- Chris D. Schubart (1)
- Nick F. Ramsey (1)
- Matthijs G. Bossong (1)
- J. Gerven van (2)
- Hendrika H. Hell van (1)
- H.H. Hell van (7)
- Matthias J.P. Osch van (1)
- G. Jager (8)
- Gerry Jager (1)
- J.M. Jansma(older publications) (1)
- J.M. Jansma (6)
- R.S. Kahn (7)
- G. Kristo (1)
- M.A. Mehta (1)
- M.J.P. Osch (1)
- E. Oudman (1)
- Marco P. Boks (1)
- N.F. Ramsey (7)
- René S. Kahn (1)
- Wesley Saane van (1)
- E. Saliasi (1)
- L.J.M.J. Vanderschuren (1)
- F. Zelaya (1)
- L. Zuurman (2)
Acute effects of ∆9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype
Bossong, Matthijs G. ; Hell, Hendrika H. van; Schubart, Chris D. ; Saane, Wesley van; Iseger, Tabitha A. ; Jager, Gerry ; Osch, Matthias J.P. van; Jansma, J.M. ; Kahn, René S. ; Boks, Marco P. ; Ramsey, Nick F. - \ 2019
European Neuropsychopharmacology 29 (2019)6. - ISSN 0924-977X - p. 766 - 776.
Arterial spin labelling - Cannabis - Catechol-methyl-transferase (COMT) - Delta9-tetrahydrocannabinol (THC) - Resting state connectivity - Salience
Cannabis produces a broad range of acute, dose-dependent psychotropic effects. Only a limited number of neuroimaging studies have mapped these effects by examining the impact of cannabis on resting state brain neurophysiology. Moreover, how genetic variation influences the acute effects of cannabis on resting state brain function is unknown. Here we investigated the acute effects of ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, on resting state brain neurophysiology, and their modulation by catechol-methyl-transferase (COMT) Val158Met genotype. Thirty-nine healthy volunteers participated in a pharmacological MRI study, where we applied Arterial Spin Labelling (ASL) to measure perfusion and functional MRI to assess resting state connectivity. THC increased perfusion in bilateral insula, medial superior frontal cortex, and left middle orbital frontal gyrus. This latter brain area showed significantly decreased connectivity with the precuneus after THC administration. THC effects on perfusion in the left insula were significantly related to subjective changes in perception and relaxation. These findings indicate that THC enhances metabolism and thus neural activity in the salience network. Furthermore, results suggest that recruitment of brain areas within this network is involved in the acute effects of THC. Resting state perfusion was modulated by COMT genotype, indicated by a significant interaction effect between drug and genotype on perfusion in the executive network, with increased perfusion after THC in Val/Met heterozygotes only. This finding suggests that prefrontal dopamine levels are involved in the susceptibility to acute effects of cannabis.
Acute and Non-acute Effects of Cannabis on Human Memory Function: A Critical Review of Neuroimaging Studies
Bossong, M.G. ; Jager, G. ; Bhattacharyya, S. ; Allen, P. - \ 2014
Current Pharmaceutical Design 20 (2014)13. - ISSN 1381-6128 - p. 2114 - 2125.
spatial working-memory - adolescent marijuana users - cerebral-blood-flow - prefrontal cortex - default network - fmri response - recognition memory - striatal function - drug-addiction - brain-function
Smoking cannabis produces a diverse range of effects, including impairments in learning and memory. These effects are exerted through action on the endocannabinoid system, which suggests involvement of this system in human cognition. Learning and memory deficits are core symptoms of psychiatric and neurological disorders such as schizophrenia and Alzheimer's disease, and may also be related to endocannabinoid dysfunction in these disorders. However, before new research can focus on potential treatments that work by manipulating the endocannabinoid system, it needs to be elucidated how this system is involved in symptoms of psychiatric disorders. Here we review neuroimaging studies that investigated acute and non-acute effects of cannabis on human learning and memory function, both in adults and in adolescents. Overall, results of these studies show that cannabis use is associated with a pattern of increased activity and a higher level of deactivation in different memory-related areas. This could reflect either increased neural effort ('neurophysiological inefficiency') or a change in strategy to maintain good task performance. However, the interpretation of these findings is significantly hampered by large differences between study populations in cannabis use in terms of frequency, age of onset, and time that subjects were abstinent from cannabis. Future neuroimaging studies should take these limitations into account, and should focus on the potential of cannabinoid compounds for treatment of cognitive symptoms in psychiatric disorders.
