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Acute LSD effects on response inhibition neural networks

Published online by Cambridge University Press:  02 October 2017

A. Schmidt ,
F. Müller ,
C. Lenz ,
P. C. Dolder ,
Y. Schmid ,
D. Zanchi ,
U. E. Lang ,
M. E. Liechti  and
S. Borgwardt
A. Schmidt*
Affiliation:
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
F. Müller
Affiliation:
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
C. Lenz
Affiliation:
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
P. C. Dolder
Affiliation:
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University of Basel, University Hospital Basel, Basel, Switzerland
Y. Schmid
Affiliation:
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University of Basel, University Hospital Basel, Basel, Switzerland
D. Zanchi
Affiliation:
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
U. E. Lang
Affiliation:
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
M. E. Liechti
Affiliation:
Division of Clinical Pharmacology and Toxicology, Department of Biomedicine and Department of Clinical Research, University of Basel, University Hospital Basel, Basel, Switzerland
S. Borgwardt
Affiliation:
Department of Psychiatry (UPK), University of Basel, Basel, Switzerland
*
Author for correspondence: A. Schmidt, Ph.D., E-mail: [email protected]
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Abstract

Background

Recent evidence shows that the serotonin 2A receptor (5-hydroxytryptamine2A receptor, 5-HT2AR) is critically involved in the formation of visual hallucinations and cognitive impairments in lysergic acid diethylamide (LSD)-induced states and neuropsychiatric diseases. However, the interaction between 5-HT2AR activation, cognitive impairments and visual hallucinations is still poorly understood. This study explored the effect of 5-HT2AR activation on response inhibition neural networks in healthy subjects by using LSD and further tested whether brain activation during response inhibition under LSD exposure was related to LSD-induced visual hallucinations.

Methods

In a double-blind, randomized, placebo-controlled, cross-over study, LSD (100 µg) and placebo were administered to 18 healthy subjects. Response inhibition was assessed using a functional magnetic resonance imaging Go/No-Go task. LSD-induced visual hallucinations were measured using the 5 Dimensions of Altered States of Consciousness (5D-ASC) questionnaire.

Results

Relative to placebo, LSD administration impaired inhibitory performance and reduced brain activation in the right middle temporal gyrus, superior/middle/inferior frontal gyrus and anterior cingulate cortex and in the left superior frontal and postcentral gyrus and cerebellum. Parahippocampal activation during response inhibition was differently related to inhibitory performance after placebo and LSD administration. Finally, activation in the left superior frontal gyrus under LSD exposure was negatively related to LSD-induced cognitive impairments and visual imagery.

Conclusion

Our findings show that 5-HT2AR activation by LSD leads to a hippocampal–prefrontal cortex-mediated breakdown of inhibitory processing, which might subsequently promote the formation of LSD-induced visual imageries. These findings help to better understand the neuropsychopharmacological mechanisms of visual hallucinations in LSD-induced states and neuropsychiatric disorders.

Keywords

Cognitive controlfMRILSDvisual hallucinations
Type
Original Articles
Information
Psychological Medicine , Volume 48 , Issue 9 , July 2018 , pp. 1464 - 1473
Copyright
Copyright © Cambridge University Press 2017 

