Research ArticleNeuroscience Open Access | 10.1172/jci.insight.172423

Gail I.S. Harmata,1,2,3,4,5,6 Ariane E. Rhone,1,2 Christopher K. Kovach,1,2 Sukhbinder Kumar,1 Md Rakibul Mowla,1 Rup K. Sainju,7 Yasunori Nagahama,1 Hiroyuki Oya,1,2 Brian K. Gehlbach,8 Michael A. Ciliberto,9 Rashmi N. Mueller,1,10 Hiroto Kawasaki,1 Kyle T.S. Pattinson,11 Kristina Simonyan,12 Paul W. Davenport,13 Matthew A. Howard III,1,2,3 Mitchell Steinschneider,14 Aubrey C. Chan,6,8 George B. Richerson,2,3,4,7,15,16 John A. Wemmie,1,2,3,4,6,8,14,16 and Brian J. Dlouhy1,2,3

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Harmata, G. in: JCI | PubMed | Google Scholar |

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Rhone, A. in: JCI | PubMed | Google Scholar |

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Kovach, C. in: JCI | PubMed | Google Scholar |

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Kumar, S. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Mowla, M. in: JCI | PubMed | Google Scholar |

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Sainju, R. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Nagahama, Y. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Oya, H. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Gehlbach, B. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Ciliberto, M. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Mueller, R. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Kawasaki, H. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Pattinson, K. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Simonyan, K. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Davenport, P. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Howard, M. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Steinschneider, M. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Chan, A. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Richerson, G. in: JCI | PubMed | Google Scholar |

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Wemmie, J. in: JCI | PubMed | Google Scholar

1Department of Neurosurgery,

2Iowa Neuroscience Institute,

3Pappajohn Biomedical Institute,

4Interdisciplinary Graduate Program in Neuroscience,

5Pharmacological Sciences Training Program,

6Department of Psychiatry,

7Department of Neurology,

8Department of Internal Medicine,

9Department of Pediatrics, and

10Department of Anesthesia, University of Iowa, Iowa City, Iowa, USA.

11Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

12Department of Otolaryngology–Head and Neck Surgery, Massachusetts Eye and Ear and Harvard Medical School, Boston, Massachusetts, USA.

13Department of Physiological Sciences, University of Florida, Gainesville, Florida, USA.

14Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.

15Department of Molecular Physiology and Biophysics, University of Iowa, Iowa City, Iowa, USA.

16Department of Veterans Affairs Medical Center, Iowa City, Iowa, USA.

Address correspondence to: Brian J. Dlouhy, Department of Neurosurgery, University of Iowa Carver College of Medicine, University of Iowa Stead Family Children’s Hospital, 200 Hawkins Drive, Iowa City, Iowa 52242, USA. Phone: 319.356.2542; Email: brian-dlouhy@uiowa.edu.

Authorship note: GISH and AER are co–first authors.

Find articles by Dlouhy, B. in: JCI | PubMed | Google Scholar |

Authorship note: GISH and AER are co–first authors.

Published October 3, 2023 - More info

Published in Volume 8, Issue 22 on November 22, 2023
JCI Insight. 2023;8(22):e172423. https://doi.org/10.1172/jci.insight.172423.
© 2023 Harmata et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published October 3, 2023 - Version history
Received: May 24, 2023; Accepted: September 29, 2023 View PDF Abstract

Postictal apnea is thought to be a major cause of sudden unexpected death in epilepsy (SUDEP). However, the mechanisms underlying postictal apnea are unknown. To understand causes of postictal apnea, we used a multimodal approach to study brain mechanisms of breathing control in 20 patients (ranging from pediatric to adult) undergoing intracranial electroencephalography for intractable epilepsy. Our results indicate that amygdala seizures can cause postictal apnea. Moreover, we identified a distinct region within the amygdala where electrical stimulation was sufficient to reproduce prolonged breathing loss persisting well beyond the end of stimulation. The persistent apnea was resistant to rising CO2 levels, and air hunger failed to occur, suggesting impaired CO2 chemosensitivity. Using es-fMRI, a potentially novel approach combining electrical stimulation with functional MRI, we found that amygdala stimulation altered blood oxygen level–dependent (BOLD) activity in the pons/medulla and ventral insula. Together, these findings suggest that seizure activity in a focal subregion of the amygdala is sufficient to suppress breathing and air hunger for prolonged periods of time in the postictal period, likely via brainstem and insula sites involved in chemosensation and interoception. They further provide insights into SUDEP, may help identify those at greatest risk, and may lead to treatments to prevent SUDEP.

Graphical Abstract Introduction

Sudden unexpected death in epilepsy (SUDEP) accounts for 10%–50% of all deaths in individuals with medically refractory epilepsy (1). Accumulating evidence indicates that the majority of SUDEP cases occur after seizures from loss of breathing (2, 3). Patients at greatest risk of SUDEP are those with pharmacoresistant epilepsy, especially those who are referred for epilepsy surgery and/or continue to have seizures after surgery (1, 4). Critical insights into SUDEP come from rare cases witnessed in epilepsy monitoring units where electroencephalographic, cardiac, and respiratory function could be assessed (