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Updated scalp heuristics for localizing the dorsolateral prefrontal cortex based on convergent evidence of lesion and brain stimulation studies in depression
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, CanadaKrembil Research Institute and Centre for Mental Health, University Health Network, Toronto, ON, Canada
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, CanadaDepartment of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, CanadaTemerty Centre for Therapeutic Brain Intervention and Campbell Family Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada
Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, CanadaKrembil Research Institute and Centre for Mental Health, University Health Network, Toronto, ON, CanadaDepartment of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, Canada
Targets from convergent maps of lesion and brain stimulation studies in depression.
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Updated scalp-based heuristic for localizing the dorsolateral prefrontal cortex.
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Calculation tool for locating targets with the input of cardinal scalp measurements.
Abstract
Background
Repetitive transcranial magnetic stimulation (rTMS) is entering wider use as a therapeutic intervention for many psychiatric illnesses. The efficacy of this therapeutic intervention may depend on accurately localizing target brain regions. Recent work investigating whole-brain maps of circuits associated with depression and its successful treatment has identified foci of interest within the dorsolateral prefrontal cortex (DLPFC).
Objective
To create an updated scalp heuristic for localizing the DLPFC based on convergent evidence of lesion and brain stimulation studies in depression.
Methods
Using the standard MNI ICBM152 anatomical template, we localized the scalp sites at minimum Euclidean distance from target MNI coordinates and performed nasion-inion, tragus-tragus, and head-circumference measurements on the anatomical template. We then derived equations to localize these scalp sites.
Results
The derived equations to calculate the arc length X and Y for these new targets are as follows: [ ; ] for the left anterior DLPFC[ ; ] for the right anterior DLPFC[ ; ] for the left posterior DLPFC[ ; ] for the right posterior DLPFC
Conclusions
This heuristic may help localize DLPFC targets identified in previous lesion-/stimulation-mapping work. A spreadsheet calculation tool is offered to support use of this heuristic.
Repetitive transcranial magnetic stimulation (rTMS) is entering wider use as a therapeutic intervention for many psychiatric illnesses. The efficacy of this therapeutic intervention may depend on accurately localizing the target brain regions [
]. For the treatment of major depressive disorder (MDD), the most commonly used stimulation target is the left dorsolateral prefrontal cortex (DLPFC). In clinical practice, widely used standard methods for localizing this target include the conventional ‘5 cm rule’ anterior to the motor ‘hotspot’ [
]. This latter location corresponds closely to a target in the DLPFC that was previously found to be maximally anti-correlated to subgenual cingulate activity on resting-state fMRI [
Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex.
Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex.
] that is used by many clinical practitioners as a guide for positioning non-invasive brain stimulation interventions that target the DLPFC, such as rTMS.
Given the variety of scalp heuristics already in use for targeting DLPFC, any updated targets/heuristics are justified only if the underlying empirical foundations are strengthened. Recently, Siddiqi et al. [
] to develop a whole-brain map derived from independent yet convergent analyses of the functional networks associated with response and non-response to DLPFC-TMS (N = 151), DBS (N = 101), and also to the emergence vs non-emergence of depression symptoms following lesions (N = 461) [
]. The convergence of these independent lines of causal (lesion, stimulation) evidence upon a common network renders that network of considerable interest for future study. Interestingly, the combined map identifies not one but two foci of interest in the DLPFC on each hemisphere, neither of which are well-approximated by F3 or F4. Here, we have developed an updated set of scalp-based heuristics similar in approach to the BeamF3 method but instead localizing the scalp sites closest to these four DLPFC foci of interest in the left and right hemispheres.
2. Methods
Our approach here closely parallels that used in our previous work [
Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex.
Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex.
]. Although Siddiqi et al., reported several maxima of interest outside the frontal lobes, we have restricted this analysis to the anterior and posterior DLPFC-region maxima identified in the left and right hemisphere in the Supplementary Material of [
], as regions outside the frontal lobe have not yet been studied in depth as rTMS targets in depression.
SimNIBS (version 3.2.3) https://simnibs.github.io/simnibs was used to identify each scalp site with the shortest Euclidean distance from its respective cortical MNI coordinate, via progressive expansion of a spherical ROI centred on the MNI coordinate to the point of intersection of the expanding sphere with the scalp surface. The scalp MNI coordinates were saved as fiducials on the standard MNI brain and exported for analysis in Horos (Version 4.0.0) https://horosproject.org. Here the standard scalp landmarks nasion (N), inion (I), left/right tragus (Tr), vertex (Cz), FpZ, and Oz were manually identified on the standard MNI 152 brain. Next, using the curvilinear distance measurement tool, 3 scalp measurements: NI, the nasion-inion distance, TrTr, the left tragus-right tragus distance through the scalp vertex (at 50% of the nasion-inion distance), and HC, the head circumference (measured through the FPz-Oz plane in the international 10–20 EEG system) were identified (Fig. 1A).
