1. Network connectivity for ADHD¶
Several studies have analyzed the connectivity of different brain networks in ADHD.
One study compared 4 of these studies and found large inconsistencies. A deviating connectivity between default mode network and executive network in ADHD proved to be robust. Furthermore, the consistency of the results was greatest in ADHD-C. It is possible that the different ADHD subtypes exhibit considerable differences in the connectivity of their brain networks.
One study achieved an ADHD diagnostic accuracy of 73 % (specificity 91.6 %, sensitivity 65.5 %) using an analysis of functional connectivity controlled by machine learning. In practice, these are still not very helpful values for a diagnosis.
1.1. Frontal-parietal attention network in ADHD¶
The frontal-parietal attention network is involved in cognitive processes, especially attention.
1.1.1. Reduced connectivity within the dorsal frontoparietal executive network¶
One study reports reduced connectivity in the dorsal frontoparietal executive network, consisting of
- Right dlPFC
-
Posterior parietal cortex
which correlates 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 in NoGo tasks.
One study found no correlates of network connectivity in relation to the symptom of cognitive flexibility that would have revealed differences between autism spectrum disorders, ADHD or non-affected individuals.
1.1.2. Altered structure of the frontal-parietal attention network¶
Children with ADHD showed the following in the frontal-parietal attention network compared to persons with ADHD
- A larger diameter
- A smaller number of leaves,
- A lower tree hierarchy
- A lower kappa
which also correlated with the ADHD symptom score.
- Clustering coefficient and
- Path length
were unchanged.
In children with ADHD, the frontal-parietal attentional network could potentially 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.
1.1.3. Altered connectivity of the frontal-parietal attention network to other brain networks¶
A meta-analysis found that in the case of ADHD
- 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 bundles of connections 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 in brain regions.
1.1.4. Reduced connectivity mPFC-dlPFC predicted later inattention¶
A study of ADHD children with ADHD found that increased connectivity between mPFC and dlPFC at age 7 correlated with decreased attention by age 11.
1.1.5. Reduced 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.
1.2. Salience network¶
One study found deviations in the connectivity of the salience network in ADHD, consisting of
- 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 and healthy control subjects. People with ADHD showed increased connectivity between the DMN and task-positive networks compared to their non-affected siblings and healthy controls. People with ADHD and their unaffected siblings did not show concordant changes in functional connectivity to healthy control subjects. These results were largely confirmed by complementary pairwise connectomic comparisons. However, the main connectivity differences between the sibling groups could not be replicated in a closely age- and sex-matched subsample (20 subject-sibling pairs and 60 TD).
1.3. Rich-Club / Hubs Connectivity reduced¶
Rich clusters or hubs are clusters of brain regions that are more strongly connected to each other than the average brain region and therefore form the functional backbone of the brain
One study found a decreased density of rich clubs among structural nodes in adults with ADHD, including
-
Bilateral precuneus
- Insula
-
Caudate nucleus
- Left putamen
- Right calcarine sulcus
Further, adults with ADHD were found to have reduced global efficacy compared to non-affected individuals, which may result from a lower density of rich-club connections in ADHD.
Another study found deviating asymmetry patterns in connectivity measurements of rich-club connectivity in people with ADHD, e.g. more feeder connections. Furthermore, a reduced right asymmetry was found in connectivity measurements of local connections to several peripheral brain regions. Furthermore, abnormal regional asymmetry scores correlated with ADHD symptoms.
Another study observed that an organization of brain networks around hubs was associated with reduced cognitive impairment under stress. It also showed that the same neurophysiological characteristics of brain connectivity under stress could be associated with quite different problems. There was no 1:1 correlation between brain network patterns and certain symptoms. Children whose brain networks were not organized around hubs showed a wide variance of symptoms in response to stress.
One study described changes in node efficiency in children with ADHD:
- Increase in the visual attention network
- Increase in the dorsal attention network
- Decrease in the somatomotor network
- Acceptance in the default mode network
Impaired functional connectivity and node efficiency correlated significantly with ADHD symptom severity.
