A human brain network derived from coma-causing brainstem lesions.
OBJECTIVE
To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network.


METHODS
We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness.


RESULTS
A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks.


CONCLUSIONS
Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA. d.b.fisch@gmail.com foxmdphd@gmail.com.
David B
DB
Fischer
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.
Aaron D
AD
Boes
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.
Athena
A
Demertzi
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.
Henry C
HC
Evrard
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.
Steven
S
Laureys
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.
Brian L
BL
Edlow
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.
Hesheng
H
Liu
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.
Clifford B
CB
Saper
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.
Alvaro
A
Pascual-Leone
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA. d.b.fisch@gmail.com foxmdphd@gmail.com.
Michael D
MD
Fox
From the Berenson-Allen Center for Noninvasive Brain Stimulation, Division of Cognitive Neurology, Department of Neurology (D.B.F., A.D.B., A.P.-L., M.D.F.), and Department of Neurology (C.B.S., A.P.-L., M.D.F., J.C.G.), Harvard Medical School and Beth Israel Deaconess Medical Center, Boston; Harvard Medical School (D.B.F.), Boston; Departments of Pediatric Neurology (A.D.B.) and Neurology (B.L.E.), Harvard Medical School and Massachusetts General Hospital, Boston, MA; Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM) (A.D.), Hôpital Pitié-Salpêtrière, Paris, France; Coma Science Group (A.D., S.L.), GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Functional and Comparative Neuroanatomy Lab (H.C.E.), Centre for Integrative Neuroscience, Tübingen; Max Planck Institute for Biological Cybernetics (H.C.E.), Tübingen, Germany; Athinoula A. Martinos Center for Biomedical Imaging (B.L.E., H.L., M.D.F.), Massachusetts General Hospital, Charlestown, MA.
Joel C
JC
Geerling
D001931:Brain Mapping; D001933:Brain Stem / Q000000981:diagnostic imaging* / Q000502:physiology / Q000503:physiopathology*; D016022:Case-Control Studies; D015331:Cohort Studies; D003128:Coma / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000502:physiology / Q000503:physiopathology; D012146:Rest; D055815:Young Adult