CM/Pf contribution to mesocircuit dynamics underlying awareness in non-human primates

Abstract Background In acute disorders of consciousness following severe brain injury, the heterogeneity and multiplicity of brain lesions make it difficult to infer a direct causal link between lesion patterns and impaired consciousness. As a result, neuroimaging analyses performed in intensive care settings can inform theories of consciousness mainly through correlational, rather than causal, evidence. The mesocircuit hypothesis proposes that interactions between the thalamus, basal ganglia, and cortex support the neural mechanisms underlying awareness. Among its key components, the intralaminar thalamic nuclei are thought to play a central role, yet their respective contributions to mesocircuit dynamics remain poorly understood. Methods In two macaque monkeys, we combined causal perturbations of three thalamic nuclei (the centromedian-parafascicular complex (CM/Pf), central lateral nucleus (CL), and mediodorsal nucleus (MD)) with a cue-guided behavioural task requiring the processing of multisensory information. Electrical microstimulation was first used to compare the behavioural consequences of perturbing each target. Reversible pharmacological inactivation using muscimol was subsequently performed in the CM/Pf and CL. Finally, the large-scale metabolic effects of CM/Pf inactivation (muscimol) and disinhibition (bicuculline) were assessed using [ 18 F]FDG PET imaging. Results Perturbation of the intralaminar nuclei disrupted behavioural performance, with the strongest and most reproducible effects observed following CM/Pf manipulation. CM/Pf inactivation reduced correct responses and increased omissions and wrong responses, particularly under conditions requiring greater behavioural engagement. Importantly, these deficits occurred without evidence of major wakefulness impairment, as animals remained responsive throughout testing and showed no substantial increase in eye-closure probability. In contrast, CL perturbation produced weaker behavioural effects, suggesting distinct functional contributions of the two intralaminar nuclei. [ 18 F]FDG PET imaging revealed that CM/Pf disinhibition increased glucose metabolism across thalamic, striatal, pallidal, and frontal cortical territories, whereas CM/Pf inactivation induced a broadly reciprocal pattern of metabolic pattern. These findings identify the CM/Pf as a major modulator of both thalamo-striatal and thalamo-cortical components of the mesocircuit. Conclusions Our results show that a unilateral intralaminar nucleus perturbation is not sufficient to affect wakefulness, suggesting that this function is mediated by a bilateral network at the thalamus level within the mesocircuit. The CM/Pf emerged as the intralaminar nucleus exerting the strongest influence on goal directed behaviours requiring the mesocircuit dynamics. Our findings also support the existence of partially distinct intralaminar pathways contributing differentially to global state regulation of awareness-related functions, and identify the CM/Pf as a key thalamo-striatal hub within the mesocircuit.