July 7- August 1, 2014 Focus Program on
NEUROVASCULAR COUPLING AND RELATED PHENOMENA

Problem Solving Workshop on Neurovascular Coupling and Developing Brain
July 21-25, 2014
Organizers: Martin Frasch (Obstetrics & Gynaecology, U de Montreal)
Huaxiong Huang and Qiming Wang (Math. & Stats., York U)

Registration on site Wrokshop fees: $100, Students and PDF: $50, Waived for invited speakers			Information for speakers
			Information for funded participants
Invited Speakers	Draft Program	Accommodation in Toronto	Toronto

Overview

Brain injury acquired antenatally remains a major cause of postnatal long-term neurodevelopmental sequelae. There is evidence for a combined role of fetal infection and inflammation and hypoxic-acidemia. Concomitant hypoxia and acidemia (umbilical cord blood pH < 7.00) during labour increase the risk for neonatal adverse outcomes and longer-term sequelae including cerebral palsy. The main manifestation of pathologic inflammation in the feto-placental unit, chorioamnionitis, affects 20% of term pregnancies and up to 60% of preterm pregnancies and is often asymptomatic.

The format of the event will be that of a problem-solving workshop, also called a Study Group (SG). The workshop will provide an informal setting for researchers from life sciences and mathematical sciences to identify key research questions related to perinatal brain development from neurovascular coupling viewpoint. On the first day of this week long workshop, specific problems will be presented to the workshop participants. It will be followed by brainstorm sessions in subsequent days and a summary session on the last day of the workshop.

Draft Program

Time	Monday	Tuesday	Wednesday	Thursday	Friday
8:45-9:00	Welcome
9:00-10:30	Problem presentation	Group discussion	Group discussion	Group discussion	Presentation
10:30-11:00	Coffee break
11:00-12:30	Group discussion	Group discussion	Group discussion	Group discussion	Summary
12:30-14:00	Lunch break
14:00-15:00	Group discussion	Group discussion	Group discussion	Group discussion
15:00-15:30	Tea Break
15:30-17:00	Summary	Summary	Summary	Summary

PROBLEMS

Electrical and mechanical restriction on the localization of cerebral blood flow.
Proposer: Patrick Drew (Engineering Science & Department of Neurosurgery, Penn State)

The arteries that supply the brain with oxygenated blood form a branching network on the surface of the brain, with the smallest branches, known as penetrating arterioles, entering into the brain at right angles, and connecting with the capillary network. The local control of blood flow is mediated through relaxation of the smooth muscles that surround arteries, which dilate the vessel and decrease resistance. The endothelial and smooth muscle cells that make up the vessel are electrically coupled and can propogate the electrical signals that mediate dilation over several hundred microns or more. It has long been assumed that the penetrating arterioles, which are thought to be bottlenecks in the system, would control local blood flow. Surprisingly, measurements in awake, behaving mice has shown that the surface vessel dilate significantly more than the penetrating arterioles they feed, only tens of microns away. This results in a less localized spread of blood flow than would be expected from the penetrating vessels dilating alone. What mechanism could underly this difference between the vessels, and what physiological role might it play? Two possible mechanisms for consideration are that the mechanical properties of the brain tissue restrict the dilation of the penetrating arteriole more than the surface arteries, which are surrounded by cerebral spinal fluid, or that non-linear excitation-contraction coupling could generate this stark change in behavior.

Modelling fetal electrocorticogram and heart rate during labour and inflammation (.pdf format)
Martin G. Frasch, MD, PhD Assistant Research Professor, Department of Obstetrics-Gynecology, Faculty of Medicine
Université de Montréal, CHU Sainte-Justine Research Center

Description
In late gestation, especially during labour, fetal well-being is typically monitored by measuring fetal heart rate (FHR). FHR monitoring, however, has low positive predictive value for detecting acidemia. As for early detection of fetal inflammation, no reliable noninvasive methods exist. Both conditions (fetal acidemia and inflammation) are associated with increased risk for brain injury at birth with lasting neurological deficits that often can only be diagnosed years after birth. We have showed that fetal electroencephalogram (EEG) is feasible during labour and would enhance the ability to detect early onset of acidemia. In addition, heart rate variability dynamics reflects temporal profile of fetal inflammatory response.
In order to develop more robust techniques for online detection of fetal inflammation during late gestation and acidemia/inflammation during labour, it will be desirable to have a physiology-based mathematical model for fetal electrocorticogram and heart rate under “stress”, e.g., when the supply of fetal oxygen is reduced because of a variety of causes and inflammatory response is ongoing due to infection or worsening acidemia (i.e., septic or aseptic).

Objectives
During the workshop, data from animal experiments will be provided for the participants. The primary goal is to develop a quantitative neuronal/cardiovascular model capable of generating electrocorticogram and heart rate signals that mimic the observed patterns from animal experiments. A secondary objective is to find a robust approach that can be used to fit model parameters using the experimental data.

Background literature
1. Radunskaya AE, Najera A, Durosier D, Louzoun Y, Peercy B, Ross MG, Richardson BS, Frasch MG. A mathematical model of nutrient delivery during labour: predicting fetal distress due to severe acidemia. Experimental Biology Meeting: April 20-24, 2013, Boston, Massachusetts. The FASEB Journal. 2013;27:1217.16.
2. Frasch MG, Keen AE, Gagnon R, Ross MG, Richardson BS (2011). Monitoring Fetal Electrocortical Activity during Labour for Predicting Worsening Acidemia: A Prospective Study in the Ovine Fetus Near Term. PLOS ONE 6(7):e22100. doi:10.1371/journal.pone.0022100.
3. Zandt BJ, ten Haken B, van Dijk JG, van Putten MJ. Neural dynamics during anoxia and the "wave of death". PLOS ONE 2011;6:e22127.
4. Frasch MG, Keen A, Matushewski B, Richardson BS. Comparability of electroenkephalogram (EEG) versus electrocorticogram (ECOG) in the ovine fetus near term. 57th Annual Scientific Meeting of the Society for Gynecologic Investigation Orlando, Florida: Reproductive Sciences, 2010 (vol 17).
5. Durosier LD, Cao M, Herry C, Batkin I, Seely AJE, Burns P, Fecteau G, Desrochers A, Frasch MG. A signature of fetal systemic inflammatory response in the pattern of heart rate variability measures matrix: a prospective study in fetal sheep model of lipopolysaccharide (LPS)-induced sepsis. Experimental Biology Meeting: April 20-24, 2013, Boston, Massachusetts. The FASEB Journal. 2013;27:926.8