The hippocampus is believed to play an important role in memory and navigation and it has been the subject of a countless number of studies that mostly have fired up and activated this region of the brain to try to understand how it works. But what about when it is at rest? Is it still at work?

The idea of a resting-state of the brain was first floated more than two decades ago, but neuroscientists have not been able to agree whether it even exists. Now, they may have some answers thanks to the work of a team of HKU biomedical engineers led by Professor Ed X Wu, Chair and Lam Woo Professor in Biomedical Engineering.

The debate has focussed on whether signals picked up through functional magnetic resonance imaging (fMRI) of the brain at resting-state are just a consequence of blood flowing through multiple interconnected regions or signs of actual large-scale neural activity.

Professor Wu’s inspired approach to this problem was to apply a basket of tools and measures, including one drawn from the team’s earlier work on the somatosensory thalamus that was published in 2016 in the Proceedings of the National Academy of Sciences of the United States of America (PNAS).

The thalamus is a region of the brain that acts as a relay for communication among sensory systems and the somatosensory system concerns touch, pain and the like. Previously, it was thought that communication was self-contained within each sensory system, so for example the somatosensory thalamus only communicated with the somatosensory cortex. But the researchers showed that at the low frequencies measured through resting-state fMRI, different sensory networks actually connected to each other. Somatosensation talked to the visual and auditory senses, so to speak. This offered a possible explanation of how the brain integrates different sensations.

Light work

The finding influenced the team to look further and investigate the effect of low-frequency stimulation in the hippocampus, said Dr Alex TL Leong, who with Dr Russell W Chan is one of the key members of Professor Wu’s team.

“The role of the hippocampus in complex brain networks has not been well understood. The literature will tell you that there are many functions that it is important for, but at the end of the day there must be a unifying observation or underlying principle of how the hippocampus actually functions in the brain,” he said.

To edge closer to that goal, the HKU researchers applied several kinds of investigations that both activated the hippocampus at low frequencies and revealed the impact on brain functions.

They first combined fMRI with optogenetics, in which they genetically modified excitatory neurons in rats’ hippocampus so they were sensitive to light. An optical fibre delivered the light stimulation so the hippocampus could be turned ‘on’ at different frequencies, with the low range as low as 0.5 to 1 Hz. This resulted in the first important finding: at low frequencies, multiple areas beyond the hippocampus lit up, especially in the visual cortex, but at high frequencies, activity was confined to the hippocampus.

Secondly, they found that low-frequency stimulation enhanced the connectivity of large-scale resting-state fMRI sensory brain networks, including visual, auditory and somatosensory, and augmented sensory functions.

Signals during resting-state

“We already knew that the hippocampus interacts a lot with the cortex at high frequencies, particularly when it comes to memory functions. But here we show that this interaction is predominant at very low frequencies, too,” Dr Leong said. This finding indicated that there was an underlying neural basis to the fMRI signals picked up from the brain at resting-state.

The researchers also tested whether disrupting normal hippocampus function would affect the results. They did this by knocking out the hippocampus pharmacologically, which caused connectivity to drop immediately in the treated rats. If the results had still held, that would have indicated the hippocampus was not involved in enhancing brain connectivity.

The findings were published in PNAS in August, 2017 and received widespread coverage in the scientific and popular media. Professor Wu said the implications extended beyond simply understanding the brain.

“Only when we understand the functions of the brain circuits or networks can we then design new therapeutic measures which are more effective for treating or curing brain disorders, such as Alzheimer’s disease, epilepsy and schizophrenia,” he said, adding their work complemented ongoing, high-level projects to understand the brain that have been initiated by both the Chinese and American governments.

From left: Dr Russell W Chan, Professor Ed X Wu and Dr Alex TL Leong.

New functions of hippocampus unveiled to bring insights to causes and treatments of brain diseases.

(Courtesy of Ed Boyden, MIT)