Bridging the Gap? Altered Thalamocortical Connectivity in Psychotic and Psychedelic States

Psychiatric research has long compared drug-induced experiences to psychotic symptoms because both involve altered perceptions and other neurocognitive changes. Classic serotonergic psychedelics (for example, psilocybin, DMT and LSD) produce altered states of consciousness by acting mainly at 5-HT2A receptors, eliciting phenomena such as visual hallucinations, ego-dissolution and other transient changes in perception and cognition. Psychotic states—acute phases of psychotic disorders—are characterised by impaired reality testing, more prominent auditory hallucinations and broader, often longer-lasting cognitive and negative symptoms. A theoretical account put forward to explain some shared features is the “thalamic filter” model, which proposes that disruptions in thalamic gating of sensory information—modulated by cortico‑striatal pathways and diverse neuromodulators—could produce sensory flooding and related symptoms in both conditions. This review by Selvaggi and colleagues examines recent neurobiological evidence for altered thalamocortical functional connectivity in psychotic and psychedelic states. The paper aims to compare and synthesise findings from human neuroimaging, animal work and multimodal studies to determine shared versus distinct patterns of thalamocortical dysconnectivity, to consider extensions to cortico‑striato‑pallido‑thalamo‑cortical (CSPTC) circuitry, and to outline clinical implications and directions for future research.

The extracted text does not present a dedicated Methods section that specifies search strategy, inclusion/exclusion criteria or formal meta-analytic methods. The paper therefore reads as a narrative synthesis of recent human and animal studies rather than as a systematic review with a reproducible search protocol. To assemble evidence the authors summarise multiple types of investigations: resting-state fMRI (rsfMRI) seed‑based functional connectivity studies that use the thalamus as a seed, ROI-to-ROI and ROI-to-voxel correlation analyses, global correlation approaches, effective connectivity analyses using spectral dynamic causal modelling, diffusion-based structural connectivity (DTI/DWI) studies, PET/SPECT metabolic and molecular imaging, and relevant animal electrophysiology. Many of the neuropharmacological rsfMRI studies reviewed used crossover designs (drug vs placebo, sometimes with receptor blockade such as ketanserin) in healthy volunteers. Clinical studies included individuals across stages of psychosis (clinical high risk, first-episode, established schizophrenia and bipolar disorder) and, where reported, unaffected relatives. The authors pay particular attention to studies that probe 5-HT2A dependence (e.g., LSD + ketanserin experiments) and to studies that relate connectivity changes to subjective perceptual measures.

