INSIGHTS | PERSPECTIVES
neurons happens via neurotransmitters,
which open ion channels in the receiving
neuron, rendering their potential either
more positive or more negative (
meaning that these channels are ligand-gated).
Therefore, opening and closing ion channels
is the key to controlling neuronal impulses.
Seemingly the most straightforward way
to interface with the brain is
via an electrical connection
(5). This has been achieved by
the introduction of electrodes,
which upon application of voltage pulses may trigger nerve
impulses by controlling volt-age-gated ion channels. Such
techniques are already used in
clinical practice—for example,
to control the tremor associated with Parkinson’s disease
(6). But, to alter brain activity
in a substantial and targeted
way, one would need electrodes
for many groups of neurons in
different regions of the brain,
which would complicate how
the electrodes are wired outside of the head. The sheer
number of neurons and the size
of conventional electrode arrays (which are huge compared
with a neuron) severely limit
The use of light may overcome these limitations. Light
can be focused, and local illumination inside tissue is possible. Upconverting NPs have been used as
transducers to improve problems of light
scattering by tissues. The special feature
of these upconverting NPs is the conversion of near-infrared (NIR) light, which is
much less scattered by tissue, into visible
light (7). Because of their chemical nature,
such NPs are highly efficient light absorbers. Thus, if upconverting NPs are close to
light-gated ion channels, they absorb NIR
light and in turn emit visible light to stimulate the light-gated ion channels (see the
figure). Chen et al. used transgenic mice engineered to express light-gated ion channels
in their neurons and implanted them with
upconverting NPs. Upon NIR excitation,
green-blue light emitted by the NPs locally
activated light-gated ion channels in the
animals’ brains. Using this approach, the
authors could control behavioral patterns of
mice, such as the expression of fear, simply
by external NIR illumination.
However, the question of how such a
technique can be extrapolated to humans
remains unclear. The technique might be
used to treat the tremor of patients with
Parkinson’s disease with on-demand opti-
cal stimulation of the relevant regions in
the brain. A number of challenges must
be overcome before this technique can
be used in patients. Specifically, neurons
have to be transfected with light-gated ion
channels. This can be achieved by direct
injection of genetic vectors, or by targeted
delivery to specific regions of the brain.
This is a substantial challenge, which any
optogenetics-based approach faces. Moreover, NPs acting as transducers must be
placed close to the target neurons. Chen et
al. achieved this by local injection, which
has limited spatial accuracy, and thus stimulation extended to relatively large regions
of the brain. Conversely, targeted delivery
of NPs via blood is limited by the blood-brain barrier, which restricts the entry of
substances from blood vessels into brain
tissue. It may even be possible to transfect
neurons so that they synthesize the required NPs. This has been demonstrated in
bacteria for fluorescent NPs (8) and magnetic NPs (9).
Additionally, the plasticity of the brain
has to be taken into account. Neuronal
networks undergo continuous changes (for
example, this is the reason our brain can
“learn”) (10). Thus, the stimulation pat-
tern and placement of NPs may have to be
adjusted over time. Furthermore, NPs are
readily taken up (endocytosed) by cells in
the brain (11). This would change their dis-
tance to membrane-bound ion channels,
which may in turn prohibit stable long-term
stimulation. Thus, it will be important to
understand distance dependence of NP–ion
Potent upconverting NPs are also needed,
which are brighter and photostable. Modern
colloidal chemistry offers a huge range of
functional NP materials (12), and thus there
is hope for brighter NPs, particularly in a
biological environment. Chen et
al. used NIR intensities at the
limit of tolerable tissue heating,
which also demonstrates the
need for more sensitive NPs.
Furthermore, NPs may change
properties over time, such as
structural degradation and loss
of functional properties, which
may be tackled with different
materials and surface coatings
(13). Long-term toxicity studies
also need to be carried out.
Despite such challenges, it
may be possible to optically
excite well-defined groups of
neurons deep inside the human
brain. Eventually, techniques
may also be developed that use
fluorescent NIR or magnetic
resonance imaging probes for
the recording of neural activ-
ity, as has been demonstrated
by measuring oxygen consump-
tion (14). However, issues with
the intensity of the signals is a
technical hurdle. Although Chen
et al. have taken a big step to-
ward noninvasive manipulation
of brain activity, the complexity of the brain
imposes an imminent challenge, and future
developments in understanding brain cir-
cuits are still needed. j
REFERENCES AND NOTES
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W.J.P. acknowledges the Deutsche Forschungsgemeinschaft
(DFG grant PA 794/21-1) and N.F. acknowledges the Swedish
Governmental Agency for Innovation Systems (Vinnova).
Cap with array
of light sources
Light-gated ion channels are opened by
visible light emitted upon NIR excitation
of upconverting nanoparticles.
Inorganic nanoparticles with organic
surface capping can convert NIR into
Activating neurons with light
With technological advances, it might be possible to optically stimulate
neurons deep in the human brain. This could aid treatment of patients with