One Small Step for Neurotechnology, One Giant Leap for an In-Depth Understanding of the Brain

Is science mostly driven by ideas or by tools? The answers to the everlasting question remain open. But the advances in techniques undoubtedly push forward scientific research to investigate both more in-breadth and in-depth aspects. In neuroscience, the door was opened for recording in vivo dynamic neuronal activity through the development of microelectrodes. However, the brain functions through highly interconnected circuits that are composed of numerous distinctly-located neurons [1, 2]. A critical technical issue has been proposed in the field of neurotechnology—how to simultaneously detect multiple neuronal spikes at both wide temporal and spatial scales? In line with this, the latest study published in Nature Biomedical Engineering by a joint research group describes ultra-flexible electrode arrays for long-term and far-ranging in vivo electrophysiological recordings (Fig. 1), which makes one giant leap in in-depth neural circuitry studies [3].

Fig. 1.

Diagram of the ultra-flexible electrode arrays for months-long high-density electrophysiological mapping of thousands of neurons in rodents (modified from the original article [3]). Arrays are implanted into multiple cortical regions, and signals of thousands of neurons are recorded simultaneously during a visual stimulus to map the cortical circuits underlying different behaviors.

In this study, based on the previously-developed ultra-flexible and biocompatible nanoelectronic thread electrodes (NETs) [4], the authors further constructed large-scale 3D electrode arrays by fabricating three types of NET modules. The authors claim that these arrays can be implanted at extremely high densities without overmuch occupation of extracellular space and tissue damage. Given that the type I arrays showed a broader volumetric coverage of neural recording, the authors used this design for further experiments. Using an optimized implantation surgery strategy, the authors achieved desirable high volumetric recording density in a certain region (>1000 electrode contacts per mm³). Then the authors reported that 1.25 sorted single units per contact were detected through an average of 1058 recording contacts per animal, of which, nearly half of the units were deemed to be single units. Given the reliable recording performance of the ultra-flexible electrode arrays, the authors further attempted to electro-physiologically map the visual cortex by implanting 10 types I NET modules into the mouse visual cortex with a spacing of 200 μm. Visual stimuli (drifting gratings at various angles) were further applied to examine the functions of dynamic local neural recordings. About 40% of the 1355 units recorded were modulated by the visual stimuli, and taking advantage of the high-density distribution of the contacts, the authors mapped the spatiotemporal structure of the visual cortical network and resolved local neuron-neuron communications when receiving visual stimuli. Then the authors moved forward to decode the stimulus orientation based on the information derived from the 1355 recorded units through all the stimuli trials. And according to the authors, the decoding errors dramatically decreased as the number of included units increased. So far, ultra-flexible electrode arrays have been demonstrated to be reliable for high-density volumetric recording.

Given that optogenetics has been widely used in neuroscience [5, 6], the authors decided to combine large-scale recording and optical stimulation in Thy1-mhChR2-EYFP transgenic mice. Blue light successfully activated neurons recorded by those contacts adjacent to the optical fiber. And optical stimulation of both long-term potentiation and long-term depression protocols further resulted in the increased coupling of neighboring populations of neurons, highlighting the great compatibility of the arrays with optogenetic tools. Then, the authors implanted multiple NET modules into extensive cortical regions (including motor, sensory, and visual cortices) of both hemispheres. Similarly, the array achieved a high-performance recording capacity across different cortices by yielding 1.32 units per contact. Then, the authors attempted to correlate behavior and neural activity by applying visual stimuli and found that different behaviors were associated with distinct neural activities in corresponding cortical regions. With the assistance of a machine learning long short-term memory regression model, the authors successfully decoded the animal’s spontaneous behavioral states from the electrophysiological signals in multiple cortical regions, indicating the great potential of the electrode array for investigating the neural circuitry dynamics of distinct regions. To fulfill the demand for long-term electrophysiological recording, the chronic stability of the arrays was examined. According to the authors, the main recording parameters remained stable for up to 3 months.

Overall, the authors have successfully developed minimal invasive ultra-flexible electrode arrays capable of stable, months-long, in vivo recording of neuronal activity. Although other kinds of electrode arrays have been developed, from the data presented, we are deeply encouraged by the high-density recording capacity, in particular, the accessibility to the simultaneous recording of single units in extensive brain regions. These characteristics, so far, have not been demonstrated in any other previously developed electrode arrays. For neuroscientists or others interested in this field, the importance of this study may not only be in improving the electrophysiological recording qualities but also greatly broadens the dimensions for designing more complex experiments, such as revealing the multilevel neural circuitry basis underlying different behaviors. In our opinion, perhaps further addressing some issues which may be concerning to potential users is somehow beneficial for further popularization and commercialization. Given that deeper regions such as the hippocampus and thalamus play roles as important as the cortices under many physiological and pathological conditions [7, 8], the first question is whether the performance of this electrode array remains excellent in other deeper areas of the brain. Then, many studies may need to design electrical stimulation or intra-cerebral pharmacology experiments [9, 10]; further testing of the compatibility of this array with stimulating electrodes or cannulas is desirable. Also, with those great improvements compared with currently available electrode arrays, these new arrays may play a vital role in directly analyzing human brain activity, especially in those intractable neurological diseases such as epilepsy and Parkinson's disease [11, 12]. As for achieving a successful clinical translation, performing experiments on non-human primates would be the initial necessary stepping stone.

Conflict of interest

The authors declare that they have no competing interest.