normal movement-related activation pattern (NMRP), a previously validated activation network deployed by healthy subjects during motor performance. In this study, NMRP expression was prospectively quantified in 15O-water PET scans from a PD patient cohort comprised of a longitudinal early stage group (n=12) scanned at baseline and at 2–3 follow-up visits two years apart, and a moderately advanced group scanned on and off treatment with either subthalamic nucleus (STN) deep brain stimulation (n=14) or intravenous levodopa infusion (n=14). For each subject and condition, we measured NMRP expression during both movement and rest. Resting expression of the abnormal PD-related metabolic covariance pattern (PDRP) was likewise determined in the same subjects.
NMRP expression was abnormally elevated (p<0.001) in PD patients scanned in the non-movement rest state. By contrast, network activity measured during movement did not differ from normal (p=0.34). In the longitudinal cohort, abnormal increases in resting NMRP expression were evident at the earliest clinical stages (p<0.05), which progressed significantly over time (p=0.003). Analogous network changes were present at baseline in the treatment cohort (p=0.001). These abnormalities improved with STN stimulation (p<0.005) but not levodopa (p=0.25). In both cohorts, the changes in NMRP expression that were observed did not correlate with concurrent PDRP measurements (p>0.22). Thus, the resting state in PD is characterized by changes in the activity of normal as well as pathological brain networks.
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
There is evidence that the right dorsolateral prefrontal cortex (DLPFC) may play a certain role in decision making related to reward value and time perception and, in particular, in the inhibitory control of impulsive decision making. Using the theta burst stimulation (TBS) and a delay discounting (DD) task, we investigated the potential role of right DLPFC in impulsive decision making defined by the rate of discounting delayed reward. Healthy right-handed volunteers underwent three stimulation sessions, intermittent TBS (iTBS), continuous TBS (cTBS), and sham. The steepness of the discount function (k-value), reaction time for choice and consistency were measured for each subjects. cTBS of the DLPFC reduced by 36.88 % the k-value of the DD task compared to sham condition. In contrast, iTBS did not affect impulsivity level. There were no changes neither in reaction time for choice nor consistency after either the iTBS or cTBS compared with the sham stimulation. These results demonstrate that cTBS-induced modulation of cortical excitability of the right DLPFC may affect and reduce impulsive decision making. These observations may provide some insights into the role of the right DLPFC in modulating impulsivity level and calculating reward value at different time scales under less ambiguous circumstances.
PMID: 20633446 CAMSID: cams3169
rTMS; theta burst stimulation; dorsolateral prefrontal cortex; decision making; impulsivity; delay discounting task
Decision making is a cognitive function relaying on a complex neural network. In particular, the right dorsolateral prefrontal cortex (DLPFC) plays a key role within this network. We used positron emission tomography (PET) combined with continuous theta burst transcranial magnetic stimulation (cTBS) to investigate neuronal and behavioral changes in normal volunteers while performing a delay discounting (DD) task. We aimed to test whether stimulation of right DLPFC would modify the activation pattern of the neural circuit underlying decision making during the DD task and influence discounting behavior.
We found that cTBS of the right DLPFC influenced decision making by reducing impulsivity and inducing participants to favor large but delayed rewards instead of immediate but small rewards. Stimulation also affected activation in several prefrontal areas associated with DD. In particular, we observed a reduced regional cerebral blood flow (rCBF) in the ipsilateral DLPFC (BA 46) extending into the rostral part of the prefrontal cortex (BA 10) as well as a disrupted relationship between impulsivity (k-value) and rCBF in these and other prefrontal areas.
These findings suggest that transcranial magnetic stimulation of the DLPFC influences the neural network underlying impulsive decision making behavior.
PMID: 22494829 CAMSID: cams3170
rTMS; Theta burst stimulation; Dorsolateral prefrontal cortex; Decision making; Impulsivity; Delay discounting task
Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinson’s disease (PD). Patients with PG have increased impulsivity and abnormalities in striatal DA, in common with behavioural and substance addictions in the non-PD population. To date, no studies have investigated the role of extrastriatal dopaminergic abnormalities in PD patients with PG. We used the PET radiotracer, [11C] FLB-457, with high-affinity for extrastriatal DA D2/3 receptors. 14 PD patients on DA agonists were imaged while they performed a gambling task involving real monetary reward and a control task. Trait impulsivity was measured with the Barratt Impulsivity Scale (BIS). Seven of the patients had a history of PG that developed subsequent to DA agonist medication. Change in [11C] FLB-457 binding potential (BP) during gambling was reduced in PD with PG patients in the midbrain, where D2/D3 receptors are dominated by autoreceptors. The degree of change in [11C] FLB-457 binding in this region correlated with impulsivity. In the cortex, [11C] FLB-457 BP was significantly greater in the anterior cingulate cortex (ACC) in PD patients with PG during the control task, and binding in this region was also correlated with impulsivity. Our findings provide the first evidence that PD patients with PG have dysfunctional activation of DA autoreceptors in the midbrain and low DA tone in the ACC. Thus, altered striatal and cortical DA homeostasis may incur vulnerability for the development of PG in PD, linked with the impulsive personality trait.
PMID: 22766031 CAMSID: cams2373
Parkinson’s disease; Dopamine agonists; Pathological gambling; Impulsivity
Dopamine plays an important role in several brain functions and is involved in the pathogenesis of several psychiatric and neurological disorders. Neuroimaging techniques such as positron emission tomography allow us to quantify dopaminergic activity in the living human brain. Combining these with brain stimulation techniques offers us the unique opportunity to tackle questions regarding region-specific neurochemical activity. Such studies may aid clinicians and scientists to disentangle neural circuitries within the human brain and thereby help them to understand the underlying mechanisms of a given function in relation to brain diseases. Furthermore, it may also aid the development of alternative treatment approaches for various neurological and psychiatric conditions.
PMID: 21536838 CAMSID: cams2366
brain imaging; dopamine; positron emission tomography; prefrontal cortex; transcranial magnetic stimulation
Radioligand positron emission tomography (PET) with dual scan paradigms can provide valuable insight into changes in synaptic neurotransmitter concentration due to experimental manipulation. The residual t-test has been utilized to improve the sensitivity of the t-test in PET studies. However, no further development of statistical tests using residuals has been proposed so far to be applied in cases when there are more than two conditions. Here, we propose the residual f-test, a one-way analysis of variance (ANOVA), and examine its feasibility using simulated [11C]raclopride PET data. We also re-visit data from our previously published [11C]raclopride PET study, in which 10 individuals underwent three PET scans under different conditions. We found that the residual f-test is superior in terms of sensitivity than the conventional f-test while still controlling for type 1 error. The test will therefore allow us to reliably test hypotheses in the smaller sample sizes often used in explorative PET studies.
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
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
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.