Examining Alterations in Brain Structure, Function, and Neurotransmitter Activity Among Those with Bipolar Disorder

Abstract

Bipolar disorder (BD) is a mental health disorder characterized by alternating manic and depressive episodes that significantly impact cognitive function, emotion regulation, and quality of life. Extensive research,  inclusive of contrasting findings in part due to methodological limitations and to the inclusion of pharmacotherapy, add to the complexity of understanding the neurobiological underpinnings of BD. This narrative review examines the current literature on the neurobiological alterations in BD in adults, with a focus on brain structure, functional connectivity, and neurotransmitter activity. Structural neuroimaging studies reveal volumetric reductions and alterations in cortical thickness and surface area among key brain regions that may underlie symptoms of both depressive and mania episodes. Functional connectivity studies highlight disruptions within and between neural networks that underlie mood instability and impaired cognitive control observed among those with BD. Furthermore, neurotransmitter dysregulation across multiple neurotransmitter systems may contribute to the fluctuating mood states observed among those with BD. Future research, specifically longitudinal studies and studies replicating brain structure related findings, may deepen our understanding of the neural basis of BD and optimize the development of targeted pharmacotherapy treatments that address both mood states more efficaciously.

Keywords: Bipolar disorder, brain structure, volume, neural networks, functional connectivity, neurotransmitters

Abbreviations:

BD = bipolar disorder
PFC = prefrontal cortex
ACC = anterior cingulate cortex
PCC = posterior cingulate cortex
DMN = default mode network
CEN = central executive network
SN = salience network

Introduction

Bipolar disorder (BD) is a mental health disorder characterized by substantial changes in mood ((American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders. Diagnostic and Statistical Manual of Mental Disorders, 5(5).)). As defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and International Classification of Diseases (ICD-11), BD includes phases of manic episodes, depressive episodes, or “mixed” episodes with symptoms of both manic and depressive episodes ((American Psychiatric Association. ).))^, ((ICD-11 for Mortality and Morbidity Statistics. (2025). Who.int.)). Manic episodes may involve elation, irritability, sleeplessness while depressive episodes induce melancholy, lack of interest in activities, and restlessness ((American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders. Diagnostic and Statistical Manual of Mental Disorders, 5(5).)). Manic and depressive episodes often occur for periods of one to two weeks, or possibly longer with interweaving states of euthymia ((American Psychiatric Association. (2013). Diagnostic and Statistical Manual of Mental Disorders. Diagnostic and Statistical Manual of Mental Disorders, 5(5).)). Subtypes of BD include type I (BD-I), consisting of at least one full manic episode present for at least 1 week that may precede or be followed by depressive episodes, and type II (BD-II), which includes at least one major depressive episode and one hypomanic episode for at least 4 consecutive days. Both types of BD may greatly influence patients’ quality of life including diminished ability to carry out daily tasks and affect social relationships with others ((Yara Massalha, Maggioni, E., Callari, A., Brambilla, P., & Delvecchio, G. (2023). A review of resting-state fMRI correlations with executive functions and social cognition in bipolar disorder. Journal of Affective Disorders, 334, 337–351.)).

The impact of BD goes beyond the patient level, leading to substantial societal burdens. BD affects approximately 0.49% of the global population, with prevalence slightly higher in females compared to males ((GBD 2019 Mental Disorders Collaborators. (2022). Global, regional, and national burden of 12 mental disorders in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. The Lancet Psychiatry, 9(2), 137–150.)). In 2017, the global disability-adjusted life years (DALYs) for BD totaled 9.29 million, also higher for females than for males ((He, H., Hu, C., Ren, Z., Bai, L., Gao, F., & Lyu, J. (2020). Trends in the incidence and DALYs of bipolar disorder at global, regional, and national levels: Results from the global burden of Disease Study 2017. Journal of Psychiatric Research, 125, 96–105.)). BD is associated with high costs, inclusive of pharmacotherapy and additional societal level costs such as increased rates of unemployment, with an estimated total annual cost of £342 million for the National Health Service (NHS) in the UK alone ((Young, A. H., Rigney, U., Shaw, S., Emmas, C., & Thompson, J. M. (2011). Annual cost of managing bipolar disorder to the UK healthcare system. Journal of Affective Disorders, 133(3), 450–456.)). BD is the 17th leading cause of global burden of disease, according to results from the 2013 Global Burden of Disease ((Vos, T., Barber, R. M., Bell, B., Bertozzi-Villa, A., Biryukov, S., Bolliger, I., Charlson, F., Davis, A., Degenhardt, L., Dicker, D., Duan, L., Erskine, H., Feigin, V. L., Ferrari, A. J., Fitzmaurice, C., Fleming, T., Graetz, N., Guinovart, C., Haagsma, J., & Hansen, G. M. (2015). Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet, 386(9995), 743–800.)). Thus, the presence of multiple mood states renders BD a complex disorder with vast implications at the individual- and societal-level.

A multitude of factors may contribute to BD. Heritability rates are high among first-degree relatives of people with BD ((James, F., & McMahon, F. J. (2020). The genetics of bipolar disorder. Molecular Psychiatry, 25(3), 544–559.)). Neurobiological studies, using neuroimaging techniques to explore brain structure and function, show varying degrees of brain atrophy, altered brain development and connectivity, and impaired neuroplasticity among those with BD ((Ekaterina Sigitova, Zdeněk Fišar, Hroudová, J., Tereza Cikánková, & Jiří Raboch. (2016). Biological hypotheses and biomarkers of bipolar disorder. Psychiatry and Clinical Neurosciences, 71(2), 77–103.)). Alterations in neurotransmitter transmitters, specifically dopamine, GABA, and noradrenaline, among those with BD may further contribute to changes in mood ((Lee, J. G., Woo, Y. S., Park, S. W., Dae-Hyun Seog, Seo, M. K., & Bahk, W.-M. (2022). Neuromolecular Etiology of Bipolar Disorder: Possible Therapeutic Targets of Mood Stabilizers. Clinical Psychopharmacology and Neuroscience, 20(2), 228–239.)). The culmination of brain structure, function, and neurotransmitter-level factors across mood states from “opposite ends” of the spectrum render BD a unique disorder with a possibly overlapping and distinct neural origins.

Despite efforts examining neurobiological factors that contribute to BD, research is still limited and contains mixed findings ((Ekaterina Sigitova, Zdeněk Fišar, Hroudová, J., Tereza Cikánková, & Jiří Raboch. (2016). Biological hypotheses and biomarkers of bipolar disorder. Psychiatry and Clinical Neurosciences, 71(2), 77–103.)). BD among adolescents still face debates regarding misdiagnosis, possibly related to the added complexity of brain development still occurring throughout adolescence ((‌Malhi, G. S., Maedeh Jadidi, & Bell, E. The diagnosis of bipolar disorder in children and adolescents: Past, present and future. Bipolar Disorders, 25(6), 469–477.)). Establishing a clear understanding of neural alterations among adults with BD may shed light on initial neural markers of the disorder among adolescents and foster the development of more effective pharmacological treatments. Therefore, the aim of this narrative review is to summarize the existent literature that examines alterations in brain structure, function, and neurotransmitter activity, among adults with BD.

Methods

The present narrative review identified peer-reviewed articles from PubMed and Google Scholar to reflect updates on this topic from primarily the last 5 – 10 years, however a few older articles were included if they provided formative information. Results included herein include a variety of article types including randomized clinical trials and review articles.

Brain structure

Grey Matter

Volume

The most common metric of brain structure that has shown alterations in multiple brain regions among those with BD is grey matter volume. Below is a brief summary of alterations in key brain regions and how they related to symptoms observed among those with BD.

The hippocampus contributes to numerous cognitive functions and emotion regulation. Disruptions in the hippocampus may underlie depressive symptoms seen in BD ((Arnone, D., McKie, S., Elliott, R., Juhasz, G., Thomas, E. J., Downey, D., Williams, S., Deakin, J. F. W., & Anderson, I. M. (2012). State-dependent changes in hippocampal grey matter in depression. Molecular Psychiatry, 18(12), 1265–1272.)). Compared to healthy controls, BD patients have lower volumes ((Haukvik, U. K., Gurholt, T. P., Nerland, S., Torbjørn Elvsåshagen, Akudjedu, T. N., Alda, M., Dag Alnæs, Alonso‐Lana, S., Bauer, J., Baune, B. T., Benedetti, F., Berk, M., Bettella, F., Erlend Bøen, Bonnín, C. M., Brambilla, P., Canales‐Rodríguez, E. J., Cannon, D. M., Caseras, X., & Orwa Dandash. (2020). In vivo hippocampal subfield volumes in bipolar disorder—A mega‐analysis from The Enhancing Neuro Imaging Genetics through Meta‐Analysis Bipolar Disorder Working Group. Human Brain Mapping, 43(1), 385–398.))^, ((Han, K.-M., Kim, A., Kang, W., Kang, Y., Kang, J., Won, E., Tae, W.-S., & Ham, B.-J. (2019). Hippocampal subfield volumes in major depressive disorder and bipolar disorder. European Psychiatry, 57, 70–77.))^, ((Cao, B., Passos, I. C., Mwangi, B., H Amaral-Silva, Tannous, J., Wu, M-J., Zunta-Soares, G. B., & Soares, J. C. (2017). Hippocampal subfield volumes in mood disorders. Molecular Psychiatry, 22(9), 1352–1358.)) but greater variability of volumetric alterations ((Ilinca Angelescu, Brugger, S. P., Borgan, F., Kaar, S. J., & Howes, O. D. (2021). The magnitude and variability of brain structural alterations in bipolar disorder: A double meta-analysis of 5534 patients and 6651 healthy controls. Journal of Affective Disorders, 291, 171–176.)) in the hippocampi. This may be due to heterogeneity in the pathophysiology underlying BD and potential sex-related differences ((Buoli, Cesana, B. M., Dell’Osso, B., Fagiolini, A., Bartolomeis, A. de, Bondi, E., Maina, G., Bellomo, A., & Altamura, A. C. (2019). Gender-related differences in patients with bipolar disorder: a nationwide study. CNS Spectrums, 24(6), 589–596.)). Males may exhibit fewer reductions in grey matter volume, which may be associated with clinical presentation as males exhibit fewer depressive episodes compared to female ((Ilinca Angelescu, Brugger, S. P., Borgan, F., Kaar, S. J., & Howes, O. D. (2021). The magnitude and variability of brain structural alterations in bipolar disorder: A double meta-analysis of 5534 patients and 6651 healthy controls. Journal of Affective Disorders, 291, 171–176.)). Mixed findings may also be due to BD subtype or medication ((Ilinca Angelescu, Brugger, S.  (2021 of Affective Disorders, 291, 171–176.)). Lithium treatment may counteract the decrease in hippocampal grey matter volumes by increasing grey matter volume ((Lyoo, I. K., Dager, S. R., Kim, J. E., Yoon, S. J., Friedman, S. D., Dunner, D. L., & Renshaw, P. F. (2010). Lithium-Induced Gray Matter Volume Increase As a Neural Correlate of Treatment Response in Bipolar Disorder: A Longitudinal Brain Imaging Study. Neuropsychopharmacology, 35(8), 1743–1750.)). Reductions in gray matter volume may play an important role, most notably for sex-related differences in depressive symptoms among those with BD.

