DMN+in+Mental+Disorders

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toc  Activation of the DMN network has been linked to a variety of introspective cognitive processes. DMN nodes such as the posterior cingulate (PCC), medial prefrontal cortex (mPFC) and limbic structures including amygdala and hippocampus are strongly implicated in social and emotional processing, self-referential thought, self monitoring of psychological states and recognition of those states in others. 1 Impairment of these processes is associated with a multiplicity of mental disorders, and since its discovery the DMN has been linked to a wide variety of abnormal behavioural and cognitive states. Depending on the manner of the disruption, atypical functioning of the D MN may produce a gamut of distinct cognitive symptoms. Active mainly during task-negative situations, the DMN is negatively correlated with activation of more externally attentive task-positive networks; disruption of this balance may lead to a general hyper- or hypo- activation of the DMN and negatively impact attention, working memory and emotional capacity. 2  Additionally, the DMN may also be abnormal at specific functional or structural connections, creating more specific social or cognitive complaints. The network undergoes significant structural and functional maturation during childhood and early adolescence and atypical development may explain the emergence of mental disorders during those periods. 3

=Schizophrenia= =Cognitive Deficits= Schizophrenia is a psychotic disorder that includes impairments in three main categories; negative, positive and cognitive symptoms. Recent work in the default mode network has shown that abnormalities within default nodes can cause cognitive impairment by affecting the brain’s ability to switch into task-positive thought modalities. Partial hyperfrontality in schizophrenia has been explained as cortical inefficiency but may instead be indicative of the DMN failing to deactivate, thus placing a higher cognitive burden on working memory4.

Most tasks used in examining the DMN of schizophrenic patients focus on frontal/executive control and suggest that anterior regions fail to deactivate during non-rest periods. In a 2010 multimodal imaging study by Pomarol-Clotet and colleagues the medial prefrontal cortex (mPFC), the anterior node of the DMN, showed obvious structural and functional abnormalities. Other affected regions include the anterior cingulate cortex (aCC), supplementary motor areas and anterior corona radiata, as well as the right dorsal lateral PFC5. Atypical activity of the aCC is believed to be heavily involved in attention and working memory deficits, acting in a monitoring capacity to allow switching between task-positive and task-negative network activity. Notably, the aCC in schizophrenics shows signs of reduced volume of activation, suggesting an impairment in modulatory function2.

The attenuation of DMN activity places added cognitive burden on the schizophrenic brain, reducing available resources and offering a possible explanation for the slow response times and working memory deficits observed during executive functioning. Schizophrenic patients show decreased connectivity with the posterior cingulate cortex (pCC) but increased connections to both the precuneus and inferior parietal lobule4. Grey matter morphology is also abnormal in DMN nodes, however the exact nature of these structural changes is unclear; several studies support grey matter decreases in mPFC only while others report grey matter loss in posterior nodes as well. The mPFC acts as a major relay point connecting posterior and anterior DMN regions, thus damage to this region may severely impair ability to modulate network activation to appropriate situations5.

Emotional Impairment
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">When performing tasks that make demands on emotional cognition, schizophrenic patients show more widespread failure to deactivate the DMN. Given a task relying on identification of facial emotion, schizophrenic patients show prolonged activation of both anterior and posterior DMN, compared to attenuation of anterior activation only during a cognitive memory task<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">2. Several studies have reported hyperactivation in facial processing regions such as the posterior cingulate and precuneus during emotional judgment tasks, however this is now believed to be a mislabeling of sustained activation, an error stemming from the type of imaging protocols used in earlier studies. It is unclear why emotional tasks produce more widespread failure in the DMN, although it may be speculated that these types of tasks rely more heavily on mentation processes that require pCC and precuneus activity<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">6. This prolonged activation may be responsible for difficulties in separating self from others, correctly identifying mental states and making correct emotional judgments. Difficulty in switching out of default mode activity may result in a constant internalizing of outside information, leading to delusions and impaired emotional control. Persistent activation of the mPFC may contribute to difficulties in emotional regulation, judgment and decision-making. It is also worth noting that several studies report lateralization of DMN abnormalities, with more severely impoverished connections to the medial temporal lobe and language areas in the left hemisphere during rest<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">6. It has been suggested that abnormal connectivity between mentation and language areas may play a role in symptoms such as thought insertion and auditory hallucination.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Anhedonia is frequently associated with schizophrenia and may act as a susceptibility factor for the condition. Schizophrenic patients report high levels of physical anhedonia, which appear to be related to areas of medial prefrontal cortex hypoactivity in the default network<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">7. This is in contrast to non-schizophrenic reports of physical anhedonia, which are not correlated with frontal DMN activity. Additionally, this anhedonia does not appear related to other negative symptoms of schizophrenia.

