Lithium has been used as a treatment for bipolar disorder for decades, but very little is known about its mechanism of action in the brain. While many newer drugs have been developed to treat the condition, lithium remains a mainstay for the treatment of bipolar disorder and other psychiatric illnesses in psychiatry’s toolbox.

Investigators at Brigham and Women’s Hospital are now using brain imaging and laboratory research to examine precisely how lithium affects the brain at the molecular, neuronal, and brain-circuit levels. They are also studying how it may actually increase the growth of certain areas of the brain and influence the organ at a structural level.

“Lithium has been shown to be very effective at treating bipolar disorder and reducing the incidence of suicide in certain populations,” says Amit Anand, MD, a psychiatrist at the Brigham. “At the same time, it’s very interesting because it’s a chemical element. Most medications belong to a class made up of similar drugs, but there is really nothing else like lithium.”

Correlating Gene Expression and Brain Changes

In a study published in Translational Psychiatry in April 2020, Dr. Anand and colleagues collected MRI scans and blood samples from 21 people with bipolar disorder before lithium treatment and at two and eight weeks after treatment. As a control, they also collected matched samples from 16 healthy, untreated individuals.

The research showed that after eight weeks of lithium treatment, the subjects had significant increases in gray matter fraction, global cortical thickness, and the thickness of frontal and parietal cortices. Volume increases were also seen for putamen, hippocampus, thalamic nuclei, and thalamic substructures.

Additionally, several genes showed significant expression changes; nine out of 14 pathways that were identified as being affected by lithium correlated significantly with the structural changes that were observed. These findings corresponded with lab research showing that lithium can boost the growth of neurons and suggest that lithium may also be useful in treating other diseases such as neurodegenerative disorders.

“Lithium goes inside neurons and has a direct effect on DNA and gene expression, particularly on neurotropic genes that help the growth of neurons,” Dr. Anand says. “We can correlate those changes with what we see happening on brain scans. This gives us more power to identify the changes in those genes, which would help in the development of other novel treatments for bipolar disorder and other psychiatric illnesses for which lithium has been found to be useful.”

Expanding Efforts to Find Drugs for Depression

Dr. Anand and his colleagues are now launching a new study to get a closer look at these effects. The National Institutes of Health has funded a larger trial that will include not only structural and functional brain scans, but also analysis of blood samples to look for changes in gene expression. Patients with bipolar disorder who are not currently taking any medications are eligible to participate. The patients will be treated with lithium and followed for six months.

“We’re using the Brigham’s 7-Tesla scanner, which is the strongest scanner approved by the U.S. Food and Drug Administration for use in human subjects and is very sensitive at picking up signals from the brain,” Dr. Anand says. “We plan to use resting-state brain connectivity and diffusion tensor imaging to look at the white matter fibers in the brain to see the changes after short- and long-term lithium treatment.”

In the future, the team plans to do similar kinds of studies looking at how other drugs, such as ketamine, affect brain structure in people who are being treated for treatment-resistant depression.

“There’s also a lot of interest in using psychedelics and MDMA to treat depression,” Dr. Anand says. “It’s important to establish experimental paradigms to do this kind of translational research and develop a deeper understanding of how these treatments work.”

About one-third of people with epilepsy do not experience adequate control of their seizures with medication alone, making them potential candidates for surgical interventions. But some of these candidates do not qualify for more traditional surgeries due to the location of seizures in the brain, so they need better options.

At Brigham and Women’s Hospital, surgeons and physicians are developing several new treatments that offer the possibility of better seizure control. These therapies require a great deal of diagnostic and surgical expertise along with the latest cutting-edge tools.

“We’re fortunate because we not only have the most advanced technology, but also have an unbelievably dedicated team of experts, including neuroradiologists, neuropsychologists and epileptologists,” says Garth Rees Cosgrove, MD, director of epilepsy and functional neurosurgery at the Brigham. “This ensures that every patient we see receives the best care available.”

