Electrophysiological characteristics of CM-pf in diagnosis and outcome of patients with disorders of consciousness.

BACKGROUND: Deep brain stimulation (DBS) in the centromedian-parafascicular complex (CM-pf) has been reported as a potential therapeutic option for disorders of consciousness (DoC). However, the lack of understanding of its electrophysiological characteristics limits the improvement of therapeutic effect. OBJECTIVE: To investigate the CM-pf electrophysiological characteristics underlying disorders of consciousness (DoC) and its recovery. METHODS: We collected the CM-pf electrophysiological signals from 23 DoC patients who underwent central thalamus DBS (CT-DBS) surgery. Five typical electrophysiological features were extracted, including neuronal firing properties, multiunit activity (MUA) properties, signal stability, spike-MUA synchronization strength (syncMUA), and the background noise level. Their correlations with the consciousness level, the outcome, and the primary clinical factors of DoC were analyzed. RESULTS: 11 out of 23 patients (0/2 chronic coma, 5/13 unresponsive wakefulness syndrome/vegetative state (UWS/VS), 6/8 minimally conscious state minus (MCS-)) exhibited an improvement in the level of consciousness after CT-DBS. In CM-pf, significantly stronger gamma band syncMUA strength and alpha band normalized MUA power were found in MCS- patients. In addition, higher firing rates, stronger high-gamma band MUA power and alpha band normalized power, and more stable theta oscillation were correlated with better outcomes. Besides, we also identified electrophysiological properties that are correlated with clinical factors, including etiologies, age, and duration of DoC. CONCLUSION: We provide comprehensive analyses of the electrophysiological characteristics of CM-pf in DoC patients. Our results support the 'mesocircuit' hypothesis, one proposed mechanism of DoC recovery, and reveal CM-pf electrophysiological features that are crucial for understanding the pathogenesis of DoC, predicting its recovery, and explaining the effect of clinical factors on DoC.

Regulation of arousal and performance of a healthy non-human primate using closed-loop central thalamic deep brain stimulation.

Application of closed-loop approaches in systems neuroscience and brain-computer interfaces holds great promise for revolutionizing our understanding of the brain and for developing novel neuromodulation strategies to restore lost function. The anterior forebrain mesocircuit (AFM) of the mammalian brain is hypothesized to underlie arousal regulation of the cortex and striatum, and support cognitive functions during wakefulness. Dysfunction of arousal regulation is hypothesized to contribute to cognitive dysfunctions in various neurological disorders, and most prominently in patients following traumatic brain injury (TBI). Several clinical studies have explored the use of daily central thalamic deep brain stimulation (CT-DBS) within the AFM to restore consciousness and executive attention in TBI patients. In this study, we explored the use of closed-loop CT-DBS in order to episodically regulate arousal of the AFM of a healthy non-human primate (NHP) with the goal of restoring behavioral performance. We used pupillometry and near real-time analysis of ECoG signals to episodically initiate closed-loop CT-DBS and here we report on our ability to enhance arousal and restore the animal's performance. The initial computer based approach was then experimentally validated using a customized clinical-grade DBS device, the DyNeuMo-X, a bi-directional research platform used for rapidly testing closed-loop DBS. The successful implementation of the DyNeuMo-X in a healthy NHP supports ongoing clinical trials employing the internal DyNeuMo system (NCT05437393, NCT05197816) and our goal of developing and accelerating the deployment of novel neuromodulation approaches to treat cognitive dysfunction in patients with structural brain injuries and other etiologies.

Central Thalamic-Medial Prefrontal Control of Adaptive Responding in the Rat: Many Players in the Chamber.

