Brain networks and connectivity in ADHD.

• 1. Network connectivity in ADHD
  • 1.1. Frontal-parietal attention network in ADHD
    • 1.1.1. Decreased connectivity within the dorsal frontoparietal executive network
    • 1.1.2. Altered structure of the frontal-parietal attentional network
    • 1.1.3. Altered connectivity of the frontal-parietal attentional network to other brain networks
    • 1.1.4. Reduced connectivity mPFC-dlPFC predicted subsequent inattention
    • 1.1.5. Decreased connectivity sgACC-dlPFC predicted later anxiety/depression symptoms
  • 1.2. Salience Network
  • 1.3. Rich club / hubs connectivity reduced
  • 1.4. Reduced connectivity in idle state
  • 1.5. Decreased synchronization of attentional networks and sensory cortex areas
  • 1.6. DMN (Default Mode Network)
    • 1.6.1. Reduced deactivability of the Default Mode Network (DMN)
    • 1.6.2. Increased connectivity of the Default Mode Network (DMN)
    • 1.6.3. Normalization of DMN by stimulants
  • 1.7. Thalamic-PFC connectivity in ADHD unidirectional
  • 1.8. Connectivity between right caudate nucleus and occipital nucleus accumbens increased
  • 1.9. Further studies on brain connectivity and ADHD
  • 1.10. Impaired signal variability of spontaneous neuronal activity
  • 1.11. Dopaminergic brain networks and ADHD
    • 1.11.1. Frontal-Striatal Loop
    • 1.11.2. Frontal cerebellar loop
    • 1.11.3. Frontal-limbic loop
  • 1.12. ADHD symptoms and brain connectivity
• 2. Brain networks
  • 2.1. Default mode network (DMN)
  • 2.2. Attention Networks
    • 2.2.1. Fronto-parietal (attentional/executive) network / anterior attentional network
    • 2.2.2. Spatial attention network / posterior attention network / dorsal attention network
    • 2.2.3. Ventral attention network / vigilance network
  • 2.3. Salience Network
  • 2.4. Visual network
  • 2.5. Auditory network
  • 2.6. Affective network
  • 2.7. Motor networks
  • 2.8. Cerebellar network
  • 2.9. Voice Network
  • 2.10. Temporal network
  • 2.11. Limbic network
  • 2.12. Cortical network
  • 2.13. Cingulo-Opercular Network
  • 2.14. Memory network
  • 2.15. Subcortical network
• 3. Neurotransmitters and functional connectivity
  • 3.1. Dopamine and connectivity of brain networks

1. Network connectivity in ADHD¶

Quite a few studies analyzed the connectivity of different brain networks in ADHD.
One study compared 4 of these studies and found large inconsistencies. Divergent connectivity between default mode network and executive network in ADHD was found to be robust. Further, consistency of results was greatest in ADHD-C.¹ It is possible that the different ADHD subtypes show substantial differences in their brain network connectivity.

One study achieved an ADHD diagnostic accuracy of 73 % (specificity 91.6 %, sensitivity 65.5 %) by means of a machine learning driven analysis of functional connectivity.² These are still not very helpful values for a diagnosis in practice.

1.1. Frontal-parietal attention network in ADHD¶

The frontal-parietal attention network is involved in cognitive processes, especially attention.

1.1.1. Decreased connectivity within the dorsal frontoparietal executive network¶

One study reports decreased connectivity in the dorsal frontoparietal executive network, consisting of

• Right dlPFC
• Posterior parietal cortex

correlated with the severity of attention problems in ADHD. This correlation was independent of age or gender
Increased connectivity was also associated with increased attention and better accuracy on NoGo tasks.³

One study found no correlates of network connectivity related to the symptom of cognitive flexibility that would have revealed differences between autism spectrum disorders, ADHD, or nonaffected individuals.⁴

1.1.2. Altered structure of the frontal-parietal attentional network¶

ADHD-affected children showed in the frontal-parietal attentional network compared to non-affected children

• A larger diameter
• A lower number of leaves,
• A lower tree hierarchy
• A lower kappa

which at the same time correlated with the ADHD symptom score.

