at Harvard Medical School

Benefactor Report

January 2026

Our work involved technical development and clinical translation. The technical development included optimizing non-invasive imaging methods to measure neurotransmitters in brain regions affected by BD; optimizing non-invasive imaging methods to measure the functional connectivity between brain regions involved in BD; and optimizing TMS treatment based on neurochemical and functional imaging to target brain areas involved in BD.

Specifically, we enhanced the specificity and sensitivity of our system to image excitatory and inhibitory neurotransmitters associated with mania and depressive states, respectively. We achieved the highest possible image resolution for neurotransmitters, which is needed to probe the brain cortex. We improved the spatial-temporal resolution and robustness of functional imaging for identifying functional connections between cortical and subcortical brain regions in BD. We accelerated and automated the computation of brain images and the calculation of brain stimulation doses, enabling real-time guidance of the TMS treatment during the procedure.

The clinical translation involved obtaining regulatory approval for the experimental study in BD patients, testing the imaging and treatment protocols in healthy control individuals, training staff to perform the protocol in BD patients, and screening and recruiting BD patients for TMS treatment. Our study is currently progressing with testing the effect of TMS treatment in BD patients with depression symptoms. In these patients, we investigate the correlation between changes in pre- and post-treatment clinical scores, imaging biomarkers, and TMS treatment.

We are excited by how this grant has brought together three lab groups with complementary expertise and catalyzed collaborations. We are preparing an NIH grant application to expand the number of participants and cohorts, with a longer follow-up time to assess the outcomes of TMS treatment.

We’re investigating how brain cells manage energy during cognitive tasks in individuals with bipolar disorder. Our focus is on lactate, a molecule produced when the brain uses sugar for energy. Abnormal lactate levels may reflect deeper disruptions in brain function and communication that contribute to psychiatric symptoms.

To study this, we’ve developed a specialized imaging approach using functional magnetic resonance spectroscopy (fMRS). This technique enables us to measure lactate and glutamate levels in real time while participants perform a working memory task in the MRI scanner. We adapted the Sternberg task—a classic working memory task involving a list of items to memorize—to align with the timing demands of fMRS and validated it on McLean’s upgraded MRI system. To improve lactate detection over previous methods, we optimized the homogeneous preparation encoding (HoPE) sequence—the series of radiofrequency pulses and changes in magnetic field we apply during the scans. This optimization significantly enhanced the clarity of lactate signals, reduced background interference, and allowed for more precise measurement of metabolic changes during cognitive effort.

We recently hired a new research assistant, Maddie Schin, who completed all necessary training and quickly became proficient in recruitment, psychiatric interviewing, and study coordination. Her contributions are instrumental in stabilizing and accelerating our data collection efforts. Despite initial delays in staffing, we’ve maintained momentum through strong collaboration. Recruitment has now picked up, with several participants enrolled and more scheduled. We’re using a multi-pronged strategy: engaging McLean outpatients, reconnecting with past participants, and advertising through Mass General Brigham’s Rally platform.

Alongside data collection, we’re preparing a technical manuscript detailing our optimized HoPE sequence and its application in measuring brain lactate and glutamate during cognitive tasks. This paper will incorporate pilot data from both human and animal studies. Building on our progress, we also received a new research grant from the National Institute of Mental Health (NIMH) to explore how lactate behaves in the brains of people with schizophrenia.

We aim to understand the mechanisms behind D2R sensitivity cycles. To achieve this, we have developed behavioral and imaging assays to investigate the dynamic activity of D2R in response to naturally occurring changes in dopamine secretion that occur as animals transition through various behavioral states. Previous mechanistic work on D2R desensitization has almost exclusively been performed in non-natural contexts (involving either agonists of D2R that are not ordinarily found in our bodies or drug-induced, widespread increases in dopamine).

We are leveraging our knowledge of fruit fly genetics and neuroscience to develop a detailed understanding of the pathways that set D2R desensitization and recovery cycles in the context of natural behavior. Specifically, we’re studying mating behavior in fruit flies to assess motivational dynamics in a system where we can make and measure precise cellular and molecular changes. We have found that prior matings make males more likely to abandon future copulations when challenged. During mating, dopamine signals promote resilience to challenges that might otherwise cause the male to switch behaviors.

