Major depressive disorder is associated with volume reductions in the frontal cortex, hippocampus, and striatum [21]. In addition, abnormal patterns of activity in the frontal cortex, striatum, globus pallidus, amygdala, and cerebellum have been observed [15]. These meta-analytic results support the view that depressive disorder involves abnormalities in the reward-punishment-related limbic circuits paralleled by dysfunctional brain structures implicated in top-down regulation. Further evidence for compromised regulation capacity and top-down regulation in depressive disorder was demonstrated in a recent meta-analysis which found lower functional connectivity between frontal and limbic structures [22]. The same study also showed that depressed patients had lower connectivity between parietal and frontoparietal regions involved in attending to the external environment but hyperconnectivity in the default network associated with internal self-referential thoughts and feelings [22]. Furthermore, the cerebellum was hypoconnected to the parietal cortex, a finding which concurs with the proposed cerebellar role in reality monitoring and predictive coding.

In agreement with conventional motor theories that conceptualize the cerebellum as a learning machine, three computational primitives for understanding the relations between homeostasis, predictive coding, and depressive disorder are important [10, 14]. Firstly, an internal forward model that is able to predict/anticipate the consequences of behavior. Secondly, an internal feedback model that is able to compare and detect mismatches between predicted and actual outcomes. Thirdly, an error minimization routine that actively modifies the internal forward and feedback models enabling more accurate predictions of the environment. From this viewpoint, behavioral adaptive responses involve the cerebellum performing Bayesian probability modeling that uses reward and punishment signals as inputs to update the priors to minimize uncertainty and regain bodily homeostasis [2]. Results from functional neuroimaging studies show that cerebellar activity correlates with error monitoring and probabilistic inferences in decision-making and context updating [23].

According to the uniform cerebellar transform function, the homogenous microstructure of the cerebellum allows for the processing of multimodal input signals originating from the rich cerebellar connections with cortical and limbic parts of the brain [9]. Anxiety and depression can be viewed as phenomenological manifestations of disrupted bodily homeostasis and uncertainty that prompts the cerebellum to update the priors of the internal model to minimize prediction errors. The conceptual framework predicts that in line with the universal cerebellar transform function, neuroticism and mood disorders are associated with problems in updating the internal model. Problems with updating the priors of the internal model will affect the prediction error minimization routine and contribute to feelings of uncertainty and loss of control. This view builds upon the central idea that the cerebellum is important for synchronizing cortical cognitive and limbic motivational information processing streams to fit contextual demands. In addition, the latter also gives a possible mechanistic account for why abnormalities in the cerebellar transform function could result in disorganized thought and feelings [9]. Abnormalities in cerebellar predictive coding may offer a theoretical framework to explain at least in part why anxiety and depression are associated with subjective reports of experiencing loss of control and feelings of helplessness. Finally, the present framework may provide a starting point for developing novel non-invasive brain stimulation protocols for the treatment of depressive disorder by targeting the cerebellum [18].

In conclusion, research has been discussed in support of the idea that the cerebellum contributes to reward- and punishment-related predictive coding and plays a role in the regulation of bodily homeostasis which is proposed to be dysfunctional in depressive disorder.