Propofol-induced loss of consciousness is associated with a decrease in thalamocortical connectivity in humans.

Although the molecular effects of many anaesthetics have been well characterized, a network-level explanation for how these changes lead to loss of consciousness remains unclear. Studies using electroencephalography have characterized changes in neural oscillations in the cortex at specific frequency bands during propofol-induced anaesthesia and modelling work suggests these changes result from changes in thalamocortical functional connectivity. However, it is unclear if the neurophysiological changes seen at the cortex are due to enhanced or disrupted thalamocortical communication. Direct recordings from these sites during anaesthesia that could be used to confirm such models are rare. We recorded local field potentials from the ventral intermediate nucleus of the thalamus and electrocorticography signals from the ipsilateral sensorimotor cortex in 10 patients undergoing deep brain stimulation surgery. Signals were acquired during induction of propofol anaesthesia while subjects were resting. After confirming direct structural connectivity between the thalamus and the cortical recording site, we investigated propofol-associated changes in thalamic and cortical local power as well as thalamocortical functional connectivity, as measured with coherence, debiased weighted phase lag index, and phase amplitude coupling. Propofol anaesthesia resulted in local power increases at α frequencies (8-12 Hz) across both thalamic and cortical areas. At sensorimotor cortices, there was a broadband power increase (12-100 Hz), while the power of this same broad frequency band was suppressed within the thalamus. Despite the increase in local α power both within the thalamus and cortex, thalamocortical coherence and debiased weighted phase lag index in the α/low ß frequencies (8-16 Hz, which was present in the awake state) significantly decreased with propofol administration (P < 0.05, two group test of coherence). Likewise, propofol administration resulted in decreased phase amplitude coupling between the phase of α/low ß in the thalamus and the amplitude of broadband gamma (50-200 Hz) in the cortex (P = 0.031, Wilcoxon signed-rank test). We also report phase amplitude coupling between the phase of slow wave oscillations (0.1-1 Hz) and amplitude of broadband frequencies (8-200 Hz) within the cortex and across thalamocortical connections, during anaesthesia, both following a peak-max pattern. While confirming α-power increases with propofol administration both in thalamus and cortex, we observed decreased thalamocortical connectivity, contradicting models that suggest increasing cortical low frequency power is necessarily related to increased thalamocortical coherence but in support of the theory that propofol-induced loss of consciousness is associated with disrupted thalamocortical communication.

Genetic Reporters of Neuronal Activity: c-Fos and G-CaMP6.

The majority of 20th century investigations into anesthetic effects on the nervous system have used electrophysiology. Yet some fundamental limitations to electrophysiologic recordings, including the invasiveness of the technique, the need to place (potentially several) electrodes in every site of interest, and the difficulty of selectively recording from individual cell types, have driven the development of alternative methods for detecting neuronal activation. Two such alternative methods with cellular scale resolution have matured in the last few decades and will be reviewed here: the transcription of immediate early genes, foremost c-fos, and the influx of calcium into neurons as reported by genetically encoded calcium indicators, foremost GCaMP6. Reporters of c-fos allow detection of transcriptional activation even in deep or distant nuclei, without requiring the accurate targeting of multiple electrodes at long distances. The temporal resolution of c-fos is limited due to its dependence upon the detection of transcriptional activation through immunohistochemical assays, though the development of RT-PCR probes has shifted the temporal resolution of the assay when tissues of interest can be isolated. GCaMP6 has several isoforms that trade-off temporal resolution for signal to noise, but the fastest are capable of resolving individual action potential events, provided the microscope used scans quickly enough. GCaMP6 expression can be selectively targeted to neuronal populations of interest, and potentially thousands of neurons can be captured within a single frame, allowing the neuron-by-neuron reporting of circuit dynamics on a scale that is difficult to capture with electrophysiology, as long as the populations are optically accessible.

Propofol-induced Changes in α-ß Sensorimotor Cortical Connectivity.

BACKGROUND: Anesthetics are believed to alter functional connectivity across brain regions. However, network-level analyses of anesthesia, particularly in humans, are sparse. The authors hypothesized that propofol-induced loss of consciousness results in functional disconnection of human sensorimotor cortices underlying the loss of volitional motor responses. METHODS: The authors recorded local field potentials from sensorimotor cortices in patients with Parkinson disease (N = 12) and essential tremor (N = 7) undergoing deep brain stimulation surgery, before and after propofol-induced loss of consciousness. Local spectral power and interregional connectivity (coherence and imaginary coherence) were evaluated separately across conditions for the two populations. RESULTS: Propofol anesthesia caused power increases for frequencies between 2 and 100 Hz across the sensorimotor cortices and a shift of the dominant spectral peak in α and ß frequencies toward lower frequencies (median ± SD peak frequency: 24.5 ± 2.6 Hz to 12.8 ± 2.3 Hz in Parkinson disease; 13.8 ± 2.1 Hz to 12.1 ± 1.0 Hz in essential tremor). Despite local increases in power, sensorimotor cortical coherence was suppressed with propofol in both cohorts, specifically in ß frequencies (18 to 29 Hz) for Parkinson disease and α and ß (10 to 48 Hz) in essential tremor. CONCLUSIONS: The decrease in functional connectivity between sensory and motor cortices, despite an increase in local spectral power, suggests that propofol causes a functional disconnection of cortices with increases in autonomous activity within cortical regions. This pattern occurs across diseases evaluated, suggesting that these may be generalizable effects of propofol in patients with movement disorders and beyond. Sensorimotor network disruption may underlie anesthetic-induced loss of volitional control.