A world without antidepressants: a new study reveals a new alternative to prescription pills
Depression is a condition that affects a person’s mood and is characterized by prolonged sadness, loss of interest in activities, or a lack of enjoyment. Although everyone experiences occasional periods of low mood, clinical depression is diagnosed when these symptoms persist for at least two weeks. Depression can be triggered by events such as death, loss, or illness, but it can also occur without any clear cause.
Approximately 26% of Americans aged 18 and above, or 1 in 4 adults, suffer from a diagnosable mental disorder each year. Many individuals experience multiple mental disorders simultaneously, with depressive illnesses commonly co-occurring with substance use and anxiety disorders.
Since the pandemic’s onset, the condition’s incidence has spiked significantly, with an estimated 53 million new cases reported.
While depression is often attributed to a chemical imbalance in the brain, the underlying causes are still not well understood. Traditional treatments for depression include medication and psychotherapy, such as cognitive-behavioral therapy. Lifestyle modifications, such as exercising, being exposed to bright light during the day, and socializing, can also help in many cases.
According to a recent study conducted by researchers from the NYU Grossman School of Medicine and the University of Szeged in Hungary, depression can be countered by restoring certain signals in the brain region responsible for processing smells. The study, which involved mice and rats, offers a potential new avenue for depression treatment.
The study, published in the online journal Neuron today, focuses on the communication between nerve cells, or neurons, which transmit information through electrical signals. Recent research has shown that effective communication between different regions of the brain requires groups of neurons to synchronize their activity patterns in oscillations of joint silence followed by joint activity. One such pattern is known as “gamma,” which repeats about 30 times per second and is critical for encoding complex information, such as emotions.
Depression is characterized by changes in gamma oscillations, according to previous studies, and is considered an electrophysiological marker of the disease in brain regions responsible for the sense of smell, which are also connected to emotions. These regions include the olfactory bulb, located adjacent to the nasal cavity, which is thought to be a source and “conductor” of brain-wide gamma oscillations, although the underlying causes of this relationship are still not well understood.
In the current study, the researchers used genetic and cell signaling techniques to deactivate the olfactory bulb’s function, which resulted in the emergence of depression-like behaviors in the rodents studied. However, they were able to reverse these behaviors by using a device that enhanced the gamma signals of the brain to their natural pace.
The study’s corresponding author, Antal Berényi, MD, PhD, who is also an adjunct assistant professor in the Department of Neuroscience and Physiology at NYU Langone Health, explains that these findings establish a clear connection between deficient gamma activity and behavioral decline in rodents experiencing depression. Furthermore, the observed changes in the olfactory and connected limbic systems were similar to those observed in depressed patients. Dr. Berényi believes that these results demonstrate the potential of gamma-enhancement as a promising approach for treating depression and anxiety in situations where traditional medications are not effective.
Gamma Waves and Emotions: Understanding the Link
Research suggests that changes in the timing and strength of gamma signals between brain regions of the limbic system, such as the olfactory bulb, piriform cortex, and hippocampus, may impact emotions. These changes could be caused by infections, trauma, or drugs, but the precise mechanism is still unclear.
One theory proposes that depression could result from alterations to the outgoing gamma patterns of the olfactory bulb to other brain targets. However, the traditional method of removing the bulb to study depression is an outdated animal model and can cause structural damage, which hinders researchers’ ability to study disease mechanisms.
To overcome this limitation, a research team developed a reversible method using a single, engineered strand of DNA encapsulated in a harmless virus. This approach, when injected into neurons in the olfactory bulbs of rodents, caused the cells to produce specific protein receptors on their surfaces without causing structural damage.
This enabled the researchers to administer a drug to the rodents, which spread throughout the body, but selectively targeted and temporarily deactivated the neurons in the olfactory bulb that had been engineered to possess the specific drug-sensitive receptors. This allowed the investigators to switch off the communication between the olfactory bulb and other brain regions involved in depression and anxiety, in a reversible manner.
The research team employed several standard tests for depression in rodents to evaluate the impact of gamma oscillation loss in the olfactory bulb. These tests assessed anxiety levels, despair, pleasure in activities, and avoidance of stressful situations, all of which are established indicators of depression. While animal models of human psychiatric conditions have their limitations, these tests have proven to be reliable measures of depressive behaviors over time.
In particular, the experiments assessed the duration of time animals spent in an exposed area (a gauge of anxiety), the duration they endured while submerged in water (an indicator of despair), their inclination to consume sugar water (a measure of diminished pleasure), and their reluctance to navigate a maze (an indication of avoidance towards stressful situations).
The scientists employed a specialized device to capture the spontaneous gamma oscillations in the olfactory bulb and then fed these synchronized signals back into the rodents’ brains through closed-loop electrical stimulation. The custom-made device could either enhance or reduce gamma in healthy animals. In healthy animals, inhibition of gamma oscillations in the olfactory lobe prompted behaviors that mimicked depression in humans. Conversely, re-injecting an amplified olfactory bulb signal into the brains of depressed rats helped reinstate regular gamma activity in the limbic system and decrease depressive behaviors by approximately 40% – almost back to the baseline level of normalcy.
According to György Buzsáki, MD, PhD, the Biggs Professor in the Department of Neuroscience and Physiology at NYU Langone Health and a member of its Neuroscience Institute, the mechanism by which gamma wave firing patterns are translated into emotions remains a mystery. As the senior author of the study, he states that their future research endeavors will concentrate on gaining a deeper understanding of this connection in the bulb and the associated regions, as behavioral changes occur.
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