Layer-specific interneuron activity: Somatostatin-expressing interneurons are an important group of inhibitory neurons in the brain that target and thus control the dendrites of pyramidal cells. These interneurons have recently been shown to play a role in sensorimotor integration, reinforcement encoding, and selective attention. Muñoz et al. used channelrhodopsin-assisted patching to investigate the spatiotemporal pattern of neocortical dendritic inhibition in vivo. They were able to record the activity of somatostatin-expressing interneurons in all neocortical layers in behaving mice. The results provide a framework for understanding the changes in dendritic inhibition that take place in the neocortex during active behaviors. This framework is very distinct from the view obtained from previous recordings that were restricted to interneurons in the superficial layers of the neocortex. Science , this issue p. 954

From sequences of speech sounds^1,2 or letters³, humans can extract rich and nuanced meaning through language. This capacity is essential for human communication. Yet, despite a growing understanding of the brain areas that support linguistic and semantic processing^4–12, the derivation of linguistic meaning in neural tissue at the cellular level and over the timescale of action potentials remains largely unknown. Here we recorded from single cells in the left language-dominant prefrontal cortex as participants listened to semantically diverse sentences and naturalistic stories. By tracking their activities during natural speech processing, we discover a fine-scale cortical representation of semantic information by individual neurons. These neurons responded selectively to specific word meanings and reliably distinguished words from nonwords. Moreover, rather than responding to the words as fixed memory representations, their activities were highly dynamic, reflecting the words’ meanings based on their specific sentence contexts and independent of their phonetic form. Collectively, we show how these cell ensembles accurately predicted the broad semantic categories of the words as they were heard in real time during speech and how they tracked the sentences in which they appeared. We also show how they encoded the hierarchical structure of these meaning representations and how these representations mapped onto the cell population. Together, these findings reveal a finely detailed cortical organization of semantic representations at the neuron scale in humans and begin to illuminate the cellular-level processing of meaning during language comprehension.

Humans are capable of generating extraordinarily diverse articulatory movement combinations to produce meaningful speech. This ability to orchestrate specific phonetic sequences, and their syllabification and inflection over subsecond timescales allows us to produce thousands of word sounds and is a core component of language^1,2. The fundamental cellular units and constructs by which we plan and produce words during speech, however, remain largely unknown. Here, using acute ultrahigh-density Neuropixels recordings capable of sampling across the cortical column in humans, we discover neurons in the language-dominant prefrontal cortex that encoded detailed information about the phonetic arrangement and composition of planned words during the production of natural speech. These neurons represented the specific order and structure of articulatory events before utterance and reflected the segmentation of phonetic sequences into distinct syllables. They also accurately predicted the phonetic, syllabic and morphological components of upcoming words and showed a temporally ordered dynamic. Collectively, we show how these mixtures of cells are broadly organized along the cortical column and how their activity patterns transition from articulation planning to production. We also demonstrate how these cells reliably track the detailed composition of consonant and vowel sounds during perception and how they distinguish processes specifically related to speaking from those related to listening. Together, these findings reveal a remarkably structured organization and encoding cascade of phonetic representations by prefrontal neurons in humans and demonstrate a cellular process that can support the production of speech.

Brain networks contain a large diversity of functionally distinct neuronal elements, each with unique properties, enabling computational capacities and supporting brain functions. Understanding their functional implications for behavior requires the precise identification of the cell types of a network and in vivo monitoring of their activity profiles. Here, we developed a channelrhodopsin-assisted patching method allowing the efficient in vivo targeted recording of neurons identified by their molecular, electrophysiological, and morphological features. The method has a high yield, does not require visual guidance, and thus can be applied at any depth in the brain. This approach overcomes limitations of present technologies. We validate this strategy with in vivo recordings of identified subtypes of GABAergic and glutamatergic neurons in deep cortical layers, subcortical cholinergic neurons, and neurons in the thalamic reticular nucleus in anesthetized and awake mice. We propose this method as an important complement to existing technologies to relate specific cell-type activity to brain circuitry, function, and behavior.

Neuropixels are silicon-based electrophysiology-recording probes with high channel count and recording-site density. These probes offer a turnkey platform for measuring neural activity with single-cell resolution and at a scale that is beyond the capabilities of current clinically approved devices. Our team demonstrated the first-in-human use of these probes during resection surgery for epilepsy or tumors and deep brain stimulation electrode placement in patients with Parkinson’s disease. Here, we provide a better understanding of the capabilities and challenges of using Neuropixels as a research tool to study human neurophysiology, with the hope that this information may inform future efforts toward regulatory approval of Neuropixels probes as research devices. In perioperative procedures, the major concerns are the initial sterility of the device, maintaining a sterile field during surgery, having multiple referencing and grounding schemes available to de-noise recordings (if necessary), protecting the silicon probe from accidental contact before insertion and obtaining high-quality action potential and local field potential recordings. The research team ensures that the device is fully operational while coordinating with the surgical team to remove sources of electrical noise that could otherwise substantially affect the signals recorded by the sensitive hardware. Prior preparation using the equipment and training in human clinical research and working in operating rooms maximize effective communication within and between the teams, ensuring high recording quality and minimizing the time added to the surgery. The perioperative procedure requires ~4 h, and the entire protocol requires multiple weeks.