About

Dr. Daniel H. Silverman is a Clinical Professor in the Department of Molecular and Medical Pharmacology at UCLA and serves as the Head of the Neuronuclear Imaging Section within the Ahmanson Biological Imaging Division at UCLA Medical Center. He is also a member of the Cancer Molecular Imaging, Nanotechnology and Theranostics program. Dr. Silverman holds an MD from Ohio State University College of Medicine and a PhD from Harvard University. He completed his internship and residency in Internal Medicine as well as a fellowship in Nuclear Medicine at UCLA School of Medicine. He is board certified in both Nuclear Medicine and Internal Medicine. Dr. Silverman's research program focuses on two major goals: exploring the interactions and neurologic bases of memory, mood, and pain perception in the living human brain, particularly in both normal and disordered states such as dementia, depression, and chronic pain syndromes; and developing noninvasive methodologies to optimize the management of breast and colorectal cancers. These objectives are connected through the use of low-level radioactive biochemicals to characterize and map biological processes in the human body that are relevant to patients seen in nuclear and internal medicine. His research extensively applies positron emission tomography (PET) to study molecular processes and human behaviors, spanning from biochemical work in vitro to clinical monitoring and treatment of patients in the Ahmanson Biological Imaging Clinic.

Research topics

• Medicine
• Neuroscience
• Psychology
• Pathology
• Biology
• Internal medicine
• Artificial Intelligence
• Machine Learning
• Oncology
• Computer Science
• Chemistry
• Data science
• Psychiatry
• Theoretical computer science
• Nuclear medicine
• Econometrics
• Audiology
• Mathematics

Selected publications

• Brainstem circuit for sickness-induced sleep

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-11 · 2 citations

  preprintOpen access

  SUMMARY Increased sleep induced by immune activation plays a crucial role in facilitating recovery from illness. However, the neural mechanisms underlying sickness-induced sleep remain poorly understood. Here, we identify a brainstem circuit originating in the nucleus of the solitary tract (NST) that mediates sickness-induced sleep. Using activity-dependent genetic labeling, we tagged NST neurons activated by lipopolysaccharide (LPS) injection and showed that their chemogenetic activation strongly promotes non-rapid eye movement (NREM) sleep. These NST neurons project extensively to the parabrachial nucleus (PB), where LPS-activated neurons also promote NREM sleep. Fiber photometry imaging of several wake-promoting neuromodulators using their biosensors showed that evoked norepinephrine (NE) release from locus coeruleus (LC) neurons is markedly reduced by either LPS injection or direct activation of NST or PB sickness neurons. These results suggest that sickness-induced sleep is mediated in part by a brainstem circuit that regulates neuromodulator signaling.

  PublisherOA PDFDOI

• Brainstem circuit for sickness-induced sleep

  Science Advances · 2025-12-10 · 2 citations

  articleOpen access

  Increased sleep induced by immune activation plays a crucial role in facilitating recovery from illness. However, the neural mechanisms underlying sickness-induced sleep remain poorly understood. Here, we identify a brainstem circuit originating in the nucleus of the solitary tract (NST) that mediates sickness-induced nonrapid eye movement (NREM) sleep. Using activity-dependent genetic labeling, we tagged NST neurons activated by lipopolysaccharide (LPS) injection and showed that their chemogenetic activation strongly promotes NREM sleep. These NST neurons project extensively to the parabrachial nucleus (PB), where LPS-activated neurons also promote NREM sleep. Fiber photometry recording of several wake-promoting neuromodulators using their biosensors showed that evoked norepinephrine release from locus coeruleus neurons is markedly reduced by either LPS injection or direct activation of NST or PB sickness neurons. These results suggest that sickness-induced NREM sleep is mediated in part by a brainstem circuit that regulates neuromodulator signaling.