Fig. 1A. Cardinal scalp measurements according to the 10–20 EEG system, as applied to the MNI152 anatomical template rendered in 3 dimensions. B. Measurement of arc length X and arc length Y on this template to localize the scalp sites of interest. C. Oblique-view rendering of the anterior and posterior DLPFC scalp sites corresponding to those reported for the frontal lobes in Siddiqi et al., 2021 and the optimized F3 and F4 locations corresponding to the scalp-site heuristic of Mir-Moghtadaei et al., 2015.
In order to derive values for X and Y for the scalp sites, the point of intersection between the scalp surface and the exported spherical markers from SimNIBS was located in Horos, and the MRI volume was again resliced along the plane from Cz to this marker. The point of intersection between this plane and the head circumference was then marked as the point X, and the length of the arc along the head circumference from the midline to this point X was measured using the curvilinear measurement tool to define arc-length X in each trail. Likewise, the length of the arc from Cz to the scalp target was measured as arc length Y (Fig. 1B).
The ratio of arc length Y to the average of N–I distance and Tr-Tr was calculated separately in 3 repetitions of the process above to ensure good consistency of result, and an average ratio was then computed across all three trials to obtain a more accurate heuristic. Finally, we measured the scalp distance between the previous DLPFC heuristic to the updated anterior and posterior DLPFC targets to quantify the discrepancy between the old and new heuristics (Fig. 1C).
3. Results
The reported maxima for the left and right anterior DLPFC in Ref. [
] were located at MNI152 coordinates [X-53 Y+41 Z+15] and [X+48 Y+38 Z+23], with the corresponding scalp sites found to be located at [X-62.4 Y+46.1 Z+17.2] and [X+61.3 Y+46.0 Z+28.3]. The left and right posterior DLPFC maxima were reported at [X-46 Y+9 Z+31] and [X+46 Y+4 Z+35] respectively, with the corresponding scalp sites found to be located at [Z-67.8 Y+18.8 Z+41.4] and [X+69.1 Y+13.1 Z+48.0]. The derived equations to calculate the arc length X and Y for these new targets are as follows: [ ; ] for the left anterior DLPFC, [ ; ] for the right anterior DLPFC, [; ] for the left posterior DLPFC, and [ ; ] for the right posterior DLPFC. For ease of locating these targets, we have included a calculation tool in the form of a locked Excel spreadsheet that takes NI, TrTr, and HC as input and outputs the corresponding X and Y values according to these equations for each of the four targets (Fig. 2) (Supplementary Material).
Fig. 2Screenshot of the calculation tool in the form of a locked Excel spreadsheet that takes nasion-inion, tragus-tragus, and head circumference as input and outputs the corresponding arc length X and Y values according to equations for each of the four targets (Supplementary Material).
Among these newer sites, the anterior L-DLPFC was 21.5 ± 1.4 mm more inferior-posterior to F3 (geodesic distance along scalp surface), while the posterior L-DLPFC is 37.0 ± 0.6 mm more posterior. Similarly, the anterior R-DLPFC is 12.3 ± 0.9 mm more inferior-posterior to F4 while the posterior R-DLPFC is 44.1 ± 0.9 mm posterior (Fig. 1C). Left and right anterior DLPFC scalp sites were 10.9 and 16.4 mm (Euclidean distance in MNI space) superficial to their respective maxima in the brain, while left and right posterior DLPFC sites were 26.1 and 28.0 mm superficial to their respective maxima. Sample applications of the heuristic in 6 individuals, showing the resultant brain surface target in native space, are provided in Supplementary Material.
4. Discussion
As we refine our understanding of the neuroanatomical substrates of depression and other illnesses, we advance the potential for individualized targeting of these substrates using MRI-based or other techniques; the resultant yield of improved remission rates may then be substantial [
]. However, until MRI-based targeting becomes feasible in routine practice, scalp-based approximations may have an important role to play for translating advances in the functional neuroanatomy of illness into the treatment techniques used in everyday clinical practice.
