Long-term memory in the cortex
'Where' and 'how' memories are encoded in a nervous system is one of the most challenging questions in biological research. The formation and recall of associative memories is essential for an independent life. The hippocampus has long been considered a centre in the brain for the long-term storage of spatial associations. Now, Mazahir T. Hasan at the Max Planck Institute for Medical Research and José Maria Delgado-Garcìa at the University Pablo de Olavide of Seville, Spain, were able to provide first experimental evidence that a specific form of memory associations is encoded in the cerebral cortex and is not localized in the hippocampus as described in most Neuroscience textbooks. The new study is a game changer since it strongly suggests that the motor cortical circuits itself, and not the hippocampus, is used as memory storage.
Henry Molaison, known widely as H.M., is a famous name in memory research. Large parts of the American’s hippocampus – the region of the brain that is a major element in learning and memory processes – were removed in the 1950s in an attempt to cure his epileptic seizures. He subsequently suffered severe memory lapses and was no longer able to remember virtually anything new he had learned. Most scientists thereby concluded that the hippocampus is the site of long-term memory.
However, the extent of H.M.’s brain damage was obviously underestimated, because other regions in addition to the hippocampus were also removed or damaged in the surgical procedure. The researchers from Heidelberg and Seville have therefore investigated the learning behaviour of genetically modified mice in which NMDA receptors are turned off only in the motor cerebral cortex. NMDA receptors bind the neurotransmitter glutamate to the synapses and become active when several signals feed into one synapse at the same time. They are the central molecular elements of learning processes, being involved in increasing or decreasing transmission of the signals to synapses.
As the new study shows, in the motor cortex this so-called synaptic plasticity no longer functions without the NMDA receptors. The scientists were thus able to rule out the hippocampus or other regions as the cause for their observations. Based on the new findings, it is the cerebral cortex, not the hippocampus that is the storage site for some forms of memory.
In behaviour tests, so called eyeblink conditioning, animals with and without NMDA receptors in the primary motor cortex had to learn to link a tone with a subsequent electrical stimulus of the eyelid. This association of two sensory inputs involves the cerebellum which coordinates the necessary movements, as well as the hippocampus and the cerebral cortex, which are important learning and memory centres. “After a learning phase, the animals’ reflex is to close their eye when they hear just the tone. Without NMDA receptors in the primary motor cerebral cortex, the genetically modified mice on the other hand cannot remember the connection between the tone and electrical stimulus, and therefore they keep their eyes open despite the tone”, explains Mazahir T. Hasan of the Max Planck Institute for Medical Research.
The researchers have thus complemented the findings of their Heidelberg-based colleagues that the hippocampus is not the seat of memory. In July 2012, Rolf Sprengel and Peter Seeburg from the Max Planck Institute for Medical Research discovered that mice without NMDA receptors in the hippocampus are still quite capable of learning. “We now think that the hippocampus provides the necessary environmental cues, which are transmitted to the cortex where learning-dependent associations take place. Memories are thus stored at various sites in the cerebral cortex on a long-term basis”, explains Hasan.
The findings of Hasan and Delgado-Garcìa thus represent a paradigm-shift in memory research as they make clear that the cerebral cortex is the brain region where memory associations are linked and stored – not the hippocampus. An advanced and detailed knowledge of the mechanisms for the acquisition, consolidation, and recall of associations in the brain is the prerequisite for a therapeutic treatment of the devastating effects of memory loss in various neurological diseases, such as amnesia, Alzheimer`s disease and dementia.
Image: Memories (red) for associating two different sensations are formed in the cortex (tone in blue and touch in yellow). Credit: MPI f. Medical Research/Splettstoesser
Complement with this illustrated chronology of physics in 250 milestones.
We don’t know if antidepressants work, so stop bashing them
Lately, it seems as if everyone is anti-antidepressants. In a recent CiF article, Giles Fraser bemoaned the apparent need to treat anything vaguely resembling unhappiness with a pill. Just a week earlier, Will Self launched a scathing attack on psychiatry along similar lines.