  PublisherDOI

• Neuroimaging studies of cognitive dysfunction following cancer and treatment

  Journal of Clinical and Experimental Neuropsychology · 2025-07-01 · 4 citations

  reviewOpen access1st authorCorresponding

  Survival rates for non-central nervous system cancers (CNS) have markedly improved in recent decades due to advancements in early detection and treatment; however, this progress has also led to a rise in survivors living with long-term side effects, including cancer-related cognitive impairment (CRCI). Neuroimaging has been vital in understanding the impact of cancer and its treatments on brain functioning, revealing changes in brain activity, structure, and connectivity associated with cognitive decline. This review summarizes current neuroimaging research on adults with non-CNS cancers, focusing on alterations in gray and white matter and functional, metabolic, and vascular changes. Consistent findings of alterations in the prefrontal cortex have been observed, with both structural and functional changes observed in patients with CRCI, and limbic and temporal structures also appear to be impacted. These brain changes have been shown to correlate with functioning on objective and self-reported measures of executive functioning and memory. Future research should further explore novel complementary techniques and analytic approaches, to provide more in-depth knowledge on various potential mechanisms contributing to CRCI. Multimodal investigations of biomarkers including genomic interactions, neuroinflammatory processes, oxidative stress, blood-brain barrier disruption, and gut-brain axis effects could yield new insights. Neuroimaging will remain essential in elucidating these mechanisms and their roles in CRCI.

  PublisherOA PDFDOI

• Oxygen-15 Labeled Water Positron Emission Tomography During External Trigeminal Nerve Stimulation

  Neuromodulation Technology at the Neural Interface · 2025-10-18

  articleOpen accessSenior author

  BACKGROUND: Neuromodulation through external trigeminal nerve stimulation (eTNS) is an emerging noninvasive wearable treatment for neuropsychiatric disorders including attention deficit disorder, epilepsy, and major depression. eTNS is now US Food and Drug Administration approved for attention deficit disorder and investigational for the treatment of epilepsy, major depression, and other neuropsychiatric disorders. Rodent studies indicate eTNS activates key brainstem nuclei, in addition to the amygdala and hippocampus. However, the effect of eTNS on cortical blood flow and metabolism is not known. A better understanding of which brain areas are activated or deactivated by eTNS would provide a scientific basis for current applications and could provide a roadmap to identify new disease targets and interventions. OBJECTIVES: O PET) to advance the understanding of the networks, pathways, and mechanisms of action of eTNS in humans. MATERIAL AND METHODS: O brain PET scans were performed using a Siemens-CTI HR+ EXACT system at the University of California Los Angeles Laboratory of Neuroimaging. Three scans were performed with trigeminal stimulation ON (scans 1, 3, and 6), and three scans were performed with trigeminal stimulation OFF (scans 2, 4, and 5). Data were analyzed comparing stimulus ON with stimulus OFF scans. Adjustments for multiple comparisons were performed using the family-wise error correction. RESULTS: eTNS of the supraorbital branches of the trigeminal nerve produced significant activations (increased cerebral blood flow) in bilateral anterior cingulate gyri; bilateral parieto-temporal cortex; left inferior frontal gyrus; and right medial and middle frontal gyri. The most significant deactivations (decreased blood flow) occurred in the left parahippocampal gyrus, right sensorimotor cortex, right superior parietal area, bilateral temporo-occipital cortex, and bilateral visual cortex. CONCLUSIONS: O PET imaging in regions associated with major depression and attention deficit disorder. Deactivations of cortical regions including the parahippocampal gyrus, sensorimotor cortex, and others provide a rationale for some of the antiseizure effects of trigeminal nerve stimulation. The results of this study advance our understanding of mechanisms of action of trigeminal nerve stimulation in neuropsychiatric disorders and epilepsy.

  PublisherDOI

• Gallbladder Volvulus

  Clinical nuclear medicine open. · 2025-07-21

  articleOpen accessSenior authorCorresponding

  Gallbladder volvulus is a very rare condition characterized by the torsion of the gallbladder on its mesentery with potentially serious complications when operative management is delayed. We present a case of an elderly woman diagnosed with gallbladder volvulus. The HIDA scan demonstrated an absence of gallbladder activity, whereas the CT and MRCP demonstrated a fluid collection superior to the liver, which represented the displaced gallbladder in retrospect. This case highlights the difficulty in preoperatively diagnosing this rare entity. Furthermore, we review the existing literature on gallbladder volvulus, exploring the features of gallbladder volvulus that may aid in making an early diagnosis as prompt surgical intervention is crucial for improving patient outcomes.

