- Email: [email protected]
Advances and challenges in neuroimaging studies on the effects of serotonergic hallucinogens: Contributions of the resting brain
ARTICLE IN PRESS
Advances and challenges in neuroimaging studies on the effects of serotonergic hallucinogens: Contributions of the resting brain Felix M€ uller*, Matthias E. Liechti†, Undine E. Lang*, Stefan Borgwardt*,1 *Department of Psychiatry (UPK), University of Basel, Basel, Switzerland Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland 1 Corresponding author: Tel.: +41-61-325-5858; Fax: +41-61-325-8180, e-mail address: [email protected]
†
Abstract The effects of hallucinogenic drugs on the human brain have been studied since the earliest days of neuroimaging in the 1990s. However, approaches are often hard to compare and results are heterogeneous. In this chapter, we summarize studies investigating the effects of hallucinogens on the resting brain, with a special emphasis on replicability and limitations. In previous studies, similarities were observed between psilocybin, LSD, and ayahuasca, with respect to decreases in cerebral blood flow and increases in global functional connectivity in the precuneus and thalamus. Additionally, LSD consistently decreased functional connectivity within distinct resting state networks. Little convergence was observed for connectivity between networks and for blood flow in other brain regions. Although these studies are limited by small sample sizes and might be biased by unspecific drug effects on physiological parameters and the vascular system, current results indicate that neuroimaging could be a useful tool to elucidate the neuronal correlates of hallucinogenic effects.
Keywords Psychedelics, Hallucinogens, LSD, Psilocybin, DMT, Mescaline, Ayahuasca, Neuroimaging, Resting state, Functional connectivity, fMRI, SPECT, PET
Progress in Brain Research, ISSN 0079-6123, https://doi.org/10.1016/bs.pbr.2018.08.004 © 2018 Elsevier B.V. All rights reserved.
1
ARTICLE IN PRESS 2
Advances and challenges in neuroimaging studies
1 INTRODUCTION Hallucinogenic drugs can be used to acutely induce various transient alterations in the cognitive, perceptual, and emotional domains (Carhart-Harris et al., 2016a; Hasler et al., 2004; Schmid et al., 2015), so that it is interesting to consider how these alterations are represented at the level of brain functioning. Since the beginning of the 1990s, this issue has been investigated using neuroimaging techniques and there has been a significant increase in such work in recent years. The acute effects on the human brain of serotonergic hallucinogens—such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT, contained in ayahuasca)—have been assessed with respect to glucose metabolism, blood oxygenation level dependent signal (BOLD), and cerebral blood flow (CBF), using the techniques of single photon emission computed tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI). On the basis of these findings, different models have been proposed to explain the mind-altering effects of hallucinogens, including hyperfrontality (Vollenweider et al., 1997) and altered thalamic (Geyer and Vollenweider, 2008) and hub functioning (Carhart-Harris et al., 2012). Although there has been considerable progress in recent years (de Araujo et al., 2012; Kaelen et al., 2016; Preller et al., 2017; Schmidt et al., 2017), this field of research is based on rather few, relatively small studies, often with different methodological approaches that are difficult to compare. Replications are therefore still scarce. However, experience in different fields of neuroimaging has shown that repeated studies often fail to replicate previous findings (Poldrack et al., 2017). It is therefore reasonable to interpret these results with caution and to regard them as preliminary. Although several publications report results on task-based neuroimaging in hallucinogens, there have been almost no investigations which allow comparison of results across studies (for an overview, see Dos Santos et al., 2016). For example, effects of hallucinogens have been examined by studies which used tasks for alertness (Daumann et al., 2010), music (Preller et al., 2017) and imagery (de Araujo et al., 2012). Emotion processing has been one of the few areas investigated in independent samples. Amygdala activity in response to fearful stimuli was consistently decreased after administration of psilocybin (Kraehenmann et al., 2015) and LSD (Mueller et al., 2017a). This finding has been replicated in different studies and laboratories. In contrast to task-based approaches, investigations of drug effects on the resting brain provide more data and a broader basis for comparisons between studies. In this chapter, we summarize current neuroimaging findings on the effects of hallucinogens on the resting brain. We specifically focus on the reproducibility of these findings in independent samples and also discuss limitations of previous studies and challenges for future studies. We identify two main areas where comparable methodological approaches have been applied: Quantification of CBF and
ARTICLE IN PRESS 2 General considerations
functional connectivity (FC) in terms of within-network FC, between-network FC, and global connectivity. As mentioned above, this comparison might provide a clearer and more reliable picture than a discussion of single studies. We do not include studies on glucose metabolism, as there is only one resting state study on this topic (Vollenweider et al., 1997), which is sometimes compared with another PET study by Gouzoulis-Mayfrank et al. (1999). However, a word repetition task and an association task were used in the latter study, so that it is unclear if the results are really comparable. Our review is further restricted to serotonergic hallucinogens, i.e., a group of classic hallucinogenic drugs which mainly act on the serotonin 5HT2Areceptor, as these drugs are likely to have at least partially overlapping neuronal signatures and have been the main focus of previous investigations. The substances reviewed in this chapter thus include psilocybin, LSD (lysergic acid diethylamide), and DMT (N,N-dimethyltryptamine; the psychoactive component of the herbal brew ayahuasca, which is used by indigenous people in South America).
2 GENERAL CONSIDERATIONS OF THE LIMITATIONS OF NEUROIMAGING STUDIES ON HALLUCINOGENS Although hallucinogenic drugs like psilocybin, LSD, and DMT all act as agonists at the 5HT2A-receptor, they exhibit different affinities to other receptors (Rickli et al., 2016). Because of these varying interactions with receptors other than the 5HT2Areceptor, hallucinogens might also affect neuronal structures in different ways, with or without consequences for subjective drug effects. It is still unclear to what extent these different substances actually show comparable effects, at either the neuronal or subjective levels. Nevertheless, it can be expected that most subjective effects are common to all serotonergic hallucinogens, as findings on different drugs in separate studies indicate that subjective effects are similar (Hasler et al., 2004; Schmid et al., 2015), even though there have been no valid direct within-subject comparisons (Hollister and Hartman, 1962; Hollister and Sjoberg, 1964). This reservation introduces some uncertainty and limits comparisons of the neuroimaging findings across different substances. As in other fields of neuroimaging, there are several general sources of bias which also affect studies in this area. Two important examples are artifacts introduced to neuroimaging data by participants’ head motion, and physiological noise induced by, for example, respiratory or cardiac cycles (Khalili-Mahani et al., 2013; Wise and Tracey, 2006). FC is regarded as particularly sensitive to bias resulting from head motion. However, other neuroimaging measures might be affected as well (Power et al., 2014). Although these factors are of general concern in neuroimaging, they might be more pronounced in this field of research, as participants might show more motion due to acute drug effects. Indeed, this problem has been reported in some (Carhart-Harris et al., 2016b; Roseman et al., 2014), but not all studies. Moreover, it has already been shown that psilocybin and LSD alter physiological
3
ARTICLE IN PRESS 4
Advances and challenges in neuroimaging studies
parameters, such as heart rate, blood pressure and body temperature (Dolder et al., 2017; Hasler et al., 2004; Schmid et al., 2015). Lastly, the administered substances might affect vascular tone or neurovascular coupling and hence CBF, thus leading to alterations which do not actually reflect neuronal activity but rather unspecific effects (Wise and Tracey, 2006).
3 ALTERATIONS IN CEREBRAL BLOOD FLOW To our knowledge, the first study in the field of neuroimaging in hallucinogens was published in 1992 by Hermle et al. (1992). Using SPECT, the authors investigated the effects of mescaline (500 mg, oral) on CBF in 18 regions of interest (ROIs) (n ¼ 11). In the left hemisphere, significant decreases were observed in the thalamus and in the central, superior-parietal, and superior-temporal regions. The right hemisphere exhibited significant increases in the inferior-temporal region. In general, the authors stated that mescaline induced a hyperfrontal pattern, most pronounced in the right hemisphere. It is hard to compare these findings with other studies (described below), as relatively gross parcellation was applied. Moreover, the results were not corrected for multiple comparisons. Over a decade later, Riba et al. (2006) investigated the effects of ayahuasca (n ¼ 15; 1 mg DMT/kg, orally) on whole brain CBF in a SPECT study (Riba et al., 2006). In contrast to the investigation by Hermle et al., only increases in CBF were observed. The authors reported alterations in the frontal lobe, anterior cingulate and amygdala/parahippocampus. The results were not corrected for multiple comparisons. The findings of this study and other investigations referred to in this section are shown in Table 1 (the study by Hermle et al. is not included in this table because it was not possible to match anatomical regions reported in this work to those of the other studies). After a second gap of several years, Carhart-Harris et al. (2012) analyzed CBF after the administration of psilocybin (n ¼ 15; 2 mg, intravenous (i.v.)) by means of arterial spin labeling (ASL). The authors reported decreases in CBF, located in various subcortical and cortical regions (please see Table 1 for more details). In order to investigate possible confounding effects, they also examined how several physiological parameters (heart rate, respiration rate, respiration depth; recorded during the MRI scan) influence CBF. Although no details were reported, these corrections did alter the results for some regions, while others were not affected (Carhart-Harris et al., 2012). This analysis is, however, limited by the fact that CBF was only examined in terms of the BOLD signal and not with ASL. A few years later, the same group also investigated the effects of LSD (n ¼ 15, 75 μg, i.v.) and found increased CBF in the visual cortex (Carhart-Harris et al., 2016b), a result that clearly contrasts with their previous results with psilocybin. Subsequently, Lewis et al. examined CBF by means of ASL, using two doses of psilocybin (0.16 and 0.215 mg/kg, orally) in a relatively large sample (n ¼ 29 for each group) (Lewis et al., 2017). The authors hypothesized that the effects after psilocybin observed by Carhart-Harris et al. might actually be due to unspecific global
ARTICLE IN PRESS 3 Alterations in cerebral blood flow
5
Table 1 Comparison of Findings on Cerebral Blood Flow (CBF) After Administration of the Hallucinogens Ayahuasca, Psilocybin, and LSD
Continued
ARTICLE IN PRESS 6
Advances and challenges in neuroimaging studies
Table 1 Comparison of Findings on Cerebral Blood Flow (CBF) After Administration of the Hallucinogens Ayahuasca, Psilocybin, and LSD—cont’d
Increased CBF is shown in red, decreased CBF in blue. Brain regions are labeled according to the automated anatomic labeling (AAL) Atlas. Regions reported for Carhart-Harris et al. (2016b) were estimated from published figures as no details were reported. Abbreviations: aCBF, absolute cerebral blood flow; ASL, arterial spin labeling; DMT, dimethyltryptamine; fMRI, functional magnetic resonance imaging; FWE, family-wise error rate; LSD, lysergic acid diethylamide; rCBF, relative cerebral blood flow; SPECT, singlephoton emission computed tomography. a This region was reported by one of the included studies only and could not be matched to the AAL atlas.
