Primate thalamic nuclei select abstract rules and shape prefrontal dynamics.

Flexible behavior depends on abstract rules to generalize beyond specific instances, and outcome monitoring to adjust actions. Cortical circuits are posited to read out rules from high-dimensional representations of task-relevant variables in prefrontal cortex (PFC). We instead hypothesized that converging inputs from PFC, directly or via basal ganglia (BG), enable primate-specific thalamus to select rules. To test this, we simultaneously measured spiking activity across PFC and two connected thalamic nuclei of monkeys applying rules. Abstract rule information first appeared in the ventroanterior thalamus (VA) - the main thalamic hub between BG and PFC. The mediodorsal thalamus (MD) also represented rule information before PFC, which persisted after rule cues were removed, to help maintain activation of relevant posterior PFC cell ensembles. MD, a major recipient of midbrain dopamine input, was first to represent information about behavioral outcomes. This persisted after the trial (also in PFC). A PFC-BG-thalamus model reproduced key findings, and thalamic-lesion modeling disrupted PFC rule representations. These results suggest a revised view of the neural basis of flexible behavior in primates, featuring a central role for thalamus in selecting high-level cognitive information from PFC and implementing post-error behavioral adjustments, and of the functional organization of PFC along its anterior-posterior dimension.

Thalamic deep brain stimulation paradigm to reduce consciousness: Cortico-striatal dynamics implicated in mechanisms of consciousness.

Anesthetic manipulations provide much-needed causal evidence for neural correlates of consciousness, but non-specific drug effects complicate their interpretation. Evidence suggests that thalamic deep brain stimulation (DBS) can either increase or decrease consciousness, depending on the stimulation target and parameters. The putative role of the central lateral thalamus (CL) in consciousness makes it an ideal DBS target to manipulate circuit-level mechanisms in cortico-striato-thalamic (CST) systems, thereby influencing consciousness and related processes. We used multi-microelectrode DBS targeted to CL in macaques while recording from frontal, parietal, and striatal regions. DBS induced episodes of abnormally long, vacant staring with low-frequency oscillations here termed vacant, perturbed consciousness (VPC). DBS modulated VPC likelihood in a frequency-specific manner. VPC events corresponded to decreases in measures of neural complexity (entropy) and integration (Φ*), proposed indices of consciousness, and substantial changes to communication in CST circuits. During VPC, power spectral density and coherence at low frequencies increased across CST circuits, especially in thalamo-parietal and cortico-striatal pathways. Decreased consciousness and neural integration corresponded to shifts in cortico-striatal network configurations that dissociated parietal and subcortical structures. Overall, the features of VPC and implicated networks were similar to those of absence epilepsy. As this same multi-microelectrode DBS method-but at different stimulation frequencies-can also increase consciousness in anesthetized macaques, it can be used to flexibly address questions of consciousness with limited confounds, as well as inform clinical investigations of other consciousness disorders.

Predictive Feedback, Early Sensory Representations, and Fast Responses to Predicted Stimuli Depend on NMDA Receptors.

Learned associations between stimuli allow us to model the world and make predictions, crucial for efficient behavior (e.g., hearing a siren, we expect to see an ambulance and quickly make way). While there are theoretical and computational frameworks for prediction, the circuit and receptor-level mechanisms are unclear. Using high-density EEG, Bayesian modeling, and machine learning, we show that inferred "causal" relationships between stimuli and frontal alpha activity account for reaction times (a proxy for predictions) on a trial-by-trial basis in an audiovisual delayed match-to-sample task which elicited predictions. Predictive ß feedback activated sensory representations in advance of predicted stimuli. Low-dose ketamine, an NMDAR blocker, but not the control drug dexmedetomidine, perturbed behavioral indices of predictions, their representation in higher-order cortex, feedback to posterior cortex, and pre-activation of sensory templates in higher-order sensory cortex. This study suggests that predictions depend on alpha activity in higher-order cortex, ß feedback, and NMDARs, and ketamine blocks access to learned predictive information.SIGNIFICANCE STATEMENT We learn the statistical regularities around us, creating associations between sensory stimuli. These associations can be exploited by generating predictions, which enable fast and efficient behavior. When predictions are perturbed, it can negatively influence perception and even contribute to psychiatric disorders, such as schizophrenia. Here we show that the frontal lobe generates predictions and sends them to posterior brain areas, to activate representations of predicted sensory stimuli before their appearance. Oscillations in neural activity (α and ß waves) are vital for these predictive mechanisms. The drug ketamine blocks predictions and the underlying mechanisms. This suggests that the generation of predictions in the frontal lobe, and the feedback pre-activating sensory representations in advance of stimuli, depend on NMDARs.