The devaluation of mating after repeated matings is the result of D2R desensitization, which depends on changes in β-arrestin signaling proteins. This desensitization temporarily renders dopamine-receiving neurons resistant to dopamine, regardless of whether it is naturally released or experimentally supplied. When local desensitization to dopamine is prevented, the male shows no signs of fatigue—he treats each mating as if it were his first. These findings explain a widespread motivational phenomenon, reveal a natural function for the susceptibility of D2R to drug-induced desensitization, and suggest that the depressive–manic cycling in BD may be a corruption of natural motivational dynamics.

Our study evaluates tFUS as a novel brain treatment for BD. tFUS uses low-intensity ultrasound waves to reach deep brain areas without surgery. We target the amygdala, a key region for mood and emotion regulation, to help improve mood control.

Our study aimed to enroll 10 adult participants. We prescreened 47 potential candidates, 27 of whom were eligible for the study. Eleven participants gave consent, and four completed all study visits, including MRI scans and tFUS sessions. One participant reported experiencing mild, short-duration headaches, which we promptly reported and addressed by updating the safety forms. No serious side effects occurred.

Brain scans and symptom ratings were collected and stored securely. Data analysis is our next step. Results will show the effects of tFUS on brain activity and mood. The findings of this study will inform and guide future larger-scale studies.

Support from the Bipolar Disorder Seed Grant enabled this pioneering trial of non-invasive ultrasound brain stimulation in BD. The team safely delivered this new therapy and gathered high-quality brain imaging and symptom data. These findings will be crucial for future larger clinical trials aimed at better, drug-free treatments for BD. This investment brings us closer to options that reduce suffering and improve the quality of life for people living with serious mood disorders.

The research team is now analyzing the imaging and clinical data to identify how tFUS changes brain networks linked to mood. They will submit these findings to scientific journals and use the results to apply for larger grants. These future studies will test tFUS in a larger population and refine treatment schedules to maximize benefit. 

Current treatment options for BD exhibit limited efficacy and are often associated with adverse effects. The molecular mechanisms underlying these challenges remain unclear. Emerging research suggests that BD, along with other neuropsychiatric disorders, is marked by disrupted brain network communication, compromised energy metabolism, and altered neurotransmitter signaling. We seek to determine whether transcranial magnetic stimulation (TMS) can modulate cerebral energy production and utilization in individuals with BD and thereby improve brain network communication and clinical outcomes.

Although TMS is a non-invasive, targeted technique for brain stimulation, its impact on patients with BD has been minimally explored. This study comprises a baseline assessment, five consecutive days of cerebellar TMS intervention, and a follow-up visit. Evaluations at both baseline and follow-up include comprehensive clinical assessments and advanced neuroimaging modalities (structural, functional, and metabolite imaging).

We aim to enroll 20 participants diagnosed with BD during this pilot project. To date, 75 individuals have completed the screening questionnaire, of whom 16 have met the eligibility criteria. Thirteen participants have enrolled, six have completed all study procedures, and three remain active. Four participants withdrew primarily due to concerns regarding the potential effects of TMS on their mental health or mood stability.

We have observed no significant adverse events related to TMS thus far. Mild headaches following TMS were reported in two out of six participants who completed the protocol. We have not yet performed data analysis because of the currently limited sample size. As additional data become available, we intend to assess changes in clinical symptoms and neuroimaging findings between the baseline and follow-up assessments. Ultimately, we hope our research leads to novel circuit-specific treatment paradigms for individuals with BD. We plan to submit a grant application toward the end of this project, supported by the preliminary data we’ve gathered thanks to the Bipolar Disorder Seed Grant.

Mutations in Akap11 are a strong genetic risk factor for psychiatric illness, particularly BD. To understand how disruption of AKAP11 protein production alters cortical development and function, we have assembled a multidisciplinary team—leveraging the complementary expertise of postdoctoral fellows Dr. Alex Wang and Dr. Suraj Honnuraiah and research assistant Dareen Bakr—to dissect both the structural and functional consequences of AKAP11 loss in the cortex.

Suraj, a biophysicist, is leading efforts to interrogate cortical anatomy at nanoscale resolution using expansion microscopy. This allows for physical enlargement of brain tissue while preserving molecular landmarks. In collaboration with Dareen, Suraj is applying immunostaining protocols to visualize excitatory and inhibitory neurons within the prefrontal cortex and visual cortex, two regions heavily implicated in cognition and mood regulation. By coupling tissue expansion with selective labeling of interneuron populations, their approach enables highly resolved mapping of circuit components that might be structurally perturbed in the absence of AKAP11. They are paying particular attention to the balance between excitatory pyramidal neurons and inhibitory interneurons—a cellular interplay often disrupted in psychiatric conditions.

