Mitochondrial impairment demonstrated via 18F-BCPP-EF mitochondrial complex I PET ligand in case study of individual with bipolar disorder and alcohol use disorder

Mitochondrial impairment demonstrated via 18F-BCPP-EF mitochondrial complex I PET ligand in case study of individual with bipolar disorder and alcohol use disorder | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Mitochondrial impairment demonstrated via 18 F-BCPP-EF mitochondrial complex I PET ligand in case study of individual with bipolar disorder and alcohol use disorder Travis P. Wigstrom, Stiven Roytman, Jeffrey L. B. Bohnen, Rebecca R. Paalanen, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4165029/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background With Bipolar Disorder (BD) having a lifetime prevalence of 4.4% and a significant portion of patients being chronically burdened by symptoms, there has been an increased focus on uncovering new targets for intervention in BD. One area that has shown early promise is the mitochondrial hypothesis, with supporting evidence in the form of mtDNA copy number, SNPs, ETC complex activity in peripheral cells, postmortem analyses of ETC function, and iPSC-derived biomarkers, among others. Despite this compelling evidence, at the time of this publication no studies have utilized PET imaging to assess mitochondrial function in the setting of BD. Case Presentation Our participant is a 58 year old male with a past medical history notable for alcohol use disorder and bipolar disorder (unspecified type) who, while enrolled as a control for a separate trial, underwent PET imaging with the mitochondrial complex 1 PET ligand 18 F-BCPP-EF. Those images were compared to normal controls which demonstrated significant overlap between areas of dysfunction identified with the 18F-BCPP-EF PET ligand and areas of dysfunction previously identified in the setting of BD with fMRI techniques. That overlap was seen in both affective and cognitive circuits, with mitochondrial dysfunction in the fronto-limbic, ventral affective, and dorsal cognitive circuits showing particularly significant differences. Conclusions Despite mounting evidence implicating mitochondria in BD, this study represents the first PET imaging study to investigate this mechanistic connection. There were key limitations in the form of comorbid alcohol use disorder, limited statistical power inherent to a case study, no sex matched controls, and the absence of a comprehensive psychiatric history. However, even with these limitations in mind, the significant overlap between areas of dysfunction previously demonstrated on fMRI and this 18F-BCPP-EF PET ligand imaging provides compelling preliminary evidence that strengthens the mechanistic link between mitochondrial dysfunction and Bipolar Disorder and warrants further investigation. Mitochondria Bipolar Disorder PET Imaging Fronto-Limbic Circuit Ventral Affective Circuit Dorsal Cognitive Circuit Default Mode Network Central Executive Network Salience Network Sensorimotor Network Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Bipolar disorder (BD) has a lifetime prevalence of 4.4% and a significant portion of patients are chronically burdened by symptoms despite standard treatment. 1 , 2 Although pharmaceutical interventions have saved countless lives, much work remains to uncover improved targets for intervention. In recent years, the mitochondrial hypothesis of bipolar disorder has been gaining increasing momentum in the scientific community, with mounting evidence supporting the key role of mitochondria in the pathogenesis of bipolar disorder. In postmortem samples of BD patients, downregulation of mitochondrial electron transport chain (ETC) complexes I, IV, and V has been observed. 3 , 4 Furthermore, a study assessing leukocytes obtained from individuals with BD compared to those derived from healthy controls found lower mitochondrial DNA (mtDNA) copy number and higher degrees of oxidative damage in cells derived from individuals with BD. 5 Another study building on that work showed that mtDNA copy number was lower in cohorts of both manic and depressed individuals with BD when compared to individuals with BD in a euthymic state. They also found a negative correlation between mtDNA copy number and the number of relapses experienced by the participants in a manic state. 6 The CAMKK2 single nucleotide polymorphism (SNP), which regulates mitochondrial function, has also been associated with BD and correlated with impaired mitochondrial function in several studies. 7 , 8 Induced pluripotent stem cells (iPSCs) generated from the fibroblasts of individuals clinically diagnosed with type 1 BD while in a manic state were found to have hyperexcitable neurons with increased mitochondrial activity and a corresponding up-regulation of mitochondrial genes—moreover, this hyperexcitability was capable of being reversed via administration of Lithium. 9 A study linking these findings and clinical symptoms found a significant negative correlation with lymphocyte ETC complex II activity and a Hamilton depression score. 10 Finally, clinical studies have revealed that individuals with mitochondrial cytopathies have a higher risk of developing BD 11 , 12 As a related consideration, the overlapping pharmacotherapies utilized for both bipolar disorder and epilepsy suggest that a mechanistic overlap may exist between these conditions. Mitochondrial dysfunction has been implicated in various forms of epilepsy. 13 , 14 As a result, researchers have increasingly focused on elucidating the role of a parallel process—that of mitochondrial dysfunction in bipolar disorder. With ~ 50% of a neuronal ATP utilized by the Na + /K + ATPase, 15 any deficiencies in mitochondrial-dependent ATP generation may result in altered membrane stability. Mitochondria also play a key role in the synthesis and regulation of neurotransmitters, epigenetic regulatory mechanisms, and calcium mechanisms central to neuronal excitability. 16 – 23 Alterations of these fundamental processes may drive dysfunctional patterns of neuronal activation and resultant changes in neural networks. Despite the mounting evidence supporting a role for mitochondrial dysfunction in BD, no positron emission tomography (PET) imaging study to date has investigated this mechanistic connection. This gap in the current literature can be addressed by utilizing the 18 F-BCPP-EF PET ligand, which binds mitochondrial complex I to serve as a proxy for mitochondrial function. Prior research has investigated the application of this tracer in neurodegenerative disorders 24 , 25 and autism spectrum disorders. 