This re-analysis study (n=20) investigated the impact of acute LSD (75μg) administration on thalamocortical connectivity in healthy volunteers. The study utilized structural and resting-state fMRI to examine the thalamus at the nucleus-specific level. LSD intake was found to increase functional connectivity between the thalamus's ventral complex, pulvinar, and non-specific nuclei, particularly with sensory cortices such as somatosensory and auditory networks, as well as parts of the associative cortex dense in serotonin type 2A receptors. The study also reported decreased connectivity between the striatum and thalamus.
The role of the thalamus in mediating the effects of lysergic acid diethylamide (LSD) was recently proposed in a model of communication and corroborated by imaging studies. However, a detailed analysis of LSD effects on nuclei-resolved thalamocortical connectivity is still missing. Here, in a group of healthy volunteers, we evaluated whether LSD intake alters the thalamocortical coupling in a nucleus-specific manner. Structural and resting-state functional Magnetic Resonance Imaging (MRI) data were acquired in a placebo-controlled study on subjects exposed to acute LSD administration. Structural MRI was used to parcel the thalamus into its constituent nuclei based on individual anatomy. Nucleus-specific changes of resting-state functional MRI (rs-fMRI) connectivity were mapped using a seed-based approach. LSD intake selectively increased the thalamocortical functional connectivity (FC) of the ventral complex, pulvinar, and non-specific nuclei. Functional coupling was increased between these nuclei and sensory cortices that include the somatosensory and auditory networks. The ventral and pulvinar nuclei also exhibited increased FC with parts of the associative cortex that are dense in serotonin type 2A receptors. These areas are hyperactive and hyper-connected upon LSD intake. At subcortical levels, LSD increased the functional coupling among the thalamus's ventral, pulvinar, and non-specific nuclei, but decreased the striatal-thalamic connectivity. These findings unravel some LSD effects on the modulation of subcortical-cortical circuits and associated behavioral outputs.
Papers cited by this study that are also in Blossom
Avram, M., Rogg, H., Korda, A. et al. · Frontiers in Psychiatry (2021)
Avram, M., Müller, F., Rogg, H. et al. · Biological Psychiatry (2022)
Carhart-Harris, R. L., Leech, R., Erritzoe, D. et al. · Schizophrenia Bulletin (2012)
Carhart-Harris, R. L., Muthukumaraswamy, S., Roseman, L. et al. · PNAS (2016)
LSD (lysergic acid diethylamide) is a classical psychedelic that disrupts perception and consciousness and has renewed research interest for both basic neuroscience and potential therapeutic applications. Previous human neuroimaging work implicates subcortical structures, and in particular the thalamus, in psychedelic effects: resting-state studies report altered thalamocortical functional connectivity with primary sensory cortices, and dynamic causal modelling suggests LSD reduces striato-thalamic inhibition while enhancing thalamo-cortical excitation. A complication for interpreting these findings is that the thalamus is heterogeneous, comprising multiple first-order and higher-order nuclei with distinct cortical targets and roles in sensory relay, cortico-cortical communication, arousal and cortico-striatal loops, and it is unclear whether LSD effects are widespread or nucleus-specific. Delli Pizzi and colleagues set out to test whether acute LSD alters thalamocortical functional coupling in a nucleus-specific manner. Using subject-specific thalamic parcellation derived from structural MRI and seed-based resting-state fMRI analysis mapped to Yeo’s cortical network parcellation, the study examined nucleus-by-network modulations of connectivity after intravenous LSD (75 μg) versus placebo in healthy volunteers. The authors also tested subcortical interactions within the thalamus and between thalamic nuclei and the striatum to identify nuclei showing LSD-induced changes in subcortical connectivity.
