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The 1982 science fiction film classic Blade Runner is a gritty detective story set in the dystopian future that raises questions about what it means to be human. In the film, Harrison Ford plays Rick Deckard, a police officer turned bounty hunter searching the streets of Los Angeles for a replicant (human-like androids) rebellion leader Roy Batty. Batty is presented as a technologically perfected being fitted with a human-template brain completely rewired to create an enemy to be deathly feared.
Fear of the perfect altered brain is prominent in science fiction—and may be particularly prevalent today, amid growing concerns about genetic editing and artificial intelligence. The prospect of a fully artificial human brain remains very distant. However, we are in the midst of a neuromodulation revolution that will increase our ability to treat disease and optimize human performance. We must, however, carefully consider the benefits and risks of these techniques in fully evaluating their potential for society as well as the individual.
A large number of patients suffering from neurological or psychiatric disorders—depression, pain, and post-traumatic stress disorder among them—are resistant to or can develop resistance to standard medication and psychotherapy, suggesting the need for new approaches. Neuromodulation may possibly be such an approach. The term (aka neurostimulation) refers to direct stimulation and modification of the nervous system through the use of electrical, chemical, or mechanical signals. Neuromodulation therapy is already used to treat many brain disorders, most commonly movement disorders, chronic pain, and depression.
There are two major categories of neuromodulation: Invasive and noninvasive. Invasive modalities are used for the most severe cases and involve surgery: they include deep brain stimulation (DBS), vagal nerve stimulation, and epidural prefrontal cortical stimulation. Noninvasive treatments include electroconvulsive therapy, transcranial magnetic stimulation (TMS), theta burst stimulation, magnetic seizure therapy, and transcranial direct current stimulation (tDCS). The neuromodulation therapies currently in use for psychiatric illnesses and traumatic brain injuries include tDCS, repetitive transcranial magnetic simulation, focused ultrasound, and DBS. Each technique can be precisely individualized based on the needs of the patient and severity of the disease.
The Origins of DBS
Deep brain stimulation has a relatively short history. Its development is mostly attributed to Alim Benabid, who, in the 1980s, discovered that electrically stimulating the basal ganglia could reduce symptoms of Parkinson’s movement disorder. Although this technique has dark episodes in its history, it holds, in the words of UC Davis Neurorobotics Laboratory Director Karen Moxon, “the promise of improving the quality of life for everyone on the planet in unimaginable ways.”
Recently, the sustained clinical benefits of continuous DBS applied to the subgenual cingulate for treatment resistant depression have created excitement around the potential of this innovative treatment strategy. However, while the effects of DBS for Parkinson’s, essential tremor, and dystonia remain impressive, the results for treatment resistant depression and other disorders are in fact mixed. That said, visible improvement in patients with severe neurological impairments and brain injuries, documented by numerous videos found online, provide persuasive testimony that this technique holds great promise.
Non-invasive Techniques Emerge
Repetitive TMS (rTMS) can modify neuronal activity locally and at distant sites by creating a strong magnetic field near the skull, which can then pass through the skull when delivered in a series of pulses. I first encountered the principle behind this technique in the 1980s in Pakistan, along with my middle school classmates, when I constructed a small electromagnet with a nail and coil and observed its effects on small metal objects. rTMS makes use of the same concept, but instead of moving metal jewelry on my armoire, I can induce plasticity between neurons in that sacred space called the synaptic cleft.
Although rTMS is already used widely to treat a number of neurological diseases and mental illnesses, its clinical benefits and risks are still being actively researched in a number of current studies. The results of past studies have been mixed, but more recent reviews have concluded that there is convincing evidence of the efficacy and safety of the technique for improving the symptoms of acute depression in treatment-resistant patients, usually through the daily stimulation of left dorsolateral prefrontal cortex. There are also many studies underway investigating the efficacy of rTMS for Post-Traumatic Stress Syndrome, anxiety, dementia, and traumatic brain injury. Clinical guidelines for this noninvasive technique have been formulated but are undergoing revision as the technique is perfected.