26 However, no studies in mood disorders have utilized this imaging modality. Case Presentation The participant is a 58-year-old male with a past medical history notable for anxiety, depression, migraines, alcohol use disorder (AUD), BD (unspecified type), and COPD who notably enrolled as a control subject for a clinical trial that assessed brain mitochondrial function in the setting of neurological disorders via the 18 F-BCPP-EF PET ligand (a PET probe for mitochondrial complex 1). On screening prior to enrollment, he indicated that he had no prior psychiatric history. However, in a subsequent interview, he disclosed that he has been diagnosed with bipolar disorder (unspecified subtype) in the past and had been treated with various mood stabilizers (all of which he reportedly discontinued due to not “believing” in the disorder). He takes no medication for his anxiety, depression, and migraines but does take Trazadone, Benadryl, and melatonin to assist with sleep difficulties. He has a smoking history of 44 pack years, reports frequent marijuana use for the last 47 years, and reports drinking more than 10 drinks weekly starting at the age of 11. The participant reported a family history which includes a cousin’s suicide and three siblings who have been diagnosed with bipolar disorder (unspecified type). Upon mental status exam, he exhibited pressured speech, irritability, and mildly elevated mood, in addition to reporting a sleep deficit (with a typical sleep duration of five hours per night). During the interview, he repeatedly insisted that he had enjoyed working long hours and had to leave as soon as possible so that he could get more work done (despite having scheduled the appointment at the earliest possible time slot that staff could accommodate, which fell outside of regular work hours). There was, therefore, limited time to undergo a more thorough diagnostic assessment in this setting, but the symptoms characteristic of bipolar disorder evident during this exchange were noted by all staff with whom the participant interacted. He also completed the Beck Depression Inventory (BDI-II) with a resulting score of 34 indicating severe depression in the preceding two weeks with predominant features of loss of interest, sadness, and agitation. Additionally, the participant got an alternating verbal fluency score of 9/20 and an action verbal fluency score of 17/30. Two healthy controls and the participant with BD additionally underwent PET imaging. PET imaging was performed in 3D imaging mode on a Biograph 6 TruPoint PET/CT scanner (Siemens Molecular Imaging, Inc., Knoxville, TN), which acquired 63 transaxial slices (slice thickness: 2.4 mm) over a 15.2 cm axial field-of-view. Images were be corrected for scatter and motion. Sixteen frames of dynamic PET imaging data were acquired over 70 minutes from the time of injection. Last two frames of the dynamic acquisition were averaged and rigidly aligned to the participant’s structural MRI scan using advanced normalization tools (ANTs). FreeSurfer software suite was used to generate segmentation labels for midsaggital corpus callosum from the structural MRI scans. The averaged PET frames were subsequently normalized by the mean value of the midsaggital corpus callosum to obtain standardized uptake value ratio (SUVR) images. Lastly, regional SUVR values were extracted using FreeSurfer labels, and between subject percent differences were calculated. Two female normal controls who underwent the same imaging protocol were available to provide approximate regional uptake comparisons. The other male normal controls who participated in the clinical trial underwent different imaging protocols (as the diffusion protocol was still going through an interactive optimization process at the time of this trial given the recent advent of this technology). Therefore, while one of the normal controls with available comparative imaging data was age-matched, no gender-matched imaging data was available for comparison, representing a key limitation in interpreting comparative findings. Nonetheless, even when compared to the 75-year old female normal control with comparative imaging data available (for whom mitochondrial function would be expected to decline with age), mitochondrial function was significantly more impaired in the younger individual with a history of bipolar disorder. The resulting processed images for the subject of this case study, the 57 year old male with BD (unspecified type), is shown below in Fig. 1 . Additionally, the processed images for the 57 year old female healthy control and the 75 year old female healthy control are shown below in Figs. 2 and 3 respectively. For the participant presented in this case study, there was an approximately 20% reduction in mitochondrial complex I activity observed in the ventrolateral prefrontal cortex, the dorsolateral prefrontal cortex, and the precuneus region in comparison to mitochondrial complex I activity observed in the age-matched control. Additionally, an approximately 15% reduction was observed in the amygdala, thalamus, and caudate nucleus. There was mild laterality observed in the degree of deficit, but all within 5%. These findings are visualized in Fig. 4 below. Conclusions It is important to note that an observed deficit in mitochondrial complex I activity does not allow us to definitively infer whether neurons in a given brain region are more or less active. Deficits in mitochondrial function would presumably affect neuronal membrane stability and result in altered resting membrane potential, which could manifest as increased frequency of action potentials (at least initially). Potential mechanisms include the accumulation of intracellular sodium, lowering the ATP-dependent resting membrane potential, or exhaustion of vesicular contents impairing synaptic transmission. The need to restore homeostasis may explain the temporal relationship observed between hypomanic and depressive episodes. Moreover, given the complex web of inhibitory and excitatory pathways throughout the central nervous system, inhibition of a given neural network may result in paradoxical excitation of associated regions. When investigating dysfunctional neural circuits implicated in bipolar disorder, neuroimaging researchers often categorically separate neural circuits into three domains: emotional regulation, cognition, and psychomotor changes. 27 When considering emotional regulation and function, there are three interconnected circuits that have been identified as major contributors to mood lability in bipolar disorder. These are detailed in Fig. 5 below. The first is the fronto-limbic circuit, which is primarily comprised of connections between the amygdala (Amy) and the ventrolateral prefrontal cortex (vlPFC), with the vlPFC assessing whether the amygdala has properly responded to a situation and then adjusting its output. 28 In individuals with BD, the amygdala shows increased activity, resulting from either dysfunction in the vlPFC, the Amy, or both. 29 In our imaging case study, both the vlPFC and Amy demonstrated significant decreases in mitochondrial function. It follows that such alterations may be related to symptoms involving emotional lability/impulsivity (e.g., pressured speech and irritability). The second circuit depicted, the ventral affective circuit, is involved in identifying salient emotional stimuli and mediating resultant autonomic responses. 30 , 31 It includes the orbital frontal cortex (OFC), the thalamus, and the ventral striatum. PET imaging of our participant exhibited significant mitochondrial dysfunction in both the thalamus and the frontal pole. Given the role of the OFC, these deficits point to a process that affects emotional reactions to both internal and external cues. 32 The third, dorsal cognitive circuit, is comprised of the dorsolateral prefrontal cortex (dlPFC), the dorsomedial Prefrontal cortex (dmPFC), the dorsal caudate (dCaud), and the thalamus (Thal). This circuit, which is responsible for selective attention, planning, and explicit emotional regulation, is broadly hypoactive in patients with bipolar disorder independent of their current mood state. 