Classic and dissociative psychedelics induce similar hyper-synchronous states in the cognitive-limbic cortex-basal ganglia system

Brys and colleagues frame the study around two linked gaps in knowledge: first, how acute psychedelic states alter neuronal activity to produce profound changes in perception and cognition; and second, what common neural mechanisms, if any, exist across phenomenologically similar but pharmacologically distinct psychedelics. Earlier work shows classic psychedelics (for example LSD, DOI) primarily act via 5-HT2A receptors and dissociative psychedelics (ketamine, PCP) via NMDA antagonism, yet both classes have been associated with increased glutamatergic signalling in cortico-limbic networks. Prior electrophysiological evidence is sparse and partly contradictory: single-cell firing changes reported in awake animals differ between drug classes, while studies of local field potentials (LFPs) have repeatedly identified aberrant high-frequency oscillations (HFOs) after both ketamine and 5-HT2A agonists. It therefore remains uncertain which physiological signatures are specific to the psychedelic state and which reflect generic psychotropic effects such as altered locomotion or arousal. This study set out to identify neuronal activity patterns that are specific to the psychedelic state by recording single-unit firing and LFPs simultaneously from multiple cortico-limbic and basal ganglia structures in freely behaving rats. Classic psychedelics (LSD, DOI) and dissociative psychedelics (ketamine, PCP) were compared with a non-psychedelic psychostimulant control (amphetamine). The investigators aimed to determine whether (a) firing-rate changes or (b) population-level oscillatory phenomena best characterise the psychedelic state, and to map the spatial extent and inter-areal relationships of any psychedelic-specific oscillations.

Nine adult Sprague-Dawley rats were implanted with custom 128-wire microelectrode arrays and allowed at least two weeks of recovery. Electrode positions were verified post mortem in five animals using computed tomography; electrode tips received fifty unique anatomical labels that were subsequently grouped into ten broader regions by presumed functional similarity. Recordings targeted multiple cortical and subcortical areas implicated in cognitive processing, including olfactory bulb/cortex, ventral striatum, orbitofrontal cortex, medial prefrontal cortex and integrative thalamus. Animals were recorded in a round open-field arena. After about 60 minutes of baseline recording, each rat received an intraperitoneal injection of one of: LSD (0.3 mg/kg), DOI (2 mg/kg), ketamine (25–50 mg/kg), PCP (5 mg/kg) or d-amphetamine (4 mg/kg). Recordings continued for another 60–120 minutes. Baseline measures were averaged over −35 to −5 minutes relative to injection and on-drug measures over 30 to 60 minutes post-injection. Behaviour was scored from video for 1 minute every 10 minutes using ordinal prevalence ratings, and locomotion/centre occupancy were quantified from centroid tracking. Head-twitch responses (HTR) were detected with onboard accelerometers where available and by manual video scoring for recordings lacking accelerometry. Neural data acquisition used Neuralynx or OpenEphys/Intan systems to capture LFPs and single-unit activity. Spike sorting used hierarchical clustering with a 2 ms refractory-period constraint; units were classified into putative principal cells, interneurons or left unclassified when assignment probability was <0.75. To emphasise local sources, bipolar LFP time series were computed from electrode pairs within the same structure. The IRASA method separated rhythmic peaks from fractal background in power spectra, with least-squares fitting used to parametrically define peak height and frequency. Instantaneous phase and amplitude of HFOs were extracted by bandpass-filtering ±5 Hz around the median HFO frequency for each recording and applying the Hilbert transform. Amplitude auto- and cross-correlations and circular statistics (resultant vector lengths, mean phase differences) quantified co-modulation and phase relationships. Phase inversion between nearby electrodes was used as evidence for local current dipoles. Granger causality in the frequency domain was estimated from bipolar LFPs using BSMART routines with 500 ms windows and model order 5; total Granger causality between regions was summarised as the median amplitude of causality peaks. Statistical testing largely used nested ANOVA and non-parametric tests (Wilcoxon) where stated.

