Psycho-pharmacology
Role of endogenous cannabinoid systems in human cognition
The key question driving this project is 'are eCB systems involved in cognitive symptoms in psychiatric disorders?'. Many of the cognitive symptoms represent normal cognitive functions that do not operate normally. Examples are emotional processing of internal and external percepts, focusing of attention, inhibition of impulses, consolidation and retrieval in long-term memory, and working memory. By investigating the role of eCB in these functions in healthy subjects, we expect to assess whether eCB compounds are candidates for treating associated symptoms.
The experiments involve THC administration via inhalation of vaporized purified THC, during acquisition of MRI scans. Effects are assessed in a double-blind cross-over placebo-controlled design. Scans include functional MRI with and without tasks, Arterial Spin Labeling and anatomy. Tasks address Associative Memory, Working Memory, Impulse Regulation, Emotional Processing, Attention and Reward (administered in different volunteers). Blood samples, ratings of subjective measures and neuropsychological tests are also acquired. The complete protocol has been validated and is published (Van Hell ea, 2010). The project is conducted in compliance with GCP regulations and with the ethics code for clinical trials in the declaration of Helsinki (2008).
Initially, the plan was to first assess eCB involvement in cognitive functions in healthy volunteers, and to then assess eCB effects in four patient groups, focusing on functions that are a) affected by THC, and b) are associated with specific symptoms observed in patients. As symptoms are the target of this project, a particular function can be relevant for more than one psychiatric disorder. For instance, long-term memory is affected in schizophrenia as well as in major depression. Impulse regulation is involved in Obsessive Compulsive disorder and in ADHD. Due to significant delays in obtaining approval of the ethics committee, we had to limit our investigation to (tobacco) addiction and ADHD, and sacrifice the plans for OCD and schizophrenia. Moreover, the MRI sessions turned out to be so demanding both for scan time and for personnel, that including all groups of patients would not be feasible. The amount of data acquired in the trimmed project turns out to be almost more than can be handled by the two PhD students and the Postdoc on the project.
Preliminary results
THC affects brain perfusion in a region-specific manner, and resting state scans display a region-specific increase in signal fluctuation. Moreover, when evaluating strength of connectivity between regions within the Default Mode Network (which increases activity during rest), we again find an effect of THC on specific regions. Taken together, these findings indicate that THC causes an increasing effect on activity in specific regions, together with decreasing connectivity. This set of scans may prove to be a unique way of measuring basic effects of drugs on selective brain regions and networks, which complements, and improves upon, the current state of the art Positron Emission Tomography scans.
Associative memory is invoked with a task where subjects have to associate two unrelated pictures with each other. One minute later they have to retrieve the association by judging which picture they had seen together. A well-known set of frontal, visual and limbic regions was activated during both association and retrieval. THC did not affect performance, as was expected because the task is relatively easy. During association frontal brain regions were less active in the THC session than in the Placebo session. Importantly, posterior regions (cuneus, precuneus, visual cortex) were more activated during retrieval in the THC session. This suggests that THC induces increased recruitment of neural resources during retrieval to maintain normal performance levels. This may be due to reduced brain activity during encoding of information.
Working memory was tested with a parametric Sternberg task, where subjects have to keep a list of letters in memory and judge whether subsequently presented letters were in the list. This paradigm reveals list-length (load) dependent activity in the working memory system, allowing for assessment of working memory capacity. THC induced a load-dependent decreases in both task performance and brain activity in frontal regions critically involved in working memory-related processes such as maintenance and rehearsal of information. These results indicate involvement of the eCB system in regulating working-memory-related brain function. Decreased frontal brain activation is generally seen when demands exceed the capacity of the working memory system. In line with this, our results could indicate that THC reduces working memory capacity, most prominently so in the ventromedial areas that are involved in maintenance and rehearsal processes. THC may produce these effects by interfering with endogenous cannabinoid mechanisms controlling GABA and glutamate signaling associated with learning and memory.