• Clustering coefficient and
• Path length

were unchanged.
In children with ADHD, the frontal-parietal attentional network could possibly be more decentrally organized (line-like topology) and less centrally organized (star-like topology). This appears to result in more random connectivity with impaired global efficiency and network decentralization in ADHD.⁵

1.1.3. Altered connectivity of the frontal-parietal attentional network to other brain networks¶

A meta-analysis found in ADHD a⁶

• Increased connectivity between
  • Fronto-parietal network and
    • Default Mode Network
    • Affective network
• Reduced connectivity between
  • Fronto-parietal network and
    • Ventral attention network
    • Somatosensory network

One study found reduced structure-function coupling in connection bundles between hubs (rich clubs?) and peripheral regions in ADHD. This particularly affected connections between the fronto-parietal network and sensory networks. Reduced structure-function coupling correlated with increased ADHD symptoms and increased heterogeneity in neuronal noise variability across brain regions.⁷

1.1.4. Reduced connectivity mPFC-dlPFC predicted subsequent inattention¶

A study of ADHD children found that increased connectivity between mPFC and dlPFC at age 7 correlated with decreased attention by age 11.⁸

1.1.5. Decreased connectivity sgACC-dlPFC predicted later anxiety/depression symptoms¶

A study of ADHD children with ADHD found that decreased connectivity between the subgenual anterior cingulate cortex (sgACC) relevant to moods and the dlPFC at age 7 correlated with increased internalizing symptoms (anxiety, depression) by age 11.⁸

1.2. Salience Network¶

One study found abnormalities in ADHD in the connectivity of the salience network, consisting of³

• Right anterior insula
• Right dorsal anterior cingulate cortex (rdACC)
• Right ventrolateral PFC (rvlPFC).

Another study found increased connectivity within the salience network and decreased connectivity between the DMN and salience network in non-ADHD-affected siblings compared to their ADHD-affected siblings as well as healthy control subjects. ADHD-affected individuals showed increased connectivity between the DMN and task-positive networks compared with their unaffected siblings and healthy control subjects. ADHD-affected individuals and their unaffected siblings did not show consistent changes in functional connectivity to healthy control subjects. These results were largely confirmed by complementary pairwise connectomic comparisons. However, the main connectivity differences between sibling groups could not be replicated in a subsample closely matched for age and sex (20 subject-sibling pairs and 60 TD).⁹

1.3. Rich club / hubs connectivity reduced¶

The term rich club or hub refers to networking clusters of brain regions that are more interconnected than the average of brain regions and therefore form the functional backbone of the brain

One study found a reduced density of rich clubs among structural nodes in adults with ADHD, including¹⁰

• Bilateral precuneus
• Insula
• Caudate nucleus
• Left putamen
• Right sulcus calcarinus

Further, reduced global efficiency was found in adults with ADHD compared with nonaffected individuals, which may result from a lower density of rich-club connections in ADHD.¹⁰

Another study found deviant asymmetry patterns in connectivity measures of rich-club connectivity in ADHD sufferers, e.g., more feeder connections. Further, reduced right asymmetry was found in connectivity measurements of local connections to multiple peripheral brain regions. Furthermore, abnormal regional asymmetry scores correlated with ADHD symptoms.¹¹

Another study observed that organization of brain networks around hubs was associated with reduced cognitive impairment under stress. Further, it was found that the same neurophysiological features of brain connectivity could be associated with quite different problems under stress. No 1:1 association was found between brain network patterns and specific symptoms. Children whose brain networks were not organized around hubs showed a wide variance in symptoms in response to stress.¹²

One study described changes in nodal efficiency (“node efficiency”) in children with ADHD:¹³

• Increase in the visual attention network
• Increase in the dorsal attention network
• Decrease in somatomotor network
• Acceptance in default mode network

Impaired functional connectivity and nodal efficiency correlated significantly with ADHD symptom severity.