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References

Arce, E et al. (2006) Individuals with schizophrenia present hypo- and hyperactivation during implicit cueing in an inhibitory task. NeuroImage 32, 704–713.Google Scholar
Bari, A and Robbins, TW (2013) Inhibition and impulsivity: behavioral and neural basis of response control. Progress in Neurobiology 108, 44–79.Google Scholar
Barnes, J and Boubert, L (2008) Executive functions are impaired in patients with Parkinson's disease with visual hallucinations. Journal of Neurology, Neurosurgery and Psychiatry 79, 190–192.Google Scholar
Bhattacharyya, S et al. (2015) Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis. European Neuropsychopharmacology 25, 26–37.Google Scholar
Bhattacharyya, S et al. (2014) Protein kinase B (AKT1) genotype mediates sensitivity to cannabis-induced impairments in psychomotor control. Psychological Medicine 44, 3315–3328.Google Scholar
Borgwardt, SJ et al. (2008) Neural basis of Delta-9-tetrahydrocannabinol and cannabidiol: effects during response inhibition. Biological Psychiatry 64, 966–973.CrossRefGoogle ScholarPubMed
Botvinick, MM et al. (2001) Conflict monitoring and cognitive control. Psychological Review 108, 624–652.Google Scholar
Braet, W et al. (2011) fMRI activation during response inhibition and error processing: the role of the DAT1 gene in typically developing adolescents and those diagnosed with ADHD. Neuropsychologia 49, 1641–1650.CrossRefGoogle ScholarPubMed
Brown, JW and Braver, TS (2005) Learned predictions of error likelihood in the anterior cingulate cortex. Science 307, 1118–1121.Google Scholar
Carhart-Harris, RL et al. (2016a) The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychological Medicine 46, 1379–1390.Google Scholar
Carhart-Harris, RL et al. (2013) Functional connectivity measures after psilocybin inform a novel hypothesis of early psychosis. Schizophrenia Bulletin 39, 1343–1351.Google Scholar
Carhart-Harris, RL et al. (2016b) Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proceedings of the National Academy of Sciences of the USA 113, 4853–4858.Google Scholar
Chudasama, Y, Doobay, VM and Liu, Y (2012) Hippocampal-prefrontal cortical circuit mediates inhibitory response control in the rat. Journal of Neuroscience 32, 10915–10924.Google Scholar
Cieslik, EC et al. (2013) Is there ‘one’ DLPFC in cognitive action control? Evidence for heterogeneity from co-activation-based parcellation. Cerebral Cortex 23, 2677–2689.Google Scholar
Corbetta, M, Kincade, JM and Shulman, GL (2002) Neural systems for visual orienting and their relationships to spatial working memory. Journal of Cognitive Neuroscience 14, 508–523.Google Scholar
Daly, E et al. (2014) Response inhibition and serotonin in autism: a functional MRI study using acute tryptophan depletion. Brain 137, 2600–2610.Google Scholar
De Gregorio, D et al. (2016) d-Lysergic acid diethylamide (LSD) as a model of psychosis: mechanism of action and pharmacology. International Journal of Molecular Sciences 17, doi: 10.3390/ijms17111953.Google Scholar
Dolder, PC, Liechti, ME and Rentsch, KM (2015a) Development and validation of a rapid turboflow LC-MS/MS method for the quantification of LSD and 2-oxo-3-hydroxy LSD in serum and urine samples of emergency toxicological cases. Analytical and Bioanalytical Chemistry 407, 1577–1584.Google Scholar
Dolder, PC et al. (2015b) Pharmacokinetics and concentration-effect relationship of oral LSD in humans. International Journal of Neuropsychopharmacology, https://doi.org/10.1093/ijnp/pyv072.Google Scholar
Dolder, PC et al. (2016) LSD acutely impairs fear recognition and enhances emotional empathy and sociality. Neuropsychopharmacology 41, 2638–2646.Google Scholar
Dolder, PC et al. (2017) Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects. Clinical Pharmacokinetics, https://doi.org.10.1007/s40262-017-0513-9.Google Scholar
du Boisgueheneuc, F et al. (2006) Functions of the left superior frontal gyrus in humans: a lesion study. Brain 129, 3315–3328.Google Scholar
Ford, JM et al. (2004) Acquiring and inhibiting prepotent responses in schizophrenia: event-related brain potentials and functional magnetic resonance imaging. Archives of General Psychiatry 61, 119–129.Google Scholar
Gama, RL et al. (2014) Structural brain abnormalities in patients with Parkinson's disease with visual hallucinations: a comparative voxel-based analysis. Brain and Cognition 87, 97–103.Google Scholar
Geyer, MA and Vollenweider, FX (2008) Serotonin research: contributions to understanding psychoses. Trends in Pharmacological Sciences 29, 445–453.Google Scholar
Godsil, BP et al. (2013) The hippocampal-prefrontal pathway: the weak link in psychiatric disorders? European Neuropsychopharmacolog 23, 1165–1181.Google Scholar
González-Maeso, J and Sealfon, S (2009) Psychedelics and schizophrenia. Trends in Pharmacological Sciences 32, 225–232.Google Scholar
Grossi, D et al. (2011) Do frontal dysfunctions play a role in visual hallucinations in Alzheimer's disease as in Parkinson's disease? A comparative study. Psychology & Neuroscience 4, 385–389.CrossRefGoogle Scholar
Halberstadt, AL and Geyer, MA (2013) Serotonergic hallucinogens as translational models relevant to schizophrenia. International Journal of Neuropsychopharmacology 16, 2165–2180.Google Scholar
Hester, R et al. (2008) Human medial frontal cortex activity predicts learning from errors. Cerebral Cortex 18, 1933–1940.Google Scholar
Ibarretxe-Bilbao, N et al. (2010) Differential progression of brain atrophy in Parkinson's disease with and without visual hallucinations. Journal of Neurology, Neurosurgery and Psychiatry 81, 650–657.Google Scholar
