The study shows that the same brain neurons are activated when we imagine something and when we perceive something. The research, led by Cedars-Sinai, is the first to provide a detailed understanding of the shared mechanism that underlies visual perception and creation of mental images in the human brain. It was published in the journal Science.

“We generate a mental image of an object that we have seen before by reactivating the brain cells we used to see it in the first place,” said Ueli Rutishauser, PhD, director of the Center for Neural Science and Medicine and professor of Neurosurgery, Neurology and Biomedical Sciences at Cedars-Sinai Health Sciences University, and the study’s joint senior author. “Our study revealed the code that we use to re-create the images.”

The findings provide a biological basis for visual imagination, a process that is also critical for creative arts.

“Further insight into this neural process has the potential to open pathways toward developing new therapies for post-traumatic stress disorder, obsessive-compulsive disorder, and other mental conditions that involve uncontrolled vivid imagery,” said Adam Mamelak, MD, director of the Functional Neurosurgery Program and professor of Neurosurgery at Cedars-Sinai, and co-author of the study.

To conduct the study, investigators asked 16 adults with epilepsy, who had electrodes temporarily implanted in their brains for diagnosing their seizures, to view a series of images of faces and objects. After viewing them, a subset of the participants were asked to imagine those same images from memory. Meanwhile, researchers recorded the electrical activity of hundreds of individual neurons in each participant’s brain.

When the patients viewed the images, neurons were activated in their fusiform gyrus, an area of the brain essential for high-level visual processing, particularly for faces. For 80% of the visually responsive neurons recorded in the study, the researchers uncovered the aspects of the images they reacted to, thereby revealing their neural code. When the patients later imagined the images, about 40% of these neurons reactivated using the same code, thereby recreating the pattern of activity that occurred during the initial viewing of the images.

“Advanced artificial intelligence tools were critical to our investigation at all stages,” said Varun Wadia, PhD, a postdoctoral scientist in Rutishauser’s laboratory and first author of the study. “We used deep visual neural networks to create numerical descriptions of objects so that we could understand the neurons’ code. We then verified the code by using generative AI to create never-before-seen images and correctly predict the brain’s responses to these images.”

The research builds on the work of Doris Y. Tsao, PhD, of the University of California, Berkeley, who is co-senior author on the study. She identified the neural code for object recognition in nonhuman primates. The current study reveals that the same neural code is present in humans and that it explains visual imagination.

“These findings support the idea that imagining and seeing share a common neural code and may have important implications for understanding psychiatric disorders marked by disruptions in mental imagery and reality discrimination,” said Hermon Gebrehiwet, DrPH, program officer at the National Institutes of Health.

Still to be determined are what triggers the neural reactivation the investigators found, and how memories lead to reactivation of just the right subset of neurons needed, the investigators said.

Other Cedars-Sinai authors include: C. M. Reed, J. M. Chung, and L. M. Bateman

Funding: The work was supported by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies® Initiative, or The BRAIN Initiative® (U01NS117839 to UR), the Howard Hughes Medical Institute (DYT), the Simons Foundation Collaboration on the Global Brain (UR and DYT) and the Chen Center for Systems Neuroscience at Caltech (DYT).

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Every minute counts when someone has a stroke, which occurs when blood flow to the brain is blocked. Without rapid treatment, brain cells begin dying within minutes, often leaving patients with permanent speech, movement or memory disabilities.

“Stroke is one of the most time-sensitive emergencies in medicine,” said Nestor Gonzalez, MD, director of the Neurovascular Laboratory in the Department of Neurosurgery at Cedars-Sinai. “The faster we restore blood flow to the brain, the more brain function we can preserve.”

Gonzalez’s advice is echoed in the American Heart Association and American Stroke Association’s new 2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke. In the first update since 2019, the guidelines recommend more reliance on imaging, catheter-based procedures and emergency first responders. The guidelines also introduce the first national guidance for treating stroke in children.

Gonzalez, co-vice chair of the American Stroke Association group that developed the guideline, sat down with the Cedars-Sinai Newsroom to discuss the updates and leading-edge stroke research.

What are the most important changes in the updated guideline for acute ischemic stroke, in which a clot blocks blood flow to part of the brain?

Stroke treatment has advanced significantly over the past few decades, particularly with the development of clot-dissolving drugs and catheter-based procedures that can remove blockages in the brain. Since the previous stroke guidelines were published in 2019, new clinical trials have expanded our understanding of which patients can benefit from these treatments.

Previous guidelines recommended endovascular [minimally invasive] clot-removal procedures within six hours of stroke onset, with only a small group of selected patients eligible for treatment up to 24 hours after onset. The updated guideline broadens those criteria, allowing more patients to be considered for treatment in the 24-hour time frame.

The guidelines also expand treatment options for patients with large-core strokes—cases in which a significant area of the brain is affected. In the past, physicians were often hesitant to treat these patients because the potential benefit was uncertain. However, several recent studies have shown that intervention can still reduce disability in some cases.

The guidelines also expand eligibility for endovascular clot-removal procedures to include patients with preexisting disabilities, reflecting evidence that treatment may help them return to their baseline level of function.

You are a faculty member at Cedars-Sinai Guerin Children’s, and the updated recommendations include the first dedicated guidance for treating stroke in children. Why is that important?

Stroke can occur at any age, including in children. However, because it is rare, clinicians may not immediately consider stroke when a child presents with sudden neurological symptoms.

The updated guidelines provide clinicians with practical guidance for recognizing and managing stroke in children. Until now, there were no dedicated recommendations specifically addressing treatment in this population. The guidelines address early recognition of stroke symptoms, imaging strategies and circumstances in which treatments such as intravenous thrombolysis [clot-dissolving medication given through an IV] or endovascular thrombectomy [procedure removing clots from the brain] may be considered.

Over the past several years, specialized centers have begun applying some of the endovascular stroke treatments developed for adults to pediatric patients, and outcomes suggest that children can benefit from these interventions.

How will the updated guidelines change the treatment stroke patients receive in hospitals?

The guidelines emphasize improving the entire system of stroke care so patients can be evaluated and treated rapidly. That process begins with recognizing symptoms in emergency medical services, prompt evaluation and use of specialized treatment. They also synthesize a large body of research into recommendations that clinicians can apply in real-world practice.

The updated recommendations also highlight the importance of coordinated stroke systems that include rapid imaging, telemedicine support for smaller hospitals, and efficient patient transport to specialized stroke centers capable of performing advanced procedures, like Cedars-Sinai Medical Center.

For adult stroke patients, many of these systems are already in place. But for pediatric stroke, the impact may be even greater, as many hospitals are still developing formal systems for diagnosing and treating stroke in children.

What areas of stroke research are you most excited about right now?

Much of the recent progress in stroke care has focused on treating patients in the acute phase, when a clot suddenly blocks blood flow to the brain. But another challenge is helping patients whose brains receive chronically reduced blood flow, putting them at risk for repeated strokes. Two conditions that can cause this are Moyamoya disease, which often affects children and young adults, and intracranial atherosclerosis, which is more common in older adults.

In Moyamoya disease, the arteries at the base of the brain narrow or become blocked. To treat it, surgeons can perform bypass procedures that create new pathways to restore blood flow to the brain. My research has focused on improving these techniques and understanding how they benefit patients.

In adults with intracranial atherosclerosis, plaque buildup narrows, thickens or hardens the arteries in the brain. Medications help many patients, but in some cases, it is not enough. Working with the National Institutes of Health, we have been studying a surgical technique called indirect revascularization, or EDAS. Originally developed for children with Moyamoya disease, this approach is now being adapted for adults with severe vascular disease. Early clinical trials have shown encouraging results, and we are working to expand those studies to multiple centers to determine whether the technique can improve outcomes for patients who currently have limited treatment options.

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This condition not only can accelerate cognitive decline but is often mistaken for an underlying neurological condition—delaying proper diagnosis and treatment.

In a recent review published in the journal Alzheimer’s & Dementia, Cedars-Sinai researchers explored how UTI-induced delirium affects brain function, why individuals with dementia are especially vulnerable, and the critical need for early recognition and intervention.

