Jonathan B Savitz

Jonathan B Savitz
Laureate Institute for Brain Research | LIBR

Ph.D

About

218
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Introduction

Publications

Publications (218)
Article
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Major Depressive Disorder (MDD) poses a significant public health challenge due to its high prevalence and the substantial burden it places on individuals and healthcare systems. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear....
Preprint
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Recent associations between Major Depressive Disorder (MDD) and measures of premature aging suggest accelerated biological aging as a potential biomarker for MDD susceptibility or MDD as a risk factor for age-related diseases. Statistical and machine learning regression models of biological age have been trained on various sources of high dimension...
Article
Full-text available
A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic inflammat...
Article
Full-text available
Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demog...
Preprint
Full-text available
Major Depressive Disorder (MDD) presents a significant public health challenge. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear. This study investigated whole-brain response patterns during rtfMRI-NF training to explain interin...
Article
Full-text available
Major depressive disorder (MDD) is associated with interoceptive processing dysfunctions, but the molecular mechanisms underlying this dysfunction are poorly understood. This study combined brain neuronal-enriched extracellular vesicle (NEEV) technology and serum markers of inflammation and metabolism with Functional Magnetic Resonance Imaging (fMR...
Article
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Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Our objective was to identify the neuroanatomical dimensions that characterize MDD and predict treatment response to selective serotonin reuptake inhibitor (SSRI) antidepressants or placebo. In the COORDINATE-MDD consortium, raw M...
Preprint
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Background: Despite being the most common psychiatric comorbidity, underlying brain and behavioral processes characterizing anxious depression are not well understood. Affective startle modulation is a process that separately probes appetitive/defensive systems and is altered transdiagnostically in individuals with mood and anxiety disorders. This...
Preprint
Full-text available
A subset of major depressive disorder (MDD) is characterized by immune system dysfunction, but the intracellular origin of these immune changes remains unclear. Here we tested the hypothesis that abnormalities in the endoplasmic reticulum (ER) stress, inflammasome activity and mitochondrial biogenesis contribute to the development of systemic infla...
Article
Full-text available
Major depressive disorder (MDD) is associated with immunologic and metabolic alterations linked to central processing dysfunctions, including attenuated reward processing. This study investigated the associations between inflammation, metabolic hormones (leptin, insulin, adiponectin), and reward-related brain processing in MDD patients with high (M...
Article
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Cytomegalovirus (CMV) is a common, neurotrophic herpesvirus that can be reactivated by inflammation and cause central nervous system disease. We hypothesize that CMV may contribute to the neuroinflammation that underlies some psychiatric disorders by (1) exacerbating inflammation through the induction of anti-viral immune responses, and (2) transla...
Article
The neurotrophic herpesvirus cytomegalovirus is a known cause of neuropathology in utero and in immunocompromised populations. Cytomegalovirus is reactivated by stress and inflammation, possibly explaining the emerging evidence linking it to subtle brain changes in the context of more minor disturbances of immune function. Even mild forms of trauma...
Preprint
Full-text available
Major depressive disorder (MDD) is associated with interoceptive processing dysfunctions, but the molecular mechanisms underlying this dysfunction are poorly understood. This study combined brain Neuronal-Enriched Extracellular Vesicle (NEEV) technology and serum markers of inflammation and metabolism with Functional Magnetic Resonance Imaging (fMR...
Article
Full-text available
Background: Obesity is highly prevalent and disabling, especially in individuals with severe mental illness including bipolar disorders (BD). The brain is a target organ for both obesity and BD. Yet, we do not understand how cortical brain alterations in BD and obesity interact. Methods: We obtained body mass index (BMI) and MRI-derived regional...
Article
Full-text available
Background Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status an...
Article
Full-text available
Ibuprofen, a non-steroidal, anti-inflammatory drug, modulates inflammation but may also have neuroprotective effects on brain health that are poorly understood. Astrocyte-enriched extracellular vesicles (AEEVs) facilitate cell-to-cell communication and – among other functions - regulate inflammation and metabolism via microribonucleic acids (miRNAs...
Preprint
Full-text available
Importance: Major depressive disorder (MDD) is a heterogeneous clinical syndrome with widespread subtle neuroanatomical correlates. Identifying neuroimaging-based biomarkers might aid in defining the disease-related dimensions that characterize MDD and predict treatment response. Objective: To investigate the neuroanatomical dimensions that charact...
Preprint
Full-text available
Cytomegalovirus (CMV) is a common, neurotrophic herpesvirus that can be reactivated by inflammation and cause neurological disease. CMV replication can in turn worsen inflammation, raising the possibility that poorly controlled CMV infections may contribute to the neuroinflammation underlying some psychiatric disorders. We investigated whether the...
Article
Full-text available
Background. The balance between neurotoxic and neuroprotective effects of kynurenine pathway (KP) components has been recently proposed as a key element in the pathophysiology of bipolar disorder (BD) and related mood episodes. This comprehensive overview explored the link of KP with symptom severity and other clinical features of BD. Methods. We s...