DMN as a target for treatment
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">There is some evidence that second-generation antipsychotics improve cognitive deficits through influence on the DMN. A longitudinal study of [|olanzapine], an atypical antipsychotic, given to previously drug-naïve schizophrenic patients suggests that the drug improves working memory function through strengthening of DMN connectivity with the ventromedial PFC<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">8. It is unclear whether this effect is achieved through dopamine signaling in the pCC directly or through altered activation in the PFC. Dopamine appears to have a makor role in modulating DMN activity as shown by previous studies on levodopa and apomorphine as well as studies of methylphenidate in ADHD. Improvement of dopaminergic signaling in the default network presents a promising pharmacological target for improving schizophrenic functioning.

=Autism & Autism Spectrum Disorders=

Social Impairment and Theory of Mind
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Autism spectrum disorders (ASDs) are defined by a triad of impairments in communicating, socializing and imaginative play<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">1. These failures have been described as an inability to use [|Theory of Mind] (ToM), suggesting that ASD deficits emerge from an inability to relate to other people and understand others’ mental states<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">9. These ToM processes are heavily supported by DMN activity. ToM has been reliably linked to a distinct neural network that closely follows the DMN and also shows high functional connectivity with the mPFC, a major DMN node. Linking ToM to distinct DMN failures has become a major area of research, tying theory to pathophysiology.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Using [|independent component analysis] to examine functional connections within the DMN <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">reveals an association between severity of ASD symptoms and decreased connectivity <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">9 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">. Consistent with the body of autism research, long-range connections between the nodes of the DMN appear to be most severely affected while local connectivity remains relatively normal. As a result of these structural connectivity deficits the default network in ASD also shows reduced functional connectivity between midline nodes. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">[|Multivariate analysis] <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;"> of the anterior and posterior regions of the DMN suggests that the different nodes play distinct roles in supporting introspective processes <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">10 <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">. Anterior regions associated with mPFC and aCC are linked to typical ASD mannerisms such as stereotyped behaviour while the pCC and precuneus support mentalizing and self-referential thought. A weaker functional connection between these nodes is associated with more severe social deficits in ASD. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Alternate studies of the DMN in ASD have focused more explicitly on abnormalities in self-referential thinking. Examination of the ASD brain while making judgments about the self-relatedness of various personality traits and physical characteristics shows significant reduction of activity only in the ventral mPFC and ventral aCC, and a slight generalized decrease across the entire network<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">11. Notably, several areas of the DMN show different activation patterns in internal versus external judgement conditions. Healthy individuals exhibit slightly higher activity in the mPFC during internal judgments (a conditional effect not seen in ASD), and ASD patients show reduced activity of the pCC when making internal judgments (a conditional effect not seen in controls). These task-specific aberrations in DMN function are not as significant or consistent as the task-independent hypoactivation of the mPFC<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">11. Further research comparing pervasive dysfunction and task-specific failures is required to shed light on the underlying source of ASD introspective deficits. Decoupling of the mPFC from pCC/precuneus remains the most commonly speculated source of core ASD dysfunction.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Although research into the DMN’s role in other ASD conditions is sparse, a study of [|Fragile X] syndrome also revealed disrupted activity in the ventral mPFC<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">12. In comparison to typically developing children this area failed to show normal levels of deactivation during task-positive testing, suggesting deficient self-state monitoring abilities. Failure to deactivate frontal DMN nodes is frequently found as a result of decoupling of the functional connections with pCC, as described in other ASD studies.

