Tag: Neuroscience

It’s time to get deep (TMS).

On August 4, 2020

Written by Jen Baily

Edited by Anna Feitzinger

Illustration by Sydney Wyatt

As I sit with earplugs in my ears, a tight velcro cap and a firmly secured helmet on my head, my right hand and right eye twitch of their own accord while the magnetic field creates a drumroll sensation two inches into my skull. It only lasts three seconds, but repeats over twenty minutes until my session is complete. This will continue every day for a month, then twice a week for two months.

As someone with drug-resistant major depressive disorder (MDD), there are few options available to treat my symptoms, especially after being on the maximum doses of 5 different medications over the last few years. Electroconvulsive therapy (ECT), colloquially known as shock therapy, is often used as a last resort; however, it can cause severe memory loss and brain damage. Anecdotally, I’ve known friends that have undergone ECT who were never the same, which took it off the table for me. It wasn’t until meeting a psychiatrist to manage my medications that I learned about deep transcranial magnetic stimulation (dTMS), and how it is a non-invasive procedure for which I was a good candidate.

From the paragraphs above, as well as the name dTMS, you probably get the idea that dTMS is a deep, skull-penetrating magnetic pulse. How can this be used specifically to treat depression? The idea behind dTMS is to use this magnetic field to affect neurons, which act as conductors.

In 1985, Anthony Barker and his associates produced the first transcranial magnetic stimulation (TMS) device. It was based on Faraday’s discovery in 1881, where a magnetic field was created by running electricity through a coil. By rapidly switching the magnetic field’s intensity or direction, you can depolarize neurons in a specific region of the brain. Though not fully fleshed out, it is thought that increasing the neural activity in the mood center of the brain, the dorsolateral prefrontal cortex (DLPFC), may be the mechanism by which dTMS alleviates symptoms of depression.

The treatment targets the DLPFC on the right side of your head. The psychiatrist or technician finds the DLPFC by applying magnetic pulses until your hands begin to twitch, indicating the magnetic fields have reached the motor cortex. This allows the doctors to position the helmet containing the magnets over the DLPFC and to induce the firing of neurons in the area. dTMS is akin to Transcutaneous Electrical Nerve Stimulation (TENS) machine, except dTMS is specialized to stimulate the brain while TENS is inTENded (pun) to reduce pain. Nevertheless, the principle of manipulating the nervous system to the benefit of the patient remains the same. The neural activity caused by the dTMS magnets increases expression of brain derived growth factor (BDGF), increased neural outgrowth and connectivity in rats (Paus, 2011), and showed a major elevation in mood of patients relative to a placebo treatment during clinical trials (Yates, 2016). BDGF accomplishes these tasks due to its role in development, maturation, and maintenance of neurons.

By increasing the activity of neurons in the brain regions typically affected in patients with MDD, a burst of growth is thought to follow the acute/intense phase of treatment, when a patient is going in every day. During the second phase, where a patient is treated a few times a week, the activity is thought to be maintained while the brain adjusts. Relative to previous models of the TMS technology, deep TMS has an excitingly high “remission rate of 32.6 in active deep TMS (vs 14.6 sham treatment)” (Levkovitz, 2015). Remission of MDD is typically thought to be a significant decrease in depressive symptoms for longer than 4-6 months (Frank, 1991). While this may seem like a low number, for someone suffering from depression, any reduction in symptoms can be helpful, and full remission of symptoms can allow someone to function normally. For the third of patients who’ve never felt relief, this is life-changing.

After extensive studies on rats and clinical trials on humans, the FDA approved dTMS use for patients who had failed 2 or more medications during their current episode of depression. Because dTMS is not a medication, simply a locally applied magnetic field, it is without the usual side effects such as “weight gain, sexual dysfunction, nausea, tremors, dry mouth, diarrhea, headaches, constipation, sweating, sleepiness or anxiety” that are associated with antidepressant use (History of dTMS). What’s wonderful, in my opinion, is that the patient can drive to and from their appointment. There are minimal side effects that usually dissolve shortly after a treatment session. Apart from the super magnets being quite noisy, the strangeness of the feeling itself, and occasionally scalp tenderness, it really is an amazing option for patients with drug-resistant MDD.