“It’s a vicious cycle where dementia increases the risk of infection, and infection-related delirium accelerates cognitive decline,” said Shouri Lahiri, MD, principal investigator of the Critical Care Neurodegenerative Medicine Lab, director of the Neurosciences Critical Care Unit and Neurocritical Care Research at Cedars-Sinai, and senior author of the review.

Previous laboratory studies by Lahiri and his colleagues revealed that the immune system’s response to UTI-induced delirium—specifically the inflammatory protein interleukin-6—can cause changes in the brain. Blocking this pathway reversed delirium-like symptoms in mice.

Lahiri sat down with the Cedars-Sinai Newsroom to discuss UTIs as a potentially preventable and treatable contributor to cognitive decline and the importance of early recognition and swift treatment.

What is delirium, and how is it different from memory loss?

Delirium is a sudden change in thinking and awareness. It affects attention, judgment and short-term memory, and develops over hours or days.

Memory loss from conditions such as Alzheimer’s disease progresses slowly over time. Delirium, by contrast, is acute and usually triggered by a medical illness, such as a urinary tract infection, dehydration or infection elsewhere in the body.

Why can urinary tract infections cause confusion, especially in older adults?

Our research shows UTIs can cause acute brain dysfunction through inflammation. An infection in the bladder releases inflammatory signals into the bloodstream, which can affect the brain and disrupt normal function, leading to delirium.

Older adults are more vulnerable because their brains are often less resilient to physiological stress.

UTIs aren’t the only infections that can trigger this response. Any systemic infection, including pneumonia, gastrointestinal infections or skin infections, can provoke widespread inflammation that affects the brain and causes acute confusion.

Why are people with Alzheimer’s disease at higher risk for UTIs?

People with Alzheimer’s may have challenges upkeeping with hygiene and age-related hormonal changes that increase UTI risk. Alzheimer’s can also impair sensation and communication, making it harder for patients to recognize or report well-known UTI symptoms such as burning or urgency to urinate. As a result, infections may go untreated until they trigger delirium.

For people without dementia, delirium increases the risk of developing dementia by about threefold. Repeated episodes further raise that risk.

Why can a UTI make Alzheimer’s symptoms suddenly worse?

A UTI can cause a rapid cognitive decline that looks like a sudden worsening of Alzheimer’s disease. The key difference is timing. Alzheimer’s progresses gradually, while delirium causes an abrupt change from a person’s baseline.

We believe inflammation related to infection places added stress on an already vulnerable brain, which can worsen dementia symptoms and, in some cases, cause lasting damage.

Is delirium from a UTI reversible?

Early treatment offers the best chance for recovery. When UTIs are identified and quickly treated, delirium symptoms can improve or resolve. However, in some cases, cognitive effects can persist or become permanent. That’s why early recognition is critical.

Because UTIs don’t always cause obvious urinary symptoms, especially in older adults, we need to change the way we diagnose UTIs, using a mix of clinical observations and urinary and blood tests that show infection, to recognize when a UTI is behind sudden confusion.

How can caregivers tell the difference between Alzheimer’s progression and a UTI?

Sudden change is the biggest warning sign. Dementia generally does not cause abrupt declines. If someone with Alzheimer’s suddenly becomes much more confused, less alert or behaves very differently, that may signal delirium.

Other changes to look out for include changes in urination patterns, incontinence, pain, or changes in urine color or odor.

What can caregivers do to help prevent UTIs and delirium?

Caregivers should make sure the person they’re taking care of maintains good hygiene and adequate hydration. Caregivers should also notify a physician if UTIs are recurrent, because treatments are available to reduce repeated episodes.

Also, being aware of sudden changes in mental status and seeking prompt medical care can make a significant difference.

Are UTIs linked to delirium in other neurological conditions?

Yes. Parkinson’s disease is a key example. Many people with Parkinson’s have difficulty fully emptying their bladder, which increases infection risk. UTIs can worsen Parkinson’s movement symptoms, just as they worsen cognition in Alzheimer’s disease.

What is your lab studying next?

We are studying new drugs that target inflammatory pathways involved in UTI-related brain dysfunction, with the goal of advancing them to clinical trials. We are also developing diagnostic approaches to better identify UTIs in patients who  don’t have the well-known urinary symptoms.

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The study shows for the first time that Chlamydia pneumoniae can reach the retina—the tissue lining the back of the eye—where it triggers immune responses linked to inflammation, nerve cell death and cognitive decline.

“Seeing Chlamydia pneumoniae consistently across human tissues, cell cultures and animal models allowed us to identify a previously unrecognized link between bacterial infection, inflammation and neurodegeneration,” said Maya Koronyo-Hamaoui, PhD, professor of Neurosurgery, Neurology, and Biomedical Sciences at Cedars-Sinai Health Sciences University and the leading, senior author of the study. “The eye is a surrogate for the brain, and this study shows that retinal bacterial infection and chronic inflammation can reflect brain pathology and predict disease status, supporting retinal imaging as a noninvasive way to identify people at risk for Alzheimer’s.”

To conduct the study, researchers used advanced imaging, genetic testing and protein analysis to examine retinal tissue from 104 individuals, some with normal cognition, some with mild cognitive impairment and some with Alzheimer’s disease.

They found significantly higher levels of Chlamydia pneumoniae in the retinas and brains of people with Alzheimer’s disease than they found in people with normal cognition. The higher the bacterial levels detected, the more severe the brain changes and cognitive decline investigators found.

Higher levels of the bacterium were more common in people who carried the APOE4 gene variant, a known risk factor for Alzheimer’s disease.

Investigators also studied human neurons in the lab and in laboratory mice with Alzheimer’s disease. In both, infection with Chlamydia pneumoniae increased inflammation, nerve cell death and cognitive decline, showing the bacterium can accelerate disease processes. The infection also triggered production of amyloid-beta, the protein that accumulates in the brains of people with Alzheimer’s.

The findings were driven by co-first authors Bhakta Gaire, PhD, and Yosef Koronyo, MSc.

“This discovery raises the possibility of targeting the infection-inflammation axis to treat Alzheimer’s,” said Timothy Crother, PhD, co-corresponding author of the study and research professor at Cedars-Sinai Guerin Children's and the Department of Biomedical Sciences at Cedars‑Sinai.

The findings suggest that targeting chronic bacterial infection—and the inflammation it triggers—could represent a new treatment strategy. The research also supports potential use of the retina as a noninvasive way to help diagnose and monitor the disease.

Additional Cedars-Sinai authors include Bhakta Gaire, Yosef Koronyo, Jean-Philippe Vit, Alexandre Hutton, Lalita Subedi, Dieu-Trang Fuchs, Natalie Swerdlow, Altan Rentsendorj, Saba Shahin, Daisy Martinon, Edward Robinson, Alexander V. Ljubimov, Keith L. Black, Jesse Meyer, and Moshe Arditi.

Other authors include Julie A. Schneider, Lon S. Schneider, Debra Hawes, Stuart L. Graham, Vivek K. Gupta, and Mehdi Mirzaei.

Funding: This work has been supported by the NIH/NIA grants R01AG056478, R01AG055865, and AG056478-04S1 (M.K.H.), R01AG075998 (M.K.H. and T.R.C.), and Alzheimer’s Association grant AARG-NTF-21-846586 (T.R.C.). MKH is also supported by The Goldrich and Snyder Foundations. ER has been supported by The Ray Charles Foundation.

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“We discovered that abnormal tau proteins accumulate in retinal ganglion cells, which are key nerve cells in the eye that send information to the brain,” said Maya Koronyo-Hamaoui, PhD, professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “We also identified a correlation between early accumulation of abnormal tau and the damage and death of retinal ganglion cells in people showing symptoms of mild cognitive impairment and Alzheimer’s disease.”

People with mild cognitive impairment and Alzheimer’s disease had 46%–57% fewer retinal ganglion cells than people with normal cognition, and their retinal ganglion cells were misshapen and prone to die. Harmful tau proteins were two to three times more common in the retinal ganglion cells of these people, and the amount of tau-related damage in the retina was linked to Alzheimer’s-related damage to the brain and a decline in cognitive function, Koronyo-Hamaoui said.

