LSD-induced changes in the functional connectivity of distinct thalamic nuclei

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.