1.4. Connectivity in idle mode¶
In ADHD, reduced global connectivity between different brain networks was found in the resting state. This was interpreted as an indication of ADHD as a developmental delay.
In contrast, another study found increased connectivity between striatal seeds and temporal, fronto-insular and supplementary motor regions and between the amygdala and the dorsal anterior cingulate cortex in adolescents with ADHD. The predominant associations centered on caudate connectivity on both sides. The findings were not associated with the frequently comorbid internalizing and externalizing problems. The effect sizes were small (maximum 0.15).
1.5. Reduced synchronization of attention networks and sensory cortex areas¶
Desynchronization of attention networks and sensory cortex areas was observed in people with ADHD who were following a conversation between several people.
1.6. DMN (Default Mode Network)¶
As the brain is active even when it is not performing any tasks, a separate network is responsible for managing rest: the Default Mode Network (DMN). It is active when the mind is not involved in another task or is “resting”. The DMN controls things like mind wandering, daydreaming, relaxing and thinking about yourself and your life. Short-term attention deficits are also said to result from the DMN. Consequences are that the DMN is deactivated when the brain is performing a task. The DMN is not a single anatomical structure, but involves connections between different areas, including
-
Anterior mPFC
-
Posterior cingulate cortex
-
Dorsomedial PFC subsystem
-
Medial temporal lobe subsystem (Precuneus)
1.6.1. Reduced deactivation capability 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 turn off the DMN and “turn on” the task-positive networks. Consequences are that people with ADHD remain in a certain mental state for longer. In order to end the persistence, a stronger sensory stimulus is required. This inability to deactivate or switch off the DMN is exacerbated by more cognitively demanding tasks.
The deactivability of the DMN in ADHD could be increased by high rewards (which we understand to cause intrinsic interest) in such a way that it corresponded to the deactivability in non-affected individuals. MPH showed the same effect.
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
- Less functional connectivity between
-
DMN (posterior cingulate cortex) and frontoparietal network (inferior parietal lobes)
-
DMN (precuneus) and cinguloopercular network (temporoparietal connection).
The authors conclude that social cognition and communication impairments and ADHD may share abnormal functional connectivity in the DMN, frontoparietal network and cinguloopercular network.
Other studies also found altered connectivity of the DMN in ADHD. Increased correlations of the DMN in the resting state between the posterior cingulate cortex / precuneus and the right middle frontal gyrus were found. These existed equally in adult persons with ADHD and their first-degree relatives, but not in unaffected control subjects. The observed connectivity changes correlated with higher sustained attention problems. Furthermore, this brain-based neurocognitive trait dimensionally explained ADHD symptom variability.
Another study found increased connectivity between the DMN and task-positive networks in people with ADHD compared to their unaffected siblings and healthy controls. Non ADHD-affected siblings showed increased connectivity within the salience network and decreased connectivity between the DMN and salience network, in contrast to their ADHD-affected siblings and healthy controls. People with ADHD and their unaffected siblings showed no concordant changes in functional connectivity to healthy control subjects. These results were largely confirmed by complementary pairwise connectomic comparisons, but the main connectivity differences between the sibling groups could not be replicated in a closely age- and sex-matched subsample (20 subject-sibling pairs and 60 TD).
One study found strong coherence of the left dorsal anterior cingulate cortex (dACC) with DMN components in children with ADHD. Furthermore, a seed-to-voxel connectivity analysis using the left dorsal anterior cingulate as a seed region found evidence of higher temporal coherence with other neural networks compared to children not affected by ADHD. Children with ADHD appear to have a more distributed resting-state connectivity pattern in the DMN and other networks.
1.6.3. Normalization of the DMN through stimulants¶
In addition, functional imaging studies in people with ADHD not only show differences in DMN regions compared to healthy controls, but also a return to normal functions when treated with stimulants (here: methylphenidate). The more intrinsically motivated attentional control in ADHD means that attention and its controllability are just as high as in non-affected individuals when there is a correspondingly high (intrinsic) interest and only deviate from the attention of non-affected individuals when there is a lower (intrinsic) interest. This is controlled by the DMN. Stimulants are able to equalize the attentional control of persons with ADHD to that of non-affected people in the absence of (intrinsic) interest.