1.4. Reduced connectivity in idle state¶

In ADHD, reduced global connectivity between different brain networks has been found in the resting state. This was interpreted as an indication of ADHD as a developmental delay.¹⁴

1.5. Decreased synchronization of attentional networks and sensory cortex areas¶

Desynchronization of attentional networks and sensory cortex areas was observed in ADHD sufferers who followed a conversation between several people.¹⁵

1.6. DMN (Default Mode Network)¶

Since the brain is active even when it is not managing tasks, a separate network is responsible for managing rest: the Default Mode Network (DMN). It is active when the mind is not engaged in another task or is “at rest.”¹⁶ The DMN controls things like mind wandering, daydreaming, relaxing, and thinking about oneself and one’s life. It follows that the DMN is deactivated when the brain is performing a task.¹⁷ The DMN is not a single anatomical structure, but includes connections between different areas, including¹⁷

• Anterior mPFC
• Posterior cingulate cortex
• Dorsomedial PFC subsystem
• Medial temporal lobe subsystem.

1.6.1. Reduced deactivability of the Default Mode Network (DMN)¶

FMRI studies of the DMN show dysfunction of the DMN in both children and adults with ADHD. ADHD impairs the ability to quickly shut down the DMN and “turn on” the task-positive networks. As a result, ADHD sufferers persist longer in a particular mental state. To end the persistence, a stronger sensory stimulus is needed.¹⁸¹⁹ This inability to deactivate or turn off the DMN is exacerbated by more cognitively demanding tasks.²⁰

The deactivability of the DMN in ADHD could be increased by high rewards (which we understand to cause intrinsic interest) such that it was equivalent to the deactivability in unaffected individuals. MPH showed the same effect.²¹

1.6.2. Increased connectivity of the Default Mode Network (DMN)¶

One study found higher total and subscale scores on SNAP-IV and SRS in adolescents with ADHD. Higher SNAP-IV and SRS scores correlated with

• Higher functional connectivity between
  • DMN (ventromedial PFC) and cinguloopercular network (anterior insula)
  • FPN (dorsolateral and prefrontal cortex) and cinguloopercular network
• Lower functional connectivity between
  • DMN (posterior cingulate cortex) and frontoparietal network (inferior parietal lobes)
  • DMN (precuneus) and cinguloopercular network (temporoparietal junction).

The authors conclude that social cognition and communication impairments and ADHD may share abnormal functional connectivity in the DMN, frontoparietal network, and cinguloopercular network.²²

Other studies also found altered connectivity of the DMN in ADHD.²³ Increased correlations of the DMN at rest were found between the posterior cingulate cortex/precuneus and the right middle frontal gyrus. These existed equally in adult ADHD sufferers and their first-degree relatives, but not in unaffected control subjects. The observed connectivity changes correlated with higher sustained attention problems. Moreover, this brain-based neurocognitive trait dimensionally explained ADHD symptom variability.²⁴

Another study found increased connectivity between the DMN and task-positive networks in ADHD-affected siblings compared with their unaffected siblings and healthy control subjects. Non-ADHD-affected siblings, unlike their ADHD-affected siblings as compared to healthy control subjects, showed increased connectivity within the salience network and decreased connectivity between the DMN and salience network. ADHD-affected and their unaffected siblings showed no consistent changes in functional connectivity to healthy control subjects. These results were largely confirmed by complementary pairwise connectomic comparisons, but the main connectivity differences between sibling groups could not be replicated in a subsample closely matched for age and sex (20 subject-sibling pairs and 60 TD).⁹

One study found strong coherence of the left dorsal anterior cingulate cortex (dACC) with DMN components in children with ADHD. Further, a seed-to-voxel connectivity analysis using the left dorsal anterior cingulate as the seed region found evidence of higher temporal coherence with other neural networks compared to unaffected children. Children with ADHD appear to have a more distributed resting-state connectivity pattern in the DMN and other networks.²⁵