The amygdala is critical to processing emotions related arousal and affect ((Pessoa, L., & Adolphs, R. (2010). Emotion processing and the amygdala: from a “low road” to “many roads” of evaluating biological significance. Nature Reviews. Neuroscience, 11(11), 773–782.)) and has numerous connections with the prefrontal cortex (PFC) involved in executive functioning. Environmental stressors may alter the nuclei within the amygdala leading to mood dysregulation in BD patients ((Pfeifer, J. C., Welge, J., Strakowski, S. M., Adler, C., & Delbello, M. P. (2008). Meta-Analysis of Amygdala Volumes in Children and Adolescents With Bipolar Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 47(11), 1289–1298.)). Age-related differences in the amygdala may impact BD among younger populations. Children and adolescents with BD have smaller left amygdala volumes ((Pfeifer, J. C., Welge, J., Strakowski, S. M., Adler, C., & Delbello, M. P. (2008). Meta-Analysis of Amygdala Volumes in Children and Adolescents With Bipolar Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 47(11), 1289–1298.))^, ((Hajek, T., Miloslav Kopecek, Kozeny, J., Gunde, E., Alda, M., & Höschl, C. (2008). Amygdala volumes in mood disorders — Meta-analysis of magnetic resonance volumetry studies. Journal of Affective Disorders, 115(3), 395–410.)), however, adults with BD generally do not exhibit significant differences in amygdala volume compared to controls ((Ilinca Angelescu, Brugger, S. P., Borgan, F., Kaar, S. J., & Howes, O. D. (2021). The magnitude and variability of brain structural alterations in bipolar disorder: A double meta-analysis of 5534 patients and 6651 healthy controls. Journal of Affective Disorders, 291, 171–176.)). Of note, some studies have shown a trend towards increased amygdala volume in adult patients ((Hajek, T., Miloslav Kopecek, Kozeny, J., Gunde, E., Alda, M., & Höschl, C. (2008). Amygdala volumes in mood disorders — Meta-analysis of magnetic resonance volumetry studies. Journal of Affective Disorders, 115(3), 395–410.))^, ((Chen, B. K., Sassi, R., Axelson, D., Hatch, J. P., Sanches, M., Nicoletti, M., Brambilla, P., Keshavan, M. S., Ryan, N. D., Birmaher, B., & Soares, J. C. (2004). Cross-sectional study of abnormal amygdala development in adolescents and young adults with bipolar disorder. Biological Psychiatry, 56(6), 399–405.)). Amygdala volumes may increase in adults with BD as a compensatory reaction to having a smaller amygdala volume during youth ((Pfeifer, J. C., Welge, J., Strakowski, S. M., Adler, C., & Delbello, M. P. (2008). Meta-Analysis of Amygdala Volumes in Children and Adolescents With Bipolar Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 47(11), 1289–1298.)). Medication may again play an important role, as lithium or valproate can increase amygdala grey matter ((Chang, K., Asya Karchemskiy, Naama Barnea-Goraly, Garrett, A., Simeonova, D. I., & Reiss, A. (2005). Reduced Amygdalar Gray Matter Volume in Familial Pediatric Bipolar Disorder. Journal of the American Academy of Child & Adolescent Psychiatry, 44(6), 565–573.)). Amygdala volume alterations in BD are dynamic across the lifespan, potentially influenced by early structural differences, compensatory mechanisms, and the effects of medication.

The anterior cingulate cortex (ACC) integrates cognitive, emotional, and autonomic functions ((Shackman, A. J., Salomons, T. V., Slagter, H. A., Fox, A. S., Winter, J. J., & Davidson, R. J. (2011). The integration of negative affect, pain and cognitive control in the cingulate cortex. Nature Reviews. Neuroscience, 12(3), 154–167.)). The PFC is also responsible for similar processes, therefore alterations in the PFC may be linked to emotional processing deficits and cognitive impairments seen in BD patients ((McKenna, B. S., & Eyler, L. T. (2012). Overlapping prefrontal systems involved in cognitive and emotional processing in euthymic bipolar disorder and following sleep deprivation: A review of functional neuroimaging studies. Clinical Psychology Review, 32(7), 650–663.)). Multiple studies have reported decreased grey matter volumes of the left ACC ((Sassi, R. B., Brambilla, P., Hatch, J. P., Nicoletti, M. A., Mallinger, A. G., Frank, E., Kupfer, D. J., Keshavan, M. S., & Soares, J. C. (2004). Reduced left anterior cingulate volumes in untreated bipolar patients. Biological Psychiatry, 56(7), 467–475.)), middle and superior left PFC, and middle and inferior right PFC ((López-Larson, M. P., DelBello, M. P., Zimmerman, M. E., Schwiers, M. L., & Strakowski, S. M. (2002). Regional prefrontal gray and white matter abnormalities in bipolar disorder. Biological Psychiatry, 52(2), 93–100.)) in individuals with BD compared to healthy controls. The reductions are particularly noted in pharmacologically untreated patients ((Sassi, R. B., Brambilla, P., Hatch, J. P., Nicoletti, M. A., Mallinger, A. G., Frank, E., Kupfer, D. J., Keshavan, M. S., & Soares, J. C. (2004). Reduced left anterior cingulate volumes in untreated bipolar patients. Biological Psychiatry, 56(7), 467–475.)), and neuroimaging evidence shows that lithium treatment may counteract this change by increasing overall grey matter volumes.

The lateral ventricles, third ventricles, and thalamus have also shown altered grey matter volume in individuals with BD. The thalamus plays a key role in cognitive processing. While increased ventricular volume is generally correlated with aging ((Luciano, Rejane, P., Vinícius, M., Porciúncula, G., & Valença, M. M. (2022). Brain ventricles, CSF and cognition: a narrative review. Psychogeriatrics, 22(4), 544–552.)), patients with BD tend to have enlarged ventricular and reduced thalamic volume ((Hibar, D. P., Westlye, L. T., Erp, van, Rasmussen, J., Leonardo, C. D., J Faskowitz, Haukvik, U. K., Hartberg, C. B., Doan, N. T., I Agartz, Dale, A. M., Gruber, O., B Krämer, Trost, S., B Liberg, C Abé, Ekman, C. J., M Ingvar, M Landén, & Fears, S. C. (2016). Subcortical volumetric abnormalities in bipolar disorder. Molecular Psychiatry, 21(12), 1710–1716.)).Variability in the lateral ventricles, third ventricles, and thalamus are similar to alterations that have been observed among those with schizophrenia ((Ilinca Angelescu, Brugger, S. P., Borgan, F., Kaar, S. J., & Howes, O. D. (2021). The magnitude and variability of brain structural alterations in bipolar disorder: A double meta-analysis of 5534 patients and 6651 healthy controls. Journal of Affective Disorders, 291, 171–176.))^, ((Brugger, S. P., & Howes, O. D. (2017). Heterogeneity and Homogeneity of Regional Brain Structure in Schizophrenia. JAMA Psychiatry, 74(11), 1104.)). Underlying structural heterogeneity in these regions could be a shared feature across both BD and schizophrenia, which may explain cognitive impairments observed in both conditions.

BD may have a neurodegenerative component. Longitudinal studies have found significant differences in progressive grey matter alterations in BD patients compared to healthy controls ((Niccolò Zovetti, Rossetti, M. G., Cinzia Perlini, Brambilla, P., & Bellani, M. (2023). Brain ageing and neurodegeneration in bipolar disorder. Journal of Affective Disorders, 323, 171–175.)). While mixed findings do exist, studies have shown that repeated mood episodes correlate with increase cortical thinning and grey matter reduction from younger (18 years) to older adults (50-60 years) ((Chen, P.-H., Hsu, J.-L., Chung, K.-H., Huang, S.-H., Huang, Y.-J., & Tsai, S.-Y. (2021). Higher body mass index associated with smaller frontal cortical volumes in older adult patients with bipolar disorder. The European Journal of Psychiatry, 35(3), 157–165.))^, ((Beyer, J. L., Maragatha Kuchibhatla, Payne, M. E., MacFall, J., Cassidy, F., & Krishnan, R. (2009). Gray and white matter brain volumes in older adults with bipolar disorder. International Journal of Geriatric Psychiatry, 24(12), 1445–1452.))^, ((Doty, T. J., Payne, M. E., Steffens, D. C., Beyer, J. L., Krishnan, K. R. R., & LaBar, K. S. (2008). Age-dependent reduction of amygdala volume in bipolar disorder. Psychiatry Research: Neuroimaging, 163(1), 84–94.)). The consensus is that recurrent mood episodes contribute to grey matter loss, particularly in the amygdala, ACC, superior frontal and medial orbitofrontal regions ((Niccolò Zovetti, Rossetti, M. G., Cinzia Perlini, Brambilla, P., & Bellani, M. (2023). Brain ageing and neurodegeneration in bipolar disorder. Journal of Affective Disorders, 323, 171–175.))^, ((Chen, P.-H., Hsu, J.-L., Chung, K.-H., Huang, S.-H., Huang, Y.-J., & Tsai, S.-Y. (2021). Higher body mass index associated with smaller frontal cortical volumes in older adult patients with bipolar disorder. The European Journal of Psychiatry, 35(3), 157–165.))^, ((Beyer, J. L., Maragatha Kuchibhatla, Payne, M. E., MacFall, J., Cassidy, F., & Krishnan, R. (2009). Gray and white matter brain volumes in older adults with bipolar disorder. International Journal of Geriatric Psychiatry, 24(12), 1445–1452.))^, ((Doty, T. J., Payne, M. E., Steffens, D. C., Beyer, J. L., Krishnan, K. R. R., & LaBar, K. S. (2008). Age-dependent reduction of amygdala volume in bipolar disorder. Psychiatry Research: Neuroimaging, 163(1), 84–94.)). Those with BD also have a larger brain age gap, the difference between an individual’s chronological age and predicted age from brain imaging data, reflect the presence of neurodegenerative processes accelerating brain ageing. To moderate these aspects, neuroprotective treatments such as lithium may be helpful  by increasing overall grey matter volume ((Sun, Y. R., Herrmann, N., Scott, C. J. M., Black, S. E., Khan, M. M., & Lanctôt, K. L. (2017). Global grey matter volume in adult bipolar patients with and without lithium treatment: A meta-analysis. Journal of Affective Disorders, 225, 599–606.)).

Cortical Thickness and Surface Area

BD is associated with widespread cortical thinning, particularly in regions critical for emotional regulation and executive function. Cortical thinning has been observed in the left insula, bilateral ACC, left inferior frontal gyrus, and the medial part of the left superior frontal gyrus ((Zhu, Z., Zhao, Y., Wen, K., Li, Q., Pan, N., Fu, S., Li, F., Joaquim Radua, Vieta, E., Kemp, G. J., Biswa, B. B., & Gong, Q. (2021). Cortical thickness abnormalities in patients with bipolar disorder: A systematic review and meta-analysis. Journal of Affective Disorders, 300, 209–218.)). Unaffected first-degree relatives have also shown cortical thinning in in the ACC, orbitofrontal cortex, dorsolateral PFC, and superior temporal cortex adding support for the hypothesis that abnormalities in these regions may represent trait markers of the disorder ((Nefize Yalin, Aybala Saricicek, Ceren Hidiroglu, Zugman, A., Nese Direk, Ada, E., Berrin Cavusoglu, Er, A., Isik, G., Ceylan,Zeliha Tunca, Kempton, M. J., & Aysegul Ozerdem. (2019). Cortical thickness and surface area as an endophenotype in bipolar disorder type I patients and their first-degree relatives. NeuroImage Clinical, 22, 101695–101695.)). Structural changes in these regions likely contribute to disruptions in affective regulation and self-referential processing, all of which are hallmark cognitive and emotional deficits in BD ((Zhu, Z., Zhao, Y., Wen, K., Li, Q., Pan, N., Fu, S., Li, F., Joaquim Radua, Vieta, E., Kemp, G. J., Biswa, B. B., & Gong, Q. (2021). Cortical thickness abnormalities in patients with bipolar disorder: A systematic review and meta-analysis. Journal of Affective Disorders, 300, 209–218.))^, ((Nefize Yalin, Aybala Saricicek, Ceren Hidiroglu, Zugman, A., Nese Direk, Ada, E., Berrin Cavusoglu, Er, A., Isik, G., Ceylan, D., Zeliha Tunca, Kempton, M. J., & Aysegul Ozerdem. (2019). Cortical thickness and surface area as an endophenotype in bipolar disorder type I patients and their first-degree relatives. NeuroImage Clinical, 22, 101695–101695.)). Moreover, age-related analyses revealed that older BD patients exhibit greater cortical thinning in the insula ((Zhu, Z., Zhao, Y., Wen, K., Li, Q., Pan, N., Fu, S., Li, F., Joaquim Radua, Vieta, E., Kemp, G. J., Biswa, B. B., & Gong, Q. (2021). Cortical thickness abnormalities in patients with bipolar disorder: A systematic review and meta-analysis. Journal of Affective Disorders, 300, 209–218.)), suggesting that BD may involve progressive neurostructural deterioration over time.