Robotic Guidance Improves Seizure Diagnosis

The first step to offering the best care for every patient is a comprehensive evaluation to determine the location of the brain seizures. Among the diagnostic tools available at the Brigham are a 7T MRI scanner, PET scanner, magnetoencephalography scanner and state-of the-art, six-bed EEG monitoring unit (EMU). Patients’ seizure activities are monitored 24 hours a day, which enables the team to hypothesize about where the seizures are coming from.

For patients in whom the seizure locations cannot be identified with regular scalp EEG monitoring in the EMU, phase two evaluations can be done by using a robotic guidance system that implants electrodes into the brain to monitor seizure activity. The Brigham also houses the Advanced Multimodality Image Guided Operating (AMIGO) suite, which holds an array of advanced imaging equipment and interventional surgical systems.

“Patients will see the best outcomes if we can accurately identify where the seizures are coming from and resect or laser ablate those areas,” Dr. Cosgrove says. “Minimally invasive approaches are also available, and this is where the AMIGO suite is so important. While patients are asleep in the MRI scanner, we use guidance systems to very precisely ensure we are in the right location. This approach is more comfortable for the patient, as well as safer and more accurate.”

Neuromodulatory and Laser Surgery Offer Seizure Relief

Open surgical resection may not be an option for patients who have multiple seizure sites in the brain or seizure sites that are within areas that control critical functions. In these cases, laser ablation, which is used when the seizure site is in a part of the brain that would be difficult to resect, and neuromodulation treatments can provide relief from seizure activity.

For patients whose seizures are located within critical areas for movement, language or thinking—and that would cause neurological deficits if destroyed—two neuromodulation approaches are increasingly used at the Brigham: responsive neural stimulation (RNS) and deep brain stimulation (DBS).

With both techniques, a surgeon implants a neurostimulation device in the brain. These specialized devices are programmed to detect and then deliver electric currents that disrupt seizure activity. With RNS, the device can detect and then stimulate the area to abort seizures. This stimulation interrupts the brain’s abnormal electrical activity. With DBS, more constant stimulation is used to reset the brain’s normal activity.

Providing Long-lasting Seizure Control

RNS and DBS have been proven to provide beneficial, long-lasting control of seizures for most patients who receive them.

“When you add a new medication to somebody’s regimen, they tend to do better for a few months, but then the brain finds a way to adapt and the seizures return,” Dr. Cosgrove says. “With these brain stimulation techniques, the results don’t happen immediately, but at the three- to five-year mark, about 75% of patients will have improvement in their seizures.”

For these patients, this can lead to an extraordinary improvement in quality of life. “It’s not a cure, but it makes a big difference for people who otherwise have no options,” Dr. Cosgrove says.

Epilepsy Research and Development

The Brigham’s focus on research will continue to drive the development of new and improved treatments in the future. Among the novel techniques being developed by Brigham investigators are low-intensity and high-intensity focused ultrasound. These noninvasive treatments, which were developed to treat Parkinson’s disease, are now being investigated in clinical trials for patients with epilepsy.

“For adults who have had epilepsy their whole lives and have tried every other kind of treatment, this research has the potential to truly be life-changing,” Dr. Cosgrove says.

A team that includes investigators from Brigham and Women’s Hospital, Massachusetts General Hospital and Boston University School of Medicine is one of three multidisciplinary groups that recently received funding from the Henrietta B. and Frederick H. Bugher Foundation to develop breakthroughs related to hemorrhagic stroke. The over $11 million gift, which the American Heart Association is overseeing, aims to improve prevention, treatment and health outcomes for patients with intracerebral hemorrhage.

The project is an important collaboration between the Brigham and Mass General, the two largest institutions in the Mass General Brigham health care system (formerly known as Partners HealthCare). The Boston-based team of the American Heart Association-Bugher Foundation Center for Excellence in Brain Health after Hemorrhagic Stroke, led by Center Director Jonathan Rosand, will focus on fundamental questions related to brain health and health care disparities. Brain health is defined as the ability to perform all of the activities of cognition, and threats to brain health include cognitive decline, depression and dementia. This work is an important research component of the McCance Center for Brain Health, of which several of the investigators are members.

