Bipolar Disorder (BD) is a serious, recurrent illness that often emerges during adolescence (Kowatch et al., 2005a; Kowatch et al., 2005b; Pavuluri et al., 2005) and its primary distinguishing feature is elevated symptoms of mania. Fifteen to twenty eight percent of adults with BD experience illness onset before age 13 years and 50–66 % before age 19 (Leverich et al., 2002; Leverich et al., 2003; Perlis et al., 2004). Approximately 5.6 % of adolescents have threshold/subthreshold manic, hypomanic, or depressive symptoms and these symptoms of BD overlap with other disorders, such as unipolar depressive disorders, Attention Deficit/Hyperactive Disorder (ADHD), or Disruptive Behavior Disorders, making it difficult to diagnose BD (Birmaher and Axelson, 2006; Lewinsohn et al., 1995) and resulting in about 7–10 years of delayed correct diagnosis and risk for inappropriate treatment (Bolge et al., 2008; Leverich et al., 2007). Even among severely ill inpatient adolescents, diagnosis of BD is often misidentified. It is thus important to identify objective biological markers that are specific to BD and its manic features with the goal to differentiate BD from other disorders and to aid in early identification and effective treatment choices.

The Inpatient Child and Adolescent Bipolar Spectrum Imaging study (InCabs Imaging) is an ongoing study of inpatient adolescents who are carefully assessed over the inpatient stay with comprehensive evaluation using the Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime (KSADS-PL) (Kaufman et al., 1997) based on Diagnostic and Statistical Manual 5 (DSM-5) (American Psychological Association, 1994), daily check-ins by research staff, daily mood ratings and actigraphy, and MRI. Study participants were diagnosed with either well-characterized bipolar I/II disorder (BD) or with other psychopathology (OP) without any threshold/subthreshold mania or hypomania, and these diagnoses include unipolar depressive disorders, ADHD, anxiety disorders, and disruptive behavior disorders. Importantly, OP participants and their parents/guardians report a complete absence of any current or lifetime mania, hypomania, and subthreshold mania/hypomania symptoms. This unique and rarified sample of very well-characterized youth with severe pathology provides a promising opportunity to identify a neural marker specific to mania. Given that some mania related symptoms of BD, such as increased goal directed and risk taking behaviors are related to reward processing, and previous studies have suggested dysfunction in reward circuitry, reward processing may be a constructive approach to distinguish BD from other psychopathologies (Frazier et al., 2005; Nusslock et al., 2014). This study aims to identify objective neural markers that distinguish BD from OP by comparing reward related neural circuitries in these two groups, and relative to healthy youth, during a monetary reward task. The following description of reward circuitry informs our understanding of reward processing. Studies with humans and nonhuman primates have established that reward circuitry comprises a interconnected network of fronto-subcortical regions connected via the thalamus (Haber and Knutson, 2010; Russo and Nestler, 2013) and these pathways interface with the motor cortex for motor planning (Haber and Knutson, 2010). The ventral (Grabenhorst and Rolls, 2011; Rolls et al., 2022), medial (Rolls et al., 2022), and orbital (Walton et al., 2011) portions of the frontal cortex (Haber and Knutson, 2010) encode the value of and features of different reward types, while the anterior cingulate cortex (ACC) is involved in reward based decisions (Bush et al., 2002). Ventral striatum (VS) is associated with prediction and prediction error (Haber, 2011) and is critically connected with amygdala for stimulus-reward associations (Haber and Knutson, 2010). These functions of regions during reward reflect symptoms and may differentiate BD from OP.

While no studies to our knowledge have striven to differentiate well characterized inpatient adolescents with BD from inpatients with other psychopathology, studies in outpatient samples have shown the reward circuitry to be differentially implicated in BD relative to unipolar depression, although the directions of the relationships are inconsistent. Relative to unipolar depressed youth, BD youth showed a pattern of elevated orbitofrontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC) (Chase et al., 2013), ACC (Chase et al., 2013; Kollmann et al., 2017), and VS (Dutra et al., 2015) activity along with reduced activity in thalamus (Chase et al., 2013; Trost et al., 2014), precentral gyrus (Chase et al., 2013; Redlich et al., 2015), and striatum/nucleus accumbens (Abler et al., 2008; Johnson et al., 2019; Redlich et al., 2015; Schreiter et al., 2016; Trost et al., 2014; Yip et al., 2015). While other pediatric studies have shown no reward related differences between BD and unipolar depression (Long et al., 2022; Satterthwaite et al., 2015; Sharma et al., 2016; Wakatsuki et al., 2022). Relative to healthy participants, BD have shown reduced activities in thalamus (Redlich et al., 2015; Singh et al., 2013), inferior temporal gyrus (Singh et al., 2013), and frontal cortex (Long et al., 2022; Redlich et al., 2015). These discrepancies may be due to diagnostic inconsistencies or clinical features of BD such as medication, affective lability, or emotional dysregulation that may not be related to mania.

Given studies showing differences in reward related neural circuitry in BD relative to unipolar depressed youth shown above, we hypothesized, reduced subcortical activation, and elevated cortical activation in BD relative to OP. Additionally, given the specific characteristics of our recruitment, it was hypothesized that these neural activity markers of reward that differentiate BD will be related to mania ratings but not to other symptom measures.