Compared to cortical thickness, findings on surface area are more heterogeneous potentially due to medication history, age, and inherited surface area differences. Across both BD-I and BD-II, studies have found shared surface area reductions in the medial prefrontal cortex, and more extensive and widespread surface area reductions—including in the superior temporal sulcus and fusiform gyrus— specific to the BD-I subgroup ((Abé, C., Ekman, C.-J., Sellgren, C., Petrovic, P., Ingvar, M., & Landén, M. (2016). Cortical thickness, volume and surface area in patients with bipolar disorder types I and II. Journal of Psychiatry and Neuroscience, 41(4), 240–250.)). Compared to healthy controls, those with BD-I have shown greater surface area of the left pars triangularis, a region implicated in language processing and affective regulation ((Nefize Yalin, Aybala Saricicek, Ceren Hidiroglu, Zugman, A., Nese Direk, Ada, E., Berrin Cavusoglu, Er, A., Isik, G., Ceylan, D., Zeliha Tunca, Kempton, M. J., & Aysegul Ozerdem. (2019). Cortical thickness and surface area as an endophenotype in bipolar disorder type I patients and their first-degree relatives. NeuroImage Clinical, 22, 101695–101695.)). Alterations in cortical thickness and surface area offer complementary perspectives on BD pathophysiology—where cortical thinning indicate progressive and symptomatic burden, and changes in surface area may reflect early neurodevelopmental divergence, compensatory reaction, or differences in BD subtype.

White Matter

White matter is extensively involved in cognitive function, connectivity and plasticity. Abnormalities in white matter volume are one of the most consistently reported findings in neuroimaging studies of BD ((Poletti, S., Bollettini, I., Mazza, E., Locatelli, C., Radaelli, D., Vai, B., Smeraldi, E., Colombo, C., & Benedetti, F. (2015). Cognitive performances associate with measures of white matter integrity in bipolar disorder. Journal of Affective Disorders, 174, 342–352.)). Many studies show regionally specific white matter volumetric abnormalities in BD that do not progress with illness duration ((Niccolò Zovetti, Rossetti, M. G., Cinzia Perlini, Brambilla, P., & Bellani, M. (2023). Brain ageing and neurodegeneration in bipolar disorder. Journal of Affective Disorders, 323, 171–175.)). Alterations in white matter volume have been primarily observed in the corpus callosum, crucial for interhemispheric communication and cognitive functioning ((Poletti, S., Bollettini, I., Mazza, E., Locatelli, C., Radaelli, D., Vai, B., Smeraldi, E., Colombo, C., & Benedetti, F. (2015). Cognitive performances associate with measures of white matter integrity in bipolar disorder. Journal of Affective Disorders, 174, 342–352.)), and the cingulate gyrus, serving an essential role in emotion regulation and decision making ((Matsuo, K., Nicoletti, M. A., Peluso, M. A. M., Hatch, J. P., Nemoto, K., Watanabe, Y., Nery, F. G., Monkul, E. S., Zunta-Soares, G. B., Bowden, C. L., & Soares, J. C. (2009). Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder. Bipolar Disorders, 11(6), 628–636.)). Meta-analyses have shown decreased white matter volume in the corpus callosum and white matter adjacent to the cingulate gyrus ((Pezzoli, S., Emsell, L., Yip, S. W., Dima, D., Giannakopoulos, P., Zarei, M., Tognin, S., Arnone, D., James, A., Haller, S., Frangou, S., Goodwin, G. M., McDonald, C., & Kempton, M. J. (2018). Meta-analysis of regional white matter volume in bipolar disorder with replication in an independent sample using coordinates, T-maps, and individual MRI data. Neuroscience & Biobehavioral Reviews, 84, 162–170.))^, ((Favre, P., Pauling, M., Stout, J., Franz Hozer, Sarrazin, S., Christoph Abé, Alda, M., Alloza, C., Alonso-Lana, S., Andreassen, O. A., Baune, B. T., Benedetti, F., Busatto, G. F., Canales-Rodríguez, E. J., Caseras, X., Chaim-Avancini, T. M., Christopher, Udo Dannlowski, Deppe, M., & Eyler, L. T. (2019). Widespread white matter microstructural abnormalities in bipolar disorder: evidence from mega- and meta-analyses across 3033 individuals. Neuropsychopharmacology, 44(13), 2285–2293.)). Disruptions in interhemispheric communication may lead to impairments with emotional regulation, a hallmark symptom of BD. Impaired connectivity in the corpus callosum could lead to difficulties in coordinating cognitive and emotional processes ((Wang, F., Kalmar, J. H., Edmiston, E. K., Chepenik, L. G., Zubin Bhagwagar, Spencer, L., Pittman, B., Jackowski, M., Xenophon Papademetris, Constable, R. T., & Blumberg, H. P. (2008). Abnormal Corpus Callosum Integrity in Bipolar Disorder: A Diffusion Tensor Imaging Study. Biological Psychiatry, 64(8), 730–733.)), while abnormalities in the cingulate gyrus may result in mood instability, impulsivity ((Matsuo, K., Nicoletti, M. A., Peluso, M. A. M., Hatch, J. P., Nemoto, K., Watanabe, Y., Nery, F. G., Monkul, E. S., Zunta-Soares, G. B., Bowden, C. L., & Soares, J. C. (2009). Anterior cingulate volumes associated with trait impulsivity in individuals with bipolar disorder. Bipolar Disorders, 11(6), 628–636.)), and impaired emotional processing. While the extant literature on white matter in BD is relatively consistent, it is limited in magnitude and given the importance of white matter functioning on cognitive and emotional processing, more research is needed to further replicate the existing findings.

Brain Function

The default mode network (DMN)  is a major neuronal network consisting of the ventromedial PFC, dorsomedial PFC, posterior cingulate cortex (PCC), precuneus, and inferior parietal lobule, which deactivates during goal-directed tasks ((Greicius, M. D., Krasnow, B., Reiss, A. L., & Menon, V. (2002). Functional connectivity in the resting brain: A network analysis of the default mode hypothesis. Proceedings of the National Academy of Sciences, 100(1), 253–258.))^, ((Raichle, M. E. (2015). The Brain’s Default Mode Network. Annual Review of Neuroscience, 38(1), 433–447.)). The DMN is typically active during rest and involved in self-referential thinking ((Davey, C. G., Pujol, J., & Harrison, B. J. (2016). Mapping the self in the brain’s default mode network. NeuroImage, 132, 390–397.)). The salience network (SN) is a large paralimbic-limbic functional network anchored to the anterior insula and dorsal ACC, as well as the anterior PFC, the supramarginal gyrus, the striatum, and the thalamus; it is involved in detecting, processing, and integrating internal and external salient information ((Uddin, L. Q., Supekar, K. S., Srikanth Ryali, & Menon, V. (2011). Dynamic Reconfiguration of Structural and Functional Connectivity Across Core Neurocognitive Brain Networks with Development. Journal of Neuroscience, 31(50), 18578–18589.)). The SN evaluates the importance of internal or external stimuli and assists the coordination of the brain’s response to those stimuli ((Uddin, L. Q. (2014). Salience processing and insular cortical function and dysfunction. Nature Reviews. Neuroscience, 16(1), 55–61.)). The central executive network (CEN) is responsible for executing various executive functions, such as planning, decision-making, and problem-solving. The following paragraphs will discuss alterations in these neural networks among those with BD.

Resting-state Functional Connectivity

Resting-state functional connectivity studies examine the brain’s intrinsic activity during rest. These studies have shown abnormal connectivity within the DMN, and between the DMN and SN in early-onset BD ((Cattarinussi, Bellani, M., Maggioni, E., Sambataro, F., Brambilla, P., & Delvecchio, G. (2022). Resting-state functional connectivity and spontaneous brain activity in early-onset bipolar disorder: A review of functional Magnetic Resonance Imaging studies. Journal of Affective Disorders, 311, 463–471.)). Increased functional connectivity at rest between the insula of the SN and medial PFC of the DMN ((Chai, X. J., Whitfield-Gabrieli, S., Shinn, A. K., Gabrieli, J. D. E., Castañón, A. N., McCarthy, J. M., Cohen, B. M., & Dost Öngür. (2011). Abnormal Medial Prefrontal Cortex Resting-State Connectivity in Bipolar Disorder and Schizophrenia. Neuropsychopharmacology, 36(10), 2009–2017.)), the ACC of the SN and superior frontal gyrus of the DMN ((Oertel-Knöchel, V., Reinke, B., Matura, S., Prvulovic, D., Linden, D. E. J., & Vincent. (2014). Functional connectivity pattern during rest within the episodic memory network in association with episodic memory performance in bipolar disorder. Psychiatry Research Neuroimaging, 231(2), 141–150.)), the anterior insula cortex of the SN toward the middle frontal gyrus of the DMN ((Li, J., Tang, Y., Womer, F., Fan, G., Zhou, Q., Sun, W., Xu, K., & Wang, F. (2017). Two patterns of anterior insular cortex functional connectivity in bipolar disorder and schizophrenia. The World Journal of Biological Psychiatry, 19(sup3), S115–S123.)), the ventral anterior insula of the SN and precuneus in the DMN ((Chai, X. J., Whitfield-Gabrieli, S., Shinn, A. K., Gabrieli, J. D. E., Castañón, A. N., McCarthy, J. M., Cohen, B. M., & Dost Öngür. (2011). Abnormal Medial Prefrontal Cortex Resting-State Connectivity in Bipolar Disorder and Schizophrenia. Neuropsychopharmacology, 36(10), 2009–2017.)), and the subgenual ACC of the SN and PCC of the DMN ((Rey, G., Piguet, C., Benders, A., Favre, S., Eickhoff, S. B., Aubry, J.-M. ., & Vuilleumier, P. (2016). Resting-state functional connectivity of emotion regulation networks in euthymic and non-euthymic bipolar disorder patients. European Psychiatry, 34, 56–63.)) has been observed among those with BD. Disruptions in connectivity within and between the DMN and SN may contribute to mood instability and manic or depressive symptoms ((Magioncalda, P., Martino, M., Conio, B., Escelsior, A., Piaggio, N., Presta, A., Marozzi, V., Rocchi, G., Anastasio, L., Vassallo, L., Ferri, F., Huang, Z., Roccatagliata, L., Pardini, M., Northoff, G., & Amore, M. (2014). Functional connectivity and neuronal variability of resting state activity in bipolar disorder—reduction and decoupling in anterior cortical midline structures. Human Brain Mapping, 36(2), 666–682.)). Greater connectivity between DMN and SN could lead to excessive focus on thoughts, emotions, and self-referential mental processes with reduced transition from idea to action. Alternatively, it could lead to excessive focus on external contents, for instance stimuli in social interactions, hence increasing expression of ideas as actions ((Cattarinussi, Bellani, M., Maggioni, E., Sambataro, F., Brambilla, P., & Delvecchio, G. (2022). Resting-state functional connectivity and spontaneous brain activity in early-onset bipolar disorder: A review of functional Magnetic Resonance Imaging studies. Journal of Affective Disorders, 311, 463–471.)). There are some mixed findings ((Gong, J., Chen, G., Jia, Y., Zhong, S., Zhao, L., Luo, X., Qiu, S., Lai, S., Qi, Z., Huang, L., & Wang, Y. (2019). Disrupted functional connectivity within the default mode network and salience network in unmedicated bipolar II disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 88, 11–18.)) for intra-network connectivity between the DMN and SN, and this may be due to methodological differences ((Favre, P., Baciu, M., Cédric Pichat, Thierry Bougerol, & Mircea Polosan. (2014). fMRI evidence for abnormal resting-state functional connectivity in euthymic bipolar patients. Journal of Affective Disorders, 165, 182–189.)) or illness duration ((Ellard, K. K., Zimmerman, J. P., Kaur, N., Dijk, V., Roffman, J. L., Nierenberg, A. A., Dougherty, D. D., Thilo Deckersbach, & Camprodon, J. A. (2018). Functional Connectivity Between Anterior Insula and Key Nodes of Frontoparietal Executive Control and Salience Networks Distinguish Bipolar Depression From Unipolar Depression and Healthy Control Subjects. Biological Psychiatry Cognitive Neuroscience and Neuroimaging, 3(5), 473–484.)). Lastly, specific to the DMN, hypo-connectivity within the DMN among those with BD ((Gong, J., Chen, G., Jia, Y., Zhong, S., Zhao, L., Luo, X., Qiu, S., Lai, S., Qi, Z., Huang, L., & Wang, Y. (2019). Disrupted functional connectivity within the default mode network and salience network in unmedicated bipolar II disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 88, 11–18.))^, ((Ellard, K. K., Zimmerman, J. P., Kaur, N., Dijk, V., Roffman, J. L., Nierenberg, A. A., Dougherty, D. D., Thilo Deckersbach, & Camprodon, J. A. (2018). Functional Connectivity Between Anterior Insula and Key Nodes of Frontoparietal Executive Control and Salience Networks Distinguish Bipolar Depression From Unipolar Depression and Healthy Control Subjects. Biological Psychiatry Cognitive Neuroscience and Neuroimaging, 3(5), 473–484.)) has also been observed among those with schizophrenia ((Hu, M.-L., Zong, X.-F., Mann, J. J., Zheng, J.-J., Liao, Y.-H., Li, Z.-C., He, Y., Chen, X.-G., & Tang, J.-S. (2016). A Review of the Functional and Anatomical Default Mode Network in Schizophrenia. Neuroscience Bulletin, 33(1), 73–84.)), suggesting an overlap in the neural aberrations between these disorders that is likely related to manic symptoms observed in BD.

