Review articleThe effects of theta burst stimulation (TBS) targeting the prefrontal cortex on executive functioning: A systematic review and meta-analysis
Introduction
Repetitive transcranial magnetic stimulation (rTMS) is a family of techniques designed to modulate the function of brain systems via the application of magnetic pulses delivered in predefined patterns (George and Aston-Jones, 2010, Hallett, 2007). The rTMS coil emits magnetic pulses—of varying length, form and intensity—that induce changes in cortical excitability (upwards or downwards) in the cortical region below the area of application. Specific brain structures are targeted by localizing the coil using either anatomical landmarks, an EEG cap, and/or a frameless stereotaxic system coupled with a co-registered MRI structural brain scan. Repetitive TMS is sometimes referred to as “non-invasive” to reflect the fact that the magnetic pulses are delivered from a coil placed over the scalp, without the necessity of surgical intervention (in contrast with deep brain stimulation, for example). The non-invasive nature of rTMS has contributed to its popularity as technique for modulating brain activity, either temporarily (for experimental purposes) or in a more long lasting manner (for clinical purposes), over the past two decades.
Repetitive TMS methods can be employed to up- or down-regulate cortical excitability with the objective of: 1) exploring the functional relation between specific cortical regions and subsequent cognitive, affective, sensory, and motor functions, 2) achieving lasting change of function in targeted brain regions for therapeutic purposes, or 3) assessing neuroplasticity. With increasing usage in laboratory and treatment contexts, there has been pressure to improve the efficiency by which rTMS methods achieve modulation of cognitive processes. Conventional high frequency rTMS requires 20–30 min of stimulation time to achieve its full effect, thereby making some experimental and clinical applications of the technique logistically challenging to implement. Theta burst stimulation (TBS) protocols promise to deal with the efficiency problem by employing protocols that achieve up- and down-regulation in the fraction of the time of conventional rTMS; stimulation time can be reduced to as little as 20 s to 3 min (i.e., <10% of the time required by conventional rTMS). However, given that TBS protocols have only been developed relatively recently (Huang et al., 2005), establishing validation is of critical importance. The latter can be accomplished in part by aggregating the effects observed across studies in relation to theoretically meaningful—and associated with activation in specific brain regions —cognitive processes.
Although many TBS studies have targeted motor regions, the vast majority of clinical treatment and experimental studies involving psychiatric (e.g., depression, eating disorders) and behavioral phenomena (e.g., food cravings, addictions) have targeted the prefrontal cortex (PFC) because of its link to several aspects of executive control processes. The current meta-analytic review will focus on this anatomical target, with theoretically-linked cognitive test performance as the outcome.
The parameters for TBS were designed to mimic theta rhythms, which are associated with induction of NMDA receptor-dependent long-term potentiation (LTP) and long-term depression (LTD; Huang et al., 2005). Specifically, TBS consists of a triplet of 50 Hz pulses repeated every 200 ms (5 Hz; Huang et al., 2005). Continuous TBS (cTBS) involves an uninterrupted train of TBS for either 20 s (300 pulses; cTBs300) or 40 s (600 pulses; cTBS600), which results in an inhibitory effect (i.e., decreased cortical excitability; Huang et al., 2005). Whereas the after-effects of cTBS600 last for up to 50 min post-stimulation, the after-effects of cTBS300 last for approximately 20 min (Wischnewski and Schutter, 2015). Conversely, intermittent TBS (iTBS) comprises a 2 s TBS train (10 TBS bursts) is delivered every 10 s (8 s inter-burst interval between trains) over a total of 190 s (600 pulses), resulting in an excitatory effect for up to 60 min post stimulation (Huang et al., 2005, Wischnewski and Schutter, 2015).
The physiological mechanisms underlying iTBS and cTBS-induced after-effects are theorized to be analogous to long-term potentiation (LTP; increased synaptic efficiency) or long-term depression (LTD; decreased synaptic efficiency; Huang et al., 2011; Suppa et al., 2016) respectively; however, the exact mechanisms have not been definitively confirmed. Further, the magnitude of the effects may be dependent on stimulation duration: differential patterns of activation have been documented when comparing cTBS300 (300 stimuli) and cTBS600 (600 stimuli) protocols, such that the cTBS300 protocols have been shown in one study to increase cortical excitability in healthy individuals (Gentner et al., 2008). Likewise, one additional study found that prolonging the duration of conventional iTBS (i.e., from 190 s (600 pulses) to 390 s (1200 pulses)) and cTBS (i.e., from 40 s (600 pulses) to 80 s (1200 pulses)) results in the inversion of normally theorized cortical excitatory/inhibitory effects (Gamboa et al., 2010). Even within conventional stimulation protocols, the responsiveness to TBS protocols among healthy individuals is subject to some level of variability (Hamada et al., 2013, Jannati et al., 2017, Suppa et al., 2016). Finally, in contrast with clinical interest in application of TBS protocols targeting the PFC, much of the early theorizing and validation work involving TBS has involved its application to motor areas.