ARTICLE IN PRESS 3 Alterations in cerebral blood flow
effects of psilocybin on vascular tone, as already seen with psilocin, the active metabolite of psilocybin (Spain et al., 2015). Lewis et al. thus conducted two separate analyses, one controlling for global effects and one without correction, in order to disentangle nonspecific vascular and “true” effects. They found that psilocybin decreased absolute perfusion in various regions but, after adjusting for global perfusion, there were increases in CBF in the right hemispheric frontal and temporal regions and bilateral anterior insula and decreased CBF in the subcortical, parietal, occipital and insular regions, which were mainly localized in the left hemisphere (Lewis et al., 2017) (see also Table 1). Therefore, these results might indicate that the findings reported by Carhart-Harris et al. (2012) were biased by the unspecific effects of psilocybin on global CBF. However, Carhart-Harris et al. did perform a breath-hold task to test cerebrovascular reactivity and reported no altered reactivity after psilocybin compared with placebo. However, breath-hold tasks have several limitations and these might explain these diverging results (Fierstra et al., 2013). On the other hand, normalization to the global mean as applied by Lewis et al. also possesses some inherent problems, e.g., this procedure might introduce artificial increases in CBF (Borghammer et al., 2009). A synopsis of all previous findings in CBF is given in Table 1. Results were summarized according to labels of the automated anatomic labeling (AAL) atlas. However, some regions could not be matched to these labels (e.g., the orbitofrontal cortex) and thus this comparison might be unreliable to some extent. In general, previous studies give a rather heterogeneous picture. Some consistencies were observed by both studies which investigated psilocybin. Carhart-Harris et al. and Lewis et al. consistently reported decreased CBF in the precentral gyrus, angular gyrus, precuneus, insula, thalamus, and putamen (Carhart-Harris et al., 2012; Lewis et al., 2017). There are no striking similarities between the different substances, apart from the increases in CBF in the frontal inferior gyrus and anterior insula—which were reported after administration of both psilocybin (Lewis et al., 2017) and ayahuasca (Riba et al., 2006). It may be asked whether these alterations in CBF really reflect disparate neuronal effects of the different hallucinogens, as there appear to be many similarities between serotonergic hallucinogens, at least between psilocybin and LSD (Hollister and Hartman, 1962; Hollister and Sjoberg, 1964). As described above, however, it is largely unclear whether and to what extent different substances show similar effects. One possible explanation for the disparate results with CBF might be that the substances exhibit different vasoactive properties. No attempts have been made to assess possible vasoactive effects of mescaline (Hermle et al., 1992), ayahuasca (Riba et al., 2006), and LSD (Carhart-Harris et al., 2016b). While Lewis et al. (2017) found that controlling for global effects significantly altered the results, in clear contrast to the findings for psilocybin, others found no evidence that psilocybin is vasoactive (Carhart-Harris et al., 2012), which complicates further interpretations. Besides vascular effects, CBF might also be affected by alterations in physiological parameters; however, this question was not covered in most studies—with the exception of a single study by Carhart-Harris et al. (2012). Although this regression analysis of heart
7
ARTICLE IN PRESS 8
Advances and challenges in neuroimaging studies
rate, respiration rate, and respiration depth did not affect BOLD results within some regions, others seemed to be affected. However, no details were reported and it is furthermore unclear if these results can be transferred to ASL data. Moreover, most studies in CBF are limited by small sample sizes, with the exception of Lewis et al. (2017), who analyzed data of 58 participants.
4 ALTERATIONS IN FUNCTIONAL CONNECTIVITY Functional connectivity (FC) is a measure used to characterize functional integration by assessing statistical dependence between brain regions (Friston, 2011). FC has been probably the most widely investigated neuroimaging measure in hallucinogens. However, this area is also limited by different approaches, which renders comparisons across studies difficult. To our knowledge, genuinely comparable FC measures have been investigated in four independent samples by six studies after the administration of psilocybin (Roseman et al., 2014; Tagliazucchi et al., 2016), ayahuasca (Palhano-Fontes et al., 2015), and LSD (Carhart-Harris et al., 2016b; M€ uller et al., 2018; Tagliazucchi et al., 2016). These investigations focus on FC of resting state networks and global FC.
4.1 WITHIN AND BETWEEN NETWORK FUNCTIONAL CONNECTIVITY Several studies have investigated the effects of individual substances on resting state networks (RSNs) (Carhart-Harris et al., 2016b; M€uller et al., 2018; Palhano-Fontes et al., 2015; Roseman et al., 2014). RSNs were analyzed with regard to FC within these networks as well as FC between different RSNs. Within-network FC is a measure of coactivation of voxels which are part of a given network (e.g., the coactivation of the precuneus with the rest of the default mode network). “Between network FC” means the connectivity of all voxels of a given network to another network as a whole (e.g., connectivity between the default mode network and the sensorimotor network). The available studies indicated that administration of psilocybin leads to relatively widespread increases in FC between various networks (Carhart-Harris et al., 2013; Roseman et al., 2014) and this is also the case with LSD (CarhartHarris et al., 2016b; M€ uller et al., 2018). Carhart-Harris et al. aggregated the findings on within- and between-RSN FC in the concept of altered “integration and segregation,” i.e., these hallucinogens act by blurring demarcations between distinct RSNs while compromising integrity within RSNs (Carhart-Harris et al., 2016b). According to the authors, this decrease in compartmentalization underlies typical hallucinogenic effects. These findings will be discussed below. Within-network FC has only been investigated for LSD (Carhart-Harris et al., 2016b). The authors reported that LSD decreased FC within several networks; no increases were observed. FC was reported to be decreased in the default mode network (DMN), the sensorimotor network, two visual networks, the parietal cortex
ARTICLE IN PRESS 4 Alterations in functional connectivity
network, and the right frontoparietal network (Carhart-Harris et al., 2016b). Our group attempted to replicate these findings in a sample of drug-naive subjects (n ¼ 20; 100 μg LSD, orally) (M€ uller et al., 2018). We found decreased FC within the DMN, the sensorimotor network and visual networks 1 and 3; thus, our findings on within-network FC very closely resembled those reported for LSD (CarhartHarris et al., 2016b). In contrast to the previous results, the frontoparietal network was not affected in our analyses and we did not assess the parietal network as in Carhart-Harris et al. Fig. 1 shows a comparison of findings by Carhart-Harris et al. (2016b) and M€ uller et al. (2018). These results are in good agreement with a recent investigation of the effects of ayahuasca on the DMN, which also found decreased FC within this network (Palhano-Fontes et al., 2015). As already pointed out elsewhere (M€ uller et al., 2018), these findings can be questioned for several reasons. A study which investigated within-network FC after the administration of a serotonin reuptake inhibitor reported decreased FC in exactly the same networks as seen in our replication study (Klaassens et al., 2015). Serotonin reuptake inhibitors increase extracellular levels of serotonin and only induce very mild subjective effects in healthy subjects, if anything. The alterations observed in studies on hallucinogens might thus represent unspecific serotonergic effects without any relevance for specific hallucinogenic drug effects. In line with this, we were not able to replicate (M€ uller et al., 2018) an association between decreased FC within the DMN and measures of subjective drug effects in the domain “ego dissolution” (the subjective experience of a comprised sense of “self” or “ego”), as previously described (Carhart-Harris et al., 2016b). No other significant associations have been described by other groups. In order to assess this issue more broadly, we investigated associations between all five subscales of the standard questionnaire 5 Dimensions of Altered States of Consciousness (5D-ASC) and found no significant differences (M€ uller et al., 2018). Between-network FC has been investigated for psilocybin (Roseman et al., 2014) (n ¼ 15, 2 mg, i.v.) and in two data sets for LSD (Carhart-Harris et al., 2016b; M€uller et al., 2018) (n ¼ 15, 75 μg, i.v. and n ¼ 20, 100 μg, orally). Studies consistently indicated increases in FC between networks. Relatively widespread alterations were found by Roseman et al. and by our group (M€uller et al., 2018), while increases were less pronounced in the findings by Carhart-Harris et al. All findings are summarized in Fig. 2. Our group also tested for possible influences of altered physiological parameters, by correlating these measures with alterations in FC. We found no relationship between FC and heart rate, blood pressure, or temperature (M€uller et al., 2018). However, this analysis was based on measures taken at a single time point directly before the MRI scan and continuous measures taken during the scan might be advantageous. Closer inspection of the alterations in between-network FC indicated that the results of the London studies on psilocybin (Carhart-Harris et al., 2013; Roseman et al., 2014) and on LSD (Carhart-Harris et al., 2016b) were inconsistent, as were these studies and our results (see Fig. 1). Given the apparently unstable nature of these findings, it is questionable how functionally meaningful these alterations really are. On the other hand, it is unclear to what extent results with psilocybin (Roseman et al., 2014)
9
ARTICLE IN PRESS 10
Advances and challenges in neuroimaging studies
FIG. 1 Comparison of findings on within-network functional connectivity (FC) in LSD, obtained in two samples. Within-network FC was consistently and significantly decreased in the default mode network (A), visual network 1 (B), visual network 3 (C), and the sensorimotor network (D). Please note that the affected region within the DMN corresponds to the precuneus/posterior cingulate gyrus. Figures reproduced from Carhart-Harris, R.L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., Tagliazucchi, E., Schenberg, E.E., Nest, T., Orban, C., Leech, R., Williams, L.T., Williams, T.M., Bolstridge, M., Sessa, B., Mcgonigle, J., Sereno, M.I., Nichols, D., Hellyer, P.J., Hobden, P., Evans, J., Singh, K.D., Wise, R.G., Curran, H.V., Feilding, A., Nutt, D.J., 2016b. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc. Natl. Acad. Sci. U.S.A. 113, 4853–8 and Mueller, F., Lenz, C., Dolder, P.C., Harder, S., Schmid, Y., Lang, U.E., Liechti, M.E., Borgwardt, S., 2017a. Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl. Psychiatry 7, e1084; Mueller, F., Lenz, C., Dolder, P.C., Lang, U.E., Schmidt, A., Liechti, M.E., Borgwardt, S., 2017b. Increased thalamic resting state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr. Scand. 136, 648–657.
and LSD (Carhart-Harris et al., 2016b; M€uller et al., 2018) are in fact comparable, even though they share a common mechanism of action at the 5HT2A-receptor (Rickli et al., 2016). However, there were also very few consistencies between studies in LSD (Carhart-Harris et al., 2016b; M€uller et al., 2018). It is possible that the observed discrepancies are due to the effects of different conditions in different studies (Carhart-Harris et al., 2016b; Roseman et al., 2014), or different methods of
ARTICLE IN PRESS 4 Alterations in functional connectivity
FIG. 2 Comparison of alterations in between-network connectivity induced by psilocybin (Roseman €ller et al., 2018). Asterisks indicate et al., 2014) and LSD (Carhart-Harris et al., 2016b; Mu significant differences between drug and placebo conditions (green, Roseman et al., 2014; €ller et al., 2018). Black indicates networks which blue, Carhart-Harris et al., 2016b; red, Mu were not investigated in Carhart-Harris et al. (2016b). Roseman et al. reported separate results for two representations of the default mode network (4) which were combined in this presentation. € Figure reproduced from Muller, F., Dolder, P.C., Schmidt, A., Liechti, M.E., Borgwardt, S., 2018. Altered network hub connectivity after acute LSD administration. NeuroImage 18, 694–701.
analysis or differences in regions covered by RSN. Different routes of administration (i.v. and oral administration) may have also affected the results.