If dTMS is such a wonder “cure” for depression and anxiety related disorders, 1) why haven’t more people heard of it and 2) why don’t more people utilize this technology? To address question one, I’ll quote my lovely psychiatrist, “stigma.” There is a certain stigma associated with a daily treatment regime, especially one that requires transportation to a clinic. Though effective, it is a new technology and can often be lumped together with ECT in the public eye, which can be a traumatic experience for patients. To address question two, dTMS is very expensive. UC student health insurance is quite good for mental health services, but even then, I had to fail out of 5 medications and rate at a specific level of depressive symptoms prior to any coverage for almost a year. Failing out of medications involved either severe side effects or lack of effect for 16 weeks of treatment. If the insurance company doesn’t think you’ve gone hard enough for long enough, they can request that you take higher doses of medication prior to approval. All this is associated with the side effects mentioned previously, and during this time the patient is suffering. Additionally, a patient may be suffering to the point of suicidal ideation, but is functional enough to score below the required threshold on a PHQ-9 form. If a patient battling with depression must be their own advocate while on heavy medications and experiencing symptoms, getting to a place where dTMS is possible can be difficult. However, things are starting to change for the better.

As dTMS becomes a more mainstream treatment option, more and more patients are seeking it out to ameliorate their symptoms. Along with the patients themselves feeling better, those in their lives are able to notice improvements. My own partner told me that I was able to carry a conversation for significantly longer after a month of treatment relative to my depressive episode. As more and more people notice the impact that this treatment has on their loved ones, word will spread. Additionally, within the past 10 years, mental health stigma has significantly decreased. Now, I can openly talk about my own experience with minimal impact to my career prospects, and am still viewed as a functional and contributing member to my community.

In learning about dTMS for my own sake, I was amazed by the scientific literature behind it. The technology brings together physics and physicians, neuroscientists and patients. Through their creative and thorough research, hope has been brought to many suffering with MDD, myself included. If you or someone you know has struggled with a severe depressive episode, perhaps now is a good time to discuss dTMS with your physician or other new technologies as treatment options. And always remember, reach out if you need help. You’ll be surprised by how many people and how many treatments out there can help.

On campus services – UCD specific

https://leadership.ucdavis.edu/strategic-plan/task-forces/mental-health

Individual counseling
Couples counseling
Group therapy
Skills groups
Case management
Career counseling
Outreach to the campus community

They only work if you use them.

Partial Hospitalization and Intensive Outpatient Programs

Group therapy at a hospital location, often using cognitive behavioral therapy, with access to on-call psychiatrist and nurse.

National Suicide Prevention Lifeline

We can all help prevent suicide. The Lifeline provides 24/7, free and confidential support for people in distress, prevention and crisis resources for you or your loved ones, and best practices for professionals.

Online Chat – Lifeline

1-800-273-8255

“Warm Line” – Talk to trained listeners before a crisis: Visit http://www.warmline.org/ to find the number for your area.

Talk to trained listeners over text: https://www.crisistextline.org/

References

http://www.brainefit.net/history-of-tms.html

Yates E, Balu G. Deep Transcranial Magnetic Stimulation: A Promising Drug-Free Treatment Modality in the Treatment of Chronic Low Back Pain. Del Med J. 2016;88(3):90‐92.

Johnson, Mark. “Transcutaneous Electrical Nerve Stimulation: Mechanisms, Clinical Application and Evidence.” Reviews in pain vol. 1,1 (2007): 7-11. doi:10.1177/204946370700100103

Levkovitz, Y., Isserles, M., Padberg, F., Lisanby, S. H., Bystritsky, A., Xia, G., … Zangen, A. (2015). Efficacy and safety of deep transcranial magnetic stimulation for major depression: a prospective multicenter randomized controlled trial. World psychiatry : official journal of the World Psychiatric Association (WPA), 14(1), 64–73. doi:10.1002/wps.20199

Tomáš Paus Manuel A. Castro‐Alamancos Michael Petrides (2011). Cortico‐cortical connectivity of the human mid‐dorsolateral frontal cortex and its modulation by repetitive transcranial magnetic stimulation. European Journal of Neuroscience. 14(8), 1405-1411. https://doi.org/10.1046/j.0953-816x.2001.01757.x

Frank E, Prien RF, Jarrett RB, Keller MB, Kupfer DJ, Lavori PW, Rush AJ, Weissman MM. Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry. 1991 Sep; 48(9):851-5.

