Distinct Symptom-Specific Treatment Targets for Circuit-Based Neuromodulation

Abstract

Objective: Treatment of different depression symptoms may require different brain stimulation targets with different underlying brain circuits. The authors sought to identify such targets, which could improve the efficacy of therapeutic brain stimulation and facilitate personalized therapy.

Methods: The authors retrospectively analyzed two independent cohorts of patients who received left prefrontal transcranial magnetic stimulation (TMS) for treatment of depression (discovery sample, N=30; active replication sample, N=81; sham replication sample, N=87). Each patient's TMS site was mapped to underlying brain circuits using functional connectivity MRI from a large connectome database (N=1,000). Circuits associated with improvement in each depression symptom were identified and then clustered based on similarity. The authors tested for reproducibility across data sets and whether symptom-specific targets derived from one data set could predict symptom improvement in the other independent cohort.

Results: The authors identified two distinct circuit targets effective for two discrete clusters of depressive symptoms. Dysphoric symptoms, such as sadness and anhedonia, responded best to stimulation of one circuit, while anxiety and somatic symptoms responded best to stimulation of a different circuit. These circuit maps were reproducible, predicted symptom improvement in independent patient cohorts, and were specific to active compared with sham stimulation. The maps predicted symptom improvement in an exploratory analysis of stimulation sites from 14 clinical TMS trials.

Conclusions: Distinct clusters of depressive symptoms responded better to different TMS targets across independent retrospective data sets. These symptom-specific targets can be prospectively tested in a randomized clinical trial. This data-driven approach for identifying symptom-specific targets may prove useful for other disorders and facilitate personalized neuromodulation therapy.

Keywords: Brain Imaging; Cognitive Neuroscience; Neuromodulation; Plasticity; TMS.

FIGURE 1.. Identifying brain circuit targets for individual depressive symptoms in a study of symptom-specific treatment targets for circuit-based neuromodulation^a

^a Patients receiving transcranial magnetic stimulation (TMS) for treatment of depression had their stimulation site recorded using MRI, revealing variability in the stimulation site across patients, as illustrated in the three patient examples in panel A. In panel B, the network of regions functionally connected to each patient’s stimulation site was computed using a large normative connectome database (N=1,000). Connections correlated with improvement in individual depression symptoms across patients were identified, as illustrated with three symptom examples in panel C. Only some symptoms were related to connectivity with the subgenual cingulate (red outline), and the peak predictor was often in other regions, such as the hippocampus (red arrow). For illustrative purposes, these example maps are thresholded at uncorrected p<0.05.

FIGURE 2.. Connections correlated with improvement in individual depressive symptoms match one of two general patterns in a study of symptom-specific treatment targets for circuit-based neuromodulation^a

^a In our discovery cohort, shown in panel A, similar connections were correlated with improvement in certain symptoms assessed in the Beck Depression Inventory, such as sadness (item 1), decreased interest/activities (item 12), and suicidal thoughts (item 9). A distinct set of connections were correlated with improvement in other symptoms, such as change in sleep pattern (item 16), sexual interest (item 21), and irritability (item 17). Based on spatial similarity, our 21 individual symptom maps split into two distinct clusters, which we termed dysphoric and anxiosomatic. A similar two-cluster solution was identified in an independent replication cohort using a different symptom inventory (the 28-item Hamilton Depression Rating Scale), as shown in panel B. One cluster contained items such as depressed mood (item 1), decreased interest/activities (item 7), and suicidality (item 3), which we again termed dysphoric. A second cluster contained items such as difficulty falling asleep (item 4), decreased libido (item 14), and worry/irritability (item 10), which we again termed anxiosomatic. The dysphoric and anxiosomatic cluster maps (right panels) were highly reproducible across data sets (spatial r=0.88, p<0.01, 10⁵ permutations).

FIGURE 3.. Distinct circuit-based transcranial magnetic stimulation (TMS) targets for dysphoric and anxiosomatic symptoms in a study of symptom-specific treatment targets for circuit-based neuromodulation^a

^a In both the discovery and replication cohorts, “optimal” TMS targets were identified at voxels whose connectivity profile most closely matched our dysphoric cluster map (panel A) and our anxiosomatic cluster map (panel B). For each data set, these maps were combined to identify a targeting atlas for predicting relative improvement in dysphoric and anxiosomatic symptoms (panel C).

FIGURE 4.. Location of stimulation site and improvement in symptoms in individual patients in a study of symptom-specific treatment targets for circuit-based neuromodulation^a

^a Three exemplary stimulation sites from the discovery cohort in relation to a targeting atlas generated from the replication cohort are shown in panel A. Patients who received stimulation at anxiosomatic sites showed greater improvement in anxiosomatic symptoms (e.g., patients 1 and 2), while patients who received stimulation at dysphoric sites showed greater improvement in dysphoric symptoms (e.g., patient 3). For each cohort, stimulation sites from each individual patient (black dots) are shown in panel B overlaid on a transcranial magnetic stimulation (TMS) targeting atlas generated from the other cohort. Across patients who received active TMS, the location of the stimulation site on the targeting atlas was correlated with improvement in dysphoric, relative to anxiosomatic, symptoms, as shown in panel C. This relationship was not seen with randomly permuted data or in patients who received sham TMS.

FIGURE 5.. The combined targeting atlas and prediction of improvement in symptoms across previous trials involving transcranial magnetic stimulation (TMS)^a

^a We identified 14 TMS clinical trials (listed in Table S4 in the online supplement) employing nine different prefrontal treatment targets, which are depicted here as open circles. These previous treatment targets are shown overlaid on our targeting atlas for dysphoric symptoms (panel A), for anxiosomatic symptoms (panel B), and for the ratio of dysphoric to anxiosomatic symptoms (panel C) derived from combining our two retrospective TMS data sets. As shown in panel D, the ratio of anxiosomatic to dysphoric symptom improvement in these trials was correlated with the position of the trial’s stimulation site on the targeting atlas. dmPFC=dorsomedial prefrontal cortex; fMRI=functional MRI; sgACC=subgenual anterior cingulate cortex.