Behavioural effects followed expected class-specific patterns. NMDA antagonists (ketamine, PCP) induced hyperlocomotion and ataxia, 5-HT2A agonists (LSD, DOI) produced head-twitch responses, and amphetamine produced hyperlocomotion with stereotypy (behavioural differences significant at p<0.001). No single overt behaviour was similarly and specifically altered by both 5-HT2A agonists and NMDA antagonists, indicating that any psychedelic-specific neural signatures are unlikely to be trivially driven by shared motor changes. Single-unit results came from 365 units recorded across 169 sites. At the global scale, 5-HT2A agonists produced widespread inhibition: 65% of cells showed significant inhibition and only 8% excitation. NMDA antagonists produced a mixed pattern (about 40% inhibited and 40% excited), while amphetamine produced 32% inhibition and 46% excitation. When units were grouped by anatomical region and cell class, 5-HT2A agonists induced net inhibitory modulation in both putative principal cells and interneurons across examined structures. By contrast, NMDA antagonists tended to inhibit principal cells while exciting interneurons in most structures. Comparing psychedelic drugs as a group with amphetamine, a psychedelic-specific firing-rate difference was observed only in integrative thalamus (psychedelics: mean z-scored change −0.3; amphetamine: +1.6; p<0.05). Cluster analyses quantified the population-response dissimilarities: the Bhattacharyya distance between 5-HT2A and NMDA response patterns was 6.6, while NMDA and amphetamine were much more similar (distance 0.43), and 5-HT2A versus amphetamine had distance 0.98. The most consistent and specific electrophysiological signature of the psychedelic state was a dramatic increase in high-frequency oscillations (HFOs) around ~150 Hz. Both 5-HT2A agonists and NMDA antagonists markedly increased HFO amplitude and prevalence across multiple structures, whereas amphetamine increased broad gamma (30–80 Hz) but did not generate HFOs. HFO detection rates shifted markedly upward in psychedelic conditions, and a classification of prevalence (persistent, prevalent, occasional, absent) produced an almost identical spatial pattern for 5-HT2A and NMDA conditions, with amphetamine resembling baseline. Analyses of HFO dynamics revealed spindle-like amplitude modulation with an autocorrelogram full-width at half-maximum of 50±18 ms. Instantaneous-amplitude cross-correlations were stronger within structures (median 0.82±0.10) than between structures (median 0.40±0.15; p<0.001), although some between-structure pairs (notably olfactory cortex, ventral striatum and orbitofrontal cortex, and mPFC–ventral striatum) showed co-modulation comparable to within-structure pairs. Simultaneous HFO frequencies across structures were tightly matched at any given moment despite variability across time and subjects. Phase analyses across 6237 electrode pairs with detectable HFOs found non-random phase relations in 86% (kappa>1), and among those 95% had absolute phase differences <π/4; in practice the mean phase deviations between the olfactory bulb and other structures ranged from 0.001 to 0.45 radians, corresponding to temporal delays of less than 1 ms. Phase inversion—interpreted as evidence of local current dipoles—was observed in about 2% of intrastructural electrode pairs and appeared in multiple regions (olfactory bulb/cortex, orbitofrontal cortex, mPFC, ventral striatum), supporting local HFO generation in several areas. Granger causality analyses showed that during the psychedelic state the spectral peak of causal influence shifted from low gamma at baseline to the HFO band. The mean Granger causality in the HFO band increased by 97% versus baseline (p<0.001). Structure-specific measures indicated the strongest directional influence was from ventral striatum to medial prefrontal cortex; among all pairwise directions only vStr→mPFC had Granger causality consistently above zero.

Brys and colleagues interpret their findings as demonstrating a dissociation between single-cell firing-rate changes and the population-level dynamics that most specifically characterise the acute psychedelic state. Although classic and dissociative psychedelics had different effects on firing rates—5-HT2A agonists producing widespread inhibition and NMDA antagonists producing mixed inhibition/excitation with interneuron excitation—the salient common physiological signature was the emergence of widespread, phase-synchronised HFOs around 150 Hz. This hypersynchrony was absent with the non-psychedelic psychostimulant amphetamine, indicating specificity to the psychedelic state rather than to general arousal or locomotor change. The authors position the HFO hypersynchrony as a plausible mechanism by which psychedelics could disrupt information integration across brain systems, because tight phase synchronisation and near-zero phase lags across multiple cortico-limbic and basal ganglia structures would profoundly affect timing-dependent computations. They outline one mechanistic hypothesis linking receptor-level effects to oscillatory dynamics: both drug classes decrease NMDA-mediated currents and increase AMPA-mediated currents, and because AMPA receptors have much faster deactivation kinetics (order of a few milliseconds versus tens of milliseconds for NMDA), the net effect could be to speed up excitatory postsynaptic temporal dynamics and thereby facilitate the emergence of faster stable oscillatory states. At the network level, the observed near-zero phase lags and the presence of local phase inversions argue against a single dominant source (for example the olfactory bulb) simply propagating HFOs unidirectionally to other regions. Instead, the data are more consistent with multiple locally generated oscillators that are weakly and rapidly coupled, producing standing-wave-like synchronous states with very small inter-regional delays. The authors note that mathematical models of coupled oscillators can produce such outcomes even with local connectivity and delayed interactions, although the biophysical substrate for rapid long-range synchronisation remains to be clarified; gap junctions, ephaptic coupling or specialised fast pathways are discussed as possibilities but not resolved by the present data. Key limitations and uncertainties acknowledged by the investigators include the remaining puzzle of how such fast oscillations synchronise across macroscopic distances given known synaptic and axonal delays, and the variability in HFO prevalence across structures and individuals. They also emphasise that this work is an initial step toward integrating single-cell pharmacology, network dynamics and global brain states; causal links between HFO hypersynchrony and subjective aspects of the psychedelic experience, or their relevance to human psychoses, require further study. Finally, the authors suggest that HFO hypersynchrony might represent a mechanistic target for understanding hallucinations and delusions in psychotic disorders and for the development of novel antipsychotic interventions, while cautioning that more mechanistic and translational work is needed to substantiate such implications.