Default+Mode+Network


 * Introduction**

The Default Mode Network (DMN) is a recently discovered functional network of brain areas that show increased activation during wakeful rest, a.k.a. task negative periods. Initially dismissed as noise in fMRI BOLD recordings, the coherent spontaneous fluctuations represent an intrinsic activity of the brain common to all animal species tested thus far 1. Although the function of the DMN is still poorly understood, its activity is believed to consume the vast majority of brain’s required energy and it has been implicated in a wide variety of normal and pathological processes.In humans, the DMN encompasses the cingulate cortex, medial pre-frontal cortex, medial temporal lobe, and angular gyrus. A range of task negative processes have been proposed as functions of the DMN, including introspection, daydreaming, and memory recall 2. Interestingly, age related changes in DMN connectivity seem to map onto age related changes in cognition, particularly during adolescence and old age.Altered connectivity between regions of the DMN is also associated with a variety of mental and developmental disorders, including schizophrenia, autism, attention deficit and anxiety disorders. In particular, involvement of the DMN in emotional modulation and self-referential thought may contribute to various symptomatic behaviours in disease 3. Hyper- and hypo-activation of resting networks may also have considerable differential effects on attention and thought processes. The DMN and dorsal attention networks have been found to work in a mutually inhibitory fashion, possibly under frontal lobe network control. Together with the dorsal networks, the DMN is thought to be involved in the generation of movement and the conscious perception of movement choice 4. Interestingly, the extent of the DMN activation correlates with level of consciousness, providing a possible diagnostic tool for differentiating between conscious and non-conscious non-communicative brain-damaged patients 5. toc

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1 Raichle, M.E. Two views of brain function. //Trends in Cognitive Science//. (2010) 14(4): 180-190. doi:10.1016/j.tics.2010.01.008 2 Buckner R. L., Andrews-Hanna J. R., Schacter D. L. The brain’s default network: anatomy, function, and relevance to disease. //Ann. N. Y. Acad. Sci.// (2008) 1124: 1–38. doi: 10.1196/annals.1440.011. 3 Broyd, S.J., Demanuele, C., Debener, S., Helps, S.K., James, C.J., Sonuga-Barke, E.J.S. //Neuroscience and Biobehavioral Reviews//. (2009) 33: 279-296. doi:10.1016/j.neubiorev.2008.09.002 4 Soon, C.S. et al. Unconscious determinants of free decisions in the human brain. //Nature Neuroscience// (2008) 11: 543 - 545. 5 Vanhaudenhuyse, A. et al. Default network connectivity reﬂects the level of consciousness in non-communicative brain-damaged patients. //Brain.// ( 2010) 133 (1): 161-171 .
 * References:**

**Anatomy & Function of the DMN**
= 1.Anatomy of the DMN = = 2. Functions of DMN =

2.3 DMN and Episodic Memory
= 3. DMN in Healthy and Pathological Aging =

**DMN in Mental Disorders**
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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 DMN 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

=1 Schizophrenia= =1.1 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 memory 4 .

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 PFC 5 . 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 function 2 .

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 lobule 4 <span style="font-family: Arial,Helvetica,sans-serif;">. 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 situations <span style="font-family: Arial,Helvetica,sans-serif; vertical-align: super;">5 <span style="font-family: Arial,Helvetica,sans-serif;">.

1.2 Emotional Impairment
<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">2 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">6 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">6 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">7 <span style="font-family: Arial,Helvetica,sans-serif;">. 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.

1.3 DMN as a target for treatment
<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">8 <span style="font-family: Arial,Helvetica,sans-serif;">. 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.

=2 Autism & Autism Spectrum Disorders=

2.1 Social Impairment and Theory of Mind
<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">1 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">9 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">Using [|independent component analysis] to examine functional connections within the DMN reveals an association between severity of ASD symptoms and decreased connectivity <span style="font-family: Arial,Helvetica,sans-serif; vertical-align: super;">9 <span style="font-family: Arial,Helvetica,sans-serif;">. 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. [|Multivariate analysis] 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; vertical-align: super;">10 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">11 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">11 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">12 <span style="font-family: Arial,Helvetica,sans-serif;">. 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.

2.2 Childhood & Development
<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">3 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">9 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">10 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">11 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">9 <span style="font-family: Arial,Helvetica,sans-serif;">. 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.

=3 Attention Disorders=

3.1 Working Memory & Attentional Control
<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">13 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">14 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">15 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">16 <span style="font-family: Arial,Helvetica,sans-serif;">.

<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">1 <span style="font-family: Arial,Helvetica,sans-serif;">. 

3.2 Attention Deficit/Hyperactivity Disorder (ADHD)
<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">13 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">3 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">13 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">13,17 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">1 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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;">4 Mood Disorders =

<span style="font-family: Arial,Helvetica,sans-serif;">4.1 Depression
<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">18 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">19 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">20 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">1 <span style="font-family: Arial,Helvetica,sans-serif;">.

<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">18, 20 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">20 <span style="font-family: Arial,Helvetica,sans-serif;">. 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;">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; vertical-align: super;">16 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">1 <span style="font-family: Arial,Helvetica,sans-serif;">. <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;">4.2 Bipolar Disorder
<span style="font-family: Arial,Helvetica,sans-serif;">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; vertical-align: super;">1 <span style="font-family: Arial,Helvetica,sans-serif;">. 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; vertical-align: super;">21 <span style="font-family: Arial,Helvetica,sans-serif;">. 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.

