Review
The role of default network deactivation in cognition and disease

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A considerable body of evidence has accumulated over recent years on the functions of the default-mode network (DMN) – a set of brain regions whose activity is high when the mind is not engaged in specific behavioral tasks and low during focused attention on the external environment. In this review, we focus on DMN suppression and its functional role in health and disease, summarizing evidence that spans several disciplines, including cognitive neuroscience, pharmacological neuroimaging, clinical neuroscience, and theoretical neuroscience. Collectively, this research highlights the functional relevance of DMN suppression for goal-directed cognition, possibly by reducing goal-irrelevant functions supported by the DMN (e.g., mind-wandering), and illustrates the functional significance of DMN suppression deficits in severe mental illness.

Section snippets

Brief history of the default-mode network (DMN)

Non-invasive neuroimaging, especially functional MRI (fMRI), has enabled the characterization of large-scale neural systems involved in human cognitive processes. A set of regions that has been identified via functional MRI (fMRI) and includes hubs around the anterior and posterior medial cortex, bilateral temporal lobes, as well as superior frontal and parietal cortices, is characterized by high activity when the mind is not engaged in specific behavioral tasks and low activity during focused

Functional relevance of DMN deactivation: can the DMN signal be thought of as a source of distraction?

Before we discuss DMN deactivation, it is important to consider briefly what functions DMN activation might reflect [13]. As noted, the prevailing hypotheses suggest that it supports computations necessary for self-referential thought (i.e., internal mentation, daydreaming, etc. 1, 2, 39, 40, 41, 42, 43, 44; for a review, see 3, 45). The dominant proposal argues that the DMN may enable internal construction of mental models that support self-referential computations 3, 42. This set of functions

The role of DMN suppression in mental illness

A growing body of work using rs-fcMRI implicates the DMN in cognitive impairments and symptoms associated with neuropsychiatric disorders, such as schizophrenia and depression (see 3, 68), both of which impact cognitive function. Schizophrenia is a disabling disorder associated with delusions and hallucinations [69], cognitive impairment [70], social isolation, and emotional dysfunction [71]. Lack of DMN suppression in schizophrenia has been observed when affected individuals perform demanding

Pharmacological neuroimaging studies: identifying the synaptic mechanisms of DMN suppression

In order to fully understand the clinical significance of DMN abnormalities, it will be important to understand the synaptic mechanisms underlying DMN suppression and suppression failures. Recently, Mayer and colleagues hypothesized that DMN suppression involves long-range projections onto inhibitory interneurons [52]. Dysfunction in inhibitory mechanisms and optimal functional antagonism across circuits has been implicated in cognitive impairment 88, 89. However, there have been few direct

Concluding remarks

In this review, we discussed evidence that reveals the functional relevance of DMN suppression and its importance in goal-directed externally-oriented cognition. Furthermore, we highlighted two neuropsychiatric conditions that exhibit a potential failure to suppress DMN signals, which impacts symptoms and cognition, possibly due to different pathophysiological mechanisms. Based on pharmacological studies, we discussed the role of both fast and slow neurotransmission in optimal modulation of DMN

Disclosure statement

J.H.K. has been a paid consultant for AbbVie, Inc. (formerly Abbott Laboratories), Aisling Capital, LLC, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, Eisai, Inc., Eli Lilly and Co., Gilead Sciences, Inc., Lundbeck Research USA, Medivation, Inc., Otsuka Pharmaceutical Development & Commercialization, Inc., Roche F. Hoffmann-La Roche Ltd, Sage Therapeutics, Inc., Shire Pharmaceuticals, Takeda Industries, and Teva Pharmaceutical Industries, Ltd. J.H.K. serves as a member of the Scientific

Acknowledgments

We thank Megan Ichinose for assistance with this manuscript and Deanna M. Barch for insightful discussions and input. We also thank three anonymous reviewers for helpful comments and constructive criticism on how to improve the manuscript. Lastly, we thank our funding sources. This work was supported by the NIH grant DP5OD012109-01 (AA), NIAAA grant 2P50AA012870-11 (JHK, AA), NIH grant MH096801 (MWC), and CTSA Grant Number UL1 RR024139 from the National Center for Research Resources (NCRR) and

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