This work re-analysed previously collected placebo-controlled MRI data. Twenty healthy volunteers with prior psychedelic experience underwent two 3T MRI sessions 14 days apart, receiving either placebo (10 mL saline) or a 75 μg dose of LSD in 10 mL saline delivered intravenously over 2 minutes. The infusion occurred 115 minutes before resting-state scanning. Of three resting-state scans acquired, the analysis used the first scan taken with eyes closed and without music. One participant aborted for anxiety and four were excluded for excessive head motion (>15% of volumes with frame-wise displacement >0.5 mm), leaving 15 subjects for the main analyses. Subjective effects were recorded using visual analogue scales during scanning and the Altered States of Consciousness (ASC) scale retrospectively. Structural T1-weighted images were processed with FreeSurfer 7.3, including the segmentThalamicNuclei.sh routine to derive a subject-specific thalamic parcellation. The initial segmentation produced fifty nuclei (25 per hemisphere), which were merged into thirteen thalamic subfields for resting-state analysis. Functional preprocessing discarded the first four volumes, applied motion and slice-timing correction, and used ICA-AROMA to remove motion-related components. Physiological confounds were reduced by regressing ventricular and white-matter signals (top five WM principal components); global signal regression was not performed. Temporal band-pass filtering (0.01–0.1 Hz) and volume censoring (scrubbing of volumes with FD>0.5 mm) were applied. Cortical time series were sampled to fsaverage surfaces, while thalamic nuclei and striatal region time series were extracted from subject-specific subcortical volumes. Functional connectivity was estimated with seed-based Pearson correlations between each thalamic seed and all brain voxels, transformed to z-scores and averaged within Yeo’s 17 cortical networks adapted to individual anatomy. Subcortical analyses correlated averaged time series among thalamic and striatal regions (nucleus accumbens, caudate, putamen). Statistical testing used LSD-minus-placebo contrasts. For thalamocortical analyses, one-sample ANOVAs tested LSD effects for each thalamic region with Bonferroni correction across thirty-four cortical targets. An exploratory subcortical analysis reduced the thalamic search space into two clusters (A: nuclei showing cortical changes; B: nuclei without cortical changes) and used repeated-measures ANOVAs to assess within- and between-cluster thalamic connectivity and one-sample ANOVAs for thalamo-striatal effects. Because mean head motion was slightly higher under LSD, the authors also checked whether FC changes correlated with mean FD across subjects.
After exclusions, 15 participants contributed to the analyses. Under placebo, thalamocortical coupling patterns matched established anatomy. LSD produced nucleus-specific modulations rather than a uniform thalamic effect. The main thalamic regions showing altered cortical connectivity were first-order ventral nuclei (VLa and the ventroposterior, VP, complex), the anterior/lateral pulvinar (PuA, PuL), and the intralaminar/non-specific (IT) complex. Key nucleus-by-network findings reported include: increased functional connectivity (FC) of the ventrolateral (VLa) region with the Default Mode Network (DMN) (p=0.025) and polarity changes in the auditory network (p=0.034); the VP complex showed increased FC with the DMN (p=0.02) and polarity changes in the auditory network (p=0.034). The IT complex and PuA exhibited altered FC with limbic networks (p=0.050). The lateral pulvinar (PuL) showed increased FC with the DMN (p=0.004) and bilateral increases with the auditory network (left p=0.004; right p=0.008), together with decreased FC with the frontoparietal control network. The mediodorsal medial subdivision (MDm) displayed increased coupling with the auditory cortex (p=0.002) but no significant change with the DMN. For all significant FC modulations, linear regressions with mean frame-wise displacement across subjects were not significant, suggesting motion did not drive the reported effects. At the subcortical level, LSD increased FC strength within thalamic subfields that showed cortical modulation (Cluster A: mean±SD 0.64±0.32, p<0.001), and also within subfields without cortical changes (Cluster B: 0.49±0.19, p<0.001) and between clusters (0.31±0.21, p<0.001). The within-cluster increase was significantly larger in Cluster A than Cluster B (p=0.002) and trended larger versus intercluster connectivity (p=0.09), supporting spatial specificity. Conversely, LSD reduced thalamo-striatal connectivity for both clusters (Cluster A mean±SD -0.56±0.17, t14=12.958, p<0.001; Cluster B -0.44±0.16, t14=10.414, p<0.001), with a significantly greater reduction for Cluster A (t14=-6.671, p<0.001).
