In vitro models of the developing brain such as 3D brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, it remains undefined what cells are generated within organoids and to what extent they recapitulate the regional complexity, cellular diversity, and circuit functionality of the brain. Here, we analyzed gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (over 9 months) enabling unprecedented levels of maturity including the formation of dendritic spines and of spontaneously-active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photoreceptor-like cells, which may offer ways to probe the functionality of human neuronal circuits using physiological sensory stimuli.

The ability to optimize behavioral performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, plays an important role in regulating cognitive control. Hypotheses regarding its function include guiding reward-based decision making1, monitoring for conflict between competing responses2, and predicting task difficulty3. Precise mechanisms of dACC function remain unknown, however, due to the limited number of human neurophysiological studies. Here we demonstrate with functional imaging and human single-neuron recordings that the firing of individual dACC neurons encodes current and recent cognitive load. We show that the modulation of current dACC activity by previous activity produces a behavioral adaptation that accelerates reactions to cues of similar difficulty as previous ones, and retards reactions to cues of differing difficulty. Furthermore, this conflict adaptation, or Gratton effect2,4, is abolished after surgically targeted dACC ablation. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioral responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands, it engenders accuracy by delaying responses.

Summary The biophysical features of neurons shape information processing in the brain. Cortical neurons are larger in humans than in other species, but it is unclear how their size affects synaptic integration. Here, we perform direct electrical recordings from human dendrites and report enhanced electrical compartmentalization in layer 5 pyramidal neurons. Compared to rat dendrites, distal human dendrites provide limited excitation to the soma, even in the presence of dendritic spikes. Human somas also exhibit less bursting due to reduced recruitment of dendritic electrogenesis. Finally, we find that decreased ion channel densities result in higher input resistance and underlie the lower coupling of human dendrites. We conclude that the increased length of human neurons alters their input-output properties, which will impact cortical computation.

The human dorsal anterior cingulate cortex (dACC) has been implicated in cognitive processes that have been proposed to play a role in integrating contextual information needed to select or modify appropriate motor responses. In humans, however, there has been little direct evidence tying the dACC to the integration of contextual information and behavioral response. We used single-neuron recordings from human subjects to evaluate the role of the dACC in reward-based decision making. Subjects undergoing planned surgical cingulotomy performed a task where they were instructed to make specific movements in response to changing monetary rewards. In many neurons, activity increased in response to a diminished reward, and was also predictive of the movement ultimately made. After dACC ablation, subjects made selectively more errors when they were required to change movement based on reward reduction. These findings suggest that the dACC in humans plays an important role in linking reward-related information with alternative actions.

Primates have the remarkable ability to rapidly adjust or modify associations between visual cues and specific motor responses. Whereas little is known as to how such adjustments in behavioral policy are implemented, recent learning models suggest that the anterior striatum is optimally positioned to have a role in this process. We recorded from single units and delivered microstimulation in the striatum of rhesus monkeys performing an associative learning task. Caudate activity during reinforcement was closely correlated with the rate of learning and peaked during the steepest portion of the learning curve when new associations were being acquired. Moreover, delivering microstimulation in the caudate during the reinforcement period significantly increased the rate of learning without altering the monkeys' ultimate performance. These findings suggest that the caudate is responsible for implementing selective adjustments to the 'associative weights' between sensory cues and motor responses during learning, thus enhancing the likelihood of selecting profitable actions.

SUMMARY A cornerstone of successful social interchange is the ability to anticipate each other’s intentions or actions. While generating these internal predictions is essential for constructive social behavior, their single neuronal basis and causal underpinnings are unknown. Here, we discover specific neurons in the primate dorsal anterior cingulate that selectively predict an opponent’s yet unknown decision to invest in their common good or defect and distinct neurons that encode the monkey’s own current decision based on prior outcomes. Mixed population predictions of the other was remarkably near optimal compared to behavioral decoders. Moreover, disrupting cingulate activity selectively biased mutually beneficial interactions between the monkeys but, surprisingly, had no influence on their decisions when no net-positive outcome was possible. These findings identify a group of other-predictive neurons in the primate anterior cingulate essential for enacting cooperative interactions and may pave a way toward the targeted treatment of social behavioral disorders.

Our findings suggest that stimulation of the anterior internal capsule may be a safe and effective procedure for the treatment of Tourette syndrome.

Recent advances in multi-electrode array technology have made it possible to monitor large neuronal ensembles at cellular resolution. In humans, however, current approaches either restrict recordings to only a few neurons per penetrating electrode or combine the signals of thousands of neurons in local field potential (LFP) recordings. Here, we describe a new probe variant and set of techniques which enable simultaneous recording from over 200 well-isolated cortical single units in human participants during intraoperative neurosurgical procedures using silicon Neuropixels probes. We characterized a diversity of extracellular waveforms with eight separable single unit classes, with differing firing rates, positions along the length of the linear electrode array, spatial spread of the waveform, and modulation by LFP events such as interictal discharges and burst suppression. While some additional challenges remain in creating a turn-key recording system, high-density silicon arrays provide a path for studying humanspecific cognitive processes and their dysfunction at unprecedented spatiotemporal resolution.Major technological advances in the past decade have led to a revolution in the neurosciences.Many research programs now routinely rely on the analysis of single-neuron action potentials from hundreds and even thousands of neurons, which provide a rich understanding of the coordinated activity of large neuronal ensembles that underlie sensory, motor, and cognitive operations [1][2][3][4] . While these developments have been most pronounced in animal models, there have been parallel, albeit slower, advances in the ability to record from single neurons in humans. Single-unit recordings in humans have been performed since the mid-1950s 5-8 , and were foundational in understanding the role of neural circuits in neurologic disease. For example, such techniques helped to establish an understanding of the relationship between .