Childhood & Development
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">The DMN undergoes extensive connectivity changes between childhood and adolescence, allowing increasingly sophisticated mental thought as it matures. Long-range connections between midline nodes such as pCC-mPFC tend to be least mature in children and undergo the most intense development<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">3. Maturation of the DMN depends on the strengthening of these inter-nodal connections, supported by development of the cingulum. These long-range connections are disrupted and disorganized in ASD individuals and adult ASD individuals show hypoactive functional connections between pCC-mPFC<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">9. Developmental difficulties in refinement of the white matter tracts linking DMN nodes may prevent children with ASD from acquiring typical social and mentation patterns.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Disruptions of the DMN are not restricted to white matter aberrations; MRI studies of children and adolescents with ASD reveal significant morphological differences in default nodes. Using multivariate pattern analysis to compare gray matter in the pCC and mPFC it is possible to discriminate between ASD and typically developing children with a 90% accuracy<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">10. Notably, the strongest outliers using this method (those individuals with the most obvious disruptions in pCC gray matter) positively correlate with ASD symptom severity. Gray matter deficits have also been reported in toddlers with ASD, however no studies specifically investigating the DMN have been performed to date<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">11. It is speculated that deficits in synaptic pruning prevent refinement of gray matter nodes in early childhood and subsequently prevent formation of strong, efficient network connections.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">In addition to its importance in ASD symptoms, the DMN represents a new way in which to study the ASD brain without depending so heavily on high-functioning cognitive ability<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">9. Although ASD patients span a wide range of varying abilities most studies to date rely on efficient completion of a task in order to provide comparative data for imaging, eliminating the possibility of data collection from low- and middle- functioning individuals. Obtaining data through analysis of rest-state activity will allow for studies on a much more broad sample of the ASD community and will likely reveal previously unknown nuances in function and pathophysiology. Additionally, the use of rest-state protocols may be used for performing studies on younger ASD patients and contribute to a better understanding of how developmental failings in white matter maturation affect DMN function.

=Attention Disorders=

Working Memory & Attentional Control
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Activation of the DMN is anti-correlated with the task-positive frontoparietal network (FPN), which is required for performance of attention-demanding tasks<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">13. In healthy controls the DMN will be disengaged during these periods of external attention focusing, but when the nodes of the default network are abnormally active the balance between DMN and FPN are disrupted. In patients experiencing attention deficits following traumatic brain injury the severity of the deficit is positively correlated with attenuated levels of DMN activity<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">14. Failure to deactivate the DMN, in particular posterior areas such as pCC and precuneus, is associated with impaired attentional control and spikes of activity in these regions can predict momentary lapses even in healthy populations. Sustained activation of the DMN during task-positive situations creates additional cognitive load, hindering the efficiency of the FPN.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Studies of [|working memory] (WM) decline in old age have also linked persistent activity in the pCC with impaired attention. As in [|ADHD] patients, geriatric populations show reduced connectivity between DMN nodes<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">15. Weak inter-nodal connections are associated with decreased ability to suppress DMN activation during task-positive situations. The pCC is a key relay point in the DMN connecting mPFC with the entorhinal cortex, with stronger mPFC-pCC connectivity robustly predictive of better WM performance. In keeping with this finding, connections between these two regions show significant weakening in correlation with age-related cognitive decline<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">16.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Effective modulation of DMN and FPN activation for appropriate situations is critical to cognitive efficiency. Many disorders that affect WM, cognitive capacity and attentional control have been associated with abnormalities within the default network. Sustained activation of the pCC has been noted in patients with mild cognitive impairment and [|Alzheimer’s disease], and weakened connections between PFC and posterior DMN regions have been associated with cognitive slowing and poor concentration in schizophrenic patients<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">1. 

Attention Deficit/Hyperactivity Disorder (ADHD)
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Studies of ADHD in adults show a generalized reduction of coherence within the DMN, suggesting an underdevelopment or lack of maturation in this network<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">13. In children the DMN is typically less coherent and less defined, showing stronger links with non-DMN regions that decrease through adolescence and give way to a more tightly delineated rest-state network<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">3. These findings have contributed to a hypothesis of altered DMN development giving rise to attention disorders. Analysis of children with ADHD reveals that functional connections between the midline nodes of the DMN are significantly weaker than controls. Additionally, children with ADHD show disturbed maturation patterns in the DMN, described as failures of normal circuit integration and segregation; connections that typically strengthen the DMN are weaker in ADHD and connections that typically become weaker with age are stronger in ADHD<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">13. Consistent with this finding, many ADHD patients show significant improvement with age indicating a very delayed maturation of cortical connections.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">It is often noted that ADHD patients are not incapable of prolonged attention; in conditions where paying attention is highly motivated performance levels may not be significantly different between patients and typical controls. The level of performance and motivation in a task is evident in imaging of the DMN – ADHD patients given a low-incentive task show attenuated activation of the DMN, however given a high-incentive task deactivation of the DMN is much stronger<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">13,17. In children being treated with [|methylphenidate] wild-type levels of DMN deactivation are produced for both motivation levels. It is hypothesized that ADHD effectively raises the motivational threshold determining whether a task is important enough to hold attention. Methylphenidate heightens attentional control by limiting glucose metabolism in the DMN, thus preventing interference with the FPN during cognitive tasks. Suppression of DMN nodes may also interfere with mentation processes during task-negative periods, producing undesirable side effects<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">1. Understanding of how situation-specific modulation of DMN activity is controlled may help to produce new pharmacologic tools to control attention disorders.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Recent evidence links polymorphism of the // DAT1 // gene with suppression of the DMN, which correlates strongly with ADHD symptom severity. Adult and childhood ADHD have been tentatively linked to distinct allelic variations of the dopamine transporter and may affect functional connectivity of the network in different ways 17. Dysfunctional dopaminergic signalling may contribute to difficulties in modulating DMN activity and a lack of functional cohesion across different nodes of the network.

