Cortical areas involved in behavioral expression of external pallidum dysfunctions: A PET imaging study in non-human primates.

The external pallidum (GPe) is a component of the indirect pathway centrally placed in the basal ganglia. Studies already demonstrated that the pharmacological disinhibition of the sensorimotor, associative, and limbic GPe produced dyskinesia, hyperactivity, and compulsive behaviors, respectively. The aim of this study was to investigate the cortical regions altered by the disinhibition of each GPe functional territory. Thus, 5 macaques were injected with bicuculline in sensorimotor, associative, and limbic sites of the GPe producing dyskinesia, hyperactivity, and compulsive behaviors, and underwent in vivo positron tomography with F-2-fluoro-2-deoxy-D-glucose to identify cortical dysfunctions related to GPe disinhibition. Blood cortisol levels were also quantified as a biomarker of anxiety for each condition. Our results showed that pallidal bicuculline injections in anesthetized animals reproducibly modified the activity of specific ipsilateral and contralateral cortical areas depending on the pallidal territory targeted. Bicuculline injections in the limbic GPe led to increased ipsilateral activations in limbic cortical regions (anterior insula, amygdala, and hippocampus). Injections in the associative vs. sensorimotor GPe increased the activity in the ipsilateral midcingulate vs. somatosensory and parietal cortices. Moreover, bicuculline injections increased blood cortisol levels only in animals injected in their limbic GPe. These are the first functional results supporting the model of opened cortico-striato-thalamo-cortical loops where modifications in a functional pallidal territory can impact cortical activities of the same functional territory but also cortical activities of other functional territories. This highlights the importance of the GPe as a crucial node in the top-down control of the cortico-striato-thalamo-cortical circuits from the frontal cortex to influence the perception, attention, and emotional processes at downstream (or non-frontal) cortical levels. Finally, we showed the implication of the ventral pallidum with the amygdala and the insular cortex in a circuit related to aversive processing that should be crucial for the production of anxious disorders.