Psychedelics in Biology and Mental Health

By Staff

On August 23, 2019

In main_pub

Written by Keith Fraga

Edited by Mikaela Louie

Psychedelic drugs are often taboo in US culture particularly since their extensive criminalization in 1970. Substances like LSD, MDMA, DMT, and those derived from fungi like psilocybin, are drugs known to have hallucinogenic effects on humans. The ability of these substances to produce mind-altering experiences lead to massive efforts to control their study and use.

However, restrictive policies surrounding psychoactive and other mind-altering substances may be changing. For example, cannabis is undergoing rapid social and legal acceptance in the US. The City of Oakland legalized the recreational use of magic mushrooms in June, another potent hallucinogenic. Substances such as ayahuasca have a long history as a traditional medicine. Whatever impact psychedelics have on treating debilitating mental illnesses deserves experimental study and mechanistic understanding. Indeed, psychedelics are in several clinical trials to treat various mental illnesses, like depression, anxiety, PTSD, with the potential to be applied to many more mental health conditions. UC Davis researchers recently published an article in Cell on a study of psychedelics’ effects on neural plasticity.

Diving into the literature, I wanted to answer a few specific questions. What is the history of psychedelic research? Where did restrictive policies surrounding psychedelics come from in the first place? What has contributed to the thawing of restrictions on clinical psychedelic use ? How has biology and neuroscience changed our understanding of these substances? And lastly, what do we not know and where should we be cautious?

HISTORY

The history of psychedelic drugs help us understand their possible future. Psychedelics refer to many substances, and naturally occurring psychedelics such as psilocybin or ayahuasca have been consumed by humans for centuries. Others are more recent in human history, being chemically synthesized in the late/early 19th-20th centuries. When consumed, psychedelics generally cause an altered state of perception. Often these altered states affect tethers to reality, mirroring what happens in psychosis. The history and story of lysergic acid diethylamide (LSD) is an important example of the use and study of psychedelic drugs.

LSD was first synthesized by Swiss scientist Albert Hofmann in 1938. Hofmann set out to synthesize compounds that could be used for blood vessel constriction, which could help in medical applications to reduce blood loss. After accidental contact with LSD, Hofmann found that this compound had hallucinogenic properties.

Hofmann self-administered doses of LSD to test and observe its effects, becoming convinced of LSD’s potency to address mental illness. Hofmann contributed to the spread of LSD from doctor to doctor, making its way to the US. It was quickly found that LSD had potent therapeutic effects for treating various psychological conditions and became wildly presubscribed by therapists across the US and Europe.

USE AND REGULATION IN THE UNITED STATES

An important aspect to the rise in LSD usage was the prescription and research by independent, unregulated clinics and therapists. In this unregulated climate, LSD found its way out of the laboratory and into the 1960s US counter-culture. The culture around psychedelic research and usage at this time was very exploratory. As with the initial discovery and subsequent spread of LSD, therapists and researchers self-experimented and shared these compounds without discretion.

The obvious potent effects of LSD spurred a generation’s worth of compelling, rigorous research. Figure 1, shown below, depicts the relative citation rate for the terms “psychedelic” or “lysergic acid diethylamide” in any journal article title/abstract. The years between 1950-1970 can be called the “golden-age” of clinical and basic research on uses for LSD. During this period, much was learned about LSD’s effects on human psychology, crucial observations on the aspects of psychedelic “trips”, effective uses of LSD in psychedelic assisted therapy, all of which are now being re-examined with modern medical and biological methods.

Figure 1: Citation rate for words “psychedelic” or “Lysergeic acid diethylamide” in journal article title/abstracts. The data series in blue is just for “psychedelic” or “Lysergeic acid diethylamide”, while the red series is a separate search with additional search terms for other psychedelic substances. Find the interactive version here.

It is also clear from Figure 1 is the “golden-age” of LSD research rapidly came to an end. In response to growing concerns for unregulated, unethical use of LSD, the Food and Drug Administration adopted new policies restricting the use, possession, and manufacturing of these drugs. A series of legal policies were installed in the ‘60s to curtail the use, possession, manufacturing, and research into these compounds, culminating in the Controlled Substances Act (CSA) in 1970. The CSA is the legal authority that established the Schedule system for controlled substances. Schedule I is the most restrictive category of compounds. With strict policies and massive legal consequences for inappropriate use of these substances, many researchers and therapists in the field ceased their work.