Article
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Rationale At least six different types of antidepressant treatments have been shown to either increase the neuroprotective kynurenine pathway (KP) metabolite, kynurenic acid (KynA), or decrease the neurotoxic KP metabolite, quinolinic acid (QA). Nonsteroidal anti-inflammatory drugs (NSAIDs) including ibuprofen have shown some efficacy in the treatm...
Article
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The identification of gene expression-based biomarkers for major depressive disorder (MDD) continues to be an important challenge. In order to identify candidate biomarkers and mechanisms, we apply statistical and machine learning feature selection to an RNA-Seq gene expression dataset of 78 unmedicated individuals with MDD and 79 healthy controls....
Chapter
Human cytomegalovirus (HCMV) is a major modulator of the immune system leading to long-term changes in T-lymphocytes, macrophages, and natural killer (NK) cells among others. Perhaps because of this immunomodulatory capacity, HCMV infection has been linked with a host of deleterious effects including accelerated immune aging (premature mortality, i...
Article
Full-text available
The aging process can have detrimental effects on the immune system rendering the elderly more susceptible to infectious disease and less responsive to vaccination. Major depressive disorder (MDD) has been hypothesized to show characteristics of accelerated biological aging. This raises the possibility that depressed individuals will show some over...
Article
Full-text available
Elevated serum concentrations (>3 mg/L) of the acute-phase protein, C-reactive protein (CRP), is used as a clinical marker of inflammation and is reported to be a strong risk factor for cardiovascular disease. In psychiatric populations, CRP concentration is reported to be higher in depressed versus healthy individuals. Positive associations betwee...
Article
Kynurenic acid (KynA) and quinolinic acid (QA) are neuroactive kynurenine pathway (KP) metabolites that have neuroprotective and neurotoxic properties, respectively. At least partly as a result of immune activation, the ratio of KynA to QA in the blood is reduced in major depressive disorder (MDD) and has been reported to be positively correlated w...
Chapter
There is increasingly compelling evidence that microorganisms may play an etiological role in the emergence of mental illness in a subset of the population. Historically, most work has focused on the neurotrophic herpesviruses, herpes simplex virus type 1 (HSV-1), cytomegalovirus (CMV), and Epstein–Barr virus (EBV) as well as the protozoan, Toxopla...
Chapter
Cytomegalovirus (CMV) is a common herpesvirus that establishes lifelong latent infections and interacts extensively with the host immune system, potentially contributing to immune activation and inflammation. Given its proclivity for infecting the brain and its reactivation by inflammatory stimuli, CMV is well known for causing central nervous syst...
Article
Full-text available
Background Dysregulation of fear learning has been associated with psychiatric disorders that have altered positive and negative valence domain function. While amygdala-insula-prefrontal circuitry is considered important for fear learning, there have been inconsistencies in neural findings in healthy and clinical human samples. This study aimed to...
Preprint
Full-text available
Background: Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status a...
Article
Full-text available
Unmedicated individuals with major depressive disorder (MDD) show abnormal interoception, but it is unclear whether antidepressant treatment via serotonergic medication alters this relationship. The current cross-sectional study examined associations between neural and behavioral indices of interoceptive processing and chronic serotonergic medicati...
Article
Full-text available
This double-blind, randomized, within-subjects design evaluated whether acute administration of an anti-inflammatory drug modulates neuron-specific, inflammation-modulating microRNAs linked to macroscopic changes in reward processing. Twenty healthy subjects (10 females, 10 males) underwent a functional magnetic resonance imaging scan while perform...
Article
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(1) Background: Growing evidence indicates that inflammation can induce neural circuit dysfunction and plays a vital role in the pathogenesis of major depressive disorder (MDD). Nevertheless, whether inflammation affects the integrity of white matter pathways is only beginning to be explored. (2) Methods: We computed quantitative anisotropy (QA) fr...
Article
Aims Rates of obesity have reached epidemic proportions, especially among people with psychiatric disorders. While the effects of obesity on the brain are of major interest in medicine, they remain markedly under-researched in psychiatry. Methods We obtained body mass index (BMI) and MRI-derived regional cortical thickness, surface area from 836 b...
Article
Full-text available
Individuals with bipolar disorders (BD) frequently suffer from obesity, which is often associated with neurostructural alterations. Yet, the effects of obesity on brain structure in BD are under-researched. We obtained MRI-derived brain subcortical volumes and body mass index (BMI) from 1134 BD and 1601 control individuals from 17 independent resea...
Article
Growing evidence suggests that sport-related concussion results in a robust inflammatory response that can be measured in serum or plasma and is predictive of symptom recovery. Recently, extracellular vesicles (EV) derived from serum or plasma have emerged as a promising source of biomarkers for neurological disorders like concussion because they m...
Article
Full-text available
Human cytomegalovirus (HCMV) is a neurotropic herpes virus known to cause neuropathology in patients with impaired immunity. Previously, we reported a reduction in the gray matter volume (GMV) of several brain regions in two independent samples of participants who were seropositive for HCMV (HCMV+) compared to matched participants who were seronega...