The medial prefrontal cortex (mPFC) has robust afferent and efferent connections with multiple nuclei clustered in the central thalamus. These nuclei are elements in large-scale networks linking mPFC with the hippocampus, basal ganglia, amygdala, other cortical areas, and visceral and arousal systems in the brainstem that give rise to adaptive goal-directed behavior. Lesions of the mediodorsal nucleus (MD), the main source of thalamic input to middle layers of PFC, have limited effects on delayed conditional discriminations, like DMTP and DNMTP, that depend on mPFC. Recent evidence suggests that MD sustains and amplifies neuronal responses in mPFC that represent salient task-related information and is important for detecting and encoding contingencies between actions and their consequences. Lesions of rostral intralaminar (rIL) and ventromedial (VM) nuclei produce delay-independent impairments of egocentric DMTP and DNMTP that resemble effects of mPFC lesions on response speed and accuracy: results consistent with projections of rIL to striatum and VM to motor cortices. The ventral midline and anterior thalamic nuclei affect allocentric spatial cognition and memory consistent with their connections to mPFC and hippocampus. The dorsal midline nuclei spare DMTP and DNMTP. They have been implicated in behavioral-state control and response to salient stimuli in associative learning. mPFC functions are served during DNMTP by discrete populations of neurons with responses related to motor preparation, movements, lever press responses, reinforcement anticipation, reinforcement delivery, and memory delay. Population analyses show that different responses are timed so that they effectively tile the temporal interval from when DNMTP trials are initiated until the end. Event-related responses of MD neurons during DNMTP are predominantly related to movement and reinforcement, information important for DNMTP choice. These responses closely mirror the activity of mPFC neurons with similar responses. Pharmacological inactivation of MD and adjacent rIL affects the expression of diverse action- and outcome-related responses of mPFC neurons. Lesions of MD before training are associated with a shift away from movement-related responses in mPFC important for DNMTP choice. These results suggest that MD has short-term effects on the expression of event-related activity in mPFC and long-term effects that tune mPFC neurons to respond to task-specific information.

Consciousness depends on integration between parietal cortex, striatum, and thalamus.

The neural substrates of consciousness remain elusive. Competing theories that attempt to explain consciousness disagree on the contribution of frontal versus posterior cortex and omit subcortical influences. This lack of understanding impedes the ability to monitor consciousness, which can lead to adverse clinical consequences. To test substrates and measures of consciousness, we recorded simultaneously from frontal cortex, parietal cortex, and subcortical structures, the striatum and thalamus, in awake, sleeping, and anesthetized macaques. We manipulated consciousness on a finer scale using thalamic stimulation, rousing macaques from continuously administered anesthesia. Our results show that, unlike measures targeting complexity, a measure additionally capturing neural integration (Φ∗) robustly correlated with changes in consciousness. Machine learning approaches show parietal cortex, striatum, and thalamus contributed more than frontal cortex to decoding differences in consciousness. These findings highlight the importance of integration between parietal and subcortical structures and challenge a key role for frontal cortex in consciousness.

Uncovering the Modulatory Interactions of Brain Networks in Cognition with Central Thalamic Deep Brain Stimulation Using Functional Magnetic Resonance Imaging.

Deep brain stimulation (DBS) is a promising treatment for neurological and psychiatric disorders. It acts by altering brain networks and facilitating synaptic plasticity. For enhancing cognitive functions, the central thalamus (CT) has been shown to be a potential DBS target. The network-level mechanisms contributing to the effect exerted by DBS on the CT (CT-DBS) remain unknown. Combining CT-DBS with functional magnetic resonance imaging (fMRI), this study explored brain areas activated while applying CT-DBS in rats, using a newly developed neural probe that was compatible with MRI and could minimize the image distortion and resolve safety issues. Results showed activation of the anterior cingulate cortex, motor cortex, primary and secondary somatosensory cortices, caudate putamen, hypothalamus, thalamus, and hippocampus, suggesting that the corticostriatal, corticolimbic, and thalamocortical brain networks were affected. Behaviorally, the CT-DBS group required a shorter time than sham controls to learn a water-reward lever-pressing task and made more correct choices in a T-maze task. Concurrent with enhanced learning performance, bilateral CT-DBS resulted in alteration in the functional connectivity of brain networks determined by resting-state fMRI. Western blot analyses showed that the protein level of both dopamine D1 and α4-nicotinic acetylcholine receptors was increased, and dopamine D2 receptor was decreased. These data suggest that CT-DBS can enhance cognitive performance as well as brain connectivity through the modulation of synaptic plasticity, such that CT is a target providing high potential for the remediation of acquired cognitive learning and memory disabilities.

Thalamus Modulates Consciousness via Layer-Specific Control of Cortex.