28 , 33 In our case study, mitochondrial deficits are observed in all four of these regions, possibly contributing to deficits in cognitive regulation of emotion. Beyond emotional regulation and function, symptoms related to both cognitive and psychomotor changes are hallmarks of BD. Cognitive changes include deficits in executive function, memory, social cognition, and response timing. Psychomotor changes seen are state-dependent, with mania involving symptoms of hyperactivity, reckless action, impulsivity, and agitation, whereas depressive episodes involve decreased activity levels, volitional inhibition, physical and mental sluggishness, and, in more extreme episodes, akinesia. These symptoms have been associated with four networks: the default mode network (DMN), the central executive network (CEN), the salience network (SN), and the sensorimotor network (SMN) – the first three networks are predominant contributors to cognition, with the SMN primarily being responsible for psychomotor symptoms. 34 – 38 Coordination and switching among these four networks is considered to be an underlying framework for cognition. 39 , 40 The DMN, comprised of medial prefrontal cortex (mPFC), the hippocampus, the lateral temporal cortex, the precuneal cortex, and the posterior cingulate cortex, is widely referred to as the “task-negative network” given that it exhibits activation at baseline and deactivation during engagement with a task. This is in contrast to the CEN, which is viewed as an antagonistic circuit to the DMN given that it is primarily active during activities. 41 The CEN comprises the dlPFC, the dorsal ACC, the posterior parietal context, and the inferior temporal gyrus and exhibits increased activity during attention-demanding and working memory tasks that require top-down modulation. 42 At the center of these two networks is the SN, which plays a central role in switching between the DMN and CEN and comprises the insular cortex, the dorsal ACC, the amygdala, and the temporal lobe. 35 Dysfunctions in these networks have been shown to be correlated with the cognitive deficits observed in BD. 43 – 45 Notably, in this case study, 18F-BCPP-EF PET imaging revealed evidence of mitochondrial dysfunction within the precuneus cortex, which is a key part of the DMN. Additionally, the amygdala, which is a part of the SN, exhibited mitochondrial dysfunction. These mitochondrial deficits could theoretically be contributing to the participant’s alternating verbal fluency score of 9/20. As with cognition, psychomotor behavioral features manifesting in BD are thought to be caused by alterations in networks, specifically the DMN and the SMN. 37 , 46 , 47 One study found that individuals with BD had reduced resting state cohesiveness of the SMN 48 and another found reduced functional within-connectivity in both the right and left primary somatosensory areas (clusters in the somatosensory network) in individuals with BD. 49 The ratio between DMN activity and SMN activity as measured by blood flow has also been an area of investigation, with studies having shown that the DMN/SMN activity ratio was significantly increased in depression and significantly decreased in mania, with computed ratios in both cases correlating with the degree of depressive or manic symptoms, respectively. 36 , 50 For our participant in the case study, there were mitochondrial deficits observed in key regions in the DMN as detailed in the prior paragraph. However, calculating a DMN/SMN activity ratio to derive potential correlations with symptom severity would require a different imaging modality, which falls outside the scope of this case study. While this case study establishes the first utilization of the 18 F-BCPP-EF PET ligand in the setting of bipolar disorder, several key limitations must be noted. Namely, in addition to the limited statistical power inherent to a case study, no sex-matched controls were available for comparison. While matching for age is vital when assessing mitochondrial function, matching for biological sex may prove to be particularly important as well as more data emerges. Third, binge drinking behavior was comorbid with bipolar disorder in this case study, making it difficult to discern to what extent observed mitochondrial deficits may be associated with underlying bipolar disorder pathophysiology vs. consumption of alcohol (a known mitochondrial toxin). Finally, given the participant’s mental status at the time of examination and preference to quickly return to work following the standard assessment, collecting a more comprehensive psychiatric history was not feasible. Even with these limitations in mind, this case study provides exciting preliminary results due to the mounting evidence implicating mitochondria in the pathogenesis of bipolar disorder. This has been established utilizing several techniques, including assessments pertaining to mtDNA copy number, SNPs, ETC complex activity in peripheral cells, postmortem analyses of ETC function, and iPSC-derived biomarkers, among others. Despite this compelling evidence, at the time of this publication no studies have utilized PET imaging to assess mitochondrial function in the setting of BD. This renders the 18F-BCPP-EF mitochondrial complex I PET ligand an exciting new tool to further characterize the role of mitochondrial dysfunction in BD. This case study opens the door for future lines of research to build on these preliminary results. Our imaging findings demonstrated significant overlap between areas of dysfunction identified with the 18F-BCPP-EF PET ligand and areas of dysfunction previously identified in the setting of BD with fMRI techniques. That overlap was seen in both affective and cognitive circuits, with mitochondrial dysfunction in the fronto-limbic, ventral affective, and dorsal cognitive circuits showing particularly significant differences. This was true even when comparing imaging with the much older healthy control, whom one would expect to have a greater degree of impairment as a function of aging. The compelling overlap between prior imaging outcomes and our findings in this case study warrant further investigation via an expanded study featuring an increased number of participants and measures aimed at controlling for confounding variables. Expanded research in this domain has the potential to better characterize the role of mitochondrial function in the pathogenesis of BD, with the ultimate goal of identifying clinically useful biomarkers and improved therapeutic targets to benefit patients suffering from BD. Abbreviations BD=Bipolar Disorder; ETC=Electron Transport Chain; mtDNA=Mitochondrial DNA; SNP=Single Nucleotide Polymorphism; iPSC=Induced Pluripotent Stem Cell; ATP=Adenosine TriPhosphate; PET=Positron Emission Tomography; AUD=Alcohol Use Disorder; COPD=Chronic Obstructive Pulmonary Disease; BDI=Beck Depression Inventory; CT=Computed Tomography; MRI=Magnetic Resonance Imaging; ANT=Advanced Normalization Tools; SUVR=Standardized Uptake Value Ratio; Amy=Amygdala; vlPFC=Ventrolateral Pre Frontal Cortex; OFC=Orbitofrontal Cortex; dm PFC=Dorsomedial Prefrontal Cortex; dCaud=Dorsal Caudate; Thal=Thalamus; DMN=Default Mode Network; CEN=Central Executive Network; SN=Salience Network; SMN=SensoriMotor Network; mPFC=Medial Prefrontal Cortex; ACC=Anterior Cingulate Cortex Declarations Ethics approval and consent to participant The trial from which this data was acquired received ethics approval from the University of Michigan IRBMED board. The participant consented prior to their involvement in the study. Consent for publication Consent for publication was acquired from the participant. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Competing Interests The authors declare that they have no competing interests. Funding Funding was provided by the Eisenberg Depression Center Impact Accelerator Grant. Authors Contributions Corresponding Author: Travis Wigstrom ( [email protected] ) analyzed the data and wrote the manuscript. Corresponding Author: Stiven Roytman ( [email protected] ) processed the images and the resulting data. Corresponding Author: Jeffery Bohnen ( [email protected] ) helped write the manuscript and provided intellectual support. Corresponding Author: Rebecca Paalanen ( [email protected] ) assisted with interviewing the patient and coordinating imaging. Corresponding Author: Alexis Griggs ( [email protected] ) assisted with interviewing the patient and coordinating imaging. Corresponding Author: Robert Vangel ( [email protected] ) assisted with interviewing the patient and coordinating imaging. Corresponding Author: Jaimie Barr ( [email protected] ) assisted with interviewing the patient and coordinating imaging. Corresponding Author: Roger Albin ( [email protected] ) organized the original clinical trial and provided intellectual contributions. Corresponding Author: Prabesh Kanel ( [email protected] ) provided intellectual contributions to the paper. Corresponding Author: Nicolaas Bohnen ( [email protected] ) NB organized the clinical trial which the data is from and provided intellectual contributions. Acknowledgments Not Applicable References Vieta, E.; Berk, M.; Birmaher, B.; Grande, I. Bipolar disorder: defining symptoms and comorbidities--Authors' reply. Lancet 2016 , 388 (10047), 869-870. DOI: 10.1016/S0140-6736(16)30966-7. 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Shared and specific functional connectivity alterations in unmedicated bipolar and major depressive disorders based on the triple-network model. Brain Imaging Behav 2020 , 14 (1), 186-199. DOI: 10.1007/s11682-018-9978-x. Park, H. J.; Friston, K. Structural and functional brain networks: from connections to cognition. Science 2013 , 342 (6158), 1238411. DOI: 10.1126/science.1238411. Syan, S. K.; Smith, M.; Frey, B. N.; Remtulla, R.; Kapczinski, F.; Hall, G. B. C.; Minuzzi, L. Resting-state functional connectivity in individuals with bipolar disorder during clinical remission: a systematic review. J Psychiatry Neurosci 2018 , 43 (5), 298-316. DOI: 10.1503/jpn.170175. Smith, S. M.; Fox, P. T.; Miller, K. L.; Glahn, D. C.; Fox, P. M.; Mackay, C. E.; Filippini, N.; Watkins, K. E.; Toro, R.; Laird, A. R.; et al. Correspondence of the brain's functional architecture during activation and rest. Proc Natl Acad Sci U S A 2009 , 106 (31), 13040-13045. DOI: 10.1073/pnas.0905267106. Menon, V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci 2011 , 15 (10), 483-506. DOI: 10.1016/j.tics.2011.08.003. Zovetti, N.; Rossetti, M. G.; Perlini, C.; Maggioni, E.; Bontempi, P.; Bellani, M.; Brambilla, P. Default mode network activity in bipolar disorder. Epidemiol Psychiatr Sci 2020 , 29 , e166. DOI: 10.1017/S2045796020000803. Liu, M.; Wang, Y.; Zhang, A.; Yang, C.; Liu, P.; Wang, J.; Zhang, K.; Sun, N. Altered dynamic functional connectivity across mood states in bipolar disorder. Brain Res 2021 , 1750 , 147143. DOI: 10.1016/j.brainres.2020.147143. Wang, J.; Wang, Y.; Huang, H.; Jia, Y.; Zheng, S.; Zhong, S.; Chen, G.; Huang, L.; Huang, R. Abnormal dynamic functional network connectivity in unmedicated bipolar and major depressive disorders based on the triple-network model. Psychol Med 2020 , 50 (3), 465-474. DOI: 10.1017/S003329171900028X. Northoff, G.; Hirjak, D.; Wolf, R. C.; Magioncalda, P.; Martino, M. All roads lead to the motor cortex: psychomotor mechanisms and their biochemical modulation in psychiatric disorders. Mol Psychiatry 2021 , 26 (1), 92-102. DOI: 10.1038/s41380-020-0814-5. Meda, S. A.; Ruaño, G.; Windemuth, A.; O'Neil, K.; Berwise, C.; Dunn, S. M.; Boccaccio, L. E.; Narayanan, B.; Kocherla, M.; Sprooten, E.; et al. Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia. Proc Natl Acad Sci U S A 2014 , 111 (19), E2066-2075. DOI: 10.1073/pnas.1313093111. Doucet, G. E.; Bassett, D. S.; Yao, N.; Glahn, D. C.; Frangou, S. The Role of Intrinsic Brain Functional Connectivity in Vulnerability and Resilience to Bipolar Disorder. Am J Psychiatry 2017 , 174 (12), 1214-1222. DOI: 10.1176/appi.ajp.2017.17010095. Ishida, T.; Donishi, T.; Iwatani, J.; Yamada, S.; Takahashi, S.; Ukai, S.; Shinosaki, K.; Terada, M.; Kaneoke, Y. Interhemispheric disconnectivity in the sensorimotor network in bipolar disorder revealed by functional connectivity and diffusion tensor imaging analysis. Heliyon 2017 , 3 (6), e00335. DOI: 10.1016/j.heliyon.2017.e00335. Russo, D.; Martino, M.; Magioncalda, P.; Inglese, M.; Amore, M.; Northoff, G. Opposing Changes in the Functional Architecture of Large-Scale Networks in Bipolar Mania and Depression. Schizophr Bull 2020 , 46 (4), 971-980. DOI: 10.1093/schbul/sbaa004. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4165029","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":284307900,"identity":"dfa95ed4-5495-4003-a227-0fd45ae97b6d","order_by":0,"name":"Travis P. Wigstrom","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYDACZijND8QSQMwDJQloOQDEkg1Ea2GAajE4ANHCQFCLwXH2y58/7rGJNr52+OANxrZtMvyzGxgfvG3Do+UwT5nEgWdpudtupyVbMLbd5pG4c4DZcC4eLWaHedIYDhw4DNSSYyYB0mIgkcAmzYtfS/IHkJbNs/O/wbSw/8avhf2ABEjLBukcNrgtzPi02B/mYZM4cyAtd8btNGOLhHNAv9xIbJaccw63Fsn+448/VBywye2fnfzwxoey2/b8M5IPfnhThlsLMAoMEOwEMMnYgE89ELA/IKBgFIyCUTAKRjwAABozVcLNs6IoAAAAAElFTkSuQmCC","orcid":"","institution":"University of Michigan","correspondingAuthor":true,"prefix":"","firstName":"Travis","middleName":"P.","lastName":"Wigstrom","suffix":""},{"id":284307901,"identity":"0b510b53-da52-4701-b747-2f9c6bb17c07","order_by":1,"name":"Stiven Roytman","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Stiven","middleName":"","lastName":"Roytman","suffix":""},{"id":284307902,"identity":"a7eb9347-01f9-45c6-892a-de587723c852","order_by":2,"name":"Jeffrey L. B. Bohnen","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Jeffrey","middleName":"L. B.","lastName":"Bohnen","suffix":""},{"id":284307903,"identity":"72d6fe0f-7f5a-42e3-aad4-4802274c7ffe","order_by":3,"name":"Rebecca R. Paalanen","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Rebecca","middleName":"R.","lastName":"Paalanen","suffix":""},{"id":284307904,"identity":"98c66880-0c41-4c87-9d8e-ee385dd8e359","order_by":4,"name":"Alexis M. Griggs","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Alexis","middleName":"M.","lastName":"Griggs","suffix":""},{"id":284307905,"identity":"c757ba64-fc2a-4d60-aa80-0e636bcebb4f","order_by":5,"name":"Robert Vangel","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Robert","middleName":"","lastName":"Vangel","suffix":""},{"id":284307906,"identity":"62d474cc-801c-4bbc-a597-89467e203e29","order_by":6,"name":"Jaime Barr","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Jaime","middleName":"","lastName":"Barr","suffix":""},{"id":284307907,"identity":"732a2e98-2b9e-443d-8948-a5da19e102fd","order_by":7,"name":"Roger Albin","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Roger","middleName":"","lastName":"Albin","suffix":""},{"id":284307908,"identity":"4f2328d8-82cf-424d-929b-624204d7c816","order_by":8,"name":"Prabesh Kanel","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Prabesh","middleName":"","lastName":"Kanel","suffix":""},{"id":284307909,"identity":"153e40b7-a79b-4299-a020-c619b599178b","order_by":9,"name":"Nicolaas I. Bohnen","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Nicolaas","middleName":"I.","lastName":"Bohnen","suffix":""}],"badges":[],"createdAt":"2024-03-25 17:58:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4165029/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4165029/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53873491,"identity":"f85bf972-3057-4942-84f3-4d4f0125d9dd","added_by":"auto","created_at":"2024-04-01 16:12:53","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1130971,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePET imaging of a 57 year old male with BD disorder obtained via the \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-BCPP-EF mitochondrial complex I PET ligand\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e‘Warmer’ colors represent greater mitochondrial activity in the brain and ‘colder’ colors represent decreased mitochondrial activity.