Correcting Inequities to Enhance Patient Outcomes

Because survivors of intracerebral hemorrhage are at increased risk for progressive deterioration of brain health — and because this deterioration is often accelerated in Blacks and Latinx patients — correcting inequities related to race and ethnicity could considerably enhance long-term patient outcomes. The initiative’s efforts are split into the areas of clinical, basic science and population-based research.

“Hemorrhagic stroke is a disease with marked disparities between white and nonwhite populations,” said Christopher David Anderson, MD, MSc, division chief of stroke and cerebrovascular diseases in the Brigham’s Department of Neurology, who is leading the population-based science effort. “The goal of our project is to improve brain health after hemorrhagic stroke, which will prevent further decline and poor outcomes for patients. We think that immediately after the patient has suffered a stroke is a good time to intervene and put them on a path toward better health.”

Building a Tool to Improve Long-Term Care in Stroke Survivors

The population-based science component of the project is focused on building a tool that will help remind physicians of the importance of ongoing care. Part of the grant will go toward building capabilities into the electronic health record that will pop up alerts and reminders that keep health care providers oriented toward longer-term issues.

“For patients who survive hemorrhagic stroke, we need to think of this time immediately afterward as a teachable moment, where physicians can intervene and provide guidance before sending them back into the community,” Dr. Anderson said. “We can remind physicians that this is a great opportunity to look at other factors that contribute to health, like cholesterol levels and diabetes control.”

He added that two of the biggest risk factors for patients who have had hemorrhagic stroke, especially older people and minorities, are social isolation caused by vision and hearing loss and obstructive sleep apnea.

“We can use this time to consult with patients on these topics and guide them toward resources,” Dr. Anderson said. “We’re using this new award to roll out these tools across all of the Mass General Brigham hospitals to hopefully improve care for everyone.”

The team plans to eventually conduct a clinical trial to evaluate whether use of the tool can lead to better patient outcomes. Another effort within Dr. Anderson’s portion of the project will involve building and testing polygenic risk scores and determining how useful they are for diverse populations.

Collaborating on Projects Related to Blood Pressure and Siderosis

A focus of the clinical portion of the project, led by Alessandro Biffi, MD, director of the Aging and Brain Health Research Group at Mass General, will be the study of social determinants of health and social networks on blood pressure control, which is a risk factor for both cognitive decline and additional intracerebral hemorrhage events.

The project’s basic science component, led by Susanne van Veluw, PhD, also of Mass General, will use human brain tissue and animal models to understand the neuropathology and mechanisms involved in cortical superficial siderosis, a more recently discovered strong risk factor for intracerebral hemorrhage. “There’s a lot of cross-talk between these three projects,” Dr. Anderson said. “The discoveries that we make in each of these areas with regard to risk factors will inform the others.”

Another aspect of Dr. Anderson’s project is being done in collaboration with investigators at Tougaloo College, a historically black institution in Jackson, Mississippi. He has previously worked with the team there on a similar project related to atrial fibrillation.

“This relationship not only gives me the opportunity to provide mentorship to someone who’s interested in medicine and to help train the next generation of investigators, but also to work with investigators who can provide a different perspective,” he concluded. “It’s a big component of the American Heart Association’s overall mission and of what this grant is supposed to accomplish.”

For most chronic diseases, improvements in care over the past few decades have resulted from early interventions that prevent disease progression. Brigham and Women’s Hospital investigators, along with collaborators at other institutions around the world, are applying a similar approach to the early detection and prevention of Alzheimer’s disease (AD).

Some of this research is being conducted through the Davis Alzheimer Prevention Program (APP), launched in July 2020. Brigham neurologists Reisa A. Sperling, MD, MMSc, and Dennis J. Selkoe, MD, are co-leading the program.

