Brain lesions disrupting addiction map to a common human brain circuit

Abstract

Drug addiction is a public health crisis for which new treatments are urgently needed. In rare cases, regional brain damage can lead to addiction remission. These cases may be used to identify therapeutic targets for neuromodulation. We analyzed two cohorts of patients addicted to smoking at the time of focal brain damage (cohort 1 n = 67; cohort 2 n = 62). Lesion locations were mapped to a brain atlas and the brain network functionally connected to each lesion location was computed using human connectome data (n = 1,000). Associations with addiction remission were identified. Generalizability was assessed using an independent cohort of patients with focal brain damage and alcohol addiction risk scores (n = 186). Specificity was assessed through comparison to 37 other neuropsychological variables. Lesions disrupting smoking addiction occurred in many different brain locations but were characterized by a specific pattern of brain connectivity. This pattern involved positive connectivity to the dorsal cingulate, lateral prefrontal cortex, and insula and negative connectivity to the medial prefrontal and temporal cortex. This circuit was reproducible across independent lesion cohorts, associated with reduced alcohol addiction risk, and specific to addiction metrics. Hubs that best matched the connectivity profile for addiction remission were the paracingulate gyrus, left frontal operculum, and medial fronto-polar cortex. We conclude that brain lesions disrupting addiction map to a specific human brain circuit and that hubs in this circuit provide testable targets for therapeutic neuromodulation.

Fig. 1. Lesions associated with addiction remission occur in many different brain locations.

a,b, Some lesions associated with smoking addiction remission intersected the insula (a) but many others did not (b). Each slice represents a different patient and lesion locations are shown in red. Lesions from all 129 patients are shown in Supplementary Fig. 1.

Fig. 2. LNM of addiction remission.

a, Lesion locations associated with remission of addiction to smoking (left, single example shown in red) and not quitting smoking (middle, single example shown in red) were compared using VLSM but with no significant findings (right). b, Next, the network of brain regions functionally connected to each lesion location was computed using LNM. Network maps are shown for the same two lesion examples from a. Positive functional connectivity values are shown in warm colors and negative functional connectivity values are shown in cool colors. Lesion network maps were statistically compared to identify connections significantly associated with smoking addiction remission (right, b). c–e, Lesion locations disrupting addiction showed a specific pattern of brain connectivity as computed using a smoker (c) or normative connectome (d,e). The maps derived using the normative connectome, which was used in all subsequent analyses, are displayed on the brain slices (d,e) and brain surface (f). This pattern included positive connectivity to the insula, dorsal cingulate and dorsolateral prefrontal cortex and negative connectivity to the medial prefrontal and temporal cortex (Supplementary Table 2). c,d, Maps were corrected for multiple comparisons using threshold-free cluster enhancement with default parameters in FSL (one-sided P_FWE < 0.05). e,f, Maps are shown unthresholded to better illustrate the dorsal/ventral dissociation in the striatum (e) and frontal cortex (f).

Fig. 3. Generalizability of the smoking addiction remission network to alcoholism.

a,b, The connectivity profile of lesions associated with addiction remission to smoking (a) was very similar to the connectivity profile of lesions associated with reduced alcoholism risk (b). Maps are shown unthresholded to facilitate visual comparison. c, This network similarity was specific to alcoholism risk since network maps generated for 37 other neuropsychological variables failed to match our addiction remission network. The alcoholism risk map was the only map that was more similar to our addiction remission network than expected by chance (permutation analysis, one-sided P = 0.04). NBR, neurobehavioral rating scale. r, map spatial correlation coefficient with the smoking addiction remission map. *P < 0.05, uncorrected.

Fig. 4. Refining neuroanatomical treatment targets for addiction.

a–c, Neuroanatomical targets for treatment of addiction based on previous work included the insula (green, a), anterior cingulate (green, b) and frontal cortex (electric field models of the H4 and H7 TMS coils shown in blue-green, c). Voxels whose connectivity profile best matched our lesion-based addiction remission network included the left operculum/insula (red-yellow, a), paracingulate gyrus (red-yellow, b) and medial fronto-polar cortex (red-yellow, c). Therapeutic targets identified using LNM overlapped previous targets (right, a–c) but also provided testable hypotheses for how these targets might be refined or improved. Additional images for the electric field models of the H4 and H7 TMS coils (c) are shown in Supplementary Fig. 12.