Faculty Bibliography

Effective treatments for chronic pain remain limited. Conceptually, a closed-loop neural interface combining sensory signal detection with therapeutic delivery could produce timely and effective pain relief. Such systems are challenging to develop because of difficulties in accurate pain detection and ultrafast analgesic delivery. Pain has sensory and affective components, encoded in large part by neural activities in the primary somatosensory cortex (S1) and anterior cingulate cortex (ACC), respectively. Meanwhile, studies show that stimulation of the prefrontal cortex (PFC) produces descending pain control. Here, we designed and tested a brain-machine interface (BMI) combining an automated pain detection arm, based on simultaneously recorded local field potential (LFP) signals from the S1 and ACC, with a treatment arm, based on optogenetic activation or electrical deep brain stimulation (DBS) of the PFC in freely behaving rats. Our multiregion neural interface accurately detected and treated acute evoked pain and chronic pain. This neural interface is activated rapidly, and its efficacy remained stable over time. Given the clinical feasibility of LFP recordings and DBS, our findings suggest that BMI is a promising approach for pain treatment.

Spatiotemporal patterns of large-scale spiking and field potentials of the rodent hippocampus encode spatial representations during maze runs, immobility, and sleep. Here, we show that multisite hippocampal field potential amplitude at ultra-high-frequency band (FPA_uhf), a generalized form of multiunit activity, provides not only a fast and reliable reconstruction of the rodent's position when awake, but also a readout of replay content during sharp-wave ripples. This FPA_uhf feature may serve as a robust real-time decoding strategy from large-scale recordings in closed-loop experiments. Furthermore, we develop unsupervised learning approaches to extract low-dimensional spatiotemporal FPA_uhf features during run and ripple periods and to infer latent dynamical structures from lower-rank FPA_uhf features. We also develop an optical flow-based method to identify propagating spatiotemporal LFP patterns from multisite array recordings, which can be used as a decoding application. Finally, we develop a prospective decoding strategy to predict an animal's future decision in goal-directed navigation.

Prefrontal cortical neurons play essential roles in performing rule-dependent tasks and working memory-based decision making. Motivated by PFC recordings of task-performing mice, we developed an excitatory"“inhibitory spiking recurrent neural network (SRNN) to perform a rule-dependent two-alternative forced choice (2AFC) task. We imposed several important biological constraints onto the SRNN and adapted spike frequency adaptation (SFA) and SuperSpike gradient methods to train the SRNN efficiently. The trained SRNN produced emergent rule-specific tunings in single-unit representations, showing rule-dependent population dynamics that resembled experimentally observed data. Under various test conditions, we manipulated the SRNN parameters or configuration in computer simulations, and we investigated the impacts of rule-coding error, delay duration, recurrent weight connectivity and sparsity, and excitation/inhibition (E/I) balance on both task performance and neural representations. Overall, our modeling study provides a computational framework to understand neuronal representations at a fine timescale during working memory and cognitive control and provides new experimentally testable hypotheses in future experiments.

Pain is a dynamic, complex and multidimensional experience. The identification of pain from brain activity as neural readout may effectively provide a neural code for pain, and further provide useful information for pain diagnosis and treatment. Advances in neuroimaging and large-scale electrophysiology have enabled us to examine neural activity with improved spatial and temporal resolution, providing opportunities to decode pain in humans and freely behaving animals. This topical review provides a systematical overview of state-of-the-art methods for decoding pain from brain signals, with special emphasis on electrophysiological and neuroimaging modalities. We show how pain decoding analyses can help pain diagnosis and discovery of neurobiomarkers for chronic pain. Finally, we discuss the challenges in the research field and point to several important future research directions.

Head direction (HD) cells form a fundamental component in the brain's spatial navigation system and are intricately linked to spatial memory and cognition. Although HD cells have been shown to act as an internal neuronal compass in various cortical and subcortical regions, the neural substrate of HD cells is incompletely understood. It is reported that HD cells in the somatosensory cortex comprise regular-spiking (RS, putative excitatory) and fast-spiking (FS, putative inhibitory) neurons. Surprisingly, somatosensory FS HD cells fire in bursts and display much sharper head-directionality than RS HD cells. These FS HD cells are nonconjunctive, rarely theta rhythmic, sparsely connected and enriched in layer 5. Moreover, sharply tuned FS HD cells, in contrast with RS HD cells, maintain stable tuning in darkness; FS HD cells' coexistence with RS HD cells and angular head velocity (AHV) cells in a layer-specific fashion through the somatosensory cortex presents a previously unreported configuration of spatial representation in the neocortex. Together, these findings challenge the notion that FS interneurons are weakly tuned to sensory stimuli, and offer a local circuit organization relevant to the generation and transmission of HD signaling in the brain.