Additional Cedars-Sinai Authors: Miyah R. Davis, Edward Robinson, Yosef Koronyo, Altan Rentsendorj, Bhakta P. Gaire, Nazanin Mirzaei, Alexander V. Ljubimov, Keith L. Black, Dieu-Trang Fuchs

Additional Authors: Elena Salobrar-Garcia, Rakez Kayed, Alfredo A. Sadun, Lon S. Schneider, Debra Hawes

Funding: This work was supported by the National Institutes of Health (NIH)/the National Institute on Aging (NIA) through the following grants: R01 AG055865 and R01 AG056478 (M.K.H.), The Hertz Innovation Fund (M.K.H.), and the Gordon, Wilstein, and Saban Private Foundations (M.K.H.). Y.K., A.R., B.P.G., D.-T.F., M.K.H. are also supported, in part, by the NIH/NIA R01AG075998 grant. M.R.D. and E.R. are supported by The Ray Charles Foundation. E.S.G. is supported by José Castillejo grants for mobility stays abroad for young doctors 2023 (CAS22/00049, Ministerio de Ciencia, Investigación y Universidades) and Complutense del Amo Grants 2023, Complutense University of Madrid.

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“Our model, called the Unified Structural and Functional Connectivity model, provides a step toward mapping how different parts of the brain functionally communicate,” said Wei Gao, PhD, director of Neuroimaging Research and professor of Biomedical Sciences at Cedars-Sinai and senior author of the study. “The model shows that certain structural pathways, especially in networks related to emotions, self-awareness, and sensory processing, are heavily used for brain communications. The model also enhances our understanding of how these interactions relate to cognitive function.”

The investigative team—led by Gao, study co-author Pascal Sati, PhD, director of the Neuroimaging Program and associate professor of Neurology, and first author Arzu Silemek, PhD, a postdoctoral fellow supervised by Gao and Sati—found that certain areas serve as crucial hubs, with a significant corridor facilitating overall brain connectivity. They believe this mapping of brain communication could inform future research on cognitive processes and neurodevelopmental disorders. Clinically, they suggested it could improve physicians’ diagnostic tools by providing insights into how structural changes affect brain function, potentially leading to better-targeted interventions for conditions such as Alzheimer’s disease and other cognitive disorders.

Additional author: Haitao Chen

Funding: This work was supported by the National Institutes of Health (R01DA042988 and R01DA043678) and by Cedars-Sinai Precision Medicine Initiative Award and institutional support (to W.G.).

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“Recording the activity of individual neurons in the brains of study participants, we found that distinct populations of neurons were dedicated to these tasks, which we call social inferences,” said Ueli Rutishauser, PhD, director of the Center for Neural Science and Medicine and professor of Neurosurgery, Neurology and Biomedical Sciences at Cedars-Sinai, and senior author of the study. “The ability to make decisions about these types of social situations is immensely important and frequently impaired by neurological disease, but the mechanisms behind it have been poorly understood.”

Investigators found that the neurons supporting social inferences were different than those supporting inferences based on nonsocial situations, such as noticing that the sidewalk is wet and inferring that it recently rained. They also found that separate neurons are dedicated to processing social information provided by hands versus that from faces and facial expressions.

Additional Cedars-Sinai authors: Julien Dubois, Adam N. Mamelak

Additional authors: Runnan Cao, Ralph Adolphs, Shuo Wang

Funding: This research was supported by the McDonnell Center for Systems Neuroscience, AFOSR (FA9550-21-1-0088), NSF (BCS-1945230, IIS-2114644), and NIH (K99EY036650 to R. C., R01MH129426 to S.W., P50MH094258 to R.A., U01NS117839 to U.R., and R01M.

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The study, published in the peer-reviewed Journal of Racial and Ethnic Health Disparities, identified multiple strategies to address low participation rates of non-Hispanic Black and Hispanic patients in a National Institutes of Health-funded trial investigating virtual reality for chronic lower back pain.

“Traditional recruitment strategies have not been effective in reaching these communities,” said Lindsey Ross, MD, assistant professor of Neurosurgery at Cedars-Sinai and first author of the study. “We conducted focus groups with Black and Hispanic patients to understand their concerns and preferences, highlighting barriers to participation such as mistrust, lack of interest, cultural differences and ineffective communication. The insights we gained allowed us to revise our recruitment materials to be more culturally responsive, updating language, imagery and outreach methods. We also used advanced digital tools to scan electronic medical records and micro-target eligible Black and Hispanic patients for the trial.”

After these changes were implemented, recruitment of Hispanic participants into the trial more than quadrupled, and recruitment of Black participants showed a notable upward trend. Ross said these results demonstrate that culturally adapted recruitment strategies and digital targeting tools can play a critical role in improving clinical trial diversity, and offer actionable insights for researchers aiming to bridge the gap in clinical trial representation of diverse communities.

Authors: Samuel Eberlein, Carine Khalil, So Yung Choi, Karma McKelvey, Brennan M. R. Spiegel. 

Funding: Open access funding provided by SCELC, Statewide California Electronic Library Consortium. This work was supported by the National Institutes of Health (NIH)/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) through the Back Pain Consortium (BACPAC) Research Program as a part of the NIH HEAL Initiative [UH3AR076573-03S1].

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Delirium causes confusion and behavior changes, affects millions of patients each year and can increase a patient’s risk of long-term neurological problems. It is common in hospitalized patients who are placed on ventilators to assist their breathing.

“Microglia, the resident immune cells in the brain, can be destructive to brain cells in some neurological diseases, but also can be protective,” said Shouri Lahiri, MD, director of the Neuroscience Critical Care Unit and director of Neurocritical Care Research in the Department of Neurology at Cedars-Sinai and senior author of the study. “While previous research has suggested that the action of microglia may cause or worsen delirium, we found that the opposite is true. When we depleted levels of microglia in laboratory animal experiments, delirium-associated brain changes and behaviors increased. And when we restored microglia levels to normal, the changes were almost completely reversed.”

Medications that activate neuron-protecting microglia could be one option for managing delirium. Investigators previously determined that a protein called interleukin-6 damages neurons, and future studies could clarify whether it or other proteins activate neuron-protecting microglia. Future research is also planned to help determine the conditions under which microglia can cause damage to neurons, said Lahiri, an associate professor in the departments of Neurology, Neurosurgery, and Biomedical Sciences.

First authors: Landon Scott, Kevin D. Winzey

Additional authors: Debbie Moreira, Catherine Bresee, Jean‐Philippe Vit, Warren G. Tourtellotte, S. Ananth Karumanchi, and Shouri Lahiri

Funding: F. Widjaja Foundation

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These cells are located in the hippocampus, the brain area affected in the earliest stages of Alzheimer’s disease, the earliest symptoms of which are working memory deficits.

“Working and long-term memory are different types of memory that were previously thought to be supported by different parts of the brain,” said Ueli Rutishauser, PhD, director of Neural Science and Medicine and professor of Neurology, Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “Based on this study and our previous work, we have concluded that the hippocampus, long known to support long-term memory, is often essential for working memory as well. In fact, neurons in the hippocampus that we have named ‘persistently active cells’ are critical for both types of memory. Protecting or restoring these cells could help in treating the devastating effects of memory disorders.”

Additional authors: Jonathan Daume, Jan Kamiński, Yousef Salimpour, Andrea Gómez Palacio Schjetnan, William S. Anderson, Taufik A. Valiante, Adam N. Mamelak

Funding: This work was supported by the National Institutes of Health (U01NS117839 to U.R.), a Postdoctoral Fellowship by the German Academy of Sciences Leopoldina (to J.D.) and a Postdoctoral Award by the Center for Neural Science and Medicine at Cedars-Sinai (to J.D.).

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“In older adults, higher levels of amyloid beta and tau have been associated with poorer memory and cognition," said Mitzi Gonzales, PhD, director of Translational Research in the Jona Goldrich Center for Alzheimer’s and Memory Disorders at Cedars-Sinai and lead author of the study. “Our study found that this was also true in adults age 55 and younger—a period thought to be important for prevention. We also found higher levels in individuals with a higher genetic risk for Alzheimer's disease. Future studies should examine memory and cognitive changes over time and look at why some individuals remain mentally sharp despite having high levels of these proteins, to provide important clues about maintaining cognitive health over the lifespan.”