Both pieces sparked debates and arguments centred around two issues. The first is a lack of understanding about what depression actually is. The second is whether antidepressants, which some argue are being unnecessarily prescribed to people with depression, are actually as effective as they’re made out to be. It’s a difficult debate to be had, because it is so often emotionally charged on both sides. The best thing that we can do is to look to the data for answers.
First and foremost, let’s get this straight: depression is not simply “being sad” or “feeling down”. Clinical depression is a persistent, often debilitating disorder that leaves the sufferer feeling sad or hopeless for weeks or months on end. In its “mild” form, it results in a loss of interest in once enjoyable things, tiredness, and near-constant low mood. In the most severe circumstances, it can leave a sufferer feeling suicidal. It affects 6.9% of the European population – some 30 million people – with about one in 10 healthy years of life lost either due to premature death or due to living with the disability. In short, it is a serious disorder.
But what sort of help is best? Are antidepressants any good? Well, this is where it gets complicated. There’s an oft-cited meta-analysis from 2008 by Irving Kirsch and colleagues, which looked at the efficacy of four different types of antidepressant – fluoxetine, venlafaxine, nefazodone and paroxetine – compared with placebo. Critically, they used data from the US Food and Drug Administration, which is responsible for the regulation of drugs in America. This meant that they had access to all research data on the effectiveness of the antidepressants in question, and not just the positive results that are more likely to get published in academic journals.
Essentially, they found that antidepressants only provide a therapeutic improvement for people who have quite severe cases of depression. For people with mild depression, the authors suggested that there was no real benefit to using them.
However, critics have argued that the statistical analyses in Kirsch’s paper were flawed, and biased against antidepressants. Furthermore, a similar, but less-often cited paper came out in the New England Journal of Medicine just a few weeks earlier than the Kirsch study, and finished with a different message. Headed up by Erick Turner, a former FDA employee, this meta-analysis also looked at the efficacy of antidepressants, but looked at 12 types of medication instead of four. They found a similar effect to that reported in the Kirsch paper, but the interpretation was very different. In using slightly different criteria for clinical significance, Turner’s team concluded that antidepressants were generally superior to placebo, regardless of the severity of depression. It’s just that when you take into account unpublished results, the efficacy of antidepressants, although still present, wasn’t as great as published findings made out.
This is why it’s difficult to say with any confidence what is actually going on with antidepressants. Some studies are statistically flawed, and some contradict each other, both in the interpretation but also in the findings (for example, a study from 2012 in JAMA by Gibson and colleagues argued that antidepressants are effective for mild or moderate depression). Drug manufacturers withhold data that show a lack of efficacy, as was the case with reboxetine in 2010.
Sadly, turning to other types of therapy doesn’t provide a clearer answer. A recent meta-analysis looking at the efficacy of psychotherapies versus placebo pills suggested that they’re no more effective than antidepressants – so whether you think psychotherapy works really depends on your stance about pills. Moreover, studies looking at psychological treatments such as cognitive behavioural therapy seem to suffer from the same problems with publication bias and withheld data as clinical trials of antidepressants.
All of this means that it’s easy to cherry-pick evidence for your side of the debate. For the anti-psychiatry/anti-antidepressant crowd, Kirsch’s meta-analysis – or rather, the interpretation of it – is solid evidence that pushing pills for depression is wrong. For the pro crowd, there are studies like the 2012 Gibson paper that you can cite in favour of their use – except there are problems with that study too. The truthful answer is that we don’t really know how effective antidepressants are.
None of this means that antidepressants don’t work. It just means that we don’t know yet. It’s a bit of a clichéd thing to say, but we really do need more research: more robust research that isn’t influenced by monetary gains or emotional predispositions towards one outcome or another. Until we get those sorts of studies, inflammatory and ill-informed posts that berate the use of antidepressants, or which casually refer to "SSRI-munching depressives", only serve to stigmatise depression and isolate sufferers.