The above provide a good rationale for examining the generality of the effects of TBS across studies that target the PFC and associated cognitive processes, particularly within conventional stimulation parameters. In contrast with existing validation work involving motor region stimulation targets, which is generally well established (Chung et al., 2016; Wischnewski and Schutter, 2015), there remains uncertainty about the effects of TBS protocols on other areas of the brain. While the application of cTBS over the prefrontal cortex (PFC) has been shown to decrease regional blood flow to the PFC (Tupak et al., 2013) and impair task-specific dopaminergic transmission in PFC-striatal network (Ko et al., 2008), the extent to which these observed physiological changes modulate PFC-dependent cognitive functions—most centrally, executive functions—remains unclear.
Executive functions can be defined as a set of higher-order cognitive processes that serve to bias lower order perceptual-motor processes in the service of goal-directed behavior and other non-stimulus driven objectives (Baddeley, 1996; Friedman & Miyake, 2017; Miyake et al., 2000; Miller & Cohen, 2001; Miyake and Friedman, 2012). Conceptually, executive function consists of a common latent construct that can be further decomposed into several interconnected, but distinguishable, subcomponents such as behavioral inhibition, working memory, and set shifting (Miyake et al., 2000, Miyake and Friedman, 2012). Together, these subcomponents potentiate complex processes and behaviours that are commonly thought of as reflecting foresighted decision-making, self-regulatory abilities, and planning (Miyake and Friedman, 2012, Norman and Shallice, 1986). Although the fronto-parietal network predominantly subserves executive function, the PFC is thought to be a particularly important cortical region wherein different sub-regions play specific roles in the overall process of control (Miller, 2000).
It is important to quantify TBS effects on cognitive task performance given that it's intended therapeutic effects are assumed to operate via mediation by cognitive processes. Most of the therapeutic usage of rTMS for treating psychiatric conditions (see Gaynes et al., 2014 and Yan et al., 2017 for recent reviews), and many of the single-session research paradigms for modulating craving responses to appetitive stimuli (Lowe et al., 2017; Hall et al., 2017; Jansen et al., 2013) target sub-regions of the PFC. In research and clinical applications, TBS's intended effects rely at least partially on theorized TBS effects on underlying cognitive processes supported by the PFC (i.e., executive control). For instance, executive control is thought to modulate negative emotionality in depression (Joormann & Gotlib, 2010), and hypo-activation of the dlPFC is a correlate of depressive status (Koenigs and Grafman, 2009). Up-regulation of executive control centres has accordingly been a theorized mechanism by which symptom improvement might take place in the treatment of depression (Koenigs and Grafman, 2009). Likewise, in the case of post traumatic stress disorder, the modulation of reactive anxiety and behavioral avoidance would be postulated to rely centrally on the same executive control substrates (Patel et al., 2012). In both of these psychiatric conditions, cognitive processes (executive control) are part of the causal chain linking neuromodulation to improved treatment outcomes.
The current study aggregates existing published and unpublished research findings using quantitative meta-analytic methods to examine the following questions: 1) is there a reliable effect of TBS protocols on theoretically meaningful cognitive mediators (i.e., executive function) when targeting PFC? 2) do cTBS and iTBS targeting the PFC modulate performance on executive function measures in the theorized directions? 3) are cTBS and iTBS effects similar in magnitude? 4) are there any moderators of effect size? In providing this organizational framework for existing TBS findings targeting the PFC, we evaluate the validity of such protocols in experimental and clinical contexts, and provide a basis from which such uses can be justified or not.
Section snippets
Literature search and study selection
A comprehensive search of PubMed, Scopus, Web of Science and PsycINFO was conducted in June 2017 and updated in January 2018 using the search terms theta burst stimulation and transcranial magnetic stimulation combined with prefrontal cortex, orbitofrontal cortex, or anterior cingulate cortex and executive function, executive control, cognition, cognitive, inhibitory control, inhibition, set shifting, task shifting, task switching, mental flexibility, working memory, updating, decision making,
Results
Individual study and sample characteristics by TBS variant are presented in Table 1. The initial literature search resulted in 911 articles (duplicates removed) of which 48 were included in the full text review; Fig. 1 presents the study selection flow chart. In addition, unpublished data from two dissertations (Maizey, 2016, Lowe, 2017) were identified-via the grey literature search- as meeting the inclusion criteria, and were included in all analyses. Together, a total of 32 (29 cTBS; 8 iTBS)
Discussion
This systematic review evaluated the reliability and effectiveness of TBS targeting the PFC for modulating executive functioning in healthy individuals (i.e., non-clinical populations). Findings revealed that cTBS targeting the prefrontal cortex reliably decreases performance on measures of executive function (g = −.244) with a high degree of uniformity across studies. This effect was not moderated by age, biological sex, or study quality. Examination of the specific subcomponents of executive
Funding
The authors have no funding to report. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
Author contributions
C.L. and P.H. conceived the idea. C.L. F.M. and A.S. conducted the literature search and data extraction. All statistical analyses were performed by C.L. C.L. and P.H. drafted and manuscript, and all authors provided revisions.
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