The findings highlight the importance of understanding the effects of amyloid beta and tau proteins on memory and thinking abilities at earlier ages. The work could also help focus dementia-prevention efforts in younger at-risk populations.

Additional authors: Adrienne O’Donnell, Saptaparni Ghosh, Emma Thibault, Georges El Fakhri, Sudha Seshadri, Jeremy Tanner, Claudia L. Satizabal, Charles S. Decarli, Keith A. Johnson, Alexa S. Beiser, Matthew Pase.

Funding: National Institutes of Health, Grant/Award Numbers: N01-HC-25195, HHSN268201500001I, 75N92019D00031; National Institute on Aging, Grant/Award Numbers: RF1AG059421, R01AG054076, R01AG049607, R01AG033090, R01AG066524, R01NS017950, R01AG077472, P30AG066546; National Health and Medical Research Council of Australia Investigator, Grant/Award Number: GTN2009264. 

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“The retina, a layer of tissue at the back of the eye, is part of the central nervous system and is directly connected with the brain,” said Maya Koronyo-Hamaoui, PhD, professor of Neurosurgery, Neurology and Biomedical Sciences at Cedars-Sinai and senior author all three studies. “It has similar cell types and vascular structures to the brain, but is not shielded by bone, so it is more accessible to noninvasive imaging. Our latest research unearths new details about the eye-brain connection.”

Tau

Tau is a protein that helps stabilize the structure of nerve cells in the brain and the retina and is one of the key markers of Alzheimer’s disease. When tau disengages from nerve cells it can form tangles that interfere with cellular function and contribute to cognitive decline.

In a study published in the peer-reviewed journal Acta Neuropathologica, Koronyo-Hamaoui and fellow investigators compared retinal tissue from 45 patients diagnosed with Alzheimer’s-related cognitive impairment or dementia with tissue from 34 individuals with normal cognition or non-Alzheimer’s forms of dementia.

Investigators found that higher levels of abnormal tau in the retina corresponded to levels of tau in the brain, other brain changes related to Alzheimer’s disease, and cognitive decline.

Vessels and amyloid plaques

Clumps of a protein called beta-amyloid, also known as amyloid plaques, are another hallmark of Alzheimer’s disease.

In a study published in the peer-reviewed journal Acta Neuropathologica Communications, Koronyo-Hamaoui and co-investigators used leading-edge imaging and image-processing technology to compare amyloid plaques in the retinas of living patients who had early-stage cognitive impairment with those in individuals who had normal cognition.

Thirty-four patients underwent retinal and brain imaging, and cognitive testing. Analysis in 28 patients revealed two to three times as many plaques clustered near blood vessels in the retinas of patients with mild cognitive impairment or Alzheimer’s disease when compared with individuals with normal cognition. The numbers and position of the plaques correlated with cognitive decline and physical changes in the brain.

Diagnosis in development

Koronyo-Hamaoui’s team also published a review article in the peer-reviewed journal Progress in Retinal and Eye Research that detailed additional Alzheimer’s disease biomarkers that have been identified in the retina.

These include reduced blood flow, deposits of amyloid-beta proteins inside blood vessel walls, damage to the barrier that prevents harmful substances from entering retinal tissue, inflammation, and damage to nerve cells.

“Imaging technology now being developed will allow us to see these changes in patients in clinical settings,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai and co-author of these studies. “This technology, which is noninvasive and affordable, allows us to see changes in the cells and blood vessels in tremendous detail.”

Black and Koronyo-Hamaoui envision this technology as a tool to screen patients in primary care settings, with those who show features suggestive of Alzheimer’s disease referred for additional testing, such as a PET brain scan or cerebrospinal fluid or blood test. The technology could also assess disease progression and the effectiveness and safety of new treatments.

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“Abstraction allows us to ignore irrelevant details and focus on the information we need in order to act, and inference is the use of knowledge to make educated guesses about the world around us,” said Ueli Rutishauser, PhD, professor and Board of Governors Chair in Neurosciences at Cedars-Sinai and co-corresponding author of the study. “Both are important parts of cognition and learning.”

Humans often use these two cognitive processes together to rapidly learn about and act appropriately in new environments. One example of this is an American driver who rents a car in London for the first time.

“The English drive on the right-hand side of the car and on the left-hand side of the road, the opposite of the way we do in the U.S.,” Rutishauser said. “For someone from the U.S., driving in London means reversing many of the rules they have learned, and making that mental shift requires abstraction to focus on driving-sidedness, and making inferences to avoid pulling directly into oncoming traffic.”

In the study, investigators worked with 17 hospitalized patients who had electrodes surgically implanted in their brains as part of a procedure to diagnose epilepsy. In total, the researchers recorded the firing of thousands of brain cells as participants performed an inference task on a computer.

Looking at the activity of so many brain cells required the use of artificial intelligence to extract the responses that were relevant, allowing investigators to see the coordination between the neurons during successful inference.

“These are high-dimensional geometrical shapes that we cannot imagine or visualize on a computer monitor,” said Stefano Fusi, PhD, a principal investigator at Columbia University’s Zuckerman Mind Brain Behavior Institute and co-corresponding author of the study. “But we can use mathematical techniques to visualize simplified renditions of them in 3D.”

During the recordings, participants were repeatedly shown four pictures—a person, a monkey, a car and a watermelon. In response to each picture, they were asked to press a left-hand or right-hand button. Individuals then received a “correct” or “incorrect” message.

Through repetition, participants eventually learned the correct response for each of the four pictures. At that point, the rules of the game were reversed without the participants being informed, and the opposite response for each picture was counted as correct.

After the switch, some participants were able to quickly figure out the rule change and infer the correct responses without relearning them, meaning they performed inference.

Investigators saw striking geometric patterns in the brains of those participants. Groups of neurons were firing together, much like birds flying in formation or a crowd of people spontaneously taking up a chant at a sporting event. The way the neurons coordinated their activity and encoded the relevant information indicated that the subjects had gained the conceptual knowledge needed to perform the task. Investigators saw no such patterns in the brains of participants who were not successful in using inference.

“Building conceptual knowledge is an important aspect of learning,” said Hristos Courellis, PhD, a researcher at Cedars-Sinai and first author of the study. “In our study, we identified a neural basis for this process, which in cognitive psychology is referred to as abstraction.”

Some subjects were initially not able to perform inference from experience with the task alone. For these subjects, investigators provided verbal instructions that allowed the subjects to then infer the correct answers.

“A remarkable discovery was that the same neural geometries emerged in participants who received verbal instructions as in those whose ability to infer was based on experiential learning,” said Adam Mamelak, MD, director of the Functional Neurosurgery Program and professor of Neurosurgery at Cedars-Sinai and co-author of the study. “This crucial discovery shows that verbal input can result in neural representations that otherwise might take a long time to learn through experience.”

The study, which relied on data from Cedars-Sinai and the University of Toronto, was led by Cedars-Sinai and conducted as part of a multi-institutional consortium funded by the National Institutes of Health’s The Brain Research Through Advancing Innovative Neurotechnologies Initiative, or The BRAIN Initiative.

“This study provides new insights into how our brains allow us to learn and carry out tasks flexibly and in response to changing conditions and experiences,” said Merav Sabri, PhD, program director for The BRAIN Initiative. “These insights build on the body of knowledge that could one day lead us toward interventions for neurologic and psychiatric conditions that involve deficits in memory and decision-making.”

A surprise to investigators was the discovery that these particular patterns of brain activity emerged only in the hippocampus, a region deep in the center of the brain that is known to be crucial for the formation of new long-term memories.

“Our finding expands our knowledge of the role of the hippocampus in learning,” Rutishauser said. “This is the first direct demonstration of the involvement of the human hippocampus in the learning of abstract knowledge and inference behavior. Many neurological conditions, including Alzheimer’s disease, obsessive-compulsive disorder and schizophrenia, affect this brain region, and our finding could help explain the impaired decision-making we see in these patients.”

Additional Cedars-Sinai authors include Juri Minxha, and Chrystal M. Reed.