Alterations in cortico-limbic connectivity have also been observed among those with BD, specifically in the occipital and frontal lobes, amygdala, hippocampus, insula, thalamus, and striatum ((Cattarinussi, Bellani, M., Maggioni, E., Sambataro, F., Brambilla, P., & Delvecchio, G. (2022). Resting-state functional connectivity and spontaneous brain activity in early-onset bipolar disorder: A review of functional Magnetic Resonance Imaging studies. Journal of Affective Disorders, 311, 463–471.)). Decreased connectivity between the right orbital frontal cortex and left amygdala, between the left superior frontal gyrus and left putamen, and between the left superior frontal gyrus and left insula in patients compared to controls, and an increase in connectivity between right superior occipital gyrus and right hippocampus was observed ((Guo, Y., Wang, J., Jiao, Q., Cao, W., Cui, D., Gao, W., Qiu, J., Su, L., & Lu, G. (2020). Altered spatiotemporal consistency of corticolimbic circuitry in euthymic pediatric bipolar disorder. Brain Imaging and Behavior, 15(3), 1290–1299.)). One hypothesis is that an imbalance between the activity of these cortical areas functioning in emotional regulation and the activation of the limbic system might cause unstable cognitive control of emotions, typically observed in adults with BD ((Phillips, M. L., Drevets, W. C., Rauch, S. L., & Lane, R. (2003). Neurobiology of emotion perception II: implications for major psychiatric disorders. Biological Psychiatry, 54(5), 515–528.)). Therefore, alterations in the DMN’s connectivity within and with SN, and the connectivity of cortico-limbic structures, may contribute to manic symptoms among those with BD.

Default Mode Network

Intra-network and inter-network changes in the DMN are among the most prevalent alterations noted in BD. Key regions that demonstrated altered resting-state functional connectivity were the medial PFC ((Gong, J., Chen, G., Jia, Y., Zhong, S., Zhao, L., Luo, X., Qiu, S., Lai, S., Qi, Z., Huang, L., & Wang, Y. (2019). Disrupted functional connectivity within the default mode network and salience network in unmedicated bipolar II disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 88, 11–18.))^, ((Chen, G., Zhao, L., Jia, Y., Zhong, S., Chen, F., Luo, X., Qiu, S., Lai, S., Qi, Z., Huang, L., & Wang, Y. (2019). Abnormal cerebellum-DMN regions connectivity in unmedicated bipolar II disorder. Journal of Affective Disorders, 243, 441–447.)), PCC ((Gong, J., Chen, G., Jia, Y., Zhong, S., Zhao, L., Luo, X., Qiu, S., Lai, S., Qi, Z., Huang, L., & Wang, Y. (2019). Disrupted functional connectivity within the default mode network and salience network in unmedicated bipolar II disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 88, 11–18.))^, ((Wang, Y., Zhong, S., Chen, G., Liu, T., Zhao, L., Sun, Y., Jia, Y., & Huang, L. (2017). Altered cerebellar functional connectivity in remitted bipolar disorder: A resting-state functional magnetic resonance imaging study. Australian & New Zealand Journal of Psychiatry, 52(10), 962–971.)), and superior frontal gyrus ((Marchand, W. R., Lee, J. N., Johnson, S., Gale, P., & Thatcher, J. (2014). Abnormal functional connectivity of the medial cortex in euthymic bipolar II disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 51, 28–33.)). The medial PFC was found to have lower global brain connectivity with respect to other regions of the frontal cortex, as well as reduced functional connectivity with other regions of the DMN such as the PCC ((Chai, X. J., Whitfield-Gabrieli, S., Shinn, A. K., Gabrieli, JE., Castañón, A. N., McCarthy, J. M., Cohen, B. M., & Dost Öngür. (2011). Abnormal Medial Prefrontal Cortex Resting-State Connectivity in Bipolar Disorder and Schizophrenia. Neuropsychopharmacology, 36(10), 2009–2017.)). The medial PFC is involved in self-reflection and is associated with cognitive and affective functions such as emotional facial recognition. The superior frontal gyrus, a region that contributes to higher cognitive functions such as working memory, was found to contain hyper-connectivity between select subregions, such as the medial and dorsolateral aspects of the left superior frontal gyrus among those with BD ((Marchand, W. R., Lee, J. N., Johnson, S., Gale, P., & Thatcher, J. (2014). Abnormal functional connectivity of the medial cortex in euthymic bipolar II disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 51, 28–33.)). Lastly, studies using task-based stimuli such as emotion recognition or cognitive tasks showed results in opposite in polarity with respect to at rest, showing increased intra-network functional connectivity in individuals with BD compared to healthy controls in non-resting states ((Townsend, J. D., Torrisi, S. J., Lieberman, M. D., Sugar, C. A., Bookheimer, S. Y., & Altshuler, L. L. (2012). Frontal-Amygdala Connectivity Alterations During Emotion Downregulation in Bipolar I Disorder. Biological Psychiatry, 73(2), 127–135.)). These results showcase the intricate role of the DMN in BD, where altered intra- and inter-network connectivity may contribute to disruptions in self-referential processing, emotional regulation, and cognitive function, influencing mood instability.

Salience Network

Intra-network functional connectivity of the SN has been shown to decrease at rest in those with BD compared to healthy controls ((Gong, J., Chen, G., Jia, Y., Zhong, S., Zhao, L., Luo, X., Qiu, S., Lai, S., Qi, Z., Huang, L., & Wang, Y. (2019). Disrupted functional connectivity within the default mode network and salience network in unmedicated bipolar II disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 88, 11–18.))^, ((Pang, Y., Chen, H., Wang, Y., Long, Z., He, Z., Zhang, H., Liao, W., Cui, Q., & Chen, H. (2018). Transdiagnostic and diagnosis-specific dynamic functional connectivity anchored in the right anterior insula in major depressive disorder and bipolar depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 85, 7–15.)). More specifically, functional connectivity was decreased between the anterior insula and ventrolateral PFC ((Ellard, K. K., Zimmerman, J. P., Kaur, N., Dijk, V., Roffman, J. L., Nierenberg, A. A., Dougherty, D. D., Thilo Deckersbach, & Camprodon, J. A. (2018). Functional Connectivity Between Anterior Insula and Key Nodes of Frontoparietal Executive Control and Salience Networks Distinguish Bipolar Depression From Unipolar Depression and Healthy Control Subjects. Biological Psychiatry Cognitive Neuroscience and Neuroimaging, 3(5), 473–484.))^, ((Pang, Y., Chen, H., Wang, Y., Long, Z., He, Z., Zhang, H., Liao, W., Cui, Q., & Chen, H. (2018). Transdiagnostic and diagnosis-specific dynamic functional connectivity anchored in the right anterior insula in major depressive disorder and bipolar depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 85, 7–15.)), between the subgenual ACC and inferior temporal gyrus ((Chai, X. J., Whitfield-Gabrieli, S., Shinn, A. K., Gabrieli, J. D. E., Castañón, A. N., McCarthy, J. M., Cohen, B. M., & Dost Öngür. (2011). Abnormal Medial Prefrontal Cortex Resting-State Connectivity in Bipolar Disorder and Schizophrenia. Neuropsychopharmacology, 36(10), 2009–2017.))^, ((Li, J., Tang, Y., Womer, F., Fan, G., Zhou, Q., Sun, W., Xu, K., & Wang, F. (2017). Two patterns of anterior insular cortex functional connectivity in bipolar disorder and schizophrenia. The World Journal of Biological Psychiatry, 19(sup3), S115–S123.)), and between the perigenual ACC and the ventrolateral PFC ((Magioncalda, P., Martino, M., Conio, B., Escelsior, A., Piaggio, N., Presta, A., Marozzi, V., Rocchi, G., Anastasio, L., Vassallo, L., Ferri, F., Huang, Z., Roccatagliata, L., Pardini, M., Northoff, G., & Amore, M. (2014). Functional connectivity and neuronal variability of resting state activity in bipolar disorder—reduction and decoupling in anterior cortical midline structures. Human Brain Mapping, 36(2), 666–682.)). There was also reduced functional connectivity between subregions of the ACC when lower supragenual and perigenual ACC connectivity was observed ((Magioncalda, P., Martino, M., Conio, B., Escelsior, A., Piaggio, N., Presta, A., Marozzi, V., Rocchi, G., Anastasio, L., Vassallo, L., Ferri, F., Huang, Z., Roccatagliata, L., Pardini, M., Northoff, G., & Amore, M. (2014). Functional connectivity and neuronal variability of resting state activity in bipolar disorder—reduction and decoupling in anterior cortical midline structures. Human Brain Mapping, 36(2), 666–682.)). The SN, particularly the anterior insula, is involved in communication between different neural networks, specifically the DMN during cognitive leisure and CEN during cognitive exertion, which is crucial for adaptive mood regulation ((Schimmelpfennig, J., Topczewski, J., Zajkowski, W., & Kamila Jankowiak-Siuda. (2023). The role of the salience network in cognitive and affective deficits. Frontiers in Human Neuroscience, 17.)). Thus, the SN is implicated in the dynamic process of switching between depressive and manic states in BD ((Zhang, G., & Zhong, Y. (2023). A Dynamic Process Model of Bipolar Disorder States Switching Based on the Salience Network. ResearchGate.)). The SN serves a critical role in salience detection and network switching, therefore disruptions in the SN among those with  BD may contribute to impaired mood regulation and specifically the transition between affective states.

