Cortical and subcortical mapping of the human allostatic-interoceptive system using 7 Tesla fMRI

Abstract

The brain continuously anticipates the body's energetic needs and prepares to meet them before they arise-a process called allostasis. To support allostasis, the brain continually models the body's sensory state, a process known as interoception. Here we replicate and extend a large-scale system that supports allostasis and interoception in the human brain using ultrahigh precision 7 Tesla functional magnetic resonance imaging (n = 90), improving precision in subgenual and pregenual anterior cingulate topography and expanding brainstem nuclei mapping. Our functional connectivity analyses provide corroborating evidence for more than 96% of the anatomical connections documented in nonhuman animal tract-tracing studies. This system also includes regions of dense intrinsic connectivity throughout the system, some of which were identified previously as part of the backbone of neural communication across the brain. These results reinforce the existing evidence for a whole-brain system that supports the modeling and regulation of the body's internal milieu.

Fig. 1. Key cortical and subcortical regions involved in interoception and allostasis.

a, Using 3 Tesla fMRI resting state connectivity, we showed a unified system consisting of the default mode network (in red) and salience network (in blue), which overlapped in many key cortical visceromotor allostatic regions (in purple) that also serve as ‘rich club’ hubs (labeled in yellow), in addition to a portion of primary interoceptive cortex (dpIns; left). We reported the system’s connectivity to some subcortical regions known to have a role in control of the autonomic nervous system, the immune system and the endocrine system, such as the thalamus, hypothalamus, hippocampus, ventral striatum, PAG, PBN and NTS (for example, refs. ^–; right). * denotes brainstem regions. Panel a is reproduced with permission from ref. . b, Expanded set of seed regions used in the present analysis. Hippo, hippocampus; hypothal, hypothalamus; IFG, inferior frontal gyrus; ITG, inferior temporal gyrus; PHG, parahippocampal gyrus; postCG, postcentral gyrus; STS, superior temporal sulcus; Thal, thalamus.

Fig. 2. Cortico-cortical functional connectivity within the allostatic–interoceptive system.

a, Left column shows cortical seed locations and right column shows group-level t-value maps (n = 90) masked by voxels that showed positive connectivity (two-tailed t test, P < 0.05) with the seed in more than 950 iterations (of 1,000) by resampling 80% of the sample in each iteration (n = 72). b, Seed-to-seed functional connectivity matrix shows connectivity strength between each pair of the cortical seeds (two-tailed t test, P < 0.05, uncorrected; white color indicates correlation = 1; n = 90). c, The allostatic–interoceptive system showed connecting regions in all the a priori interoceptive and visceromotor control regions. Connecting regions belonging to the ‘rich club’ are labeled in yellow. ‘Rich club’ hubs image in panel c is adapted with permission from ref. . lvAIns, lateral vAIns; mIns, mid insula; mvAIns, medial vAIns.

Fig. 3. The two large-scale intrinsic networks composing the cortical allostatic–interoceptive system correspond to the default mode network and salience/somatomotor networks.

a, The cortical allostatic–interoceptive system is composed of two large-scale intrinsic networks. The k-means clustering (k = 2, 1,000 iterations) yielded the most optimal solution, where Network 1 (resembling the default mode network) included a cluster of maps seeded in the sgACC, aMCC, pACC and mvAIns, and Network 2 (resembling the salience network) included a cluster of maps seeded in the lvAIns, dmIns and dpIns. All displayed maps result from the conjunction of binarized maps (two-tailed t test, P < 0.05) in the same cluster. Cortical ROIs are outlined in yellow (ROI names are labeled in the top panel). b, We computed Dice overlap between network maps and the Yeo 7-network cortical parcellation using the Network Correspondence Toolbox (https://github.com/rubykong/cbig_network_correspondence). In the grids, cells with significant Dice overlap at P < 0.05 (that is, showing substantial correspondence) are denoted with an asterisk. Network 1 showed significant Dice overlap solely with the default mode network, while Network 2 showed significant Dice overlap with the salience/ventral attention network and somatomotor network.