“The overall goal of the Davis APP is to accelerate finding a successful preventative treatment for AD,” said Dr. Sperling, an internationally recognized expert in AD and director of the Brigham’s Center for Alzheimer Research and Treatment. “To help reach this goal, we want to select drugs for clinical trials that are more likely to work, as well as more quickly eliminate those that don’t. We also aim to develop more sensitive ways to detect changes in the brain — both with biomarkers in the blood and imaging methods.”

She added that in addition to accelerating work in both of these areas, another important initiative under the Davis APP is to increase the diversity of patients in AD clinical trials. This includes a focus on outreach and community partnerships.

Launching Innovative AD Clinical Trials

Dr. Sperling also serves as principal investigator for the National Institutes of Health-funded Alzheimer’s Clinical Trials Consortium (ACTC), a network of 35 sites across the country focused on finding new ways to prevent and treat AD.

Two trials recently launched under the ACTC are AHEAD 3 and AHEAD 45. Both are investigating the effectiveness of the antibody drug BAN2401 (lecanemab) to slow or stop the accumulation of ß-amyloid in individuals who are at greatest risk of developing AD. The risks are determined by age, family history and PET scans of the brain.

“The AHEAD studies are some of the first to use targeted dosing, where we screen people who are cognitively normal and assign them to a trial based on the amount of ß-amyloid seen on their PET scan,” Dr. Sperling said. “This is a way of offering more personalized medicine.”

In the AHEAD 3 study, patients with low levels of ß-amyloid get monthly dosing of the drug. The AHEAD 45 study includes people with higher levels of ß-amyloid, even though their cognitive function is normal. “With this group, we want to be more aggressive in trying to knock their ß-levels down,” Dr. Sperling said. These trial participants get doses every two weeks for the first two years, then a monthly maintenance dose.

The AHEAD trials were launched last summer in the United States, funded as a public-private partnership with the National Institutes of Health. The AHEAD Study opened its first site in Japan this fall, and up to 100 sites around the world will participate in the coming years.

Different Approaches to Drug Development

As a neurologist who treats AD patients in all levels of cognitive decline, Dr. Sperling recognizes the need to develop better treatments for active disease and preventative drugs. She also has witnessed AD in her own family, with her father and grandfather.

“For people who already have clinical symptoms of Alzheimer’s, I think we will need to do something more aggressive,” she noted. “That will likely be a combination of drugs that target ß-amyloid and drugs that target tau.”

Dr. Sperling stressed the importance of good trial design for some of these combination approaches. “We are now working on how to combine anti-amyloid antibodies with anti-tau drugs and how to measure potential synergistic effects with tau PET imaging,” she said.

Better Screening Methods Support Clinical Trials

Developing and evaluating new interventions to prevent AD progression as well as new treatments to alleviate AD symptoms will require better assays to predict cognitive decline. In a recent study published in Nature Communications, Dr. Sperling co-led a team that looked at a blood test that measures levels of N-terminal fragment of tau (NT1, a protein secreted by neurons in response to ß-amyloid pathology). The test was evaluated in participants in the Harvard Aging Brain Study, a group of cognitively normal older adults who are being followed over time.

The study analyzed the predictive value of NT1 in 236 study participants who were cognitively normal and followed them for an average of five years. The researchers found that participants whose blood samples had higher levels of NT1 at the beginning of the testing period had a higher risk of advancing to mild cognitive impairment. Imaging showed that higher levels of NT1 were also associated with more ß-amyloid plaques and greater accumulation of tau tangles.

“We don’t know yet how dynamic levels of NT1 are in the blood over time, but we know that NT1 goes up pretty early before people have cognitive symptoms,” Dr. Sperling said. “We have high hopes that this may work as an indicator of whether drugs are working, as we move into more prevention trials.”