=<span style="font-family: Arial,Helvetica,sans-serif;">Mood Disorders =

<span style="font-family: Arial,Helvetica,sans-serif;">Depression
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Considered to be involved in key aspects of self-referential thought and mentation processes, the DMN is believed to play a role in the pathophysiology of [|major depressive disorder] (MDD). [|Rumination] and overgeneral autobiographical memory (OGM), both symptoms and risk factors for MDD, are more severe in drug naïve patients with greater functional connectivity abnormalities between midline DMN nodes<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">18. Across MDD individuals imaging of the resting brain reveals increased connectivity between aCC and mPFC and decreased connectivity in pCC, precuneus and the angular gyrus.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Abnormality in the ventral aCC and mPFC appears to be linked and mutually reinforcing, such that reduction of activity in one area will also decrease hyperactivity in the other<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">19. This heightened functional connectivity between aCC and mPFC likely play a critical role in distorted self-thoughts, being positively correlated with rumination scores. Alternate studies suggest that during task-negative time periods MDDs demonstrate hyperactivity of the subgenual cingulate area of the mPFC and increased connectivity between this region and the pCC. This neural mechanism may act to constrain memories and thoughts, trapping patients into negative rumination<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">20. The subgenual cingulate has been linked to sadness and depression in multiple studies and is a frequent target for deep brain stimulation in treatment-resistant depression; sustained activation of this area in association with the DMN may be a key mechanism for pervasive negative thoughts and mentation. These abnormalities are not as apparent during task-positive situations, as activation of DMN areas (and pCC particularly) is diminished when attention networks are active<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">1.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Decreased functional connections in posterior DMN nodes correlated strongly with higher OGM scores, indicating an important role for the DMN in retrieval of autobiographical memories and adaptive construction of a personal narrative<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">18, 20. Decoupling of DMN activity may increase the difficulty of breaking away from negative thoughts, restricting memory retrieval and producing an illusion of constant misery through selectivity.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">In accordance with imaging studies, MDD patients show abnormal bloodflow throughout the DMN with reduced negative BOLD responses in anterior midline nodes and increased responses in posterior nodes compared to controls. In a task requiring judgments of self-relatedness of pictures, judgments by healthy controls were strongly related to modulation of dorsal mPFC activation<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">20. This relationship is not apparent in the brains of depressed individuals and may promote disproportionate levels of self-focus in MDD.

<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Analysis of DMN function has also been demonstrated in late-life depression, however the nature of the disruptions are not identical to that seen in mid-life depression<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">16. Consistent with the vascular theory of late-life depression, geriatric patients show high levels of white matter hyperintensity in the DMNin addition to the abnormal structural connections in mPFC seen in mid-life patients. Differences in DMN pathophysiology seen in late-life depression and mild cognitive impairment may aid in earlier diagnoses and treatment, as well as helping to predict severity of episodes and likelihood of recurring episodes<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">1. <span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">media type="youtube" key="MXz-XhbAZXc" height="315" width="560"

<span style="font-family: Arial,Helvetica,sans-serif;">Bipolar Disorder
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt;">Abnormalities in anterior DMN nodes including the aCC and mPFC have been uncovered in [|bipolar disorder] patients (BD) but the pathophysiological role of the DMN is unclear<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">1. Imaging of BD patients using fMRI has revealed several unusual DMN features; incorporation of atypical regions such as the occipital, lateral parietal and pontine areas and also reduced coherence between typical DMN nodes such as the fusiform gyrus and hippocampus<span style="font-family: Arial,Helvetica,sans-serif; font-size: 12pt; vertical-align: super;">21. These disturbances seem particular to BD in contrast to more general mPFC abnormalities that are also seen in psychotic disorders such as schizophrenia. In manic episodes in particular, the largest areas of disturbance appear to be in the mPFC and hippocampus, both of which are crucial to limbic system function and control. Additionally, BD patients seem to show reduced activation of posterior DMN nodes but more research is required to confirm this finding.