Removal of circadian influence in the signals revealed significant but diminished correlations in non-circadian (ultradian) HFA and glucose variations. Second, to understand the source of correlation, we performed wavelet coherence analysis and identified strong circadian coupling across corticolimbic areas between HFA and peripheral glucose variations, which was partly explained by hypothalamic connectivity. Across several corticolimbic sites, we also observed significant HFA-glucose correlations that were diurnally mediated. In one subject, we had the unique opportunity to directly record from the ventral diencephalon including the hypothalamus.įirst, we found that HFA in the bilateral hypothalami was strongly correlated with peripheral glucose variations in a diurnally mediated fashion. To test this hypothesis, we obtained intracranial electrographic recordings from corticolimbic structures alongside time-synchronized interstitial glucose concentrations using a CGM device over a multi-day period. Given known presence of glucose-responsive neuronal populations in the hypothalamus and across multiple corticolimbic structures, we hypothesize that distributed CNS population neural activity encodes information regarding ongoing and future energy demand that are reflected in peripheral glucose dynamics. Here, we provide an in-human study combining longitudinal intracranial recordings with continuous glucose monitoring (CGM), a similar technology used in previous CNS-glucose studies 9, 17, 18. However, a longitudinal human (i.e., over the course of days) study simultaneously assessing large-scale neuronal activity across multiple brain regions and peripheral glucose levels has not been performed. Further support for an anatomically distributed brain network involved in glucose regulation comes in part via coupling of spectral power measured by scalp EEG with glucose fluctuations 17. Thus far, non-invasive functional imaging studies coupled with an insulin or glucose challenge in humans have implicated various corticolimbic regions such as the insula and orbitofrontal cortex as potential regulators of glucose homeostasis 15, 16. In humans, direct evidence supporting intracranial regulation of peripheral metabolism remains limited. Other direct glucose-sensing neurons have also been found in the nucleus accumbens 12, the thalamus 13, and the prefrontal cortex 14. Further, the habenular nucleus has been implicated in regulation of glucose metabolism, as lesion in this area increased insulin sensitivity 11. The amygdalohippocampal complex (AHC) has also been shown to harbor these neurons 8, 9, 10 and recently, the rodent hippocampus was reported to exert a modulatory effect on peripheral glucose level changes through sharp wave-ripples (SPW-Rs) 9. The most well-studied location of these neurons is the hypothalamus, whereby multiple nuclei, including the arcuate, paraventricular, ventromedial and lateral nuclei, have demonstrated effector functions that alter peripheral glucose levels 4, 5, 6, 7. Growing evidence suggests the presence of distributed CNS ‘glucose-responsive’ neuronal populations, which respond either directly through glucose sensing or indirectly as a part of the glucose-modulatory circuit 2, 3, 4. As such, there is a teleologic basis to hypothesize that the CNS closely surveils and regulates body glucose levels. The central nervous system (CNS) is heavily reliant glucose as a fuel, as it has the highest energy demand in the body 1. Maintenance of peripheral glucose levels represents one of the most vital homeostatic control loops. Our findings demonstrate proactive encoding of homeostatic glucose dynamics by the CNS. Spectro-spatial features of neural activity enable decoding of peripheral glucose levels both in the present and up to hours in the future. Correlations are further present between non-circadian (ultradian) HFA and glucose levels which are higher during awake periods. Correlations between high frequency activity (HFA, 70–170 Hz) and peripheral glucose levels are found across multiple brain regions, notably in the hypothalamus, with correlation magnitude modulated by sleep-wake cycles, circadian coupling, and hypothalamic connectivity. To better understand this process, we simultaneously measured interstitial glucose concentrations and local field potentials in 3 human subjects from cortical and subcortical regions, including the hypothalamus in one subject. However, how these CNS gluco-regulatory regions modulate peripheral glucose levels is not well understood. Glucose responsive neuronal populations have been identified in the hypothalamus and several corticolimbic regions. Mounting evidence demonstrates that the central nervous system (CNS) orchestrates glucose homeostasis by sensing glucose and modulating peripheral metabolism.
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