Brain Stimulation (2011) 4, 1–6

www.brainstimjrnl.com

ORIGINAL ARTICLES

A new technique for controlling the brain: optogenetics

and its potential for use in research and the clinic
Ryan T. LaLumiere

Department of Psychology, University of Iowa, Iowa City, Iowa

The recent development of optogenetic techniques has generated considerable excitement in

neuroscience research. Optogenetics uses light to control the activity of neurons which have been
modified to express light-sensitive proteins. Some proteins, such as channelrhodopsin, are cation
channels that produce depolarization of neurons when illuminated. In other cases, neuronal activity can
be inhibited through illumination of proteins, such as the chloride pump halorhodopsin, that
hyperpolarize neurons. Because these proteins can be selectively expressed in specific cell types
and/or in specific locations, optogenetics avoids several of the non-specific effects of electrical or
pharmacological brain stimulation. This short review will explain the physiology of this technique,
describe the basic and technical aspects of the method, and highlight some of the research as well as the
clinical potential of optogenetics.
Ó 2011 Elsevier Inc. All rights reserved.

Keywords channelrhodopsin; halorhodopsin; ChR2; NpHR

Over the past few years, optogenetics has begun to
revolutionize the field of neuroscience as well as opening
up new possibilities in the field of brain stimulation. The
optogenetic technique uses light to control the activity of
neurons expressing light-sensitive proteins, thus enabling
those using the technique to avoid the nonspecific effects of
electrical stimulation or pharmacologic manipulation.
Moreover, because the expression of the proteins is genet-
ically targetable, optogenetics limits the population of
neurons that respond to the light, providing an important
level of resolution. This review will provide a brief
explanation of the physiology and technical aspects
involved in this technique and address recent uses of
Correspondence: Ryan T. LaLumiere, Department of Psychology, 11
Seashore Hall E, University of Iowa, Iowa City, IA 52242.
E-mail address: ryan-lalumiere@uiowa.edu
Submitted June 17, 2010; revised September 3, 2010. Accepted for
publication September 24, 2010.
optogenetics and the potential for its use in research as
well as in the clinic.
Physiology of light-sensitive proteins
for control of neuronal activity
In the first report on the use of the light-gated cation
channel channelrhodopsin-2 (ChR2; Figure 1 for a depiction
of ChR2), Boyden et al.1 showed that pulses of blue light at
approximately 470 nm wavelengths induce spikes of action
potentials in cells expressing the ChR2 protein. Hippo-
campal neurons expressing these channels can follow trains
of light pulses up to 50 Hz with 95% fidelity. 2 Importantly,
long-term ChR2 expression does not appear to alter the
basal physiology of transduced neurons or show evidence
of toxicity,1 suggesting that neuronal expression of ChR2
produces optically controllable, physiologically relevant
systems. Studies in mice with retinal photoreceptor

1935-861X/$ - see front matter Ó 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.brs.2010.09.009
2 LaLumiere

Na+ Cl-

Channelrhodopsin Halorhodopsin
Figure 1 Channelrhodopsin (left, in blue) is a light-sensitive, membrane-bound cation channel that opens and closes with the onset and
offset of w470 nm (blue) light, respectively. When activated, channelrhodopsin produces depolarization of the expressing neuron, leading
to temporally precise control of action potential firing. Halorhodopsin (right, in yellow) is a light-sensitive, membrane-bound chloride pump
that, like channelrhodopsin, works with excellent temporal fidelity to the onset and offset of w580 nm (yellow) light. When activated,
halorhodopsin hyperpolarizes the neuron, preventing action potentials.