Delli Pizzi and colleagues interpret their results as evidence that LSD induces spatially specific changes in thalamocortical and intra-thalamic functional connectivity, with a notable emphasis on ventral (first-order) nuclei and the intralaminar/non-specific complex rather than a uniform effect across all thalamic subdivisions. The VLa and VP complexes showed altered coupling with sensorimotor and auditory networks, while PuA, PuL and IT nuclei also exhibited distinctive modulations. The MD nucleus did not show a robust change with the DMN at corrected thresholds, though uncorrected results suggested MD modulation with auditory cortex. The authors relate these findings to the cortico-striatal-thalamo-cortical (CSTC) model: LSD may reduce thalamic filtering through altered prefrontal–striatal–thalamo circuits and serotonin 5-HT2A receptor-mediated changes, producing an overflow of sensory information to cortex that plausibly contributes to perceptual disturbances such as synesthesia and hallucinations. Increased intra-thalamic coupling and decreased thalamo-striatal connectivity were stronger for nuclei that also showed thalamocortical modulation, reinforcing the idea of nucleus-specific circuit effects. The observed pattern suggests that some previously reported widespread cortical hyper-connectivity under psychedelics might reflect direct cortical 5-HT2A effects together with selective thalamic contributions. The authors note several limitations they acknowledge: the modest sample size (n=15 after exclusions) limits statistical power; the spatial resolution of 3T rs-fMRI precluded reliable assessment of very small thalamic structures such as the medial geniculate nucleus (MGN); and partial volume/time-series mixing between adjacent nuclei may influence results despite seeds containing at least six fMRI voxels. They also highlight concordance between placebo-condition functional coupling and known anatomical connectivity as supportive of the parcellation approach. Finally, the authors suggest future work should use larger samples, higher-resolution imaging, and examine whether similar nucleus-specific thalamic effects occur with other psychedelic compounds and what implications these processes may have for neuropsychiatric treatment and for models of psychosis.
The study provides new, anatomy-informed evidence that acute LSD administration modulates thalamocortical and intra-thalamic functional connectivity in a nucleus-specific manner. Specific ventral and non-specific thalamic nuclei appear to mediate changes in sensory and associative network coupling that could contribute to the perceptual and experiential effects of LSD. The authors recommend further studies to determine whether these thalamic mechanisms generalise across other psychedelics and to explore potential relevance for neuropsychiatric disorders.
All the reported statistical tests are two-tailed. LSD effects were estimated from FC differences between the two conditions (LSD-PCB). For the analyses examining the connectivity of the thalamic seeds with the cortical networks, one-sample ANOVAs were used to assess the presence of a significant effect of LSD for each thalamic region. Considering the inclusion of thirty-four cortical targets in the model, the Bonferroni correction was applied to account for multiple comparisons. We also performed an exploratory analysis to assess the effect of LSD on subcortical interactions. To increase statistical power, we performed a reduction of the search space by subdividing the thalami into two clusters based on the results of the previous analysis [thalamic regions that changed (A) or did not change (B) their connectivity with the cortex]. A within-thalamus analysis assessed the presence of a significant effect of LSD on within-cluster (A, B) and between-cluster (A-B) connectivity, using one-sample repeated-measures ANOVAs. A thalamo-striatal analysis assessed the presence of a significant effect of LSD between the two thalamic clusters (A, B) and the striatum, using one-sample ANOVAs. .
In the present study, we conducted a comprehensive analysis of the spatial modulation of thalamocortical connectivity induced by LSD, through the parcellation of thalamic nuclei based on individual anatomy and the assessment of nucleus-specific connectivity with cortical resting-state networks. Upon placebo, the overall pattern of thalamocortical connectivity was in line with previous studies that assessed the functional connections of thalamic subregions with the cortex. We found that LSD modifies the connectivity of the first-order VLa and VP complex, the high-order PuA nucleus, and the IT complex. While the VLa complex enhanced FC with the sensorimotor network, the three other nuclei displayed altered FC with the auditory network. The administration of LSD also resulted in increased subcortical FC within the thalamus and a reduction of FC between the thalamus and the striatum. These effects were stronger for the nuclei that also exhibited a modulation of thalamocortical connectivity. The present findings are partially consistent with the results of a recent study that has attempted to disentangle the effect of LSD on different thalamic nuclei. Our study differs as we did not limit the analysis to interactions that involve only two cortical networks. By expanding the analysis to all the main resting-state networks and evaluating anatomically defined thalamic seeds, we also revealed LSD effects on the functional connectivity between the ventral thalamic nuclei and auditory-somatomotor networks. However, unlike the work by Avram and colleagues, we found a modulation of the anterior, rather than medial, pulvinar FC. We also failed to see a statistically significant modulation of FC involving the mediodorsal nucleus. While this latter result