A degraded state of consciousness in healthy awake humans?

The perturbational complexity index (PCI) measures the spatiotemporal dynamics of transcranial magnetic stimulation (TMS)-evoked electroencephalography (EEG) potentials (TEPs) [[1]Casali A.G. et al.A theoretically based index of consciousness independent of sensory processing and behavior.Sci Transl Med. 2013; 5 (198ra105)Crossref PubMed Scopus (548) Google Scholar]. High PCI values reflect the joint presence of integration and differentiation in thalamocortical networks of conscious brains [[1]Casali A.G. et al.A theoretically based index of consciousness independent of sensory processing and behavior.Sci Transl Med. 2013; 5 (198ra105)Crossref PubMed Scopus (548) Google Scholar]. Low PCI values have been reported during natural non-rapid eye movement sleep, in disorders of consciousness, and during unresponsiveness caused by general anesthetics [[2]Casarotto S. et al.Stratification of unresponsive patients by an independently validated index of brain complexity.Ann Neurol. 2016; 80: 718-729Crossref PubMed Scopus (170) Google Scholar,[3]Sarasso S. et al.Consciousness and complexity during unresponsiveness induced by propofol, xenon, and ketamine.Curr Biol. 2015; 25: 3099-3105Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar]. The PCI can reliably dissociate different states of unconsciousness in a graded fashion [[1]Casali A.G. et al.A theoretically based index of consciousness independent of sensory processing and behavior.Sci Transl Med. 2013; 5 (198ra105)Crossref PubMed Scopus (548) Google Scholar,[3]Sarasso S. et al.Consciousness and complexity during unresponsiveness induced by propofol, xenon, and ketamine.Curr Biol. 2015; 25: 3099-3105Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar]. In contrary to the widely accepted existence of distinct levels of unconsciousness (e.g., coma, unresponsive wakefulness syndrome, minimally conscious state, and emerging consciousness), the question of whether a conscious brain has distinct measurable states has remained elusive. When investigating pharmacophysiological factors influencing the PCI during wakefulness, we surprisingly found this to be the case. We investigated the effects of three antiepileptic drugs (AEDs) on the PCI in 15 healthy awake human volunteers. Study drugs included 1) carbamazepine (CBZ), a voltage-gated sodium channel blocker, 2) brivaracetam (BRV), a modulator of GABAergic neurotransmission through binding to the presynaptic vesicle protein SV2A, and 3) tiagabine (TGB), a selective GABA reuptake inhibitor. The standard TMS–EEG and TMS–electromyography metrics of this sample have already been analyzed and published [[4]Darmani G. et al.Effects of antiepileptic drugs on cortical excitability in humans: a TMS-EMG and TMS-EEG study.Hum Brain Mapp. 2019; 40: 1276-1289Crossref PubMed Scopus (29) Google Scholar]. Subjects received 600 mg CBZ, 100 mg BRV, or 15 mg TGB in the corresponding drug session. All 15 subjects participated in four sessions (including a placebo control session), however, only a subset of 12 subjects was able to complete the experimental session after intake of TGB due to adverse drug reactions in the other three participants. Using a neuronavigation system, TMS pulses (at 100% resting motor threshold intensity) were applied over the left primary motor cortex while brain responses were recorded using 64-channel EEG. We analyzed the PCILZ which is the original algorithm for calculating the PCI values [[5]Comolatti R. et al.A fast and general method to empirically estimate the complexity of brain responses to transcranial and intracranial stimulations.Brain Stimul. 2019; 12: 1280-1289Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar] (see Supplementary Information for details). As depicted in Fig. 1A, out of the three AEDs tested, only TGB significantly reduced the average PCILZ in the subject sample from 0.57 ± 0.03 to 0.41 ± 0.03 (mean ± SEM, p < 0.001, Wilcoxon signed-rank test), equating a 28% loss of complexity. This was confirmed by using a more recent PCI algorithm (PCIST, see Supplementary Information). During all measurements we continuously checked that subject had their eyes open and did not fall asleep. Furthermore, offline sleep scoring of the resting-state EEG data according to the American Academy of Sleep Medicine scoring manual [[6]Iber C. Ancoli-Israel S. Chesson Jr., A.L. Quan S.F. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. American Academy of Sleep Medicine, Westchester, IL, USA2007Google Scholar] confirmed that there were no wake–sleep transitions during the recordings. A previous study with a large sample of alert healthy subjects has reported 0.39–0.70 as the range of the PCILZ during wakefulness and identified PCILZ = 0.31 as a reliable cut-off threshold between consciousness and unconsciousness [[2]Casarotto S. et al.Stratification of unresponsive patients by an independently validated index of brain complexity.Ann Neurol. 