degeneration have demonstrated that virally delivered
ChR2 in retinal cells restores the ability of the neurons to
transmit information to the visual cortex in response to light
in a safe, stable long-term manner.3
Since the development of ChR2, other opsins have been
identified or engineered and used to control neural activity.
Halorhodopsin (NpHR) is a light-sensitive chloride pump
(see Figure 1 for a depiction of halorhodopsin) that, when
activated, provides significant hyperpolarization of the
transduced neuron.4 Although early work with NpHR
demonstrated problems with efficacy and intracellular
aggregates with high levels of NpHR expression, alterations
to the NpHR protein have produced second generation
(eNpHR) and third generation (eNpHR3.0) NpHRs that
do not produce aggregates and have improved hyperpola-
rizing functioning.5 NpHR has the advantage of being
sensitive to a wavelength spectrum with a peak at approx-
imately 580 nm, producing minimal overlap with the
optimal wavelength spectrum for stimulation of ChR2
(w470 nm). As a result, it is possible to transduce neurons
with both opsins and stimulate or inhibit neuronal activity
with pulses of light of different wavelengths.4
Considerable advances continue to be made in the
development of opsins for neurobiologic use. For example,
optoXRs are optically controllable G-protein-coupled
receptors that trigger traditional intracellular signaling
pathways.6 Recent engineering has produced a ChR2
mutant labeled ChETA that reduces double-spiking in
response to light, a problem with ChR2, and can follow
trains up to 200 Hz, far beyond the 40-50 Hz ceiling for
many cells expressing ChR2.7 Recent screening of micro-
bial opsins has led to the discovery and characterization
of archaerhodopsin-3 (Arch) and the Leptosphaeria macu-
lans opsin (Mac), two light-activated proton pumps that
provide powerful inhibition of neurons without the
inactivation that can occur with NpHR.8 As new opsins
are developed, they will continue to expand the kinds of
questions that are tractable with optogenetics.
Technical aspects in the use of optogenetics
Opsin expression
Transgenic animals can be created with opsin expression
under the control of general or specific promoters,9,10
though, with cell class-specific promoters, the protein
expression is often weak. To achieve the high opsin expres-
sion levels necessary for optogenetic control, a mouse with
the transgene Cre-recombinase under a cell-specific
promoter can be used. This system then uses a viral vector
that transduces the neuron with the opsin gene, requiring
the action of Cre for opsin expression.11 This system
enables the opsin itself to be under the control of a strong
but general promoter, as the neuronal specificity is
conferred by the promoter for the Cre-recombinase and
opsin expression cannot occur without the action of Cre.
This has permitted experiments in which the opsin expres-
sion is limited to dopaminergic neurons of the ventral
tegmental area.11 The major disadvantage of this method
is that it requires the use of transgenic animals, thus
limiting it to certain species and nonclinical use.
For optogenetics in other species that are less tractable
for transgenic models, such as rats, or for potential human
therapeutic use, viral transduction of cells provides the best
route for opsin expression. In particular, the specificity and
localization of virally mediated expression would be highly
desirable in clinical use. Adeno-associated virus (AAV) has
already been used to deliver genes into neurons of humans
as part of gene therapy,12-14 making AAV a highly feasible
Optogenetics and neuroscience 3

A B

M
P
X N
Z
Y
O

Figure 2 A, One method of targeting specific neurons using optogenetics uses cell-specific promoters that control the expression of the
opsin. In this case, neurons X and Y are different classes of neurons but are located in the same structure. Thus, a virus containing
channelrhodopsin and a promoter specific to neurons like X can be injected into the structure, but only neuron X will express channelrho-
dopsin, enabling cell-type specific control of activity in the structure. B, In another method for gaining specificity, the structure on the left
(in yellow) is transduced with a channelrhodopsin-containing virus but only the axon terminal region for neuron M is illuminated with the
appropriate light. This method allows for selective control of a specific pathway without affecting other efferent pathways from the
transduced structure (e.g., neuron N) or other afferent pathways entering the illuminated structure (e.g., neuron O).