Transcranial direct current stimulation (tDCS), another non-invasive technique, passes direct current through the cortex, the brain’s outer layer. This differs from rTMS in that instead of inducing action potentials, which are a rapid rise and then fall in the electrical potential across the membrane of particular neurons, tDCS modulates spontaneous cortical activity, bursts of action potentials that emerge from clusters of neurons. In other words, while rTMS directly induces the firing of the specific neurons that it stimulates, tDCS changes preexisting patterns of spontaneous action potentials across a range of cells.
Although initial studies focused on immediate responses to stimulation of the motor cortex, more recent studies have explored effects on the left dorsolateral prefrontal cortex, which is also a frequent target of rTMS. As with rTMS, results have been mixed, with some studies finding that tDCS can alleviate cognitive impairments (such as the memory problems that begin to appear in the early stages of Alzheimer’s disease), and others finding no effects. More research needs to be conducted, especially in fibromyalgia, depression, addiction-related craving, and traumatic brain injury, areas in which tDCS holds much promise.
Findings in neuromodulation studies remain largely based on self-report data, which are often difficult to interpret because participants tend to be influenced by such extraneous factors as social expectations, stigma, and their own past responses. This makes it especially important to identify valid and reliable biomarkers (biological indicators of treatment effect, such as stress hormones in the blood), whenever possible, to provide objective and repeatable means of measuring treatment response and identifying future targets for treatment, such as effective TMS targets.
A final non-invasive technique is low intensity focused ultrasound pulsation. Although ultrasound has been used in a variety of medical applications for at least 50 years, its use for neuromodulation is a recently developed technique (the first published clinical application appeared in 2016, when it was employed to “wake up” vegetative patients). This technique focuses low energy sound waves through the skin and skull without surgery, precisely targeting deep structures in the brain to modify neural activity and alleviate disease symptoms.
In a recent review article, authors summarized the focused ultrasound neuromodulation studies that have been carried out in animal models and humans. Most research to date has been aimed at the treatment of various psychiatric and neurological disorders, and the development of preliminary brain mapping techniques. Because this technique is new, it is important to determine which parameters (e.g., dose, duration, and frequency) are most effective for neuromodulation. One important advantage of focused ultrasound pulsation is its ability to reach deep cortical areas inaccessible to other noninvasive methods. Because patients cannot perceive whether the device is turned on or not, there is no difficulty with creating a sham or placebo condition.
Every field begins, to put it a little bluntly, in retrospect. You use what you have to locate the area in the brain you want to stimulate, modify, treat, or improve. Thanks to recent advances in neuroscience, Magnetic Resonance Imaging in particular, we are able to locate appropriate stimulation sites not only structurally but functionally. In addition, with respect to the disease in question, we can specifically target the area of stimulation to enhance or decrease neuronal activity (e.g., when TMS is used to treat depression, specific areas in left dorsolateral prefrontal cortex are targeted). While the potential of these methods may sound a bit God-like (to someone of my generation, at least), if one assesses the effort and the intense level of inquiry needed to perfect them, the sense of power can quickly fade. We have lots of work to do, as has always been the case when we attempt to expand the sphere of human potential.
A Look to the Future
As neuromodulation research goes forward, important concerns include increased accessibility, reduced cost, and shorter duration. Theta burst stimulation—a newer form of rTMS characterized by short bursts of stimulation at high frequencies, applied five times per second—has shown great promise for the enhancement of TMS in all three areas. Single pulse TMS devices that deliver a very brief pre-set magnetic pulse against the back of the head for less than a second are already on the market and may empower at-home treatment of migraine. (Unlike rTMS, which carries a small risk of seizure, at-home single pulse devices are highly unlikely to produce any adverse outcomes).
Precise targeting is another important area for development. Most importantly, the integration of data obtained from a patient’s wearable (such as a Fitbit, Apple watches, or other monitoring devices) with noninvasive neuromodulatory devices is where we close the gap between precise location and accurate stimulus delivery. What I foresee is this: a patient will give a blood sample, have a neurological and physical exam, and provide demographic information that the physician will integrate with massive amounts of data downloaded from the patient’s wearable. Based on such copious information, the patient will be prescribed a device that targets the specific brain area that needs “fixing,” calibrated to the right dose as predicted by an algorithm and positioned by a robotic arm.
This will be true precision medicine.