4.2 GLOBAL FUNCTIONAL CONNECTIVITY Global functional connectivity (GFC) is another broad, data-driven assessment of FC. GFC is calculated from the average correlation of each voxel or ROI to each other voxel or ROI. Global correlation was investigated in two studies with LSD (Mueller et al., 2017b; Tagliazucchi et al., 2016) and in one study with psilocybin (Tagliazucchi et al., 2016). In a reanalysis of the data sets of Carhart-Harris et al. (2016b) and Roseman et al. (2014), Tagliazucchi et al. investigated the effects of
11
ARTICLE IN PRESS 12
Advances and challenges in neuroimaging studies
psilocybin (n ¼ 15, 2 mg, i.v.) and LSD (n ¼ 15, 75 μg, i.v.) on GFC—using the same approach for both substances. More specificially, the authors parcellated the brain into 401 ROIs and reported relatively widespread increases in GFC in the frontal, parietal, and temporal cortical regions. The authors described increased GFC in the precuneus and thalamus, but no details were reported for other regions, so comparisons between substances are limited. With a slightly different approach, our group (Mueller et al., 2017b) (n ¼ 20, 100 μg LSD orally) calculated GFC based on voxels. This gave higher spatial resolution, but also a stricter correction for multiple comparisons. This analysis revealed no alterations in cortical regions, but increased global FC of thalamic regions, as well as parts of the basal ganglia. For a comparison of the findings by Tagliazucchi et al. and M€ uller et al., please see Fig. 3. As a consistent result, increased FC in thalamic
FIG. 3 Comparison of findings on global functional connectivity (GFC) in psilocybin and LSD, obtained in three different samples. GFC was found to be significantly increased in thalamic regions in three studies after psilocybin and LSD, and in the precuneus in two independent data sets after psilocybin and LSD. Figures reproduced from Tagliazucchi, E., Roseman, L., Kaelen, M., Orban, C., Muthukumaraswamy, S.D., Murphy, K., Laufs, H., Leech, R., Mcgonigle, J., Crossley, N., Bullmore, E., Williams, T., Bolstridge, M., Feilding, A., Nutt, D.J., Carhart-Harris, R., 2016. Increased global functional connectivity correlates with LSDinduced ego dissolution. Curr. Biol. 26, 1043–50 and Mueller, F., Lenz, C., Dolder, P.C., Harder, S., Schmid, Y., Lang, U.E., Liechti, M.E., Borgwardt, S., 2017a. Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl. Psychiatry 7, e1084; Mueller, F., Lenz, C., Dolder, P.C., Lang, U.E., Schmidt, A., Liechti, M.E., Borgwardt, S., 2017b. Increased thalamic resting state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr. Scand. 136, 648–657.
ARTICLE IN PRESS 5 Summary and conclusions
regions was found in three independent data sets after the administration of LSD and psilocybin. Differences between Tagliazucchi et al. and our analysis in the findings in cortical regions might be due to slightly different approaches and statistical thresholds. Tagliazucchi et al. used ROI-to-ROI approaches, rather than the voxel-to-voxel approach in our analysis. Moreover, we employed a more conservative threshold. These factors might result in greater sensitivity to detect alterations in GFC in Tagliazucchi et al. As Tagliazucchi et al. re-analyzed data sets that have already been described above (Carhart-Harris et al., 2016b; Roseman et al., 2014), the same limitations apply. In both data sets, there were significant differences in head motion between conditions. The authors conducted additional analyses in order to investigate the potential impact of motion on FC results, but found no relationship (Tagliazucchi et al., 2016). However, neither these studies nor our own analysis investigated whether differences in physiological parameters can modify these results, so this question remains open. In addition, the specificity of increased thalamic GFC for hallucinogenic drug effects might also be questioned on similar grounds to those described for withinnetwork FC (see above). Increases in thalamic FC (as well as global decreases in other regions) were also observed after intake of a serotonin reuptake inhibitor (Schaefer et al., 2014). Although a different FC measure (degree-centrality, i.e., a count of the number of connections of a specific voxel) was used in this study, these findings suggest that thalamic FC can also be altered by the natural ligand of the serotonin receptor.
5 SUMMARY AND CONCLUSIONS In summary, study of the acute effects of hallucinogenic drugs using advanced neuroimaging methods is progressing, but many questions remain open. Research in this area currently employs several heterogeneous analyses which are difficult to compare and there have been few replications; the field is dominated by single reports based on small sample sizes. For CBF, previous studies have found few similarities for different substances (ayahuasca, psilocybin, and LSD). In two recent studies, some consistent results were found with psilocybin (Carhart-Harris et al., 2012; Lewis et al., 2017), with both reporting decreased CBF in the precentral gyrus, angular gyrus, precuneus, insula, thalamus, and putamen. These findings indicate that psilocybin does indeed affect the neuronal functioning of these structures, some of which (precuneus, thalamus) are known hubs. Impairment of hubs would potentially have a relatively widespread impact—given the importance of these structures for overall brain functioning (Crossley et al., 2014)—and might provide a neuronal basis for hallucinogenic effects. In terms of functional connectivity, psilocybin and LSD have been associated with widespread alterations across various regions in one sample after administration of psilocybin (Roseman et al., 2014), and in two samples after LSD (Carhart-Harris
13
ARTICLE IN PRESS 14
Advances and challenges in neuroimaging studies
et al., 2016b; M€ uller et al., 2018). LSD has been consistently associated with decreased connectivity within several resting state networks, i.e., DMN, the sensorimotor network, and visual networks (Carhart-Harris et al., 2016b; M€uller et al., 2018). These findings fit well with the concept that hallucinogens disrupt FC within RSNs. As discussed above, however, these changes might also represent unspecific serotonergic effects. It would be an interesting question whether such effects are already present at significantly lower doses of LSD that are associated with only subtle effects (as described in so-called micro-dosing) and this will have to be investigated in the future. Between-network FC was found to be increased after psilocybin (Roseman et al., 2014) and LSD (Carhart-Harris et al., 2016b; M€uller et al., 2018). However, although these effects pointed in the same direction, there was almost no consistency in the detailed findings, i.e., FC between specific RSNs was not consistently increased across substances. It therefore seems doubtful whether these measures really represent a characteristic and meaningful effect of hallucinogens. Increased GFC of the precuneus was observed after administration of psilocybin and LSD (Tagliazucchi et al., 2016) in two data sets, and increased GFC in thalamic regions was found in three independent data sets after psilocybin and LSD (M€uller et al., 2018; Tagliazucchi et al., 2016). Both precuneus and thalamus are structures known as hubs, i.e., structures serving integration and large scale interactions between brain areas (van den Heuvel and Sporns, 2013). It is interesting that the precuneus, an important hub within the DMN, was also found to be affected in previous investigations of the within-network FC of the DMN (Carhart-Harris et al., 2016b; M€ uller et al., 2018) after LSD and after ayahuasca (Palhano-Fontes et al., 2015). As we have already pointed out elsewhere (Mueller et al., 2017b), it has long been speculated that alteration in thalamic functioning is a crucial mechanism of action of hallucinogens. An important model suggested that hallucinogens disrupt thalamic screening of external and internal signals, thus leading to increased passage of information across the cortex (Geyer and Vollenweider, 2008). The thalamus exhibits widespread connections to other brain regions (Jones, 2007; Parent and Hazrati, 1995) and is part of the so-called rich club, a set of highly connected regions that are densely connected among themselves (van den Heuvel and Sporns, 2011). Hub lesions are regarded as important factors in brain disorders in general (Crossley et al., 2014). More specifically, alterations in thalamocortical FC have long been suspected to be involved in the pathophysiology of schizophrenia (Ferrarelli and Tononi, 2011; Lisman et al., 2010; Pinault, 2011) and have been one of the few neuroimaging findings that have been repeatedly replicated in the search for the neural correlates of this disease (for an overview, see Giraldo-Chica and Woodward, 2017). On the other hand, several effects induced by hallucinogen drugs resemble symptoms observed in schizophrenia (Gouzoulis-Mayfrank et al., 1998) and these drugs are therefore thought to serve as models of psychosis (Geyer and Vollenweider, 2008). Overall, these observations might indicate that alterations in thalamic FC are indeed a relatively reliable neuroimaging correlate of acute effects of hallucinogens and that these alterations might have common features with changes seen in schizophrenia.
ARTICLE IN PRESS References
If all modalities for all investigated substances are considered, it may be concluded that the precuneus and thalamus were the most consistently identified regions affected by the administration of hallucinogens. Studies have indicated that these regions are particularly affected by hallucinogens in terms of CBF (with decreased CBF after psilocybin in two studies), within-network FC (with decreased FC of the precuneus regions within the DMN after LSD and ayahuasca in three studies), and GFC (with increased GFC of the thalamus after psilocybin and LSD in three studies and increased GFC of the precuneus after psilocybin and LSD in two studies). Interestingly, these two structures (precuneus and thalamus) have been linked by a recent model for the mechanism of action of hallucinogens (Winkelman, 2017). According to this model, hallucinogens act by impairing normal functioning of the DMN (precuneus and other regions), which subsequently leads to the emergence of normally suppressed “lower level” brain systems, such as the thalamus. However, prior studies also reported many divergent results. The available data reviewed in this chapter are limited by potential confounding factors, such as drug-induced alterations in physiological parameters, as well as vasoactive effects of the investigated substances. These issues have remained largely unaddressed, so that there is some uncertainty regarding the interpretation of results. Furthermore, several results might be biased by head motion artifacts. The question as to how subjective hallucinogenic effects relate to alterations at a neuronal level remains largely unresolved. Although several singular associations between neuroimaging measures and subjective drug effects have been described, none of these findings has been replicated so far. As we have pointed out, activation of the serotonin receptor by its natural ligand seems to induce widespread alterations in FC, some of which closely resemble those seen after administration of LSD. These observations should be kept in mind when interpreting FC measures after hallucinogens. For the future, it would be desirable to perform larger and thus maybe more reliable studies. Additionally, many of the present findings were obtained from the same clinical studies, assessed by different modalities and with many secondary and exploratory outcomes within the same study; this increases the risk of chance findings (Liechti, 2017). Furthermore, several of the studies did not include random treatment assignment and the pharmaceutical formulations of the substances were sometimes different (intravenous vs. oral administration of the drugs) (Liechti, 2017). It would also be of advantage to address potential difficulties of these pharmacological neuroimaging studies in a more consistent manner. For example, it would be desirable to report both absolute and relative changes in CBF or to implement specific procedures in data acquisition for potential confounding factors.
REFERENCES Borghammer, P., Cumming, P., Aanerud, J., Gjedde, A., 2009. Artefactual subcortical hyperperfusion in PET studies normalized to global mean: lessons from Parkinson’s disease. NeuroImage 45, 249–257.
