Tracing the psychopathology of bipolar disorder to the functional architecture of intrinsic brain activity and its neurotransmitter modulation: a three-dimensional model

Bipolar disorder (BD) shows complex alterations in psychomotor, affective, and thought dimensions, as described by Kraepelin in his fundamental model of manic-depressive illness. In turn, the expression of behavioral/phenomenological dimensions is traceable to intrinsic brain activity. We reported a data overview on intrinsic brain functioning and its changes in BD. Accordingly, we proposed a three-dimensional model of the relationship between brain functioning and behavioral/phenomenological patterns, along with its application to BD. In this model, intrinsic brain activity is organized in distinct units in accordance to connectivity patterns and related setting of input/output processing, underlying the different behavioral/phenomenological dimensions. An external unit (mainly involving the sensorimotor network) is connected with the external environment and sets the exteroceptive input/somatomotor output processing, underlying the psychomotor dimension. An internal unit (mainly involving the salience network) is connected to the internal/body environment and sets the interoceptive input/visceromotor output processing, underlying the affective dimension. Finally, an associative unit (mainly involving the default-mode network) is not connected with the environment and sets the processing of associative inputs/outputs, underlying the thought dimension. In each unit, neurotransmitter signaling couples the subcortical-cortical loop, which modulates the network activity levels, in turn setting input/output processing and related expression levels of the behavioral/phenomenological dimension. Different combinations in neurotransmitter signaling favor network balancing into distinct functional brain states, which manifest in different combinations of excitation or inhibition in psychomotricity, affectivity, and thought, resulting in the manic, depressive, and mixed states of BD. Our working model might provide a coherent framework for tracing the complex BD psychopathology to core functional brain alterations.