Functional MRI and electrophysiology studies suggest that consciousness depends on large-scale thalamocortical and corticocortical interactions. However, it is unclear how neurons in different cortical layers and circuits contribute. We simultaneously recorded from central lateral thalamus (CL) and across layers of the frontoparietal cortex in awake, sleeping, and anesthetized macaques. We found that neurons in thalamus and deep cortical layers are most sensitive to changes in consciousness level, consistent across different anesthetic agents and sleep. Deep-layer activity is sustained by interactions with CL. Consciousness also depends on deep-layer neurons providing feedback to superficial layers (not to deep layers), suggesting that long-range feedback and intracolumnar signaling are important. To show causality, we stimulated CL in anesthetized macaques and effectively restored arousal and wake-like neural processing. This effect was location and frequency specific. Our findings suggest layer-specific thalamocortical correlates of consciousness and inform how targeted deep brain stimulation can alleviate disorders of consciousness.

Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury.

Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.

Modulation of Theta-Band Local Field Potential Oscillations Across Brain Networks With Central Thalamic Deep Brain Stimulation to Enhance Spatial Working Memory.

Deep brain stimulation (DBS) is a well-established technique for the treatment of movement and psychiatric disorders through the modulation of neural oscillatory activity and synaptic plasticity. The central thalamus (CT) has been indicated as a potential target for stimulation to enhance memory. However, the mechanisms underlying local field potential (LFP) oscillations and memory enhancement by CT-DBS remain unknown. In this study, we used CT-DBS to investigate the mechanisms underlying the changes in oscillatory communication between the CT and hippocampus, both of which are involved in spatial working memory. Local field potentials (LFPs) were recorded from microelectrode array implanted in the CT, dentate gyrus, cornu ammonis (CA) region 1, and CA region 3. Functional connectivity (FC) strength was assessed by LFP-LFP coherence calculations for these brain regions. In addition, a T-maze behavioral task using a rat model was performed to assess the performance of spatial working memory. In DBS group, our results revealed that theta oscillations significantly increased in the CT and hippocampus compared with that in sham controls. As indicated by coherence, the FC between the CT and hippocampus significantly increased in the theta band after CT-DBS. Moreover, Western blotting showed that the protein expressions of the dopamine D1 and α4-nicotinic acetylcholine receptors were enhanced, whereas that of the dopamine D2 receptor decreased in the DBS group. In conclusion, the use of CT-DBS resulted in elevated theta oscillations, increased FC between the CT and hippocampus, and altered synaptic plasticity in the hippocampus, suggesting that CT-DBS is an effective approach for improving spatial working memory.

Robust modulation of arousal regulation, performance, and frontostriatal activity through central thalamic deep brain stimulation in healthy nonhuman primates.

The central thalamus (CT) is a key component of the brain-wide network underlying arousal regulation and sensory-motor integration during wakefulness in the mammalian brain. Dysfunction of the CT, typically a result of severe brain injury (SBI), leads to long-lasting impairments in arousal regulation and subsequent deficits in cognition. Central thalamic deep brain stimulation (CT-DBS) is proposed as a therapy to reestablish and maintain arousal regulation to improve cognition in select SBI patients. However, a mechanistic understanding of CT-DBS and an optimal method of implementing this promising therapy are unknown. Here we demonstrate in two healthy nonhuman primates (NHPs), Macaca mulatta, that location-specific CT-DBS improves performance in visuomotor tasks and is associated with physiological effects consistent with enhancement of endogenous arousal. Specifically, CT-DBS within the lateral wing of the central lateral nucleus and the surrounding medial dorsal thalamic tegmental tract (DTTm) produces a rapid and robust modulation of performance and arousal, as measured by neuronal activity in the frontal cortex and striatum. Notably, the most robust and reliable behavioral and physiological responses resulted when we implemented a novel method of CT-DBS that orients and shapes the electric field within the DTTm using spatially separated DBS leads. Collectively, our results demonstrate that selective activation within the DTTm of the CT robustly regulates endogenous arousal and enhances cognitive performance in the intact NHP; these findings provide insights into the mechanism of CT-DBS and further support the development of CT-DBS as a therapy for reestablishing arousal regulation to support cognition in SBI patients.

Frequency-selective control of cortical and subcortical networks by central thalamus.

