My mind raced for potential titles to a post when I read the recent report from Science, ‘The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex,’ by a team headed by José Fernando Maya Vetencourt (abstract), but I’ve opted to be demure, rather than go with some of my other options (like ‘Anti-depressants the “Cocoon” pool for brain?’ or something similarly outrageous).
The research team investigated wither fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could restore plasticity in the visual system of adult rats. They chose fluoxetine because long-term regimens of the drug promote neurogenesis and synaptogenesis in the hippocampus and increased activity of neurotrophin brain-derived neurotrophic factor (BDNF) and its primary receptor, TrkB (close paraphrase to the original article). These effects have been shown essential to the drug’s effect; block one of these processes, and the anti-depressant doesn’t work nearly as well. In order to test plasticity, the team studied how rats responded to monocular deprivation — covering one eye — both the initial shift in ocular dominance and then the recovery of visual function after long-term monocular deprivation. In general, the fluoxetine-treated rats responded in exaggerated fashion to both conditions, suggesting that plasticity was greater with long-term administration of the drug. From the abstract:
We found that chronic administration of fluoxetine reinstates ocular dominance plasticity in adulthood and promotes the recovery of visual functions in adult amblyopic animals, as tested electrophysiologically and behaviorally. These effects were accompanied by reduced intracortical inhibition and increased expression of brain-derived neurotrophic factor in the visual cortex. Cortical administration of diazepam prevented the effects induced by fluoxetine, indicating that the reduction of intracortical inhibition promotes visual cortical plasticity in the adult. Our results suggest a potential clinical application for fluoxetine in amblyopia as well as new mechanisms for the therapeutic effects of antidepressants and for the pathophysiology of mood disorders.
The team tested a number of control conditions in order to isolate the possibility that neurotrophic factors were responsible for the increased plasticity, and the results sound robust across a range of conditions. The team based in Scuola Normale Superiore, Pisa, report: ‘Our data suggest that the enhanced serotonergic transmission induced by chronic treatment with fluoxetine promotes functional and/or structural mechanisms that shift the intracortical inhibitory-excitatory balance, triggering plasticity in the adult visual cortex’ (from the original Science article).
The researchers also report: ‘The effects induced by fluoxetine in adult visual cortical plasticity are surprisingly similar to those caused by environmental enrichment, a condition characterized by increased exploratory behavior and sensory-motor stimulation, which we recently found to promote amblyopia recovery in adulthood through a reduction of intracortical inhibition’ (from the Science article). Daniel has discussed how some of the same brain mechanisms activated by pharmaceuticals may also be manifest with non-pharmaceutical interventions. That shouldn’t surprise us: we have the same brain all the time, whether drugs or other interventions are affecting us, so some of the same mechanisms are likely involved.
There are many caveats on this research, but the results do suggest that there might be medical ways in which to induce heightened plasticity in the neural system, something a lot of people have speculated about in the wake of discoveries of neuroplasticity. It’s rats, the monocular deprivation regimen is severe, the visual system is particularly susceptible to environmental influences (after all, it’s a sensory system), and so on. But even with these caveats, I find this report pretty fascinating.
Although we’re nowhere near the Matrix stage, when someone’s brain can be opened up to learn martial arts in hours, the results are promising, especially for therapy when added neural plasticity might really advantage recovery. For example, added plasticity in the visual system might be very useful when treating children born with congenital glaucoma. Again, this research is way too early to be talking about application, but this finding, in my opinion, does bring that possibility closer. I’m just surprised how quickly the research team found this effect. I shouldn’t be; in so many cases, we really know very little about the biological mechanisms that actually give pharmaceuticals their effects. Fluoxetine was a great candidate for this research.
But I also think that the research should be a cautionary note on anti-depressants. If one of the primary methods through which they affect the brain is an overall increase in brain plasticity, then the environment in which the patient lives while on long-term treatment with the drug is actually made more important to the patient’s mental and emotional states by the drug, not less. If a person undergoes deprivation (like say, a hospital environment without adequate stimuli or social support), then the drug might actually increase the susceptibility of the patient to the effects of these environments. The drug doesn’t just fight depression, it opens up the possibility of greater, faster neural change, potentially for better or worse.
The same thing would go for attempts to use these drugs to aid learning or recovery, for example. If the environment of recovery or study was very stressful, the drug might actually increase vulnerability to the long-term effects of the environment. A number of authors (such as Norman Doidge) have written about how neural plasticity can be a double-edged sword, leading both to increases in functioning and to losses of function in deprived situations; increasing neuroplasticity with pharmaceuticals or environments likely has the same double-edged potential. The fact that the research effects of an ‘anti-depressant’ were on the visual system should be a cautionary note about the law of unintended consequence. I can imagine situations, for example, where chronic pain might be exacerbated or consolidated by heightening neural plasticity, if these systems are also susceptible to the pharmaceutical manipulation (and I can’t think of any reason off the top of my head that they wouldn’t be).
José Fernando Maya Vetencourt, Alessandro Sale, Alessandro Viegi, Laura Baroncelli, Roberto De Pasquale, Olivia F. O’Leary, Eero Castrén, and Lamberto Maffei. 2008. The Antidepressant Fluoxetine Restores Plasticity in the Adult Visual Cortex. Science 320 (5874) (18 April): 385-388. DOI: 10.1126/science.1150516 (abstract).