Article
Full-text available
Major depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in adult MDD patients, and whether this process is associated with clinical characteristics in a large multicenter international dataset. We performed a mega-analysis by pooling bra...
Preprint
Full-text available
This double-blind, randomized, repeated measures study evaluated whether acute administration of an anti-inflammatory drug modulates neuron-specific, inflammation-modulating microRNAs linked to macroscopic changes in reward processing. Twenty healthy subjects (10 females,10 males) completed a monetary incentive delay (MID) task and provided blood s...
Article
Full-text available
Human cytomegalovirus (HCMV) infection is associated with neuropathology in patients with impaired immunity and/or inflammatory diseases. However, the association between gray matter volume (GMV) and HCMV has never been examined in major depressive disorder (MDD) despite the presence of inflammation and impaired viral immunity in a subset of patien...
Article
Full-text available
Growing evidence suggests that a dysregulation of the kynurenine pathway (KP) occurs in bipolar disorder (BD). This systematic review and meta-analysis aimed at assessing the possible differences in peripheral blood levels of KP metabolites between individuals with BD and healthy controls. We searched Medline, Embase, and PsycInfo electronic databa...
Article
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen have shown initial promise in producing antidepressant effects. This is perhaps due to these drugs being peroxisome proliferator-activated receptor gamma (PPARy) agonists, in addition to their inhibition of cyclooxygenase enzymes. Some, albeit mixed, evidence suggests that PPARy agonis...
Article
Traumatic brain injury (TBI) is an established risk factor for the development of psychiatric disorders, especially depression and anxiety. Yet the mechanistic pathways underlying this risk remain unclear, limiting treatment options and hindering the identification of clinically-useful biomarkers. One salient pathophysiological process implicated i...
Article
Objective: To test sleep quality as one mechanistic pathway through which repeated concussion increases risk of depression later in life among former contact sport athletes. Setting: Multicenter study enrolled former American collegiate football players from 16 different National Collegiate Athletic Association member institutions. Participants...
Article
Background Substance use disorders (SUD) with comorbid depression and anxiety are linked to poor treatment outcome and relapse. Although some depressed individuals exhibit elevated blood-based inflammation (interleukin-6 [IL-6] and C reactive protein [CRP]), few studies have examined whether the presence of SUD exacerbates inflammation. Methods Tr...
Article
Background Major depressive disorder (MDD) is the leading cause of years lived with disability worldwide, and up to 40% of individuals with MDD do not respond to current treatments. Studies suggest that peripheral inflammation plays an important role in the striatal mesolimbic dopamine pathway and corticostriatal reward circuitry in MDD. Although M...
Article
Full-text available
Major depressive disorder (MDD) is associated with reductions in white matter microstructural integrity as measured by fractional anisotropy (FA), an index derived from diffusion tensor imaging (DTI). The neurotropic herpesvirus, human cytomegalovirus (HCMV), is a major cause of white matter pathology in immunosuppressed populations but its relatio...
Article
Full-text available
Real-time fMRI neurofeedback (rtfMRI-nf) left amygdala (LA) training is a promising intervention for major depressive disorder (MDD). We have previously proposed that rtfMRI-nf LA training may reverse depression-associated regional impairments in neuroplasticity and restore information flow within emotion-regulating neural circuits. Inflammatory cy...
Article
Background An inflammation-induced imbalance in the kynurenine pathway (KP) has been reported in major depressive disorder but the utility of these metabolites as predictive or therapeutic biomarkers of behavioral activation (BA) therapy is unknown. Methods Serum samples were provided by 56 depressed individuals before BA therapy and 29 of these i...
Article
The molecular mechanisms underlying the diverse psychiatric and neuropathological sequalae documented in subsets of athletes with concussion have not been identified. We have previously reported elevated quinolinic acid (QuinA), a neurotoxic kynurenine pathway metabolite, acutely following concussion in football players with prior concussion. Simil...
Article
Full-text available
The hippocampus consists of anatomically and functionally distinct subfields that may be differentially involved in the pathophysiology of bipolar disorder (BD). Here we, the Enhancing NeuroImaging Genetics through Meta‐Analysis Bipolar Disorder workinggroup, study hippocampal subfield volumetry in BD. T1‐weighted magnetic resonance imaging scans f...
Article
Depression is one of the most prevalent, disabling, and costly mental illnesses currently affecting over 300 million people worldwide. A subset of depressed patients display inflammation as indicated by increased levels of proinflammatory mediators in the blood and cerebrospinal fluid. Longitudinal and experimental studies suggest that this inflamm...
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Background There is a lack of neuroscience-based biomarkers for the diagnosis, treatment and monitoring of individuals with substance use disorders (SUD). The resource allocation index (RAI), a measure of the interrelationship between salience, executive control and default-mode brain networks (SN, ECN, and DMN), has been proposed as one such bioma...
Article
Background There is a need to determine why prior concussion has been associated with adverse outcomes in some retired and active athletes. We examined whether serum inflammatory markers moderate the associations of prior concussion with hippocampal volumes and neurobehavioral functioning in active high school and collegiate athletes. Methods Athl...