Old Techniques, and New Results
Functional neurosurgery techniques re-applied for addiction
Not your Regular Story
“As a child I would go through periods where I couldn’t sleep, I didn’t want to go to school and I was constantly sick”. This statement was made by Beth McKay after she had Deep-Brain Stimulation (DBS) surgery performed on her by Dr. Kiss, a functional neurosurgeon in Calgary, AB. Beth’s story is one similar to many patients of treatment-resistant depression. She grew up pessimistic and a cynic which she thought was rooted in her realism. Even after she was prescribed anti-depressants and therapy Beth still noticed she functioned differently than everyone around her and she struggled getting out of bed. She spent years pretending to be okay and put on a front, but no matter what she tried, it seemed nothing made her life manageable. After the surgery Beth notes that she was “nearly dead and now I’m mostly alive. I’m still figuring out what life feels like, because it feels so different and so much better than before the implant”.
Beth did not suffer from addiction, but her story is not indifferent to those who do suffer from it. Many patients who have addiction may also suffer from depression. There is also drug-induced depressive disorders connected to substance abuse.
The parts of the brain impacted by both depression and addiction are different but the possibility to begin treating those who are are treatment resistant to depression and/or addiction remains an exciting possibility.
What is Deep-Brain Stimulation?
Deep-Brain stimulation (DBS) is a procedure which involves implanted electrodes into the brain which produce electrical signals. These electrical signals regulate abnormal impulses in the brain which can affect certain cells and chemicals.
DBS is similar to implanting a pacemaker for the heart. Only, instead of managing irregular rhythms in the heart, it’s abnormal neural impulses.
The term “abnormal neural impulses” refers to a variety of illnesses which are treated by DBS including:
- Dystonia — Characterized by the uncontrollable muscle contractions and is a symptom of early onset parkinsons disease.
- Essential Tremor — The most common movement disorder which is characterized by consistent shaking in a localized part of the body.
- Parkinsons — Caused by the depletion of dopaminergic neurons in the substantia niagra. Leads to shaking, stiffness, and difficulty with various coordinated activity.
DBS is also used for conditions like epilepsy and OCD.
Research on DBS for chronic pain, dementia, and depression is ongoing but yielding positive results as seen in the linked article in the first paragraph.
What I’m interested in, and something that has the opportunity to revolutionize treatment for an illness which claims 100 Americans everyday is the application of DBS for addiction.
Why Addiction?
The opioid-crisis is a catastrophic event which we are still in the middle of. It has killed people from every background, class, and country. Opioid-related deaths have skyrocketed the past 20 years and have only gotten worse. Beyond opioid addiction, alcohol, nicotine, and cocaine addiction have also resulted in significant morbidity and mortality.
Current treatments for addiction, whether that may cognitive behavioural therapy, pharmacological interventions, or a combination of the two, for drug addiction, have relapse rates as high as 40%–60%. Due to these high dropout rates, psychosurgery has been attempted in the past including:
- Cingulotomy — A procedure that targets the anterior cingulate region. a part of the brain responsible for feeling chronic pain. A lesion is created and the patient would ideally have been effectively treated with the surgery.
- Hypothalamotomy — A type of psychosurgery which involves creating lesions on the hypothalamus, the part of the brain responsible for releasing hormones, managing circadian rhythms among other physiological functions.
- Resection of Substantia Innominata — An band of the anterior perforated substance which is a part of the basal fore-brain and has been connected to addiction.
These procedures, as well as psychosurgery as a whole, became unfavourable with the introduction of new medications and concerns for breach in ethical standards. However, DBS is an ethical and low-risk way of better helping patients who are treatment resistant and could make a real difference in the lives of these patients.
Stages of Addiction
- Binge/Intoxication — This is the first stage of addiction where drug use produces a reward mediated by dopamine increases in the mesolimbic system. The mesolimbic pathway is one of the four main dopaminergic pathways and one of the two impacted by addiction. This pathway is a reward circuit made of the medial forebrain bundle, which connects the ventral tegmental area (VTA) and hypothalamus with the olfactory tubercle and nucleus accumbens (NAc). It is drug-induced dopamine creases at the NAc which facilitates reward. Continued substance abuse facilitates drug-evoked synaptic plasticity. Specifically, these changes include elevations in mesolimbic dopaminergic excitability. This effect is short-lived since repeated drug use results in limitation on mesolimbic dopamine activity → decreases in dopamine at the NAc in response to a high. This is when a tolerance develops.
- Withdrawal — Decreased mesolimic activity dopaminergic activity is hypothesized to be responsible for the inability to feel pleasure (anhedonia) and pyschomotor depression. This state of negative emotion is mediated by the activation of the extended amygdala (the amygdala is a structure in the brain involved in the encoding of memories with emotion). This activation is potentiated by the increase of corticotropin-releasing hormone is produced by the hypothalamus, norepinehprine produced by the adrenal medulla, and dynorphin which is a class of opioid peptides (peptides are combinations of amino acids which are monomers of proteins). These substances also activate stress responses and helps explain anxiety and irritability during withdrawal. This is one of the most dangerous times for someone struggling with addiction because it creates a feedback loop: Conditioned negative response to withdrawal mediated by the amygdala and hippocampus → avoidance of going through withdrawal and an increase in tolerance → increase in drug seeking behaviour → addiction reinstated and withdrawal symptoms removed.
