Mental health and the brain

The science behind the stigma

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This rendering from the Feng Lab highlights major neuromodulatory circuits in the mouse brain. Investigating these circuits in animal models may help us understand their human analogs.
Courtesy of Guoping Feng

Research into the human brain has rapidly grown in the past few decades, and scientists and patients alike are beginning to understand the importance of mental health awareness. While there is much academic research being done to explore the complexity of the brain, practical applications and treatments remain imperfect. According to the National Institute for Mental Health, approximately 20 percent of the world is affected by brain disorders. At MIT, there are a number of groups dedicated to studying brain disorders specifically. Some labs focus on the genetic origins of neurological disorders, while others use imaging to predict and respond to indications of mental health conditions.

Guoping Feng at the McGovern Institute for Brain Research at MIT works on developing animal models of disorders such as obsessive compulsive disorder (OCD), autism, schizophrenia, and bipolar disorder. He studies the connections within the brain, called synapses, and explores how these circuits can correlate with mental disorders. His lab also researches how genetics can influence brain disorders. By studying genetic and environmental factors, his group can create useful animal models for these conditions.

Across the hall, at the Gabrieli Laboratory, John Gabrieli studies how the brain operates differently in people who have anxiety, depression, autism, or other brain issues using functional MRI, an imaging technique used to assess brain activity. Much of his research focuses on cognitive development in children and attempts to identify indicators of mental health issues so as to treat and prevent them early on. The group specifically seeks signs of  susceptibility to anxiety, depression, and other mental health issues or learning disabilities so that in the future, children can be properly supported before they face serious struggles. The longer it takes to identify and treat a disorder, the less effective that treatment can be. Identifying features that might make someone prone to depression and anxiety would provide an opportunity to reach and support those who are vulnerable earlier rather than later.  

Gabrieli’s current research is now more relevant to the MIT community than ever. His new project, Boston Adolescent Neuroimaging of Depression and Anxiety (BANDA), is part of the Human Connectome Project (HCP), founded by the National Institutes of Health. The HCP is a collaborative project that compiles state-of-the-art brain measures to use over wide populations for effective analyses of various brain disorders. Gabrieli works with local hospitals including McLean Hospital, Massachusetts General Hospital, and Boston University to study adolescent anxiety and depression, using behavioral data and brain imaging to find differences in the brains of patients affected by the disorders.

The connections in the human brain can vary from person to person, and interpreting human brain images is a complex and involved process.  While depression and anxiety are influenced by biological factors, the onset of these disorders is also affected by environment, family, and other outside influences that a researcher cannot study with an animal model. Animal models are often more useful to develop new treatments, but animal models for complex human experiences are flawed. “Humans are fantastically complicated,” Gabrieli says, “which is amazing about people but terrible for research.” It’s hard to notice an onset of anxiety or depression in a mouse but very easy to see in a human. To Gabrieli, all of this speaks to the complexity and beauty of the human brain. “The brain’s amazing biological capacity to substantiate the human experience — our wishes, our fears, our frustrations, our skills — it’s amazing that a biological thing drives that.”

Since Feng works primarily with animal models, he recognizes their limitations as well as their advantages. Although a mouse brain cannot replicate the complexity of a human brain, a mouse model can be successful in depicting monogenic disorders, disorders caused by a single gene. In Feng’s field, some of the most successful animal models are monogenic models for certain cases of autism. However, monogenic conditions only represent approximately 10–30 percent of the autistic community, and most brain disorders are polygenic, corresponding to different combinations of genes. This is yet another complication that arises when studying the intricate and multifactorial influences that cause mental illness. These correlations are a huge challenge in studying mental disorders and demonstrate the sheer complexity of the brain. Brain disorders themselves are also known to have similar genetic profiles. For example, Feng describes how even though schizophrenia and autism are dissimilar in symptoms, they might still arise from mutations in the same  genes. Furthermore, the contribution of environmental factors versus genetic factors in these conditions is still not well understood.

While Feng uses animal models to elucidate the genetic factors behind brain conditions, Gabrieli uses functional MRI (fMRI) to assess the brain activity of humans with these conditions.  He shows his patients some sort of stimulus like an image, and then looks for areas of the brain that exhibit increased or decreased activity. “A common stimulus for that is to show them things like faces that are happy or sad to provoke parts of the brain that respond to positive or negative experiences — or reward in depression, for example,” Gabrieli explains. He often finds under-responsive reward centers in the brains of depressed patients, “which is perhaps part of the reason why a person finds life less happy, because few things are provoking a response from the reward mechanism that, in many people, is very powerful for everyday happiness.” Within diagnostic categories, Gabrieli hopes to find individual differences in patients as different patients with the same diagnosis may respond very differently to the same drug.

Typically, medicated treatment of depression involves first giving a patient a treatment and seeing how they respond. If the treatment causes unwanted side effects or is not helpful to the patient, the practitioner prescribes something else.  This process is semi-random — one type of medicine may only work for a third of patients, and there is no systematic way to see what medications will work for whom. Pharmaceutical companies market their products as being effective for the entire population of those with anxiety and depression, even though only a small fraction of the population responds. As a result, they conduct little to no research about the range of patients that any particular medication could treat. Many of these drugs were discovered by chance, and there has been little progress over the past 10 years in developing drugs that treat mental health conditions. This lack of advancement has to do with the complexity of disorders like depression and anxiety. Feng points out that diseases such as depression and anxiety cannot simply be attributed to genetics: there is so much we do not know about a person’s life and their internal balance. Until more precise medications are developed,  a prescriber's only option is to cycle through the existing drugs until one happens to work for the patient they are treating.