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4165029/v1/ae65b999913342875c393ba9.png"},{"id":53873489,"identity":"fd7a5597-09cc-4036-b293-67eb03b2eeef","added_by":"auto","created_at":"2024-04-01 16:12:53","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1291334,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePET imaging of a 57 year old female healthy control using the \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-BCPP-EF mitochondrial complex I PET ligand\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e‘Warmer’ colors represent greater mitochondrial activity in the brain and ‘colder’ colors represent decreased mitochondrial activity.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-4165029/v1/a17805ae27d0b453cded37ab.png"},{"id":53874576,"identity":"fb237e31-a3ea-4d56-8077-0b341dabfabf","added_by":"auto","created_at":"2024-04-01 16:20:53","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":139776,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePET imaging of a 75 year old female healthy control using the \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-BCPP-EF mitochondrial complex I PET ligand\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e‘Warmer’ colors represent greater mitochondrial activity in the brain and ‘colder’ colors represent decreased mitochondrial activity.\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-4165029/v1/e9838e901da6e52a1b3b0fde.jpeg"},{"id":53873488,"identity":"9c53f623-fe08-4bd2-b0be-e44b6b998a9b","added_by":"auto","created_at":"2024-04-01 16:12:53","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":300297,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRelative degree of mitochondrial impairment: Inter-participant comparisons\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4165029/v1/0aae11000b769f1a1158ec06.jpg"},{"id":53873492,"identity":"4564f105-bedc-43af-be68-6b06ad10b075","added_by":"auto","created_at":"2024-04-01 16:12:53","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":279543,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eInterconnected circuits identified as major contributors to mood lability in bipolar disorder\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-4165029/v1/0ab10df74600a3016f3f391a.png"},{"id":57433380,"identity":"6e334dbb-8b82-4d05-83a4-2eba579e352e","added_by":"auto","created_at":"2024-05-30 15:16:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3749234,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4165029/v1/e7ee0b26-88a5-43a0-bc4f-616dbcdd4c29.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eMitochondrial impairment demonstrated via \u003csup\u003e18\u003c/sup\u003eF-BCPP-EF mitochondrial complex I PET ligand in case study of individual with bipolar disorder and alcohol use disorder\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eBipolar disorder (BD) has a lifetime prevalence of 4.4% and a significant portion of patients are chronically burdened by symptoms despite standard treatment.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Although pharmaceutical interventions have saved countless lives, much work remains to uncover improved targets for intervention. In recent years, the mitochondrial hypothesis of bipolar disorder has been gaining increasing momentum in the scientific community, with mounting evidence supporting the key role of mitochondria in the pathogenesis of bipolar disorder.\u003c/p\u003e \u003cp\u003eIn postmortem samples of BD patients, downregulation of mitochondrial electron transport chain (ETC) complexes I, IV, and V has been observed.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e Furthermore, a study assessing leukocytes obtained from individuals with BD compared to those derived from healthy controls found lower mitochondrial DNA (mtDNA) copy number and higher degrees of oxidative damage in cells derived from individuals with BD.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Another study building on that work showed that mtDNA copy number was lower in cohorts of both manic and depressed individuals with BD when compared to individuals with BD in a euthymic state. They also found a negative correlation between mtDNA copy number and the number of relapses experienced by the participants in a manic state.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e The CAMKK2 single nucleotide polymorphism (SNP), which regulates mitochondrial function, has also been associated with BD and correlated with impaired mitochondrial function in several studies.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Induced pluripotent stem cells (iPSCs) generated from the fibroblasts of individuals clinically diagnosed with type 1 BD while in a manic state were found to have hyperexcitable neurons with increased mitochondrial activity and a corresponding up-regulation of mitochondrial genes\u0026mdash;moreover, this hyperexcitability was capable of being reversed via administration of Lithium.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e A study linking these findings and clinical symptoms found a significant negative correlation with lymphocyte ETC complex II activity and a Hamilton depression score.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e Finally, clinical studies have revealed that individuals with mitochondrial cytopathies have a higher risk of developing BD\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eAs a related consideration, the overlapping pharmacotherapies utilized for both bipolar disorder and epilepsy suggest that a mechanistic overlap may exist between these conditions. Mitochondrial dysfunction has been implicated in various forms of epilepsy.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e As a result, researchers have increasingly focused on elucidating the role of a parallel process\u0026mdash;that of mitochondrial dysfunction in bipolar disorder. With ~\u0026thinsp;50% of a neuronal ATP utilized by the Na\u003csup\u003e+\u003c/sup\u003e/K\u003csup\u003e+\u003c/sup\u003e ATPase,\u003csup\u003e15\u003c/sup\u003e any deficiencies in mitochondrial-dependent ATP generation may result in altered membrane stability. Mitochondria also play a key role in the synthesis and regulation of neurotransmitters, epigenetic regulatory mechanisms, and calcium mechanisms central to neuronal excitability.\u003csup\u003e\u003cspan additionalcitationids=\"CR17 CR18 CR19 CR20 CR21 CR22\" citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Alterations of these fundamental processes may drive dysfunctional patterns of neuronal activation and resultant changes in neural networks.\u003c/p\u003e \u003cp\u003eDespite the mounting evidence supporting a role for mitochondrial dysfunction in BD, no positron emission tomography (PET) imaging study to date has investigated this mechanistic connection. This gap in the current literature can be addressed by utilizing the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-BCPP-EF PET ligand, which binds mitochondrial complex I to serve as a proxy for mitochondrial function. Prior research has investigated the application of this tracer in neurodegenerative disorders\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e,\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e and autism spectrum disorders.