15
ARTICLE IN PRESS 16
Advances and challenges in neuroimaging studies
Carhart-Harris, R.L., Erritzoe, D., Williams, T., Stone, J.M., Reed, L.J., Colasanti, A., Tyacke, R.J., Leech, R., Malizia, A.L., Murphy, K., Hobden, P., Evans, J., Feilding, A., Wise, R.G., Nutt, D.J., 2012. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc. Natl. Acad. Sci. U.S.A. 109, 2138–2143. Carhart-Harris, R.L., Leech, R., Erritzoe, D., Williams, T.M., Stone, J.M., Evans, J., Sharp, D.J., Feilding, A., Wise, R.G., Nutt, D.J., 2013. Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis. Schizophr. Bull. 39, 1343–1351. Carhart-Harris, R.L., Kaelen, M., Bolstridge, M., Williams, T.M., Williams, L.T., Underwood, R., Feilding, A., Nutt, D.J., 2016a. The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychol. Med. 46, 1379–1390. Carhart-Harris, R.L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., Tagliazucchi, E., Schenberg, E.E., Nest, T., Orban, C., Leech, R., Williams, L.T., Williams, T.M., Bolstridge, M., Sessa, B., Mcgonigle, J., Sereno, M.I., Nichols, D., Hellyer, P.J., Hobden, P., Evans, J., Singh, K.D., Wise, R.G., Curran, H.V., Feilding, A., Nutt, D.J., 2016b. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc. Natl. Acad. Sci. U.S.A. 113, 4853–4858. Crossley, N.A., Mechelli, A., Scott, J., Carletti, F., Fox, P.T., McGuire, P., Bullmore, E.T., 2014. The hubs of the human connectome are generally implicated in the anatomy of brain disorders. Brain 137, 2382–2395. Daumann, J., Wagner, D., Heekeren, K., Neukirch, A., Thiel, C.M., Gouzoulis-Mayfrank, E., 2010. Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis. J. Psychopharmacol. 24, 1515–1524. De Araujo, D.B., Ribeiro, S., Cecchi, G.A., Carvalho, F.M., Sanchez, T.A., Pinto, J.P., De Martinis, B.S., Crippa, J.A., Hallak, J.E., Santos, A.C., 2012. Seeing with the eyes shut: neural basis of enhanced imagery following Ayahuasca ingestion. Hum. Brain Mapp. 33, 2550–2560. Dolder, P.C., Schmid, Y., Steuer, A.E., Kraemer, T., Rentsch, K.M., Hammann, F., Liechti, M.E., 2017. Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects. Clin. Pharmacokinet. 56, 1219–1230. Dos Santos, R.G., Osorio, F.L., Crippa, J.A., Hallak, J.E., 2016. Classical hallucinogens and neuroimaging: a systematic review of human studies: hallucinogens and neuroimaging. Neurosci. Biobehav. Rev. 71, 715–728. Ferrarelli, F., Tononi, G., 2011. The thalamic reticular nucleus and schizophrenia. Schizophr. Bull. 37, 306–315. Fierstra, J., Sobczyk, O., Battisti-Charbonney, A., Mandell, D.M., Poublanc, J., Crawley, A.P., Mikulis, D.J., Duffin, J., Fisher, J.A., 2013. Measuring cerebrovascular reactivity: what stimulus to use? J. Physiol. 591, 5809–5821. Friston, K.J., 2011. Functional and effective connectivity: a review. Brain Connect. 1, 13–36. Geyer, M.A., Vollenweider, F.X., 2008. Serotonin research: contributions to understanding psychoses. Trends Pharmacol. Sci. 29, 445–453. Giraldo-Chica, M., Woodward, N.D., 2017. Review of thalamocortical resting-state fMRI studies in schizophrenia. Schizophr. Res. 180, 58–63. Gouzoulis-Mayfrank, E., Habermeyer, E., Hermle, L., Steinmeyer, A., Kunert, H., Sass, H., 1998. Hallucinogenic drug induced states resemble acute endogenous psychoses: results of an empirical study. Eur. Psychiatry 13, 399–406. Gouzoulis-Mayfrank, E., Schreckenberger, M., Sabri, O., Arning, C., Thelen, B., Spitzer, M., Kovar, K.A., Hermle, L., Bull, U., Sass, H., 1999. Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine
ARTICLE IN PRESS References
in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG. Neuropsychopharmacology 20, 565–581. Hasler, F., Grimberg, U., Benz, M.A., Huber, T., Vollenweider, F.X., 2004. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebocontrolled dose-effect study. Psychopharmacology 172, 145–156. Hermle, L., Funfgeld, M., Oepen, G., Botsch, H., Borchardt, D., Gouzoulis, E., Fehrenbach, R.A., Spitzer, M., 1992. Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research. Biol. Psychiatry 32, 976–991. Hollister, L.E., Hartman, A.M., 1962. Mescaline, lysergic acid diethylamide and psilocybin comparison of clinical syndromes, effects on color perception and biochemical measures. Compr. Psychiatry 3, 235–242. Hollister, L.E., Sjoberg, B.M., 1964. Clinical syndromes and biochemical alterations following mescaline, lysergic acid diethylamide, psilocybin and a combination of the three psychotomimetic drugs. Compr. Psychiatry 5, 170–178. Jones, E., 2007. The Thalamus. Cambridge University Press, New York. Kaelen, M., Roseman, L., Kahan, J., Santos-Ribeiro, A., Orban, C., Lorenz, R., Barrett, F.S., Bolstridge, M., Williams, T., Williams, L., Wall, M.B., Feilding, A., Muthukumaraswamy, S., Nutt, D.J., Carhart-Harris, R., 2016. LSD modulates musicinduced imagery via changes in parahippocampal connectivity. Eur. Neuropsychopharmacol. 26, 1099–1109. Khalili-Mahani, N., Chang, C., Van Osch, M.J., Veer, I.M., Van Buchem, M.A., Dahan, A., Beckmann, C.F., Van Gerven, J.M., Rombouts, S.A., 2013. The impact of “physiological correction” on functional connectivity analysis of pharmacological resting state fMRI. NeuroImage 65, 499–510. Klaassens, B.L., van Gorsel, H.C., Khalili-Mahani, N., van der Grond, J., Wyman, B.T., Whitcher, B., Rombouts, S.A., van Gerven, J.M., 2015. Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity. NeuroImage 122, 440–450. Kraehenmann, R., Preller, K.H., Scheidegger, M., Pokorny, T., Bosch, O.G., Seifritz, E., Vollenweider, F.X., 2015. Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Biol. Psychiatry 78, 572–581. Lewis, C.R., Preller, K.H., Kraehenmann, R., Michels, L., Staempfli, P., Vollenweider, F.X., 2017. Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow. NeuroImage 159, 70–78. Liechti, M.E., 2017. Modern clinical research on LSD. Neuropsychopharmacology 42, 2114–2127. Lisman, J.E., Pi, H.J., Zhang, Y., Otmakhova, N.A., 2010. A thalamo-hippocampal-ventral tegmental area loop may produce the positive feedback that underlies the psychotic break in schizophrenia. Biol. Psychiatry 68, 17–24. Mueller, F., Lenz, C., Dolder, P.C., Harder, S., Schmid, Y., Lang, U.E., Liechti, M.E., Borgwardt, S., 2017a. Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl. Psychiatry 7, e1084. Mueller, F., Lenz, C., Dolder, P.C., Lang, U.E., Schmidt, A., Liechti, M.E., Borgwardt, S., 2017b. Increased thalamic resting state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr. Scand. 136, 648–657. M€uller, F., Dolder, P.C., Schmidt, A., Liechti, M.E., Borgwardt, S., 2018. Altered network hub connectivity after acute LSD administration. NeuroImage 18, 694–701.
17
ARTICLE IN PRESS 18
Advances and challenges in neuroimaging studies
Palhano-Fontes, F., Andrade, K.C., Tofoli, L.F., Santos, A.C., Crippa, J.A., Hallak, J.E., Ribeiro, S., de Araujo, D.B., 2015. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. PLoS One 10, e0118143. Parent, A., Hazrati, L.N., 1995. Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res. Brain Res. Rev. 20, 91–127. Pinault, D., 2011. Dysfunctional thalamus-related networks in schizophrenia. Schizophr. Bull. 37, 238–243. Poldrack, R.A., Baker, C.I., Durnez, J., Gorgolewski, K.J., Matthews, P.M., Munafo, M.R., Nichols, T.E., Poline, J.B., Vul, E., Yarkoni, T., 2017. Scanning the horizon: towards transparent and reproducible neuroimaging research. Nat. Rev. Neurosci. 18, 115–126. Power, J.D., Mitra, A., Laumann, T.O., Snyder, A.Z., Schlaggar, B.L., Petersen, S.E., 2014. Methods to detect, characterize, and remove motion artifact in resting state fMRI. NeuroImage 84, 320–341. Preller, K.H., Herdener, M., Pokorny, T., Planzer, A., Kraehenmann, R., Stampfli, P., Liechti, M.E., Seifritz, E., Vollenweider, F.X., 2017. The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation. Curr. Biol. 27, 451–457. Riba, J., Romero, S., Grasa, E., Mena, E., Carrio, I., Barbanoj, M.J., 2006. Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant. Psychopharmacology 186, 93–98. Rickli, A., Moning, O.D., Hoener, M.C., Liechti, M.E., 2016. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur. Neuropsychopharmacol. 26, 1327–1337. Roseman, L., Leech, R., Feilding, A., Nutt, D.J., Carhart-Harris, R.L., 2014. The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers. Front. Hum. Neurosci. 8, 204. Schaefer, A., Burmann, I., Regenthal, R., Arelin, K., Barth, C., Pampel, A., Villringer, A., Margulies, D.S., Sacher, J., 2014. Serotonergic modulation of intrinsic functional connectivity. Curr. Biol. 24, 2314–2318. Schmid, Y., Enzler, F., Gasser, P., Grouzmann, E., Preller, K.H., Vollenweider, F.X., Brenneisen, R., Muller, F., Borgwardt, S., Liechti, M.E., 2015. Acute effects of lysergic acid diethylamide in healthy subjects. Biol. Psychiatry 78, 544–553. Schmidt, A., Muller, F., Lenz, C., Dolder, P.C., Schmid, Y., Zanchi, D., Lang, U.E., Liechti, M.E., Borgwardt, S., 2017. Acute LSD effects on response inhibition neural networks. Psychol. Med. 1–13. Spain, A., Howarth, C., Khrapitchev, A.A., Sharp, T., Sibson, N.R., Martin, C., 2015. Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain. Neuropharmacology 99, 210–220. Tagliazucchi, E., Roseman, L., Kaelen, M., Orban, C., Muthukumaraswamy, S.D., Murphy, K., Laufs, H., Leech, R., Mcgonigle, J., Crossley, N., Bullmore, E., Williams, T., Bolstridge, M., Feilding, A., Nutt, D.J., Carhart-Harris, R., 2016. Increased global functional connectivity correlates with LSD-induced ego dissolution. Curr. Biol. 26, 1043–1050. van den Heuvel, M.P., Sporns, O., 2011. Rich-club organization of the human connectome. J. Neurosci. 31, 15775–15786. van den Heuvel, M.P., Sporns, O., 2013. Network hubs in the human brain. Trends Cogn. Sci. 17, 683–696.
ARTICLE IN PRESS References
Vollenweider, F.X., Leenders, K.L., Scharfetter, C., Maguire, P., Stadelmann, O., Angst, J., 1997. Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 16, 357–372. Winkelman, M.J., 2017. The mechanisms of psychedelic visionary experiences: hypotheses from evolutionary psychology. Front. Neurosci. 11, 539. Wise, R.G., Tracey, I., 2006. The role of fMRI in drug discovery. J. Magn. Reson. Imaging 23, 862–876.