1.7. Thalamic PFC connectivity in ADHD unidirectional¶
One study found a one-way transmitting connection from the cortex to the thalamus in the alpha, beta and gamma bands in persons with ADHD, while non-affected people showed bidirectional connectivity between the cortex and thalamus.
1.8. Increased connectivity between right caudate nucleus and occipital nucleus accumbens¶
Functional connectivity between the right parietal caudate and the nucleus accumbens correlates with ADHD.
1.9. Impaired signal variability of spontaneous neuronal activity, reduced entropy¶
One study reported reduced brain signal variability and reduced multiscale entropy in the higher-order functional networks as well as in the primary brain networks, e.g. in the default mode, frontoparietal network, attention network and visual network, in children with ADHD. The deviations of reduced 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.
Another study found decreased amplitude of multiscale entropy in ADHD. Absolute spectral power showed higher variability values in ADHD. Multiscale entropy changes with age and increases with increasing number of scales. ADHD appears to have increased EEG variability and lower EEG complexity.
A reversal of entropy in various brain networks has been described from high to low stress.
1.10. Connectivity and coherence altered in ADHD¶
Several studies report interhemispheric connectivity changes in ADHD:
- Reduced interhemispheric coherence in the delta band in frontal brain regions
- Increased coherence in the theta band in posterior regions (only with eyes open)
- Increased coherence in the theta band in central areas
In one study, methylphenidate normalized reduced global connectivity in ADHD 400-700 ms after a stimulus and reduced an increase in network disconnection 100-400 ms after the stimulus. These global changes caused by methylphenidate occurred mainly in the task-relevant frontal and parietal regions and were more significant and lasting than in the non-treated comparison subjects. The results of the study indicate that methylphenidate corrects impaired network flexibility in ADHD.
Several studies have analyzed the peculiarities of communication and connection within the brain in ADHD by measuring EEG and QEEG values.
Measuring the synchronization or coherence of the brain’s EEG in the resting state is a common method for measuring cortical functional connectivity.
In ADHD, there is a clear pattern of reduced connectivity between anterior (front-facing) and posterior (back-facing) brain regions.
Similarly, in ADHD there is reduced connectivity in the frontostriatal connections.
Adults with ADHD showed reduced activation of the bilateral inferior PFC, caudate and thalamus during stop tasks and cognitive switch tasks, as well as in the left parietal lobe (only) during the switch task. The more severe the ADHD behavioral symptoms were, the lower the increase in activation of similar regions in fronto-striatal, parietal and cerebellar brain areas. During stop tasks, people with ADHD showed reduced inter-regional functional connectivity between right anterior frontal, fronto-striatal and fronto-parietal neural networks.
Another study found a lack of connectivity between the brain hemispheres in ADHD at rest and a stimulus-induced state of hyperconnectivity within and between frontal hemispheres. According to the study, there is an altered functional connectivity in ADHD, particularly between frontal regions.
At shorter distances between the measuring electrodes, ADHD children showed intrahemispheric coherence in the theta band and reduced lateral differences in the theta and alpha bands. At larger electrode spacing, ADHD children showed lower intrahemispheric coherence in the alpha band than non-affected children. In the frontal brain area, children with ADHD had increased interhemispheric coherence in the delta and theta bands and decreased interhemispheric coherence in the alpha band. Coherence in the alpha band was reduced 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, persons with ADHD of the mixed type have increased interhemispheric coherence in the delta and theta bands compared to people with ADHD of the purely inattentive subtype (ADHD-I). In people with ADHD-C, the coherence in the beta band is increased in central / parietal / occipital brain regions.
Another study used EEG signals, particularly in the beta band, to find evidence of altered effective connectivity in brain networks in children with ADHD.