Triple Network

The triple network, composed of the DMN, SN, and CEN ((Menon, V. (2011). Large-scale brain networks and psychopathology: A unifying triple network model. Trends in Cognitive Sciences, 15(10), 483–506.)), has shown altered patterns of connectivity among those with BD. Those with BD have shown hyper-connectivity between the DMN and SN as previously noted, however, reduced connectivity between the CEN-SN and CEN-DMN has also been observed. For the CEN-SN, reduced functional connectivity between the insula of the SN and inferior parietal lobule of the CEN was associated with greater impairment in perceived emotion control and inhibition ((Ellard, K. K., Zimmerman, J. P., Kaur, N., Dijk, V., Roffman, J. L., Nierenberg, A. A., Dougherty, D. D., Thilo Deckersbach, & Camprodon, J. A. (2018). Functional Connectivity Between Anterior Insula and Key Nodes of Frontoparietal Executive Control and Salience Networks Distinguish Bipolar Depression From Unipolar Depression and Healthy Control Subjects. Biological Psychiatry Cognitive Neuroscience and Neuroimaging, 3(5), 473–484.)), often seen in manic episodes ((Christodoulou, T., Lewis, M., G.B. Ploubidis, & S. Frangou. (2006). The relationship of impulsivity to response inhibition and decision-making in remitted patients with bipolar disorder. European Psychiatry, 21(4), 270–273.)). Mixed findings have been reported with some showing increased connectivity between the dorsal anterior insula of the SN and inferior parietal lobule of the CEN at rest ((Pang, Y., Chen, H., Wang, Y., Long, Z., He, Z., Zhang, H., Liao, W., Cui, Q., & Chen, H. (2018). Transdiagnostic and diagnosis-specific dynamic functional connectivity anchored in the right anterior insula in major depressive disorder and bipolar depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 85, 7–15.)). For the CEN-DMN, functional decoupling has been observed between the dorsolateral PFC and inferior frontal gyrus of the CEN and the medial PFC of the DMN at rest in those with BD compared to healthy controls ((Chai, X. J., Whitfield-Gabrieli, S., Shinn, A. K., Gabrieli, J. D. E., Castañón, A. N., McCarthy, J. M., Cohen, B. M., & Dost Öngür. (2011). Abnormal Medial Prefrontal Cortex Resting-State Connectivity in Bipolar Disorder and Schizophrenia. Neuropsychopharmacology, 36(10), 2009–2017.))^, ((Favre, P., Baciu, M., Cédric Pichat, Thierry Bougerol, & Mircea Polosan. (2014). fMRI evidence for abnormal resting-state functional connectivity in euthymic bipolar patients. Journal of Affective Disorders, 165, 182–189.))^, ((Roberts, G., Lord, A., Frankland, A., Wright, A., Lau, P., Levy, F., Lenroot, R. K., Mitchell, P. B., & Breakspear, M. (2017). Functional Dysconnection of the Inferior Frontal Gyrus in Young People With Bipolar Disorder or at Genetic High Risk. Biological Psychiatry, 81(8), 718–727.)), meaning that the networks are lacking synchronization or functioning independently when their activity should be coordinated. While healthy controls show anticorrelation between the CEN and DMN ((Menon, V. (2011). Large-scale brain networks and psychopathology: A unifying triple network model. Trends in Cognitive Sciences, 15(10), 483–506.)), weakened or reversed functional connectivity between the two may indicate an imbalance in the brain’s ability to segregate between a state of rest and a task-positive state (when the brain is engaged in goal-directed cognitive tasks) in those with BD. Functional connectivity among those with BD shows dysregulation of large-scale brain networks in BD, in addition to altered connectivity within and between the DMN, SN, and CEN leading to disruptions in cognitive and emotional processing, thus leading to mood instability and impaired executive function.

Neurotransmitter Activity

Dopamine

Dopamine regulates various physiological and cognitive functions and plays an essential role in the brain’s reward system, reinforcing goal-directed behaviors ((Speranza, L., Porzio, U. di, Viggiano, D., Donato, A. de, & Volpicelli, F. (2021). Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control. Cells, 10(4), 735–735.)). In BD, dysregulation of dopamine receptors—particularly D2 and D3 receptors—has been observed, particularly in limbic and striatal brain regions leading to heightened motivation, reward sensitivity, and impulsive behaviors ((Speranza, L., Porzio, U. di, Viggiano, D., Donato, A. de, & Volpicelli, F. (2021). Dopamine: The Neuromodulator of Long-Term Synaptic Plasticity, Reward and Movement Control. Cells, 10(4), 735–735.))^, ((Drevets, W. C., Gautier, C., Price, J. C., Kupfer, D. J., Kinahan, P. E., Grace, A. A., Price, J. L., & Mathis, C. A. (2001). Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria. Biological Psychiatry, 49(2), 81–96.)). This may cause increased striatal dopamine transporter levels as compensation, lowering dopaminergic transmission. These fluctuations influence dopamine turnover, and disrupt the balance of signaling across mood states, explaining the alternating manic and depressive symptoms characteristic of BD ((Berk, M., Dodd, S., M. Kauer‐Sant’Anna, Malhi, G. S., M. Bourin, F. Kapczinski, & Norman, T. (2007). Dopamine dysregulation syndrome: implications for a dopamine hypothesis of bipolar disorder. Acta Psychiatrica Scandinavica, 116(s434), 41–49.)). Increases in homovanillic acid (HVA), a metabolite used to assess dopamine activity, provides more support for an overactive dopaminergic system in BD during manic episodes ((Cousins, D. A., Butts, K., & Young, A. H. (2009). The role of dopamine in bipolar disorder. Bipolar Disorders, 11(8), 787–806.))^, ((Pålsson, E., Sellgren, C., Aurimantas Pelanis, Zetterberg, H., Kaj Blennow, & Mikael Landén. (2023). Altered brain dopamine metabolism is a trait marker for bipolar disorder. Biomarkers in Neuropsychiatry, 9, 100078–100078.)). Dopamine depletion is thus associated with depressive symptoms, including lack of motivation and cognitive impairment.

Medication provides additional support for the role of dopamine. Dopamine receptor antagonists, such as atypical antipsychotics, are commonly used to manage mania by reducing excessive dopamine activity ((Lee, J. G., Woo, Y. S., Park, S. W., Dae-Hyun Seog, Seo, M. K., & Bahk, W.-M. (2022). Neuromolecular Etiology of Bipolar Disorder: Possible Therapeutic Targets of Mood Stabilizers. Clinical Psychopharmacology and Neuroscience, 20(2), 228–239.)). On the other hand, some dopaminergic medications, like psychostimulants and certain antidepressants, have been reported to trigger manic episodes in susceptible individuals, reinforcing the link between dopamine dysregulation and BD symptomatology ((Ashok, A. H., Marques, T. R., Jauhar, S., Nour, M. M., Goodwin, G. M., Young, A. H., & Howes, O. D. (2017). The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment. Molecular Psychiatry, 22(5), 666–679.)).

Noradrenaline

Noradrenaline (also named norepinephrine) is involved in the brain’s arousal and stress response systems, playing a crucial role in regulating mood ((Hussain, L. S., Reddy, V., & Maani, C. V. (2023, May). Physiology, Noradrenergic Synapse. Nih.gov; StatPearls Publishing.)). Fluctuations in noradrenaline levels have been directly linked to symptomatic shifts in BD, as changes in its metabolism correlate with different mood states ((Kurita, M. (2016). Noradrenaline plays a critical role in the switch to a manic episode and treatment of a depressive episode. Neuropsychiatric Disease and Treatment, Volume 12, 2373–2380.)). The primary metabolites of noradrenaline, 3-methoxy-4-hydroxyphenylglycol (MHPG) and 3,4-dihydroxyphenylglycol (DHPG), serve as biomarkers for noradrenergic activity. Higher concentrations of MHPG levels have been detected during manic episodes and lower concentrations during depressive phases ((Kurita, M. (2016). Noradrenaline plays a critical role in the switch to a manic episode and treatment of a depressive episode. Neuropsychiatric Disease and Treatment, Volume 12, 2373–2380.)), suggesting MHPG may serve as a potential biomarker for mood fluctuations. Alterations in adrenergic receptors, including downregulation of β-adrenergic receptors, may impair feedback regulation of noradrenaline release and contribute to emotional dysregulation and heightened stress sensitivity ((van Enkhuizen, J., Janowsky, D. S., Olivier, B., Minassian, A., Perry, W., Young, J. W., & Geyer, M. A. (2015). The catecholaminergic–cholinergic balance hypothesis of bipolar disorder revisited. European Journal of Pharmacology, 753, 114–126.)).

Pharmacological interventions targeting the noradrenergic system further highlight its role in BD. Selective noradrenaline reuptake inhibitors (NRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs) are commonly used to treat depressive symptoms ((Lee, J. G., Woo, Y. S., Park, S. W., Dae-Hyun Seog, Seo, M. K., & Bahk, W.-M. (2022). Neuromolecular Etiology of Bipolar Disorder: Possible Therapeutic Targets of Mood Stabilizers. Clinical Psychopharmacology and Neuroscience, 20(2), 228–239.)). However, they may increase the risk of manic episodes, as they elevate synaptic noradrenaline levels, which may overstimulate neural circuits ((Lee, J. G., Woo, Y. S., Park, S. W., Dae-Hyun Seog, Seo, M. K., & Bahk, W.-M. (2022). Neuromolecular Etiology of Bipolar Disorder: Possible Therapeutic Targets of Mood Stabilizers. Clinical Psychopharmacology and Neuroscience, 20(2), 228–239.))^, ((Fountoulakis, K. N., Kasper, S., Andreassen, O., Blier, P., Okasha, A., Severus, E., Marcio Versiani, Tandon, R., Hans-Jürgen Möller, & Vieta, E. (2012). Efficacy of pharmacotherapy in bipolar disorder: a report by the WPA section on pharmacopsychiatry. European Archives of Psychiatry and Clinical Neuroscience, 262(S1), 1–48.)). Given noradrenaline’s strong association with BD symptomatology, future research aims to refine treatment strategies by developing biomarker-driven interventions.

GABA

Gamma-aminobutyric acid (GABA) is the brain’s primary inhibitory neurotransmitter ((Roberts, E. (1975). GABA in nervous system function – An overview. ResearchGate, 1.))^, ((Li, K., & Xu, E. (2008). The role and the mechanism of γ-aminobutyric acid during central nervous system development. Neuroscience Bulletin, 24(3), 195–200.)). It counterbalances excitatory neurotransmitters preventing excessive neural activity that could lead to mood disturbances ((Wu, C., & Sun, D. (2014). GABA receptors in brain development, function, and injury. Metabolic Brain Disease, 30(2), 367–379.)). Neuroimaging and postmortem studies have revealed altered GABAergic signaling in BD, particularly in the prefrontal cortex, amygdala, and hippocampus, regions involved in mood regulation, impulse control, and emotional processing ((Drevets, W. Price, J. L., & Furey, M. L. (2008). Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Structure and Function, 213(1-2), 93–118.)). Individuals with BD often exhibit lower GABA levels, particularly during depressive episodes, suggesting that GABA deficits may contribute to heightened neural excitability, which in turn leads to mood instability, anxiety, and cognitive impairments ((Luca dSteardo, D’Angelo, M., Monaco, F., Stefano, V. D., & Luca Steardo. (2025). Decoding Neural Circuit Dysregulation in Bipolar Disorder: Toward an Advanced Paradigm for Multidimensional Cognitive, Emotional, and Psychomotor Treatment. Neuroscience & Biobehavioral Reviews, 169, 106030–106030.))^, ((Luscher, B., Shen, Q., & N Sahir. (2010). The GABAergic deficit hypothesis of major depressive disorder. Molecular Psychiatry, 16(4), 383–406.)). Conversely, some evidence suggests that GABA levels may increase during manic episodes, potentially reflecting a compensatory mechanism in response to excessive excitatory activity ((Lee, J. G., Woo, Y. S., Park, S. W., Dae-Hyun Seog, Seo, M. K., & Bahk, W.-M. (2022). Neuromolecular Etiology of Bipolar Disorder: Possible Therapeutic Targets of Mood Stabilizers. Clinical Psychopharmacology and Neuroscience, 20(2), 228–239.)).

Medications that modulate GABAergic activity, such as Valproate and lithium, enhance GABAergic transmission, helping to restore neural balance and prevent mood swings ((Wang, & Ketter. (2005, September). The Emerging Role of GABAergic Mechanisms in Mood Disorders. Psychiatric Times.)). Benzodiazepines, which directly enhance GABA receptor function, are occasionally prescribed as adjunctive treatments for managing acute mania or anxiety symptoms ((Wang, & Ketter. (2005, September). The Emerging Role of GABAergic Mechanisms in Mood Disorders. Psychiatric Times.)). Changes in GABA receptor composition have also been observed. Postmortem studies report reduced expression of GABA_A​ receptor subunits α2, β1, and ε in the cerebellum of individuals with BD ((Fatemi, S. H., Folsom, T. Rooney, R. J., & Thuras, P. D. (2013). Expression of GABAA α2-, β1- and ɛ-receptors are altered significantly in the lateral cerebellum of subjects with schizophrenia, major depression and bipolar disorder. Translational Psychiatry, 3(9), e303–e303.)), while increased benzodiazepine site binding in the hippocampus suggests regional upregulation or altered receptor configuration, possibly involving the α5 subunit ((Kaufman, R. E., Ostacher, M. J., Marks, E. H., Simon, N. M., Sachs, G. S., Jensen, J. E., Renshaw, P. F., & Pollack, M. H. (2009). Brain GABA levels in patients with bipolar disorder. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33(3), 427–434.)). GABA_B​ receptor expression has also been found to be reduced ((Fatemi, S. H., Folsom, T. D., Rooney, R. J., & Thuras, P. D. (2013). Expression of GABAA α2-, β1- and ɛ-receptors are altered significantly in the lateral cerebellum of subjects with schizophrenia, major depression and bipolar disorder. Translational Psychiatry, 3(9), e303–e303.))^, ((Brambilla, P., Perez, J., F Barale, Schettini, G., & Soares, J. C. (2003). GABAergic dysfunction in mood disorders. Molecular Psychiatry, 8(8), 721–737.)), further implicating receptor-level dysfunction and underscoring the potential of GABA receptor modulators as promising targets for future BD treatments.