might reflect the use of a more stringent statistical threshold, uncorrected results indicate that the MD nucleus modulates its connectivity with the auditory cortex, rather than with the salience or the DMN, as might have been expected. The present study also provides evidence for the involvement of the IT nuclei. This result fits better with the prediction of the CSTC model, according to which these nuclei are responsible, along with the ventral nuclei, for the altered filtering of peripheral information caused by LSD. Overall, the present findings are consistent with the idea that psychedelics affect thalamocortical connectivity by altering the thalamic gating of sensory inputs. On the other hand, our results do not provide much support for the crucial involvement of high-order nuclei (i.e., the MD and the medial pulvinar) in the shaping of associative cortical-cortical interactions. We, therefore, propose that the widespread effect of LSD on the connectivity of the DMN and frontoparietal networks, indicated by previous studies, is the likely consequence of a direct LSD influence on cortical serotonin receptors located in these cortical regions. This idea is also consistent with the limited expression of serotonin receptors in subcortical compared to cortical structures. This suggests that the thalamus is indirectly affected by LSD through top-down cortico-thalamic connections. The most straightforward result of the present study is the altered FC modulation between first-order VLa (FC increase) and VP (polarity changes) complexes with the sensorimotor and auditory networks. On the one hand, lesion studiesindicate that the VL complex is not only involved in motor controlbut also in sensory processing. Specifically, small lesions restricted to the VL region cause a reorganization of thalamocortical connectivity that enhances excitatory connections between the auditory and somatosensory cortex. The process generates synesthesia and sensory input overflow to the cortex. On the other hand, the VP complex is part of the somatosensory system and has been defined as the "sensory thalamus". Of note, the inferior VP portion, via projections to the primary vestibular cortex, relays vestibule-cortical information. Both lines of evidence support the hypothesis that altered FC of the ventral nuclei contributes to the perceptual effects of psychedelics, through a process leading to erroneous multisensory integration and processing by the primary cortex, which, in turn, becomes flooded with unfiltered inputs originated by the thalamus. Another result that fits with the prediction stemming from the CSTC model is the significant modulation of connectivity patterns of the IT complex. The IT nuclei, long thought to be a non-specific arousing system in the brain, have been more recently also associated with sensory processing. The paraventricular thalamic nucleus, in particular, is implicated in awareness of viscerosensory stimuliwhile the centromedian-parafascicular (CM/Pf) complex exhibits reciprocal connections with the superior temporal area involved in auditory processing. Specifically, the CM-Pf receives inputs from the auditory cortex and sends outputs back to the cortex, suggesting an involvement in the integration of auditory stimuli in the processing of multimodal sensory information. These anatomical connections mirror the positive functional coupling that we observed, under a placebo, between the IT complex and both the sensorimotor and auditory networks. Herein, we found a significant increase in IT complex FC with the auditory network and a trend toward a significant disconnection with the limbic system. While the former effect could be considered as further evidence to disentangle the sensorial misperception under psychedelic experience, the altered FC with the limbic network could be relevant in the context of mood disorders. In that respect, the IT complex, and especially the paraventricular nucleus, has been found to receive inputs from regions closely implicated in arousal and emotional processing. Thus, the LSD-induced modulation of IT connectivity could offer promising options for the treatment of mood disorders. An additional finding of the present study concerns the effect of LSD on the FC modulation of the PuA nucleus. This nucleus is critically involved in somatosensory processing and proprioception. The PuA exhibits anatomical connections with the primary somatosensory areas, the superior (area 5) and inferior (area 7b) somatosensory association cortices, and the lateral parietal cortex. In line with these structural data, we have shown that, under placebo intake, the PuA nucleus displays functional connections with the somatosensory/parietal components of associative cortices (i.e., the dorsal attention, salience/ventral attention, and sensorimotor networks). While these connections remain stable under LSD, we found an FC disconnection of the PuA nucleus with the auditory cortex. Neuro-anatomical tracer studies indicated that labeled cells from auditory cortex injections are commonly found within the PuA. Moreover, the altered FC of PuA with the auditory cortex could have a behavioral relevance. Recent studies indicated that a correlation between atrophy of the PuA and persistent auditory hallucinations occurs in persons with schizophrenia. The cortical targets of LSD-driven increased thalamocortical FC are areas that mainly include the sensorimotor and auditory networks. Behavioral investigations have demonstrated physiological perceptual interactions between the auditory and somatosensory modalities. Likewise, MRI studies have proposed the existence of highly tuned multisensory integration processes for gathering coherent somatosensory and auditory stimuli from the environment. These studies have also