Fig. 4. Subcortico-cortical intrinsic connectivity within the allostatic–interoceptive system.

a, Left column shows subcortical seed locations and right column shows group-level t-value maps (n = 90) masked by voxels that showed positive connectivity (two-tailed t test, P < 0.05) with the seed in more than 950 iterations (of 1,000 iterations) by resampling 80% of the sample in each iteration (n = 72). b, Seed-to-seed functional connectivity matrix shows connectivity strength between pairs of subcortical and cortical seeds (two-tailed t test, P < 0.05, uncorrected; gray color indicates subthreshold correlations; n = 90). c, Conjunction map shows the number of binarized maps (two-tailed t test, P < 0.05) with shared connecting regions (ranging from 9 to 14). dACC, dorsal ACC.

Fig. 5. Clustering solution (k = 3) for cortical maps of subcortical allostatic–interoceptive seeds.

Cluster 1 included maps that were seeded in small lower brainstem ROIs (LC, PBN, VSM). Cluster 2 included maps that were seeded in small upper brainstem ROIs (PAG and DR) and the hypothalamus. Cluster 3 included maps that were seeded in larger subcortical seeds (mdThal, LGN, hippocampus, dAmy, NAcc, SC, SN and VTA). All displayed maps result from the conjunction of binarized maps (P < 0.05) in the same cluster. Cortical ROIs are outlined in yellow (ROI names are labeled in the top panel).

Fig. 6. Subcortico-subcortical intrinsic connectivity within the allostatic–interoceptive system.

a, Left column shows subcortical seed locations and right column shows group-level t-value maps (n = 90) masked by voxels that showed positive connectivity (two-tailed t test, P < 0.05) with the seed in more than 950 iterations (of 1,000 iterations) by resampling 80% of the sample in each iteration (n = 72). b, Seed-to-seed functional connectivity matrix showed connectivity strength between each pair of the subcortical seeds (two-tailed t test, P < 0.05, uncorrected; white color indicates correlation = 1 and gray color indicates subthreshold correlations; n = 90). Several seeds had functional connectivity with a subset of voxels within target ROIs, as shown by binarized maps at P < 0.05 (two-tailed t test; target ROI outline is shown in blue).

Fig. 7. Summary of the allostatic–interoceptive system based on 7 Tesla fMRI functional connectivity.

a, Circuit diagram indicates dense within-system connectivity between the 21 cortical and subcortical seeds. All seeds are shown as spherical nodes located at their respective centers of gravity. Pairwise connectivity strengths between ROIs are shown as edges between nodes (two-tailed t test, ranging from P < 0.05 in red to P < 10⁻¹⁰ in yellow, uncorrected; n = 90). Nodes and edges in the glass brain were visualized using BrainNet Viewer. b, Conjunction map shows the number of binarized maps (two-tailed t test, P < 0.05) that shared overlapping regions (ranging from 15 to 21, total number of cortical and subcortical seeds = 21).

Extended Data Fig. 1. Bootstrapped cortico-cortical functional connectivity maps.

Bootstrapped functional connectivity maps depict all voxels whose time course was correlated (two-tailed t-test, p < 0.05) with that of the seed in more than 950 iterations (out of 1000) by resampling 80% of the sample in each iteration (n = 72). aMCC: anterior midcingulate cortex; dmIns: dorsal mid insula; dpIns: dorsal posterior insula; lvAIns: lateral ventral anterior insula; mvAIns: medial ventral anterior insula; pACC: pregenual anterior cingulate cortex; sgACC: subgenual anterior cingulate cortex.

Extended Data Fig. 2. Bootstrapped subcortico-cortical functional connectivity maps.

Bootstrapped functional connectivity maps depict all voxels whose time course was correlated (two-tailed t-test, p < 0.05) with that of the seed in more than 950 iterations (out of 1000) by resampling 80% of the sample in each iteration (n = 72). dAmy: dorsal amygdala; DR: dorsal raphe; hippo: hippocampus; hypothal: hypothalamus; LC: locus coeruleus; LGN: lateral geniculate nucleus; mdThal: mediodorsal thalamus; NAcc: nucleus accumbens; PAG: periaqueductal gray; PBN: parabrachial nucleus; SC: superior colliculus; SN: substantia nigra; VSM: medullary viscero-sensory-motor nuclei complex, including the nucleus tractus solitarius, dorsal motor nucleus of the vagus, nucleus ambiguus, and hypoglossal nucleus; VTA: ventral tegmental area.