Anatomical and functional context: The thalamocortical system consists of topographically organised reciprocal connections between cortical regions and thalamic nuclei. First-order nuclei relay peripheral/subcortical input to primary sensory and motor cortices, while higher-order nuclei support cortico‑cortical communication. Functional connectivity measured with rsfMRI captures slow co-fluctuations in these networks and abnormalities are described as dysconnectivity. Psychotic states: Across a large body of in vivo imaging work, a consistent functional connectivity pattern emerges in psychotic states: (i) hyperconnectivity between the thalamus and sensorimotor cortical regions (motor, temporal, occipital), often localised to ventral lateral/posterior thalamic nuclei, and (ii) hypoconnectivity between the thalamus and prefrontal (and cerebellar) regions, frequently implicating mediodorsal/anterior nuclei. The sensorimotor hyperconnectivity has been associated with psychotic symptoms and, in some studies, predicts transition to psychosis in clinical high-risk samples. Prefrontal hypoconnectivity correlates with cognitive disturbances. Structural DTI/DWI studies report a parallel pattern of reduced thalamo‑prefrontal and increased thalamo‑sensorimotor structural connectivity in patients, and altered patterns have also been reported in unaffected siblings for some measures. Multimodal evidence links these functional patterns to dopaminergic abnormalities: a fluorodopa PET–rsfMRI study found associations between dopamine synthesis/storage and thalamic hypo‑ and hyperconnectivity with prefrontal and sensorimotor areas respectively. Overall, in psychotic disorders thalamocortical dysconnectivity appears embedded in larger CSPTC circuit alterations. Psychedelic states: Human rsfMRI pharmacological studies—most notably using LSD and psilocybin in crossover designs—report increased thalamic functional connectivity with sensorimotor and primary sensory cortices after psychedelic administration. Specific findings include increased thalamus–task‑positive network connectivity after psilocybin, increased thalamus–primary sensory cortex connectivity after LSD and widespread increases in thalamic coupling across many ROIs following LSD. Müller et al. additionally reported increased basal ganglia connectivity with the rest of the brain under LSD, suggesting CSPTC involvement. Several studies found that 5-HT2A blockade with ketanserin both abolished LSD-induced subjective effects and prevented many of the connectivity changes, supporting 5-HT2A dependence. An effective connectivity study using spectral dynamic causal modelling reported LSD-related increases in thalamus→posterior cingulate connectivity and decreases in PCC→thalamus, plus a 5-HT2A-independent decrease in ventral striatum→thalamus, consistent with striatal disinhibition. Thalamic hyperconnectivity under psychedelics correlated with subjective measures of altered vision and audition (e.g., subscales of the 5D‑ASC). Parallel findings from acute ketamine studies (NMDA antagonism) also report thalamocortical hyperconnectivity with temporal and sensorimotor cortices and transient psychotic-like symptoms. Comparative patterns and constraints: The shared signal across both conditions is thalamic hyperconnectivity with sensorimotor cortices, linked to altered perceptions. However, a prominent feature of psychotic states—thalamocortical hypoconnectivity with prefrontal cortices and corresponding structural disorganisation—has not been observed in the psychedelic rsfMRI literature reviewed. Thalamocortical hyperconnectivity in psychedelic studies is transient and can be blocked by ketanserin, whereas in psychotic states the pattern is more stable and may represent a trait/ vulnerability marker as well as a state marker. The authors note methodological caveats: LSD-dominated data in the psychedelic literature, heterogeneous analytic pipelines (including controversial preprocessing steps such as global signal regression), and potential confounding effects of antipsychotic medication in clinical samples, although altered connectivity has been reported in some unmedicated high-risk and drug‑naive patients.

Selvaggi and colleagues interpret the convergent observation of thalamic hyperconnectivity with sensorimotor cortices in psychotic and psychedelic states as evidence for a shared biological mechanism contributing to abnormal perception. They propose that dysregulation within CSPTC loops—modulated by serotonergic, dopaminergic and glutamatergic systems—can alter thalamic gating and thereby produce sensory flooding or altered perceptual experiences. Evidence supporting neuromodulatory contributions includes PET associations with dopamine synthesis in psychosis and the blockade of LSD effects by the 5-HT2A antagonist ketanserin. The authors situate these findings within predictive coding frameworks, contrasting a bottom‑up ‘‘thalamic filter’’ account (sensory flooding due to thalamic disinhibition) with top‑down explanations such as the REBUS model (relaxed high‑level priors under psychedelics). They note these accounts are not mutually exclusive because cortical layer V projections can modulate thalamic activity, allowing both top‑down and bottom‑up mechanisms to contribute. Key limitations and uncertainties are highlighted: the reviewed psychedelic literature is heavily weighted toward LSD, studies differ in preprocessing and connectivity metrics (which can affect results), and thalamocortical dysconnectivity is not unique to psychosis but also appears in bipolar disorder and to a lesser extent in depression. Medication effects remain a concern for clinical studies, though some unmedicated samples show similar dysconnectivity. For future work the authors recommend finer-grained mapping of thalamic subnuclei and their cortical connections (including voxel-wise cortical→thalamic analyses), greater use of directional/effective connectivity methods, cross-substance within-subject comparisons, and multimodal approaches to clarify neurotransmitter contributions. They conclude that while psychedelics reproduce at least some perceptual and neural features of psychosis—particularly thalamocortical hyperconnectivity with sensorimotor areas—further research is required to characterise overlapping and distinct mechanisms before valid psychedelic-based models of psychotic disorders can be established.