Optogenetics is a technique that uses light to control genetically-modified neural cells. It has given researchers unprecedented access to the workings of the brain, allowing them not only to observe its precise neural circuitry in lab animals but to control behavior through the direct manipulation of specific cells. In typical neuroscience research, neurons have been analysed and altered by tiny electrodes—a method that has poor precision in terms of targeting individual cells. But by genetically modifying cells that can be “switched on and off” by bursts of light, optogenetics allows them to be individually examined, leading to a better understanding of how the brain works as a whole. This is significant for patients with neurological or psychiatric disorders.
Optogenetics began a decade ago from the combination of genetics, optics, neuroscience and materials science. Optogenetics could allow much more precise manipulation of the brain than conventional implanted electrodes, let alone drugs, transcranial electromagnetic stimulation or electroconvulsive therapy (a.k.a. shock treatment).
Experts in the Field
Susanne Ahmari, who researches how optogenetics can be used to understand and treat psychiatric disorders, is hopeful that it could be used to help change the chemistry of the brain; she compares it to deep brain stimulation, which is already used to treat Parkinson’s and depression.
Christof Koch, the chief scientific officer of the Allen Institute for Brain Science, in Seattle, calls optogenetics one of the most momentous developments in neuroscience in the past hundred and sixty years—from the original dye-staining of cell types, in the late nineteenth century, through the use of electrodes, in the fifties and sixties, to the advent of fMRI. “Optogenetics is the fourth wave. I can now begin to intervene in the network of the brain in a very delicate, deliberate, and specific way.” Experiments have shed light on many brain functions, including learning, memory, metabolism, hunger, sleep, reward, motivation, fear, smell, and touch.
Gary Lynch, a professor of psychiatry and human behavior at the University of California, Irvine, and an expert on memory, says that optogenetics has become an indispensable tool in neuroscience. “The tremendous power is that it lets you take specific populations of neurons that are mixed up with other kinds of neurons and stimulate the type you want to stimulate”—as in some parts of the amygdala, where neurons relevant to emotion, memory, and sociability intermingle. The problem with previous experiments on the amygdala, Lynch says, is that “when you stimulated it with electrodes and you got effects, you didn’t know if it was because of this population or that population of neurons.”
Among scientists, Karl Deisseroth is best known for his development of optogenetics. Deisseroth, who is also a practicing psychiatrist, has made mental illness a major focus of his optogenetic research. Other scientists around the world are using the method to investigate unanswered questions of neuroscience.
Several new studies have shown the potential of optogenetic stimulation to rapidly modify depression- and anxiety-related behaviours in animal models. In addition to acute studies, the chronic studies are important because they show that in addition to immediate effects, optogenetic stimulation can be used to modify long-term behavior and further broaden the ability of light-activated channels to modify behavior. However, the studies in mice are extremely invasive and involve microinjection of virus into deep brain regions, implantation of light fibres in the brain above the injected brain areas and attachment to laser or LED devices. In order to clinically use optogenetics, it will be necessary to overcome these obstacles.
In 2012, Michelle M. Sidor, PhD, published an article (Psychiatry’s age of enlightenment: optogenetics and the discovery of novel targets for the treatment of psychiatric disorders) that discussed the uses and potential for optogenetics to be applied as treatment for mental illness. In terms of depressive behaviors, it has been recently shown that optogenetic stimulation of the medial prefrontal cortex exerted a potent antidepressant effect in mice susceptible to the effects of chronic social defeat stress, suggesting that lower prefrontal cortex (PFC) activity mediates depressive-like behaviours. This offers up the possibility that interventions aimed at increasing PFC neural activity could prove to be a novel anti-depressant.
Dr. Sidor states in her article that “moving forward, it is essential for both basic and clinical scientists to become familiar with this ground-breaking and innovative technology to appreciate and fully understand its applications to, and implications for, the field of psychiatry.”
Here is an article from Scientific American, in which Dr. Karl Deisseroth discusses his work and how researchers can probe how the nervous system works using optogenetics. Here is another article from 2010 written by Dr. Deisseroth regarding the role of optogenetics in psychiatric treatment.
At present, optogenetics can be used only on animals like mice and rats, whose brain functions associated with elemental emotions, like fear and anxiety and reward, are similar to those in humans. But Deisseroth’s work with patients whose VNS implants allow him to control emotions and behavior, hints at what may one day be possible.
Optogenetics was a major spur to the Obama Administration’s announcement, in 2013, of the brain Initiative, a $300 million program for developing technologies to treat such neurological ailments as Alzheimer’s disease, autism, schizophrenia, and traumatic brain injury. Deisseroth was part of the working group that created the Initiative and has vetted grant applications for it.
The number of optogenetic tools, along with the diversity of their capabilities, has expanded rapidly. Investigators are adding new opsins to their tool kits and applying molecular engineering to tweak the known opsins to make them even more useful for diverse experiments in a wider range of organisms.
Deep Brain Stimulation (“DBS”)
Deep brain stimulation (DBS) was first developed as a treatment for Parkinson’s disease to reduce tremor, stiffness, walking problems and uncontrollable movements. In DBS, a pair of electrodes is implanted in the brain and controlled by a generator that is implanted in the chest. Stimulation is continuous and its frequency and level are customized to the individual.
