By: Paul Croarkin, DO & Roger Pottanat, MD
The theta range refers to EEG waves between 4-7Hz in humans, regardless of where they originate. The term “theta burst” has been applied to this protocol, because 3-pulse 50Hz bursts are applied with an interburst interval of 200ms or 5Hz and is in the range of theta frequency. There are currently two forms in which this protocol is provided (Chung et al., 2015).
Continuous (cTBS) provides a train of uninterrupted burst and has been shown to induce long-term depression-like (LTD) reduction of cortical excitability and preferentially decrease I1 wave. cTBS produces 20 minutes of suppression effects after only 20 seconds of uninterrupted bursts or 300 pulses, whereas 1Hz rTMS requires a minimum of 20 minutes of stimulation for the same results (Li et al., 2014). In rat models, cTBS influences the inhibitory activity of interneurons expressing calbidin D-28k that regulate the synaptic inputs to pyramidal cells. In human models, Magnetic Resonance Spectroscopy revealed an increase [GABA] in M1 after cTBS stimulation, with no significant changes in glutamate/ glutamine levels. A proposed mechanism of action is that cTBS decreases the postsynaptic calcium level through a cumulative effect of presynaptic inhibition that outlasts facilitatory responses (Chung et al, 2015).
Intermittent (iTBS) provides a two second train of bursts (30 pulses), repeated every 10 seconds. iTBS has been shown to cause long-term potentiation-like (LTP) effects of cortical excitability. Stimulation to the motor cortex can produce facilitatory effects, outlasting stimulation for at least 15 minutes and preferentially increased I2 & I3 waves (Li et al., 2014). Based on evidence found using rat models, iTBS may target the inhibition of pyramidal cell output by decreasing interneuronal parvalbumin expression (Chung et al., 2015).
Between 2013-2016 Blumberger, et al, conducted a non-inferiority study, comparing standard 10Hz rTMS depression protocol and an iTBS protocol that delivered 600 pulses in approximately three minutes. Both protocols delivered pulses to the dorsolateral prefrontal cortex (DLPFC) and most patients participating in the study have had failed 1-2 anti-depressant trials. 177 patients and 184 patients between the ages of 18-65 from the 10Hz rTMS and iTBS protocols respectively were included in the sensitivity analysis. The groups demonstrated similar rates of adverse events, response, and remission (Blumberger et al., 2018).
Numerous studies have indicated that majority of patients demonstrate the expected LTD and LTP responses to cTBS and iTBS respectively. However, there are studies that highlight interinvidivual variability with a lack of response or an opposite response in some patients (Hinder et al., 2014 & Hordacare et al., 2017). Therefore, it is possible that the same is true for our current rTMS protocols given the near 30% of non-responders.
Theta burst is a promising new form of TMS delivery that is possibly both more efficient and enduring than standard TMS through effects on LTP and LTD. Lower intensity stimulation is often used in theta burst protocols. This could potentially lead to an increase in access of this treatment to patients by possibly decreasing the cost and time required for successful treatment. Theta burst stimulation is currently not cleared by the US FDA or covered by insurance plans in the Unites States; however, it has been found to be safe when applied to children (Hong et al., 2015 & Allen et al., 2017).
- Chung SW, Hoy KE, Fizgerald PB. Theta-burst Stimulation: A New Form of TMS Treatment for Depression? Depression and Anxiety 2015; 32: 182-192
- Li CT, Chen MH, Juan CH, et al. Efficacy of prefrontal theta-burst stimulation in refractory depression: a randomized sham-controlled study Brain 2014; 137: 2088-2089
- Blumberger DM, Vila-Rodriguez F, Thorpe KE, et al. Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in patients with depression (THREE-D): a randomized non-inferiority trial Lancet 2018 Apr 28; 391: 1683-1692
- Hong Y, Wu S, Pedapti E, et al. Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects Frontiers in Human Neuroscience 2015 Feb 03; 09: 1-5
- Allen C, Kluger B, Buard I Safety of Transcranial Magnetic Stimulation in Children: A Systematic Review of the Literature Pediatric Neurology 2017; 68: 3-17
- Hinder M, Goss E, Fujiyama H, et al. Inter- and Intra-Individual Variability Following Intermittent Theta Burst Stimulation: Implications for Rehabilitation and Recovery Brain Stimulation 2014; 7: 365-371
- Hordacare B, Goldworthy M, Vallence Am, et al. Variability in neural excitability and plasticity induction in the human cortex: A brain stimulation study Brain Stimulation 2017; 10: 588-595