The Structural Connectome of the Human Central Homeostatic Network

Homeostatic adaptations to stress are regulated by interactions between the brainstem and regions of the forebrain, including limbic sites related to respiratory, autonomic, affective, and cognitive processing. Neuroanatomic connections between these homeostatic regions, however, have not been thoroughly identified in the human brain. In this study, we perform diffusion spectrum imaging tractography using the MGH-USC Connectome MRI scanner to visualize structural connections in the human brain linking autonomic and cardiorespiratory nuclei in the midbrain, pons, and medulla oblongata with forebrain sites critical to homeostatic control. Probabilistic tractography analyses in six healthy adults revealed connections between six brainstem nuclei and seven forebrain regions, several over long distances between the caudal medulla and cerebral cortex. The strongest evidence for brainstem-homeostatic forebrain connectivity in this study was between the brainstem midline raphe and the medial temporal lobe. The subiculum and amygdala were the sampled forebrain nodes with the most extensive brainstem connections. Within the human brainstem-homeostatic forebrain connectome, we observed that a lateral forebrain bundle, whose connectivity is distinct from that of rodents and nonhuman primates, is the primary conduit for connections between the brainstem and medial temporal lobe. This study supports the concept that interconnected brainstem and forebrain nodes form an integrated central homeostatic network (CHN) in the human brain. Our findings provide an initial foundation for elucidating the neuroanatomic basis of homeostasis in the normal human brain, as well as for mapping CHN disconnections in patients with disorders of homeostasis, including sudden and unexpected death, and epilepsy.

[1]  J. Feldman,et al.  Understanding the rhythm of breathing: so near, yet so far. , 2013, Annual review of physiology.

[2]  V. Pieribone,et al.  Midbrain serotonergic neurons are central pH chemoreceptors , 2003, Nature Neuroscience.

[3]  J. Noebels,et al.  Spreading depolarization in the brainstem mediates sudden cardiorespiratory arrest in mouse SUDEP models , 2015, Science Translational Medicine.

[4]  R. Harper,et al.  Cardiac and Respiratory Correlations with Unit Discharge in Epileptic Human Temporal Lobe , 1990, Epilepsia.

[5]  F. Arman,et al.  Factors that affect interictal cardiovascular autonomic dysfunction in temporal lobe epilepsy: Role of hippocampal sclerosis , 2009, Epilepsy & Behavior.

[6]  W. Nauta,et al.  Hippocampal projections and related neural pathways to the midbrain in the cat. , 1958, Brain : a journal of neurology.

[7]  M. Granner,et al.  Sudden unexpected death in epilepsy: Fatal post-ictal respiratory and arousal mechanisms , 2013, Respiratory Physiology & Neurobiology.

[8]  R. Vertes,et al.  Projections of the median raphe nucleus in the rat , 1999, The Journal of comparative neurology.

[9]  Thomas R. Knösche,et al.  White matter integrity, fiber count, and other fallacies: The do's and don'ts of diffusion MRI , 2013, NeuroImage.

[10]  D. Leopold,et al.  Anatomical accuracy of brain connections derived from diffusion MRI tractography is inherently limited , 2014, Proceedings of the National Academy of Sciences.

[11]  S. Spencer Neural Networks in Human Epilepsy: Evidence of and Implications for Treatment , 2002, Epilepsia.

[12]  Thomas Deller,et al.  Neuroanatomical characteristics of the human pre-Bötzinger complex and its involvement in neurodegenerative brainstem diseases. , 2011, Brain : a journal of neurology.

[13]  J. Bellanger,et al.  Neural networks involving the medial temporal structures in temporal lobe epilepsy , 2001, Clinical Neurophysiology.

[14]  S Mraovitch,et al.  Interactions between limbic, thalamo‐striatal‐cortical, and central autonomic pathways during epileptic seizure progression , 1999, The Journal of comparative neurology.

[15]  J. Herman,et al.  Neural regulation of endocrine and autonomic stress responses , 2009, Nature Reviews Neuroscience.