In parallel, Alex is pursuing a complementary strategy that addresses the functional side of cortical organization. Building on his expertise in physiology and advanced optical methods, he has employed a modified two-photon microscopy system that integrates prism-assisted optics to achieve unprecedented access to deep cortical layers. This innovation overcomes the depth limitations of conventional two-photon approaches, enabling visualization of activity patterns in circuits that lie beneath superficial layers. To assay network activity, Alex uses transgenic mice in which calcium dynamics serve as a proxy for neuronal firing. To add specificity, we use our knowledge of gene enhancers to selectively label interneuron subtypes. This strategy allows simultaneous monitoring of both excitatory neurons and identified inhibitory subtypes during behavior. The team aims to detect disruptions in the excitation–inhibition balance and alterations in interneuron–pyramidal neuron interactions.

Together, these anatomical and functional approaches provide a powerful, integrative framework for understanding how Akap11 mutations reshape cortical circuitry. We will use expansion microscopy to look for structural changes—such as altered interneuron density, misplaced projections, or synaptic remodeling—and prism-assisted two-photon imaging to test whether inhibitory control over pyramidal ensembles is functionally compromised.

Although the project is still in its early stages, initial data from wild-type animals confirms the robustness of both pipelines, setting the stage for direct comparison with Akap11 mutants. If significant differences emerge, they will clarify how a single genetic perturbation cascades into cortical dysfunction and psychiatric risk. More broadly, this work exemplifies how combining next-generation imaging methods with precise genetic targeting can bridge the gap between molecular genetics and systems neuroscience. Ultimately, understanding the cortical alterations driven by Akap11 mutations may provide insight into the neural circuitry underlying BD, and potentially highlight new avenues for therapeutic intervention.

Actigraphy is an easily accessible, non-invasive tool for studying rest–activity rhythms in people outside of the clinic. It holds great promise as a potential biomarker that clinicians could use to monitor the health of patients with various mental health conditions.

We conducted a one-week, naturalistic, actigraphy-based study designed to assess relationships between chronobiological and clinical characteristics in bipolar type I disorder. Our preliminary research demonstrated that a greater severity of mania is associated with less robust circadian rhythmicity. Our current study, still underway, is designed to identify and quantify complex patterns in this “noisy” actigraphy dataset—with the overarching aim of establishing biomarkers in BD.

We are expanding on our initial findings by conducting more sophisticated rest–activity rhythm modeling and assessing how these variables are interrelated to further our understanding of the relationships among rest–activity rhythm variables, mood states, and clinical characteristics in BD. Our team has made significant progress towards this aim by conducting a substantive data extraction and knowledge discovery from the parent studies’ robust clinical dataset. Importantly, we have used a combination of clinician-rated and patient-reported assessments to characterize and identify patterns in mood state. We have also defined patterns in the self-reported assessment of daily sleep characteristics and quality, and the degree of lifestyle regularity and daily activities.

From the raw actigraphy data, we have calculated the degree of complexity and disorder (known as “sample entropy”) and the most prominent patterns of variation (known as “functional principal components”). Our team is currently explaining how these patterns change over time and quantifying wave-like components in the raw actigraphy data. Once these analyses are complete, the team will examine the relationships between the rest–activity rhythms as identified in the actigraphy data and the assessments and patterns of mood state and other clinical characteristics.

We will disseminate our findings via publications and presentations at local, national, and international conferences. The data and insights generated from this study will enable the research team to competitively apply for a large-scale, externally funded research grant to conduct a longitudinal study examining the relationships between rest–activity rhythms, mood state, and clinical characteristics in BD, a fundamental knowledge gap in the field. The research team has already begun to design the protocol for this grant submission. The knowledge gained by conducting these protocols will allow us to design actigraphy-based illness-monitoring paradigms that support earlier intervention.

Many people with BD struggle with food-related difficulties, such as strong aversions to certain textures. For example, some cannot tolerate foods that feel “rough” or “grainy” in the mouth. These problems can cause nutritional issues, worsen mood symptoms, reduce overall quality of life, and even exacerbate other BD-related symptoms. Although this is a common challenge, the biological reasons for food texture sensitivity in BD have remained unknown.

With the support of this grant, we are using mouse models to better understand how the nervous system processes food textures and how this processing differs in people with BD. We focused on a gene called Shank3, which is strongly linked to BD and related conditions. We found that mice with mutations in this gene show behaviors that mirror human food texture sensitivities, making them a powerful model for studying these conditions.

