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Brain Sciences Article

Arousal Regulation by the External Globus Pallidus: A New Node for the Mesocircuit Hypothesis

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Zheng, Z. S., Reggente, N., & Monti, M. M. (2023). Arousal regulation by the external globus pallidus: a new node for the mesocircuit hypothesis. Brain Sciences, 13(1), 146. https://doi.org/10.3390/brainsci13010146

Zheng, Zhong Sheng, et al. “Arousal regulation by the external globus pallidus: a new node for the mesocircuit hypothesis.” Brain Sciences, vol. 13, no. 1, Jan. 2023, p. 146, doi:10.3390/brainsci13010146.

@article{Zheng_Reggente_Monti_2023, title={Arousal regulation by the external globus pallidus: a new node for the mesocircuit hypothesis}, volume={13}, url={https://doi.org/10.3390/brainsci13010146}, DOI={10.3390/brainsci13010146}, number={1}, journal={Brain Sciences}, author={Zheng, Zhong Sheng and Reggente, Nicco and Monti, Martin M.}, year={2023}, month=jan, pages={146} }

Introduction

In the intricate architecture of the brain, the External Globus Pallidus (GPe) has traditionally been recognized as a cornerstone in motor control. However, recent research reveals a more profound narrative—one where the GPe emerges not just as a facilitator of movement, but as a pivotal regulator of arousal and consciousness. This evolving perspective invites us to reconsider the Mesocircuit Hypothesis, integrating the GPe as a crucial node that orchestrates the delicate interplay between wakefulness and sleep.

The Mesocircuit Hypothesis and the GPe’s Expanding Role

The Mesocircuit Hypothesis (MH) offers a framework for understanding consciousness, focusing primarily on the thalamus as the central relay in sustaining arousal. Yet, the basal ganglia, particularly the GPe, have often been overlooked in this context. The GPe, once seen merely as a relay in motor pathways, now emerges as an integral regulator within the mesocircuit, influencing both motor and non-motor functions.

Enhancing the MH Framework: Integrating the GPe into the MH enriches our understanding of arousal regulation, bridging the gap between motor control and cognitive states.
Interconnected Networks: The GPe’s extensive connections with cortical and subcortical structures underscore its role in harmonizing neural processes essential for maintaining consciousness.
Dynamic Modulation: The GPe’s ability to modulate inhibitory and excitatory signals positions it as a dynamic regulator, vital for adaptive arousal responses.

GPe’s Role in Sleep-Wake Regulation

The GPe’s influence extends deeply into the regulation of sleep-wake cycles, orchestrating the transitions that govern our daily rhythms. Animal studies illuminate the GPe’s dual capacity to promote wakefulness and facilitate restful sleep, underscoring its significance in maintaining sleep architecture.

Damage to the GPe: Disruption of the GPe leads to heightened wakefulness intertwined with fragmented sleep patterns, revealing its role in stabilizing sleep.
Stimulation of the GPe: Enhancing GPe activity promotes sleep, particularly non-REM (NREM) sleep, crucial for restorative processes.
Connection with the Thalamic Reticular Nucleus (TRN): The GPe’s interaction with the TRN plays a vital role in sensory gating, ensuring that extraneous stimuli do not disrupt sleep by modulating thalamocortical neuron activity.

Neurochemical Insights: Adenosine and Dopamine

The GPe’s interactions with neurochemicals such as adenosine and dopamine reveal the biochemical underpinnings of arousal regulation.

Adenosine (A2A) Receptors: Abundant in the striatum, these receptors facilitate sleep promotion when activated. The GPe’s interaction with adenosine receptors positions it as a mediator in the transition to sleep.
Dopamine (D2) Receptors: Dopamine modulates GPe activity through D2 receptors, influencing arousal states. In conditions like Parkinson’s Disease, where dopamine levels are compromised, sleep disturbances often manifest, highlighting the GPe’s role in maintaining sleep-wake balance.

The GPe in Disorders of Consciousness

Beyond its role in normal sleep-wake regulation, the GPe emerges as a key player in disorders of consciousness (DOC), offering new avenues for understanding and treatment.

Functional Connectivity and Atrophy: In DOC patients, pallidal atrophy, particularly within the GPe, correlates with measures of behavioral arousal and neural complexity, suggesting its vital role in sustaining consciousness.
Pharmacological Interventions: Medications like Zolpidem (Ambien), typically used for insomnia, paradoxically enhance arousal in some DOC patients. This effect is likely mediated by the GPe’s extensive GABAergic connections, which modulate thalamocortical activity.
Differential Connectivity: The GPe’s robust connections with the prefrontal cortex (PFC) and central thalamic nuclei, as opposed to the GPi’s motor-centric connections, indicate a specialized role in cognitive arousal and consciousness.

Integrative Perspectives on the GPe’s Functionality

The GPe’s complex role in the broader neural landscape extends beyond traditional motor control, embedding itself within the nuanced interplay of consciousness and arousal.

