Depression is a leading
cause of disability worldwide, and treatment-resistant symptoms of depression
have a terrible personal and societal cost. They can devastate lives, careers,
and families. Some severely ill patients may be unable to attend to even the
basic elements of self-care, while others attempt or complete suicide.
Because of the clinical
urgency, deep brain stimulation (DBS) treatments for depression have been developed
over the past 15 years. These treatments require surgery to make a small hole
in the skull through which an electrode is passed into a specific brain region.
Once positioned, a standard electrical stimulation procedure is initiated,
which is modeled after highly effective DBS treatments that are used for
Parkinson’s disease, essential tremor, and other neurologic conditions.
DBS does not damage healthy
brain tissue. It works by using electrical pulses to ‘block’ neural signals
from the targeted brain area that is the known or suspected source of the
symptoms.
A large number of relatively
small open-label studies have supported the effectiveness of various forms of
DBS for both depression and obsessive-compulsive disorder.
In the current issue of Biological Psychiatry, Dr. Darin Dougherty
and his colleagues report the results of the first large-scale, randomized,
sham-controlled trial of deep brain stimulation treatment for treatment-resistant
symptoms of depression. Thirty patients received active DBS or sham ‘placebo’ stimulation
for 16 weeks, targeted at the ventral capsule and ventral striatum, brain
regions implicated in reward and motivation. A two-year open-label continuation
phase followed.
This study, conducted at
five medical centers across the U.S. that collaborated on the project, failed
to find that DBS reduced depression symptoms better than sham stimulation.
“While initial open-label
trials of DBS at the ventral capsule/ventral striatum target were promising,
the results of this first controlled trial were negative,” explained Dougherty,
Director of Neurotherapeutics at Massachusetts General Hospital and Associate Professor
at Harvard Medical School.
Dr. Thomas Schlaepfer, an
expert on DBS treatment unaffiliated with this study, from Johns Hopkins
University and University Hospital Bonn in Germany, wrote a companion piece to
this article and commented, “On first sight, this might be seen as a crisis for
the whole field of neurostimulation therapies for depression… [but we] believe
that these are examples of failed studies
and not failed treatments.”
“This study raises serious
questions about the advisability of continuing to stimulate these reward
regions in the manner employed in this study,” said Dr. John Krystal, Editor of
Biological Psychiatry. “It is
critical to understand that this study is not a universal indictment of DBS as
a strategy for depression. It may turn out that stimulating other brain regions
or stimulating these regions in different ways could provide important
benefit.”
“Given the degree of
response that we have seen in some of the most treatment refractory patients, we
agree with Dr. Schlaepfer and Dr. Krystal. Alternative study designs will have
to be considered as we conduct future clinical trials in this critical area,” concluded
Dougherty.
Finding the right questions to ask is also tough, but you’ll find that these five can help you evaluate exactly where you are, exactly where you want to go, and how you’re going to get there:
If your eyes deceive you, blame your brain. Many optical illusions work because what we see clashes with what we expect to see.
That 3D movie? Give credit to filmmakers who exploit binocular
vision, or the way the brain merges the slightly different images from
the two eyes to create depth.
These are examples of the brain making sense of the information
coming from the eyes in order to produce what we “see.” The brain
combines signals that reach your retina with the models your brain has
learned to predict what to expect when you move through the world. Your
brain solves problems by inferring what is the most likely cause of any
given image on your retina, based on knowledge or experience.
(Image caption: Experiments
tested detection of changes in direction of motion (left-hand pathway)
or depth (right-hand pathway, in blue) after neurons in V2/V3 were
inactivated. Credit: Born lab)
Individual tuning
Scientists have explored the complex puzzle of visual perception with
increasing precision, discovering that individual neurons are tuned to
detect very specific motions: up, but not down; right, but not left; and
in all directions. These same neurons, which live in the brain’s middle
temporal visual area, are also sensitive to relative depth.
Now a Harvard Medical School team led by Richard Born
has uncovered key principles about the way those neurons work,
explaining how the brain uses sensory information to guide the decisions
that underlie behaviors. Their findings, reported in Neuron, illuminate the nature and origin of the neural signals used to solve perceptual tasks.
Based on their previous work, the researchers knew that they could
selectively interfere with signals concerning depth, while leaving the
signals for direction of motion intact. They wanted to learn what
happened next, after the visual information was received and used to
make a judgment about the visual stimulus.
Was the next step based on “bottom-up” information coming from the
retina as sensory evidence? Or, as in optical illusions, did top-down
information originating in the brain’s decision centers influence what
happened in response to a visual stimulus?
“We were able to show that there’s a direct bottom-up contribution to
these signals,” said Born, HMS professor of neurobiology and senior
author of the paper. “It’s told us some very interesting things about
how the brain makes calculations and combines information from different
sources, and how that information influences behaviors.”
Selective blocking
In their experiments with nonhuman primates, the researchers cooled
specific neurons to temporarily block their signals, in the same way
that ice makes a sprained ankle feel better because it prevents pain
neurons from firing.
The team selectively blocked pathways that provide information about
visual depth—how far something is from the viewer—but not the direction
of motion. The animals were trained to watch flickering dots on a
screen, something like “snow” on an old television, and detect when the
dots suddenly lined up and moved in one direction or changed in depth.
If the animal detected motion or a change in depth, making an eye
movement to look at the changed stimulus would result in delivery of a
reward.
When the neurons were inactivated, the animals were less likely to
detect depth, but their ability to detect motion was not affected. This
told the scientists that feed-forward information, not feedback, was
being used by the animal to make its decision. Their findings help
explain how relative motion and depth work together.
Two pathways
“Combining two pathways that compute two different things in the same
neurons is essential for vision, we think,” Born said. “But for these
two particular calculations, first you have to compute them separately
before you can put them together.”
Born believes there are other implications of their work.
“We think that the same operations that are happening in the visual
system are happening at higher levels of the brain, so that by
understanding these circuits that are easier to study we think we will
gain traction on those higher level questions,” Born said.