1.6.3. Normalization of DMN by stimulants¶

Moreover, functional imaging studies in ADHD sufferers show not only differences in DMN regions compared to healthy controls, but also a return to normal functions upon treatment with stimulants (here: methylphenidate).^26272829 The more intrinsically motivated attentional control in ADHD causes attention and its controllability to be as high as in unaffected individuals when interest is appropriately high (intrinsic) and to deviate from the attention of unaffected individuals only when interest is lower (intrinsic). This is controlled by the DMN. Stimulants are able to bring the attentional control of ADHD sufferers in the absence of (intrinsic) interest into line with that of non-affected individuals.³⁰

1.7. Thalamic-PFC connectivity in ADHD unidirectional¶

One study found unidirectional transmitting connectivity from the cortex to the thalamus in the alpha, beta, and gamma bands in ADHD -affected individuals, whereas nonaffected individuals had bidirectional connectivity between the cortex and thalamus.³¹

1.8. Connectivity between right caudate nucleus and occipital nucleus accumbens increased¶

Functional connectivity between the right parietal caudate and the nucleus accumbens correlates with ADHD.³²

1.9. Further studies on brain connectivity and ADHD¶

Several studies report interhemispheric connectivity changes in ADHD:³³

• Reduced interhemispheric coherence in the delta band in frontal brain regions³⁴
• Increased coherence in the theta band in posterior regions (only with eyes open)³⁴
• Increased coherence in the theta band in central areas³⁴

Methylphenidate normalized decreased global connectivity existing in ADHD 400-700 ms after a stimulus and decreased an increase in network separation 100-400 ms after the stimulus in one study. These global changes by methylphenidate occurred mainly in task-relevant frontal and parietal regions and were more significant and sustained than in nontreated comparison subjects. The results of the study suggest that methylphenidate corrects impaired network flexibility that exists in ADHD.³⁵

Quite a few studies have analyzed the peculiarities of communication and linkage within the brain in ADHD by measuring EEG and QEEG values.

Measuring the synchronization or coherence of the brain’s resting state EEG is a common way to measure cortical functional connectivity.³⁶

In ADHD, there is a clear pattern of decreased connectivity between anterior (front-lying) and posterior (back-lying) brain regions.³⁷

Similarly, in ADHD, there is reduced connectivity in frontostriatal connections.³⁸³⁹

Adults with ADHD showed reduced activation of the bilateral inferior PFC, caudate, and thalamus during stop tasks as during cognitive switch tasks, and in the left parietal lobe (only) during the switch task. The more severe the ADHD behavioral symptoms were, the smaller the increase in activation of similar regions in fronto-striatal, parietal, and cerebellar brain areas. During stop tasks, ADHD subjects showed reduced inter-regional functional connectivity between right anterior frontal, fronto-striatal, and fronto-parietal neural networks.³⁹

Another study found a deficient connectivity between the brain hemispheres in ADHD at rest as well as a stimulus-induced state of overconnectivity within and between frontal hemispheres. According to this study, there is an altered functional connectivity in ADHD, especially between frontal regions.⁴⁰

At shorter distances between the measurement electrodes, ADHD children showed intrahemispheric coherence in the theta band and reduced lateral differences in the theta and alpha bands. At larger electrode distances, ADHD children showed lower intrahemispheric coherence in the alpha band than did non-ADHD children. In the frontal brain area, ADHD-affected children had increased interhemispheric coherences in the delta and theta bands and decreased interhemispheric coherences in the alpha band. Coherence in the alpha band was decreased in the temporal brain area. Coherence in the theta band was increased in central/parietal/occipital brain regions.
ADHD sufferers of the mixed type had greater intrahemispheric theta and beta coherence than ADHD sufferers of the purely inattentive subtype. Frontally, ADHD sufferers of the mixed type had increased interhemispheric coherence in the delta and theta bands compared with ADHD sufferers of the purely inattentive subtype (ADHD-I). In ADHD-affected ADHD-C, coherence in the beta band is increased in central/parietal/occipital brain regions.⁴¹
Another study found evidence of altered effective connectivity in brain networks in children with ADHD using EEG signals, particularly in the beta band.⁴²

