Development of spontaneous activity in the human fetal brain

The rudimentary structures and major compartments of the human brain and central nervous system are largely formed by 8 weeks gestation (GW), at the end of embryonic period1. Following this, there is large-scale neurogenesis and gliogensis to form the six-layered cortical plate by midgestation1,2. Although spontaneous activity is a hallmark of most developing neural systems, little is currently known about the development of spontaneous activity in the human fetal brain. In mice, spontaneous neural activity is initially mediated by gap junctions. Local synchronous spontaneous activity emerges subsequently with the appearance of electrical synapses and activity then decorrelates into sparse sequential patterns of spontaneous activity3,4. During development, spontaneous activity is thought to help establish correct wiring and maturation of cortical circuits5,6. Together, this creates the framework for the distinct patterns of distributed long-range activity seen across the lifespan with non-invasive neuroimaging methods7.

Research looking at spontaneous cortical activity in the human fetus is scarce due to clear challenges associated with studying neural activity in utero. Previous work has shown it is possible to record in vitro spontaneous neuronal activity in the subplate of acute human fetal cortical slices8. Preliminary work in the lab has shown it is possible to culture human fetal cortical slices from samples aged 13 to 21 GW, and to transduce viral expression in neuronal populations using adeno-associated viruses (AAVs), in line with previous literature9. However, culturing techniques and viral transduction will require optimisation. Together, this opens the opportunity to use fetal neural organotypic cultures combined with calcium imaging to investigate spontaneous neural activity in fetal neural tissue.

Spontaneous neural activity can be studied in vivo using functional magnetic resonance imaging (fMRI) and electroencephalography (EEG)10,11. Using these methods, large scale activity has been identified in preterm infants as young as 24 post-menstrual weeks. However, multiple studies have demonstrated that preterm birth can significantly alter brain development and is associated with altered functional connectivity and cortical processing 12,13. Importantly, recent advances in MR image acquisition and processing now allow in utero study of human brain development. This has also enabled investigation of the typical development of spontaneous activity and has demonstrated that crude patterns of large-scale neural activity can be identified which are likely precursors to the resting state networks seen later in life. However, although detailed studies of this kind of activity in preterm infants have shown that significant maturation occurs across the equivalent period to the third trimester of gestation, these developmental changes have not been investigated in the fetal brain. This will now be possible through data collected and processed as part of the developing Human Connectome Project (dHCP) which includes >1000 fetal and neonatal MRI brain data sets.

The work of this PhD will therefore focus on using these unique datasets and state of the art methods to characterise how spontaneous neural activity first develops in the human brain from 12 GW up to full term (37 GW). In addition to providing new insight into how activity changes from within local circuitry to across large-scale networks during this key period, it will also potentially inform about how activity and cortical maturation are linked and how the brain's connectivity framework first emerges. This has implications for understanding about how disruptions through environment or pathology can ultimately lead to neurodevelopmental disorders.