Cushing’s disease, caused by a pituitary adenoma, is the most common type of endogenous excessive cortisol production and results in Cushing’s syndrome. This is a particularly challenging disease to diagnose and treat. Surgery to remove the pituitary tumors that drive the disease can bring it under control, but these tumors can’t always be completely removed. In addition, they frequently recur, even a decade or more after surgery.

Brigham and Women’s Hospital has a long history of expertise in Cushing’s, going back to neurosurgeon Harvey Cushing, who founded the Department of Neurosurgery in 1913 and after whom the disease and syndrome are named. Now a unique collaboration between the Brigham’s Division of Endocrinology, Diabetes and Hypertension and its Department of Neurosurgery is taking a deeper look at why these tumors are so often unmanageable.

Part of this research is focused on studying the genetic underpinnings of these tumors. One of the goals is to develop drugs for treating the disease. Investigators are also looking for better ways to diagnosis it and to prevent recurrence or detect it at an earlier stage.

“Cushing’s disease is one of the most difficult things that we as neurosurgeons face,” said Edward R. Laws, MD, director of the Brigham’s Pituitary and Neuroendocrine Center.

“Every day that a patient lives with excess cortisol, it is doing damage to their bodies and their lives. If we can’t succeed in bringing those cortisol levels down, we’re not doing our jobs.”

Searching for Targetable Genetic Drivers

The first challenge of Cushing’s disease is getting a correct diagnosis. “In addition to treating patients with Cushing’s disease, we also work with patients who have an excess of cortisol that’s not due to pituitary disorders,” said physician-scientist Ana Paula Abreu Metzger, MD, PhD, co-director of the Endocrine Genetics Clinic at the Division of Endocrinology, Diabetes and Hypertension. “We first have to find out what’s causing overproduction of cortisol, because the tumors secreting ACTH that cause Cushing’s disease can be very small and hard to detect.”

In the laboratory, Dr. Abreu Metzger is also studying a more aggressive type of tumor in the pituitary gland that does not secrete ACTH, called silent ACTH pituitary adenomas. “They come from the same lineage as the tumors causing Cushing’s disease but become clinically distinct,” she said. “We want to understand the genetic drivers of these tumors to develop a more personalized approach to treating them.”

Her expectation is that by learning more about the signaling pathways that drive these tumors, drugs can be developed to treat them, similar to the way targeted therapies for cancer increasingly are being employed. She’s performing whole-exome sequencing on both somatic and germline DNA to identify driver mutations as well as RNA sequencing to determine the effects that the genetic changes that are observed have on gene expression.

Searching for Accurate Biomarkers

Dr. Laws is also working with endocrinologist Le Min, MD, PhD, associate director of neuroendocrinology in the Division of Endocrinology, Diabetes and Hypertension, to study postoperative cortisol levels as a biomarker for predicting remission versus recurrence after surgery. Their research on this topic was recently published in The Journal of Clinical Endocrinology & Metabolism.

“Patients always ask us what the chance is that their disease will come back,” Dr. Min said. “Our goal is to identify a biomarker that can reliably predict long-term remission of postoperative Cushing disease.” He added that their research has found that postoperative day one morning cortisol level has significant correlation to the recurrence of Cushing’s disease. This measure is useful as guidance for clinicians performing patient follow-up after surgery, he said.

Drs. Laws, Min and Abreu Metzger also are studying corticotroph hyperplasia, which has the same symptoms as Cushing’s disease caused by pituitary tumors, despite the fact that no pituitary tumor can be detected. Because this condition is much more difficult to manage surgically, it underscores the importance of developing better medical treatments that can target the overproduction of ACTH or related products.

The symptoms of Cushing’s disease, including weight gain, diabetes and high blood pressure, can wreak havoc on a patient’s health. But according to Dr. Laws, some of the most devastating effects on patients are the psychological ones, including depression and anxiety.

“Patients usually know when their disease has recurred even before tumors show up on scans, because they remember what it feels like,” he noted. “It’s heartbreaking for them when they don’t stay in remission, and we want to do everything we can to be able to help.”