Sexual and aggressive behaviors are vital for species survival and individual reproductive success. Although many limbic regions have been found relevant to these behaviors, how social cues are represented across regions and how the network activity generates each behavior remains elusive. To answer these questions, we utilize multi-fiber photometry (MFP) to simultaneously record Ca²⁺ signals of estrogen receptor alpha (Esr1)-expressing cells from 13 limbic regions in male mice during mating and fighting. We find that conspecific sensory information and social action signals are widely distributed in the limbic system and can be decoded from the network activity. Cross-region correlation analysis reveals striking increases in the network functional connectivity during the social action initiation phase, whereas late copulation is accompanied by a "dissociated" network state. Based on the response patterns, we propose a mating-biased network (MBN) and an aggression-biased network (ABN) for mediating male sexual and aggressive behaviors, respectively.

BACKGROUND:The striatal-pallidal pathway plays an important role in cognitive control and modulation of behaviors. Globus pallidus interna (GPi), as a primary output structure, is crucial in modulating excitation and inhibition. Studies of GPi in psychiatric illnesses are lacking given the technical challenges of examining this small and functionally diverse subcortical structure. METHODS:71 medication-naïve first episode schizophrenia (FES) participants and 73 healthy controls (HC) were recruited at the Shanghai Mental Health Center. Clinical symptoms and imaging data were collected at baseline and, in a subset of patients, 8 weeks after initiating treatment. Resting-state functional connectivity of sub-regions of the GP were assessed using a novel mask that combines two atlases to create 8 ROIs in the GP. RESULTS: = 0.486, p < 0.001). CONCLUSIONS:Our results implicate striatal-pallidal-thalamic pathways in antipsychotic efficacy. If replicated, these findings may reflect failure of neurodevelopmental processes in adolescence and early adulthood that decrease functional connectivity as an index of failure of the limbic/associative GPi to appropriately inhibit irrelevant signals in psychosis.

Neurons in the prefrontal cortex (PFC) can provide top-down regulation of sensory-affective experiences such as pain. Bottom-up modulation of sensory coding in the PFC, however, remains poorly understood. Here, we examined how oxytocin (OT) signaling from the hypothalamus regulates nociceptive coding in the PFC. In vivo time-lapse endoscopic calcium imaging in freely behaving rats showed that OT selectively enhanced population activity in the prelimbic PFC in response to nociceptive inputs. This population response resulted from the reduction of evoked GABAergic inhibition and manifested as elevated functional connectivity involving pain-responsive neurons. Direct inputs from OT-releasing neurons in the paraventricular nucleus (PVN) of the hypothalamus are crucial to maintaining this prefrontal nociceptive response. Activation of the prelimbic PFC by OT or direct optogenetic stimulation of oxytocinergic PVN projections reduced acute and chronic pain. These results suggest that oxytocinergic signaling in the PVN-PFC circuit constitutes a key mechanism to regulate cortical sensory processing.

Injuries of various types occur commonly in the lives of humans and other animals and lead to a pattern of persistent pain and recuperative behaviour that allows safe and effective recovery. In this Perspective, we propose a control-theoretic framework to explain the adaptive processes in the brain that drive physiological post-injury behaviour. We set out an evolutionary and ethological view on how animals respond to injury, illustrating how the behavioural state associated with persistent pain and recuperation may be just as important as phasic pain in ensuring survival. Adopting a normative approach, we suggest that the brain implements a continuous optimal inference of the current state of injury from diverse sensory and physiological signals. This drives the various effector control mechanisms of behavioural homeostasis, which span the modulation of ongoing motivation and perception to drive rest and hyper-protective behaviours. However, an inherent problem with this is that these protective behaviours may partially obscure information about whether injury has resolved. Such information restriction may seed a tendency to aberrantly or persistently infer injury, and may thus promote the transition to pathological chronic pain states.

Chronic pain is characterized by discrete pain episodes of unpredictable frequency and duration. This hinders the study of pain mechanisms and contributes to the use of pharmacological treatments associated with side effects, addiction and drug tolerance. Here, we show that a closed-loop brain-machine interface (BMI) can modulate sensory-affective experiences in real time in freely behaving rats by coupling neural codes for nociception directly with therapeutic cortical stimulation. The BMI decodes the onset of nociception via a state-space model on the basis of the analysis of online-sorted spikes recorded from the anterior cingulate cortex (which is critical for pain processing) and couples real-time pain detection with optogenetic activation of the prelimbic prefrontal cortex (which exerts top-down nociceptive regulation). In rats, the BMI effectively inhibited sensory and affective behaviours caused by acute mechanical or thermal pain, and by chronic inflammatory or neuropathic pain. The approach provides a blueprint for demand-based neuromodulation to treat sensory-affective disorders, and could be further leveraged for nociceptive control and to study pain mechanisms.