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e However, no studies in mood disorders have utilized this imaging modality.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eThe participant is a 58-year-old male with a past medical history notable for anxiety, depression, migraines, alcohol use disorder (AUD), BD (unspecified type), and COPD who notably enrolled as a control subject for a clinical trial that assessed brain mitochondrial function in the setting of neurological disorders via the \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-BCPP-EF PET ligand (a PET probe for mitochondrial complex 1). On screening prior to enrollment, he indicated that he had no prior psychiatric history. However, in a subsequent interview, he disclosed that he has been diagnosed with bipolar disorder (unspecified subtype) in the past and had been treated with various mood stabilizers (all of which he reportedly discontinued due to not \u0026ldquo;believing\u0026rdquo; in the disorder). He takes no medication for his anxiety, depression, and migraines but does take Trazadone, Benadryl, and melatonin to assist with sleep difficulties. He has a smoking history of 44 pack years, reports frequent marijuana use for the last 47 years, and reports drinking more than 10 drinks weekly starting at the age of 11. The participant reported a family history which includes a cousin\u0026rsquo;s suicide and three siblings who have been diagnosed with bipolar disorder (unspecified type).\u003c/p\u003e\n\u003cp\u003eUpon mental status exam, he exhibited pressured speech, irritability, and mildly elevated mood, in addition to reporting a sleep deficit (with a typical sleep duration of five hours per night). During the interview, he repeatedly insisted that he had enjoyed working long hours and had to leave as soon as possible so that he could get more work done (despite having scheduled the appointment at the earliest possible time slot that staff could accommodate, which fell outside of regular work hours). There was, therefore, limited time to undergo a more thorough diagnostic assessment in this setting, but the symptoms characteristic of bipolar disorder evident during this exchange were noted by all staff with whom the participant interacted.\u003c/p\u003e\n\u003cp\u003eHe also completed the Beck Depression Inventory (BDI-II) with a resulting score of 34 indicating severe depression in the preceding two weeks with predominant features of loss of interest, sadness, and agitation. Additionally, the participant got an alternating verbal fluency score of 9/20 and an action verbal fluency score of 17/30. Two healthy controls and the participant with BD additionally underwent PET imaging.\u003c/p\u003e\n\u003cp\u003ePET imaging was performed in 3D imaging mode on a Biograph 6 TruPoint PET/CT scanner (Siemens Molecular Imaging, Inc., Knoxville, TN), which acquired 63 transaxial slices (slice thickness: 2.4 mm) over a 15.2 cm axial field-of-view. Images were be corrected for scatter and motion. Sixteen frames of dynamic PET imaging data were acquired over 70 minutes from the time of injection. Last two frames of the dynamic acquisition were averaged and rigidly aligned to the participant\u0026rsquo;s structural MRI scan using advanced normalization tools (ANTs). \u003cem\u003eFreeSurfer\u003c/em\u003e software suite was used to generate segmentation labels for midsaggital corpus callosum from the structural MRI scans. The averaged PET frames were subsequently normalized by the mean value of the midsaggital corpus callosum to obtain standardized uptake value ratio (SUVR) images. Lastly, regional SUVR values were extracted using FreeSurfer labels, and between subject percent differences were calculated. Two female normal controls who underwent the same imaging protocol were available to provide approximate regional uptake comparisons. The other male normal controls who participated in the clinical trial underwent different imaging protocols (as the diffusion protocol was still going through an interactive optimization process at the time of this trial given the recent advent of this technology). Therefore, while one of the normal controls with available comparative imaging data was age-matched, no gender-matched imaging data was available for comparison, representing a key limitation in interpreting comparative findings. Nonetheless, even when compared to the 75-year old female normal control with comparative imaging data available (for whom mitochondrial function would be expected to decline with age), mitochondrial function was significantly more impaired in the younger individual with a history of bipolar disorder. The resulting processed images for the subject of this case study, the 57 year old male with BD (unspecified type), is shown below in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Additionally, the processed images for the 57 year old female healthy control and the 75 year old female healthy control are shown below in Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e respectively.\u003c/p\u003e\n\u003cp\u003eFor the participant presented in this case study, there was an approximately 20% reduction in mitochondrial complex I activity observed in the ventrolateral prefrontal cortex, the dorsolateral prefrontal cortex, and the precuneus region in comparison to mitochondrial complex I activity observed in the age-matched control. Additionally, an approximately 15% reduction was observed in the amygdala, thalamus, and caudate nucleus. There was mild laterality observed in the degree of deficit, but all within 5%. These findings are visualized in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e below.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIt is important to note that an observed deficit in mitochondrial complex I activity does not allow us to definitively infer whether neurons in a given brain region are more or less active. Deficits in mitochondrial function would presumably affect neuronal membrane stability and result in altered resting membrane potential, which could manifest as increased frequency of action potentials (at least initially). Potential mechanisms include the accumulation of intracellular sodium, lowering the ATP-dependent resting membrane potential, or exhaustion of vesicular contents impairing synaptic transmission. The need to restore homeostasis may explain the temporal relationship observed between hypomanic and depressive episodes. Moreover, given the complex web of inhibitory and excitatory pathways throughout the central nervous system, inhibition of a given neural network may result in paradoxical excitation of associated regions.\u003c/p\u003e \u003cp\u003eWhen investigating dysfunctional neural circuits implicated in bipolar disorder, neuroimaging researchers often categorically separate neural circuits into three domains: emotional regulation, cognition, and psychomotor changes.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e When considering emotional regulation and function, there are three interconnected circuits that have been identified as major contributors to mood lability in bipolar disorder. These are detailed in Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e5\u003c/span\u003e below.\u003c/p\u003e \u003cp\u003eThe first is the fronto-limbic circuit, which is primarily comprised of connections between the amygdala (Amy) and the ventrolateral prefrontal cortex (vlPFC), with the vlPFC assessing whether the amygdala has properly responded to a situation and then adjusting its output.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e In individuals with BD, the amygdala shows increased activity, resulting from either dysfunction in the vlPFC, the Amy, or both.