THAWING OF RESTRICTIONS ON PSYCHEDELIC RESEARCH

It is difficult to identify a singular cause for the increase in interest and research on psychedelics. That being said, I find two specific developments particularly informative to the growing acceptance of psychedelic research. First is the research on how psychedelics can improve the quality of life for patients with life-threatening disease or terminal illness. Patients with life-threatening diseases, terminal illness, and associated chronic pain experience lower quality of life, higher rates of depression, and lower life-expectancy. While researching for this article, I found the following interview with Michael Pollan, a journalist who studies the impacts of psychedelics and their potential growing role in society. In this interview, he relates what sparked his interest in therapeutic use of psychedelics was their ability to improve the mental health of terminally ill patients. Numerous recent studies and reviews have recently contributed to this area of research. Psychedelics in end-of-life care was actually studied in the 60’s, and it is now being revived. Current research on therapeutic effects of psychedelics has demonstrated they can dispel anxiety, fear, and despair in these patients safely, and social taboos and legal policies are slowly changing in order to increase access and study of these benefits.

Psychedelic assisted therapy is also being explored for an array of mental health conditions. Numerous psychotherapy drug trials currently ongoing. The MultiDisciplinary Association of Psychedelic Studies (MAPS) is a central scientific research coalition propeling psychotherapy trials forward. MAPS independently supports trials for psychotherapy with a wide array of substances to tackle a diverse set of mental health conditions. Specifically, MAPS is currently working with the FDA for MDMA assisted psycho-therapy.

Psychedelic assisted psychotherapy presents an alternative therapy regimen for mental illness in part because of the global effects psychedelics have in the brain. A significant hypothesis in this field is psychedelics and psychiatric medications address mental illness at different scales. Psychiatric medications, like antidepressants, offer to rectify chemical and functional imbalances in the brain. These often target specific neuro-transmitter/receptor imbalances. However, psychedelics impact brain activity at a systems level, disrupting default neural networks and activating connections between disparate regions of the brain. The golden-age of psychedelic research in ‘60s intuitively reached many of these ideas concerning the global effects in the brain psychedelics have. With modern developments in science, medicine, and biology, researchers can interrogate psychedelic compounds’ effects on brain function at greater resolution.

A BIOLOGICAL MAGNIFYING GLASS TO PSYCHEDELICS

A significant motivation of this article is a study by a team of UC Davis scientists studying the effects that a battery of psychedelic drugs have on structure and dynamics of neurons. This study experimentally demonstrated that many psychedelic compounds promote neurons to make new synapses, growth of new neuron axons, and altered neurophysiological functionality. In part, this is why psychedelic compounds are termed by the authors of this study “psychoplastogens” for their ability to promote plasticity at the level of the brain. These investigators also experimentally tested mechanistic models for how these large-scale structural and functional changes in response to psychedelics. Investigations similar to the UC Davis study represent how advanced techniques in biology can garner quantitative insights into the mode of action for these potent compounds.

A greater understanding of how psychedelics functionally work in the brain can lead to the generation of new compounds that have similar functional effects demonstrated in the above study, with the idea being these newly designed compounds may induce similar subjective experiences, or “trips”. In other words, the generation of novel “psychoplastogens” is possible when we learn more about what determines their function in the brain. Alternatively, psychoplastogens can be used to perturb aspects of the brain to piece together the mechanisms for subjective experience. Biology has a rich tradition of using tools to perturb a biological system and measuring its output to uncover the mechanisms that make it work in the first place. Psychedelics can serve a similar role in potentially understanding perception, cognition, and consciousness.

CAUTIONARY TALES

Nearly every editorial, podcast, or interview I have heard on this subject includes strong cautionary tales. Psychoactive drugs can have unintended consequences.The mind-altering capabilities for these drugs are so potent that they may do more harm than good for some people, which is one reason why I am particularly excited about the prospect of trained therapists guiding a patient’s trip. How the chemistry of these molecules and their therapeutic use come together to help people is an exciting new venture in medicine.