Other study authors include Araceli R. Cardenas, Daniel Kimmel, Taufik A. Valiante, and C. Daniel Salzman.

Funding: This work was supported by The BRAIN Initiative through the NIH Office of the Director (U01NS117839 to U.R.) and the Simons Foundation Collaboration on the Global Brain (to S.F., and U.R.).

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This could lead to new applications for the therapy, allowing it to influence higher-level functions such as learning and memory.

“Deep brain stimulation has typically been used to overexcite or shut down all neurons in a target area,” said Costas Anastassiou, PhD, associate professor of Neurology, Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “We found that by varying the shape of the electrical pulse waves we apply, we can selectively influence specific neuron types while leaving others unaffected.”

In the study, investigators applied electrical fields to individual cells in tissue samples from the visual cortex and the hippocampal regions of the brains of patients and laboratory mice. The investigators recorded the activity of excitatory and inhibitory neurons, which act as the gas pedal and brakes, respectively, in brain circuits.

Results showed that different electrical wave frequencies influenced the timing of spikes, which are changes in electrical voltage that travel down neuron fibers and are transmitted to other neurons. Anastassiou called spikes “the coin of communication between neurons.”

“We found that electrical frequencies that influenced one cell type did not necessarily influence another, and vice versa,” Anastassiou said. “Surprisingly, the effects on each cell type were the same in both brain areas we examined, and in both species—though more pronounced in humans than in mice.”

Given that previous research has found that higher-level functions in the brain require coordination and communication between different cell types, the ability to manipulate this communication could be of great importance, Anastassiou said.

“This study offers new understanding of how to stimulate the human brain to promote or suppress specific activity patterns, and could pave the way for new directions in basic research and clinical applications,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai. “These results offer the possibility for electrical protocols that are more selective, more controlled, and allow for different parts of the brain neural network to be manipulated in different ways.”

Investigators are now working to determine the exact mechanisms required to produce various results in the brain, and to replicate their brain tissue experiments in living patients.

“This data supports the idea that electrical brain stimulation could be used in new ways that target specific groups of brain cells,” said Adam Mamelak, MD, director of the Functional Neurosurgery Program at Cedars-Sinai. “This gives us an exciting opportunity to imagine new uses for this therapy and the chance to address disorders involving learning and memory.” 

Other Cedars-Sinai authors involved in the study include Konstantinos Kozalakis, PhD.

Funding: This work was supported by National Institutes of Health grants R01 NS120300 and RO1 NS130126.

Conflict of interest: Anastassiou is listed as an inventor on a patent application related to this work.

Learn more on the Cedars-Sinai Blog: A Patient’s Journey With Deep Brain Stimulation

The study detailing their discovery was published in the peer-reviewed journal Nature.

“We have identified for the first time a group of neurons, influenced by two types of brain waves, that coordinate cognitive control and the storage of sensory information in working memory,” said Jonathan Daume, PhD, a postdoctoral scholar in the Rutishauser Lab at Cedars-Sinai and first author of the study. “These neurons don’t contain or store information, but are crucial to the storage of short-term memories.”

Working memory, which requires the brain to store information for only seconds, is fragile and requires continued focus to be maintained, said Ueli Rutishauser, PhD, director of the Center for Neural Science and Medicine at Cedars-Sinai and senior author of the study. It can be affected by different diseases and conditions.

“In disorders such as Alzheimer's disease or attention-deficit hyperactivity disorder, it is often not memory storage, but rather the ability to focus on and retain a memory once it is formed that is the problem,” said Rutishauser, who is a professor of Neurosurgery, Neurology and Biomedical Sciences at Cedars-Sinai. “We believe that understanding the control aspect of working memory will be fundamental for developing new treatments for these and other neurological conditions.”

To explore how working memory functions, investigators recorded the brain activity of 36 hospitalized patients who had electrodes surgically implanted in their brains as part of a procedure to diagnose epilepsy. The team recorded the activity of individual brain cells and brain waves while the patients performed a task that required use of working memory.

On a computer screen, patients were shown either a single photo or a series of three photos of various people, animals, objects or landscapes. Next, the screen went blank for just under three seconds, requiring patients to remember the photos they just saw. They were then shown another photo and asked to decide whether it was the one (or one of the three) they had seen before.

When patients performing the working memory task were able to respond quickly and accurately, investigators noted the firing of two groups of neurons: “category” neurons that fire in response to one of the categories shown in the photos, such as animals, and “phase-amplitude coupling,” or PAC, neurons.

PAC neurons, newly identified in this study, don’t hold any content, but use a process called phase-amplitude coupling to ensure the category neurons focus and store the content they have acquired. PAC neurons fire in time with the brain’s theta waves, which are associated with focus and control, as well as to gamma waves, which are linked to information processing. This allows them to coordinate their activity with category neurons, which also fire in time to the brain’s gamma waves, enhancing patients’ ability to recall information stored in working memory.

“Imagine when the patient sees a photo of a dog, their category neurons start firing ‘dog, dog, dog’ while the PAC neurons are firing ‘focus/remember,’” Rutishauser said. “Through phase-amplitude coupling, the two groups of neurons create a harmony superimposing their messages, resulting in ‘remember dog.’ It is a situation where the whole is greater than the sum of its parts, like hearing the musicians in an orchestra play together. The conductor, much like the PAC neurons, coordinates the various players to act in harmony.”

PAC neurons do this work in the hippocampus, a part of the brain that has long been known to be important for long-term memory. This study offers the first confirmation that the hippocampus also plays a role in controlling working memory, Rutishauser said.

This study was conducted as part of a multi-institutional consortium funded by the National Institutes of Health’s Brain Research Through Advancing Innovative Neurotechnologies Initiative, or the BRAIN Initiative, and led by Cedars-Sinai. The data in this study is pooled across Cedars-Sinai, the University of Toronto, and the Johns Hopkins School of Medicine, resulting in a statistically powerful study that a single institution could not accumulate on its own given the difficulty of these experiments.

"One of the aims of the BRAIN Initiative is to uncover—through the use of innovative technologies—properties of the human brain that have so far been difficult, if not impossible, to study,” said Dr. John Ngai, PhD, director of the NIH BRAIN Initiative. “Here, by leveraging unusual opportunities supported by the initiative to illuminate complex processes in humans, the Rutishauser Lab is shedding light on the way certain neurons support how memories are stored in the brain—a process that is far from understood in devastating brain disorders such as Alzheimer’s disease and other dementias.”

Other Cedars-Sinai authors involved in this study include Jan Kaminski, Umais Khan, Michael Kyzar, Chrystal Reed, and Adam Mamelak. Also involved in the study were Andrea Schjetnan and Taufik Valiante of the University of Toronto, and Yousef Salimpour and William Anderson of Johns Hopkins School of Medicine.

Funding: This work was supported by a German National Academy of Sciences Leopoldina Postdoctoral fellowship, a Cedars-Sinai Center for Neural Science and Medicine Postdoctoral fellowship, National Institute of Neurological Disorders and Stroke BRAIN initiative grants number U01NS103792 and U01NS117839, and National Science Foundation grant number BCS-2219800.

Conflict of interest: Authors declare no competing interests.

Read more on the Cedars-Sinai Blog: When Should I Be Concerned About Memory Loss?

Neuroprosthetics, a technology that allows the brain to control external devices such as robotic limbs, is beginning to emerge as a viable option for patients disabled by amputation or neurological conditions such as stroke. Cedars-Sinai investigators, in a study published in the peer-reviewed journal

“Neuroprosthetics have largely tapped the brain’s outermost cerebral cortex. The cerebellum has a well-known role in movement but has been ignored in neuroprosthetic research,” said Tanuj Gulati, PhD, assistant professor of Biomedical Sciences and Neurology and researcher in the Center for Neural Science and Medicine at Cedars-Sinai, and senior author of the study. “We are the first to record what is happening in the cerebellum as the brain learns to manipulate these devices, and we found that its involvement is essential for device use.”

Patients who use neuroprosthetic devices have electrodes permanently implanted in the portion of the brain—usually the cerebral cortex—that controls movement for the function the device is replacing. This technique can be used to help patients control a robotic limb, a motorized wheelchair or a computer keyboard, among other devices.

