Mapping mania symptoms based on focal brain damage

Abstract

BACKGROUNDAlthough mania is characteristic of bipolar disorder, it can also occur following focal brain damage. Such cases may provide unique insight into brain regions responsible for mania symptoms and identify therapeutic targets.METHODSLesion locations associated with mania were identified using a systematic literature search (n = 41) and mapped onto a common brain atlas. The network of brain regions functionally connected to each lesion location was computed using normative human connectome data (resting-state functional MRI, n = 1000) and contrasted with those obtained from lesion locations not associated with mania (n = 79). Reproducibility was assessed using independent cohorts of mania lesions derived from clinical chart review (n = 15) and of control lesions (n = 490). Results were compared with brain stimulation sites previously reported to induce or relieve mania symptoms.RESULTSLesion locations associated with mania were heterogeneous and no single brain region was lesioned in all, or even most, cases. However, these lesion locations showed a unique pattern of functional connectivity to the right orbitofrontal cortex, right inferior temporal gyrus, and right frontal pole. This connectivity profile was reproducible across independent lesion cohorts and aligned with the effects of therapeutic brain stimulation on mania symptoms.CONCLUSIONBrain lesions associated with mania are characterized by a specific pattern of brain connectivity that lends insight into localization of mania symptoms and potential therapeutic targets.FUNDINGFundação para a Ciência e Tecnologia (FCT), Harvard Medical School DuPont-Warren Fellowship, Portuguese national funds from FCT and Fundo Europeu de Desenvolvimento Regional, Child Neurology Foundation Shields Research, Sidney R. Baer, Jr. Foundation, Nancy Lurie Marks Foundation, Mather's Foundation, and the NIH.

Keywords: Bipolar disorder; Neuroimaging; Neuroscience; Psychiatric diseases.

Conflict of interest statement

Conflict of interest: AJOM is recipient of a grant from Schuhfried GmBH for norming and validation of cognitive tests, and is national coordinator for Portugal of a noninterventional study (EDMS-ERI-143085581, 4.0) to characterize a Treatment-Resistant Depression Cohort in Europe, sponsored by Janssen-Cilag, Ltd., and of a trial of psilocybin therapy for treatment-resistant depression, sponsored by Compass Pathways, Ltd. (EudraCT number 2017-003288-36). JBBC received honoraria in 2018 as member of the local Advisory Board for Trevicta from Janssen-Cilag Ltd.

Figures

Figure 1. Lesional mania cohorts CONSORT diagrams.

Forty-one and 15 lesional mania cases were included in our literature (A) and clinical (B) lesional mania cohorts, respectively.

Figure 2. Lesions associated with mania occur in multiple different brain locations.

Six representative lesions (green) selected from 41 literature cases demonstrate heterogeneity in lesion location.

Figure 3. Deriving a mania network from brain lesions in the literature.

The location of brain damage associated with mania (A) or with other unrelated symptoms (B) was identified based on published images and mapped to the MNI standard brain atlas. (C and D) Brain regions functionally connected to each lesion location were identified based on a large normative resting-state functional connectivity database connectivity database (N = 1000). Results were combined across the 1000 subjects to generate a statistical T map for each lesion. Statistically significant differences in functional connectivity between mania lesions (n = 41) and control lesions (n = 79) define a “mania lesion network map.” In this map (E), regions more connected to mania lesions are shown in warm colors, while regions more connected to control regions are shown in cool colors. (F) Lesion locations from literature mania cases (green) overlap positive nodes in the network. Maps in E and F were obtained using a voxel-wise permutation-based 2-sample t test performed within FSL PALM (2000 permutations) and are displayed at an FWE-corrected level of P < 0.05.

Figure 4. Validation and replication of lesion mania network with an independent data set.

(A) Lesion locations from a clinical mania lesion cohort (green, 6 of 15 lesions shown) intersect positive nodes in the mania lesion network map derived from literature cohorts. The mania lesion network map derived from literature cohorts (n = 41 vs. 79 mania vs. control lesions) (B) was reproducible when using data from clinical cohorts (n = 15 vs. n = 490 mania vs. control lesions) (C). A conjunction analysis shows significant regions identified across both mania lesion network maps (overlap of B and C) (D) and a single mania lesion network map combining both literature and clinical cohorts shows regions that are strongly associated with mania when using a high statistical threshold (n = 56 vs. n = 569 mania vs. control lesions) (E). Connectivity maps were obtained using a voxel-wise permutation-based 2-sample t test performed within FSL PALM (2000 permutations). Connectivity maps in A and C are displayed at an FWE-corrected level of P < 0.05. Connectivity maps in B and E are displayed at more stringent FWE-corrected levels (P < 3.0 × 10–4 and P < 1.0 × 10–4, respectively), in order to best show the peak regions of each map. For additional details on peak locations see Supplemental Table 3 and Supplemental Figure 5. The map in D was obtained by binarizing B and C and computing the sum of their overlap. The maps in B–E are at MNI space z = –18. Regions more connected to mania lesions are shown in warm colors, while regions more connected to control regions are shown in cool colors.