Disentangling the influences of multiple thalamic nuclei on prefrontal cortex and cognitive control.

The prefrontal cortex (PFC) has a complex relationship with the thalamus, involving many nuclei which occupy predominantly medial zones along its anterior-to-posterior extent. Thalamocortical neurons in most of these nuclei are modulated by the affective and cognitive signals which funnel through the basal ganglia. We review how PFC-connected thalamic nuclei likely contribute to all aspects of cognitive control: from the processing of information on internal states and goals, facilitating its interactions with mnemonic information and learned values of stimuli and actions, to their influence on high-level cognitive processes, attentional allocation and goal-directed behavior. This includes contributions to transformations such as rule-to-choice (parvocellular mediodorsal nucleus), value-to-choice (magnocellular mediodorsal nucleus), mnemonic-to-choice (anteromedial nucleus) and sensory-to-choice (medial pulvinar). Common mechanisms appear to be thalamic modulation of cortical gain and cortico-cortical functional connectivity. The anatomy also implies a unique role for medial PFC in modulating processing in thalamocortical circuits involving other orbital and lateral PFC regions. We further discuss how cortico-basal ganglia circuits may provide a mechanism through which PFC controls cortico-cortical functional connectivity.

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.

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.

Topographic organization of connections between prefrontal cortex and mediodorsal thalamus: Evidence for a general principle of indirect thalamic pathways between directly connected cortical areas.

Our ability to act flexibly, according to goals and context, is known as cognitive control. Hierarchical levels of control, reflecting different levels of abstraction, are represented across prefrontal cortex (PFC). Although the mediodorsal thalamic nucleus (MD) is extensively interconnected with PFC, the role of MD in cognitive control is unclear. Tract tracer studies in macaques, involving subsets of PFC areas, have converged on coarse MD-PFC connectivity principles; but proposed finer-grained topographic schemes, which constrain interactions between MD and PFC, disagree in many respects. To investigate a unifying topographic scheme, we performed probabilistic tractography on diffusion MRI data from eight macaque monkeys, and estimated the probable paths connecting MD with each of all 19 architectonic areas of PFC. We found a connectional topography where the orderly progression from ventromedial to anterior to posterolateral PFC was represented from anteromedial to posterolateral MD. The projection zones of posterolateral PFC areas in MD showed substantial overlap, and those of ventral and anteromedial PFC areas in MD overlapped. The exception was cingulate area 24: its projection zone overlapped with projections zones of all other PFC areas. Overall, our data suggest that nearby, functionally related, directly connected PFC areas have partially overlapping projection zones in MD, consistent with a role for MD in coordinating communication across PFC. Indeed, the organizing principle for PFC projection zones in MD appears to reflect the flow of information across the hierarchical, multi-level PFC architecture. In addition, cingulate area 24 may have privileged access to influence thalamocortical interactions involving all other PFC areas.

A Subcortical Pathway for Rapid, Goal-Driven, Attentional Filtering.

Prefrontal cortex can exercise goal-driven attentional control over sensory information via cortical pathways. However, recent work demonstrates that prefrontal cortex can also influence thalamic relay nuclei via the thalamic reticular nucleus. This suggests the prefrontal-thalamic pathway mediates rapid and goal-driven attentional filtering at the earliest stages of sensory processing.