To learn how the cerebellum helps in learning neuroprosthetic control, Gulati and his team trained laboratory rats to use only their motor cortex activity to move a neuroprosthetic tube that delivered them water. The rats had electrodes implanted in the motor cortex and the cerebellum, and investigators listened in on the activity of neurons in both brain regions during the experiments.

“We found that activity of the neurons in the cerebellum was coordinated with the motor cortex, and that activity in the cerebellum was critical for neuroprosthetic task performance,” said Aamir Abbasi, PhD, a postdoctoral scientist in the Gulati Lab and the first author of the study.

Investigators next used an advanced technology called optogenetics to selectively silence different neuron populations in the laboratory rats’ brains during experiments. Optogenetics delivers light-sensitive proteins into brain cells, allowing light exposure to control these cells’ activity.

When they silenced neurons in the outer layer of the cerebellum, where the cerebellum receives input from other brain regions, they found that the laboratory rats had a difficult time learning to control movement of the pipe. When they silenced neurons deep in the cerebellum, which are responsible for outward communication from the cerebellum to the motor cortex, the rats had difficulty maintaining accurate control of the pipe.

“These results could help make neuroprosthetics an option for patients with damage to the motor cortex due to brain injury, stroke or diseases such as Parkinson’s or multiple sclerosis,” said Nancy L. Sicotte, MD, chair of the Department of Neurology and the Women’s Guild Distinguished Chair in Neurology at Cedars-Sinai. “It’s possible that, eventually, implants in the cerebellar region could be used to help these patients manipulate external devices.”

It’s an exciting era for neuroprosthetics, said David Underhill, PhD, chair of the Department of Biomedical Sciences at Cedars-Sinai.

“There is a lot of buzz about neuroprosthetic technology, but there are still many unsolved problems,” Underhill said. “This study suggests that some of those could be resolved by involving the cerebellum as well as the motor cortex to help patients gain use of neuroprosthetic devices more quickly and improve their ability to control them accurately.”

Other authors involved in the study include Rohit Rangwani, Daniel W. Bowen, Andrew W. Fealy, and Nathan P. Danielsen.

This work was supported by American Heart Association postdoctoral fellowship 897265, American Heart Association predoctoral fellowship 1018175, American Heart Association career development award 847486, National Institutes of Health grants R00NS097620 and R01NS128469, National Science Foundation grant 2048231, and a Cedars-Sinai Medical Center’s Center for Neural Science and Medicine postdoctoral fellowship.

No conflicts of interest to disclose.

Read more on the Cedars-Sinai Blog: Bolster Your Brain by Stimulating the Vagus Nerve

The Rutishauser Lab collaborates with several leading universities and medical centers, including the California Institute of Technology, Johns Hopkins University, the University of Toronto, Boston Children’s Hospital and the University of Colorado at Denver. A key aspect of this collaboration is open data-sharing. Cedars-Sinai is part of the National Institutes of Health BRAIN Initiative Research Opportunities in Humans Consortium, representatives of which recently penned an article for the peer-reviewed journal Neuron on the benefits of data-sharing.

“Dr. Rutishauser’s work advances our understanding of the workings of the human brain and also connects Cedars-Sinai with top medical institutions across the country and beyond,” said Jeffrey Golden, MD, vice dean of Research and Research Education at Cedars-Sinai. “Work of this caliber simply isn’t possible if institutions guard their discoveries and data, encumbering collaboration.”

Rutishauser, who holds the Board of Governors Chair in Neurosciences, sat down with the Cedars-Sinai Newsroom to discuss the role of data-sharing and scientific collaboration in his work and the broader scientific community.

What type of data does your lab’s research generate, and how has it advanced our understanding of the human brain?

Our data is acquired from patients with epilepsy who are undergoing depth-electrode monitoring, which means they have tiny electrodes surgically inserted into the brain to monitor seizure activity.

We use these recordings of the electrical pulses sent between individual neurons within the brain to study how the brain records and recalls memories, how we make decisions, and how these processes go wrong under certain conditions. For example, we have discovered how we monitor our own behavior for errors using this approach.

The same data, which is rare and difficult to acquire, can also be used to study many other aspects of the human brain, but this is only possible if the data is made accessible to other investigators inside and outside of Cedars-Sinai.

What is the current state of data-sharing in human neuroscience?

Funding agencies and journals require that research teams make their data available to others. However, they require sharing of only the exact data needed to reproduce a given study, often only on request.

This requirement is often viewed as a burden by investigators. But in our recent editorial, we point out the many benefits of investigators sharing all of their data freely and in a standardized format, so it is easily accessible. We found that when we, as the data producer, released data in this way, we discovered new collaborators who used our data to explore questions we had never thought about. Within our own lab, using a standardized data format also facilitated reuse of that data. And schools and universities have even used the data for teaching purposes.

Why is cross-institutional collaboration so important to the future of science?

Collaborating and sharing data is a way for us to broaden our impact. One of the inherent difficulties of the work I do is that the experiments are challenging to perform and the number of patients available is limited. To increase the amount of data available, we collaborate with research groups at other institutions. This allows us to perform large, well-powered studies and increases confidence in our findings by replicating findings at other institutions.

What challenges need to be overcome to increase data-sharing in neuroscience?

There are three challenges. First, the field has to agree on a standard data format. While there are formats that could fill this requirement, there’s no universal agreement on which should be the standard format. The use of a single standard data format in the field of neuroimaging, for example, shows the immense benefits of the practice. Second, we need data archives where very large files can be uploaded, stored and made available. Third, and perhaps most challenging, investigators must be willing to openly share their data.

What is your advice for investigators who want to share their data?

I strongly advise using a standardized data format. We chose to use the Neural Data Without Borders (NWB) format. Develop an expectation in your lab that when a project is finished, your team will export the data in that format, document it and publicly release it upon publication.

Multiple sclerosis is a disease of the brain and spinal cord in which the body’s immune system attacks the protective sheaths that surround nerves, disrupting communication between the brain and the rest of the body. Brain imaging, which allows physicians to see the lesions that form at the point of attack, is essential for diagnosing the condition and guiding patient treatment.

Sicotte and Sati are among co-authors of a consensus statement from the North American Imaging in MS Cooperative that seeks to standardize imaging techniques for identifying chronic active lesions, an important indicator of chronic brain inflammation in MS. The statement, published in the peer-reviewed journal Brain, is designed to set guidelines for imaging chronic active lesions and how imaging will be used for diagnosis, predicting patient outcomes, and clinical trials.

They recently spoke with the Cedars-Sinai Newsroom about the role of imaging in MS today and in the future.

How has imaging changed treatment for patients with MS?

Sicotte: When I started treating patients with MS more than two decades ago, there were essentially no treatments, and now we have more than 25. One of the reasons we have these medications is because of advancements in the use of MRI to track disease activity in the brain and spinal cord of people who have MS. Because MRI is more sensitive than clinical attacks, it became a powerful tool to test the effectiveness of new therapies, and that energized research and led to the development of a whole suite of new MS treatments that decrease the likelihood of new lesions appearing.

How do lesions appear on an MRI?

Sicotte: In patients with active MS, the blood-brain barrier, which keeps potentially harmful substances from reaching the brain, breaks down due to immune activation. This results in what we call a contrast-enhancing lesion, the classic acute inflammatory lesion. These lesions show up as bright spots that are easily detected using MRI after injection of contrast. Over time, the blood-brain barrier repairs itself and leaves behind a chronic lesion that is akin to a scar that can also be tracked over time using dedicated MRI techniques.

What are the newest lesions that have been identified?

Sati: We and others have recently identified a new type of lesion, called a paramagnetic rim lesion, that we think is an indicator of chronic brain inflammation that may be the primary driver of disease progression in treated patients who do not have acute inflammatory lesions.

In paramagnetic rim lesions, microglia, the primary immune cells that respond to tissue injury and clean up debris in the brain, form a rim around lesions where the blood-brain barrier has healed. This is a sign that the inflammation is persisting at low intensity behind a closed blood-brain barrier. The rims are like a smoldering fire that continues to burn and slowly propagate. MS patients with a lot of paramagnetic rim lesions are more likely to have increased disability, so we think the lesions might be a good biomarker for progressive disease. Because our current therapies can’t cross a closed blood-brain barrier, we don’t have a way to treat these lesions at present.