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e In our imaging case study, both the vlPFC and Amy demonstrated significant decreases in mitochondrial function. It follows that such alterations may be related to symptoms involving emotional lability/impulsivity (e.g., pressured speech and irritability).\u003c/p\u003e \u003cp\u003eThe second circuit depicted, the ventral affective circuit, is involved in identifying salient emotional stimuli and mediating resultant autonomic responses.\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e It includes the orbital frontal cortex (OFC), the thalamus, and the ventral striatum. PET imaging of our participant exhibited significant mitochondrial dysfunction in both the thalamus and the frontal pole. Given the role of the OFC, these deficits point to a process that affects emotional reactions to both internal and external cues.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe third, dorsal cognitive circuit, is comprised of the dorsolateral prefrontal cortex (dlPFC), the dorsomedial Prefrontal cortex (dmPFC), the dorsal caudate (dCaud), and the thalamus (Thal). This circuit, which is responsible for selective attention, planning, and explicit emotional regulation, is broadly hypoactive in patients with bipolar disorder independent of their current mood state.\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e In our case study, mitochondrial deficits are observed in all four of these regions, possibly contributing to deficits in cognitive regulation of emotion.\u003c/p\u003e \u003cp\u003eBeyond emotional regulation and function, symptoms related to both cognitive and psychomotor changes are hallmarks of BD. Cognitive changes include deficits in executive function, memory, social cognition, and response timing. Psychomotor changes seen are state-dependent, with mania involving symptoms of hyperactivity, reckless action, impulsivity, and agitation, whereas depressive episodes involve decreased activity levels, volitional inhibition, physical and mental sluggishness, and, in more extreme episodes, akinesia. These symptoms have been associated with four networks: the default mode network (DMN), the central executive network (CEN), the salience network (SN), and the sensorimotor network (SMN) \u0026ndash; the first three networks are predominant contributors to cognition, with the SMN primarily being responsible for psychomotor symptoms.\u003csup\u003e\u003cspan additionalcitationids=\"CR35 CR36 CR37\" citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCoordination and switching among these four networks is considered to be an underlying framework for cognition.\u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e,\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e The DMN, comprised of medial prefrontal cortex (mPFC), the hippocampus, the lateral temporal cortex, the precuneal cortex, and the posterior cingulate cortex, is widely referred to as the \u0026ldquo;task-negative network\u0026rdquo; given that it exhibits activation at baseline and deactivation during engagement with a task. This is in contrast to the CEN, which is viewed as an antagonistic circuit to the DMN given that it is primarily active during activities.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e The CEN comprises the dlPFC, the dorsal ACC, the posterior parietal context, and the inferior temporal gyrus and exhibits increased activity during attention-demanding and working memory tasks that require top-down modulation.\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e At the center of these two networks is the SN, which plays a central role in switching between the DMN and CEN and comprises the insular cortex, the dorsal ACC, the amygdala, and the temporal lobe.\u003csup\u003e\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e Dysfunctions in these networks have been shown to be correlated with the cognitive deficits observed in BD.\u003csup\u003e\u003cspan additionalcitationids=\"CR44\" citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e Notably, in this case study, 18F-BCPP-EF PET imaging revealed evidence of mitochondrial dysfunction within the precuneus cortex, which is a key part of the DMN. Additionally, the amygdala, which is a part of the SN, exhibited mitochondrial dysfunction. These mitochondrial deficits could theoretically be contributing to the participant\u0026rsquo;s alternating verbal fluency score of 9/20.\u003c/p\u003e \u003cp\u003eAs with cognition, psychomotor behavioral features manifesting in BD are thought to be caused by alterations in networks, specifically the DMN and the SMN.\u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e One study found that individuals with BD had reduced resting state cohesiveness of the SMN\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e and another found reduced functional within-connectivity in both the right and left primary somatosensory areas (clusters in the somatosensory network) in individuals with BD.\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e The ratio between DMN activity and SMN activity as measured by blood flow has also been an area of investigation, with studies having shown that the DMN/SMN activity ratio was significantly increased in depression and significantly decreased in mania, with computed ratios in both cases correlating with the degree of depressive or manic symptoms, respectively.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e,\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e For our participant in the case study, there were mitochondrial deficits observed in key regions in the DMN as detailed in the prior paragraph. However, calculating a DMN/SMN activity ratio to derive potential correlations with symptom severity would require a different imaging modality, which falls outside the scope of this case study.\u003c/p\u003e \u003cp\u003eWhile this case study establishes the first utilization of the \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003eF-BCPP-EF PET ligand in the setting of bipolar disorder, several key limitations must be noted. Namely, in addition to the limited statistical power inherent to a case study, no sex-matched controls were available for comparison. While matching for age is vital when assessing mitochondrial function, matching for biological sex may prove to be particularly important as well as more data emerges. Third, binge drinking behavior was comorbid with bipolar disorder in this case study, making it difficult to discern to what extent observed mitochondrial deficits may be associated with underlying bipolar disorder pathophysiology vs. consumption of alcohol (a known mitochondrial toxin). Finally, given the participant\u0026rsquo;s mental status at the time of examination and preference to quickly return to work following the standard assessment, collecting a more comprehensive psychiatric history was not feasible.