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

Abstract

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 [ 11 C]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 [ 11 C]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.

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex enhances working memory

“…In addition, repetitive TMS causes slow and long-lasting neuroplastic changes of the stimulated area following multiple TMS treatment sessions. These include neurotransmitter regulation of the dopaminergic (Strafella et al 2001;Cho and Strafella 2009;Ko et al 2008) and adrenergic system (Lisnaby and Belmaker 2000), as well as gene expression (Hausmann et al 2000;Funamizu et al 2005) and morphological regulation (Fujiki et al 2003). TMS stimulation causes not only local physical effects, but also excitation of remote brain areas and modulation of longdistance functional connectivities.…”

The Neural Circuitry of Executive Functions in Healthy Subjects and Parkinson's Disease

“…These findings suggest that striatal DA neurotransmission increases significantly during the performance of specific executive processes. Although [ 11 C]raclopride may offer important insights in striatal DA neurotransmission during executive functions (Ko et al, 2008a;Monchi et al, 2006a), its low affinity limits its application to extrastriatal regions such as the PFC .…”

“…Changes in [ 11 C]raclopride-binding potential (BP) provide a reasonable estimate of synaptic dopamine (DA) release in the striatum (Farde et al, 1986). This method has been widely used for investigation of the striatal dopaminergic transmission during various cognitive tasks (Goerendt et al, 2003;Ko et al, 2008a;Monchi et al, 2006a;Ouchi et al, 2002;Zald et al, 2004). To investigate the contribution of striatal DA during set shifting, Monchi et al (2006a) tested young healthy subjects using PET during retrieval with and without shift on a variant of the WCST, the MCST.…”

“…The aim of the study by Ko et al (2008a) was to transiently disrupt the function of DLPFC and to measure MCST performance and striatal DA release during [ 11 C]raclopride PET. A significant hemispheric asymmetry was observed.…”

“…Owing to its potent inhibitory effects, cTBS is suitable to study TMSinduced effects on cognitive behavior. To investigate the contribution of the DLPFC during set shifting in the MCST and its effect on the striatal dopaminergic system, Ko et al (2008a) applied cTBS to left and right DLPFC (Figure 7). Three cTBS blocks (20 s each) were applied to the left and right DLPFC, and to the vertex before the MCST.…”