Ketamine-induced modulation of the thalamo-cortical network in healthy volunteers as a model for schizophrenia

This double-blind, randomized, placebo-controlled, within-subjects crossover study (n=30) investigated the effects of S-Ketamine (23.1mg/70kg) on the modulation of thalamocortical circuitry during resting state in healthy volunteers, to investigate whether their brain connectivity exhibits a similar profile as patients with schizophrenia. They found that a subanesthetic dose of ketamine leads to significantly higher functional connectivity in the thalamus hub network, and the strengthening of functional cortico-thalamic connectivity for the somatosensory and temporal seed regions but not for prefrontal, occipital, and parietal regions, in accordance with the connectivity profile of schizophrenia.

Abstract

“Background: Schizophrenia has been associated with disturbances of thalamic functioning. In light of recent evidence suggesting a significant impact of the glutamatergic system on key symptoms of schizophrenia, we assessed whether modulation of the glutamatergic system via blockage of the N-methyl-D-aspartate (NMDA)-receptor might lead to changes of thalamic functional connectivity.

Methods: Based on the ketamine model of psychosis, we investigated changes in cortico-thalamic functional connectivity by intravenous ketamine challenge during a 55-minute resting-state scan. Thirty healthy volunteers were measured with pharmacological functional magnetic resonance imaging using a double-blind, randomized, placebo-controlled, crossover design.

Results: Functional connectivity analysis revealed significant ketamine-specific changes within the thalamus hub network, more precisely, an increase of cortico-thalamic connectivity of the somatosensory and temporal cortex.

Conclusions: Our results indicate that changes of thalamic functioning as described for schizophrenia can be partly mimicked by NMDA-receptor blockage. This adds substantial knowledge about the neurobiological mechanisms underlying the profound changes of perception and behavior during the application of NMDA-receptor antagonists.”

Authors: Anna Höflich, Andreas Hahn, Martin Küblböck, Georg S. Kranz, Thomas Vanicek, Christian Windischberger, Alois Saria, Siegfried Kasper, Dietmar Winkler & Rupert Lanzenberger

Summary

Schizophrenia has been associated with disturbances of thalamic functioning. Blockage of the NMDA-receptor may lead to changes in functional connectivity.

Introduction

Evidence has been raised that the glutamatergic system plays a major role in the neurobiology of schizophrenia.

Ketamine has been shown to have a significant impact on neuronal activation and functional connectivity in healthy volunteers and in patients with schizophrenia during self-monitoring, attentional functions, and affective processing. Studies in patients with schizophrenia showed abnormalities of glutamatergic pathways, and clinical response to antipsychotic treatment was associated with the degree of glutamatergic dysfunction as assessed with magnetic resonance spectroscopy.

The thalamus as a major modulator of integration of sensory, cognitive, and emotional information has gained particular attention. The glutamatergic system is disturbed in patients with schizophrenia.

A number of resting-state functional networks have been defined and investigated in healthy individuals, patients suffering from neuropsychiatric disorders, and during pharmacological interventions. These networks have been shown to be associated with a number of functions, including the sensory gating function of the thalamus.

Several fMRI investigations in patients with schizophrenia have shown significant disruption of thalamo-cortical connectivity, with a reduction in prefrontal-thalamic connectivity and an increase in motor/somatosensory-thalamic connectivity.

Based on the vast scientific evidence relating the glutamatergic system and NMDA receptor to the neurobiology of schizophrenia, we assessed time-dependent changes of functional connectivity of the thalamus in healthy volunteers before, during, and after intravenous application of a subanaesthetic dose of ketamine.

Participants

Thirty-five healthy volunteers were included in the study, who underwent a medical examination and a psychiatric interview performed by experienced psychiatrists. Exclusion criteria included the history of any psychiatric, neurological, or relevant somatic illness, current or former substance abuse, and current use of any prescribed or nonprescribed medication.

Study Design and Medication

Thirty of 35 participants completed 2 fMRI sessions, with one arm receiving ketamine at first measurement and placebo at second measurement.

The study drug was administered using an MR-compatible fully-automated infusion system in the MRI scanner. The ketamine dosage was 0.11 mg/kg body weight given as a 1-minute bolus followed by a maintenance infusion of 0.12 mg/kg for 19 minutes. This dosage was chosen to provoke reliable psychoactive effects and show tolerability of an application in the MRI scanner. The infusion protocol was timed to begin 5 minutes after the start of the resting state scan. A 0.90% NaCl solution was infused for 5 minutes with increasing injection speed. After the MRI measurement, participants were observed for 2 hours to ensure the lack of side effects. They were also asked if they fell asleep during the scan.

Psychometric Measures

Ketamine was used to assess psychoactive effects. PANSS, BPRS and 5D-ASC were used.

Resting-State fMRI Acquisition and Analysis

During a resting-state scan, subjects were instructed to relax with eyes open, let their mind wander, and not think of anything specific. The scan was performed at 3 Tesla using single-shot gradient-recalled echo planar imaging.

Functional Connectivity Analysis

Preprocessing was performed using SPM8 with default parameters unless specified, and resting-state data were corrected using linear regression and a 12-term finite impulse response filter. Functional connectivity analysis was carried out by applying a seed-based approach.

