Effective Connectivity of LSD-induced Ego Dissolution

CONCLUSION

This investigation seeks to understand how effective connectivity between anticorrelated large-scale brain networks is related to ego dissolution. Our analysis reveals between network effective connectivity changes that occur with a diminution of the pattern of anticorrelation under the peak effects of LSD. Bidirectional changes in effective connectivity between the DMN and DAN were investigated for their relationship to subject-object boundaries. We identified reduced inhibition of the DMN to the DAN under the peak effects of LSD. The reduced inhibition is largely lost in the later effects, when ego dissolution dissipates. This indicates reduced inhibition of the DMN to DAN as a feature of peak LSD effects that may relate to the fading of the functional anticorrelation between the two networks. Reduced DMN to DAN inhibition may also represent an increased transmission and connection of the narrative self to the sense of object. Moreover, hierarchical organisation and strength of networks were calculated using efferent vs afferent connections. The DMN and DAN showed increased hierarchical connectivity strength during the peak effects of LSD and segregate from SN, under the peak effects of LSD (See Supplementary S4). The increase in hierarchical connectivity strength of the DMN and DAN reinforces evidence of their fading anticorrelation that may contribute to the dissolution of the boundary between the subject and the object. The opposite effective connectivity from DAN to DMN also displays reduced inhibition under LSD. However, this change remains over the course of time suggesting it is not a primary mechanism of the reduced functional anticorrelation between them or ego dissolution. Network level DMN-DAN changes are supported by the lAG to rAG connectivity. The AG serves functions in autobiographical memory and bodily awareness. AG also operates complex language functions and makes meaning out of visually perceived self-related words. Excitatory change in the connection from lAG to rAG in placebo to the peak effects of LSD is greater than in the later effects suggesting the importance of this connection in the peak effects. Inclusion of the SN in this analysis enabled measurement of its effective connectivity to the DMN and DAN under LSD. The change to the coordinated balance of networks, under the control of SN, by LSD may be an important but overlooked neural mechanism of ego dissolution suggested by the superiority of SN in this hierarchy of triple networks. Previous reports of reduced anticorrelation, reduced SN integrityin occurrences of ego dissolution, and its hypothesised function in basic conscious-awareness also indicate the value of measuring SN connectivity in the anticorrelation between DMN and DAN. Moreover, ego dissolution has previously been suggested to involve the breakdown of sub-personal processes underlying the minimal self, a suggestion that is consistent with Bayesian models of phenomenal selfhood in which the subjective structure of conscious experience is determined from the optimisation of prediction in perception and action. The change in the SN effective connectivity under the peak effects of LSD is our most pronounced finding. SN connectivity to the DMN changes from inhibitory to excitatory before returning to inhibitory in the later effects. This flip of valence suggests SN connectivity change to the DMN is mechanistic in the peak effects of LSD and may indirectly influence the DMN-DAN interactions. The opposite connection, the DMN to SN, shows an inverse pattern of change from placebo, suggesting reduced DMN influence over the SN which lasts over time. The SN to DMN connectivity change may therefore be a more likely mechanism of ego dissolution representing a quietening of narrative self in the peak effects of LSD that reduces in the later effects. This change in DMN function to minimise free energy and suppress prediction errors that in Freudian terms may liberate the ego from the reality principle. SN to DMN change is accompanied by reduced hierarchical connectivity strength of the SN that is characterised by increased SN afferent connections and increased DMN efferent connections. The SN has previously been identified to be hierarchically superior to the DMN and DAN. We demonstrate the divergence of SN and DMN hierarchical strength under the peak effects of LSD shift the hierarchical order of the SN beneath the DMN. The changes to region level effective connectivity underlying the SN are demonstrated by dACC selfconnectivity under the peak effects of LSD. The dACC is a central brain hub involved in cognitive functions, social emotionsand performance monitoringand has previously been noted in social cognition under psilocybin. Enlargement of the ACC has also been reported after regular use of ayahuasca. We find dACC self-connectivity inhibition and inhibitory connectivity from the lAI to the dACC under the peak effects of LSD, compared to placebo. In the later effects dACC inhibition become less inhibitory while the lAI changes to excitatory. The AI is involved in interoceptive awarenessand the shift of internal and external perception. Damage to SN connectivity predicts dysregulated DMN functionand alteration of SN anticorrelated interactions share association with psychosis and internalising disorders. dACC and lAI inhibition at the peak effects of LSD may indicate the role of SN inhibition that is relevant to ego dissolution and psychedelic assisted therapy. Connectivity between the DMN and SN is also noted in region changes from the rAG to rAI. This connection follows the lAI to dACC pattern of inhibition in the peak effects and excitation in the later effects, suggesting a reduced influence of the DMN to the SN during peak effects, when ego dissolution occurs that may suggest a shifting sense of self. The PCC and dACC represent cardinal regions of the DMN and SN respectively and are related to the narrative and minimal aspects of self. The connectivity changes between them are reported in association to meditation and the mindfulness capacities of meditators (Judson A.. We provided