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D2 receptor block abolishes θ burst stimulation-induced neuroplasticity in the human motor cortex.

ABSTRACT: Dopamine (DA) is a neurotransmitter with an important influence on learning and memory, which is thought to be due to its modulatory effect on plasticity at central synapses, which in turn depends on activation of D1 and D2 receptors. Methods of brain stimulation (transcranial direct current stimulation, tDCS; paired associative stimulation, PAS) lead to after-effects on cortical excitability that are thought to resemble long-term potentization (LTP)/long-term depression (LTD) in reduced preparations. In a previous study we found that block of D2 receptors abolished plasticity induced by tDCS but had no effect on the facilitatory plasticity induced by PAS. We postulated that the different effect of D2 receptor block on tDCS- and PAS-induced plasticity may be due to the different focality and associativity of the stimulation techniques. However, alternative explanations for this difference could not be ruled out. tDCS also differs from PAS in other aspects, as tDCS induces plasticity by subthreshold neuronal activation, modulating spontaneous activity, whereas PAS induces plasticity via phasic suprathreshold stimulation. The present study in 12 volunteers examined effects of D2 receptor blockade (sulpiride (SULP) 400 mg), on the LTP/LTD-like effects of theta burst transcranial magnetic stimulation (TBS), which has less restricted effects on cortical synapses than that of PAS, and does not induce associative plasticity, similar to tDCS, but on the other hand induces cortical excitability shifts by suprathreshold (rhythmic) activation of cortical neurons similarly to PAS. Administration of SULP blocked both the excitatory and inhibitory effects of intermittent (iTBS) and continuous TBS (cTBS), respectively. As the reduced response to TBS following SULP resembles its effect on tDCS, the results support an effect of DA on plasticity, which might be related to the focality and associativity of the plasticity induced.

SUBMITTER: Monte-Silva K

PROVIDER: S-EPMC3158306 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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Project description:IntroductionCognitive symptoms from Parkinson's disease cause severe disability and significantly limit quality of life. Little is known about mechanisms of cognitive impairment in PD, although aberrant oscillatory activity in basal ganglia-thalamo-prefrontal cortical circuits likely plays an important role. While continuous high-frequency deep brain stimulation (DBS) improves motor symptoms, it is generally ineffective for cognitive symptoms. Although we lack robust treatment options for these symptoms, recent studies with transcranial magnetic stimulation (TMS), applying intermittent theta-burst stimulation (iTBS) to dorsolateral prefrontal cortex (DLPFC), suggest beneficial effects for certain aspects of cognition, such as memory or inhibitory control. While TMS is non-invasive, its results are transient and require repeated application. Subcortical DBS targets have strong reciprocal connections with prefrontal cortex, such that iTBS through the permanently implanted lead might represent a more durable solution. Here we demonstrate safety and feasibility for delivering iTBS from the DBS electrode and explore changes in DLPFC electrophysiology.MethodsWe enrolled seven participants with medically refractory Parkinson's disease who underwent DBS surgery targeting either the subthalamic nucleus (STN) or globus pallidus interna (GPi). We temporarily placed an electrocorticography strip over DLPFC through the DBS burr hole. After placement of the DBS electrode into either GPi (n = 3) or STN (n = 4), awake subjects rested quietly during iTBS (three 50-Hz pulses delivered at 5 Hz for 2 s, followed by 8 s of rest). We contrasted power spectra in DLPFC local field potentials during iTBS versus at rest, as well as between iTBS and conventional high-frequency stimulation (HFS).ResultsDominant frequencies in DLPFC at rest varied among subjects and along the subdural strip electrode, though they were generally localized in theta (3-8 Hz) and/or beta (10-30 Hz) ranges. Both iTBS and HFS were well-tolerated and imperceptible. iTBS increased theta-frequency activity more than HFS. Further, GPi stimulation resulted in significantly greater theta-power versus STN stimulation in our sample.ConclusionAcute subcortical iTBS from the DBS electrode was safe and well-tolerated. This novel stimulation pattern delivered from the GPi may increase theta-frequency power in ipsilateral DLPFC. Future studies will confirm these changes in DLPFC activity during iTBS and evaluate whether they are associated with improvements in cognitive or behavioral symptoms from PD.