[16]  E. Azmitia,et al.  The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis. , 1986, Advances in neurology.

[17]  John M Stern,et al.  Connectomics and epilepsy. , 2013, Current opinion in neurology.

[18]  J. W. Papez A PROPOSED MECHANISM OF EMOTION , 1937 .

[19]  Mark W. Youngblood,et al.  Ictal spread of medial temporal lobe seizures with and without secondary generalization: An intracranial electroencephalography analysis , 2014, Epilepsia.

[20]  Timothy Edward John Behrens,et al.  Characterization and propagation of uncertainty in diffusion‐weighted MR imaging , 2003, Magnetic resonance in medicine.

[21]  Heidi Johansen-Berg,et al.  Tractography: Where Do We Go from Here? , 2011, Brain Connect..

[22]  J. R. Augustine Circuitry and functional aspects of the insular lobe in primates including humans , 1996, Brain Research Reviews.

[23]  G. Richerson,et al.  Mechanisms of sudden unexpected death in epilepsy: the pathway to prevention , 2014, Nature Reviews Neurology.

[24]  Jon H Kaas,et al.  The evolution of brains from early mammals to humans. , 2013, Wiley interdisciplinary reviews. Cognitive science.

[25]  H. Blumenfeld Impaired consciousness in epilepsy , 2012, The Lancet Neurology.

[26]  Mark W. Woolrich,et al.  Probabilistic diffusion tractography with multiple fibre orientations: What can we gain? , 2007, NeuroImage.

[27]  S. Ogbonnaya,et al.  Vagal nerve stimulator: Evolving trends , 2013, Journal of natural science, biology, and medicine.

[28]  Volker A Coenen,et al.  MEDIAL FOREBRAIN BUNDLE STIMULATION AS A PATHOPHYSIOLOGICAL MECHANISM FOR HYPOMANIA IN SUBTHALAMIC NUCLEUS DEEP BRAIN STIMULATION FOR PARKINSON'S DISEASE , 2009, Neurosurgery.

[29]  Russell S. Ray,et al.  Impaired Respiratory and Body Temperature Control Upon Acute Serotonergic Neuron Inhibition , 2011, Science.

[30]  C. Saper The central autonomic nervous system: conscious visceral perception and autonomic pattern generation. , 2002, Annual review of neuroscience.

[31]  P. Basser,et al.  Estimation of the effective self-diffusion tensor from the NMR spin echo. , 1994, Journal of magnetic resonance. Series B.

[32]  J. Girvin,et al.  Cardiovascular effects of human insular cortex stimulation , 1992, Neurology.

[33]  G. Richerson,et al.  Functional and developmental identification of a molecular subtype of brain serotonergic neuron specialized to regulate breathing dynamics. , 2014, Cell reports.

[34]  E. Nattie,et al.  Catecholamine neurones in rats modulate sleep, breathing, central chemoreception and breathing variability , 2006, The Journal of physiology.

[35]  Amy E. Chadwick,et al.  Sudden Death in Toddlers Associated with Developmental Abnormalities of the Hippocampus: A Report of Five Cases , 2007, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[36]  Nicole Barger,et al.  Evidence for evolutionary specialization in human limbic structures , 2014, Front. Hum. Neurosci..

[37]  R. Vertes A lectin horseradish peroxidase study of the origin of ascending fibers in the medial forebrain bundle of the rat. The lower brainstem , 1984, Neuroscience.

[38]  Julien Cohen-Adad,et al.  Pushing the limits of in vivo diffusion MRI for the Human Connectome Project , 2013, NeuroImage.

[39]  G. Dai,et al.  Neuroanatomic Connectivity of the Human Ascending Arousal System Critical to Consciousness and Its Disorders , 2012, Journal of neuropathology and experimental neurology.

[40]  P. Maclean Some psychiatric implications of physiological studies on frontotemporal portion of limbic system (visceral brain). , 1952, Electroencephalography and clinical neurophysiology.