Extended Data Fig. 3. Bootstrapped subcortico-subcortical functional connectivity maps.

Bootstrapped functional connectivity depict all voxels whose time course was correlated (two-tailed t-test, p < 0.05) with that of the seed in more than 950 iterations (out of 1000) by resampling 80% of the sample in each iteration (n = 72). dAmy: dorsal amygdala; DR: dorsal raphe; hippo: hippocampus; hypothal: hypothalamus; LC: locus coeruleus; LGN: lateral geniculate nucleus; mdThal: mediodorsal thalamus; NAcc: nucleus accumbens; PAG: periaqueductal gray; PBN: parabrachial nucleus; SC: superior colliculus; SN: substantia nigra; VSM: medullary viscero-sensory-motor nuclei complex, including the nucleus tractus solitarius, dorsal motor nucleus of the vagus, nucleus ambiguus, and hypoglossal nucleus; VTA: ventral tegmental area.

Extended Data Fig. 4. Intrinsic connectivity of PAG and its subregions within the allostatic-interoceptive system.

a, Bootstrapped connectivity maps obtained from resampling 80% of the sample (n = 72) 1000 times. b, Connectivity strength between PAG seeds and all other seeds (two-tailed t-test, p < 0.05, uncorrected; white color indicates correlation = 1 and gray color indicates subthreshold correlations; n = 90). c, Contrasts obtained by paired-sample t-tests between subregional maps (p < 0.05, uncorrected). lPAG and vlPAG showed more robust and more extensive connectivity than dmPAG and dlPAG, with stronger connectivity especially with aMCC, mvAIns and dAmy. aMCC: anterior midcingulate cortex; dAmy: dorsal amygdala; dmIns: dorsal mid insula; dmPAG: dorsomedial periaqueductal gray; dlPAG: dorsolateral periaqueductal gray; dpIns: dorsal posterior insula; DR: dorsal raphe; hippo: hippocampus; hypothal: hypothalamus; LC: locus coeruleus; LGN: lateral geniculte nucleus; lPAG: lateral periaqueductal gray; lvAIns: lateral ventral anterior insula; mdThal: mediodorsal thalamus; mvAIns: medial ventral anterior insula; NAcc: nucleus accumbens; pACC: pregenual anterior cingulate cortex; PAG: periaqueductal gray; PBN: parabrachial nucleus; SC: superior colliculus; sgACC: subgenual anterior cingulate cortex; SN: substantia nigra; vlPAG: ventrolateral periaqueductal gray; VSM: medullary viscero-sensory-motor nuclei complex, including the nucleus tractus solitarius, dorsal motor nucleus of the vagus, nucleus ambiguus, and hypoglossal nucleus; VTA: ventral tegmental area.

Extended Data Fig. 5. Intrinsic connectivity of the hippocampus and its subregions within the allostatic-interoceptive system.

a, Bootstrapped connectivity maps obtained from resampling 80% of the sample (n = 72) 1000 times. b, Seed-to-seed connectivity strength between hippocampal seeds and all other seeds (two-tailed t-test, p < 0.05, uncorrected; white color indicates correlation = 1 and gray color indicates subthreshold correlations; n = 90). c, Contrasts obtained by paired-sample t-tests between subregional maps (two-tailed t-test, p < 0.05, uncorrected). Hippocampal head and body showed stronger connectivity to default mode nodes such as the MPFC, PCC, AG and lateral temporal cortex. Hippocampal body and tail showed stronger connectivity to salience nodes such as ACC, PCC, SMA, MFG and SMG. ACC: anterior cingulate cortex; aMCC: anterior midcingulate cortex; dAmy: dorsal amygdala; dmIns: dorsal mid insula; dpIns: dorsal posterior insula; DR: dorsal raphe; hypothal: hypothalamus; LC: locus coeruleus; LGN: lateral geniculate nucleus; lvAIns: lateral ventral anterior insula; mdThal: mediodorsal thalamus; MFG: middle frontal gyrus; mvAIns: medial ventral anterior insula; NAcc: nucleus accumbens; pACC: pregenual anterior cingulate cortex; PAG: periaqueductal gray; PBN: parabrachial nucleus; PCC: posterior cingulate cortex; SC: superior colliculus; sgACC: subgenual anterior cingulate cortex; SMA: supplementary motor area; SMG: supramarginal gyrus; SN: substantia nigra; VSM: medullary viscero-sensory-motor nuclei complex, including the nucleus tractus solitarius, dorsal motor nucleus of the vagus, nucleus ambiguus, and hypoglossal nucleus; VTA: ventral tegmental area.