Central thalamus plays a critical role in forebrain arousal and organized behavior. However, network-level mechanisms that link its activity to brain state remain enigmatic. Here, we combined optogenetics, fMRI, electrophysiology, and video-EEG monitoring to characterize the central thalamus-driven global brain networks responsible for switching brain state. 40 and 100 Hz stimulations of central thalamus caused widespread activation of forebrain, including frontal cortex, sensorimotor cortex, and striatum, and transitioned the brain to a state of arousal in asleep rats. In contrast, 10 Hz stimulation evoked significantly less activation of forebrain, inhibition of sensory cortex, and behavioral arrest. To investigate possible mechanisms underlying the frequency-dependent cortical inhibition, we performed recordings in zona incerta, where 10, but not 40, Hz stimulation evoked spindle-like oscillations. Importantly, suppressing incertal activity during 10 Hz central thalamus stimulation reduced the evoked cortical inhibition. These findings identify key brain-wide dynamics underlying central thalamus arousal regulation.

NMDA receptors in central medial thalamus participate in propofol-induced unconsciousness / 天津医药

Objective To investigate the role of NMDA receptors in central medial thalamus (CMT) in the unconscious?ness induced by general anesthesia. Methods A total of 60 rat models for microinfusion were assigned into 4 groups (n=15 for each group). After induction with propofol, 10 mmol/L (NMDA10 group), 20 mmol/L (NMDA 20 group) and 40 mmol/L (NMDA40 group) of NMDA and normal saline (group C) with equal volume were microinfused into CMT. The incidence of purposeful movement and recovery time of righting reflex were observed in each group respectively. Infusion sites were local?ized by histological method. Results When the microinfusion site localized within CMT, comparing with group C, the recov?ery time of righting reflex reduced notably in three NMDA groups (P0.05). Conclusion Microinfusion of NMDA agonist into CMT reverses propofol anesthesia, indicating that NMDA receptor in CMT may contribute to the propofol-induced unconsciousness.

Temporally-patterned deep brain stimulation in a mouse model of multiple traumatic brain injury.

We report that mice with closed-head multiple traumatic brain injury (TBI) show a decrease in the motoric aspects of generalized arousal, as measured by automated, quantitative behavioral assays. Further, we found that temporally-patterned deep brain stimulation (DBS) can increase generalized arousal and spontaneous motor activity in this mouse model of TBI. This arousal increase is input-pattern-dependent, as changing the temporal pattern of DBS can modulate its effect on motor activity. Finally, an extensive examination of mouse behavioral capacities, looking for deficits in this model of TBI, suggest that the strongest effects of TBI in this model are found in the initiation of any kind of movement.

Common resting brain dynamics indicate a possible mechanism underlying zolpidem response in severe brain injury.

Zolpidem produces paradoxical recovery of speech, cognitive and motor functions in select subjects with severe brain injury but underlying mechanisms remain unknown. In three diverse patients with known zolpidem responses we identify a distinctive pattern of EEG dynamics that suggests a mechanistic model. In the absence of zolpidem, all subjects show a strong low frequency oscillatory peak ∼6-10 Hz in the EEG power spectrum most prominent over frontocentral regions and with high coherence (∼0.7-0.8) within and between hemispheres. Zolpidem administration sharply reduces EEG power and coherence at these low frequencies. The ∼6-10 Hz activity is proposed to arise from intrinsic membrane properties of pyramidal neurons that are passively entrained across the cortex by locally-generated spontaneous activity. Activation by zolpidem is proposed to arise from a combination of initial direct drug effects on cortical, striatal, and thalamic populations and further activation of underactive brain regions induced by restoration of cognitively-mediated behaviors. DOI: http://dx.doi.org/10.7554/eLife.01157.001.

Awakened by a sleeping pill.

Characteristic changes in brain activity accompany the paradoxical increase in alertness observed in some patients with severe brain injury when they are treated with the sleeping pill zolpidem.

Cognitive control of movement via the cerebellar-recipient thalamus.

The cognitive control of behavior was long considered to be centralized in cerebral cortex. More recently, subcortical structures such as cerebellum and basal ganglia have been implicated in cognitive functions as well. The fact that subcortico-cortical circuits for the control of movement involve the thalamus prompts the notion that activity in movement-related thalamus may also reflect elements of cognitive behavior. Yet this hypothesis has rarely been investigated. Using the pathways linking cerebellum to cerebral cortex via the thalamus as a template, we review evidence that the motor thalamus, together with movement-related central thalamus have the requisite connectivity and activity to mediate cognitive aspects of movement control.