Here, new DLPFC stimulation sites are derived from a convergent multimodal study that combines brain stimulation (rTMS and DBS) and brain lesion mapping to derive brain circuits with nodes that have therapeutic potential for treating depression [
] by i) avoiding reliance on a priori seeds, ii) using three independent causal methods, and iii) providing a whole-brain map of multiple target candidates rather than a single cortical target. The newly derived prefrontal stimulation targets prove to diverge somewhat from F3 and F4. Of note is the asymmetry of these updated left vs. right DLPFC scalp sites compared to previously derived heuristics. The present heuristic does not purport to target a specific cytoarchitectonic region in DLPFC, but rather provides a scalp-based heuristic to approximate the prefrontal sites identified as being of maximal correlation to depression symptoms across multiple independent causal lines of evidence [
Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex.
It bears emphasizing that the anterior/posterior DLPFC sites were derived from retrospective analyses correlating functional connectivity to therapeutic effect. However, there are as yet no prospective randomized comparisons of BeamF3 vs. anterior vs. posterior DLPFC target effects on overall symptoms or symptom clusters. As such, it would be premature to claim superior therapeutic efficacy for the updated sites over other heuristics, and premature to recommend these heuristics for routine clinical use pending prospective studies of treatment outcomes.
Moreover, when applying these heuristics in individuals in native rather than standardized space, we note that residual inter-individual variability may ensue not only in the anatomical target of stimulation but, perhaps more crucially, in the functional networks associated with a particular site in any given patient. The effects of residual inter-individual variability in brain-anatomical target and functional network remain to be quantified in a novel patient sample; thus, it would be premature to recommend use of the method for individualized targeting in clinical rather than research settings.
It is also worth noting that other maxima outside the frontal lobes were also reported in Siddiqi et al., 2021, and that the therapeutic efficacy of these non-frontal sites in MDD or other disorders has yet to be formally assessed. These topics should be considered priorities for future study, until such time as personalized, MRI-guided neuronavigation is feasible on a widespread scale for those undergoing therapeutic brain stimulation [
Daniel M. Blumberger: conceptualization, supervision, writing - review and editing
Fidel Vila-Rodriguez: conceptualization, writing - review and editing
Zafiris J. Daskalakis: writing - review and editing
Michael D.Fox: methodology, resources, writing - review and editing
Jonathan Downar: conceptualization, methodology, resources, supervision, writing - review and editing
Declaration of competing interest
DMB reports research grants from the Canadian Institutes of Health Research (CIHR), US National Institutes of Health, Weston Brain Institute, Brain Canada, the Temerty Family Foundation (through the Centre for Addiction and Mental Health Foundation and the Campbell Research Institute), and Brainsway; reports receiving in-kind equipment support for investigator-initiated studies (including this study) MagVenture; is the site principal investigator for three sponsor-initiated studies for Brainsway; and has been on an advisory board for Janssen Pharmaceutical. FVR receives research support from CIHR, Brain Canada, Michael Smith Foundation for Health Research, Vancouver Coastal Health Research Institute, and Weston Brain Institute for investigator-initiated research. Philanthropic support from Seedlings Foundation. In-kind equipment support for this investigator-initiated trial from MagVenture. He has received honoraria for participation in an advisory board for Janssen. JD reports research grants from CIHR, the National Institute for Mental Health, Brain Canada, the Canadian Biomarker Integration Network in Depression, the Ontario Brain Institute, the Klarman Family Foundation, the Arrell Family Foundation, and the Edgestone Foundation; reports travel stipends from Lundbeck and ANT Neuro; reports in-kind equipment support for this investigator-initiated trial from MagVenture; and is an advisor for BrainCheck. S.H.S. serves as a clinical consultant for Kaizen Brain Center. S.H.S. and M.D.F. have jointly received investigator-initiated research support from Neuronetics. None of these organizations were involved in the present work. S.H.S. and M.D.F. each own independent intellectual property on the use of brain network mapping to target neuromodulation. The present work did not utilize any of this intellectual property. ZJD has received research and equipment in-kind support for an investigator-initiated study through Brainsway Inc and Magventure Inc. His work has been supported by the Canadian Institutes of Health Research (CIHR), the National Institutes of Mental Health (NIMH), Brain Canada and the Temerty Family and Grant Family and through the Centre for Addiction and Mental Health (CAMH) Foundation and the Campbell Institute. AM and KM report no conflicts of interest or significant financial support associated with this publication.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
Concordance between BeamF3 and MRI-neuronavigated target sites for repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex.
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