We created a simple but powerful test in which mice drink sweetened milk from bowls with different textures at the bottom. This allows us to measure whether mice prefer smooth textures over rough ones. Using this test, we found that mice with mutations in Shank3 strongly prefer smooth textures, showing a clear aversion to rough textures. This mirrors the texture sensitivities many people with BD experience.

Next, we asked why these mice show texture sensitivity differences. We discovered that the sensory nerves in the tongue—specifically, trigeminal ganglion (TG) neurons—are overactive in Shank3 mutant mice. These neurons respond more strongly to touch or pressure on the tongue than in wild-type mice, which likely contributes to heightened texture sensitivity.

We then tested a compound that reduces nerve activity in the tongue. Early results suggest that this treatment can reduce the activity of overactive TG neurons in Shank3 mutant mice. This raises the exciting possibility that similar strategies could one day help reduce oral texture hypersensitivity in people with BD.

Finally, we began developing new methods to measure how information about food texture from the tongue is processed in the brain. Using advanced recording techniques, we can now track how brain cells respond when mice lick smooth or rough surfaces. This allows us to connect changes in tongue sensory neurons to changes in brain activity and feeding behavior.

Our discoveries so far suggest that these difficulties often begin in the peripheral sensory nerves of the tongue, which may explain why food texture hypersensitivity is so common in BD. By identifying both the neural basis of this issue and potential treatments, we are laying the groundwork for strategies to improve eating behaviors, nutrition, and quality of life for individuals with BD.

Dr. Yao Zhou and Karen San Agustin lead this project. We are currently preparing a manuscript that includes discoveries that were enabled by this award, with Yao and Karen as co-first authors.

We sought to test the hypothesis that the gene Foxp2 regulates emotional learning through its actions in the amygdala. To do this, we used local Foxp2 knockdown (KD) with a genetic process to “turn down” gene expression. More specifically, we used viral vectors—a method for introducing genetic material into cells without causing disease—to express short hairpin RNA (shRNA) designed to reduce levels of the FOXP2 protein in the medial intercalated cell (ITC) cluster of the amygdala. This is a region known to be critical for relaying information to parts of the amygdala responsible for regulating fear responses (such as freezing).

Conducting behavioral experiments in which mice learn to associate a tone with a light foot shock, we found that fear learning is significantly decreased in mice with Foxp2 KD in the ITCs. This effect on fear was not due to decreases in cell viability, nor to impaired ability to detect the shock, hear the sound, or alter locomotor behavior.

FOXP2 is a molecule that binds to DNA and affects how much of a gene is made into a functional protein. It binds to and regulates different genes in different contexts—for instance, in different parts of the brain, and under conditions of stress versus a neutral environment. To test what genes are regulated by FOXP2 during fear learning, we sequenced RNA from amygdala samples of mice after again decreasing levels of FOXP2 using shRNA in the ITC region of the amygdala; we compared these samples to samples from control mice. We fear-conditioned mice in these experiments with our standard protocol and harvested bulk RNA from their amygdalae two hours after this procedure. We identified 1,726 significantly downregulated and 738 upregulated genes following Foxp2 KD. Multiple genes previously implicated in fear learning, such as Tac2, CRH, NPY, various thyroid-related genes, and Wnt pathway–related genes, were downregulated after Foxp2 KD. These molecular results are consistent with the reduced fear learning observed in our behavioral experiments. 

Beyond molecular and behavioral studies, we also sought to understand how Foxp2 KD affects the electrical activity patterns of neurons, which are critical for the functioning of brain circuits. To evaluate the electrophysiological response of ITCs to Foxp2 KD, Lauren Seabrook, PhD (a colleague from the Carlezon lab at McLean Hospital), performed recordings of medial ITCs following Foxp2 shRNA vs. control injection. We found that Foxp2 KD leads to increased excitability of ITC cells. This is consistent with an increased inhibitory drive to neuronal projections in the central amygdala, which mediates subsequent behavioral response to fear learning.

This grant enabled us to establish that Foxp2 functions in the ITC region of the amygdala to regulate fear learning, and has helped us unravel the molecular and electrophysiological processes underlying its actions. We are preparing a manuscript and will use our preliminary data to support an NIH R01 application that advances our understanding of the role of Foxp2 in BD and identifies new targets for treatment based on these discoveries.