2016; 80: 718-729Crossref PubMed Scopus (170) Google Scholar]. Our pre-TGB PCILZ values are within this range. Furthermore, very drowsy but still responsive and conscious subjects who had undergone mild sedation with propofol have also been shown to express an intermediate range of PCILZ values (between 0.34 and 0.42) [[1]Casali A.G. et al.A theoretically based index of consciousness independent of sensory processing and behavior.Sci Transl Med. 2013; 5 (198ra105)Crossref PubMed Scopus (548) Google Scholar]. Considering 0.41 as the average post-TGB PCILZ in our study reveals that increasing GABAergic inhibition by TGB reduced brain complexity to a level very close to mild sedation, i.e., below the typical range observed in wakefulness but above the values corresponding to unconscious states. It further suggests that the transition to unconsciousness can be continuous rather than an abrupt state shift and that intermediate brain states exist, i.e., a degraded conscious state during wakefulness. The present findings raise the caveat that AEDs, which are sometimes administered to patients with disorders of consciousness, may actually interfere with the level of consciousness and its detection. How does TGB degrade the emergence of complex spatiotemporal dynamics in the brain response to TMS that are typically seen in wakefulness? One possible explanation could be a reduction in cortical excitability due to the anticonvulsant effects of the drug, however, our previous study showed no significant cortical or corticospinal excitability changes following TGB intake when tested with TMS–EEG and TMS–electromyography [[4]Darmani G. et al.Effects of antiepileptic drugs on cortical excitability in humans: a TMS-EMG and TMS-EEG study.Hum Brain Mapp. 2019; 40: 1276-1289Crossref PubMed Scopus (29) Google Scholar]. As also depicted in Fig. 1B, TEPs in pre- and post-TGB were not different while the PCILZ values dropped significantly following TGB intake (see also Fig. S1A for an example subject’s TEPs). Since highly specific patterns of spontaneous oscillatory activity have been found to reflect the functional architecture of neural networks, we investigated whether drug-induced effects on resting-state EEG oscillations, specially delta and theta oscillations, explain the observed changes in the PCILZ values. TGB, and to a lesser degree CBZ, enhanced low-frequency oscillations at rest (see Fig. 1C and Supplementary Information). Hitherto, high-amplitude slow oscillations, especially delta, have been mainly associated with unconscious states. Nevertheless, there is ample evidence that high-amplitude delta oscillations can be observed in special circumstances during consciousness such as in Rett syndrome, Angelman syndrome, schizophrenia and seizure-like EEG events without convulsions or clouding of consciousness [[7]Frohlich J. Toker D. Monti M.M. Consciousness among delta waves: a paradox?.Brain. 2021; https://doi.org/10.1093/brain/awab095Crossref Scopus (9) Google Scholar]. Our results expand the previous body of literature showing that elevated delta and theta oscillations can be observed in healthy awake humans during (slightly degraded levels of) consciousness after TGB and CBZ intake. The fact that only TGB but not CBZ decreased the PCILZ also highlight the notion that elevated low-frequency oscillations per se are not sufficient to degrade consciousness as indexed by PCILZ. While this study was not initially designed to assess the cognitive state of the subjects quantitatively, several subjects reported vertigo, spatial disorientation, headache, and confusion after TGB intake. These observations suggest that the degraded state of consciousness during wakefulness can be manifested in abnormal cognitive and spatial orientation functions, yet all of our participants had volitional control over their behavior. In vitro experiments have revealed that both excess and lack of inhibition result in decreased complexity of neural activity, suggesting that an optimal excitation/inhibition balance is critical for reaching maximum complexity [[8]Barbero-Castillo A. et al.Impact of GABAA and GABAB inhibition on cortical dynamics and perturbational complexity during synchronous and asynchronous activity.2020https://doi.org/10.5281/zenodo.3856665Crossref Google Scholar]. TGB enhances low-frequency oscillations in the thalamus through activation of GABA receptors [[9]Lancel M. Faulhaber J. Deisz R.A. Effect of the GABA uptake inhibitor tiagabine on sleep and EEG power spectra in the rat.Br J Pharmacol. 1998; 123: 1471-1477Crossref PubMed Scopus (61) Google Scholar], hence altering overall excitatory/inhibitory balance in thalamocortical networks profoundly. Our results corroborate this notion, suggesting that a widespread low-frequency oscillatory regime may impede effective communication between brain areas and degrade consciousness during wakefulness. In light of pathologic oscillations, such as in epileptic seizures, in which a slow rhythm hypersynchronizes a large number of brain areas, leading to loss of consciousness, the degraded consciousness in our study is reminiscent of mild nonconvulsive cases of status epilepticus which are similarly accompanied by rhythmic slow waves [[10]Walton N.Y. Gunawan S. Treiman D.M. Treatment of experimental status epilepticus with the GABA uptake inhibitor, tiagabine.Epilepsy Res. 1994; 19: 237-244Crossref PubMed Scopus (50) Google Scholar]. Altogether, our findings suggest that the transition from consciousness to unconsciousness can be continuous rather than an abrupt state shift and that intermediate brain states exist in conscious mind even though without universally accepted clinical definitions. None. The study has received funding from the Academy of Finland (Decisions No. 294625 and 306845 ) to J.N. and from the German Research Foundation ( ZI 542/9–1 ) to U.Z. The following is the Supplementary data to this article: Download .docx (.64 MB) Help with docx files Multimedia component 1

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