Network

To investigate connectivity changes in the thalamus during ketamine infusion, we used the averaged time courses of 4 seeds, namely the thalamus bilaterally, the cingulate cortex, and the lingual gyrus.

Ketamine infusion was split into 2.5 minute periods to evaluate the effect of ketamine on functional connectivity. Correlation maps were converted to z-values to enable statistic comparisons across subjects.

Analysis 2: Cortico-Thalamic Functional Connectivity

For the calculation of thalamo-cortical connectivity, the cortex was divided in nonoverlapping regions of interest, and correlation maps were converted to z-values. Statistical evaluation was focused on the thalamus.

Statistical Analysis

Using repeated-measures ANOVA, the interaction effect of time and drug was evaluated for cortico-thalamic connectivity and thalamus hub network analysis. Posthoc t tests were computed following an overall F-test.

Blood Samples

Ketamine levels were measured on blood samples taken 60, 75, 90, and 120 minutes after the end of the drug application.

Results

Descriptive data are summarized in Table 1. Intravenous ketamine led to a significant increase on the positive and negative syndrome scale and the Altered State of Consciousness Scale compared with placebo.

Analysis 1: Ketamine Effects on the Thalamus Hub Network

The thalamus hub network showed significantly higher functional connectivity in the ketamine condition compared with placebo. The connectivity increased 2.5 minutes after the start of the ketamine infusion and remained significant until 17.5 minutes after the end of the ketamine infusion.

Analysis 2: Ketamine Effects on Cortico-Thalamic Connectivity

Using the method recently published by Zhang et al. (2010) and Woodward et al. (2012), we investigated the dynamics of cortico-thalamic connectivity during and after ketamine infusion. The results largely overlapped with findings reported previously using the same methodology.

Ketamine infusion affected cortico-thalamic connectivity in the somatosensory and temporal cortices, but not in the prefrontal, motor, posterior parietal, and occipital cortex.

The somatosensory cortex showed a significant increase in functional connectivity with the ventrolateral region of the thalamus after ketamine infusion. The temporal seed region showed a significant increase in functional connectivity with the medial dorsal nucleus, ventral lateral, and ventral anterior nucleus.

Discussion

Here, we show that ketamine has a substantial impact on thalamic functioning in healthy volunteers, with significant increases in functional connectivity in the thalamus hub network and in cortico-thalamic connections.

Our study shows that the glutamatergic system has a significant impact on thalamic functioning, and that this impact is similar in healthy volunteers to patients with schizophrenia.

Previous studies have found thalamic alterations in schizophrenia, including volume reductions in specific nuclei and disruption of functional connectivity.

In animal studies, NMDA antagonists have been shown to affect thalamic nuclei and thalamo-cortical networks. Furthermore, FDG-PET studies in unmedicated patients with schizophrenia have revealed metabolic disconnectivity of the mediodorsal nucleus of the thalamus and medial temporal areas.

Ketamine induces hyperconnectivity in the brain, both on a larger network level and on thalamus-specific connectivity.

Woodward et al. (2012) found increased motor/somatosensory-thalamic connectivity in patients with schizophrenia, and Klingner et al. (2013) found increased thalamo-cortical connectivity in patients with schizophrenia.

Results found with the ketamine model of psychosis in healthy volunteers seem to only partly overlap with results found in patients with schizophrenia. In particular, we could not replicate the finding of decreased prefrontal-thalamic connectivity, which may be a highly relevant finding given the vast number of evidence reporting deficits of top-down functional control of prefrontal areas in schizophrenia.

Changes in connectivity within the thalamus network have been shown in patients with schizophrenia, and may partly explain psychosis-like symptoms. Furthermore, the calcarine, which covers the primary visual cortex (V1), shows an absence of contextual modulation in patients with schizophrenia.

The neurochemical mechanisms linking glutamatergic modulation via NMDA blockage and large-scale changes in distinct cortico-thalamic networks are not fully understood. Current models propose that the blockage of NMDA receptors on GABAergic interneurons leads to a disinhibition of the activity of pyramidal cells, resulting in an increase of glutamate release within afferent and connected regions. This increase of glutamate is thought to have a significant impact on the BOLD signal.

Ketamine has gained attention as a treatment for treatment-resistant depression, and fMRI studies in depressed patients show that thalamic functioning is altered. This study might point toward the relevance of the results gained in this study also in the context of depression.

Ketamine has a relevant impact on a number of physiological parameters, including heart rate, respiratory rate, and blood pressure, which might have influenced the results retrieved in our analysis.

fMRI does not allow for a very accurate discrimination of thalamic nuclei, so MNI coordinates were used. However, this approach does not account for potential individual differences.

The present study shows that blockage of the NMDA receptor can create a psychosis-like state in healthy volunteers, explaining the loss of sensory filtering observed in these individuals.

Acknowledgments

This research was funded by the Austrian National Bank and was conducted at the MRI center.

Statement of Interest

S. Kasper, R. Lanzenberger, D. Winkler, and CSC Pharmaceuticals have received grant/research support, lecture fees, and honoraria from various companies, including AstraZeneca, Eli Lilly, Lundbeck A/S, Bristol-Myers Squibb, Servier, Sepracor, GlaxoSmithKline, Organon, and Novartis.

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