Can advanced imaging techniques help identify therapies to treat chronic inflammation in MS patients?

Sati: We think so! We have received funding from the National Multiple Sclerosis Society and the National Institutes of Health to evaluate paramagnetic rim lesions as a diagnostic biomarker using detection techniques we developed. We are now exploring novel techniques to measure the amount of chronic inflammation and tissue damage in these lesions to evaluate the effects of new brain-penetrant therapies. We hope that these new quantitative techniques combined with AI will enable us to measure paramagnetic rim lesions in a fast, efficient way that could be put into practice in most imaging facilities and be deployed in clinical trials.

We’re doing this work in collaboration with all the stakeholders: the MRI physicists at our institution, the MRI vendors that provide the scanners and imaging technology, the neuroradiologists who read these scans, and the pharmaceutical industry that develops the therapies. We hope to prove that our concepts can be applied on different MRI scanners, so that they can be used in international clinical trials testing new therapies that can target these lesions and change the course of the disease.

What are your hopes for the future of MS care?

Sicotte: We're really lucky here at Cedars-Sinai. We have a large group of patients who are eager to participate in research, and we have been collecting MRI data over many years. Added to that, we're employing these newer techniques. We're hoping that the data we are collecting will tell us more about the drivers of progressive disease, how to predict which patients might not require treatment, and which we should treat aggressively from the outset.

Read more on the Cedars-Sinai Blog: Cedars-Sinai Neurology Chair Honored by National MS Society for COVID-19 Work

is designed to help medical staff tailor care to best serve these patients.

“People with dementia or cognitive impairment can be especially vulnerable in the hospital if their care team is unaware,” said Zaldy Tan, MD, MPH, medical director of the Jona Goldrich Center for Alzheimer’s and Memory Disorders at Cedars-Sinai and first author of the study. “Our study is the first to investigate the feasibility of utilizing the electronic health record to identify these patients and alert the hospital team to help guide clinical care.”

If a patient with dementia is hospitalized for an unrelated condition, such as a fall or infection, they might not be able to accurately describe their medical history or safely make decisions about their medical care, Tan said. Patients with dementia might also need help to understand discharge instructions or just to stay calm in the hospital environment.

“Diagnoses such as Alzheimer’s disease, dementia or cognitive impairment are often not documented in a patient’s medical records,” said Tan, who is also director of the Memory and Healthy Aging Program and the C.A.R.E.S. Program at Cedars-Sinai. “And if providers are not aware that their patient has dementia, they may not call a loved one who can provide critical information, help with decision-making, and provide support.”

To identify these patients, investigators created a secure algorithm to search patients’ electronic health records for a diagnosis of dementia and for prescriptions for medications approved by the Food and Drug Administration to treat dementia.

“The biggest challenge in creating the algorithm was the variety of clinical scenarios that led to a potential diagnosis of dementia,” said Cameron Escovedo, MD, MS, physician leader of Enterprise Information Services at Cedars-Sinai and co-author of the study. “We had to account for multiple scenarios to ensure the algorithm was complex enough to capture everyone.”

When the algorithm detects a patient with possible dementia, a yellow banner pops up on the patient’s chart to make hospital staff aware.

“Given the poor patient outcomes currently associated with dementia care in the hospital setting—including increased risks for falls, use of restraints, and prescription of antipsychotic medications—there was a need for a method to accurately identify these patients,” said Nancy Sicotte, MD, chair of the Department of Neurology at Cedars-Sinai and senior author of the study. “Our algorithm alerts the hospital team to the presence of cognitive impairment so that they can employ targeted interventions and ultimately improve outcomes for vulnerable hospitalized patients.”

To help ensure that medical staff understand how to respond to these patients once identified, a team of nurses and physicians at Cedars-Sinai created and tested a training program and published their results in the peer-reviewed journal Geriatric Nursing.

“About 25% of the nursing staff on the units where we tested this training felt they had not previously received comprehensive training in the care of persons with dementia,” said nurse practitioner Deana Rhinehart, DNP, first author of the study. “Our goal was to help bridge the gap in knowledge and confidence within our nursing teams.”

The training was conducted over multiple 45-minute virtual sessions led by Rhinehart and nurse practitioner Dyane Gatmaitan, NP, a co-author of the study. Sessions included interactive case studies and question-and-answer segments.

“Topics included effective communication, documentation of behaviors, delirium versus dementia, refusal of medications, general behavior management and patient advocacy,” said Gatmaitan. “We are finalizing a rollout plan to expand this training to additional units in March.”

Tan said that the identification system will be expanded to all medical and some surgical units, and that the system and the training—currently in use only at Cedars-Sinai—could easily be deployed at other institutions as well.

Learn more on the Cedars-Sinai Blog: When Should I Be Concerned About Memory Loss?

“This is the best data to date on the question of surgery versus medical management in patients with this rare but serious condition,” said Adam Mamelak, MD, co-director of the Pituitary Center, director of the Functional Neurosurgery Program at Cedars-Sinai and lead author of the study. “It demonstrates in a prospective, controlled way what previous studies had begun to suggest, namely that pituitary apoplexy is very rarely a surgical emergency.”

The pituitary gland, located at the base of the brain, controls the function of several hormone-producing glands. Pituitary apoplexy occurs when a benign tumor in the pituitary gland area begins to bleed or dies, causing the tumor to grow and press on the surrounding brain tissues. This, in turn, causes symptoms such as severe headache, fatigue, confusion and vision problems that may include vision loss. Most commonly, these tumors are undetected prior to the apoplexy event.

To relieve the pressure on brain tissues and mitigate the symptoms of apoplexy, patients can either have the tumor surgically removed or be treated with medications to relieve pain and other symptoms while they wait for it to naturally shrink over time. In both cases, patients generally also need hormone-replacement therapy, Mamelak said.

Pituitary apoplexy has long been considered an emergency requiring rapid surgical treatment to achieve best results. Small retrospective studies, where investigators look back at previously collected data, have suggested that pituitary apoplexy patients have equally good outcomes with medical management, but these observations have failed to significantly change clinical practice.

“While we’ve seen a growing trend toward clinicians being a little more comfortable with medical management of pituitary apoplexy, in general, most patients still end up getting surgery,” Mamelak said. “Those small retrospective studies really didn’t move the needle that much.”

To provide a more solid basis for clinical decision-making, Mamelak and fellow investigators from the Department of Neurosurgery and the Pituitary Center at Cedars-Sinai—as well as colleagues from 11 other medical centers in North America, Japan, South Korea and Europe—developed the Pituitary Apoplexy Surgical Timing and Outcomes Registry (PASTOR).

The registry enrolled 97 patients with pituitary apoplexy at the time of diagnosis and compared outcomes for the 67 patients who had surgery with those for the 30 patients whose symptoms were medically managed. This type of prospective registry allows investigators to draw stronger conclusions because data collection is the same for all participants.

Investigators found that:

• Length of hospital stay was the same for patients who had surgery as for those who did not.
• Patients who had surgery experienced the same outcomes whether they had surgery right away or days after the onset of symptoms.
• There were no statistically significant differences in hormone function, vision or quality of life between the two groups of patients three and six months after treatment.

Mamelak noted that patients experiencing more severe vision symptoms were more likely to have surgery than those experiencing milder symptoms but that surgery didn’t necessarily lead to better outcomes.

“Cedars-Sinai and the other sites taking part in this study all have expert pituitary neurosurgery and endocrinology teams, which could help account for the positive outcomes experienced by surgical patients,” said Keith L. Black, MD, chair of the Department of Neurosurgery and the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai. “A wealth of solid research tells us that outcomes from pituitary surgery are directly tied to surgical experience.”

Mamelak said that further research specifically looking at outcomes for people with visual field deficits would be needed to determine whether surgery is best in those cases. Meanwhile, the current findings could especially benefit medical centers that do not have the expertise to surgically treat pituitary tumors.