ADHD sufferers showed increased coherence in the lower alpha band (8 Hz) and decreased coherence in the upper alpha band (10-11 Hz). The increase in coherence at 8-Hz in ADHD sufferers and at 2- to 6-Hz in the control group was independent of stimulus presentation. In response to visual stimulation, ADHD-affected subjects showed decreased evoked power and increased frontal coherence. Unaffected subjects differed from medicated ADHD subjects only in coherence level at 8 Hz. The results suggest persistent deficient connectivity and stimulus-induced overconnectivity within and between frontal hemispheres in ADHD.⁴⁰

1.10. Impaired signal variability of spontaneous neuronal activity¶

One study reported decreased brain signal variability and multiscale entropy in children with ADHD in the higher order functional networks as well as in the primary brain networks, e.g., default mode, frontoparietal network, attentional network, and visual network. The abnormalities of decreased brain signal variability correlated negatively with ADHD symptoms in the frontoparietal network and negatively with reaction time variability in the frontoparietal, default mode, somatomotor, and attention networks.⁴³

At high to low stress, a reversal of entropy in various brain networks has been described.⁴⁴

1.11. Dopaminergic brain networks and ADHD¶

Further, three brain networks and their influence on ADHD are described.⁴⁵⁴⁶⁴⁷

Altered dopaminergic function cannot adequately modulate nondopaminergic signaling (mainly glutamate and GABA).⁴⁸

1.11.1. Frontal-Striatal Loop¶

“Cold” executive functions that involve the “what.”⁴⁹

Correlated with problems with

• Response inhibition
• Distractibility
• Working memory
  • Organization
  • Planning

Mesocortical dopamine system:⁴⁸

• Attention Deficits
  • Inadequate orientation reactions
  • Impaired saccadic eye movements
  • Poorer attentional responses to a target
• Poor behavior planning (poor executive functions)

1.11.2. Frontal cerebellar loop¶

“Hot” executive functions involving “when.”⁴⁹

Correlated with problems with

• Motor coordination
• Timing and timeliness of behavior

Nigrostriatal dopamine system:⁴⁸

• Disturbed modulation of motor functions
• Impairment of non-declarative habituation learning and memory.
• These lead to obvious developmental delays

1.11.3. Frontal-limbic loop¶

Executive functions involving “why”

Correlated with problems with

• Emotional dysregulation
• Motivation problems
• Hyperactivity/impulsivity
  • Hyperactivity especially in new situations
• Vulnerability to aggression

Mesolimbic loop:⁴⁸

• Modified reinforcement of the behavior reinforcement
• Inadequate extinction of a previously reinforced behavior
• Continuous attention problems
• Increased behavioral variability
• Inhibition problems with “inhibition” of responses (“disinhibition”)

1.12. ADHD symptoms and brain connectivity¶

One study identified four corresponding patterns of dynamic functional brain connectivity (dFC) for different dimensions of behavioral or cognitive functions:⁵⁰

• Dimension Inattention/Hyperactivity
  • positively associated with dFC within Default Mode Network (DMN)
  • negatively associated with dFC between DMN and sensorimotor network (SMN)
• Dimension somatization
  • positively associated with dFC within the DMN and the SMN
• Dimension inhibition and flexibility
  • positively associated with dFC within DMN
  • positively associated with dFC between DMN and SMN
  • negatively associated with dFC between DMN and fronto-parietal network
• Dimension fluency and memory
  • positively associated with dFC within the DMN
  • positively associated with dFC between DMN and SMN
  • negatively associated with dFC between DMN and fronto-parietal network
    The cognitive functions of inhibition and flexibility mediated the relationship between brain dynamics and the behavioral manifestations of inattention and hyperactivity.

2. Brain networks¶

The literature does not use consistent terms for the different brain networks
The following is an attempted representation of the brain networks.