DBS has been studied as a treatment for depression or obsessive compulsive disorder (OCD). Currently, there is a Humanitarian Device Exemption for the use of DBS to treat OCD, but its use in depression remains only on an experimental basis. A review of all 22 published studies testing DBS for depression found that only three of them were of high quality because they not only had a treatment group but also a control group which did not receive DBS. The review found that across the studies, 40-50% of people showed receiving DBS greater than 50% improvement.
Here is a link to questions and answers you may have regarding DBS.
Dr. Helen Mayberg is an American neurologist who has researched and conducted studies of deep brain stimulation. She is a professor in the Departments of Psychiatry and Behavioral Sciences, Neurology and Radiology at Emory University School of Medicine. Here is a link to descriptions of the studies she has conducted regarding DBS and mood disorders.
Low Field Magnetic Stimulation
Boston startup Tal Medical is developing a neuromodulation device, based on MRI technology, that – within a half hour, potentially- could improve the symptoms of depression and bipolar disease.
Here is a link to an article describing the development of the new device.
Repetitive Transcranial Magnetic Stimulation (rTMS)
Repetitive transcranial magnetic stimulation (rTMS) uses a magnet to activate the brain. First developed in 1985, rTMS has been studied as a treatment for depression, psychosis, anxiety, and other disorders.
Unlike ECT (electroconvulsive therapy), in which electrical stimulation is more generalized, rTMS can be targeted to a specific site in the brain. Scientists believe that focusing on a specific site in the brain reduces the chance for the types of side effects associated with ECT. But opinions vary as to what site is best.
In 2008, rTMS was approved for use by the FDA as a treatment for major depression for patients who do not respond to at least one antidepressant medication in the current episode. It is also used in other countries as a treatment for depression in patients who have not responded to medications and who might otherwise be considered for ECT.
The evidence supporting rTMS for depression was mixed until the first large clinical trial , funded by NIMH, was published in 2010. The trial found that 14% achieved remission with rTMS compared to 5% with an inactive (sham) treatment. After the trial ended, patients could enter a second phase in which everyone, including those who previously received the placebo treatment, was given rTMS. Remission rates during the second phase climbed to nearly 30%.
Here is a link to an in-depth description of rTMS and its side effects.
Vagus Nerve Stimulation (VNS)
Implantable wireless brain devices are being tested as a means of relieving depression, post-traumatic stress disorder, bipolar disorder and traumatic brain injury, as well as restoring movement in those with severe physical limitations. These devices represent a trend towards neural engineering, which seeks to manipulate brain signals in order to treat neurological diseases and impairments.
Vagus nerve stimulation (VNS) works through a device implanted under the skin that sends electrical pulses through the left vagus nerve, half of a prominent pair of nerves that run from the brainstem through the neck and down to each side of the chest and abdomen. The vagus nerves carry messages from the brain to the body’s major organs (e.g. heart, lungs and intestines) and to areas of the brain that control mood, sleep, and other functions.
VNS was originally developed as a treatment for epilepsy. However, scientists noticed that it also had favorable effects on mood, especially depressive symptoms. Using brain scans, scientists found that the device affected areas of the brain that are involved in mood regulation. The pulses appeared to alter the levels of certain neurotransmitters (brain chemicals) associated with mood, including serotonin, norepinephrine, GABA and glutamate.
In 2005, the U.S. Food and Drug Administration (FDA) approved VNS for use in treating treatment-resistant depression in certain circumstances:
- If the patient is 18 years of age or over; and
- If the illness has lasted two years or more; and
- if it is severe or recurrent; and
- if the depression has not eased after trying at least four other treatment
According to the FDA, it is not intended to be a first-line treatment, even for patients with severe depression. And, despite FDA approval, VNS remains infrequently used because results of early studies testing its effectiveness for major depression were mixed. But a newer study, which pooled together findings from only controlled clinical trials, found that 32% of depressed people responded to VNS and 14% had a full remission of symptoms after being treated for nearly 2 years.
Here is a link to an in-depth description of how VNS works.
Deep transcranial magnetic stimulation (dTMS)
Deep transcranial magnetic stimulation (dTMS), a non-invasive procedure that uses magnetic fields to stimulate brain cells, may be useful when added to medication to treat bipolar depression, according to a February 2017 study published in the journal Neuropsychopharmacology. dTMS has already been shown to improve symptoms in patients with major depression.
Here is a link to some details of the study as well as its implications for mental health treatment.
Harvard Brain Science Initiative – Work in Bipolar Disorder Research
In 2004, Harvard established the Center for Brain Science (CBS) within the Faculty of Arts and Sciences. CBS brings neuroscientists together with physical scientists and engineers to develop new tools for neuroscience. Members are drawn from the Faculty of Arts and Sciences, the Department of Neurobiology at the Harvard Medical School, the School of Engineering, and the Harvard-affiliated hospitals.
The Harvard Brain Science Initiative (HBI) represents a “One Harvard” approach to coordinating and serving the neuroscience research, teaching and medical community as a whole.
Bipolar Disorder Seed Grants
The HBI Bipolar Disorder Seed Grant Program supports research that advances the basic understanding and eventual treatment of bipolar disorder. Supported by a generous gift from Kent and Liz Dauten, this program seeks innovative, visionary projects with new ideas and approaches that otherwise may not attract seed funding from conventional sources. A first round of awards was made November 2015, and a second in February 2017.