vector for delivery of opsins in future clinical studies. In
optogenetics, viruses such as AAV or lentivirus (LV) can
be packaged with the transgenic elements containing the
sequence for the opsin as well as a promoter.15 Both viruses
produce long-term expression of the opsin protein. Full,
stable in vivo expression of the opsins in rodents is depen-
dent on both vector and promoter choice and typically
requires 1-3 weeks for the cell body and 6 or more weeks
for the distal ends of axons, depending on the distance
and virus used.16 If the virus is administered via microin-
jections into the neural structure of interest, successful
transduction will occur only in the population of neurons
within a geographically circumscribed area around the
site of the injection, depending on, among other factors,
the viral titer, volume infused and, for AAV, serotype
used. Thus, spatial specificity of the opsin expression can
be controlled by the location of the infusion as well as titer
and type of virus used. In combination with the physical
limits of illumination, viral transduction of opsins can
produce a powerful method of gaining spatial resolution.
As with transgenic animals, opsin production mediated
by viral transduction is controlled by promoters in the
transgene cassette. These promoters can confer specificity
in terms of the types of cells that will express the protein.
Figure 2A provides a visual explanation of the benefits of
this kind of specificity. For example, use of the CaMKIIa
promoter will permit the protein to be selectively expressed
within excitatory glutamatergic neurons in certain
regions.17 Alternatively, a general neuronal or ubiquitous
promoter can be used if such specificity is not necessary.
The major limitation, however, for viruses is that the size
of the construct that can be packaged into the virus is
limited. For AAVs, the construct must be under w5.2 kilo-
bases,18 whereas for LVs, it must be under 8 kilobases.15 In
practical terms, this has limited the promoters that can be
used to those small enough to be packaged with the opsin
gene in the virus.
With optogenetic methods, one can thus stimulate
neurons of a particular cell type in a specific location
(anatomy) with tremendous temporal precision and control.
This kind of precision outstrips traditional electrical
stimulation methods and has already provided valuable
information on thorny neuroscience questions such as the
possible mechanisms of action of deep brain stimulation
(DBS) for Parkinson’s Disease (PD) and the origins of the
blood oxygen level dependent (BOLD) imaging signal
commonly used in fMRI studies.19,20 These examples will
be discussed below.
Technical methods for conducting optogenetic
experiments
When expression of the opsin has occurred, stimulation of
the opsin typically occurs via light transmitted through
a fiber optic cable. Because the opsins are expressed in the
membranes of the neurons, from the cell bodies to the axon
terminals, the location of the fiber optic tip in the brain can
confer specificity with regard to spatial resolution in the
control of neurons. The cell bodies of neurons can be
illuminated, as in Figure 2A, or alternatively, the fiber
optic tip can be placed in the axon terminal region, as in
Figure 2B. Illumination of the axon terminals allows for
control over specific pathways without directly affecting
other afferent pathways to the illuminated structure or
other efferent pathways from the transgene-expressing
structure.16,19
Traditionally, the light source used in most optogenetics
experiments has been lasers (e.g., ref 19), high-power light-
emitting diodes, or Xenon lamps with the appropriate
wavelength filters (e.g., ref 21). Opsins have a peak
4 LaLumiere
sensitivity to a particular wavelength of light. Thus, the
choice of a light source with the appropriate power and
wavelength to produce strong activation is critical.
The light-generating source is then connected to a fiber
optic cable. The end of the fiber can then be inserted into
the brain region of interest (i.e., either the cell body region
or the axon terminal region). Given the conical shape of
light produced by the fiber and sufficient light being
produced by the fiber, the tip of the fiber frequently
terminates approximately 0.3-0.5 mm before the center of
intended stimulation for optimal activation and minimal
damage to the structure of interest,19 though the area of
tissue receiving sufficient light for opsin activation
depends, in part, on the amount of light output at fiber tip
and numerical aperture of the fiber. In awake behaving
animals, placement of the fiber has typically been accom-
plished by insertion of the fiber optic tip through a previ-
ously implanted intracranial cannula. For behaving
animals, it may also be necessary to have an optical
commutator between the light source and the fiber optic
that is inserted into the brain to prevent torsion on the fiber
optic cable, which can damage the fiber. In addition, if
bilateral illumination is desired, a fiber splitter can also
be placed after the commutator. Our own unpublished find-
ings, however, indicate that commutators and splitters
produce a significant loss of light, making the power of
the light source a crucial variable.
Instrumental research findings
The use of optogenetics in research will undoubtedly