19
Advances and challenges in neuroimaging studies on the effects of serotonergic hallucinogens: Contributions of the resting brain Felix M€ uller*, Matthias E. Liechti†, Undine E. Lang*, Stefan Borgwardt*,1 *Department of Psychiatry (UPK), University of Basel, Basel, Switzerland Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland 1 Corresponding author: Tel.: +41-61-325-5858; Fax: +41-61-325-8180, e-mail address: [email protected]
†
Abstract The effects of hallucinogenic drugs on the human brain have been studied since the earliest days of neuroimaging in the 1990s. However, approaches are often hard to compare and results are heterogeneous. In this chapter, we summarize studies investigating the effects of hallucinogens on the resting brain, with a special emphasis on replicability and limitations. In previous studies, similarities were observed between psilocybin, LSD, and ayahuasca, with respect to decreases in cerebral blood flow and increases in global functional connectivity in the precuneus and thalamus. Additionally, LSD consistently decreased functional connectivity within distinct resting state networks. Little convergence was observed for connectivity between networks and for blood flow in other brain regions. Although these studies are limited by small sample sizes and might be biased by unspecific drug effects on physiological parameters and the vascular system, current results indicate that neuroimaging could be a useful tool to elucidate the neuronal correlates of hallucinogenic effects.
Keywords Psychedelics, Hallucinogens, LSD, Psilocybin, DMT, Mescaline, Ayahuasca, Neuroimaging, Resting state, Functional connectivity, fMRI, SPECT, PET
Progress in Brain Research, ISSN 0079-6123, https://doi.org/10.1016/bs.pbr.2018.08.004 © 2018 Elsevier B.V. All rights reserved.
1
ARTICLE IN PRESS 2
Advances and challenges in neuroimaging studies
1 INTRODUCTION Hallucinogenic drugs can be used to acutely induce various transient alterations in the cognitive, perceptual, and emotional domains (Carhart-Harris et al., 2016a; Hasler et al., 2004; Schmid et al., 2015), so that it is interesting to consider how these alterations are represented at the level of brain functioning. Since the beginning of the 1990s, this issue has been investigated using neuroimaging techniques and there has been a significant increase in such work in recent years. The acute effects on the human brain of serotonergic hallucinogens—such as lysergic acid diethylamide (LSD), psilocybin, and N,N-dimethyltryptamine (DMT, contained in ayahuasca)—have been assessed with respect to glucose metabolism, blood oxygenation level dependent signal (BOLD), and cerebral blood flow (CBF), using the techniques of single photon emission computed tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI). On the basis of these findings, different models have been proposed to explain the mind-altering effects of hallucinogens, including hyperfrontality (Vollenweider et al., 1997) and altered thalamic (Geyer and Vollenweider, 2008) and hub functioning (Carhart-Harris et al., 2012). Although there has been considerable progress in recent years (de Araujo et al., 2012; Kaelen et al., 2016; Preller et al., 2017; Schmidt et al., 2017), this field of research is based on rather few, relatively small studies, often with different methodological approaches that are difficult to compare. Replications are therefore still scarce. However, experience in different fields of neuroimaging has shown that repeated studies often fail to replicate previous findings (Poldrack et al., 2017). It is therefore reasonable to interpret these results with caution and to regard them as preliminary. Although several publications report results on task-based neuroimaging in hallucinogens, there have been almost no investigations which allow comparison of results across studies (for an overview, see Dos Santos et al., 2016). For example, effects of hallucinogens have been examined by studies which used tasks for alertness (Daumann et al., 2010), music (Preller et al., 2017) and imagery (de Araujo et al., 2012). Emotion processing has been one of the few areas investigated in independent samples. Amygdala activity in response to fearful stimuli was consistently decreased after administration of psilocybin (Kraehenmann et al., 2015) and LSD (Mueller et al., 2017a). This finding has been replicated in different studies and laboratories. In contrast to task-based approaches, investigations of drug effects on the resting brain provide more data and a broader basis for comparisons between studies. In this chapter, we summarize current neuroimaging findings on the effects of hallucinogens on the resting brain. We specifically focus on the reproducibility of these findings in independent samples and also discuss limitations of previous studies and challenges for future studies. We identify two main areas where comparable methodological approaches have been applied: Quantification of CBF and
ARTICLE IN PRESS 2 General considerations
functional connectivity (FC) in terms of within-network FC, between-network FC, and global connectivity. As mentioned above, this comparison might provide a clearer and more reliable picture than a discussion of single studies. We do not include studies on glucose metabolism, as there is only one resting state study on this topic (Vollenweider et al., 1997), which is sometimes compared with another PET study by Gouzoulis-Mayfrank et al. (1999). However, a word repetition task and an association task were used in the latter study, so that it is unclear if the results are really comparable. Our review is further restricted to serotonergic hallucinogens, i.e., a group of classic hallucinogenic drugs which mainly act on the serotonin 5HT2Areceptor, as these drugs are likely to have at least partially overlapping neuronal signatures and have been the main focus of previous investigations. The substances reviewed in this chapter thus include psilocybin, LSD (lysergic acid diethylamide), and DMT (N,N-dimethyltryptamine; the psychoactive component of the herbal brew ayahuasca, which is used by indigenous people in South America).
2 GENERAL CONSIDERATIONS OF THE LIMITATIONS OF NEUROIMAGING STUDIES ON HALLUCINOGENS Although hallucinogenic drugs like psilocybin, LSD, and DMT all act as agonists at the 5HT2A-receptor, they exhibit different affinities to other receptors (Rickli et al., 2016). Because of these varying interactions with receptors other than the 5HT2Areceptor, hallucinogens might also affect neuronal structures in different ways, with or without consequences for subjective drug effects. It is still unclear to what extent these different substances actually show comparable effects, at either the neuronal or subjective levels. Nevertheless, it can be expected that most subjective effects are common to all serotonergic hallucinogens, as findings on different drugs in separate studies indicate that subjective effects are similar (Hasler et al., 2004; Schmid et al., 2015), even though there have been no valid direct within-subject comparisons (Hollister and Hartman, 1962; Hollister and Sjoberg, 1964). This reservation introduces some uncertainty and limits comparisons of the neuroimaging findings across different substances. As in other fields of neuroimaging, there are several general sources of bias which also affect studies in this area. Two important examples are artifacts introduced to neuroimaging data by participants’ head motion, and physiological noise induced by, for example, respiratory or cardiac cycles (Khalili-Mahani et al., 2013; Wise and Tracey, 2006). FC is regarded as particularly sensitive to bias resulting from head motion. However, other neuroimaging measures might be affected as well (Power et al., 2014). Although these factors are of general concern in neuroimaging, they might be more pronounced in this field of research, as participants might show more motion due to acute drug effects. Indeed, this problem has been reported in some (Carhart-Harris et al., 2016b; Roseman et al., 2014), but not all studies. Moreover, it has already been shown that psilocybin and LSD alter physiological
3
ARTICLE IN PRESS 4
Advances and challenges in neuroimaging studies
parameters, such as heart rate, blood pressure and body temperature (Dolder et al., 2017; Hasler et al., 2004; Schmid et al., 2015). Lastly, the administered substances might affect vascular tone or neurovascular coupling and hence CBF, thus leading to alterations which do not actually reflect neuronal activity but rather unspecific effects (Wise and Tracey, 2006).
3 ALTERATIONS IN CEREBRAL BLOOD FLOW To our knowledge, the first study in the field of neuroimaging in hallucinogens was published in 1992 by Hermle et al. (1992). Using SPECT, the authors investigated the effects of mescaline (500 mg, oral) on CBF in 18 regions of interest (ROIs) (n ¼ 11). In the left hemisphere, significant decreases were observed in the thalamus and in the central, superior-parietal, and superior-temporal regions. The right hemisphere exhibited significant increases in the inferior-temporal region. In general, the authors stated that mescaline induced a hyperfrontal pattern, most pronounced in the right hemisphere. It is hard to compare these findings with other studies (described below), as relatively gross parcellation was applied. Moreover, the results were not corrected for multiple comparisons. Over a decade later, Riba et al. (2006) investigated the effects of ayahuasca (n ¼ 15; 1 mg DMT/kg, orally) on whole brain CBF in a SPECT study (Riba et al., 2006). In contrast to the investigation by Hermle et al., only increases in CBF were observed. The authors reported alterations in the frontal lobe, anterior cingulate and amygdala/parahippocampus. The results were not corrected for multiple comparisons. The findings of this study and other investigations referred to in this section are shown in Table 1 (the study by Hermle et al. is not included in this table because it was not possible to match anatomical regions reported in this work to those of the other studies). After a second gap of several years, Carhart-Harris et al. (2012) analyzed CBF after the administration of psilocybin (n ¼ 15; 2 mg, intravenous (i.v.)) by means of arterial spin labeling (ASL). The authors reported decreases in CBF, located in various subcortical and cortical regions (please see Table 1 for more details). In order to investigate possible confounding effects, they also examined how several physiological parameters (heart rate, respiration rate, respiration depth; recorded during the MRI scan) influence CBF. Although no details were reported, these corrections did alter the results for some regions, while others were not affected (Carhart-Harris et al., 2012). This analysis is, however, limited by the fact that CBF was only examined in terms of the BOLD signal and not with ASL. A few years later, the same group also investigated the effects of LSD (n ¼ 15, 75 μg, i.v.) and found increased CBF in the visual cortex (Carhart-Harris et al., 2016b), a result that clearly contrasts with their previous results with psilocybin. Subsequently, Lewis et al. examined CBF by means of ASL, using two doses of psilocybin (0.16 and 0.215 mg/kg, orally) in a relatively large sample (n ¼ 29 for each group) (Lewis et al., 2017). The authors hypothesized that the effects after psilocybin observed by Carhart-Harris et al. might actually be due to unspecific global
ARTICLE IN PRESS 3 Alterations in cerebral blood flow
5
Table 1 Comparison of Findings on Cerebral Blood Flow (CBF) After Administration of the Hallucinogens Ayahuasca, Psilocybin, and LSD
Continued
ARTICLE IN PRESS 6
Advances and challenges in neuroimaging studies
Table 1 Comparison of Findings on Cerebral Blood Flow (CBF) After Administration of the Hallucinogens Ayahuasca, Psilocybin, and LSD—cont’d
Increased CBF is shown in red, decreased CBF in blue. Brain regions are labeled according to the automated anatomic labeling (AAL) Atlas. Regions reported for Carhart-Harris et al. (2016b) were estimated from published figures as no details were reported. Abbreviations: aCBF, absolute cerebral blood flow; ASL, arterial spin labeling; DMT, dimethyltryptamine; fMRI, functional magnetic resonance imaging; FWE, family-wise error rate; LSD, lysergic acid diethylamide; rCBF, relative cerebral blood flow; SPECT, singlephoton emission computed tomography. a This region was reported by one of the included studies only and could not be matched to the AAL atlas.
