Major depressive disorder (MDD) is characterized by a wide range of psychopathological symptoms, including affective, cognitive, perceptual, sensorimotor, and social symptoms. The underlying neuronal mechanisms of these co-occurring symptoms remain unclear. This perspective proposes a global and dynamic topographic approach to understand MDD, suggesting that global brain activity changes during rest and task states show topographic reorganization, shifting from unimodal to transmodal regions. Two candidate mechanisms are proposed: dynamic shifts from shorter to longer timescales and abnormalities in the excitation-inhibition balance. These topographic shifts relate to the various psychopathological symptoms in MDD, including their co-occurrence. This concept, termed 'Topographic dynamic reorganization,' extends the earlier 'Resting state hypothesis of depression' and complements other models of MDD. Recent evidence shows that the brain exhibits 'global' activity, similar to economic and climate systems, modulating non-uniformly across local regions and networks. This modulation involves subcortical nuclei like the raphe nucleus, nucleus basalis meynert, and substantia nigra affecting cortical activity. Animal studies suggest that behavior like motor action is mediated not only by the motor cortex but also by the whole brain, featuring various regions and different timescales. In humans, global brain activity is often measured in fMRI by the global signal (GS) and its representation in specific regions or networks. Studies show that global signal topography is altered in MDD, with decreased task-related GSCORR in the DMN and premotor cortical regions when exposed to negative and fast-presented visual stimuli. These changes correlate with the severity of psychomotor retardation in MDD patients. The dysfunction in transitioning from unimodal to transmodal regions, coupled with altered global signal dynamics, underpins many of the cognitive and emotional disturbances observed in MDD. The abnormal uni-/transmodal gradients in MDD suggest a shift from unimodal lower-order sensory and motor regions to more transmodal higher-order associative regions. Recent studies show that the uni-/transmodal gradient explains lower variance of resting state signals in MDD than in healthy subjects. These findings are compatible with the observation that transmodal DMN activity is abnormally correlated with unimodal sensory activity. The abnormal excitation-inhibition balance (EIB) in MDD is also linked to changes in the unimodal transmodal topography. Findings in healthy subjects show that the unimodal transmodal topography is accompanied by corresponding gradients in the EIB. Specifically, the level of excitation relative to inhibition increases from unimodal to transmodal regions. This is in line with the observation of brain-wide changes in the GABAergic and glutamatergic levels of EIB in MDD. The topographic reorganization from unimodal to transmodal regions is accompanied by corresponding dynamic shifts from shorter to longer timescales. This is supportedMajor depressive disorder (MDD) is characterized by a wide range of psychopathological symptoms, including affective, cognitive, perceptual, sensorimotor, and social symptoms. The underlying neuronal mechanisms of these co-occurring symptoms remain unclear. This perspective proposes a global and dynamic topographic approach to understand MDD, suggesting that global brain activity changes during rest and task states show topographic reorganization, shifting from unimodal to transmodal regions. Two candidate mechanisms are proposed: dynamic shifts from shorter to longer timescales and abnormalities in the excitation-inhibition balance. These topographic shifts relate to the various psychopathological symptoms in MDD, including their co-occurrence. This concept, termed 'Topographic dynamic reorganization,' extends the earlier 'Resting state hypothesis of depression' and complements other models of MDD. Recent evidence shows that the brain exhibits 'global' activity, similar to economic and climate systems, modulating non-uniformly across local regions and networks. This modulation involves subcortical nuclei like the raphe nucleus, nucleus basalis meynert, and substantia nigra affecting cortical activity. Animal studies suggest that behavior like motor action is mediated not only by the motor cortex but also by the whole brain, featuring various regions and different timescales. In humans, global brain activity is often measured in fMRI by the global signal (GS) and its representation in specific regions or networks. Studies show that global signal topography is altered in MDD, with decreased task-related GSCORR in the DMN and premotor cortical regions when exposed to negative and fast-presented visual stimuli. These changes correlate with the severity of psychomotor retardation in MDD patients. The dysfunction in transitioning from unimodal to transmodal regions, coupled with altered global signal dynamics, underpins many of the cognitive and emotional disturbances observed in MDD. The abnormal uni-/transmodal gradients in MDD suggest a shift from unimodal lower-order sensory and motor regions to more transmodal higher-order associative regions. Recent studies show that the uni-/transmodal gradient explains lower variance of resting state signals in MDD than in healthy subjects. These findings are compatible with the observation that transmodal DMN activity is abnormally correlated with unimodal sensory activity. The abnormal excitation-inhibition balance (EIB) in MDD is also linked to changes in the unimodal transmodal topography. Findings in healthy subjects show that the unimodal transmodal topography is accompanied by corresponding gradients in the EIB. Specifically, the level of excitation relative to inhibition increases from unimodal to transmodal regions. This is in line with the observation of brain-wide changes in the GABAergic and glutamatergic levels of EIB in MDD. The topographic reorganization from unimodal to transmodal regions is accompanied by corresponding dynamic shifts from shorter to longer timescales. This is supported