At the end of the day, the aim of studying why these tumors are often so difficult to cure is what drives this exceptional research program forward.

Brigham and Women’s Hospital recently opened its innovative Center for Brain Circuit Therapeutics. A joint clinical, research and education initiative, the new center brings together experts from neurology, psychiatry, neurosurgery and neuroradiology to develop innovative treatment methods for brain disorders that don’t respond to medication.

“This center was created to leverage what’s been a long-term initiative on the part of the Brigham: to develop unique approaches for taking care of brain diseases,” said Michael D. Fox, MD, PhD, director of the center. He is also the Raymond D. Adams Distinguished Chair in Neurology and the Kaye Family Director of Psychiatric Brain Stimulation.

A world-renowned investigator in brain imaging and brain stimulation, Dr. Fox recently joined the Brigham from Beth Israel Deaconess Medical Center. He has published many studies on the identification of human brain circuits that underlie neuropsychiatric symptoms.

The Center for Brain Circuit Therapeutics will provide treatments including deep-brain stimulation (DBS), focused ultrasound (FUS) and transcranial magnetic stimulation (TMS). Through its clinical trials program, the center will also seek to expand the applications for these therapies and study new treatment approaches. Translational research will be aimed at learning more about brain circuitry and lesion network mapping, among other investigations, to advance understanding of how the brain is wired and how that wiring could be targeted to treat different brain diseases.

In addition, the center will focus on training the next generation of leaders in neurology, psychiatry, neurosurgery and neuroradiology so that they can provide these therapies to patients.

Combining Circuit-Focused Treatments With Medication

Brain circuit-focused treatments work in a completely different way than medication. Rather than targeting chemical changes in the brain, they target specific anatomical brain regions or brain networks that are malfunctioning. The Brigham is a leader in many of these approaches, including MRI-guided FUS, which can noninvasively treat tissues deep in the brain. Furthermore, thanks to its advanced MRI technologies, the Brigham offers asleep DBS within an MRI scanner in addition to traditional awake DBS.

“Medication is still the first approach for almost all neurologic and psychiatric symptoms, but these symptoms can become refractory over time, or may not respond at all,” Dr. Fox said. “Patients who don’t respond to medication are ideal for referral to this center.”

Dr. Fox estimated that only one in five Parkinson’s patients who could benefit from DBS currently are referred for this therapy, even though studies show many of these patients do better after receiving it. He said that part of the problem may be a lack of understanding among other medical professionals about how much these therapies can improve outcomes.

“When someone comes to us for treatment, we work as a team with the neurologist or psychiatrist who referred them,” Dr. Fox explained. “The treatments we offer are not a replacement for medical therapy, and communication between our team and the patient’s other doctors is very important for successful treatment.”

Making TMS Treatments More Precise

Shan H. Siddiqi, MD, a neuropsychiatrist and director of psychiatric neuromodulation research for the center, is leading much of the research on TMS. He is currently leading a clinical trial looking at whether the treatment can be modulated to more specifically treat depression versus anxiety based on which circuit in the brain is being targeted with the magnetic stimulation.

“In the past, TMS has been aimed based on scalp landmarks,” he said. “We now know that imaging can help to determine whether we can more precisely target this therapy to choose the right target for the right patient.”

Dr. Siddiqi noted that besides providing better treatment for patients who don’t respond to medication, TMS may also be preferred in some cases because it has milder side effects. But he pointed out that insurance usually does not cover TMS unless patients have tried antidepressant medications.

The large amounts of data generated by research into brain circuits, including pinpointing specific areas to make treatment more personalized, require computational approaches. “The purpose of the Center for Brain Circuit Therapeutics more broadly is to break down all this research and data to find better real-world treatment targets that we can influence with these various approaches,” Dr. Siddiqi said.

“This initiative involves people from many different areas across the Brigham, including some of the best neurosurgeons, psychiatrists and other experts anywhere in the country,” Dr. Fox concluded. “It is the strength of this collection of individuals that makes this program so exciting.”