The endocannabinoid system and emotional processing: A pharmacological fMRI study with Delta 9-tetrahydrocannabinol
Bossong, M.G. ; Hell, H.H. van; Jager, G. ; Kahn, R.S. ; Ramsey, N.F. ; Jansma, J.M. - \ 2013
European Neuropsychopharmacology 23 (2013)12. - ISSN 0924-977X - p. 1687 - 1697.
cb1 cannabinoid receptors - happy facial expressions - healthy-volunteers - antagonist rimonabant - major depression - memory function - functional mri - amygdala - brain - involvement
Various psychiatric disorders such as major depression are associated with abnormalities in emotional processing. Evidence indicating involvement of the endocannabinoid system in emotional processing, and thus potentially in related abnormalities, is increasing. In the present study, we examined the role of the endocannabinoid system in processing of stimuli with a positive and negative emotional content in healthy volunteers. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist Delta 9-tetrahydrocannabinol (THC) on brain function related to emotional processing in 11 healthy subjects. Performance and brain activity during matching of stimuli with a negative ('fearful faces') or a positive content ('happy faces') were assessed after placebo and THC administration. After THC administration, performance accuracy was decreased for stimuli with a negative but not for stimuli with a positive emotional content. Our task activated a network of brain regions including amygdala, orbital frontal gyrus, hippocampus, parietal gyrus, prefrontal cortex, and regions in the occipital cortex. THC interacted with emotional content, as activity in this network was reduced for negative content, while activity for positive content was increased. These results indicate that THC administration reduces the negative bias in emotional processing. This adds human evidence to support the hypothesis that the endocannabinoid system is involved in modulation of emotional processing. Our findings also suggest a possible role for the endocannabinoid system in abnormal emotional processing, and may thus be relevant for psychiatric disorders such as major depression. (C) 2013 Elsevier B.V. and ECNP. All rights reserved.
Default Mode Network in the Effects of ¿9-Tetrahydrocannabinol (THC) on Human Executive Function
Bossong, M.G. ; Jansma, J.M. ; Hell, H.H. van; Jager, G. ; Kahn, R.S. ; Ramsey, N.F. - \ 2013
PLoS ONE 8 (2013)7. - ISSN 1932-6203 - 10 p.
deficit hyperactivity disorder - working-memory - endocannabinoid system - healthy-volunteers - prefrontal cortex - synaptic plasticity - error awareness - brain-function - neural basis - fmri
Evidence is increasing for involvement of the endocannabinoid system in cognitive functions including attention and executive function, as well as in psychiatric disorders characterized by cognitive deficits, such as schizophrenia. Executive function appears to be associated with both modulation of active networks and inhibition of activity in the default mode network. In the present study, we examined the role of the endocannabinoid system in executive function, focusing on both the associated brain network and the default mode network. A pharmacological functional magnetic resonance imaging (fMRI) study was conducted with a placebo-controlled, cross-over design, investigating effects of the endocannabinoid agonist ¿9-tetrahydrocannabinol (THC) on executive function in 20 healthy volunteers, using a continuous performance task with identical pairs. Task performance was impaired after THC administration, reflected in both an increase in false alarms and a reduction in detected targets. This was associated with reduced deactivation in a set of brain regions linked to the default mode network, including posterior cingulate cortex and angular gyrus. Less deactivation was significantly correlated with lower performance after THC. Regions that were activated by the continuous performance task, notably bilateral prefrontal and parietal cortex, did not show effects of THC. These findings suggest an important role for the endocannabinoid system in both default mode modulation and executive function. This may be relevant for psychiatric disorders associated with executive function deficits, such as schizophrenia and ADHD
THC reduces the anticipatory nucleus accumbens response to reward in subjects with a nicotine addiction
Jansma, J.M. ; Hell, H.H. van; Vanderschuren, L.J.M.J. ; Bossong, M.G. ; Jager, G. ; Kahn, R.S. ; Ramsey, N.F. - \ 2013
Translational Psychiatry 3 (2013). - ISSN 2158-3188 - 10 p.
