SBIR-STTR Award

Transcranial magnetic stimulation (TMS) is an FDA-approved treatment for treatment-resistant major depression(TRD). However, at present the approach is only partially effective, due in part to relatively ineffective targetingapproaches. Over recent years, there has been increasing realization that TMS for anhedonic-like symptoms ofmajor depressive disorder (MDD) is most effective when targeted at the region of left dorsolateral prefrontalcortex (L-DLPFC) that is maximally anti-correlated with subgenual anterior cingulate cortex (sgACC) asdetermined using resting-state functional connectivity MRI (rsfcfMRI). Ideal approaches for identifying thislocation for individual subjects, however, still depend on processing pipelines that are not FDA cleared and thusand are not accessible to the TMS treatment community. In general, 3D brain reconstructions can be analyzedusing either traditional, volumetric approaches, or more recently developed surface-based approachesdeveloped as part of the human connectome project (HCP) and leading to publication of the HCP multimodalbrain atlas (HCP MMP1.0). In volumetric approaches, structurally and functionally based approaches have bothbeen implemented. In the surface-based HCP MMP1.0 approach, structural and functional data are merged toidentify functionally discrete brain parcels across individuals. Here, during phase I we will first develop aninvestigational software package ("TMSMap") that will permit TMS researchers to utilize either volumetric orsurface-based analytic approaches for determining MR-based personalized L-DLPFC target locations on-line,and will create a parallel off-line virtual neuro-navigation tool to permit neuro-navigated TMS even for"community" practioners without access to on-line neuro-navigation capabilities. During phase II we will createa Picture Archiving and Communication System (PACS) compliant clinic-ready version, which we evaluate in amulticenter randomized controlled trial in TMS-resistant TRD individuals. We will ensure that all device (softwaredeveloped to medical standards) and data (clinical validation) requirements are complete by Phase II end, toenable pursuing either a 510(k) or de-novo submission with positive clinical outcome. The project builds bothfrom the long-standing interest of Soterix Medical Inc.(SMI) in 1) the use of combined TMS and neuro-navigation,and 2) the development of automated targeting software for non-invasive brain stimulation; and from recentresearch by the principal investigator at Columbia University Irving Medical Center (CUIMC) demonstrating 1)anti-correlation of HCP MMP1.0 parcel 46 with sgACC across individuals within the HCP sample and 2) 100%response rate among TMS-resistant TRD patients (n=10) treated with TMS targeted to HCP MMP1.0 parcel 46.Moreover, both effective electroconvulsive therapy and effective TMS were associated with rsfc changesinvolving DLPFC parcel 46 and additional brain regions. This will be the first software to permit FDA-clearedfunctional targeting of TMS coil placement using functional as well as structural information, the first to permitvirtual as well as on-line neuro-navigation and the first study to evaluate efficacy of surface-based parcel-guidedTMS vs. standard of care. If successful, this project will permit improved, targeting of TMS target location acrossindividuals, as well as implementation of personalized, MR-targeted TMS even within community treatmentsettings.1

Public Health Relevance Statement:
NARRATIVE Transcranial magnetic stimulation for the treatment of treatment resistant depression is partially effective (~40% response and ~35% remission), in part, due to ineffective targeting strategies. The standard "5-cm rule" approach dominates clinical practice but is known to miss the LDLPFC- the intended target. While on-line neuronavigation approaches that allow incorporating the patient's LDLPFC from individual MRI are being considered, adoption is slow. Furthermore, DLPFC is divided into 13 distinct parcels and regions. In a pilot study (n=10) of TMS-resistant TRD individuals, by targeting parcel 46 of LDLPFC, we were able to obtain 100% response and 50% remission. We aim to develop a software that will enable not only TMS groups that do not currently have navigation equipment but also groups that do have access to one. The software ("TMSMap") will provide scalp and brain coordinates corresponding to popular volumetric targeting approaches and our surface-based approach. The approaches will be clinically validated and all FDA device and regulatory requirements addressed. We aim to obtain either a 510(k) clearance or a de-novo approval immediately post Phase-2 pending favorable clinical outcome. 1

