Ji Hyun Ko

Therapeutic application of transcranial magnetic stimulation in Parkinson's disease: the contribution of expectation.

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 Parkinsons 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.

Corticostriatal functional interactions in Parkinson's disease: a rTMS/[11C]raclopride PET study

Several animal studies have shown that striatal dopamine can be released under direct control of glutamatergic corticostriatal efferents. In Parkinsons 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.

Dorsolateral prefrontal and orbitofrontal cortex interactions during self-control of cigarette craving

Drug-related cues induce craving, which may perpetuate drug use or trigger relapse in addicted individuals. Craving is also under the influence of other factors in daily life, such as drug availability and self-control. Neuroimaging studies using drug cue paradigms have shown frontal lobe involvement in this contextual influence on cue reactivity, but have not clarified how and which frontal area accounts for this phenomenon. We explored frontal lobe contributions to cue-induced drug craving under different intertemporal drug availability conditions by combining transcranial magnetic stimulation and functional magnetic resonance imaging in smokers. We hypothesized that the dorsolateral prefrontal cortex (DLPFC) regulates craving during changes in intertemporal availability. Subjective craving was greater when cigarettes were immediately available, and this effect was eliminated by transiently inactivating the DLPFC with transcranial magnetic stimulation. Functional magnetic resonance imaging demonstrated that the signal most proportional to subjective craving was located in the medial orbitofrontal cortex across all contexts, whereas the DLPFC most strongly encoded intertemporal availability information. The craving-related signal in the medial orbitofrontal cortex was attenuated by inactivation of the DLPFC, particularly when cigarettes were immediately available. Inactivation of the DLPFC also reduced craving-related signals in the anterior cingulate and ventral striatum, areas implicated in transforming value signals into action. These findings indicate that DLPFC builds up value signals based on knowledge of drug availability, and support a model wherein aberrant circuitry linking dorsolateral prefrontal and orbitofrontal cortices may underlie addiction.

Continuous theta burst stimulation of right dorsolateral prefrontal cortex induces changes in impulsivity level.

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.

Reduced dopamine transporter density in the ventral striatum of patients with Parkinson's disease and pathological gambling

Pathological gambling (PG) represents a behavioral side effect of dopamine replacement therapy in a minority of patients with Parkinsons disease (PD). Using striatal dopamine transporter (DAT) with single photon emission tomography we assessed presynaptic dopaminergic function in 8 PD patients with PG, 21 matched PD control subjects, and 14 healthy subjects. Statistical Parametric Mapping was applied for image analysis. The analysis of variance (ANOVA) revealed that the three groups differed in dorsal and ventral striata bilaterally. The post-hoc analysis displayed a reduced tracer binding in the ventral striatum of PD patients with PG compared to PD controls, possibly reflecting either a reduction of mesolimbic projections or, alternatively, a lower membrane DAT expression on presynaptic terminals. The latter hypothesis is most likely given that the functional reduction of presynaptic reuptake would be more consistent with the increased dopamine levels in the ventral striatum recently reported in PD gamblers.

Striatal dopamine release during performance of executive functions: A [11C] raclopride PET study

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 [(11)C] raclopride PET in healthy subjects while performing the Montreal Card Sorting Task (MCST). We observed a striatal reduction in [(11)C] 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 Parkinsons disease.

Extrastriatal dopaminergic dysfunction in tourette syndrome

Tourette syndrome (TS) is a neuropsychiatric disorder presenting with tics and a constellation of nonmotor symptoms that includes attention deficit hyperactivity disorder, obsessive–compulsive disorder, and impulse control disorders. Accumulated evidence from pharmacological trials and postmortem analyses suggests that abnormalities of dopaminergic neurotransmission play a key role in the pathogenesis of TS. A substantial body of evidence has also accrued to implicate regions outside the striatum in the generation of tics.

Pathological gambling in patients with Parkinson's disease is associated with fronto‐striatal disconnection: A path modeling analysis

Pathological gambling may occur in Parkinsons disease (PD) as a complication of dopaminergic therapy. Neuroimaging studies have suggested an abnormal dopamine transmission within the reward system, but the changes in the neural network characterizing PD patients with pathological gambling have never been investigated.

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson’s patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

Impulse control disorders such as pathological gambling (PG) are a serious and common adverse effect of dopamine (DA) replacement medication in Parkinsons 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.

Acute prefrontal cortex TMS in healthy volunteers: Effects on brain 11C-αMtrp trapping

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (LDLPFC) is a technique with purported efficacy as a treatment for major depression. Here, we assessed in vivo, in healthy volunteers, the effect of acute rTMS of the LDLPFC, relative to the stimulation of the left occipital cortex (LOC), on brain regional serotonin synthesis capacity, using the [(11)C]-alpha-methyl-tryptophan ((11)C-alphaMtrp)/PET method. Ten subjects were studied twice, once following rTMS of the LDLPFC and once following rTMS of the LOC in a randomized counterbalanced order. Three blocks of 15 trains of 10 Hz rTMS were delivered 10 min apart. Behavioural and autonomic measures were recorded before and after each rTMS session. Comparisons of TMS-related changes in regional normalized brain uptake and trapping of (11)C-alphaMtrp (K*) values were carried out using SPM99. Statistically significant regional differences were identified on the basis of an extent threshold of 50 voxels, with a peak threshold of p=0.005 uncorrected. Behavioural and autonomic measures were unaffected by rTMS. Relative to LOC stimulation, LDLPFC rTMS was associated with marked changes in normalized K* in limbic areas, with significantly lower values in the left parahippocampal gyrus (BA 28) and the right insula (BA 13), and higher values in the right cingulate gyrus (BA 31) and cuneus (BA 18). These findings indicate that acute rTMS of the LDLPFC in healthy volunteers modulates aspects of tryptophan/5-HT metabolism in limbic areas. Such adaptive changes may contribute to the mechanism of action of prefrontal rTMS in major depression.