Nature subjournal: Pinpoint synaptic connections by recording neurons

How human thoughts and dreams arise from electrical impulses in the brain with an estimated 100 trillion synapses is a mystery
.
Chong Xie, a neuroengineer at Rice University, dreams of changing that by
creating a system that can record all the electrical activity in the living brain.

The researchers describe their latest achievement in this area, using a three-dimensional electrode array to map the location and activity
of up to 1 million potential synaptic links in living brains based on millisecond-level electrical impulse evolution records of tens of thousands of neurons in a cubic millimeter of brain tissue.

"The novelty of this work is the recording density, and the microcircuits in the brain are very mysterious
.
We don't have many ways to plot their activity, especially on volume
.
We hope to provide very dense cortical recordings because these recordings are scientifically important
for understanding how brain circuits work.
”

Xie conducted the study in collaboration with colleagues at Rice University and UCSF, including Roland Frank of UCSF and Luan Lan
of Rice University.

Neurons are small
.
Each cubic millimeter of brain tissue contains about 100,000.

This density is about the same for humans and other mammals, including rodents
in Xie's lab.
The brain's processing power comes from synaptic connections
between neurons.
Synaptic pairs of neurons are connected by narrow tissue bridges called axons, which are only a millionth of a meter
in diameter.

Xie's team spent years developing a material called nanoelectronic wires (NETs), which are thin, ultra-flexible and biocompatible with three properties
to make minimally invasive electrode implants.
In previous studies, Xie's team has demonstrated technology
that can implant tightly packed NET arrays with up to 128 electrodes.
The researchers also showed that their array could stay in place for up to 10 months, recording pulsed peak currents or action potentials
from nearby neurons.

"When neurons generate action potentials, they emit very weak electrical signals," Xie said
.
"To capture the signal, you have to place the electrodes very close to each neuron
.
Usually, this means that the distance is less than 100 microns
.
”

The use of electrodes to record nerve spikes has been a dominant technique in neuroscience for decades, but the evolution of electrode materials has gradually shifted the implantation of neural electrodes from a highly invasive procedure to one
that does not cause measurable tissue damage.

One of the main focuses of Xie's lab is to expand the size
of its implanted array.
In the new study, Xie and his colleagues, including Hanlin Zhu, one of the project's lead graduate students, implanted 1,024 NET electrode arrays
into 1 cubic millimeter of brain tissue.

"The main signal we were trying to measure was electrical spikes coming from neurons, and that's how
they communicated.
One thing we care a lot about and want to know very much is how neurons are connected
.
”

Xie said there is currently no direct way to probe synaptic connections

"Axons can be very long, and each neuron can be connected by thousands of other neurons," he said
.
"It's a very, very chaotic network
.
Exploring it is an extremely challenging task, especially when the
brain is still working.
”

The density of the new electrode array, and its ability to capture millisecond-to-millisecond changes in individual neurons' electrical peaks, allowed Xie and his collaborators to decipher potential synaptic links
between pairs of neurons.

"When synapses work, when you look at the firing activity of two neurons, you usually see a typical pattern," Xie said
.

He said it takes a while
for electrical impulses that start in presynaptic neurons to travel down the axon and activate postsynaptic neurons.

"We recorded many, many spikes, and then we needed to classify the peaks and classify each peak as a single neuron
," he said.
"We know the location of
each electrode or channel.
No more than a few
neurons are recorded per channel.
Each neuron is usually also recorded
by more than one contact.
So, you can do something similar to triangulation to determine the position of
individual neurons.
”

Once neurons are mapped, it is relatively easy to calculate the distance between them, from which the propagation time
of synaptic activation is calculated.

The 1,024-electrode array gave Xie's team about one electrode
per 100 neurons in the cubic millimeter brain tissue being studied.
The lab is working on creating denser arrays that pack more electrodes
in the same volume.

Although our brains typically consume about as much energy as the body can provide, the vast majority of neurons in the human brain are unused
.
Neuroscientists don't yet fully understand why the brain has so many unused neurons, which Xie says is a factor
his team considered when designing the electrode array.

"I want to capture as much interaction
as possible," he says.
"I don't think we need a 1:1 ratio of electrodes and neurons to capture all the information, and capturing all the interactions is really my dream
.
"