Project Terms:
<3-D><3D><3-Dimensional>

Transcranial magnetic stimulation (TMS) is an FDA-approved treatment for treatment-resistant major depression(TRD). However, at present the approach is only partially effective, due in part to relatively ineffective targetingapproaches. Over recent years, there has been increasing realization that TMS for anhedonic-like symptoms ofmajor depressive disorder (MDD) is most effective when targeted at the region of left dorsolateral prefrontalcortex (L-DLPFC) that is maximally anti-correlated with subgenual anterior cingulate cortex (sgACC) asdetermined using resting-state functional connectivity MRI (rsfcfMRI). Ideal approaches for identifying thislocation for individual subjects, however, still depend on processing pipelines that are not FDA cleared and thusand are not accessible to the TMS treatment community. In general, 3D brain reconstructions can be analyzedusing either traditional, volumetric approaches, or more recently developed surface-based approachesdeveloped as part of the human connectome project (HCP) and leading to publication of the HCP multimodalbrain atlas (HCP MMP1.0). In volumetric approaches, structurally and functionally based approaches have bothbeen implemented. In the surface-based HCP MMP1.0 approach, structural and functional data are merged toidentify functionally discrete brain parcels across individuals. Here, during phase I we will first develop aninvestigational software package ("TMSMap") that will permit TMS researchers to utilize either volumetric orsurface-based analytic approaches for determining MR-based personalized L-DLPFC target locations on-line,and will create a parallel off-line virtual neuro-navigation tool to permit neuro-navigated TMS even for"community" practioners without access to on-line neuro-navigation capabilities. During phase II we will createa Picture Archiving and Communication System (PACS) compliant clinic-ready version, which we evaluate in amulticenter randomized controlled trial in TMS-resistant TRD individuals. We will ensure that all device (softwaredeveloped to medical standards) and data (clinical validation) requirements are complete by Phase II end, toenable pursuing either a 510(k) or de-novo submission with positive clinical outcome. The project builds bothfrom the long-standing interest of Soterix Medical Inc.(SMI) in 1) the use of combined TMS and neuro-navigation,and 2) the development of automated targeting software for non-invasive brain stimulation; and from recentresearch by the principal investigator at Columbia University Irving Medical Center (CUIMC) demonstrating 1)anti-correlation of HCP MMP1.0 parcel 46 with sgACC across individuals within the HCP sample and 2) 100%response rate among TMS-resistant TRD patients (n=10) treated with TMS targeted to HCP MMP1.0 parcel 46.Moreover, both effective electroconvulsive therapy and effective TMS were associated with rsfc changesinvolving DLPFC parcel 46 and additional brain regions. This will be the first software to permit FDA-clearedfunctional targeting of TMS coil placement using functional as well as structural information, the first to permitvirtual as well as on-line neuro-navigation and the first study to evaluate efficacy of surface-based parcel-guidedTMS vs. standard of care. If successful, this project will permit improved, targeting of TMS target location acrossindividuals, as well as implementation of personalized, MR-targeted TMS even within community treatmentsettings.1

Public Health Relevance Statement:
NARRATIVE Transcranial magnetic stimulation for the treatment of treatment resistant depression is partially effective (~40% response and ~35% remission), in part, due to ineffective targeting strategies. The standard "5-cm rule" approach dominates clinical practice but is known to miss the LDLPFC- the intended target. While on-line neuronavigation approaches that allow incorporating the patient's LDLPFC from individual MRI are being considered, adoption is slow. Furthermore, DLPFC is divided into 13 distinct parcels and regions. In a pilot study (n=10) of TMS-resistant TRD individuals, by targeting parcel 46 of LDLPFC, we were able to obtain 100% response and 50% remission. We aim to develop a software that will enable not only TMS groups that do not currently have navigation equipment but also groups that do have access to one. The software ("TMSMap") will provide scalp and brain coordinates corresponding to popular volumetric targeting approaches and our surface-based approach. The approaches will be clinically validated and all FDA device and regulatory requirements addressed. We aim to obtain either a 510(k) clearance or a de-novo approval immediately post Phase-2 pending favorable clinical outcome. 1

Project Terms:
<3-D><3D><3-Dimensional>