  PublisherDOI

• Activation of locus coeruleus noradrenergic neurons rapidly drives homeostatic sleep pressure

  Science Advances · 2025-01-17 · 24 citations

  articleOpen access1st author

  Homeostatic sleep regulation is essential for optimizing the amount and timing of sleep for its revitalizing function, but the mechanism underlying sleep homeostasis remains poorly understood. Here, we show that optogenetic activation of locus coeruleus (LC) noradrenergic neurons immediately increased sleep propensity following a transient wakefulness, contrasting with many other arousal-promoting neurons whose activation induces sustained wakefulness. Fiber photometry showed that repeated optogenetic or sensory stimulation caused a rapid reduction of calcium activity in LC neurons and steep declines in noradrenaline/norepinephrine (NE) release in both the LC and medial prefrontal cortex (mPFC). Knockdown of α 2 A adrenergic receptors in LC neurons mitigated the decline of NE release induced by repetitive stimulation and extended wakefulness, demonstrating an important role of α 2 A receptor–mediated auto-suppression of NE release. Together, these results suggest that functional fatigue of LC noradrenergic neurons, which reduces their wake-promoting capacity, contributes to sleep pressure.

  PublisherDOI

• Dark continuous noise from mutant G90D-rhodopsin predominantly underlies congenital stationary night blindness

  Proceedings of the National Academy of Sciences · 2024-05-14 · 9 citations

  articleOpen access

  Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y. In this study, we made a knock-in (KI) mouse line with a very low expression of G90D-Rho (equal in amount to ~0.1% of normal rhodopsin, WT-Rho, in WT rods), with the remaining WT-Rho replaced by REY-Rho, a mutant with a very low efficiency of activating transducin due to a charge reversal of the highly conserved ERY motif to REY. We observed two kinds of constitutive noise: one being spontaneous isomerization (R*) of G90D-Rho at a molecular rate (R* s −1 ) 175-fold higher than WT-Rho and the other being G90D-Rho-generated dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s −1 from WT-Rho. Neither noise type originated from G90D-Opsin because exogenous 11- cis -retinal had no effect. Extrapolating the above observations at low (0.1%) expression of G90D-Rho to normal disease exhibited by a KI mouse model with Rho G90D/WT and Rho G90D/G90D genotypes predicts the disease condition very well quantitatively. Overall, the continuous noise from G90D-Rho therefore predominates, constituting the major equivalent background light causing rod desensitization in CSNB.

  PublisherOA PDFDOI

• Longitudinal Analysis of BCAA Levels and Hypometabolism in ApoE4‐Positive Alzheimer’s Patients Over A 48‐Month Period

  Alzheimer s & Dementia · 2024-12-01

  articleOpen accessSenior author

  Abstract Background Alzheimer’s Disease (AD) is a chronic, incurable neurodegenerative condition characterized by extensive systemic, cellular, and molecular abnormalities. One such aspect recent studies have highlighted is the reduction in plasma branched‐chain amino acid (BCAA) concentrations, identifying them as a potential emerging marker for the disease. Although BCAAs have been implicated in the pathogenesis of AD, their utility in clinical prognosis remains unexplored. This study aims to investigate the role of BCAA levels in AD progression, considering the presence or absence of the APOE4 phenotype over a period of forty‐eight months. Method Biomarker and clinical diagnosis data for 31 subjects with varying cognitive statuses were obtained from the Alzheimer’s Disease Neuroimaging Initiative (CN, n = 10; LMCI, n = 21). Cognitive status was assessed using the Hypometabolic Convergence Index (HCI), a tool designed to quantify the magnitude and severity of cerebral hypometabolism typical in probable Alzheimer’s Disease patients. BCAA levels were measured through a nuclear magnetic resonance‐based blood biomarker analysis and expressed as concentrations in plasma. Result A significant correlation was observed between the initial HCI and BCAA measurements and HCI values taken forty‐eight months later, indicating cognitive decline (n = 31, r = 0.362, p‐value = 0.0383). Stratification by APOE4 phenotype revealed more nuanced insights: subjects with zero alleles showed no significant correlation (n = 16, r = 0.165, p‐value = 0.0542), while those with one or two alleles demonstrated a stronger, tighter correlation (n = 15, r = 0.564, p‐value = 0.0183). Conclusion This study corroborates prior research on the association between diminished plasma BCAA levels and reduced neuronal activity in regions pertinent to AD, as reflected by HCI assessments over a forty‐eight month period. Importantly, our findings reveal a significant correlation between BCAA concentrations and cognitive decline predominantly in individuals carrying one or two APOE4 alleles. This observation highlights the potential influence of the APOE4 allele on the impaired transport of BCAAs to the brain, contributing to cognitive deterioration in these groups. Further research is needed to explore the diagnostic value of BCAA levels in broader AD populations and to understand the mechanistic links in non‐carriers of the APOE4 allele.

