A Neuronal Basis of ASC: The CSTC Model of Information Processing
"Recent theories about the neuronal basis of ASC posit that deficits in early information processing may underlie the diversity of psychotic symptoms and cognitive disturbances observed in both drug-induced model psychoses [142,144] and naturally occurring psychoses [17,47]. In particular, it is thought that a fundamental feature of information-processing dysfunction in both hallucinogen-induced states and schizophrenia-spectrum disorders is the inability of these subjects to screen out, inhibit, filter, or gate extraneous stimuli and to attend selectively to salient features of the environment. Gating deficits may cause these subjects to become overloaded with excessive exteroceptive and interoceptive stimuli, which, in turn, could lead to a breakdown of cognitive integrity and difficulty in distinguishing self from nonself [13,70, 71,94,110,144]. Impaired sensorimotor gating and loosening of ego boundaries could lead to positive symptoms such as delusions, hallucinations, thought disturbances, persecution, and the loss of a coherent ego experience. In addition, various negative symptoms, such as emotional and social withdrawal, could result from and be understood as efforts to protect from input overload."
"we have hypothesized that a reduction of NMDA-mediated neurotransmission, e.g., by ketamine, or a stimulation of postsynaptic sites of serotonergic projections, e.g., by psilocybin, should lead to a sensory overload of the cortex, and presumably to an activation of the prefrontal cortex (“hyper-frontality”). Indeed, in a comparative study using PET and the radioligand FDG, we found that both ketamine and psilocybin produced a marked activation of metabolism in the fronto-medial and -lateral cortices including the anterior cingulate, as well as a number of overlapping changes in the basal ganglia, thalamus, and other cortical regions in healthy human volunteers (for an overview [149,150]). Moreover, this hyper-frontality was associated with mania-like symptoms, ego dissolution, derealization, and thought disturbances [145,149,150] and was corroborated by comparable PET or SPECT studies using ketamine, psilocybin, or mescaline [19,56,62]"
"Indeed, according to current views, in conjunction with parietal and limbic areas, the frontal cortex is critical for the construction and maintenance of a coherent self. In its executive faculty, the frontal cortex, including the anterior cingulate, has an active role in structuring time, directing attention to relevant extero- or interoceptive stimuli, and initiating and expressing appropriate behaviors [44,99,104]. The parietal cortex is important for determining the relationship of the self to extrapersonal space, based on visuo-spatial input from the dorsal stream [98,105]. It is noteworthy that the fronto-parietal factor also includes somatosensory and motor cortical areas, which contribute essential information to the formation of body image and physical representation of the self. As an interrelated network, the areas of the fronto-parietal factor are sometimes called “Central Neural Authority”  to express the idea that they constitute a functional system crucially involved in ego-structuring processes and the formation of a coherent self that is defined in time and space. Based on these theoretical concepts, it appears plausible that overstimulation of the Central Neural Authority may lead to profound alterations of self-experience and space/time perception, as reflected by the increased OB scores in hallucinogen-induced ASC."
Whole Brain Analysis
"Analysis of mean clustering coefficient revealed that ego-dissolution was strongly associated with disintegration of the salience network (See Table IV and Fig. 3C). This finding was also supported when assessing differences between the placebo and postpsilocybin states."
Spontaneous pain is associated with lower BDNF, and disruption of hippocampus -> medial prefrontal cortext connectivity
"Analyzing functional connectivity in a whole-brain, hypothesis-free manner, we found that experiencing ego dissolution was associated with reduced interhemispheric interplay and disconnection of the MTL areas from parietal lobes (See Fig. 3D). This analysis was repeated after excluding negative edges, and the resulting pattern was still the same."
"Behaviorally, BDNF overexpression alleviated spontaneous pain (Figure 7J), thermal hyperalgesia (Figure 7K, left), mechanical allodynia (Figure 7K, right), and anxiety-like behaviors (Figures 7L–7O), indicating accelerated recovery from inflammatory pain. Together, these data suggest that BDNF deficits underlie disrupted vCA1-IL connectivity in inflammatory pain."
"Finally, environmental enrichment alleviates established inflammatory and neuropathic pain in rodents, at least partially through promoting hippocampal functions (Zheng et al., 2017). Many clinically applied analgesics and non-drug pain treatment such as cognitive behavioral therapies, acupuncture, noninvasive electrical stimulation, and dietary interventions, affect hippocampal neurogenesis and functions (Heberden, 2016, Kobelt et al., 2014, Lledo et al., 2006, Nam et al., 2015). Among these non-drug therapies, neuromodulation, including transcranial magnetic/current stimulation, is under active investigation (Graff-Guerrero et al., 2005, Stagg et al., 2013). mPFC may be an ideal target for such modulation, given its easily accessible localization and abundant anatomical interconnection with other pain-modulatory areas (Cheriyan and Sheets, 2018). Our findings provide a mechanistic basis for these therapies and suggest that combined pharmacological therapeutics with non-pharmacological paradigms could be of clinical significance.
Together, the present study reveals that spontaneous pain disrupts vCA1-IL connectivity and modulates pain chronicity in rats with peripheral inflammation and supports the significance of using a circuit dynamics-based strategy for more comprehensive understanding of central mechanisms underlying chronic pain."
- Vollenweider, F. X., & Geyer, M. A. (2001). A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain research bulletin, 56(5), 495-507. https://doi.org/10.1016/S0361-9230(01)00646-3
- Lebedev, A. V., Lövdén, M., Rosenthal, G., Feilding, A., Nutt, D. J., & Carhart‐Harris, R. L. (2015). Finding the self by losing the self: Neural correlates of ego‐dissolution under psilocybin. Human brain mapping, 36(8), 3137-3153. https://doi.org/10.1002/hbm.22833
- Ma, L., Yue, L., Zhang, Y., Wang, Y., Han, B., Cui, S., ... & Yi, M. (2019). Spontaneous Pain Disrupts Ventral Hippocampal CA1-Infralimbic Cortex Connectivity and Modulates Pain Progression in Rats with Peripheral Inflammation. Cell Reports, 29(6), 1579-1593. https://doi.org/10.1016/j.celrep.2019.10.002