Figure 5. Stability of mania lesion network when controlling for various confounds.

The combined mania lesion network, using data from literature and clinical cohorts, remained similar when it was recomputed controlling for lesion size (n = 56 vs. n = 569 mania vs. control lesions) (A), when using a different set of control lesions (n = 56 vs. n = 409 mania vs. control lesions; see Methods for details) (B), and when using a subset of mania cases with shorter temporal association between lesion and symptom onset (n = 28 vs. n = 569 mania vs. control lesions) (C) or the remaining mania cases (n = 28 vs. n = 569 mania vs. control lesions; see Methods for details) (D). The lesion network was also similar when restricting analyses to subsets of lesional mania cases presenting with all core mania symptoms as listed in DSM 5 (n = 46 vs. n = 569 mania vs. control lesions) (E), with no personal or family history of relevant neuropsychiatric syndromes (n = 39 vs. n = 569 mania vs. control lesions) (F), caused by ischemic stroke (n = 23 vs. n = 569 mania vs. control lesions) (G), or accumulating all of the restrictions mentioned in E–G (n = 19 vs. n = 569 mania vs. control lesions) (H). Connectivity maps were obtained using a voxel-wise permutation-based 2-sample t test performed within FSL PALM (2000 permutations) and are displayed at an FWE-corrected level of P < 0.05, at MNI space z = –18. Regions more connected to mania lesions are shown in warm colors, while regions more connected to control lesions are shown in cool colors.

Figure 6. Intersection of our mania lesion network with other lesion locations.

(A) We explored a diagnostically challenging case of lesional mania (2), where mania symptoms were attributed to an acute infarct. This acute infarct intersected a negative node of our mania lesion network, making it an unlikely contributor to mania symptoms. (B) In contrast, a previous lesion intersected a positive node of our network, consistent with a history of mania-like symptoms predating the acute infarct. (C) In a separate analysis, lesion locations associated with other neuropsychiatric symptoms, such as criminality (purple) and delusions (pink), intersected our mania lesion network map. (D) This intersection differed significantly across different neuropsychiatric symptoms. The y axis in D represents the sum of the voxel intensities in the mania lesion network map at the location of each lesion. Connectivity maps in A–C were obtained using a voxel-wise permutation-based 2-sample t test performed within FSL PALM (2000 permutations) and were corrected for multiple comparisons using threshold-free cluster enhancement and displayed at an FWE-corrected level of P < 0.05. Regions more connected to mania lesions are shown in warm colors, while regions more connected to control regions are shown in cool colors. ****P < 0.0001 in a general linear model controlling for lesion size.

Figure 7. Potential therapeutic relevance of the mania lesion network.

(A) High-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (red region) has been reported to improve mania symptoms (–35, 92), while high-frequency rTMS and anodal transcranial direct current stimulation of the left dorsolateral prefrontal cortex (blue region) can induce mania (, , –97). (B) These stimulation sites overlay areas of mostly positive connectivity in the mania lesion network map (red outline), and mostly negative connectivity (blue outline). (C) rTMS trials targeting a brain region identified with the 5-cm rule (red region) reported increased therapeutic efficacy for mania compared with trials targeting a region identified using the EEG F4 coordinate (blue region). (D) The more effective target intersects our mania lesion network (red outline), while the less effective target does not (blue outline). (E) Deep brain stimulation (DBS) sites reported to induce mania (red region) are slightly offset compared with the standard deep brain stimulation site in the ventral capsule/ventral striatum (VC/VS) (blue region). (F) The site reported to induce mania intersects our mania lesion network (red outline), while the standard site does not (blue outline). DBS sites in panels E and F are shown on a coronal brain slice (MNI space y = 7). Connectivity maps in B, D, and F were obtained using a voxel-wise permutation-based 2-sample t test performed within FSL PALM (2000 permutations). B and D are displayed at an FWE-corrected level of P < 0.05. In these panels, regions more connected to mania lesions are shown in warm colors, while regions more connected to control regions are shown in cool colors.