revealed the activation of the secondary somatosensory cortex in response to sound. To explain this phenomenon, it has been hypothesized that auditory stimuli first evoke activity in the auditory cortex, and the activity then spreads via cortico-cortical connections to the somatosensory cortex. Notably, the sensory cortices are specific targets of LSD-driven functional hyper-connectivity with the whole thalamus. Moreover, the alteration of these thalamocortical connections is associated with subjective visual and auditory misperceptions. Finally, LSD, via direct modulation of 5HT 2A receptors, increases the sensitivity to auditory stimuli from the dorsal cochlear nucleus (Tang and Trussell 2015) along the primary auditory pathway (Hurley 2006; Hurley and Sullivan 2012) to the primary auditory cortex. LSD also alters intrinsic FC in primary auditory areas and attenuates the top-down suppression of prediction errors in response to auditory stimuli. At the subcortical level, LSD increased the functional coupling between VLa/VP, PuA, and non-specific thalamic nuclei but decreased striatal-thalamic connectivity. The ventral nuclei also showed increased connectivity with parts of the associative cortex that are rich in 5-HT 2A receptors as well as hyperactive and hyper-connected upon LSD intake. From a physiological standpoint, the thalamic filtering of incoming external/internal stimuli is regulated through 5-HT 2A receptors within the dorsal raphe and prefrontal regions (Figure, panel A). Specifically, ascending serotoninergic projection from the dorsal raphe and descending glutamatergic projections from the prefrontal associative areas regulate, directlyor through the striatum, the activity of ventral and non-specific thalamic nuclei. While the ventral and IT nuclei selectively target the primary sensory cortex, the IT complex also exerts a feedback modulation of the striatum. In particular, several studies have reported that the CM nucleus modulates the sensorimotor striatum (i.e., putamen), whereas the Pf regulates the limbic/associative striatum (i.e., the nucleus accumbens, caudate) and pallidum. Therefore, we propose that, under LSD, the binding on 5-HT 2A promotes increased excitatory neurotransmission along the prefrontal striatum and dorsal raphe-striatum projections (Figure, panel B). This process, besides activating glutamatergic neurons that directly descend to the thalamus, also triggers the activity of GABA-ergic interneurons connecting the ventral/dorsal striatum to the pallidum and the pallidum to the ventral and non-specific thalamic nuclei. The process generates a downregulation of thalamic filtering and an overflow of sensory stimuli to the cortex. Our results contribute to understanding the neurobiological processes occurring upon the production of psychotic symptoms. Indeed, although thalamocortical dysrhythmia has been proposed as a key factor promoting psychosis in neurological and psychiatric disorders, the individual contribution of different thalamic nuclei to these processes is still poorly understood. Notably, the present data did not find a major effect of LSD on LGN activity, a phenomenon associated with hallucinations. However, we observed an interesting trend toward a significant increased FC between the PuL nucleus and the DMN, thereby suggesting a possible involvement of aberrant connectivity along this pathway in the generation of visual hallucinations. The PuL, together with the PuI, constitutes the "visual pulvinar", an associative thalamic complex that actively relays and critically integrates the flux of visual stimuli to multimodal areas. Structural alterations of the visual pulvinar and its projections to the posterior cortical areas have also been associated with the presence of visual hallucinations in dementia with Lewy bodies. On the other hand, increased FC within the DMN has been associated with the occurrence of visual hallucinations in Parkinson's diseaseand during psychedelic experiences induced by LSD intake. Our study presents some limitations. First, the sample size is relatively small, and our findings must be confirmed with larger datasets. This issue reflects the difficulty of collecting data from healthy subjects undergoing LSD administration because the protocol requires rigid inclusion/exclusion criteria and complex management of the data collection. Second, the investigation of whether LSD modulates the thalamocortical FC of the medial geniculate nucleus (MGN), a portion of the auditory thalamus acting as a relay station between the inferior colliculus and the auditory cortex is not allowed due to intrinsic limitation of the resolution of the MRI data. The MGN is too small in size to be covered by a sufficient number of rs-fMRI voxels in a seed-based approach and higher resolution information will be needed for further studies. Third, we recognize that the spatial resolution of the rs-fMRI images acquired with a 3T scanner inherently constrains the measure of thalamocortical functional connections and that the time series from adjacent nuclear regions may impinge on our results. However, the smaller seeds used for the FC analyses consist of at least 6 fMRI voxels. Moreover, we would also highlight the good correspondence between the known anatomic connections of thalamic nucleiand the functional coupling of seeds with the cortex that we observed under the placebo condition. Consistent with our prediction, in the placebo condition, the mediodorsal nuclei displayed positive functional coupling with the DMN. The inferior/lateral pulvinar nuclei were positively coupled with the attention and sensory networks. The medial pulvinar and LGN, respectively, exhibited positive functional coupling with the DMN and visual network.
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