Bridging Motor and Cognitive Domains: The GPe’s involvement in both motor and non-motor functions positions it as a crucial intersection within the brain’s network, influencing cognitive processes as well as physical actions.
Therapeutic Potential: Understanding the GPe opens new avenues for therapeutic interventions, particularly in treating sleep disorders, DOC, and neuropsychiatric conditions through targeted modulation of its activity.

Figure 1

Proposed Striato-Pallidal Circuitries for Promoting Sleep. Two potential routes by which the GPe may mediate cortical activity are illustrated: (A) the Cortico-Striato-Pallido-Cortical route and (B) the Cortico-Striato-Pallido-Reticulo-Thalamo-Cortical route. These circuits highlight the GPe’s role in regulating sleep-wake cycles through its connections with the cortex and thalamic reticular nucleus.

Conclusion

The External Globus Pallidus, once a peripheral player in the orchestra of neural functions, now takes center stage as a conductor of arousal and consciousness. Its integration into the Mesocircuit Hypothesis not only broadens our understanding of the brain’s regulatory mechanisms but also offers new insights into the treatment of disorders related to consciousness and sleep. As we continue to explore the GPe’s intricate pathways and interactions, we open the door to innovative therapies and a deeper understanding of the brain’s orchestration of wakefulness and rest.

Musings

Excerpt adapted from Buddha in the Float Tank

What is a float tank? What does it teach us about perception, selfhood, and out-of-body experiences?

The tank is a lightproof, soundproof chamber filled with saline water. This solution, saturated with Epson salt, is so dense that one floats effortlessly, with no muscle tension. What’s more, the water is heated to the temperature of the skin. Thus, besides being dark and silent, the tank is also absent of any gravitational, tactile, or thermal sensations. The so-called proprioceptive sense, which operates outside the traditional five senses to locate limbs and other body parts in space, also goes dormant in the tank. Once the body is still, floating effortlessly, all that’s left is the mind.

Except, the mind is all you ever had to begin with. Everything you ever see, hear, or touch is happening in the mind. How could it be otherwise? Nothing really changes in the tank. The tank just reveals the nondual nature of consciousness.

What is nonduality?

Here, we need to get philosophical for a moment. The term nondual emphasizes that subject and object are not separate. The world is not “out there” while the self is “in here”. The perceiver and the perceived are one. Consider this illustration below from Wikipedia. If “I” am located somewhere internal to my head, watching the world outside like a person in a movie theater, then how does this little homunculus perceive the inside of the theater? There would need to be a little person in his head, and so forth, ad infinitum.

The ordinary, dualistic way of thinking about perception leads to an infinite regress. Illustration by Wikimedia users Reverie, Pbroks13, and Was a bee. CC-BY-SA-2.5,2.0,1.0

It’s one thing to grasp nonduality intellectually. It’s another thing entirely to grasp it through direct experience. The illusion of separateness from the world is so convincing that we rarely glimpse through it.

The float tank makes it easier to see through this illusion. The ordinary sense of being a subject in the head looking out at objects in the world ceases when that world disappears in the tank. One no longer feels that they are experiencing things from a distance. Rather, there is just consciousness.

Out-of-body experiences

There’s another curious consequence of the zero-stimulus environment called dissociation, or extreme psychological detachment. Here, we encounter a paradox: the body is perceived more clearly, but in a new, non-self context. On the one hand, it’s unsurprising that one becomes more aware of bodily sensations in the float tank, for these are the only sensory channels that are still buzzing with information. Indeed, enhanced cardiorespiratory awareness in the tank has been reported in scientific research. On the other hand, because one no longer feels like a subject internal to the body, the body is no longer the center of awareness. Nondual awareness is centerless, which probably explains reports of out-of-body experiences in the tank (including my own brief experience).Except where noted otherwise, the above reflections on floating and nondual awareness are anecdotal, based on my own float sessions. However, the idea that floating alters self-perception in a manner similar to meditation or even psychedelics drugs is also supported by a neuroimaging study of healthy volunteers who had brain scans before and after three float sessions. These volunteers showed changes in the brain’s default mode network—widely regarded as a neural substrate of the autobiographical self—similar to what has been reported in other studies of meditation and psychedelic substances like psilocybin and LSD.

Functional connectivity, or statistical relationships, between and within hubs of the default mode network is reduced by floating in healthy volunteers. Blue lines show relationships that are **weaker** after the experience. A similar yet weaker pattern was observed for a control condition in which volunteers reclined in a chair in a dark and quiet room instead of floating. Source: Al Zoubi et al. 2021 Human Brain Mapping

Conclusion

Of course, there’s still much that we don’t know about how floating compares to other altered states of consciousness, and whether it has similar (and likely safer) therapeutic potential as psychedelics seem to have for mental illness. I strongly advocate for future research to address these questions.This exert was adapted from a recent post, Buddha in the Float Tank, on Joel Frohlich’s Substack newsletter, Something It’s Like. Click to the link above to read the full post, including Joel’s perspective on inner and outward journeys in the context of travel.

Day: October 3, 2024