Glutamate

Glutamate serves as the main excitatory neurotransmitter and is critical for neural circuit function ((Reiner, A., & Levitz, J. (2018). Glutamatergic Signaling in the Central Nervous System: Ionotropic and Metabotropic Receptors in Concert. Neuron, 98(6), 1080–1098.)). Balancing the ratio of glutamine (the primary metabolite of glutamate) / glutamate levels is necessary to prevent neuronal damage ((Andersen, J. V., Markussen, K. H., Jakobsen, E., Arne Schousboe, Waagepetersen, H. S., Rosenberg, P. A., & Aldana, B. I. (2021). Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration. Neuropharmacology, 196, 108719–108719.)). Those with BD have shown higher levels of glutamate and glutamine, particularly in the ACC and the PFC ((Kubo, H., Masahito Nakataki, Satsuki Sumitani, Jun-ichi Iga, Numata, S., Kameoka, N., Watanabe, S., Hidehiro Umehara, Kinoshita, M., Masatoshi Inoshita, Tamaru, M., Ohta, M., Chiaki Nakayama-Yamauchi, Funakoshi, Y., Harada, M., & Tetsuro Ohmori. (2016). 1H-magnetic resonance spectroscopy study of glutamate-related abnormality in bipolar disorder. Journal of Affective Disorders, 208, 139–144.))^, ((Ino, H., Honda, S., Yamada, K., Horita, N., Tsugawa, S., Yoshida, K., Noda, Y., Meyer, J. H., Mimura, M., Nakajima, S., & Moriguchi, S. (2023). Glutamatergic Neurometabolite Levels in Bipolar Disorder: A Systematic Review and Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 8(2), 140–150.)), and higher glutamine/glutamate ratio suggesting hyperactivity in glutamatergic neurotransmission and potential disruptions in neuronal-glial interactions ((Kubo, H., Masahito Nakataki, Satsuki Sumitani, Jun-ichi Iga, Numata, S., Kameoka, N., Watanabe, S., Hidehiro Umehara, Kinoshita, M., Masatoshi Inoshita, Tamaru, M., Ohta, M., Chiaki Nakayama-Yamauchi, Funakoshi, Y., Harada, M., & Tetsuro Ohmori. (2016). 1H-magnetic resonance spectroscopy study of glutamate-related abnormality in bipolar disorder. Journal of Affective Disorders, 208, 139–144.))^, ((Dost Öngür, Jensen, J. E., Prescot, A. P., Stork, C., Lundy, M., Cohen, B. M., & Renshaw, P. F. (2008). Abnormal Glutamatergic Neurotransmission and Neuronal-Glial Interactions in Acute Mania. Biological Psychiatry, 64(8), 718–726.)). Some studies have noted this heightened ratio is present primarily when BD patients are experiencing a manic episode ((Kubo, H., Masahito Nakataki, Satsuki Sumitani, Jun-ichi Iga, Numata, S., Kameoka, N., Watanabe, S., Hidehiro Umehara, Kinoshita, M., Masatoshi Inoshita, Tamaru, M., Ohta, M., Chiaki Nakayama-Yamauchi, Funakoshi, Y., Harada, M., & Tetsuro Ohmori. (2016). 1H-magnetic resonance spectroscopy study of glutamate-related abnormality in bipolar disorder. Journal of Affective Disorders, 208, 139–144.))^, ((Dost Öngür, Jensen, J. E., Prescot, A. P., Stork, C., Lundy, M., Cohen, B. M., & Renshaw, P. F. (2008). Abnormal Glutamatergic Neurotransmission and Neuronal-Glial Interactions in Acute Mania. Biological Psychiatry, 64(8), 718–726.))^, ((Whitton, A. E., Kumar, P., Treadway, M. T., Rutherford, A. V., Ironside, M. L., Foti, D., Fitzmaurice, G., Du, F., & Pizzagalli, D. A. Mapping Disease Course Across the Mood Disorder Spectrum Through a Research Domain Criteria Framework. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 6(7), 706–715.)), consistent with the elevated cerebral metabolic rate that accompanies racing thoughts, irritability and distractibility observed in mania ((Ino, H., Honda, S., Yamada, K., Horita, N., Tsugawa, S., Yoshida, K., Noda, Y., Meyer, J. H., Mimura, M., Nakajima, S., & Moriguchi, S. (2023). Glutamatergic Neurometabolite Levels in Bipolar Disorder: A Systematic Review and Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 8(2), 140–150.)). Glutamate dysregulation may also affect synaptic function and neuroplasticity through structural alterations in the synapse ((Guglielmo, R., & Hasler, G. (2022). The neuroprotective and neuroplastic potential of glutamatergic therapeutic drugs in bipolar disorder. Neuroscience & Biobehavioral Reviews, 142, 104906.)). This corresponds to the recent reconceptualization of BD as a synaptic plasticity-related disorder instead of as one simply due to neurotransmitters in deficit or excess ((Guglielmo, R., & Hasler, G. (2022). The neuroprotective and neuroplastic potential of glutamatergic therapeutic drugs in bipolar disorder. Neuroscience & Biobehavioral Reviews, 142, 104906.)).

Abnormalities in glutamate receptors are also observed. Overactivation of NMDA receptors can increase calcium influx and oxidative stress, potentially leading to neuronal damage ((Ino, H., Honda, S., Yamada, K., Horita, N., Tsugawa, S., Yoshida, K., Noda, Y., Meyer, J. H., Mimura, M., Nakajima, S., & Moriguchi, S. (2023). Glutamatergic Neurometabolite Levels in Bipolar Disorder: A Systematic Review and Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 8(2), 140–150.)). On the other hand, reduced expression of AMPA receptors—another type of glutamate receptor—can impair synaptic transmission and plasticity, further contributing to cognitive and emotional symptoms in BD ((Dost Öngür, Jensen, J. E., Prescot, A. P., Stork, C., Lundy, M., Cohen, B. M., & Renshaw, P. F. (2008). Abnormal Glutamatergic Neurotransmission and Neuronal-Glial Interactions in Acute Mania. Biological Psychiatry, 64(8), 718–726.)). These changes not only affect glutamate metabolism and clearance but also alter the excitatory/inhibitory balance across functional networks. In reference to medications that modulate glutamate, Ketamine may increase in glutamate neurotransmission, rapidly rebooting synaptic connectivity that leads to antidepressant effects ((Antos, Z., Żukow, X., Bursztynowicz, L., & Jakubów, P. (2024). Beyond NMDA Receptors: A Narrative Review of Ketamine’s Rapid and Multifaceted Mechanisms in Depression Treatment. International Journal of Molecular Sciences, 25(24), 13658.)). Lamotrigine and other mood stabilizers prevent glutamate release, dampening overactive excitatory circuits to avoid manic switching and to potentially have neuroprotective benefits ((Costa, B., & Vale, N. (2023). Understanding Lamotrigine’s Role in the CNS and Possible Future Evolution. International Journal of Molecular Sciences, 24(7), 6050.)). These findings underscore glutamate’s multifaceted involvement in BD, acting as both a potential driver of excitotoxic damage and a key modulator of synaptic plasticity, mood regulation, and treatment response.

Serotonin

Serotonin (5-hydroxytryptamine, 5-HT) is involved in mood regulation, sleep, and impulse control ((Bakshi, A., & Prasanna Tadi. (2022, October 5). Biochemistry, Serotonin. Nih.gov; StatPearls Publishing.)). Serotonin activity is typically reduced during depressive episodes, leading to symptoms such as low mood, fatigue, and emotional dysregulation ((Luca d, D’Angelo, M., Monaco, F., Stefano, V. D., & Luca Steardo. (2025). Decoding Neural Circuit Dysregulation in Bipolar Disorder: Toward an Advanced Paradigm for Multidimensional Cognitive, Emotional, and Psychomotor Treatment. Neuroscience & Biobehavioral Reviews, 169, 106030–106030.)). Lower rates of the main metabolite and indicator of serotonin turnover rate in the brain, 5-hydroxyindoleacetic acid (5-HIAA), have also been observed ((Manji, H. K., Quiroz, J. A., Payne, J. L., Singh, J., Lopes, B. P., Viegas, J. S., & Zarate, C. A. (2003). The underlying neurobiology of bipolar disorder. World Psychiatry, 2(3), 136.)). However, others have also found a lack of correlation between 5-HIAA levels and BD, suggesting mixed results ((Lee, J. G., Woo, Y. S., Park, S. W., Dae-Hyun Seog, Seo, M. K., & Bahk, W.-M. (2022). Neuromolecular Etiology of Bipolar Disorder: Possible Therapeutic Targets of Mood Stabilizers. Clinical Psychopharmacology and Neuroscience, 20(2), 228–239.)), that may be due to medication correcting for serotonin dysregulation. Additionally, serotonin transporter (SERT) function is altered in BD, with studies showing higher SERT availability during depressive states, which may lead to excessive serotonin reuptake and decreased serotonin signaling ((Bartlett, E. A., Zanderigo, F., Shieh, D., Miller, J., Hurley, P., Rubin-Falcone, H., Oquendo, M. A., Sublette, M. E., Ogden, R. T., & Mann, J. J. (2022). Serotonin transporter binding in major depressive disorder: impact of serotonin system anatomy. Molecular Psychiatry, 27(8), 3417–3424.)).

Selective serotonin reuptake inhibitors (SSRIs), commonly used for depression and increase serotonin levels by blocking its reuptake, can trigger manic episodes among those with BD, especially when used without a mood stabilizer ((Viktorin, A., Lichtenstein, P., Thase, M. E., Larsson, H., Lundholm, C., Magnusson, P. K. E., & Mikael Landén. (2014). The Risk of Switch to Mania in Patients With Bipolar Disorder During Treatment With an Antidepressant Alone and in Combination With a Mood Stabilizer. American Journal of Psychiatry, 171(10), 1067–1073.)). This phenomenon, known as an antidepressant-induced switch, highlights serotonin’s role in mood destabilization. Mood stabilizers such as lithium and atypical antipsychotics help regulate serotonin signaling, preventing extreme mood fluctuations ((Kong, L., Wang, H., Yan, N., Xu, C., Chen, Y., Zeng, Y., Guo, X., Lu, J., & Hu, S. (2024). Effect of antipsychotics and mood stabilisers on metabolism in bipolar disorder: a network meta-analysis of randomised-controlled trials. EClinicalMedicine, 71, 102581–102581.)). Continued research is needed to understand how these medications can be effectively used while reducing the risk of inducing mania.

Integration of Brain Structure, Brain Function, and Neurotransmitter Alterations

A growing body of research highlights the interconnected nature of structural abnormalities, functional network disruptions, and neurotransmitter imbalances in BD. Table 1 briefly summarizes key findings from each domain. Key regions such as the ACC, dorsolateral PFC, ventromedial PFC, and hippocampus are also central nodes in functional networks like the DMN, SN, and fronto-limbic circuit ((Magioncalda, P., Capobianco, L., Russo, D., Adavastro, G., Tumati, S., Tan, Z., Lee, H.-C., Lane, T. J., Amore, M., Inglese, M., & Northoff, G. (2019). Abnormal Functional Relationship of Sensorimotor Network With Neurotransmitter-Related Nuclei via Subcortical-Cortical Loops in Manic and Depressive Phases of Bipolar Disorder. Schizophrenia Bulletin, 46(1), 163–174.)). These regions are embedded in systems responsible for emotional regulation, cognitive flexibility, and motor behavior, and densely populated with neurotransmitter receptors, particularly for serotonin, dopamine, and GABA ((Drevets, W. C., Price, J. L., & Furey, M. L. (2008). Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Structure and Function, 213(1-2), 93–118.)). Reduced gray matter volumes and impaired white matter tracts between the PFC and amygdala have been observed particularly among those with rapid cycling or mixed episodes of BD ((Luca d, D’Angelo, M., Monaco, F., Stefano, V. D., & Luca Steardo. (2025). Decoding Neural Circuit Dysregulation in Bipolar Disorder: Toward an Advanced Paradigm for Multidimensional Cognitive, Emotional, and Psychomotor Treatment. Neuroscience & Biobehavioral Reviews, 169, 106030–106030.)). Functionally, this circuit shows state-dependent dysregulation: during manic states, hyperconnectivity between the ventromedial PFC and amygdala coincides with heightened emotional intensity, while depressive phases are marked by hypoactivity and emotional blunting. At the neurochemical level, the same fronto-limbic areas are influenced by serotonergic and glutamatergic signaling. Abnormal serotonin activity in the ventromedial PFC and heightened glutamate levels in the limbic system may underlie the emotional instability that characterize BD ((Magioncalda, P., & Martino, M. (2021). A unified model of the pathophysiology of bipolar disorder. Molecular Psychiatry, 27(1), 202–211.)).