[41]  Thomas Benner,et al.  Disconnection of the ascending arousal system in traumatic coma. , 2013, Journal of neuropathology and experimental neurology.

[42]  S. Mueller,et al.  Evidence for brainstem network disruption in temporal lobe epilepsy and sudden unexplained death in epilepsy , 2014, NeuroImage: Clinical.

[43]  E. Benarroch The central autonomic network: functional organization, dysfunction, and perspective. , 1993, Mayo Clinic proceedings.

[44]  H. Barnhart,et al.  The emerging science of quantitative imaging biomarkers terminology and definitions for scientific studies and regulatory submissions , 2015, Statistical methods in medical research.

[45]  V. Napadow,et al.  The Autonomic Brain: An Activation Likelihood Estimation Meta-Analysis for Central Processing of Autonomic Function , 2013, The Journal of Neuroscience.

[46]  H. Blumenfeld What is a seizure network? Long-range network consequences of focal seizures. , 2014, Advances in experimental medicine and biology.

[47]  John D. Van Horn,et al.  Circular representation of human cortical networks for subject and population-level connectomic visualization , 2012, NeuroImage.

[48]  Mark P Richardson,et al.  Large scale brain models of epilepsy: dynamics meets connectomics , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[49]  C. Beaulieu,et al.  The basis of anisotropic water diffusion in the nervous system – a technical review , 2002, NMR in biomedicine.

[50]  Amy E. Chadwick,et al.  Sudden Death, Febrile Seizures, and Hippocampal and Temporal Lobe Maldevelopment in Toddlers: A New Entity , 2009, Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society.

[51]  L. Wald,et al.  A 64‐channel 3T array coil for accelerated brain MRI , 2013, Magnetic resonance in medicine.

[52]  Volker A Coenen,et al.  Human medial forebrain bundle (MFB) and anterior thalamic radiation (ATR): imaging of two major subcortical pathways and the dynamic balance of opposite affects in understanding depression. , 2012, The Journal of neuropsychiatry and clinical neurosciences.

[53]  Jun Lu,et al.  Locus Ceruleus and Anterior Cingulate Cortex Sustain Wakefulness in a Novel Environment , 2010, The Journal of Neuroscience.

[54]  E. Cavalheiro,et al.  Epileptiform activity in the limbic system. , 2011, Frontiers in bioscience.

[55]  Jonathan D. Cohen,et al.  An integrative theory of locus coeruleus-norepinephrine function: adaptive gain and optimal performance. , 2005, Annual review of neuroscience.

[56]  R. Harper,et al.  Sleep-disordered breathing: Effects on brain structure and function , 2013, Respiratory Physiology & Neurobiology.

[57]  S. Schuele,et al.  Ictal central apnea as a predictor for sudden unexpected death in epilepsy , 2011, Epilepsy & Behavior.

[58]  Leonardo Bonilha,et al.  Medial temporal lobe epilepsy is associated with neuronal fibre loss and paradoxical increase in structural connectivity of limbic structures , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[59]  G. Chrousos,et al.  Stress, the Stress System and the Role of Glucocorticoids , 2014, Neuroimmunomodulation.

[60]  Jeremy D. Schmahmann,et al.  Diffusion spectrum magnetic resonance imaging (DSI) tractography of crossing fibers , 2008, NeuroImage.

[61]  C. A. Lowry,et al.  Functional Subsets of Serotonergic Neurones: Implications for Control of the Hypothalamic‐Pituitary‐Adrenal Axis , 2002, Journal of neuroendocrinology.

[62]  Julien Cohen-Adad,et al.  The Human Connectome Project and beyond: Initial applications of 300mT/m gradients , 2013, NeuroImage.

[63]  H. Kinney,et al.  Dentate gyrus abnormalities in sudden unexplained death in infants: morphological marker of underlying brain vulnerability , 2014, Acta Neuropathologica.

[64]  F. H. Lopes da Silva,et al.  Epileptic Neuronal Networks: Methods of Identification and Clinical Relevance , 2012, Front. Neurol..