Neurochemical Effects of Theta Burst Stimulation as Assessed by Magnetic Resonance Spectroscopy

Centre for Functional Resonance Imaging of the Brain, University of Oxford, Oxford, United Kingdom.
Journal of Neurophysiology (Impact Factor: 2.89). 05/2009; 101(6):2872-7. DOI: 10.1152/jn.91060.2008
Source: PubMed


Continuous theta burst stimulation (cTBS) is a novel transcranial stimulation technique that causes significant inhibition of synaptic transmission for <or=1 h when applied over the primary motor cortex (M1) in humans. Here we use magnetic resonance spectroscopy to define mechanisms mediating this inhibition by noninvasively measuring local changes in the cortical concentrations of gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx). cTBS to the left M1 led to an increase in GABA compared with stimulation at a control site without significant change in Glx. This direct evidence for increased GABAergic interneuronal activity is framed in terms of a new hypothesis regarding mechanisms underlying cTBS.

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Available from: Charlotte J Stagg, Nov 17, 2014
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    • "Theta-burst TMS decreases the magnitude of evoked potentials in motor [50] and somatosensory [67] regions, decreases motor excitability [68], increases saccade latencies [69], and increases phosphene thresholds [70]. Furthermore, studies of theta-burst TMS have suggested that it alters inhibitory systems, as assessed with electrophysiological recordings from the spinal cord [68] and MR spectroscopy measurements [71] in humans, and with electrophysiological recordings and measurement of protein expression in rats [72]. "
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    ABSTRACT: Transcranial Magnetic Stimulation (TMS) is an important tool for testing causal relationships in cognitive neuroscience research. However, the efficacy of TMS can be variable across individuals and difficult to measure. This variability is especially a challenge when TMS is applied to regions without well-characterized behavioral effects, such as in studies using TMS on multi-modal areas in intrinsic networks. Here, we examined whether perfusion fMRI recordings of Cerebral Blood Flow (CBF), a quantitative measure sensitive to slow functional changes, reliably index variability in the effects of stimulation. Twenty-seven participants each completed four combined TMS-fMRI sessions during which both resting state Blood Oxygen Level Dependent (BOLD) and perfusion Arterial Spin Labeling (ASL) scans were recorded. In each session after the first baseline day, continuous theta-burst TMS (TBS) was applied to one of three locations: left dorsolateral prefrontal cortex (L dlPFC), left anterior insula/frontal operculum (L aI/fO), or left primary somatosensory cortex (L S1). The two frontal targets are components of intrinsic networks and L S1 was used as an experimental control. CBF changes were measured both before and after TMS on each day from a series of interleaved resting state and perfusion scans. Although TBS led to weak selective increases under the coil in CBF measurements across the group, individual subjects showed wide variability in their responses. TBS-induced changes in rCBF were related to TBS-induced changes in functional connectivity of the relevant intrinsic networks measured during separate resting-state BOLD scans. This relationship was selective: CBF and functional connectivity of these networks were not related before TBS or after TBS to the experimental control region (S1). Furthermore, subject groups with different directions of CBF change after TBS showed distinct modulations in the functional interactions of targeted networks. These results suggest that CBF is a marker of individual differences in the effects of TBS.
    PLoS ONE 07/2014; 9(7):e101430. DOI:10.1371/journal.pone.0101430 · 3.23 Impact Factor
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    • "Previously, MRS has been used to demonstrate an increase in GABA concentration following the application of cTBS to the motor cortex [11], raising the question of whether such effects are reproducible in non-motor cortical areas. Furthermore, the application of MRS to study functional changes in GABA is a relatively new and unconfirmed approach, the implementation of which can differ widely between laboratories. "
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    ABSTRACT: This series of experiments investigated the neural basis of conscious vision in humans using a form of transcranial magnetic stimulation (TMS) known as continuous theta burst stimulation (cTBS). Previous studies have shown that occipital TMS, when time-locked to the onset of visual stimuli, can induce a phenomenon analogous to blindsight in which conscious detection is impaired while the ability to discriminate 'unseen' stimuli is preserved above chance. Here we sought to reproduce this phenomenon using offline occipital cTBS, which has been shown to induce an inhibitory cortical aftereffect lasting 45-60 minutes. Contrary to expectations, our first experiment revealed the opposite effect: cTBS enhanced conscious vision relative to a sham control. We then sought to replicate this cTBS-induced potentiation of consciousness in conjunction with magnetoencephalography (MEG) and undertook additional experiments to assess its relationship to visual cortical excitability and levels of the inhibitory neurotransmitter γ-aminobutyric acid (GABA; via magnetic resonance spectroscopy, MRS). Occipital cTBS decreased cortical excitability and increased regional GABA concentration. No significant effects of cTBS on MEG measures were observed, although the results provided weak evidence for potentiation of event related desynchronisation in the β band. Collectively these experiments suggest that, through the suppression of noise, cTBS can increase the signal-to-noise ratio of neural activity underlying conscious vision. We speculate that gating-by-inhibition in the visual cortex may provide a key foundation of consciousness.
    PLoS ONE 06/2014; 9(6):e100350. DOI:10.1371/journal.pone.0100350 · 3.23 Impact Factor
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    • "On the basis of these data, an effectiveness of TBS in the treatment of MD is definitely plausible although the specific mechanisms of action have not yet been fully clarified. Besides the well documented effects on local cortical activity, modulations of broader functional network, (Hubl, et al., 2008), neurochemical effects (Stagg, et al., 2009), and oscillatory activity (Noh et al., 2012) are most likely involved in the effects of TMS in general and TBS in particular. In any case, an optimization of the existing TMS-paradigms would be desirable and the quicker application of TBS compared to rTMS would be very useful (Fitzgerald et al., 2012). "
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    ABSTRACT: Current efforts to improve clinical effectiveness and utility of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depression (MD) include theta burst stimulation (TBS), a patterned form of rTMS. Here, we investigated the efficacy of bilateral TBS to the dorsolateral prefrontal cortex (dlPFC) in patients with MD in additon to ongoing medication and psychotherapy. In this randomized-controlled trial, thirty-two patients with MD were treated for six weeks (thirty sessions) with either successively intermittent, activity enhancing TBS (iTBS) to the left and continuous, inhibiting TBS (cTBS) to the right dlPFC or with bilateral sham stimulation. Primary outcome measure was the proportion of treatment response defined as a Montgomery-Åsberg Depression Rating Scale (MADRS)≤50% compared to baseline. Secondary outcomes comprised response and remission rates of the Hamilton Depression Rating Scale (HAMD) and the Beck Depression Inventory (BDI). A larger number of responders were found in the cTBS (n=9) compared to the sham-stimulation (n=4) group (odds ratio: 3.86; Wald χ(2)=3.9, p=0.048). On secondary endpoint analysis, patient-reported outcome as assessed by the BDI, pointed towards a higher rate of remitters in the cTBS (n=6) than in the sham (n=1) group (odds ratio: 9; Wald χ(2)=3.5, p=0.061). With regard to the pilot character of the study and the small sample size, the results have to be considered as preliminary. These findings provide first evidence that six weeks treatment of MDD with iTBS to the left and cTBS to the right dlPFC for six weeks is safe, feasible and superior to sham stimulation applied add-on to pharmacological and psychotherapeutic treatment.
    Journal of Affective Disorders 12/2013; 156. DOI:10.1016/j.jad.2013.12.025 · 3.38 Impact Factor
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