“These findings take some of the urgency out of managing these cases,” Mamelak said. “Clinicians at these centers now know that they can safely manage these patients medically and transfer them when it’s reasonable and available, or allow patients to forgo surgery entirely if they are comfortable with that.”

Read more on the Cedars-Sinai Blog: Neuroendoscopy Revolutionizes Skull Base Surgery

A recent study published in Frontiers in Immunology offers broader insight into the protein networks that allow immune cells to respond to harmful substances. This discovery could lead to treatments that leverage the body’s natural healing processes.

“This study demonstrates enormous potential for exploiting the natural immune process to better fight disease,” said Maya Koronyo-Hamaoui, PhD, a professor of Neurosurgery and Biomedical Sciences at Cedars-Sinai and senior author of the study. “White blood cells—which we studied here in the context of Alzheimer’s disease—are one of the first lines of defense against a variety of foreign and internal threats and are key for regulating tissue repair and maintenance.”

The study demonstrates the significance of osteopontin (OPN), a protein expressed by macrophages, a type of white blood cell that surrounds and destroys harmful organisms and clears cell debris and the buildup of abnormal proteins. Investigators, in collaboration with the Van Eyk Research Lab at Cedars-Sinai, concluded that OPN deficiency disrupts the balance of proteins in macrophages, eventually causing them to die.

“Macrophages clear toxic proteins, reduce inflammation, and help regenerate, rejuvenate, and encourage newly formed connections in the brain,” said Koronyo-Hamaoui.

The study builds on two previous studies from the Koronyo-Hamaoui Llab—published in Brain Behavior and Immunity and Brain—detailing the critical role played by bone-marrow derived macrophages and OPN expressed in macrophages in clearing Alzheimer’s disease-related amyloid-beta peptides and supporting central nervous system repair and regeneration.

“Our work supports further study into gene editing or immunotherapies that could have multifaceted impact,” said Altan Rentsendorj, PhD, a senior research associate in the Koronyo-Hamaoui Lab and first author of the study.

Investigators studied macrophages in laboratory mice. They compared normal cells, diseased cells treated with an FDA-approved multiple sclerosis treatment that caused them to overexpress OPN, and cells without the ability to produce OPN.

They found that diseased macrophages treated with the multiple sclerosis medication more effectively cleared amyloid-beta proteins and increased their anti-inflammatory activity. However, in cells without the ability to produce OPN, treatment with the multiple sclerosis medication did not restore normal protein expression.

Investigators also discovered that the presence of OPN is necessary to produce two other crucial anti-inflammatory molecules. Dysfunction of the first, ubiquitin C-terminal hydrolase L1, has been implicated in neurodegenerative diseases such as Alzheimer’s. The second, heme oxygenase 1, plays a critical role in preventing vascular inflammation.

“We were surprised to find that other neuroprotective proteins are dependent on OPN,” Rentsendorj said. “This work shows that OPN is critical for the machinery of rejuvenation in these innate immune cells.”

The Koronyo-Hamaoui Lab also recently published a review paper in Frontiers in Physiology synthesizing knowledge about angiotensin converting enzyme (ACE) and its role in Alzheimer’s disease. ACE, expressed by immune cells, degrades amyloid-beta and improves immune response.

The review outlines findings from 1975 onward, including numerous studies from the Koronyo-Hamaoui Lab in collaboration with the Bernstein Lab at Cedars-Sinai.

Significant among these are a 2020 paper published in Brain, which demonstrated that overexpression of ACE enhances the ability of white blood cells called monocytes to rid the body of toxic forms of amyloid-beta oligomers and fibrils, and a 2014 paper published in The Journal of Clinical Investigation. The review also notes that an analysis of human genome sequencing found people with a genetic variant that leads to lower expression of ACE in their blood had higher risk for Alzheimer's disease.

“This review builds a strong case for targeting monocytes and ACE in Alzheimer's disease,” said neurology fellow Ron Danziger, MD, first author of the review paper. “In extensive studies by the Koronyo-Hamaoui and Bernstein labs, we have consistently found an amazing effect of ACE on the characteristics of macrophages in the context of Alzheimer’s disease.”

Taken together, the new papers support the need for further research into therapies that might leverage immune function in blood or bone marrow cells to fight neurodegenerative disease.

“We need a much more effective treatment to address many aspects of Alzheimer’s disease,” said Keith L. Black, MD, chair of the Department of Neurosurgery, the Ruth and Lawrence Harvey Chair in Neuroscience at Cedars-Sinai, and co-author of both studies. “Genetically manipulating monocytes to enhance ACE or OPN, which would target more than plaque clearance, could be a very promising technique.”

Funding: The study appearing in Frontiers in Immunology was funded by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG056478, R01AG055865, AG056478-04S1 and R01AG075998) and the Tom Gordon, Haim Saban and Wilstein foundations.

The study appearing in Frontiers in Physiology was supported by the National Institute on Aging of the National Institutes of Health (grant numbers R01AG055865, R01AG056478, R01AG075998 and R01AG042195); a BrightFocus Foundation Award; The Coins for Alzheimer’s Research Trust (CART) Fund; the Cedars-Sinai Jona Goldrich Center for Alzheimer’s and Memory Disorders; the Saban, Gordon, Marciano and Wilstein private foundations; and the National Center for Advancing Translational Sciences (CTSI grant UL1TR000124).

Read more from the Cedars-Sinai Blog: How to Help a Loved One With Alzheimer’s or Dementia

The discovery, published in the peer-reviewed journal Nature Communications, has given investigators a potential target for treating stress-induced eating disorders in women.

“These results are very exciting because they help us understand an important aspect of how stress is regulated,” said Celine Riera, PhD, assistant professor of Biomedical Sciences and Neurology at Cedars-Sinai and senior author of the study. “We hope to leverage this knowledge to help develop treatments for anxiety-related eating disorders.”

The study is the first to examine specific neurons responsible for the body’s metabolic response to stress, Riera said, and the first to compare results in male and female laboratory mice to identify sex-based differences in the brain’s stress response.

Riera and fellow investigators induced stress by exposing both male and female laboratory mice to predator odor. Both male and female mice were more active and ate less when exposed to stress, but the effect was more pronounced and lasted longer in female mice than in male mice.

Investigators, including Predrag Jovanovic, PhD, then used two different methods to determine which brain cells were responsible for this reaction.

The investigators recorded which neurons were expressing high levels of a protein called c-Fos, which indicated they were activated by the scent. The investigators then traced the connections of the activated neurons, using a virus that makes a fluorescent probe, from the part of the brain receiving scent information from the nose to the neurons activated in another part of the brain by the scent.

Both experiments pointed to the dorsomedial hypothalamus, a brain region established as important for the regulation of feeding and energy expenditure. The region is known to contain neurons that signal when the body is full, and neurons that regulate body temperature, but this study pinpointed a third type of neuron in the region.  

“We're showing for the first time that there is another population of neurons,” Riera said. “They are called cholecystokinin-expressing, or CCK, neurons, and they play a role in metabolism by suppressing feeding and increasing energy expenditure in response to stress or fear.”

The team next plans to examine these same neurons in the context of obesity, Riera said.

“We want to investigate whether chronically activating these neurons will promote weight loss, and whether that effect is stronger in females compared with males,” she said. “We’re hoping we can confirm these neurons as a therapeutic target for treating metabolic disorders.”

Scientists and health experts are trying to learn more about why obesity rates worldwide continue to rise, and why the prevalence of obesity is higher in women than in men, Riera said.

“Male-female differences in response to stress and eating are poorly understood from a neurological perspective,” said Nancy Sicotte, MD, chair of the Department of Neurology and the Women’s Guild Distinguished Chair in Neurology at Cedars-Sinai. “This line of inquiry and the focus of these investigators on including females in their work offers a potential key to better understanding these issues–and possibly improving the health of millions.”

Funding: The study was funded by American Diabetes Association Pathway to Stop Diabetes Grant number 1-15-INI-12, the Klingenstein-Simons foundation, the Larry L. Hillblom Foundation fellowship, and the Cedars-Sinai Center for Research in Women’s Health and Sex Differences.

Read more on the Cedars-Sinai Blog: Women’s Health and Sex Differences.