- Preoccupation/Anticipation (Craving)— The amygdala projects to the Prefrontal cortex (PFC) which is made up of smaller sections such as the dorsolateral PFC (switching attention, working memory, maintaining abstract rules, and inhibiting inappropriate responses), anterior cingulate gyrus (has been implicated in several complex cognitive functions, such as empathy, impulse control, emotion, and decision-making), and medial orbitofrontal cortex (involved in decision making, emotional processing, and memory). These areas among others are responsible for your executive function which optimizes your decision making process. Drug use results in synaptic changes to reward and memory circuits which causes a impaired PFC → impaired decision making.
Various substances produce different effects, and genetics and environmental factors are critical in this process as well, but the above explanation helps explain the fundamental neurobiology of addiction and drug-evoked synaptic plasticity.
Working with Animals
Most of the studies identified by the above table found a decrease in drug seeking behaviour. These studies generally targeted the NAc core or shell. Addictive behaviours in animals are tested through 3 main models: self-administered (SA), conditioned place preference (CPP), and pyschomotor sensitization. CPP and pyschomotor sensitization are experimental administered tests.
In the SA test (most common form of testing for drug addiction and DBS), animals are place in a chamber with access to the drug in form of a liquid (e.g. ethanol) or a lever press which causes an injection (e.g. cocaine). These animals will spend a prolonged period of time inside these chambers until they reach a steady state of drug intake (“SA stage”). This is when drug availability is terminated and animals may be subject to extinction training where responding to the lever or press to longer produces the drug. The next stage is reinstatement where animals are re-exposed to the same cues of new supply of the drug (e.g. a sound or light paired with drug delivery). Intervention practices to stop addictive behaviour can occur at any stage.
While animal studies are helpful, it it difficult to capture the response of humans effectively without testing on humans.
Does it work? — Testing with Humans
NAc DBS has been investigated in the past with neuropychiatric conditions such as anxiety, depression, and OCD. In many of these reports (including the ones linked), NAc DBS helped resolve co-morbid drug addiction.
Following results of NAc DBS improving symptoms of addiction for many patients, small studies began documenting the effect of DBS on the NAc primarily for addiction, all with a decrease in drug use.
Unfortunately, these studies had a number of limiting factors which make them less than perfect. These vary, but include:
- Small patient numbers
- Various long-term follow ups
- Potential publication bias
- Lack of blinded stimulation
Due to these shortcomings, additional preclinical and clinical studies need to be performed to better understand the impact of Deep Brain Stimulation on addiction.
“Drug addiction remains a significant public health concern, with significant morbidity and mortality. Current therapies for drug addiction have high rates of relapse, and therefore within the past 15 years DBS has been investigated as a potential treatment. Much of the preclinical data has been promising; however, DBS has yet to be widely used in humans for drug addiction. The human experience with DBS for drug addiction is primarily limited to case reports without blinded assessments or standardized outcome measures. Additional preclinical and clinical research needs to occur in order to determine the role of DBS in the treatment of drug addiction.” — Review of DBS for addiction
Musk at it Again
In 2016, Elon Musk created the company Neuralink. The company’s focus is on developing brain-computer interfaces (BCIs). BCI’s are systems which translate measurements of neural activity into actions by a machine. A simple example of this is using EEG data — which collects 5 types of brain waves: Delta, Theta, Alpha, Beta, and Gamma — and this data can be used to move a computer mouse.
The use of Neurlink’s BCIs vary. Elon Musk has said it can be used for everything from calling your Tesla to replaying memories and downloading thoughts. However, one particular use of Neuralink’s N1 chip is it’s use in treating depression and addiction.
One twitter user asked Musk: “Can Neuralink be use to re-train the part of the brain which is responsible for causing addiction or depression? It’d be great if neuralink can be used for something like curing addiction/depression 🧠”
Musk responded with:
“For sure. This is both great & terrifying. Everything we’ve ever sensed or thought has been electrical signals. The early universe was just a soup of quarks & leptons. How did a very small piece of the Universe start to think of itself as sentient?”
Musk stated the goal of Neuralink was to “solve important brain and spine problems with a seamlessly implanted device” during his presentation in August. Examples of potential illnesses that could be aided with Neuralink’s N1 chip include:
- Memory/Hearing loss
- Blindness
- Paralysis
- Seizures
- Depression
- Addiction
Musk also mentioned DBS during his presentation in passing, but referred to it as a crude and unrealistic process which was not applicable to the mass population.
The change in size and increased precision in placement with Neuralink’s neurosurgical robot offer the potential to have exponentially better results than traditional DBS surgery.
If DBS itself can be used to treat addiction, the potential for this new technology (which is exponentially better) to treat patients could revolutionize old techniques for new results.
