A computational modelling study of transcranial direct current stimulation montages used in depression
Introduction
Transcranial direct current stimulation (tDCS) is a neuromodulatory technique which involves passing a mild electric current to the brain through electrodes placed on the scalp. This direct constant flow of current modulates underlying cortical activity with specific outcomes related to anodal or cathodal stimulation (Nitsche and Paulus, 2000, Nitsche and Paulus, 2001). The relative position (electrode montage) and size of the anode and cathode determine the distribution of current density throughout the brain (Bikson et al., 2010, Datta et al., 2011, Lee et al., 2012, Miranda et al., 2009, Wagner et al., 2007). Thus there is potential for stimulation to be focussed on specific cortical brain regions for therapeutic or investigative purposes or more diffuse effects can be produced if widespread activation of brain regions is desired.
A key application of tDCS has been investigated in the treatment of depression. Several recent open label and placebo-controlled trials, and a meta-analysis of mean change in depression scores from placebo-controlled studies suggest that tDCS may have clinically meaningful efficacy (Boggio et al., 2008, Brunoni et al., 2011, Fregni et al., 2006a, Fregni et al., 2006b, Kalu et al., 2012, Loo et al., 2012, Martin et al., 2011, Palm et al., 2011). These studies focused on anodal stimulation of the left dorsolateral prefrontal cortex (DLPFC), based on observations that this area has been associated with underactivity in depression (Grimm et al., 2008). However, studies differed in the location of the cathode, i.e. the return electrode — right supraorbital, right lateral orbitofrontal, right DLPFC or in an extracephalic position. Though the anodal left DLPFC electrode is often considered the “active” electrode, the placement of the cathode is important for several reasons: shunting of much of the current over the scalp may occur if the inter-electrode distance is too close (Datta et al., 2008, Miranda et al., 2006, Weaver et al., 1976), current density under the anode is affected by the placement of the reference or “return” electrode (Bikson et al., 2010, Datta et al., 2011), and the pattern of brain areas stimulated will be determined by the overall montage. All of these factors may have important therapeutic implications.
Pathophysiological changes in depression are system-wide, involving a network of various cortical and limbic structures rather than a solitary brain region such as the left DLPFC (Mayberg, 2007). Hypoactivity in cortical regions and hyperactivity in subcortical and limbic regions is often associated with symptoms of depression (Fitzgerald et al., 2008, Mayberg, 1997). Meta-analyses have identified frontal and temporal cortices, the insula and cerebellum as regions of hypoactivity while subcortical and limbic regions tend to be hyperactive. This distributed network of structures includes the DLPFC, medial prefrontal cortex (MPFC), orbitofrontal cortex (OFC), as well as the anterior cingulate cortex (ACC), insula and hippocampus (Fox et al., 2012, Mayberg, 2003). Most recently, functional connectivity studies have suggested altered activity at a network level during the resting state (Carballedo et al., 2011). In particular, there is increased functional connectivity in the subgenual anterior cingulate (sgACC), thalamus and OFC in people with depression (Greicius et al., 2007). Further, overactivity in the sgACC has been shown to be strongly negatively correlated with resting state underactivity in the left DLPFC (Fox et al., 2012).
Studies of deep brain stimulation (DBS) in depression have also provided insight into the critical regions involved in depression. Consistent with imaging studies, DBS interventions targeted at the sgACC have demonstrated efficacy in reducing symptoms of depression (Lozano et al., 2012, Mayberg et al., 2005). DBS to specific regions of the basal ganglia such as the nucleus accumbens (NAcc) and the ventral capsule/ventral striatum (VC/VS) have also been found to have significant antidepressant effects (Anderson et al., 2012, Bewernick et al., 2010, Bewernick et al., 2012, Malone et al., 2009).