**3 DMN in Consciousness**
The advent of the resting state functional MRI (R-fMRI) has provided a powerful method of studying functional changes in the Default Mode Network (DMN) with varying levels of consciousness, one of the proposed functions of the DMN. R-fMRI connectivity analyses of regions of the DMN across different states of consciousness reveal a connection between the functional connectivity within certain DMN regions and the degree of consciousness in the patient, indicating that the DMN may be central in creating states of consciousness. Studies supporting this relation have studied patients with consciousness that has been altered naturally (by sleep), via sedation, or due to brain damage.

**3.1 DMN in States of Sedation**
R-fMRI sedation studies in humans and monkeys indicate that quantitative, but not qualitative, connectivity measures within DMN regions correlate with the level of consciousness. Temporal coherence of blood oxygen level-dependent (BOLD) signal oscillations in a brain region are taken as evidence of the activity of the studied region, where the presence of BOLD signals in the DMN in resting but not task-dependent states helped implicate the network. The fact that BOLD signal oscillations across the human DMN are also present in both rest and conscious sedation with midazolam indicate that the qualitative presence of the BOLD oscillations also does not to correlate with the level of consciousness 1. These results echo the findings of previous studies on the DMN in monkeys sedated with isoﬂurane, where it was similarly found that BOLD oscillations were present across states of consciousness 2. These results indicate that the DMN is capable of supporting aspects of our being that are consistent across different levels of consciousness. On the other hand, when regions of the DMN are examined separately, there emerge differences from rest to conscious sedation. Both region-of-interest (ROI)-based analysis of fMRI acquired during conscious sedation and through use of independent component analysis (ICA) 3 show that the primary sensory and sensory-motor networks of the DMN have higher functional connectivity during conscious sedation than during wakeful rest. Thus, while a qualitative estimate of the presence or absence of DMN activity does not appear to correspond to the presence or absence of consciousness, quantitative measures of reduced connectivity within the DMN may reliably correlate with the level of consciousness.

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** 3.2 DMN in The Sleep Cycle **

R-fMRI studies in humans reveal a correlation between the sleep-induced reduction of consciousness and changes in functional correlation between DMN network components. These DMN changes are seen only in deep, but not light, sleep 4. Though the transition from rest to light sleep is associated with signiﬁcant changes in several cortical areas (most notably the visual cortex (ref to other wiki)) light sleep shows conserved correlations among the brain regions of the DMN, as measured by BOLD fMRI ﬂuctuations 5. This suggests that that activity in the DMN does not require the level of consciousness seen in wakefulness or rest. In deep sleep, however, the DMN's activity is different from that of rest or light sleep. The most notably reduced correlation within the DMN is that between its frontal and posterior areas 6 (Fig.1). Given that the frontal cortex is known to be a main contributor to such executive processes as logical reasoning 7, its changing correlation with the posterior DMN and other brain networks may be related to the illogic and nonsense contained within dreams, which are generally only noted by the dreamer until the wakefulness-associated correlations of the frontal cortex return. Notably, despite changes in correlation, activity levels in the individual network components of the DMN are preserved, “suggesting that it is not activity per se but rather the coherent activation of all parts within the net work that leads to a conscious experience”8.

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**3.3 In Brain-damaged Persons**
 Yet another patient group to show that DMN connectivity reﬂects the level of the patient's consciousness is that of non-communicative brain-damaged patients 9 (Fig. 2). In these studies, though several areas of the DMN were implicated as relating to consciousness, the greatest predictor of consciousness was found to be the connectivity of the PCC/precuneus (Fig. 3), where connectivity is significantly lesser in unconscious patients compared with minimally conscious patients 10. The strength of this correlation was found to be strong enough to differentiate minimally conscious (vegetative) from unconscious

(comatose) patients; a result with powerful clinical implications (selfwiki link). The precuneus is a medial part of the superior parietal lobule, and has consistently been linked to consciousness; its activity is disrupted in altered states of consciousness beyond that of brain damage (for ex. In epilepsy), and the precuneus has the brain's highest rates of cerebral glucose metabolism during wakefulness but the lowest rates of cerebral glucose metabolism during anesthesia 11. Additionally, the precuneus is one of the brain areas that is most deactivated during deep sleep and rapid eye movement (REM) sleep 12.



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**3.4 Clinical Significance of the Consciousness and DMN Connectivity Correlate**
Differentiating between minimally conscious (vegetative) and unconscious (coma) patients presents a clinical challenge, both groups of patients being non-communicative, and given the current lack of an objective measure consciousness. Currently, the consciousness of non-communicative patients is estimated following scales assessing the patient's response to behavioural tests and the presentation of certain clinical signs. Many such scales have been developed for the quantiﬁcation of assessed consciousness, the most commonly used being the Glasgow Coma Scale. Though useful in many clinical situations, these scales have proved disconcertingly unreliable in differentiating minimally conscious from unconscious patients, where rates of misdiagnosis having been reported up to 40%. For instance, a 1993 U.S report found that 37% of patients admitted more than 1 month post-injury and diagnosed with coma or persistent vegetative state 13 and 43% of patients admitted to a profound brain injury unit at least 6 months following their brain damage 14 had some level of awareness despite their consciousness-precluding diagnosis.

To be able to supply the ethically and medically optimal treatments, a reliable differentiation between that minimally conscious and unconscious patients is critical. The resting state fMRI may prove to be a useful tool in this process; the fact that connectivity within areas of the DMN may be quantitatively related (self ref) to the level of consciousness suggest a new, more objective way of assessing consciousness. The fact that resting state fMRIs are much easier to administer than a standard fMRI is hoped to prove the tool practical on top of reliable.

Importantly, the reports on the misdiagnosis of non-communicative patients show that there is also a large potential for improvement within the current diagnostic system; in the patients included in the reports on the rates of misdiagnosis, a correct diagnosis using existing paradigms was possible - otherwise the diagnosis could not have been corrected.

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