  PublisherOA PDFDOI

• Dark continuous noise from visual pigment as a major mechanism underlying rod–cone difference in light sensitivity

  Proceedings of the National Academy of Sciences · 2024-12-10 · 7 citations

  articleOpen access

  Retinal rods and cones underlie scotopic and photopic vision, respectively. Their pigments exhibit spontaneous isomerizations (quantal noise) in darkness due to intrinsic thermal energy. This quantal noise, albeit exceedingly low in rods, dictates the light threshold for scotopic vision. The same quantal noise in cones, however, is too low to explain the much higher diurnal light threshold. Separately, a dark continuous noise is present in rods, long accepted to originate from an intrinsic random activation of the cyclic guanosine monophosphate (cGMP)-phosphodiesterase enzyme mediating phototransduction downstream of the pigment. Here, we report the surprising finding that most of this rod dark continuous noise actually originates from rhodopsin itself. Importantly, we found the same continuous noise with a much higher magnitude from cone pigments. The rod and cone continuous noises are apparently both associated with a hitherto unrecognized "metastable" pigment conformational state physiologically resembling that in apo-opsin (opsin devoid of chromophore) and is intermittently active for very brief moments. The cone holopigment's high continuous noise is expected to act as an intrinsic equivalent light and adapt the cone dramatically, accounting for a major part of the light-sensitivity difference between rods and cones in darkness.

  PublisherOA PDFDOI

• Microglia regulate sleep through calcium-dependent modulation of norepinephrine transmission

  Nature Neuroscience · 2024-01-18 · 109 citations

  articleOpen access

  Abstract Sleep interacts reciprocally with immune system activity, but its specific relationship with microglia—the resident immune cells in the brain—remains poorly understood. Here, we show in mice that microglia can regulate sleep through a mechanism involving G i -coupled GPCRs, intracellular Ca 2+ signaling and suppression of norepinephrine transmission. Chemogenetic activation of microglia G i signaling strongly promoted sleep, whereas pharmacological blockade of G i -coupled P2Y12 receptors decreased sleep. Two-photon imaging in the cortex showed that P2Y12–G i activation elevated microglia intracellular Ca 2+ , and blockade of this Ca 2+ elevation largely abolished the G i -induced sleep increase. Microglia Ca 2+ level also increased at natural wake-to-sleep transitions, caused partly by reduced norepinephrine levels. Furthermore, imaging of norepinephrine with its biosensor in the cortex showed that microglia P2Y12–G i activation significantly reduced norepinephrine levels, partly by increasing the adenosine concentration. These findings indicate that microglia can regulate sleep through reciprocal interactions with norepinephrine transmission.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21NS071385

  NIH · $424k · 2014

• NIH Grant R21MH064679

  NIH · $305k · 2005

Frequent coauthors

• John C. Morris

  Washington University in St. Louis

  198 shared

• Andrew J. Saykin

  Indiana University

  185 shared

• Clifford R. Jack

  WinnMed

  174 shared

• Adam Fleisher

  Eli Lilly (United States)

  174 shared

• Michael W. Weiner

  University of California, San Francisco

  167 shared

• Michael Donohue

  Janssen (United States)

  166 shared

• Robert C. Green

  Ariadne Diagnostics (United States)

  162 shared

• Chris Hosein

  Jewish General Hospital

  152 shared

Education

• Ph.D. in Biochemistry, Cellular and Molecular Biology, Neuroscience

  Johns Hopkins School of Medicine

  2018