2.1. Default mode network (DMN)¶

• Active when individual is in wakeful resting state
• Prefers active with focus on intern-oriented tasks such as daydreaming, imagining the future, recapitulating memories, Theory of Mind (ToM).
• Not active when other brain networks focus on external (visual) stimuli
  • DMN can be deactivated tonically⁵¹ and phasically⁵².²¹
• The DMN is not a single anatomical structure, but includes connections between different areas, including¹⁷
  • Anterior medial PFC
  • Posterior cingulate cortex
  • Dorsomedial PFC subsystem
  • Medial temporal lobe subsystem.
• Connected with⁵³
  • Ventromedial PFC
  • Dorsomedial PFC
  • Posterior cingulum
  • Retrosplenial cortex
  • Inferior parietal lobe
  • Lateral temporal cortex
  • Hippocampus

Besides, a posterior default mode network was named.

2.2. Attention Networks¶

2.2.1. Fronto-parietal (attentional/executive) network / anterior attentional network¶

• Probable synonyms:

  • Executive Network
    The executive network is thought to be primarily associated with impulsivity⁵⁴

    • Left
      • Left executive network
      • Left fronto-parietal network
    • Right
      • Right-wing executive network

  • Task Control Network

• Initiates and modulates cognitive control⁵⁵
  • Inhibition
  • Task change
  • Conflict Resolution
  • Resource Allocation
  • Planning
  • Selective detection of sensory and semantic events.⁵⁶
• Components³
  • Right dlPFC
  • Posterior parietal cortex

2.2.2. Spatial attention network / posterior attention network / dorsal attention network¶

Control of spatial orientation of attention to sensory stimuli.

• Voluntary use of attention and refocusing on unexpected events
• Dopaminerg

The attentional shift consists of three subprocesses:⁵⁷

• Detachment of the focus of attention (“disengagement”)
• Shifting the focus of attention (“shifting”)
• Focusing on the new object of attention (“engagement”).

Three brain areas appear to be involved in the spatial attention network:⁵⁸

• Posterior parietal cortex
  • Detachment of the focus of attention (“disengagement”)
• Superior colliculus
  • Shifting the focus of attention (“shifting”)
• Lateral pulvinar of the thalamus
  • Focusing on the new object of attention (“engagement”)

2.2.3. Ventral attention network / vigilance network¶

Generating and maintaining a baseline level of activation or readiness to respond.⁵⁹

• Reacts when behaviorally relevant stimuli occur unexpectedly
• Predominantly subcortical⁵⁷
  • Mesencephalic structures
  • Right hemispheric cortical areas
    • Right PFC
• Noradrenerg⁵⁵

2.3. Salience Network¶

• Monitors the significance of external inputs and internal brain events
• Components³
  • Right anterior insula
  • Right dorsal anterior cingulate cortex (rdACC)
  • Right ventrolateral PFC (rvlPFC)

2.4. Visual network¶

• Lateral visual network
  • Involved in complex emotional stimuli

2.5. Auditory network¶

2.6. Affective network¶

2.7. Motor networks¶

• Sensorimotor network
  • This is said to be primarily associated with inattention⁵⁴
• Somatomotor network
• SM Mouth Network
• SM Hand Network

2.8. Cerebellar network¶

2.9. Voice Network¶

2.10. Temporal network¶

2.11. Limbic network¶

2.12. Cortical network¶

The cortical network is described as a network of⁶⁰

• DlPFC
• Dorsomedial PFC
• Anterior cingulate cortex (ACC)
• Inferior frontal gyrus
• Insula
• Parietal regions.

2.13. Cingulo-Opercular Network¶

2.14. Memory network¶

2.15. Subcortical network¶

3. Neurotransmitters and functional connectivity¶

3.1. Dopamine and connectivity of brain networks¶

Dopamine appears to specifically affect the functional connectivity of certain brain regions. Amisulpride (a D2/D3 antagonist) increased functional connectivity from the putamen to the precuneus and from the ventral striatum to the precentral gyrus, according to one study. L-DOPA (a dopamine precursor) increased functional connectivity from the VTA to the insula/operculum and between the ventral striatum and vlPFC and decreased functional connectivity between the ventral striatum and dorsal caudate with the medial PFC.⁶¹