The Effect of Psychedelic Drugs on Neural Integration
So far, only the effects of psychedelic drugs on neural differentiation has been considered and it has been implicitly assumed that the set of neural elements that constitutes the maximally integrated conceptual structure (complex) are unchanged by the drug. However, this is certainly an unreasonable assumption. At any point in time there should be a dominant complex of high Φ that comprises a specific set of neural elements across the cortex. However, even during normal waking consciousness, this is likely to be highly dynamic, with the composition of the complex changing from moment to moment, as certain subsets of neural elements are excluded from, or brought into, the complex (Oizumi et al., 2014). The phenomenology of the psychedelic state, which can include synesthesia and expanded awareness, might suggest that the integrated complex is more expansive during the psychedelic state, encompassing more of the cortex (i.e., more neural elements within the complex), but more empirical measures of integration are required.

Neural integration is commonly measured by the synchronization of neural activation –functional connectivity analysis using fMRI and coherence analysis to assess oscillatory synchrony using EEG or MEG. However, it is important to distinguish between functional and effective connectivity. Functional connectivity refers to the temporal correlations between spatially remote neurophysiological events (Friston, 1994), but provides no direct information about the origin of these correlations. Effective connectivity describes the causal influence of neural systems over each other (Friston, 1994). Once functional connectivity has been observed, measures of effective connectivity must be used to establish the nature of the causal interactions between neural systems (i.e., the effective connectivity); functional connectivity alone does not necessarily imply effective connectivity (Friston, 1994; Lee et al., 2003). In order to establish neural integration as defined by IIT, it is essential that effective connectivity be established, as it is the causal interactions between neural elements that are fundamental to generating an irreducible complex.

The phase synchronization of neural oscillations across a range of frequency bands has become the dominant model to explain how integration is achieved (Varela et al., 2001), as well as specific thalamocortical circuits regulating information transfer between disparate cortical regions (Guillery and Sherman, 2002). Phase locking allows disparate cortical columns to engage in synchronized causal interactions, and neural elements can exchange and share information via forced oscillations, resonant loops, and transient oscillatory coupling (Buzsaki, 2006). Synchronization can occur across a range of spatial scales; local integration might refer to synchronized activity within a single cortical column or within a tight cluster of functionally related columns. Large-scale integration can include the synchronization of neural assemblies separated by great distances, between lobes or across hemispheres. The dense and reciprocal connections between thalamocortical columns enable a large number of neural elements to synchronize within a few hundred milliseconds to generate a unified, integrated neuronal assembly (Tononi et al., 1998; Tononi and Edelman, 2000). Oscillations in the gamma range (30–100 Hz) have received the most attention with regards to perceptual integration (Varela et al., 2001; Merker, 2013; Burwick, 2014) and such oscillations coexist with perceptual binding during normal waking consciousness (Gray and Singer, 1989; Joliot et al., 1994) and during dreaming (Llinas and Ribary, 1993). In fact, the synchronization of gamma oscillations unconstrained by sensory input has been invoked as a model for hallucinations and perceptual aberrations that occur during psychosis and in certain psychedelic states (Behrendt, 2003; Behrendt and Young, 2004). Synchronous firing of fast-spiking inhibitory interneurons, which strongly inhibit cortical pyramidal cells, generates cortical gamma oscillations (Cardin et al., 2009). Pertinently, these oscillations are regulated by 5HT1A and 5HT2A receptors on both pyramidal cells and their associated fast-spiking interneurons (Puig et al., 2010). 5HT1A activation is largely inhibitory on both types of cell and 5HT2A activation is excitatory. By activating fast-spiking interneurons, 5HT2A activation potentiates cortical gamma oscillations and their synchronization, whilst 5HT1A activation suppresses them (Puig et al., 2010; Puig and Gulledge, 2011). As the classical psychedelics are partial agonists at the 5HT2A receptor, it is tempting to suggest that the combination of pyramidal cell depolarization and the promotion of gamma oscillations might explain many of the perceptual effects of these drugs. Increased sensitivity to incoming sensory data coupled with the generation of highly coherent gamma oscillations less constrained by external sensory inputs might result in the perceptual distortions, illusions and even hallucinations observed in the psychedelic state. Furthermore, as gamma oscillations are closely associated with neural integration, it is reasonable to surmise that the psychedelic state might be characterized by an increase in integration compared to a normal waking state. Although limited to measuring temporal correlations, coherence analysis of EEG and MEG traces is often used to quantify neural integration and studies exist that employed this technology to measure the effect of psychedelic drugs, including psilocybin, LSD, and ayahuasca (containing N,N-dimethyltryptamine, DMT) on brain function. However, the effect of these drugs on coherence is not consistent across all studies. A small study employing quantitative EEG (QEEG) to measure changes in oscillatory power and coherence following ayahuasca ingestion observed a highly integrated brain state (Stuckey et al., 2005). Dramatic increases in gamma coherence were widely distributed across the cortex, but especially over the occipital lobe (Stuckey et al., 2005). This is consistent with an earlier study showing an increase in power in the gamma band in ayahuasca users (Don et al., 1998). However, this result contrasts with other studies that found generalized decreases in power across all frequency bands (Riba et al., 2002, 2004).

A more recent psilocybin MEG study (Muthukumaraswamy et al., 2013) suggested that the psychedelic state is one of “dis-integrated” neural activity, with reduction in both oscillatory power and synchronization observed across all frequency bands. The authors suggest that this desynchronization results from 5HT2A-mediated excitation of deep layer pyramidal cells. However, it is noteworthy that the fMRI functional connectivity motifs unique to the post-psilocybin state were the most highly connected possible (Tagliazucchi et al., 2014). A disintegration of DMN integrity does not necessarily imply a reduction in overall neural integration and, indeed, an increase in between-network functional connectivity was consistently observed post-psilocybin (Roseman et al., 2014). This is further supported by a later network analysis of the psilocybin fMRI functional connectivity data, which shows the post-psilocybin state to be characterized by an increase in the integration between cortical areas (Petri et al., 2014). Together, this data suggests that psilocybin disrupts the organization of neural integration, but the overall effect appears to be an increase in the degree of integration.

Although this data is highly suggestive, the major limitation of functional connectivity and coherence analyses with regards to neural integration is that these temporal correlations do not necessarily imply effective connectivity. For example, propofol-induced anesthesia is associated with hypersynchronous oscillations in the alpha band (Supp et al., 2011), and yet effective connectivity, and thus integration as defined by IIT, is markedly reduced (Schroter et al., 2012; Casali et al., 2013; Gomez et al., 2013). Also, inferring causal interactions from functional imaging data requires additional techniques (Lee et al., 2003), including cortical perturbation approaches, discussed below. The currently available functional imaging data falls short of providing a definitive account of the effect of psychedelic drugs on neural integration across the brain. If the psychedelic state is to be understood as either a state of heightened consciousness or, conversely, a state of lower consciousness that lies between wakefulness and sleep, then techniques for measuring both information and integration concurrently must be considered.