evidence of the excitation from the dACC to PCC in our effective connectivity analysis under peak effects (see Supplementary Fig.), which may suggest dACC cognitive control functions influence on self-related functions of PCC. Interestingly, self-connectivity of the PCC, a hub region of DMN, increases excitation during the peak effects of LSD. PCC involvement in self-awareness is well documented (J. A.and activity of this region is commonly observed to decrease under psychedelics (see Supplementary Table). Other notable regions in our analysis include the FEF and IPS. The FEF operates visual attentionand the IPS serves functions directing attention and memory. The nearby right inferior parietal lobule (rIPL) is also associated with the sense of agency and self-other discrimination. Smaller effect sizes involving these regions were identified in our analysis (see Supplementary Fig.) suggesting more subtle widespread brain changes occur under the effects of LSD. Taken together, under the peak effects of LSD, a strong increase in change of effective connectivity, and a widening of gap between the hierarchical connectivity strength of the SN vs the DMN and DAN shifts in a direction antithetical to normal hierarchical organisation. This may be said to resemble a collapseor flatteningof the hierarchy, during peak effects of LSD, when ego dissolution occurs (See Fig.and Supplementary S4). Effective connectivity explains this effect as increased excitatory connectivity from the SN to the DMN. These directed connection changes and the hierarchical strength changes may function to alter the relationship between the minimal and narrative senses of self. The direction of this change suggests the influence of the minimal-self traverses over the narrative-self and may relate to the shift in sense of self described under ego dissolution. Modelling the connectivity of ego dissolution can provide a means to determine the neural mechanisms that underlie the perception of inner and outer reality. The present research establishes important steps to identify the change in network interactions associated with the dichotomy of the subject-object relationship under LSD. The networks involved in this interaction are important in cognitive function and mental wellbeing, suggesting that understanding their change due to psychedelics may elucidate mechanisms of psychedelic clinical therapy. Consideration of practical and theoretical challenges may aid future research directed to study ego dissolution and the anticorrelation between brain networks. Our relatively small sample size (n=20) is clearly a limitation. Sample size and processing pipeline strongly impact the reliability of results. Small sample size may also account for unexpected placebo effective connectivity in our group of subjects. A second practical limitation is the large variance of participant subjective responses to a standard dose of LSD (100mg). Averaging the connectivity of participants experiencing highly variable subjective shifts in consciousness may dilute the effective connectivity representing LSD's subjective effects. An alternative to increased sample size may be predetermining participant dose-response and including only participants with high subjective responses in the analysis. Replicating the investigation of anticorrelated networks with alternate classic psychedelic substances including psilocybin, ayahuasca and mescaline in addition to LSD will be a worthy direction to validate our results. Furthermore, comparisons with similar altered forms of consciousness reporting ego change such as psychosis and meditation may also help discern the function of components in the anticorrelated networks. The selection of regions and region coordinates composing the networks of interest require careful attention. For example, some studies define the DAN as composed by the posterior prefrontal cortex, the inferior precentral sulcus, the superior occipital gyrus, the middle temporal motion complex, and the superior parietal lobule. Similarly, the DMN may be composed using the inferior parietal lobuleclosely situated to the IPS used in the DAN in this analysis. The composition of regions composing networks can strongly impact results. Furthermore, selection of region centroids can also affect the results. Previous work using this LSD data set used different coordinates for the PCC and identified its increased self-inhibition, although our analysis identified decreased PCC inhibition. Avoiding this problem is challenging due to anatomical variability between participants, variability in the method of determining coordinates and the selection of regions composing networks. However, the standardisation of these considerations across studies is important to improve the accuracy and reliability of findings across studies. Future work to extend the current scope of analysis to include connectivity dynamics of additional task positive networks anticorrelated to the DMN and under control of the SN is required. For example, nonpsychedelic research involving the CEN (central executive network, also known as the frontoparietal central executive network (FPCEN)) has been conducted to investigate schizophrenia, meditationand control of attention. Its importance is further signified by investigations of large-scale network interactions and anticorrelations with the DMN. Inclusion of the CEN in anticorrelation investigations may provide a more complete account of anticorrelated network changes associated to ego dissolution. Theoretical challenges include consensus on the nature and situation of ego dissolution within the taxonomy of psychedelic-induced effects. Psychometric investigations of psychoanalytic based concepts of egofunctions and measurement of their brain connectivity are recommended future directions. Psychedelics may contribute to these investigations by altering and allowing measurement of brain mechanisms hypothesised to underlie psychoanalytic constructs. Integration of psychoanalytic theory and brain connectivity processes may be important to identifying processes involved in enabling the sense of self and experiences of ego dissolution.