ARTICLE IN PRESS 3 Alterations in cerebral blood flow
effects of psilocybin on vascular tone, as already seen with psilocin, the active metabolite of psilocybin (Spain et al., 2015). Lewis et al. thus conducted two separate analyses, one controlling for global effects and one without correction, in order to disentangle nonspecific vascular and “true” effects. They found that psilocybin decreased absolute perfusion in various regions but, after adjusting for global perfusion, there were increases in CBF in the right hemispheric frontal and temporal regions and bilateral anterior insula and decreased CBF in the subcortical, parietal, occipital and insular regions, which were mainly localized in the left hemisphere (Lewis et al., 2017) (see also Table 1). Therefore, these results might indicate that the findings reported by Carhart-Harris et al. (2012) were biased by the unspecific effects of psilocybin on global CBF. However, Carhart-Harris et al. did perform a breath-hold task to test cerebrovascular reactivity and reported no altered reactivity after psilocybin compared with placebo. However, breath-hold tasks have several limitations and these might explain these diverging results (Fierstra et al., 2013). On the other hand, normalization to the global mean as applied by Lewis et al. also possesses some inherent problems, e.g., this procedure might introduce artificial increases in CBF (Borghammer et al., 2009). A synopsis of all previous findings in CBF is given in Table 1. Results were summarized according to labels of the automated anatomic labeling (AAL) atlas. However, some regions could not be matched to these labels (e.g., the orbitofrontal cortex) and thus this comparison might be unreliable to some extent. In general, previous studies give a rather heterogeneous picture. Some consistencies were observed by both studies which investigated psilocybin. Carhart-Harris et al. and Lewis et al. consistently reported decreased CBF in the precentral gyrus, angular gyrus, precuneus, insula, thalamus, and putamen (Carhart-Harris et al., 2012; Lewis et al., 2017). There are no striking similarities between the different substances, apart from the increases in CBF in the frontal inferior gyrus and anterior insula—which were reported after administration of both psilocybin (Lewis et al., 2017) and ayahuasca (Riba et al., 2006). It may be asked whether these alterations in CBF really reflect disparate neuronal effects of the different hallucinogens, as there appear to be many similarities between serotonergic hallucinogens, at least between psilocybin and LSD (Hollister and Hartman, 1962; Hollister and Sjoberg, 1964). As described above, however, it is largely unclear whether and to what extent different substances show similar effects. One possible explanation for the disparate results with CBF might be that the substances exhibit different vasoactive properties. No attempts have been made to assess possible vasoactive effects of mescaline (Hermle et al., 1992), ayahuasca (Riba et al., 2006), and LSD (Carhart-Harris et al., 2016b). While Lewis et al. (2017) found that controlling for global effects significantly altered the results, in clear contrast to the findings for psilocybin, others found no evidence that psilocybin is vasoactive (Carhart-Harris et al., 2012), which complicates further interpretations. Besides vascular effects, CBF might also be affected by alterations in physiological parameters; however, this question was not covered in most studies—with the exception of a single study by Carhart-Harris et al. (2012). Although this regression analysis of heart
7
ARTICLE IN PRESS 8
Advances and challenges in neuroimaging studies
rate, respiration rate, and respiration depth did not affect BOLD results within some regions, others seemed to be affected. However, no details were reported and it is furthermore unclear if these results can be transferred to ASL data. Moreover, most studies in CBF are limited by small sample sizes, with the exception of Lewis et al. (2017), who analyzed data of 58 participants.
4 ALTERATIONS IN FUNCTIONAL CONNECTIVITY Functional connectivity (FC) is a measure used to characterize functional integration by assessing statistical dependence between brain regions (Friston, 2011). FC has been probably the most widely investigated neuroimaging measure in hallucinogens. However, this area is also limited by different approaches, which renders comparisons across studies difficult. To our knowledge, genuinely comparable FC measures have been investigated in four independent samples by six studies after the administration of psilocybin (Roseman et al., 2014; Tagliazucchi et al., 2016), ayahuasca (Palhano-Fontes et al., 2015), and LSD (Carhart-Harris et al., 2016b; M€ uller et al., 2018; Tagliazucchi et al., 2016). These investigations focus on FC of resting state networks and global FC.
4.1 WITHIN AND BETWEEN NETWORK FUNCTIONAL CONNECTIVITY Several studies have investigated the effects of individual substances on resting state networks (RSNs) (Carhart-Harris et al., 2016b; M€uller et al., 2018; Palhano-Fontes et al., 2015; Roseman et al., 2014). RSNs were analyzed with regard to FC within these networks as well as FC between different RSNs. Within-network FC is a measure of coactivation of voxels which are part of a given network (e.g., the coactivation of the precuneus with the rest of the default mode network). “Between network FC” means the connectivity of all voxels of a given network to another network as a whole (e.g., connectivity between the default mode network and the sensorimotor network). The available studies indicated that administration of psilocybin leads to relatively widespread increases in FC between various networks (Carhart-Harris et al., 2013; Roseman et al., 2014) and this is also the case with LSD (CarhartHarris et al., 2016b; M€ uller et al., 2018). Carhart-Harris et al. aggregated the findings on within- and between-RSN FC in the concept of altered “integration and segregation,” i.e., these hallucinogens act by blurring demarcations between distinct RSNs while compromising integrity within RSNs (Carhart-Harris et al., 2016b). According to the authors, this decrease in compartmentalization underlies typical hallucinogenic effects. These findings will be discussed below. Within-network FC has only been investigated for LSD (Carhart-Harris et al., 2016b). The authors reported that LSD decreased FC within several networks; no increases were observed. FC was reported to be decreased in the default mode network (DMN), the sensorimotor network, two visual networks, the parietal cortex
ARTICLE IN PRESS 4 Alterations in functional connectivity
network, and the right frontoparietal network (Carhart-Harris et al., 2016b). Our group attempted to replicate these findings in a sample of drug-naive subjects (n ¼ 20; 100 μg LSD, orally) (M€ uller et al., 2018). We found decreased FC within the DMN, the sensorimotor network and visual networks 1 and 3; thus, our findings on within-network FC very closely resembled those reported for LSD (CarhartHarris et al., 2016b). In contrast to the previous results, the frontoparietal network was not affected in our analyses and we did not assess the parietal network as in Carhart-Harris et al. Fig. 1 shows a comparison of findings by Carhart-Harris et al. (2016b) and M€ uller et al. (2018). These results are in good agreement with a recent investigation of the effects of ayahuasca on the DMN, which also found decreased FC within this network (Palhano-Fontes et al., 2015). As already pointed out elsewhere (M€ uller et al., 2018), these findings can be questioned for several reasons. A study which investigated within-network FC after the administration of a serotonin reuptake inhibitor reported decreased FC in exactly the same networks as seen in our replication study (Klaassens et al., 2015). Serotonin reuptake inhibitors increase extracellular levels of serotonin and only induce very mild subjective effects in healthy subjects, if anything. The alterations observed in studies on hallucinogens might thus represent unspecific serotonergic effects without any relevance for specific hallucinogenic drug effects. In line with this, we were not able to replicate (M€ uller et al., 2018) an association between decreased FC within the DMN and measures of subjective drug effects in the domain “ego dissolution” (the subjective experience of a comprised sense of “self” or “ego”), as previously described (Carhart-Harris et al., 2016b). No other significant associations have been described by other groups. In order to assess this issue more broadly, we investigated associations between all five subscales of the standard questionnaire 5 Dimensions of Altered States of Consciousness (5D-ASC) and found no significant differences (M€ uller et al., 2018). Between-network FC has been investigated for psilocybin (Roseman et al., 2014) (n ¼ 15, 2 mg, i.v.) and in two data sets for LSD (Carhart-Harris et al., 2016b; M€uller et al., 2018) (n ¼ 15, 75 μg, i.v. and n ¼ 20, 100 μg, orally). Studies consistently indicated increases in FC between networks. Relatively widespread alterations were found by Roseman et al. and by our group (M€uller et al., 2018), while increases were less pronounced in the findings by Carhart-Harris et al. All findings are summarized in Fig. 2. Our group also tested for possible influences of altered physiological parameters, by correlating these measures with alterations in FC. We found no relationship between FC and heart rate, blood pressure, or temperature (M€uller et al., 2018). However, this analysis was based on measures taken at a single time point directly before the MRI scan and continuous measures taken during the scan might be advantageous. Closer inspection of the alterations in between-network FC indicated that the results of the London studies on psilocybin (Carhart-Harris et al., 2013; Roseman et al., 2014) and on LSD (Carhart-Harris et al., 2016b) were inconsistent, as were these studies and our results (see Fig. 1). Given the apparently unstable nature of these findings, it is questionable how functionally meaningful these alterations really are. On the other hand, it is unclear to what extent results with psilocybin (Roseman et al., 2014)
9
ARTICLE IN PRESS 10
Advances and challenges in neuroimaging studies
FIG. 1 Comparison of findings on within-network functional connectivity (FC) in LSD, obtained in two samples. Within-network FC was consistently and significantly decreased in the default mode network (A), visual network 1 (B), visual network 3 (C), and the sensorimotor network (D). Please note that the affected region within the DMN corresponds to the precuneus/posterior cingulate gyrus. Figures reproduced from Carhart-Harris, R.L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., Tagliazucchi, E., Schenberg, E.E., Nest, T., Orban, C., Leech, R., Williams, L.T., Williams, T.M., Bolstridge, M., Sessa, B., Mcgonigle, J., Sereno, M.I., Nichols, D., Hellyer, P.J., Hobden, P., Evans, J., Singh, K.D., Wise, R.G., Curran, H.V., Feilding, A., Nutt, D.J., 2016b. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc. Natl. Acad. Sci. U.S.A. 113, 4853–8 and Mueller, F., Lenz, C., Dolder, P.C., Harder, S., Schmid, Y., Lang, U.E., Liechti, M.E., Borgwardt, S., 2017a. Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl. Psychiatry 7, e1084; Mueller, F., Lenz, C., Dolder, P.C., Lang, U.E., Schmidt, A., Liechti, M.E., Borgwardt, S., 2017b. Increased thalamic resting state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr. Scand. 136, 648–657.
and LSD (Carhart-Harris et al., 2016b; M€uller et al., 2018) are in fact comparable, even though they share a common mechanism of action at the 5HT2A-receptor (Rickli et al., 2016). However, there were also very few consistencies between studies in LSD (Carhart-Harris et al., 2016b; M€uller et al., 2018). It is possible that the observed discrepancies are due to the effects of different conditions in different studies (Carhart-Harris et al., 2016b; Roseman et al., 2014), or different methods of
ARTICLE IN PRESS 4 Alterations in functional connectivity
FIG. 2 Comparison of alterations in between-network connectivity induced by psilocybin (Roseman €ller et al., 2018). Asterisks indicate et al., 2014) and LSD (Carhart-Harris et al., 2016b; Mu significant differences between drug and placebo conditions (green, Roseman et al., 2014; €ller et al., 2018). Black indicates networks which blue, Carhart-Harris et al., 2016b; red, Mu were not investigated in Carhart-Harris et al. (2016b). Roseman et al. reported separate results for two representations of the default mode network (4) which were combined in this presentation. € Figure reproduced from Muller, F., Dolder, P.C., Schmidt, A., Liechti, M.E., Borgwardt, S., 2018. Altered network hub connectivity after acute LSD administration. NeuroImage 18, 694–701.
analysis or differences in regions covered by RSN. Different routes of administration (i.v. and oral administration) may have also affected the results.
