Does Marijuana impair cognition?

A recent study in the Nature Group journal Neuropsychopharmacology investigates the acute effects of smoking marijuana on cognition. I've always assumed that smoking makes you dumb while you're high, and certainly had never seen any study on the acute effects. Yet it seems those assumptions might be misguided. The double-blinded study looked at a group of 8 females and 10 males who regularly use the drug (average of 24 joints a week!), which were given a ride to the lab then given cigarettes with various concentration of THC, underwent a battery of tests and were finally fed. Great care was taken in preparing the joints:

"During each session, participants smoked a single one-gram marijuana cigarette (0, 1.8, 3.9% Delta9-THC w/w, provided by the National Institute on Drug Abuse). Participants took three standardized puffs from the marijuana cigarette: each puff consisted of a 5-sec preparation interval, followed by 5-sec of inhalation, 10-sec of breath-hold, and 40-sec of exhalation and rest. Cigarettes were tightly rolled at both ends and were smoked through a hollow plastic cigarette holder so that the contents were not visible."

The authors first remark that other than memory recall very little has been investigated about the acute effects of THC, and the only other metric investigated, reaction time in psychomotor tasks, seems unaffected.
The tests they tried was a reaction time test, using both auditory and visual cues on a computer where the test subjects had to press a key. Memory test involved recalling details about stories and sequences of digits. There were also visuo-spatial tasks, mental calculations and various other standardised tasks. The results were somewhat surprising:

" In summary, while subjective ratings and heart rate were significantly elevated in a Delta9-THC concentration-related fashion, cognitive performance was minimally affected following acute marijuana smoking. Participants experienced greater difficulties inhibiting inappropriate responding following the high Delta9-THC concentration cigarette and they required more time to complete several cognitive tests, but their test accuracy rates were unaffected. The finding that accuracy was unaffected by smoked marijuana indicates that heavy, daily, marijuana smokers will not fulfill the DSM-IV criterion for marijuana intoxication that requires impairment of complex cognitive functioning. The consistent slowing of cognitive performance may have significant behavioral effects under some circumstances requiring complex operations that must be accomplished in a limited time frame, such as certain workplace tasks and the operation of machinery and automobiles."

So I guess it doesn't make you dumber, but it does slow you down...

Williams syndrome

My fascination with Williams-Beuren syndrome started a few months ago when I saw a documentary on that subject on the french CBC show Découverte. On the show, they interviewed people who had the disease, and talked about their unusual musical abilities. It turns out that they are really good at memorising music or singing, and that when they listen to music, their whole cortex lights up with activity, compared to very small limited regions in normal people. This is particularly surprising considering they have limited abilities to write or do maths because of their learning and memory problems. Yet they can sing a song after hearing it once, and use very advanced vocabulary when they speak. They also have difficulties with visuo-spatial perception, and motor skills and are hyper-social, meaning they have no social anxiety. Additionally they have characteristic elfin-like facial features, like pointy ears, prominent cheeks and upturned nose and a short stature which have lead to the theory that they might be the origin of the folk tales about pixies.

When you think about it, some of these features are quite unique, and they are all linked to a relatively small deletion affecting 20 or so genes on chromosome 7. The fact that gene dosing could be responsible to these striking changes in musical abilities, speech and social behaviour, things that are so characteristically human, is an incredible window into how genes dictate cognition. Additionally, while the syndrome was initially included in the autism spectrum disorder, the hypersocial aspect and the "islands" of cognitive strength are in stark contrast to what is observed in autism. Maybe we could we learn about social behaviour, empathy, and how the brain makes us social animals by comparing both diseases.
And so I started examining the genes which were hemizigous as a result of the disease. While a few genes are thought to contribute to the cognitive aspects of the disease, two really stand out: LIMK1 and ELN. They are part of the minimally deleted region that can give rise to the syndrome (since the size of the deletion varies from patient to patient). Elastin (eln) is a structural protein and its deficiency is linked to the cardio-vascular problems and to the facial features of the disease. LIMK1 is a kinase that is expressed in the brain and which regulates actin threadmilling (via cofilin) to allow synaptic plasticity and remodelling.

So I thought, maybe LIMK1 can tell us what is the neural substrate for cognitive processes that are affected by the disease such as social behaviour, musical abilities, visuo-spatial cognition etc... Using the Allen brain project data, which we've spoke about on the blog in the past, I looked at where the gene is expressed in the brain. To my surprise it wasn't expressed in the cortex or the limbic system, the structures which are thought to regulate higher cognition and behaviour. Instead it was very limited to the brainstem (see my figure above). Yet all the studies done so far have focused on the hippocampus, the amygdala and the cortex, because that is where everyone expected the defects occurred. People with lesions in those areas have memory problems, social behaviour problems, so it was only natural to assume, that it was the neural substrate of the disease. After reading quite a bit about brain areas and behaviour I came across a few very rare papers dealing with the brainstem in cognition and behaviour. The authors suggested that maybe higher brain function is dependent on integration of incoming sensory signals (or outgoing motor signals) from the brainstem. If the brainstem doesn't do its job at pre-processing that information, the higher brain structures don't know how to deal with the signals, and how to relay it to the specialized areas like say the Broca area for speech for example. This in turn may explain why Williams patients have difficulties with motor skills, visuo-spatial integration. And so is behaviour also dependent on the brainstem? While I don't have the resources to prove it, I certainly think it's a possibility. After-all many primitive animals that have complex behaviour have a mostly brain-stem centric brain and underdeveloped cortex. The brain stem is responsible for the basic stuff like breathing, eating, vomiting so why not also of basic behaviour like anxiety...

Which leads me to my final point, if you restore the synaptic plasticity in the brainstem, can the brain adapt and the symptoms associated with Williams syndrome disappear? A recent paper in science (Guy et al, 2007) demonstrated that restoration of MeCP2 expression post-nataly in mouse models of Rett syndrome, can correct the neurological defects. This suggests that mental retardation syndromes which are not neuro-degenerative can be corrected and reversed. So I am very optimistic that one day, there will be therapies available to these people, or maybe even, that we might harness that knowledge to enhance our own brains. Have you ever wanted to have a musical brain?