revolutionize many fields. Already, the safe and long-term
expression of ChR2 in nonhuman primates, as well as
optical stimulation of the ChR2-expressing neurons in those
animals, has been demonstrated.21 This is a finding of
significant value as primate experiments typically last
much longer than rodent experiments and can model behav-
iors much closer to humans’ behavior. In the field of
cortical mapping, optogenetics has led to the use of an auto-
mated system for generating such maps, permitting consid-
erably faster mapping with fewer of the problems normally
found with electrical stimulation-based methods.22
Although it is beyond the scope of this perspective to
review every study using optogenetics, the following in-
depth examples demonstrate the breadth of potential uses
of the optogenetic technique, the ability of optogenetics
to provide a new method of interrogation for long-
standing questions, and the potential clinical impact of
optogenetics.
DBS has become increasingly common as a treatment
for a variety of neurologic and psychiatric diseases and its
use continues to be explored for other diseases.23,24 In
particular, DBS has become known as the treatment of
last resort for cases of PD.25 Although it is apparent that
DBS of the subthalamic nucleus (STN) is effective at
reducing the symptoms of PD,26 it has not been clear
how DBS produces these effects, and various hypotheses
have been suggested for its effects. Because DBS would
be expected to affect activity of the STN principal neurons
as well as any afferent axons, it is impossible to know
precisely how DBS is reducing PD symptoms.
Recent findings using optogenetics,19 however, have
begun to provide some answers for how DBS might amelio-
rate PD symptoms. Using an animal model of PD, based on
a unilateral nigrostriatal lesion, researchers used optoge-
netics to isolate specific sets of neurons to investigate this
issue. Across several experiments using either rats with vir-
ally mediated transduction or transgenic mice, the authors
demonstrated that high-frequency stimulation of ChR2-
expressing STN cells or inhibition of eNpHR-expressing
STN cells had no effect on PD symptoms. In contrast,
high-frequency stimulation of the incoming STN afferents,
as well as of the M1 motor cortical region that projects to
the STN, potently reduced the symptoms in this model.
That finding strongly suggests that DBS-induced alterations
in M1-STN pathway activity are responsible for the thera-
peutic effects of DBS in PD patients. In this study, the op-
togenetic method has provided a clue about the mechanism
of action of a different brain stimulation method (i.e., DBS)
and even points to other ways of therapeutic stimulation,
such as direct cortical stimulation. By resolving the mech-
anisms underlying clinical therapies, such as DBS, optoge-
netics may provide a method by which such therapies can
be improved.
Recent work has also illustrated how the genetic
targeting of optogenetics enables previously impossible
experiments to be performed. Using a combination of
transgenic mice and AAV, Tsai et al.11 were able to selec-
tively express ChR2 in dopamine neurons of the ventral
tegmental area to investigate the role of these neurons in
appetitive conditioning. Although pharmacologic and elec-
trophysiologic techniques have been used to manipulate the
ventral tegmental area to address this issue, the interpreta-
tion of results using such methods has always been limited
by the knowledge that the ventral tegmental area contains
a heterogeneity of cell types.27 With selective control of
the ventral tegmental area dopamine neurons, phasic (50
Hz), but not tonic (1 Hz), stimulation of these neurons
induced conditioned place preference for the phasic
stimulation-paired chamber,11 opening up an entire host
of questions that can now been directly investigated
through such methods.
Other experiments have also used optogenetics with
functional magnetic resonance imaging (fMRI) to investi-
gate the relationship between local neuronal activity and
the BOLD signals measured in the fMRI.28 In particular,
with BOLD signals, it has not been clearly demonstrated
whether such signals result from local excitatory activity,
inhibitory neurons, modulatory neurons, or even fibers of
passage. Therefore, the authors used the ability to geneti-
cally isolate neuronal subtypes with optogenetics to
Optogenetics and neuroscience
selectively stimulate principal neurons of the M1 region
and produce positive BOLD signals. In contrast, photosti-
mulation of putative GABAergic neurons produced
a zone of negative BOLD signals surrounding the local
positive BOLD signals. Moreover, the authors demon-
strated that the use of optogenetics with fMRI could eluci-
date the connections among structures found with BOLD
signals, in contrast to the difficulties found with traditional
electrical stimulation of structures that would be expected
to activate local neurons, afferent inputs, and fibers of
passage and, thereby, confound results. These findings
illustrate the clear benefits of optogenetics in terms of
resolving long-standing questions, particularly in regard
to issues that will have a major therapeutic impact.
Potential future uses in research and
therapeutics
The research highlighted above illustrates the types of
clinically relevant questions that optogenetics has already