4.2 GLOBAL FUNCTIONAL CONNECTIVITY Global functional connectivity (GFC) is another broad, data-driven assessment of FC. GFC is calculated from the average correlation of each voxel or ROI to each other voxel or ROI. Global correlation was investigated in two studies with LSD (Mueller et al., 2017b; Tagliazucchi et al., 2016) and in one study with psilocybin (Tagliazucchi et al., 2016). In a reanalysis of the data sets of Carhart-Harris et al. (2016b) and Roseman et al. (2014), Tagliazucchi et al. investigated the effects of
11
ARTICLE IN PRESS 12
Advances and challenges in neuroimaging studies
psilocybin (n ¼ 15, 2 mg, i.v.) and LSD (n ¼ 15, 75 μg, i.v.) on GFC—using the same approach for both substances. More specificially, the authors parcellated the brain into 401 ROIs and reported relatively widespread increases in GFC in the frontal, parietal, and temporal cortical regions. The authors described increased GFC in the precuneus and thalamus, but no details were reported for other regions, so comparisons between substances are limited. With a slightly different approach, our group (Mueller et al., 2017b) (n ¼ 20, 100 μg LSD orally) calculated GFC based on voxels. This gave higher spatial resolution, but also a stricter correction for multiple comparisons. This analysis revealed no alterations in cortical regions, but increased global FC of thalamic regions, as well as parts of the basal ganglia. For a comparison of the findings by Tagliazucchi et al. and M€ uller et al., please see Fig. 3. As a consistent result, increased FC in thalamic
FIG. 3 Comparison of findings on global functional connectivity (GFC) in psilocybin and LSD, obtained in three different samples. GFC was found to be significantly increased in thalamic regions in three studies after psilocybin and LSD, and in the precuneus in two independent data sets after psilocybin and LSD. Figures reproduced from Tagliazucchi, E., Roseman, L., Kaelen, M., Orban, C., Muthukumaraswamy, S.D., Murphy, K., Laufs, H., Leech, R., Mcgonigle, J., Crossley, N., Bullmore, E., Williams, T., Bolstridge, M., Feilding, A., Nutt, D.J., Carhart-Harris, R., 2016. Increased global functional connectivity correlates with LSDinduced ego dissolution. Curr. Biol. 26, 1043–50 and Mueller, F., Lenz, C., Dolder, P.C., Harder, S., Schmid, Y., Lang, U.E., Liechti, M.E., Borgwardt, S., 2017a. Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl. Psychiatry 7, e1084; Mueller, F., Lenz, C., Dolder, P.C., Lang, U.E., Schmidt, A., Liechti, M.E., Borgwardt, S., 2017b. Increased thalamic resting state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr. Scand. 136, 648–657.
ARTICLE IN PRESS 5 Summary and conclusions
regions was found in three independent data sets after the administration of LSD and psilocybin. Differences between Tagliazucchi et al. and our analysis in the findings in cortical regions might be due to slightly different approaches and statistical thresholds. Tagliazucchi et al. used ROI-to-ROI approaches, rather than the voxel-to-voxel approach in our analysis. Moreover, we employed a more conservative threshold. These factors might result in greater sensitivity to detect alterations in GFC in Tagliazucchi et al. As Tagliazucchi et al. re-analyzed data sets that have already been described above (Carhart-Harris et al., 2016b; Roseman et al., 2014), the same limitations apply. In both data sets, there were significant differences in head motion between conditions. The authors conducted additional analyses in order to investigate the potential impact of motion on FC results, but found no relationship (Tagliazucchi et al., 2016). However, neither these studies nor our own analysis investigated whether differences in physiological parameters can modify these results, so this question remains open. In addition, the specificity of increased thalamic GFC for hallucinogenic drug effects might also be questioned on similar grounds to those described for withinnetwork FC (see above). Increases in thalamic FC (as well as global decreases in other regions) were also observed after intake of a serotonin reuptake inhibitor (Schaefer et al., 2014). Although a different FC measure (degree-centrality, i.e., a count of the number of connections of a specific voxel) was used in this study, these findings suggest that thalamic FC can also be altered by the natural ligand of the serotonin receptor.
5 SUMMARY AND CONCLUSIONS In summary, study of the acute effects of hallucinogenic drugs using advanced neuroimaging methods is progressing, but many questions remain open. Research in this area currently employs several heterogeneous analyses which are difficult to compare and there have been few replications; the field is dominated by single reports based on small sample sizes. For CBF, previous studies have found few similarities for different substances (ayahuasca, psilocybin, and LSD). In two recent studies, some consistent results were found with psilocybin (Carhart-Harris et al., 2012; Lewis et al., 2017), with both reporting decreased CBF in the precentral gyrus, angular gyrus, precuneus, insula, thalamus, and putamen. These findings indicate that psilocybin does indeed affect the neuronal functioning of these structures, some of which (precuneus, thalamus) are known hubs. Impairment of hubs would potentially have a relatively widespread impact—given the importance of these structures for overall brain functioning (Crossley et al., 2014)—and might provide a neuronal basis for hallucinogenic effects. In terms of functional connectivity, psilocybin and LSD have been associated with widespread alterations across various regions in one sample after administration of psilocybin (Roseman et al., 2014), and in two samples after LSD (Carhart-Harris
13
ARTICLE IN PRESS 14
Advances and challenges in neuroimaging studies
et al., 2016b; M€ uller et al., 2018). LSD has been consistently associated with decreased connectivity within several resting state networks, i.e., DMN, the sensorimotor network, and visual networks (Carhart-Harris et al., 2016b; M€uller et al., 2018). These findings fit well with the concept that hallucinogens disrupt FC within RSNs. As discussed above, however, these changes might also represent unspecific serotonergic effects. It would be an interesting question whether such effects are already present at significantly lower doses of LSD that are associated with only subtle effects (as described in so-called micro-dosing) and this will have to be investigated in the future. Between-network FC was found to be increased after psilocybin (Roseman et al., 2014) and LSD (Carhart-Harris et al., 2016b; M€uller et al., 2018). However, although these effects pointed in the same direction, there was almost no consistency in the detailed findings, i.e., FC between specific RSNs was not consistently increased across substances. It therefore seems doubtful whether these measures really represent a characteristic and meaningful effect of hallucinogens. Increased GFC of the precuneus was observed after administration of psilocybin and LSD (Tagliazucchi et al., 2016) in two data sets, and increased GFC in thalamic regions was found in three independent data sets after psilocybin and LSD (M€uller et al., 2018; Tagliazucchi et al., 2016). Both precuneus and thalamus are structures known as hubs, i.e., structures serving integration and large scale interactions between brain areas (van den Heuvel and Sporns, 2013). It is interesting that the precuneus, an important hub within the DMN, was also found to be affected in previous investigations of the within-network FC of the DMN (Carhart-Harris et al., 2016b; M€ uller et al., 2018) after LSD and after ayahuasca (Palhano-Fontes et al., 2015). As we have already pointed out elsewhere (Mueller et al., 2017b), it has long been speculated that alteration in thalamic functioning is a crucial mechanism of action of hallucinogens. An important model suggested that hallucinogens disrupt thalamic screening of external and internal signals, thus leading to increased passage of information across the cortex (Geyer and Vollenweider, 2008). The thalamus exhibits widespread connections to other brain regions (Jones, 2007; Parent and Hazrati, 1995) and is part of the so-called rich club, a set of highly connected regions that are densely connected among themselves (van den Heuvel and Sporns, 2011). Hub lesions are regarded as important factors in brain disorders in general (Crossley et al., 2014). More specifically, alterations in thalamocortical FC have long been suspected to be involved in the pathophysiology of schizophrenia (Ferrarelli and Tononi, 2011; Lisman et al., 2010; Pinault, 2011) and have been one of the few neuroimaging findings that have been repeatedly replicated in the search for the neural correlates of this disease (for an overview, see Giraldo-Chica and Woodward, 2017). On the other hand, several effects induced by hallucinogen drugs resemble symptoms observed in schizophrenia (Gouzoulis-Mayfrank et al., 1998) and these drugs are therefore thought to serve as models of psychosis (Geyer and Vollenweider, 2008). Overall, these observations might indicate that alterations in thalamic FC are indeed a relatively reliable neuroimaging correlate of acute effects of hallucinogens and that these alterations might have common features with changes seen in schizophrenia.
ARTICLE IN PRESS References
If all modalities for all investigated substances are considered, it may be concluded that the precuneus and thalamus were the most consistently identified regions affected by the administration of hallucinogens. Studies have indicated that these regions are particularly affected by hallucinogens in terms of CBF (with decreased CBF after psilocybin in two studies), within-network FC (with decreased FC of the precuneus regions within the DMN after LSD and ayahuasca in three studies), and GFC (with increased GFC of the thalamus after psilocybin and LSD in three studies and increased GFC of the precuneus after psilocybin and LSD in two studies). Interestingly, these two structures (precuneus and thalamus) have been linked by a recent model for the mechanism of action of hallucinogens (Winkelman, 2017). According to this model, hallucinogens act by impairing normal functioning of the DMN (precuneus and other regions), which subsequently leads to the emergence of normally suppressed “lower level” brain systems, such as the thalamus. However, prior studies also reported many divergent results. The available data reviewed in this chapter are limited by potential confounding factors, such as drug-induced alterations in physiological parameters, as well as vasoactive effects of the investigated substances. These issues have remained largely unaddressed, so that there is some uncertainty regarding the interpretation of results. Furthermore, several results might be biased by head motion artifacts. The question as to how subjective hallucinogenic effects relate to alterations at a neuronal level remains largely unresolved. Although several singular associations between neuroimaging measures and subjective drug effects have been described, none of these findings has been replicated so far. As we have pointed out, activation of the serotonin receptor by its natural ligand seems to induce widespread alterations in FC, some of which closely resemble those seen after administration of LSD. These observations should be kept in mind when interpreting FC measures after hallucinogens. For the future, it would be desirable to perform larger and thus maybe more reliable studies. Additionally, many of the present findings were obtained from the same clinical studies, assessed by different modalities and with many secondary and exploratory outcomes within the same study; this increases the risk of chance findings (Liechti, 2017). Furthermore, several of the studies did not include random treatment assignment and the pharmaceutical formulations of the substances were sometimes different (intravenous vs. oral administration of the drugs) (Liechti, 2017). It would also be of advantage to address potential difficulties of these pharmacological neuroimaging studies in a more consistent manner. For example, it would be desirable to report both absolute and relative changes in CBF or to implement specific procedures in data acquisition for potential confounding factors.
REFERENCES Borghammer, P., Cumming, P., Aanerud, J., Gjedde, A., 2009. Artefactual subcortical hyperperfusion in PET studies normalized to global mean: lessons from Parkinson’s disease. NeuroImage 45, 249–257.