\u003c/p\u003e \u003cp\u003eEven with these limitations in mind, this case study provides exciting preliminary results due to the mounting evidence implicating mitochondria in the pathogenesis of bipolar disorder. This has been established utilizing several techniques, including assessments pertaining to mtDNA copy number, SNPs, ETC complex activity in peripheral cells, postmortem analyses of ETC function, and iPSC-derived biomarkers, among others. Despite this compelling evidence, at the time of this publication no studies have utilized PET imaging to assess mitochondrial function in the setting of BD. This renders the 18F-BCPP-EF mitochondrial complex I PET ligand an exciting new tool to further characterize the role of mitochondrial dysfunction in BD. This case study opens the door for future lines of research to build on these preliminary results. Our imaging findings demonstrated significant overlap between areas of dysfunction identified with the 18F-BCPP-EF PET ligand and areas of dysfunction previously identified in the setting of BD with fMRI techniques. That overlap was seen in both affective and cognitive circuits, with mitochondrial dysfunction in the fronto-limbic, ventral affective, and dorsal cognitive circuits showing particularly significant differences. This was true even when comparing imaging with the much older healthy control, whom one would expect to have a greater degree of impairment as a function of aging. The compelling overlap between prior imaging outcomes and our findings in this case study warrant further investigation via an expanded study featuring an increased number of participants and measures aimed at controlling for confounding variables. Expanded research in this domain has the potential to better characterize the role of mitochondrial function in the pathogenesis of BD, with the ultimate goal of identifying clinically useful biomarkers and improved therapeutic targets to benefit patients suffering from BD.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBD=Bipolar Disorder; ETC=Electron Transport Chain; mtDNA=Mitochondrial DNA; SNP=Single Nucleotide Polymorphism; iPSC=Induced Pluripotent Stem Cell; ATP=Adenosine TriPhosphate; PET=Positron Emission Tomography; AUD=Alcohol Use Disorder; COPD=Chronic Obstructive Pulmonary Disease; BDI=Beck Depression Inventory; CT=Computed Tomography; MRI=Magnetic Resonance Imaging; ANT=Advanced Normalization Tools; SUVR=Standardized Uptake Value Ratio; Amy=Amygdala; vlPFC=Ventrolateral Pre Frontal Cortex; OFC=Orbitofrontal Cortex; dm PFC=Dorsomedial Prefrontal Cortex; dCaud=Dorsal Caudate; Thal=Thalamus; DMN=Default Mode Network; CEN=Central Executive Network; SN=Salience Network; SMN=SensoriMotor Network; mPFC=Medial Prefrontal Cortex; ACC=Anterior Cingulate Cortex\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participant\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe trial from which this data was acquired received ethics approval from the University of Michigan IRBMED board. The participant consented prior to their involvement in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConsent for publication was acquired from the participant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFunding was provided by the Eisenberg Depression Center Impact Accelerator Grant.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Travis Wigstrom ([email protected]) analyzed the data and wrote the manuscript.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Stiven Roytman ([email protected]) processed the images and the resulting data.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Jeffery Bohnen ([email protected]) helped write the manuscript and provided intellectual support.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Rebecca Paalanen ([email protected]) assisted with interviewing the patient and coordinating imaging.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Alexis Griggs ([email protected]) assisted with interviewing the patient and coordinating imaging.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Robert Vangel ([email protected]) assisted with interviewing the patient and coordinating imaging.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Jaimie Barr ([email protected]) assisted with interviewing the patient and coordinating imaging.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Roger Albin ([email protected]) organized the original clinical trial and provided intellectual contributions.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Prabesh Kanel ([email protected]) provided intellectual contributions to the paper.\u003c/p\u003e\n\u003cp\u003eCorresponding Author: Nicolaas Bohnen ([email protected]) NB organized the clinical trial which the data is from and provided intellectual contributions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVieta, E.; Berk, M.; Birmaher, B.; Grande, I. 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DOI: 10.1093/schbul/sbaa004.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Mitochondria, Bipolar Disorder, PET Imaging, Fronto-Limbic Circuit, Ventral Affective Circuit, Dorsal Cognitive Circuit, Default Mode Network, Central Executive Network, Salience Network, Sensorimotor Network","lastPublishedDoi":"10.21203/rs.3.rs-4165029/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4165029/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith Bipolar Disorder (BD) having a lifetime prevalence of 4.4% and a significant portion of patients being chronically burdened by symptoms, there has been an increased focus on uncovering new targets for intervention in BD. One area that has shown early promise is the mitochondrial hypothesis, with supporting evidence in the form of mtDNA copy number, SNPs, ETC complex activity in peripheral cells, postmortem analyses of ETC function, and iPSC-derived biomarkers, among others. Despite this compelling evidence, at the time of this publication no studies have utilized PET imaging to assess mitochondrial function in the setting of BD.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur participant is a 58 year old male with a past medical history notable for alcohol use disorder and bipolar disorder (unspecified type) who, while enrolled as a control for a separate trial, underwent PET imaging with the mitochondrial complex 1 PET ligand \u003csup\u003e18\u003c/sup\u003eF-BCPP-EF. Those images were compared to normal controls which demonstrated significant overlap between areas of dysfunction identified with the 18F-BCPP-EF PET ligand and areas of dysfunction previously identified in the setting of BD with fMRI techniques. That overlap was seen in both affective and cognitive circuits, with mitochondrial dysfunction in the fronto-limbic, ventral affective, and dorsal cognitive circuits showing particularly significant differences.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDespite mounting evidence implicating mitochondria in BD, this study represents the first PET imaging study to investigate this mechanistic connection. There were key limitations in the form of comorbid alcohol use disorder, limited statistical power inherent to a case study, no sex matched controls, and the absence of a comprehensive psychiatric history. However, even with these limitations in mind, the significant overlap between areas of dysfunction previously demonstrated on fMRI and this 18F-BCPP-EF PET ligand imaging provides compelling preliminary evidence that strengthens the mechanistic link between mitochondrial dysfunction and Bipolar Disorder and warrants further investigation.\u003c/p\u003e","manuscriptTitle":"Mitochondrial impairment demonstrated via 18F-BCPP-EF mitochondrial complex I PET ligand in case study of individual with bipolar disorder and alcohol use disorder","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-01 16:12:48","doi":"10.21203/rs.3.rs-4165029/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"50ea5209-6a5a-4ea9-a513-72f920fca756","owner":[],"postedDate":"April 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-30T15:08:50+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-01 16:12:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4165029","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4165029","identity":"rs-4165029","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}