endogenous cannabinoid anandamide - increasing monetary reward - endocannabinoid system - drug-addiction - cb1 receptors - brain - dependence - rats - inhibition - humans
Recent evidence has implicated the endocannabinoid (eCB) system in nicotine addiction. The eCB system also has an important role in reward mechanisms, and nicotine addiction has been associated with aberrant reward processing. Motivated by this evidence, we tested the hypothesis that eCB modulation of reward processing is altered in subjects with a nicotine addiction (NAD). For this purpose, we compared reward-related activity in NAD with healthy controls (HC) in a pharmacological magnetic resonance imaging (MRI) study using ¿9-tetrahydrocannabinol (THC) administration to challenge the eCB system. Eleven HC and 10 NAD participated in a 3-T functional MRI (fMRI) study with a double-blind, cross-over, placebo-controlled design, using a Monetary Incentive Delay (MID) paradigm with three reward levels. Reward activity in the nucleus accumbens (NAcc) and caudate putamen during anticipation and feedback of reward was compared after THC and placebo. fMRI results indicated a significant reduction of reward anticipation activity in the NAcc in NAD after THC administration, which was not present in HC. This is indicated by a significant group by drug by reward interaction. Our data show that THC significantly reduces the NAcc response to monetary reward anticipation in NAD. These results suggest that nicotine addiction is associated with altered eCB modulation of reward processing in the NAcc. This study adds important human data to existing evidence implicating the eCB system in nicotine addiction.
Effects of ¿9-Tetrahydrocannabinol Administration on human encoding and recall memory function: a pharmacological fMRI study
Bossong, M.G. ; Jager, G. ; Hell, H.H. van; Zuurman, L. ; Jansma, J.M. ; Mehta, M.A. ; Gerven, J. van; Kahn, R.S. ; Ramsey, N.F. - \ 2012
Journal of Cognitive Neuroscience 24 (2012)3. - ISSN 0898-929X - p. 588 - 599.
long-term-memory - impairs spatial memory - medial temporal-lobe - recognition memory - episodic retrieval - prefrontal cortex - smoked marijuana - semantic memory - oral delta(9)-tetrahydrocannabinol - healthy-volunteers
Deficits in memory function are an incapacitating aspect of various psychiatric and neurological disorders. Animal studies have recently provided strong evidence for involvement of the endocannabinoid (eCB) system in memory function. Neuropsychological studies in humans have shown less convincing evidence but suggest that administration of cannabinoid substances affects encoding rather than recall of information. In this study, we examined the effects of perturbation of the eCB system on memory function during both encoding and recall. We performed a pharmacological MRI study with a placebo-controlled, crossover design, investigating the effects of ¿9-tetrahydrocannabinol (THC) inhalation on associative memory-related brain function in 13 healthy volunteers. Performance and brain activation during associative memory were assessed using a pictorial memory task, consisting of separate encoding and recall conditions. Administration of THC caused reductions in activity during encoding in the right insula, the right inferior frontal gyrus, and the left middle occipital gyrus and a network-wide increase in activity during recall, which was most prominent in bilateral cuneus and precuneus. THC administration did not affect task performance, but while during placebo recall activity significantly explained variance in performance, this effect disappeared after THC. These findings suggest eCB involvement in encoding of pictorial information. Increased precuneus activity could reflect impaired recall function, but the absence of THC effects on task performance suggests a compensatory mechanism. These results further emphasize the eCB system as a potential novel target for treatment of memory disorders and a promising target for development of new therapies to reduce memory deficits in humans
Effects of ¿9-Tetrahydrocannabinol on human working memory function
Bossong, M.G. ; Jansma, J.M. ; Hell, H.H. van; Jager, G. ; Oudman, E. ; Saliasi, E. ; Kahn, R.S. ; Ramsey, N.F. - \ 2012
Biological Psychiatry 71 (2012)8. - ISSN 0006-3223 - p. 693 - 699.