15
ARTICLE IN PRESS 16
Advances and challenges in neuroimaging studies
Carhart-Harris, R.L., Erritzoe, D., Williams, T., Stone, J.M., Reed, L.J., Colasanti, A., Tyacke, R.J., Leech, R., Malizia, A.L., Murphy, K., Hobden, P., Evans, J., Feilding, A., Wise, R.G., Nutt, D.J., 2012. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc. Natl. Acad. Sci. U.S.A. 109, 2138–2143. Carhart-Harris, R.L., Leech, R., Erritzoe, D., Williams, T.M., Stone, J.M., Evans, J., Sharp, D.J., Feilding, A., Wise, R.G., Nutt, D.J., 2013. Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis. Schizophr. Bull. 39, 1343–1351. Carhart-Harris, R.L., Kaelen, M., Bolstridge, M., Williams, T.M., Williams, L.T., Underwood, R., Feilding, A., Nutt, D.J., 2016a. The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychol. Med. 46, 1379–1390. Carhart-Harris, R.L., Muthukumaraswamy, S., Roseman, L., Kaelen, M., Droog, W., Murphy, K., Tagliazucchi, E., Schenberg, E.E., Nest, T., Orban, C., Leech, R., Williams, L.T., Williams, T.M., Bolstridge, M., Sessa, B., Mcgonigle, J., Sereno, M.I., Nichols, D., Hellyer, P.J., Hobden, P., Evans, J., Singh, K.D., Wise, R.G., Curran, H.V., Feilding, A., Nutt, D.J., 2016b. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc. Natl. Acad. Sci. U.S.A. 113, 4853–4858. Crossley, N.A., Mechelli, A., Scott, J., Carletti, F., Fox, P.T., McGuire, P., Bullmore, E.T., 2014. The hubs of the human connectome are generally implicated in the anatomy of brain disorders. Brain 137, 2382–2395. Daumann, J., Wagner, D., Heekeren, K., Neukirch, A., Thiel, C.M., Gouzoulis-Mayfrank, E., 2010. Neuronal correlates of visual and auditory alertness in the DMT and ketamine model of psychosis. J. Psychopharmacol. 24, 1515–1524. De Araujo, D.B., Ribeiro, S., Cecchi, G.A., Carvalho, F.M., Sanchez, T.A., Pinto, J.P., De Martinis, B.S., Crippa, J.A., Hallak, J.E., Santos, A.C., 2012. Seeing with the eyes shut: neural basis of enhanced imagery following Ayahuasca ingestion. Hum. Brain Mapp. 33, 2550–2560. Dolder, P.C., Schmid, Y., Steuer, A.E., Kraemer, T., Rentsch, K.M., Hammann, F., Liechti, M.E., 2017. Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects. Clin. Pharmacokinet. 56, 1219–1230. Dos Santos, R.G., Osorio, F.L., Crippa, J.A., Hallak, J.E., 2016. Classical hallucinogens and neuroimaging: a systematic review of human studies: hallucinogens and neuroimaging. Neurosci. Biobehav. Rev. 71, 715–728. Ferrarelli, F., Tononi, G., 2011. The thalamic reticular nucleus and schizophrenia. Schizophr. Bull. 37, 306–315. Fierstra, J., Sobczyk, O., Battisti-Charbonney, A., Mandell, D.M., Poublanc, J., Crawley, A.P., Mikulis, D.J., Duffin, J., Fisher, J.A., 2013. Measuring cerebrovascular reactivity: what stimulus to use? J. Physiol. 591, 5809–5821. Friston, K.J., 2011. Functional and effective connectivity: a review. Brain Connect. 1, 13–36. Geyer, M.A., Vollenweider, F.X., 2008. Serotonin research: contributions to understanding psychoses. Trends Pharmacol. Sci. 29, 445–453. Giraldo-Chica, M., Woodward, N.D., 2017. Review of thalamocortical resting-state fMRI studies in schizophrenia. Schizophr. Res. 180, 58–63. Gouzoulis-Mayfrank, E., Habermeyer, E., Hermle, L., Steinmeyer, A., Kunert, H., Sass, H., 1998. Hallucinogenic drug induced states resemble acute endogenous psychoses: results of an empirical study. Eur. Psychiatry 13, 399–406. Gouzoulis-Mayfrank, E., Schreckenberger, M., Sabri, O., Arning, C., Thelen, B., Spitzer, M., Kovar, K.A., Hermle, L., Bull, U., Sass, H., 1999. Neurometabolic effects of psilocybin, 3,4-methylenedioxyethylamphetamine (MDE) and d-methamphetamine
ARTICLE IN PRESS References
in healthy volunteers. A double-blind, placebo-controlled PET study with [18F]FDG. Neuropsychopharmacology 20, 565–581. Hasler, F., Grimberg, U., Benz, M.A., Huber, T., Vollenweider, F.X., 2004. Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebocontrolled dose-effect study. Psychopharmacology 172, 145–156. Hermle, L., Funfgeld, M., Oepen, G., Botsch, H., Borchardt, D., Gouzoulis, E., Fehrenbach, R.A., Spitzer, M., 1992. Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research. Biol. Psychiatry 32, 976–991. Hollister, L.E., Hartman, A.M., 1962. Mescaline, lysergic acid diethylamide and psilocybin comparison of clinical syndromes, effects on color perception and biochemical measures. Compr. Psychiatry 3, 235–242. Hollister, L.E., Sjoberg, B.M., 1964. Clinical syndromes and biochemical alterations following mescaline, lysergic acid diethylamide, psilocybin and a combination of the three psychotomimetic drugs. Compr. Psychiatry 5, 170–178. Jones, E., 2007. The Thalamus. Cambridge University Press, New York. Kaelen, M., Roseman, L., Kahan, J., Santos-Ribeiro, A., Orban, C., Lorenz, R., Barrett, F.S., Bolstridge, M., Williams, T., Williams, L., Wall, M.B., Feilding, A., Muthukumaraswamy, S., Nutt, D.J., Carhart-Harris, R., 2016. LSD modulates musicinduced imagery via changes in parahippocampal connectivity. Eur. Neuropsychopharmacol. 26, 1099–1109. Khalili-Mahani, N., Chang, C., Van Osch, M.J., Veer, I.M., Van Buchem, M.A., Dahan, A., Beckmann, C.F., Van Gerven, J.M., Rombouts, S.A., 2013. The impact of “physiological correction” on functional connectivity analysis of pharmacological resting state fMRI. NeuroImage 65, 499–510. Klaassens, B.L., van Gorsel, H.C., Khalili-Mahani, N., van der Grond, J., Wyman, B.T., Whitcher, B., Rombouts, S.A., van Gerven, J.M., 2015. Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity. NeuroImage 122, 440–450. Kraehenmann, R., Preller, K.H., Scheidegger, M., Pokorny, T., Bosch, O.G., Seifritz, E., Vollenweider, F.X., 2015. Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Biol. Psychiatry 78, 572–581. Lewis, C.R., Preller, K.H., Kraehenmann, R., Michels, L., Staempfli, P., Vollenweider, F.X., 2017. Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow. NeuroImage 159, 70–78. Liechti, M.E., 2017. Modern clinical research on LSD. Neuropsychopharmacology 42, 2114–2127. Lisman, J.E., Pi, H.J., Zhang, Y., Otmakhova, N.A., 2010. A thalamo-hippocampal-ventral tegmental area loop may produce the positive feedback that underlies the psychotic break in schizophrenia. Biol. Psychiatry 68, 17–24. Mueller, F., Lenz, C., Dolder, P.C., Harder, S., Schmid, Y., Lang, U.E., Liechti, M.E., Borgwardt, S., 2017a. Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl. Psychiatry 7, e1084. Mueller, F., Lenz, C., Dolder, P.C., Lang, U.E., Schmidt, A., Liechti, M.E., Borgwardt, S., 2017b. Increased thalamic resting state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr. Scand. 136, 648–657. M€uller, F., Dolder, P.C., Schmidt, A., Liechti, M.E., Borgwardt, S., 2018. Altered network hub connectivity after acute LSD administration. NeuroImage 18, 694–701.
17
ARTICLE IN PRESS 18
Advances and challenges in neuroimaging studies
Palhano-Fontes, F., Andrade, K.C., Tofoli, L.F., Santos, A.C., Crippa, J.A., Hallak, J.E., Ribeiro, S., de Araujo, D.B., 2015. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. PLoS One 10, e0118143. Parent, A., Hazrati, L.N., 1995. Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop. Brain Res. Brain Res. Rev. 20, 91–127. Pinault, D., 2011. Dysfunctional thalamus-related networks in schizophrenia. Schizophr. Bull. 37, 238–243. Poldrack, R.A., Baker, C.I., Durnez, J., Gorgolewski, K.J., Matthews, P.M., Munafo, M.R., Nichols, T.E., Poline, J.B., Vul, E., Yarkoni, T., 2017. Scanning the horizon: towards transparent and reproducible neuroimaging research. Nat. Rev. Neurosci. 18, 115–126. Power, J.D., Mitra, A., Laumann, T.O., Snyder, A.Z., Schlaggar, B.L., Petersen, S.E., 2014. Methods to detect, characterize, and remove motion artifact in resting state fMRI. NeuroImage 84, 320–341. Preller, K.H., Herdener, M., Pokorny, T., Planzer, A., Kraehenmann, R., Stampfli, P., Liechti, M.E., Seifritz, E., Vollenweider, F.X., 2017. The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation. Curr. Biol. 27, 451–457. Riba, J., Romero, S., Grasa, E., Mena, E., Carrio, I., Barbanoj, M.J., 2006. Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant. Psychopharmacology 186, 93–98. Rickli, A., Moning, O.D., Hoener, M.C., Liechti, M.E., 2016. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur. Neuropsychopharmacol. 26, 1327–1337. Roseman, L., Leech, R., Feilding, A., Nutt, D.J., Carhart-Harris, R.L., 2014. The effects of psilocybin and MDMA on between-network resting state functional connectivity in healthy volunteers. Front. Hum. Neurosci. 8, 204. Schaefer, A., Burmann, I., Regenthal, R., Arelin, K., Barth, C., Pampel, A., Villringer, A., Margulies, D.S., Sacher, J., 2014. Serotonergic modulation of intrinsic functional connectivity. Curr. Biol. 24, 2314–2318. Schmid, Y., Enzler, F., Gasser, P., Grouzmann, E., Preller, K.H., Vollenweider, F.X., Brenneisen, R., Muller, F., Borgwardt, S., Liechti, M.E., 2015. Acute effects of lysergic acid diethylamide in healthy subjects. Biol. Psychiatry 78, 544–553. Schmidt, A., Muller, F., Lenz, C., Dolder, P.C., Schmid, Y., Zanchi, D., Lang, U.E., Liechti, M.E., Borgwardt, S., 2017. Acute LSD effects on response inhibition neural networks. Psychol. Med. 1–13. Spain, A., Howarth, C., Khrapitchev, A.A., Sharp, T., Sibson, N.R., Martin, C., 2015. Neurovascular and neuroimaging effects of the hallucinogenic serotonin receptor agonist psilocin in the rat brain. Neuropharmacology 99, 210–220. Tagliazucchi, E., Roseman, L., Kaelen, M., Orban, C., Muthukumaraswamy, S.D., Murphy, K., Laufs, H., Leech, R., Mcgonigle, J., Crossley, N., Bullmore, E., Williams, T., Bolstridge, M., Feilding, A., Nutt, D.J., Carhart-Harris, R., 2016. Increased global functional connectivity correlates with LSD-induced ego dissolution. Curr. Biol. 26, 1043–1050. van den Heuvel, M.P., Sporns, O., 2011. Rich-club organization of the human connectome. J. Neurosci. 31, 15775–15786. van den Heuvel, M.P., Sporns, O., 2013. Network hubs in the human brain. Trends Cogn. Sci. 17, 683–696.
ARTICLE IN PRESS References
Vollenweider, F.X., Leenders, K.L., Scharfetter, C., Maguire, P., Stadelmann, O., Angst, J., 1997. Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis. Neuropsychopharmacology 16, 357–372. Winkelman, M.J., 2017. The mechanisms of psychedelic visionary experiences: hypotheses from evolutionary psychology. Front. Neurosci. 11, 539. Wise, R.G., Tracey, I., 2006. The role of fMRI in drug discovery. J. Magn. Reson. Imaging 23, 862–876.
19