Johnston, K et al. (2007) Top-down control-signal dynamics in anterior cingulate and prefrontal cortex neurons following task switching. Neuron 53, 453–462.Google Scholar
Kaladjian, A et al. (2007) Blunted activation in right ventrolateral prefrontal cortex during motor response inhibition in schizophrenia. Schizophrenia Research 97, 184–193.Google Scholar
Kometer, M et al. (2013) Activation of serotonin 2A receptors underlies the psilocybin-induced effects on α oscillations, N170 visual-evoked potentials, and visual hallucinations. Journal of Neuroscience 33, 10544–10551.Google Scholar
Kometer, M and Vollenweider, FX (2016) Serotonergic hallucinogen-induced visual perceptual alterations. Current Topics in Behavioral Neurosciences, https://doi:org/10.107/7854_2016_461.Google Scholar
Krus, DM et al. (1963) Differential behavioral responsivity to LSD-25, study in normal and schizophrenic adults. Archives of General Psychiatry 8, 557–563.CrossRefGoogle ScholarPubMed
Kumari, V et al. (2008) Cortical grey matter volume and sensorimotor gating in schizophrenia. Cortex 44, 1206–1214.Google Scholar
Lawrence, EJ et al. (2009) The neural basis of response inhibition and attention allocation as mediated by gestational age. Human Brain Mapping 30, 1038–1050.Google Scholar
Liechti, ME, Dolder, PC and Schmid, Y (2016) Alterations of consciousness and mystical-type experiences after acute LSD in humans. Psychopharmacology 234, 1499–1510.Google Scholar
Meltzer, HY et al. (2010) Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of Parkinson's disease psychosis. Neuropsychopharmacology 35, 881–892.Google Scholar
Preller, KH et al. (2017) The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation. Current Biology 27, 451–457.Google Scholar
Quednow, BB et al. (2011) Psilocybin-induced deficits in automatic and controlled inhibition are attenuated by ketanserin in healthy human volunteers. Neuropsychopharmacology 37, 630–640.Google Scholar
Ramírez-Ruiz, B et al. (2008) Brain response to complex visual stimuli in Parkinson's patients with hallucinations: a functional magnetic resonance imaging study. Movement Disorders 23, 2335–2343.Google Scholar
Roth, BL, Hanizavareh, SM and Blum, AE (2004) Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology 174, 17–24.Google Scholar
Roth, JK et al. (2009) Similar and dissociable mechanisms for attention to internal versus external information. NeuroImage 48, 601–608.Google Scholar
Rubia, K et al. (2001) An fMRI study of reduced left prefrontal activation in schizophrenia during normal inhibitory function. Schizophrenia Research 52, 47–55.Google Scholar
Rubia, K et al. (2003) Right inferior prefrontal cortex mediates response inhibition while mesial prefrontal cortex is responsible for error detection. NeuroImage 20, 351–358.Google Scholar
Rubia, K et al. (2006) Progressive increase of frontostriatal brain activation from childhood to adulthood during event-related tasks of cognitive control. Human Brain Mapping 27, 973–993.Google Scholar
Schmid, Y et al. (2015) Acute effects of lysergic acid diethylamide in healthy subjects. Biological Psychiatry 78, 544–553.Google Scholar
Schmidt, A et al. (2017) Comparative effects of methylphenidate, modafinil and MDMA on response inhibition neural networks in healthy subjects. International Journal of Neuropsychopharmacology 20, 712–720.Google Scholar
Schmidt, A et al. (2013) Inferior frontal cortex modulation with an acute dose of heroin during cognitive control. Neuropsychopharmacology 38, 2231–2239.Google Scholar
Schmitz, N et al. (2006) Neural correlates of executive function in autistic spectrum disorders. Biological Psychiatry 59, 7–16.Google Scholar
Sigurdsson, T and Duvarci, S (2015) Hippocampal-prefrontal interactions in cognition, behavior and psychiatric disease. Frontiers in Systems Neuroscience 9, 190.Google Scholar
Simmonds, DJ, Pekar, JJ and Mostofsky, SH (2008) Meta-analysis of Go/No-go tasks demonstrating that fMRI activation associated with response inhibition is task-dependent. Neuropsychologia 46, 224–232.Google Scholar
Steeds, H, Carhart-Harris, RL and Stone, JM (2015) Drug models of schizophrenia. Therapeutic Advances in Psychopharmacology 5, 43–58.Google Scholar
Štrac, DŠ, Pivac, N and Mück-Šeler, D (2016) The serotonergic system and cognitive function. Translational Neuroscience 7, 35–49.Google Scholar
Studerus, E, Gamma, A and Vollenweider, FX (2010) Psychometric evaluation of the altered states of consciousness rating scale (OAV). PLoS ONE 5, e12412.Google Scholar
Swick, D, Ashley, V and Turken, U (2011) Are the neural correlates of stopping and not going identical? Quantitative meta-analysis of two response inhibition tasks. NeuroImage 56, 1655–1665.Google Scholar
Tully, LM et al. (2014) Impaired cognitive control mediates the relationship between cortical thickness of the superior frontal gyrus and role functioning in schizophrenia. Schizophrenia Research 152, 358–364.Google Scholar
Vollenweider, F et al. (1998) Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9, 3897–3902.Google Scholar
Vollenweider, FX and Geyer, MA (2001) A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Research Bulletin 56, 495–507.Google Scholar
Wapner, S and Krus, DM (1960) Effects of lysergic acid diethylamide, and differences between normals and schizophrenics on the Stroop Color-Word Test. Journal of Neuropsychiatry 2, 76–81.Google Scholar
Woo, CW, Krishnan, A and Wager, TD (2014) Cluster-extent based thresholding in fMRI analyses: pitfalls and recommendations. NeuroImage 91, 412–419.Google Scholar
Zhang, G and Stackman, RW (2015) The role of serotonin 5-HT2A receptors in memory and cognition. Frontiers in Pharmacology 6, 225.CrossRefGoogle ScholarPubMed
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