dorsolateral prefrontal cortex - catechol-o-methyltransferase - endogenous cannabinoids - genetic-variation - brain-function - schizophrenia - dysfunction - fmri - mri - cognition
Background Evidence indicates involvement of the endocannabinoid (eCB) system in both the pathophysiology of schizophrenia and working memory (WM) function. Additionally, schizophrenia patients exhibit relatively strong WM deficits. These findings suggest the possibility that the eCB system is also involved in WM deficits in schizophrenia. In the present study, we examined if perturbation of the eCB system can induce abnormal WM activity in healthy subjects. Methods A pharmacological functional magnetic resonance imaging study was conducted with a placebo-controlled, cross-over design, investigating effects of the eCB agonist ¿9-tetrahydrocannabinol on WM function in 17 healthy volunteers, by means of a parametric Sternberg item-recognition paradigm with five difficulty levels. Results Performance accuracy was significantly reduced after ¿9-tetrahydrocannabinol. In the placebo condition, brain activity increased linearly with rising WM load. ¿9-Tetrahydrocannabinol administration enhanced activity for low WM loads and reduced the linear relationship between WM load and activity in the WM system as a whole and in left dorsolateral prefrontal cortex, inferior temporal gyrus, inferior parietal gyrus, and cerebellum in particular. Conclusions ¿9-Tetrahydrocannabinol enhanced WM activity network-wide for low loads, while reducing the load-dependent response for increasing WM loads. These results indicate that a challenged eCB system can induce both abnormal WM activity and WM performance deficits and provide an argument for the possibility of eCB involvement in WM deficits in schizophrenia
Involvement of the endocannabinoid system in reward processing in the human brain
Hell, H.H. van; Jager, G. ; Bossong, M.G. ; Brouwer, A. ; Jansma, J.M. ; Zuurman, L. ; Gerven, J. van; Kahn, R.S. ; Ramsey, N.F. - \ 2012
Psychopharmacology 219 (2012)4. - ISSN 0033-3158 - p. 981 - 990.
acute oral delta(9)-tetrahydrocannabinol - cannabinoid cb1 receptors - healthy-volunteers - clinical-research - dopamine release - decision-making - human striatum - neural-basis - thc - delta-9-tetrahydrocannabinol
Rationale Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. Objectives The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist ¿9-tetrahydrocannabinol (THC) on reward-related brain activity. Methods Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with administration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded (“reward trial”) or not (“neutral trial”). Results Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. Conclusions These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction
Evidence for involvement of the insula in the psychotropic effects of THC in humans: a double-blind, randomized pharmacological MRI study
Hell, H.H. van; Bossong, M.G. ; Jager, G. ; Kristo, G. ; Osch, M.J.P. ; Zelaya, F. ; Kahn, R.S. ; Ramsey, N.F. - \ 2011
International Journal of Neuropsychopharmacology 14 (2011)10. - ISSN 1461-1457 - p. 1377 - 1388.
cerebral-blood-flow - low-frequency fluctuation - central-nervous-system - resting-state fmri - neural-basis - anterior insula - healthy-volunteers - marijuana smoking - functional mri - cannabis use
The main reason for recreational use of cannabis is the ‘high’, the primary psychotropic effect of ¿9-tetrahydrocannabinol (THC). This psychoactive compound of cannabis induces a range of subjective, physical and mental reactions. The effect on heart rate is pronounced and complicates bloodflow-based neuroimaging of psychotropic effects of THC. In this study we investigated the effects of THC on baseline brain perfusion and activity in association with the induction of ‘feeling high’. Twenty-three subjects participated in a pharmacological MRI study, where we applied arterial spin labelling (ASL) to measure perfusion, and resting-state functional MRI to assess blood oxygen level-dependent signal fluctuation as a measure of baseline brain activity. Feeling high was assessed with a visual analogue scale and was compared to the imaging measures. THC increased perfusion in the anterior cingulate cortex, superior frontal cortex, and insula, and reduced perfusion in the post-central and occipital gyrus. Baseline brain activity was altered, indicated by increased amplitude of fluctuations in resting-state functional MRI signal after THC administration in the insula, substantia nigra and cerebellum. Perfusion changes in frontal cortex were negatively correlated with ratings of feeling high, suggesting an interaction between cognitive control and subjective effects of THC. In conclusion, an acute THC challenge altered baseline brain perfusion and activity, especially in frontal brain areas involved in cognitive and emotional processes, and the insula, associated with interoceptive awareness. These changes may represent the THC-induced neurophysiological correlates of feeling high. The alterations in baseline brain perfusion and activity also have relevance for studies on task-related effects of THC on brain function.