As the therapeutic potential of tDCS in psychiatric disorders is further explored, information on how different electrode arrangements determine current density in key brain regions, is essential. This study compared the effects of several DCS montages, with realistic head models reconstructed from MRI head scans, by investigating the brain electric field (E-field) distribution and the average E-field in various brain regions. tDCS montages modelled were those used in recent tDCS depression studies: the F3–supraorbital (F3–SO) montage first used when interest was rekindled in tDCS from 2006 onwards (Boggio et al., 2008, Fregni et al., 2006a, Fregni et al., 2006b, Loo et al., 2010, Palm et al., 2011), and modified approaches in which the cathode was moved more laterally to reduce shunting, F3–F8 (Loo et al., 2012), to the right DLPFC, F3–F4 (Brunoni et al., 2011, Brunoni et al., 2013, Dell'Osso et al., 2012, Ferrucci et al., 2009a, Ferrucci et al., 2009b), or to an extracephalic position to achieve a more widespread pattern of brain activation, F3–extracephalic (F3–EC, brain sites based on the 10–20 EEG system; Martin et al., 2011). The bilateral supraorbital–extracephalic (SO–EC) montage most commonly used in earlier, pre-2000 studies, involving two small anodes at the frontal poles and an extracephalic cathode was also modelled (Arul-Anandam and Loo, 2009, Lippold and Redfearn, 1964, Redfearn et al., 1964). In addition, several hypothetical montages were modelled: supraorbital–occipital (SO–OCC), premised on maximal stimulation of the sgACC and other central and midline subcortical structures; temporal–extracephalic (TMP–EC), prioritising temporal lobe stimulation as neurotrophic changes in this region may have a key role in the pathophysiology of depression (Pittenger and Duman, 2007), and supraorbital–cerebellum (SO–CB), as abnormal cerebellar modulation of the cerebello-thalamo-cortical pathway has been implicated in the mood and cognitive symptoms associated with several psychiatric disorders, including bipolar disorder and depression (Hoppenbrouwers et al., 2008).
The montages were modelled in two subjects — one male and one female — to examine the extent to which inter-individual differences in head anatomy affect variation in electric field with different montages. Finally, a sensitivity analysis was performed to examine the effects of displacing the anodal electrode by ~ 1 cm, to inform on the likely importance of accuracy in electrode placement in clinical applications.
Section snippets
Image segmentation and mesh generation
Two different high-resolution computational head models were reconstructed from human subjects. One subject was a 35-year-old Asian male whose MRI head scan, labelled “Msub” (short for male subject), was truncated at the level of cervical vertebra 6. The other was a 42-year-old Caucasian female, labelled “Fsub” (female subject, Fig. 1S in Supplementary data): her scan was truncated at the level of the atlas-axis, i.e., cervical vertebrae 1–2. T1-weighted MRI scans of both subjects were obtained
Results
Fig. 4 shows the E-field magnitude and direction on the cortical surface of the brain for six selected tDCS electrode montages with Msub-aniso. Fig. 5 shows the E-field profile with the same head model in cross-sectional slices of the brain for the selected tDCS electrode montages. The montages which utilised the F3 anode and a contralateral frontal cephalic cathode (F3–SO, F3–F8, F3–F4-1 as shown in Fig. 4) exhibited higher current density predominately in the frontal lobes of the brain. F3–F8
Clinical implications of electrode montages
A number of recent tDCS studies have reported positive antidepressant effects in depressed patients (Boggio et al., 2008, Brunoni et al., 2011, Brunoni et al., 2013, Fregni et al., 2006a, Fregni et al., 2006b, Kalu et al., 2012, Loo et al., 2012, Martin et al., 2011, Palm et al., 2011). The rationale guiding the choice of electrode montage in these trials is up-regulation of the left DLPFC, with the anode placed on F3 (Boggio et al., 2008, Brunoni et al., 2011, Brunoni et al., 2013, Dell'Osso
Conclusion
With the aid of computational modelling, this study presented a systematic analysis of various tDCS electrode montages that have been used in clinical trials, as well as hypothetical montages specifically for the treatment of depression. The overall profile of E-field magnitude and direction, as well as the average E-field magnitudes in key brain regions were presented. While the clinical significance of these outcomes is not as yet well understood, these results may form a useful reference for
Acknowledgment
The authors would like to thank Prof. Caroline Rae and Dr. John Geng from Neuroscience Research Australia for their support in acquiring and processing the structural MRI and DT-MRI data, Dr. Elizabeth Tancred from the University of New South Wales for her expertise in the head anatomy, and Dr. Angelo Alonzo from the Black Dog Institute for his help in determining the accurate position of scalp electrodes.
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2023, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Martin and colleagues observed that tDCS antidepressant efficacy improved after moving the cathode from F4 to an extracephalic position, i.e. switching from bifrontal to fronto-extracephalic montage, although these observations stem from the treatment of a small and mixed sample (9 unipolar, 2 bipolar) (Martin et al., 2011). A fronto-extracephalic montage may induce greater antidepressant effects by more direct and widespread activation of limbic areas associated with the pathophysiology of depression, including the anterior cingulate, the insula, the basal ganglia, and the superior temporal gyrus (Bai et al., 2014; Bikson et al., 2008). Moreover, preliminary results showed that alternative tDCS montages, such as bitemporal electrodes positioning, might also be useful for the treatment of depression (Ho et al., 2015).