Project description:BackgroundOver the past decade, the number of experimental and clinical studies using theta-burst-stimulation (TBS) protocols of transcranial magnetic stimulation (TMS) to modulate brain activity has risen substantially. The use of TBS is motivated by the assumption that these protocols can reliably and lastingly modulate cortical excitability despite their short duration and low number of stimuli. However, this assumption, and thus the experimental validity of studies using TBS, is challenged by recent work showing large inter- and intra-subject variability in response to TBS protocols.ObjectivesTo date, the reproducibility of TBS effects in humans has been exclusively assessed with motor evoked potentials (MEPs), which provide an indirect and limited measure of cortical excitability. Here we combined TMS with electroencephalography (TMS-EEG) and report the first comprehensive investigation of (1) direct TMS-evoked cortical responses to intermittent (iTBS) and continuous TBS (cTBS) of the human motor cortex, and (2) reproducibility of both iTBS- and cTBS-induced cortical response modulation against a robust sham control across repeat visits with commonly used cortical responsivity metrics.ResultsWe show that although single pulse TMS generates stable and reproducible cortical responses across visits, the modulatory effects of TBS vary substantially both between and within individuals. Overall, at the group level, most measures of the iTBS and cTBS-induced effects were not significantly different from sham-TBS. Most importantly, none of the significant TBS-induced effects observed in visit-1 were reproduced in visit-2.ConclusionsOur findings suggest that the generally accepted mechanisms of TBS-induced neuromodulation, i.e. through changes in cortical excitability, may not be accurate. Future research is needed to determine the mechanisms underlying the established therapeutic effects of TBS in neuropsychiatry and examine reproducibility of TBS-induced neuromodulation through oscillatory response dynamics.

Project description:BackgroundTheta burst stimulation (TBS) is an efficient noninvasive neuromodulation paradigm that has been widely adopted, clinically. However, the efficacy of TBS treatment remains similarly modest as conventional 10 Hz repetitive transcranial magnetic stimulation (rTMS).Objective/hypothesisTo develop a new TBS paradigm that enhances the effects of TMS administration while maintaining high time-efficiency.MethodsWe describe here a new TMS paradigm, named High-Density Theta Burst Stimulation (hdTBS). This paradigm delivers up to 6 pulses per burst, as opposed to only 3 in conventional TBS, while maintaining the inter-burst interval of 200 ms (or 5 Hz) - a critical parameter in inducing long-term potentiation. This paradigm was implemented on a TMS stimulator developed in-house; its physiological effects were assessed in the motor cortex of awake rats using a rodent specific focal TMS coil. Microwire electrodes were implanted into each rat's limb muscles to longitudinally record motor-evoked potential (MEP). Four different TBS paradigms (3, 4, 5 or 6 pulses per burst, 200 s per session) were tested; MEP signals were recorded immediately before (baseline) and up to 35 min post each TBS session.ResultsWe developed a stimulator based on a printed-circuit board strategy. The stimulator was able to deliver stable outputs of up to 6 pulses per burst. Animal experiments (n = 15) revealed significantly different aftereffects induced by the four TBS paradigms (Friedman test, p = 0.018). Post hoc analysis further revealed that, in comparison to conventional 3-pulse TBS, 5- and 6-pulse TBS enhanced the aftereffects of MEP signals by 56% and 92%, respectively, while maintaining identical time efficiency.Conclusion(s)A new stimulation paradigm is proposed, implemented and tested in the motor cortex of awake rats using a focal TMS coil developed in the lab. We observed enhanced aftereffects as assessed by MEP, with no obvious adverse effects, suggesting the translational potentials of this paradigm.

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D2 receptor block abolishes θ burst stimulation-induced neuroplasticity in the human motor cortex.

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