This is especially discouraging to patients with depression, whose struggle to find a  compatible medication makes it less likely that they’ll come back for subsequent appointments. “We have these labels like depression and anxiety or even labels like memory and attention for everybody, and they cover such a complicated range of actual things in people,” Gabrieli says, noting the many individual differences in patients with the same disorder. Gabrieli uses brain imaging to tell who will respond to different kinds of treatments rather than directing them to one medicine without knowing if it will work for that particular patient. This is often termed “personalized” or “precision” medicine. “If you can know enough about a person beyond the diagnostic label, you might be able to steer them almost immediately to a treatment that’s effective for them instead of having them try different treatments almost randomly now,” Gabrieli says. “There is incredibly little evidence about which individual responds to which form of treatment.” The idea is that getting data from a large range of individuals will help develop the database of behavioral and brain imaging so that it becomes possible to predict whether or not a patient will respond to medication.

For now, those who seek medication for anxiety or depression must contend with the struggle to find something that works. According to Gabrieli, “It’s the nature of these disorders that it’s easy to get defeated and not come back for more help.” Clinicians cannot compel their patients to return, and many patients give up when they realize that no antidepressant is guaranteed to be compatible with them.  Feng cites the current clinical environment as a contributor to the dearth of more specific and useful treatments. He notes that doctors are financially discouraged to see patients, and this causes many people in the field to focus solely on contributing to research rather than to therapy.

Nonetheless, research like Feng’s and Gabrieli’s has the potential to help patients understand their conditions. Those affected by mental health disorders are often blamed for their symptoms, especially ones that result in behaviors that are seen as socially unacceptable.  If researchers are able to connect brain disorders to certain functional or genetic brain differences, patients are able to see that their symptoms are driven by something concrete. Gabrieli notes that this appears to be very liberating for the patient to understand why they feel the way they do.

Feng reiterates this point as well. “If your neighbor has cancer or a heart attack, everyone will feel very sympathetic and likely visit, but say, if your neighbor has schizophrenia, people will stay away from them. However, these are the same things: they are both diseases afflicting certain organs, except in the case of mental disorders, this organ is the brain,” he says. Feng also highlights how these stigmas differ across cultures. In Asian countries, for example, parents are generally more hesitant to admit that their child has a mental disorder. A study conducted in South Korea showed that on a phone interview, almost zero percent of families will admit that they have a child with autism. In comparison, this statistic amounted to approximately one percent in the United States. However, after conducting door-to-door interviews, the percentage of South Korean families who said they had autistic children was two percent. This study demonstrated how certain societal pressures can make people feel ashamed to admit that they have a mental disability. Across cultures, there are very different social environments that might prevent people from recognizing the importance of understanding mental disability.

Feng believes that a major misconception is that psychiatric disorders have no impact on the brain itself. Functional changes in the brain can happen and are happening, all the time; it is simply a matter of not being able to see these changes. “For example, when your liver malfunctions, it might produce toxins. When the brain malfunctions, it produces abnormal behaviors. If you feel depressed, it is not something that you can simply snap out of. So, the question is how do we help people understand that the brain is just like any other organ, but it’s just much more complex?”

In addition to helping people understand that the brain is functionally changed by mental health conditions,  Gabrieli stresses the importance of encouraging people to get help for themselves or for others. “Leaving a person in crisis is the least good thing you can do for yourself or for them,” he says.

Gabrieli worries particularly about MIT students when it comes to the problem of asking for help. “I have this intuition that many MIT students got here by the strength of their motivation,” he explains. “That same characteristic of a person that has made them fairly determined in certain ways can make them not seek help because maybe they would worry that it’s a signal of weakness.” Many students do use MIT Mental Health services — about a quarter of students use them by the time they graduate —  but Gabrieli feels this is fewer than the number of people who actually need these services. Gabrieli thinks that if students knew how many of their peers used mental health services, they would understand that it is not at all a weakness — rather, a common problem — and would be encouraged to get help. Feng agrees. “It is really important particularly for young people to understand that they should not be ashamed,” he says. “Just like your liver or your kidney can malfunction, your brain can as well. It is really important to tell this to younger generations, and it has been really encouraging to me that in the past few years, students have come up to me and told me when they are struggling. So I do think that the culture around mental health is changing in a good way.”

Though cultural perspectives on mental health treatment are changing, healthcare infrastructure in the United States has yet to meet the needs of those suffering from mental health disorders. Feng notes that in the United States, there are simply not enough beds in inpatient treatment centers to host patients and not enough funding to study mental health conditions. Furthermore, most medical insurance policies do not cover testing for mental health disorders. This lack of resources and access to care demonstrates a need for changes in infrastructure and treatment. Feng argues that early diagnosis and prevention are crucial because the brain is plastic: there is still time to change a young brain. He believes that a combination of medicine and behavioral therapy can play a huge role in treating mental disorders from an early age.

According to Gabrieli, it is important to understand that the stigmatizing behaviors associated with disorders like anxiety and depression are out of a person’s control. “It’s not a voluntary issue; it’s not a character flaw issue; it’s a brain difference.” Feng further emphasizes the difficulties that those suffering from mental health conditions face: “There is no suffering more painful than mental pain. It is really difficult for people who are not afflicted by these disorders to understand.”