begun to address. In particular, as noted, such questions
may have previously been intractable but can now be
investigated with optogenetic tools. With viral delivery of
the opsin genes, control of a genetically targetable cell
population occurs through localized transduction of cells as
well as through the limited expression depending on the
promoter used. Moreover, as the photostimulation can be
provided at the cell body region or anywhere along the
axon, including the terminal region, this provides another
controlled level of spatial resolution. Because these systems
work not only in reduced systems but also in awake,
behaving animals, the questions that can be addressed by
this technique are limited by the imagination of the
researcher.
Can this technique ever be used therapeutically in
human patients? Certainly, there are significant hurdles
that would need to be overcome for this technique’s clinical
use. Recent work has used virally mediated transduction of
ChR2 in nonhuman primate cortex and found safe, stable,
long-term expression of ChR2 with excellent control over
neuronal firing, suggesting that, at least between rodents
and primates, there are no significant problems in the use
of optogenetics.21 Using viruses to introduce transgenes,
although a relatively old concept, has only recently had
the appropriate technical advancement to show its promise
for the treatment of disease. In recent trials, AAV-mediated
gene therapy has been shown to be at least modestly effec-
tive and safe.12,13,28,29 Although AAV is generally consid-
ered unlikely to produce immune responses, it should be
noted that it is capable of eliciting an immune response
in the brain and, thus, work must be monitored for such
safety issues.29 On a smaller scale, the development of
very small, implantable yet powerful light sources with
long-lasting batteries will be a necessity for clinical use
of optogenetics.
5
Despite these and other unknown potential problems,
optogenetics would offer some immediate benefits as
a replacement for treatments such as DBS. As DBS
stimulates all cells and fibers within a given area, it is not
surprising that unwanted side effects are a problem in the
use of DBS. Optogenetics would largely avoid this issue
through the selective transduction of only the appropriate
neurons as well as the application of the photostimulation
to the ideal region, which may not be the same region
where DBS electrodes are placed. Recent findings also
demonstrate the precision with which neurotransmitters can
be released via optogenetic control of neurons as well as
a lack of change in blood flow and pH resulting from
optogenetic stimulation of neurons,30 suggesting that opto-
genetically controlled brain stimulation may have other
significant advantages over other stimulation techniques.
As with the research potential for optogenetics, it is difficult
to predict the clinical future for this technique. Nonetheless,
for any psychiatric disease or neurologic disorder in which
dysfunction is at least expressed through alterations in
neuronal or network activity, it remains a distinct possibility
that photocontrol over specific neurons or even larger
networks will reduce or eliminate the symptoms of the
disorder, even if it does not provide a ‘‘cure’’ for the disease.
For example, PD results from the loss of dopamine input to the
caudate-putamen. Although DBS of the STN provides one
potential therapeutic avenue, optogenetics may also provide
a means by which the effects of dopamine itself on basal
ganglia activity can be replicated, perhaps through increased
stimulation of the remaining substantia nigra neurons. In fact,
recent work has used optogenetic control of rat dopamine
neurons in the substrantia nigra to produce dopamine release
in the dorsal striatum in a temporally precise manner,30
providing the groundwork for potential clinical uses in the
future. Likewise, evidence showing that photostimulation of
cortical interneurons can induce gamma oscillations,31,32
which are believed to be critical in attention and focusing,
may provide the foundation for treatments of a variety of disor-
ders, such as attention deficit hyperactivity disorder, in which
attentional problems are a significant symptom.
Even without direct clinical use of optogenetics, optical
control of neurons in animal models of human diseases and
disorders will enable a far more precise exploration of the
parameters and sites of stimulation necessary for symp-
tomatic relief. The results of optogenetics studies could
therefore be applied to less precise techniques such as DBS,
transcranial magnetic stimulation (TMS), or even the more
recent discovery of using ultrasound to stimulate neuronal
activity in deeper brain structures.33 Thus, this technique
will almost certainly begin having significant clinical
impact through knowledge gained about brain stimulation
methods already in use. Optogenetics is a technique for
controlling neuronal activity that has burst onto the scene
within the past 5 years and has already begun to revolu-
tionize our ability to interrogate the nervous system and
potentially to control it for clinical purposes.
6 LaLumiere
Acknowledgments
I thank Drs. David Moorman and Elena Vazey for their
helpful comments on a draft of this manuscript.
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