Extended Data Fig. 6. Intrinsic connectivity of the superficial and deep layers of the SC within the allostatic-interoceptive system.

a, Bootstrapped connectivity maps obtained from resampling 80% of the sample (n = 72) 1000 times. b, Seed-to-seed connectivity strength between SC subregions and all other seeds (two-tailed t-test, p < 0.05, uncorrected; n = 90). c, Contrasts obtained by paired-sample t-tests between subregional maps (two-tailed t-test, p < 0.05, uncorrected). Superficial SC showed stronger connectivity to primary sensory cortices in the posterior insular, occipital and pericentral regions. Deep SC showed stronger connectivity to allostatic-interoceptive hubs in the vAIns and the entire cingulate cortex. aMCC: anterior midcingulate cortex; dAmy: dorsal amygdala; dmIns: dorsal mid insula; dpIns: dorsal posterior insula; DR: dorsal raphe; hippo: hippocampus; hypothal: hypothalamus; LC: locus coeruleus; LGN: lateral geniculate nucleus; lvAIns: lateral ventral anterior insula; mdThal: mediodorsal thalamus; mvAIns: medial ventral anterior insula; NAcc: nucleus accumbens; pACC: pregenual anterior cingulate cortex; PAG: periaqueductal gray; PBN: parabrachial nucleus; PCC: posterior cingulate cortex; SC: superior colliculus; sgACC: subgenual anterior cingulate cortex; SN: substantia nigra; VSM: medullary viscero-sensory-motor nuclei complex, including the nucleus tractus solitarius, dorsal motor nucleus of the vagus, nucleus ambiguus, and hypoglossal nucleus; VTA: ventral tegmental area.

Extended Data Fig. 7. Intrinsic connectivity of the hypothalamus and its subregions within the allostatic-interoceptive system.

a, Bootstrapped connectivity maps obtained from resampling 80% of the sample (n = 72) 1000 times. b, Seed-to-seed connectivity strength between hypothalamic subregions and all other seeds (two-tailed t-test, p < 0.05, uncorrected; n = 90; white color indicates correlation = 1 and gray color indicates subthreshold correlations; n = 90). c, Contrasts obtained by paired-sample t-tests between subregional maps (two-tailed t-test, p < 0.05, uncorrected). The middle tuberal-posterior and superior communities showed more robust and extensive connectivity to midcingulate cortex and ventral mid insula than the anteroventral-tuberal and anterior communities, and the middle tuberal-posterior community further showed more extensive connectivity to posterior cingulate cortex and posterior insula. aMCC: anterior midcingulate cortex; AT HT: anteroventral-tuberal hypothalamus; dAmy: dorsal amygdala; dmIns: dorsal mid insula; dpIns: dorsal posterior insula; DR: dorsal raphe; hippo: hippocampus; HT: hypothalamus; LC: locus coeruleus; LGN: lateral geniculate nucleus; lvAIns: lateral ventral anterior insula; mdThal: mediodorsal thalamus; MTP HT: middle tuberal-posterior hypothalamus; mvAIns: medial ventral anterior insula; NAcc: nucleus accumbens; pACC: pregenual anterior cingulate cortex; PAG: periaqueductal gray; PBN: parabrachial nucleus; PCC: posterior cingulate cortex; SC: superior colliculus; sgACC: subgenual anterior cingulate cortex; SN: substantia nigra; VSM: medullary viscero-sensory-motor nuclei complex, including the nucleus tractus solitarius, dorsal motor nucleus of the vagus, nucleus ambiguus, and hypoglossal nucleus; VTA: ventral tegmental area.