The DMN further illustrates this multilevel disruption. Structurally, regions such as the PCC and ventromedial PFC—core DMN nodes—show volume reductions and reduced myelination ((Luca d, D’Angelo, M., Monaco, F., Stefano, V. D., & Luca Steardo. (2025). Decoding Neural Circuit Dysregulation in Bipolar Disorder: Toward an Advanced Paradigm for Multidimensional Cognitive, Emotional, and Psychomotor Treatment. Neuroscience & Biobehavioral Reviews, 169, 106030–106030.)). Functionally, these same areas exhibit hyperconnectivity and hyperactivation during depressive states, contributing to ruminative thought patterns and cognitive inflexibility ((Luca d, D’Angelo, M., Monaco, F., Stefano, V. D., & Luca Steardo. (2025). Decoding Neural Circuit Dysregulation in Bipolar Disorder: Toward an Advanced Paradigm for Multidimensional Cognitive, Emotional, and Psychomotor Treatment. Neuroscience & Biobehavioral Reviews, 169, 106030–106030.)). Neurochemically, serotonin and GABA signaling modulate DMN activity and when they fail to adequately suppress DMN overactivity, the result is persistent self-focused rumination and emotional dysregulation. This triple convergence—structural atrophy, functional hyperconnectivity, and neurotransmitter imbalance—helps explain why the DMN has been proposed as a potential biomarker for BD diagnosis and severity ((‌Bi, B., Che, D., & Bai, Y. (2022). Neural network of bipolar disorder: Toward integration of neuroimaging and neurocircuit-based treatment strategies. Translational Psychiatry, 12(1).)). Evidence across networks underscores the necessity of viewing BD as a disorder of systems-level dysregulation rather than dysfunction in any single domain.

Manic versus Depressive Episodes

Neurobiological alterations in BD are not static but vary significantly across manic and depressive episodes. Structurally, certain regions such as the amygdala and prefrontal cortex show mood-state dependent activation. Functional MRI studies have revealed hyperactivity in the amygdala and decreased activation in the ventrolateral prefrontal cortex during manic episodes, suggesting impaired top-down emotional regulation and heightened salience detection ((Adnan Alahmadi, Alali, A. G., Alzhrani, B. M., Alzhrani, R. S., Alsharif, W., Shrooq Aldahery, Duaa Banaja, Njoud Aldusary, Alghamdi, J., Kanbayti, I. H., & Hakami, N. Y. (2024). Unearthing the Hidden Links: Investigating the Functional Connectivity between Amygdala Subregions and Brain Networks in Bipolar Disorder through Resting-State fMRI. Heliyon, 10(19), e38115–e38115.)). In contrast, depressive episodes are associated with hypoactivity in reward-related areas and heightened connectivity within the DMN, potentially reflecting increased self-referential thought. Cortical thinning and volumetric reductions in regions like the ACC have been associated with depressive states, while manic episodes may involve more dynamic alterations in limbic-prefrontal circuits ((Christoph Abé, Liberg, B., Klahn, A. L., Petrovic, P., & Mikael Landén. (2023). Mania-related effects on structural brain changes in bipolar disorder – a narrative review of the evidence. Molecular Psychiatry, 28(7), 2674–2682.))^, ((‌Pomarol-Clotet, E., Alonso-Lana, S., Moro, N., Sarró, S., Bonnin, M. C., Goikolea, J. M., Paloma Fernández-Corcuera, Amann, B. L., Romaguera, A., Vieta, E., Blanch, J., McKenna, P. J., & Salvador, R. (2014). Brain functional changes across the different phases of bipolar disorder. The British Journal of Psychiatry, 206(2), 136–144.)).

On a functional level, brain arousal regulation also appears to differ between mood states. Depressive episodes are marked by sustained arousal whereas manic episodes demonstrate unstable arousal regulation, with rapid fluctuations toward lower arousal states ((Wittekind, D. A., Spada, J., Gross, A., Hensch, T., Jawinski, P., Ulke, C., Sander, C., & Hegerl, U. (2016). Early report on brain arousal regulation in manic vs depressive episodes in bipolar disorder. Bipolar Disorders, 18(6), 502–510.)). These findings support the arousal regulation model, which asserts that the contrasting behavioral features of mania and depression may reflect compensatory responses to unstable or hyper-stable arousal states, respectively. Neurochemically, dopamine and norepinephrine signaling fluctuate with mood states: manic episodes often feature heightened dopaminergic and noradrenergic activity, while depressive episodes show attenuated transmission, as evidenced by variations in receptor availability and neurotransmitter turnover ((Siopa, C., Calaça, M., Pestana, P. C., & Filipa Novais. (2024). Targeting Neurotransmitter Systems in Bipolar Disorder: A comprehensive Review of novel pharmacological approaches. Current Treatment Options in Psychiatry, 11(3), 188–202.)). These dynamic, state-dependent alterations offer insight into the episodic nature of BD and highlight the need for phase-specific diagnostic and therapeutic strategies.

Other Relevant Factors

Genetic and Epigenetic Components

BD, particularly the type I subtype, is one of the most heritable psychiatric conditions. Heritability estimates have been shown to be as high as approximately 80% among type I subtype ((James, F., & McMahon, F. J. (2020). The genetics of bipolar disorder. Molecular Psychiatry, 25(3), 544–559.)). Linkage and association studies have revealed several chromosomal regions of interest, including 18q21–23, 4p12–13, and 13q31–33. Rather than being driven by a single major gene, BD is most often discussed in the context of oligogenic epistatic models involving multiple interacting loci ((Ekaterina Sigitova, Zdeněk Fišar, Hroudová, J., Tereza Cikánková, & Jiří Raboch. (2016). Biological hypotheses and biomarkers of bipolar disorder. Psychiatry and Clinical Neurosciences, 71(2), 77–103.)). Genome-wide association studies (GWAS) and candidate gene analyses have highlighted the following genes: DRD1, DRD4, and DAT1, which regulate dopamine neurotransmission; HTTLPR and HTR2A, involved in serotonergic signaling; and BDNF and NCAM1, which are linked to neural development and synaptic plasticity ((Ekaterina Sigitova, Zdeněk Fišar, Hroudová, J., Tereza Cikánková, & Jiří Raboch. (2016). Biological hypotheses and biomarkers of bipolar disorder. Psychiatry and Clinical Neurosciences, 71(2), 77–103.)). Moreover, the involvement of genes governing circadian rhythms (e.g., CLOCK, ARNTL) provide compelling evidence linking disruptions in sleep-wake cycles to the pathophysiology of BD. These findings show that BD risk is polygenic, with multiple variants of small effect contributing to susceptibility.

In addition to genetic vulnerability, epigenetic mechanisms—which regulate gene expression without altering the underlying DNA sequence—are increasingly recognized as key contributors to BD. Altered DNA methylation in the promoter region of the catechol-O-methyltransferase (COMT) gene in the frontal cortex of BD patients is associated with increased gene expression and dopamine degradation in regions implicated in mood regulation ((Ekaterina Sigitova, Zdeněk Fišar, Hroudová, J., Tereza Cikánková, & Jiří Raboch. (2016). Biological hypotheses and biomarkers of bipolar disorder. Psychiatry and Clinical Neurosciences, 71(2), 77–103.)). In individuals with a high familial risk of BD, specific DNA methylation signatures have been detected in genes such as VARS2, which is involved in mitochondrial function, pointing to an epigenetic response to underlying polygenic risk ((James, F., & McMahon, F. J. (2020). The genetics of bipolar disorder. Molecular Psychiatry, 25(3), 544–559.)). These epigenetic alterations appear to overlap with genetic risk loci associated with BD and related disorders, reinforcing the complex gene-environment interplay in shaping disease trajectory.

Sex Differences

Select symptoms and features of BD have been shown to differ in prevalence and presentation between males and females. Women are more likely to experience frequent depressive episodes, rapid cycling between mood states, and higher rates of suicide attempts, while men are more likely to show symptoms of mania and earlier onset of the disorder ((Dell’Osso, B., Cafaro, R., & Ketter, T. A. (2021). Has Bipolar Disorder become a predominantly female gender related condition? Analysis of recently published large sample studies. International Journal of Bipolar Disorders, 9(1).))^, ((‌Ziemka-Nalecz, M., Pawelec, P., Ziabska, K., & Zalewska, T. (2023). Sex Differences in Brain Disorders. International Journal of Molecular Sciences, 24(19), 14571.)). Sex differences in BD are reflected in brain structure and function. Females have shown smaller volume in the right hippocampus ((Shi, J., Guo, H., Fan, F., Fan, H., An, H., Wang, Z., Tan, S., Yang, F., & Tan, Y. (2018). Sex differences of hippocampal structure in bipolar disorder. Psychiatry Research: Neuroimaging, 273, 35–41.)), while males have shown larger grey matter volumes in the thalamus and caudate, as well as altered resting-state functional connectivity between the left thalamus and the right angular gyrus ((‌Lee, M.-Y., Zhu, J.-D., Tsai, H.-J., Tsai, S.-J., & Yang, A. C. (2024). Investigating sex-related differences in brain structure and function in bipolar I disorder using multimodal MRI. BMC Psychiatry, 24(1).)). The angular gyrus is involved with processing language, number information, and memory, suggesting that in males, information routing through the thalamus may be reorganized in a way that could cause some of the cognitive symptoms observed in BD. Dysfunctional genomics among males in the dorsolateral PFC, involved with higher-level thinking and emotional control, may influence mood symptoms, namely mania and risk for psychosis ((‌Zhang, L., & Swaab, D. F. (2024). Sex differences in bipolar disorder: The dorsolateral prefrontal cortex as an etiopathogenic region. Frontiers in Neuroendocrinology, 72, 101115.)). These differences in brain and behavior highlight the importance of considering sex as a meaningful factor when studying BD and developing more personalized treatment strategies.

Neurobiological Mechanisms

Blood Brain Barrier (BBB) Permeability

The BBB, a protective structure that controls which substances can pass from the bloodstream into the brain, may be implicated in the progression of BD. When this barrier becomes weakened or disrupted, harmful molecules—including inflammatory proteins and toxins—can enter the brain and potentially disturb its normal functioning ((Andreazza, A. C., Kauer-Sant’Anna, M., Frey, B. N., Bond, D. J., Kapczinski, F., Young, L. T., & Yatham, L. N. (2008). Oxidative stress markers in bipolar disorder: A meta-analysis. Journal of Affective Disorders, 111(2-3), 135–144.)). Individuals with BD show increased levels of markers in the blood that suggest BBB dysfunction, such as elevated S100B protein and matrix metalloproteinases ((Wakonigg Alonso, C., McElhatton, F., O’Mahony, B., Campbell, M., Pollak, T. A., & Stokes, P. R. A. (2024). The blood-brain barrier in bipolar disorders: A systematic review. Journal of Affective Disorders, 361, 434–444.)). These markers are linked to neural inflammation in regions such as the hippocampus and prefrontal cortex and have been observed more frequently in patients during mood episodes compared to euthymia. Understanding the connection between BBB breakdown and mood instability may open new paths for treatment, such as therapies that focus on strengthening the barrier or reducing inflammation in the brain ((Drevets, W. C., Price, J. L., & Furey, M. L. (2008). Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression. Brain Structure and Function, 213(1-2), 93–118.)).

