• Interfering fields stimulate the brain without surgery

Deep brain stimulation can help treat patients with drug-resistant brain disorders. The treatment, however, requires invasive surgery to implant an electrode inside the brain. Non-invasive brain stimulation from external electric fields, meanwhile, lacks the precision required to be an effective substitute. Now, researchers have developed a non-invasive alternative: temporal interference stimulation, a technique that provides targeted neural stimulation without the need for neurosurgery.

Temporal interference stimulation works by delivering multiple electric fields into the brain using currents with slightly different kilohertz frequencies. As neurons don't respond to such high frequencies, the outer layers of the brain are not affected. But where the fields intersect deep within the brain, the neurons are sensitive to the difference frequency, which is low enough to drive neural activity. "Until now, to reach a deep structure you needed to implant an electrode in the head, and that is associated with a high risk," explained lead author Nir Grossman of Imperial College London and MIT. "We believe we've opened the way to do it in a non-invasive manner, essentially revolutionizing the risk--benefit ratio of such a therapy."

Grossman and collaborators tested the new technique in living mice. They showed that temporal interference stimulation with a difference frequency of 10 Hz could non-invasively activate the hippocampus, a deep brain structure involved in memory, without activating the overlying cortex. They also demonstrated that the site of activation could be steered by changing the ratio of amplitudes of the applied currents. The technology currently activates larger volumes than those activated by implanted electrodes, but Grossman says that the team is working to improve the focusing capability at greater depth.

• MAPseq maps connections of individual neurons

Neurons in the brain are connected in a highly organized manner via long-range axonal projections. The patterns of these projections can reveal how the brain transports information, which cells and regions are connected, and how the connections give rise to function. As yet, however, there has been no comprehensive survey of the long-range connectivity of the mammalian cortex at single neuron resolution. To fill this gap, a team from Cold Spring Harbor Laboratory has developed MAPseq (multiplexed analysis of projections by sequencing), a technique that can discern the pattern of connections between individual neurons and their targets in the brains of mice. Identifying connections at the single cell level could help researchers understand brain function and dysfunction.

MAPseq works by using a virus to label individual neurons in the mouse cortex with unique RNA sequences called barcodes. Within each cell, the barcodes attach to a protein that is then transported to the axon terminal, which abuts the neuron's target. After sectioning the brain, the amount of each RNA barcode in each section indicates the strength of projection from the corresponding neuron to that section.

Mapping cortico-cortical projections at single-cell resolution

The team demonstrated the use of MAPseq to determine the full projection map of an individual mouse in a single experiment, labelling over 30,000 neurons in the animal's brain. After infecting the neurons in one cortical hemisphere with a MAPseq barcode viral library, the researchers dissected the cortex into several hundred cuboids and sequenced the barcodes in each to determine the location and projection targets of each neuron. "By uncovering the entire cortico-cortical projection structure at single-cell resolution, we may provide insight into the principles that underlie the organization and function of cortical circuits," explained lead author Longwen Huang.

• Gene editing tool minimizes complications

Gene editing offers the potential to halt the progression of neurological disorders with a defined genetic cause, such as Huntington's disease or certain types of Parkinson's and Alzheimer's disease. The CRISPR-Cas9 system is a gene editing tool that uses the enzyme Cas9, a type of molecular scissors, to cut out a particular gene – enabling replacement or deletion of problematic genes. To achieve this, a gene that causes continuous expression of Cas9 is inserted into cells. This approach, however, can cause long-term problems such as off-target editing, triggering the immune response or even insertion of the gene itself into the cell's DNA.

To mitigate such potential complications, a US–Swiss research team has proposed the use of a Cas9 ribonucleoprotein complex that can be inserted directly into cells as an assembled and functional enzyme, rather than a gene. They injected this complex into the brains of mice, where it successfully deleted a segment of DNA from within neurons. Importantly, the injected complex degraded and cleared from the body.

"We've taken one step forward by showing that we can edit neurons in adult animals using a non-genetically encoded Cas9 molecule," said lead author Brett Staahl from the University of California, Berkeley. "The animal doesn't seem to have an innate immune response against our Cas9 molecule, it's well tolerated and the scale of editing is significant." Staahl noted that this approach can be used to edit neurons in different regions of the brain. "This is a platform technology that can be applied to various neurological disorders," he added.

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