May 14, 2016
Last year, in an operating room at the University of Toronto, a 63-year-old women with Alzheimer's disease experienced something she hadn't for 55 years: a memory of her 8-year-old self playing with her siblings on their family farm in Scotland.
The
woman is a patient of Dr. Andres
Lozano, a neurosurgeon who is among a growing number of researchers
studying the potential of deep brain stimulation to treat Alzheimer's and other
forms of dementia. If the approach pans out, it could provide options for
patients with fading cognition and retrieve vanished memories.
Right
now, deep brain stimulation is used primarily to treat Parkinson's disease and
tremor, for which it's approved by the Food and Drug Administration. DBS
involves delivering electrical impulses to specific areas of the brain through
implanted electrodes. The technique is also approved for obsessive-compulsive
disorder and is being looked at for a number of other brain disorders,
including depression, chronic pain and, as in Lozano's work, dementia.
In
2008, Lozano's group published a study in which an obese patient was treated
with deep brain stimulation of the hypothalamus. Though no bigger than a pea,
the hypothalamus is a crucial bit of brain involved in appetite regulation and
other bodily essentials such as temperature control, sleep and circadian
rhythms. It seemed like a reasonable target in trying to suppress excessive
hunger. To the researcher's surprise, following stimulation the patient
reported a sensation of deja vu. He also perceived feeling 20
years younger and recalled a memory of being in a park with friends, including
an old girlfriend. With increasing voltages, his memories became more vivid,
including remembering their clothes.
Using
a 3-dimensional brain mapping technique called standardized low-resolution
brain electromagnetic tomography, or sLORETA, Lozano's group
uncovered an explanation for the unexpected findings. They found that stimulating
the hypothalamus was in turn driving increased brain activity in the
hippocampus, a key cog in the brain's memory circuitry. As Alzheimer's
progresses, not only does the hypothalamus atrophy, but electrical
communication between neurons in the region also gradually becomes impaired.
That
our memories — so entwined with our personalities and senses of self — might be
so vulnerable to a brown out is, existentially speaking, rather alarming.
There's something palpably dehumanizing about reducing our past selves to the
exchange of electricity between neurons, and also about retrieving memories by
hot-wiring the brain.
Yet
the prospect of the latter is undeniably intriguing. Given that Alzheimer's
affects 1 in 9 people over the age of 65 and that current therapies are in many
patients dismally ineffective, Lozano felt all but obligated to dig further.
His group launched a test in six patients and published the results in the Annals
of Neurology in 2010.
The
study included patients with mild and severe disease who received stimulation
in the fornix continuously for 1 year. "The fornix is like the highway
leading into the hippocampus," explains Lozano. "It's easier to
stimulate than the hippocampus itself and crucial to memory function." As
expected those with more severe disease continued to mentally deteriorate,
however it appeared that in those with mild disease, cognitive decline slowed
with stimulation.
Next,
Lozano launched a randomized trial involving 42 patients from the US and
Canada, all of whom had electrodes implanted in the fornix on both sides of the
brain. In half the patients the stimulation was turned on right away. In the
other half the stimulation wasn't turned on for a year, though they didn't know
it.
Preliminary
results,
published in December 2015 in the Journal of Neurosurgery, were
mixed but encouraging.
Given
that so few people have had electrical stimulation applied to memory circuits,
perhaps the most significant finding was that both the surgery itself and DBS
of the fornix appear safe. No serious long-term neurological side effects were
seen in either patient group, supporting future research in the field.
In
terms of efficacy, however, after one year there were no significant
differences in cognition between the groups, as measured by two scales commonly
used to measure Alzheimer's disease symptoms, the ADAS-Cog
and CDR-SB. Alzheimer's tends to progress slowly and reversing or slowing the
neurodegeneration associated with condition may take time to become noticeable.
Lozano's final results won't be reported until four years out.
More
intriguing for now were comparisons of glucose utilization. Glucose is our
brains' primary fuel. The degree to which glucose is burned is a commonly used
measure of brain activity. Patients with Alzheimer's typically have reduced
glucose activity in their brains, as well as, again, shrinking memory circuits.
The older patients in Lozano's study who had stimulation turned on exhibited
markedly increased glucose use in the brain's memory regions. Not only that,
the hippocampus of some study patients who received DBS actually increased in
size.
Reversing
withering hippocampi by encouraging the growth of new neurons is seen as a holy
grail in Alzheimer's research, and Lozano's finding is supported by a recent animal study demonstrating
that DBS in rats causes the release of growth factors that induce neuronal
growth in the hippocampus.
Lozano
acknowledges that retrieving childhood memories, which he says has occurred in
about one-third of his patents — requires lofty voltages that he would be
uncomfortable sending patients home on. Yet he's encouraged by the early
findings that suggest the procedure is safe. "We also know that in
patients who receive stimulation there is an increase in glucose utilization in
memory areas of the brain," he says, a finding that could mean there's a
way to overcome some of the damage from Alzheimer's.
Evidence
supporting DBS in dementia is emerging from other research groups as well. A 2012 study
published in the New England Journal of Medicine
reported that in seven patients receiving DBS to a brain region called the
entorhinal cortex, spatial memory improved – meaning they could more easily
remember the locations of newly learned landmarks. The entorhinal cortex works
in concert with the hippocampus to solidify memories.
A
group at the University of Cologne in Germany is instead focusing on delivering
DBS to a part of the brain called the nucleus basalis of Meynert, another
region in which impaired neuron function is thought to contribute to
Alzheimer's. Last year they published a study in Molecular
Psychiatry in which four of six patients either remained cognitively
stable or improved in response to DBS, as measured by the ADAS-cog. Like in
Lozano's study no serious side effects were seen.
Despite
the mounting evidence for DBS, not everyone is convinced.
Referring
to Lozano's second clinical study, Dr. Nader Pouratian, a neurosurgeon and DBS
researcher at UCLA, comments, "The recent deep brain stimulation trial for
Alzheimer's disease clearly demonstrates the safety of this approach for trying
to treat the progression of disease. Unfortunately, [the findings] suggest that
the therapy may not be as robust as initially proposed."
However
he acknowledges Lozano's results suggest that DBS to the fornix might be
promising for a subgroup of patients, those being older people with less severe
disease.
"The
most promising areas are likely the fornix or the entorhinal area," he
says. "But I believe further studies are necessary to better elucidate the
efficacy of this treatment before proceeding to a larger scale randomized trial."
In a
2008 episode of the medical television drama House, the
show's main character Dr. Gregory House survives a bus crash that leaves his
memory murky. In an attempt to remember the medical history of a fellow
collision victim – and inspired by Lozano's initial paper — House voluntarily
undergoes deep brain stimulation. Following the procedure the grouchy TV
doctor's memory returns. As is customary on the show, he cracks the case.
DBS
for treatment of Alzheimer's and other dementias is a field in its infancy.
Unlike on TV, in all likelihood it won't be widely used anytime soon to
retrieve specific memories. "Even though House did this, we're not doing
it yet," cautions Lozano.
Yet
the fact that the therapy can in some people rescue recollections – albeit
random ones – and possibly induce new neuron growth in memory regions of the
brain seems reason enough to pursue it further.
"We're
hoping to use electricity to drive activity in areas of the brain involved in
memory and cognition," says Lozano. "We want to turn these brain
networks back on."
http://nhpr.org/post/reviving-memory-electrical-current
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