Circadian System Dysfunction

Circadian rhythm disturbances have been strongly linked to the development and course of BD. Those with BD that show alterations in key circadian genes—such as CLOCK, BMAL1, and PER3 ((Melo, M. C. A., Abreu, R. L. C., Linhares, V. B., F.C, P., & de, M. S. (2016). Chronotype and circadian rhythm in bipolar disorder: A systematic review. Sleep Medicine Reviews, 34, 46–58.)). Abnormalities in these genes may lead to irregular sleep patterns, increased vulnerability to mood episodes, and difficulty stabilizing mood across time. Furthermore, BD patients often experience changes in sleep-wake cycles even before full mood episodes occur ((McClung, C. A. (2007). Circadian genes, rhythms and the biology of mood disorders. Pharmacology & Therapeutics, 114(2), 222–232.)), suggesting that circadian rhythm disruption may be a potential early trigger of the disorder. Improving sleep hygiene and stabilizing daily routines could be valuable strategies in managing BD symptoms. This is a growing body of research, with potentially large implications in our understanding of the etiology and possible behavioral treatment strategies.

Mitochondrial Dysfunction

Mitochondrial dysfunction has been increasingly recognized as a contributing factor in the pathophysiology of BD. Patients with BD have shown altered mitochondrial DNA content, impaired oxidative phosphorylation, and elevated levels of lactate in the brain, especially the cingulate cortex, which signals inefficient energy metabolism ((Kato, T. (2022). Mitochondrial dysfunction in bipolar disorder. Elsevier EBooks, 141–156.)). These abnormalities can lead to impaired neuronal signaling, increased oxidative stress, and disruptions in calcium homeostasis—all of which are implicated in BD symptoms such as mood swings, cognitive instability, and fatigue ((Kato, T. (2022). Mitochondrial dysfunction in bipolar disorder. Elsevier EBooks, 141–156.)). Mitochondrial dysfunction is closely tied to the regulation of apoptosis and neuroplasticity, suggesting that long-term mitochondrial abnormalities may contribute to the structural and functional brain changes observed in BD ((Ekaterina Sigitova, Zdeněk Fišar, Hroudová, J., Tereza Cikánková, & Jiří Raboch. (2016). Biological hypotheses and biomarkers of bipolar disorder. Psychiatry and Clinical Neurosciences, 71(2), 77–103.)).

Oxidative Stress

Oxidative stress occurs when there is an imbalance between the production of reactive oxygen species (ROS)—which are harmful byproducts of normal cellular metabolism—and the body’s ability to neutralize them using antioxidants. Those with BD show increased levels of lipid peroxidation and protein oxidation, both signs of oxidative damage to cells ((Andreazza, A. C., Kauer-Sant’Anna, M., Frey, B. N., Bond, D. J., Kapczinski, F., Young, L. T., & Yatham, L. N. (2008). Oxidative stress markers in bipolar disorder: A meta-analysis. Journal of Affective Disorders, 111(2-3), 135–144.)), and are most noticeable during manic and depressive episodes, suggesting a link between mood instability and oxidative imbalance. Damage caused by ROS can impair mitochondrial function, disrupt neurotransmitter systems, and lead to neuronal cell death—all of which are processes believed to play a role in the unstable symptoms of BD. Antioxidant defense systems, including enzymes like superoxide dismutase (SOD), are also altered in individuals with BD, further contributing to oxidative burden ((Andreazza, A. C., Kauer-Sant’Anna, M., Frey, B. N., Bond, D. J., Kapczinski, F., Young, L. T., & Yatham, L. N. (2008). Oxidative stress markers in bipolar disorder: A meta-analysis. Journal of Affective Disorders, 111(2-3), 135–144.)). Treatments targeting oxidative stress—such as antioxidant supplementation—might offer new therapeutic avenues in the management of BD.

Discussion

The present narrative review aims to provide an overview of abnormalities in brain structure, function, and neurotransmitter activity in those with BD. Grey matter alterations include reduced volumes in key regions such as the hippocampus, amygdala, ACC, and PFC, all of which play a crucial role in emotion regulation, cognitive function, and mood stability. Longitudinal studies, while limited, suggest that repeated mood episodes contribute to progressive grey matter loss, particularly in the amygdala, ACC, and PFC, highlighting the potential neurodegenerative aspects of BD. In contrast, white matter abnormalities, particularly in the corpus callosum and cingulate gyrus, disrupt interhemispheric communication and emotional regulation, further exacerbating BD symptoms.

Functional connectivity research consistently shows disruptions in the DMN, SN, and CEN—the triple network model. Altered DMN connectivity may underlie depressive symptoms. Hypo- and hyper-connectivity patterns in the SN contribute to the emotional instability observed in BD. Reduced connectivity within the CEN impairs cognitive control and executive functioning, leading to difficulties in impulse regulation and decision-making. Disruptions in communication between these networks may explain the abrupt shifts between manic and depressive states. Thus, BD is characterized by both intra-network and inter-network dysconnectivity disrupting emotional and cognitive processes.

Neurochemical research highlights the role of neurotransmitter dysregulation in BD. Dopamine and norepinephrine are often elevated during manic episodes and depleted during depressive states, contributing to the fluctuating mood patterns. GABA appears to be reduced in BD patients, particularly during depressive episodes, while heightened glutamine / glutamate ratio may underlie symptoms of mania. Lastly, reduced serotonergic activity linked to depressive symptoms and increased serotonin receptor sensitivity potentially contributing to mania.

While significant progress has been made in elucidating the neurobiological basis of BD, many questions remain unanswered. Other related factors outside of the direct scope of this review but are worth noting include the role of multiple genes associated with BD, sex-differences across brain structure and brain function, and various neurobiological mechanisms that may interact with alterations in brain structure, function, and neurotransmitter activity. Understanding BD as a disorder of disrupted brain structure, networks, and neurotransmitter imbalances, rather than focusing solely on individual brain regions or chemicals, may pave the way for more comprehensive treatment approaches.

Limitations

While this review provides an overview of neurobiological alterations in BD, it is not an exhaustive examination of BD etiology. Variability in episode severity, inclusion of patients across manic and depressive states, and subtypes make it difficult to establish universal neurobiological markers. Differences in neuroimaging techniques and task paradigms, in addition to neurotransmitter studies using varying sample collection methods, may contribute to mixed findings. Additionally, cross-sectional studies dominate the literature, limiting the ability to establish causal relationships between brain alterations and disease progression. The lack of studies distinguishing medicated from unmedicated patients makes it difficult to isolate BD-specific alterations from medication effects. Environmental and genetic factors also play a role in BD, but few studies integrate these factors leading to difficulties in reproducibility.

Future Research Directions

Future research should aim for large-scale, multi-center longitudinal studies to address the limitations of cross-sectional designs, include thorough assessment of additional factors that may alter neurobiological components (i.e., genetic predisposition, environmental stressors), and analyze data in a way that accounts for additional variables such as sex, medication status, or BD subtype. Additionally, recruiting medication-naïve patients would help distinguish BD-specific alterations from medication effects. Standardized methodologies across studies—such as consistent imaging techniques, neurotransmitter measurement protocols, and diagnostic criteria—would enhance comparability and reproducibility of findings. Lastly, examining interactions between genetic predisposition, life stressors, age (expanding studies among adolescents), and comparisons with pre-clinical models may offer deeper insights into BD’s etiology.

Conclusion

BD is a highly complex and heterogeneous psychiatric disorder with significant alterations in brain structure, functional connectivity, and neurotransmitter activity. While extensive research has sought to identify neurobiological markers of BD, findings remain inconsistent due to methodological challenges, patient heterogeneity, and medication effects. This narrative review focused on adults with BD integrates the current literature to provide a comprehensive understanding of the neurobiological basis of BD. Future research is needed to further understand how the neural basis of BD may be used to optimize pharmacological treatment options.

Brain Structure
Brain Region	Cortical Metric	Relationship to BD	Reference
Hippocampus	Volume	Reduced volume, high variability; possibly sex- and treatment-related	Cao et al., 2017; Haukvik et al., 2020; Han et al., 2019; Angelescu et al., 2021; Lyoo et al., 2010
Amygdala	Volume	Developmental changes; increase in adults, decrease in youth	Hajek et al., 2008; Pfeifer et al., 2008; Chen et al., 2004; Chang et al., 2005; Sun et al., 2017
ACC	Volume	Decreased volume; related to emotional and cognitive dysfunction	Sassi et al., 2004; López-Larson et al., 2002; Shackman et al., 2011
Lateral ventricles	Volume	Increased volume; associated with aging and cognitive impairments	Luciano et al., 2022; Hibar et al., 2016
Corpus callosum	Volume	Decreased volume; impairs interhemispheric communication	Wang et al., 2008; Pezzoli et al., 2018; Favre et al., 2019
Cingulate gyrus	Volume	Decreased volume; linked to mood instability and impulsivity	Poletti et al., 2015; Matsuo et al., 2009
Brain Function
Neural Network	Brain Regions Involved	Relationship to BD	Reference
Default Mode Network	Ventromedial PFC, dorsomedial PFC, PCC, precuneus	Hypoconnectivity at rest; hyperconnectivity during tasks	Chai et al., 2011; Favre et al., 2014; Magioncalda et al., 2014
Salience Network	anterior insula, dorsal ACC, anterior PFC, supramarginal gyrus, striatum, thalamus	Hypoconnectivity at rest; affects salience processing and state switching	Rey et al., 2016; Hu et al., 2016; Ellard et al., 2018
DMN-SN	Combined nodes of DMN and SN	Hyperconnectivity; excessive internal or external focus	Cattarinussi et al., 2022; Gong et al., 2019
CEN-SN	Insula (SN) and inferior parietal lobule (CEN)	Reduced connectivity; relates to impaired emotion control and inhibition	Roberts et al., 2017; Zhang & Zhong, 2023
CEN-DMN	Dorsolateral PFC and inferior frontal gyrus (CEN) and medial PFC (DMN)	Functional decoupling; impairs task-positive/resting-state transitions	Magioncalda et al., 2014; Menon, 2011
Neurotransmitter Activity
Neurotransmitter	Area of Alteration	Relationship to BD	Reference
Dopamine	Striatum, limbic system	Increased during mania, decreased during depression; drives mood switching	Speranza et al., 2021; Cousins et al., 2009; Ashok et al., 2017; Palsson et al., 2023
Noradrenaline	MHPG levels in plasma/CSF	Higher in mania, lower in depression; linked to arousal and stress response	Kurita, 2016; Hussain et al., 2023; van Enkhuizen et al., 2015
GABA	PFC, amygdala, hippocampus	Low in depression; increased excitability and mood instability	Kaufman et al., 2009; Brambilla et al., 2003; Fatemi et al., 2013; Wang & Ketter, 2005
Glutamate	ACC, PFC	Elevated in mania; contributes to excitotoxicity and emotional dysregulation	Kubo et al., 2016; Ino et al., 2023; Dost Öngür et al., 2008; Guglielmo & Hasler, 2022
Serotonin	PFC, brainstem nuclei	Reduced in depression; altered receptors affect emotional reactivity	Bakshi & Tadi, 2022; Manji et al., 2003; Bartlett et al., 2022; Viktorin et al., 2014
Other Relevant Factors
Factor	Relationship to BD		Reference
Genetic	High heritability; polygenic with risk genes affecting neurotransmission		James & McMahon, 2020; Sigitova et al., 2016
Epigenetic	Environmental factors influence gene expression; treatment may modify epigenetics		Angelescu et al., 2021; James & McMahon, 2020
Sex differences	Affects brain volume, functional connectivity, and symptom presentation		Shi et al., 2018; Lee et al., 2024; Zhang & Swaab, 2024
Blood Brain Barrier	Disruption allows harmful proteins into brain; linked to inflammation		Wakonigg Alonso et al., 2024
Circadian System Dysfunction	Gene mutations and rhythm misalignment can trigger mood episodes		Melo et al., 2016; McClung, 2007
Mitochondrial Dysfunction	Impaired energy production and calcium regulation affect neuronal function		Kato, 2022
Oxidative Stress	Excess ROS causes cell damage		Andreazza et al., 2008

References