Brain Circuit Mapping Refines Targets for Neurostimulation

Focal brain lesions, transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS) have all been used to link depression symptoms to specific brain circuits. However, previous research has been unable to establish that damage to those circuits is causing the symptoms.

Now, researchers at Brigham and Women’s Hospital have developed a novel brain mapping method that suggests lesions, TMS and DBS converge on a common brain circuit for depression—which may represent a better target for therapeutic neurostimulation. Even more exciting, the approach seems to be generalizable to other neuropsychiatric diseases.

Shan H. Siddiqi , MD, MBBS, director of Psychiatric Neuromodulation Research, Frederic L.W.V.J. Schaper, MD, PhD, research fellow at the Center for Brain Circuit Therapeutics, and Andreas Horn , MD, PhD, director of DBS Research at the center, and colleagues report their results in Nature Human Behavior.

Similar “Depression Circuits” Across Datasets

The team collected 14 datasets that identified 461 lesions, 151 TMS sites and 101 DBS sites associated with depression or change in depression score:

  • Seven datasets—patients treated for primary major depressive disorder (MDD) with either TMS or DBS
  • Five datasets—patients evaluated for depression severity after penetrating brain injury or stroke
  • Two datasets—patients receiving DBS for Parkinson’s disease (PD) or epilepsy who reported change in depressive symptoms as a potential side effect

Connectome data on 1,000 healthy subjects was used to estimate the connectivity of each lesion and stimulation site to every voxel in the brain. At each voxel, the researchers computed the correlation between depression score and the lesion/stimulation site connectivity to that voxel.

That process yielded a “circuit map” for each dataset. The 14 circuit maps were consistently similar to one another (mean r= 0.24; P<0.001).

Convergence on the Same Circuit

Furthermore, lesions and stimulation sites converged on the same circuit:

  • Depression circuit maps derived from brain lesion datasets were similar to those derived from TMS datasets (r=0.28; P=0.0025), DBS datasets (r=0.19; P=0.0037) and the two modalities combined (r=0.25; P<0.001)
  • Depression circuit maps derived from TMS were similar to those derived from DBS (r=0.25; P<0.001)

The Depression Circuit Is Transdiagnostic

The team compared depression circuit maps derived from the seven datasets of patients with MDD (n=199), with maps derived from the seven datasets of patients with neurologic diagnoses (n=518). Depression circuit maps were similar between MDD and non-MDD patients (r=0.26; P<0.001).

This suggests depression symptoms map to a similar neuroanatomical substrate whether they’re caused by a primary psychiatric disorder, a structural brain lesion or a side effect of DBS.

Combined Circuit Map Predicts Treatment Outcomes

The team took the mean of all 14 depression circuit maps, weighted by the number of patients in each dataset, to create a combined depression circuit map. For each TMS and DBS dataset, they predicted treatment-induced change in depression score using a map constructed from the other 13 datasets.

Connectivity to the combined depression circuit predicted the efficacy of TMS (weighted mean r=0.24; P=0.0034) and DBS (weighted mean r=0.21; P=0.033).

Generalizability Beyond Depression

As an example of the generalizability of the brain mapping approach, the researchers applied it to PD. A circuit derived from 29 patients with lesion-induced parkinsonism was similar to one derived from 95 patients who received DBS. The PD circuit predicted motor symptom improvement with DBS (r=0.26; P=0.01) and was confirmed to be distinct from the depression circuit.

Therapeutic Implications

This study provides the strongest evidence to date that invasive and noninvasive brain stimulation targets the same circuit to treat the same symptom. Recent trials of DBS and TMS for depression have been negative, and the newly identified circuit may represent a refined therapeutic target.

More broadly, circuit mapping may be useful to define targets for neurostimulation treatment of other neuropsychiatric disorders.

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