Learningdrugsreawakengrownupbrain'sinnerchild

13:1708January2014byHelenThomson
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A drug for perfect pitch is just the start: mastering new skills could become easy if we
can restore the brain's youthful ability to create new circuits
WANNABE maestros, listen up. A mood-stabilising drug can help you achieve perfect
pitch the ability to identify any note you hear without inferring it from a reference note.
Since this is a skill that is usually acquired only early in life, the discovery is the first
evidence that it may be possible to revert the human brain to a childlike state, enabling
us to treat disorders and unlock skills that are difficult, if not impossible, to acquire
beyond a certain age.
From bilingualism to sporting prowess, many abilities rely on neural circuits that are laid
down by our early experiences. Until the age of 7 or so, the brain goes through several
"critical periods" during which it can be radically changed by the environment. During
these times, the brain is said to have increased plasticity.
In order to take advantage of these critical periods, the brain needs to be stimulated
appropriately so it lays down the neuronal circuitry needed for a particular ability. For
example, young children with poor sight in one eye may develop lazy eye, or amblyopia.
It can be treated by covering the better eye, forcing the child to use the lazy eye but
this strategy only works during the critical period.
These windows of opportunity are fleeting, but now researchers are beginning to
understand what closes them and how they might be reopened.
"We used to have this dogmatic view that the young brain is full of plasticity factors that
disappear with age, and that's why critical periods close," saysTakao Hensch, professor
of neurology at Harvard University. "Then we realised that regardless of when the critical
period is triggered, its length is finite. That suggested gene programs are unleashed that
wind down plasticity."
Hensch's team has shown that several physiological changes close the door on plasticity
in animals. A key player is histone deacetylase (HDAC), an enzyme that acts on DNA
and makes it harder to switch genes on or off.
Hensch and his colleagues reasoned that reversing this molecular brake might allow the
brain's plasticity machinery to kick in again. "And that's exactly what we found," he says.
In 2010, they used valproate a drug that inhibits HDAC and is used to treat bipolar
disorder to cure amblyopia in adult mice.
To test whether valproate might reawaken the critical period in humans, Hensch,
together with Allan Young at King's College London and colleagues, had to settle on a
skill that appears impossible for adults to acquire. They chose perfect pitch because it is
a rare ability and is usually seen only in some people who were taught music before the
age of 6. There are no conclusive examples of adults acquiring it, although people who
do months of training can gain some ability to identify notes.

The team gave 24 men with little or no musical training a dose of valproate or a placebo
every day for 15 days. During the second week, participants watched a 10-minute
training video daily, which taught them to associate six different tones over three octaves
with six names, such as Sarah, David and Jimmy. The researchers used people's names
rather than the names of notes to ensure any existing familiarity with musical notation
would not influence the results.
On the final day, the group heard 18 different tones and had to give the name associated
with them. Men who took valproate identified 5.09 notes on average, a significantly
better performance than those given the placebo, who got an average of 3.5 notes
correct no better than chance (Frontiers in Systems Neuroscience, doi.org/qq8).
The study is a promising first step towards demonstrating that critical-period learning can
happen in adults, says Diana Deutsch, a psychologist at the University of California, San
Diego. "The number of subjects explored here was small," she says. "However the
results were significant, and they should be taken very seriously."
The team will now try to replicate the results in a bigger study, which will include an
additional group taking a mood stabiliser that does not affect HDAC.
Studies looking at other drugs are already under way. One hinges on a second brake
mechanism that could affect plasticity, involving genes that dampen the transmission
of the nutrient choline around a cell. Donepezil, an Alzheimer's drug, increases this
transmission, so a team at Boston Children's Hospital, which includes Hensch,
is investigating whether it can help reverse amblyopia in older children and adults. The
results are promising, says Hensch. "The first wave of subjects have improved. We don't
know how long it will last; we're looking at that now." Another study is focusing on the
antidepressant fluoxetine, better known as Prozac.
Researchers are treading with caution, however. The brain shuts down critical periods
for good reason it would be disastrous to have it rewiring itself extensively for the rest
of your life. Hensch says he would have been timid about testing valproate's effects in
humans except for the fact that it is an approved treatment for mood disorders and
epilepsy. "We're not opening the brain up to a massive rewrite. We're enhancing its
potential for plasticity which, when paired with training, can manifest in changes we
want."
It's difficult to predict the ramifications of this work, says Young, but they could be major.
Several disorders, including autism, may be a result of mistimed critical periods (see
"Timing is everything for blooming talents") so switching them back on could be useful
therapeutically. Then there is the potential to endow us with new skills. "If you can
reopen that critical period, you could potentially reawaken learning in all," says Young.

Timing is everything for blooming talents

Our developing brain is incredibly malleable, capable of structuring and

restructuring connections between neurons in response to different experiences.
Times of greatest change or "sensitivity" are called critical periods. These begin
and end at certain ages (see graph) to allow the brain to build and cement circuitry
for processes such as hearing, vision, emotion and language.
Sculpting these circuits involves a delicate balance of excitation and inhibition.
Neurons that are excited, or active, at the same time will form robust connections,
helping new circuits to form, while neurons that are inhibited or fire out of sync may
become pruned.
Researchers have now shown that certain drugs might open up critical periods in
adults (see main story). As well as potentially giving us a way to learn new skills, it
may offer a path to tackle neurological disorders. For example, many genes
implicated in autism are involved in establishing or maintaining the balance
between excitation and inhibition. Some researchers believe the cognitive deficits
seen in autism might be the result of mistimed critical periods. Studies of mice bred
to express different autism-related genes have found evidence for such mistimings.
If critical periods don't occur at the correct time, the brain may lay down some
circuits too early, which means they may link up with underdeveloped brain areas.
Or it can happen too late, in which case the functions these circuits handle, for
example the ability to identify facial features, will not integrate with more
sophisticated neural processes such as those that help us interpret others'
emotions.