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. 2021 Dec;5(12):1707-1716.
doi: 10.1038/s41562-021-01161-1. Epub 2021 Jul 8.

Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease

Shan H Siddiqi  1   2 , Frederic L W V J Schaper  3   4   5 , Andreas Horn  3   4   6 , Joey Hsu  7 , Jaya L Padmanabhan  3 , Amy Brodtmann  8 , Robin F H Cash  8   9 , Maurizio Corbetta  10   11 , Ki Sueng Choi  12 , Darin D Dougherty  13   14 , Natalia Egorova  15   16 , Paul B Fitzgerald  17 , Mark S George  18   19 , Sophia A Gozzi  20 , Frederike Irmen  21 , Andrea A Kuhn  6 , Kevin A Johnson  22 , Andrew M Naidech  23 , Alvaro Pascual-Leone  4   24   25 , Thanh G Phan  20 , Rob P W Rouhl  5   26   27 , Stephan F Taylor  28 , Joel L Voss  23 , Andrew Zalesky  8   9 , Jordan H Grafman  23   29 , Helen S Mayberg  12 , Michael D Fox  3   4
Affiliations

Brain stimulation and brain lesions converge on common causal circuits in neuropsychiatric disease

Shan H Siddiqi et al. Nat Hum Behav. 2021 Dec.

Abstract

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions (n = 461, five datasets), transcranial magnetic stimulation (n = 151, four datasets) and deep brain stimulation (n = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets (P < 0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar (P < 0.0005), as were circuits derived from patients with major depression versus other diagnoses (P < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain stimulation sites (P < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson's disease (P < 0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other disorders.

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Figures

Figure 1:
Figure 1:. Lesion locations and brain stimulation sites across 14 datasets.
Our analysis included: (a) 461 brain lesions across five datasets and three different diagnoses. (b) 151 TMS sites across four datasets, one diagnosis (major depressive disorder), and four different TMS targets. (c) 101 DBS sites across five datasets, three different diagnoses, and four different DBS targets. VHIS = Vietnam Head Injury Study, OPT-TMS = Optimizing TMS for the Treatment of Depression Study, sgACC = subgenual anterior cingulate cortex, MDD = major depressive disorder, VC/VS = ventral capsule/ventral striatum, STN = subthalamic nucleus, ANT = anterior nucleus of the thalamus.
Figure 2:
Figure 2:. Identifying depression circuit maps for each cohort.
Brain lesions (a), TMS sites (b), and DBS sites (c) were all mapped to a common brain atlas (top row in each panel). Functional connectivity of each lesion location or stimulation site was computed using a normative connectome database (bottom row in each panel). Positive functional connectivity is shown in warm colors and negative functional connectivity in cool colors. Connections most associated with depression score (lesion datasets) or change in depression score (brain stimulation datasets) were identified for each dataset (right column in each panel). The color scale was inverted for TMS datasets because TMS sites that improve depression are thought to be anti-correlated to DBS sites that improve depression or lesion sites associated with lower risk of depression.
Figure 3:
Figure 3:. Depression circuit maps are similar across 14 datasets (n=713).
(a) The 14 circuit maps were consistently similar to one another (mean r=0.24, 95%CI 0.19–0.29), as depicted in this cross-correlogram comparing different datasets. Permutation testing confirmed that the weighted mean cross-correlation was significantly stronger than expected by chance (p<0.001, 10,000 permutations) Green colors represent high spatial correlation between circuit maps, black boxes represent neutral correlation, and red boxes represent negative correlation. (b) Representative example of correlation between circuit maps generated from randomly-permuted data. This analysis confirmed that no overall cross-correlation is expected by chance (mean r = 0.00, 95%CI −0.01–0.01). (c) Depression circuit maps were similar between lesion datasets (n=461), TMS datasets (n=151), and DBS datasets (n=101). Permutation testing confirmed that each comparison was significantly stronger than expected by chance (p<0.005, 10,000 permutations). For display purposes, depression circuit maps were averaged (weighted mean) across datasets within each modality. The color scale on TMS circuit maps is inverted to facilitate visual comparison to lesion and DBS circuit maps.
Figure 4:
Figure 4:. Depression circuit maps are similar across lesions, neuromodulation, and diagnoses
(a) Depression circuit maps were similar between lesion datasets and neuromodulation datasets (mean r=0.25, 95%CI 0.16–0.34). Permutation testing confirmed that this similarity was stronger than expected by chance (p<0.001, 10,000 permutations). In a control analysis, there was no similarity between depression circuit maps from lesion datasets and age-based circuit maps from neuromodulation datasets (r= −0.11, 95%CI −0.21 – −0.01, p=0.93). (b) Depression circuit maps were similar between MDD patients and non-MDD patients (mean r=0.26, 95%CI 0.16–0.36, p<0.001). Permutation testing confirmed that this similarity was stronger than expected by chance (p<0.001, 10,000 permutations). In a control analysis, there was no similarity between depression circuit maps from MDD datasets and “other symptom severity” circuit maps in non-MDD datasets (r= −0.03, 95%CI −0.12–0.06, p=0.77). MDD = major depressive disorder.
Figure 5:
Figure 5:. Combining all circuit maps and predicting clinical variance.
(a) A combined “depression circuit” was generated from all 14 datasets. Peaks in this circuit are depicted with white circles. Positive peaks included the dorsolateral prefrontal cortex, frontal eye fields, inferior frontal gyrus, intraparietal sulcus, and extrastriate visual cortex. Negative peaks included the subgenual cingulate cortex and ventromedial prefrontal cortex. Peaks are listed in Supplementary Table 2. (b) Across the 9 neuromodulation cohorts (n=252), antidepressant efficacy was predicted by stimulation site connectivity to a circuit generated from the remaining 13 cohorts (mean r=0.22). Permutation testing confirmed that this similarity was stronger than expected by chance (p<0.001, 10,000 permutations). This was true for both TMS (n=151, r=0.24, p=0.0034 with 10,000 permutations) and DBS (n=101, r=0.21, p=0.033 with 10,000 permutations). Line = median, box limits = interquartile range, whiskers = outliers, points = individual correlation value for each neuromodulation dataset.
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