People with ADHD showed increased coherence in the lower alpha band (8 Hz) and decreased coherence in the upper alpha band (10-11 Hz). The coherence increase at 8-Hz in people with ADHD and at 2- to 6-Hz in the control group was independent of stimulus presentation. In response to visual stimulation, people with ADHD showed decreased evoked power and increased frontal coherence. Non-affected people with ADHD differed only in the coherence level at 8 Hz from medicated persons with ADHD. The results indicate a persistent lack of connectivity and stimulus-induced hyperconnectivity within and between frontal hemispheres in ADHD.
One study identified four corresponding patterns of dynamic functional brain connectivity (dFC) for different dimensions of behavioral or cognitive functions:
- 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
-
Inhibition and flexibility dimension
- positively associated with dFC within DMN
- positively associated with dFC between DMN and SMN
- negatively associated with dFC between DMN and fronto-parietal network
- Fluency and memory dimension
- 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.
A study of adults with ADHD found widespread intrahemispheric hypoconnectivity in networks that included:
- subcortical structures
- cortical structures
-
dorsal attention network
-
ventral attention networks
- visual systems
- somatomotor systems
In addition, hypo-connectivity in a predominantly left-frontal network correlated with increased commission errors in CPT-2.
In addition to reduced functional connectivity (especially in visual and sensorimotor brain networks), increased connectivity of peripheral networks was found.
1.11. Dopaminergic brain networks and ADHD¶
Three brain networks and their influence on ADHD are described.
Altered dopaminergic function cannot adequately modulate non-dopaminergic signaling (mainly glutamate and GABA).
1.11.1. Frontal-Striatal Loop¶
“Cold” executive functions that concern the “what”.
Correlates with problems with
- Response inhibition
- Distractibility
- Working memory
Mesocortical dopamine system:
- Attention deficits
- Inadequate orientation reactions
- Impaired saccadic eye movements
- Poorer attention reactions to a target
- Poor behavioral planning (poor executive functions)
1.11.2. Frontal-cerebellar loop¶
“Hot” executive functions that concern the “when”.
Correlates with problems with
- Motor coordination
- Timing and timeliness of behavior
Nigrostriatal dopamine system:
- 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 that concern the “why”
Correlates with problems with
- Emotional dysregulation
-
Motivation problems
- Hyperactivity/impulsivity
- Hyperactivity, especially in new situations
- Susceptibility to aggression
Mesolimbic loop:
- Modified reinforcement of the behavioral reinforcement
- Inadequate extinction of a previously reinforced behavior
- Problems with sustained attention
- Increased behavioral variability
-
Inhibition problems with the “inhibition” of reactions (“disinhibition”)
2. Brain networks¶
The specialist literature does not use standardized terms for the various brain networks
The following diagram attempts to illustrate the brain networks.
2.1. Default mode network (DMN)¶
- Active when the individual is awake and at rest
- Preferably active when focusing on internal-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 tonically and phasically.
- The DMN is not a single anatomical structure, but comprises connections between different areas, including
-
Anterior medial PFC
-
Posterior cingulate cortex
-
Dorsomedial PFC subsystem
-
Medial temporal lobe subsystem.
- Connected to
- Ventromedial PFC
-
Dorsomedial PFC
-
Posterior cingulum
- Retrosplenial cortex
-
Inferior parietal lobe
-
Lateral temporal cortex
-
Hippocampus
A posterior default mode network was also named.
2.2. Attention networks¶
2.2.1. Fronto-parietal (attention/executive) network / anterior attention network¶
- Probable synonyms:
- Initiates and modulates cognitive control
-
Inhibition
- Task change
- Conflict resolution
- Allocation of resources
- Planning
- Selective discovery of sensory and semantic events.
- Components
- Right dlPFC
-
Posterior parietal cortex
2.2.2. Spatial attention network / posterior attention network / dorsal attention network¶
Control of the spatial orientation of attention to sensory stimuli.
- Voluntary use of attention and reorientation to unexpected events
-
Dopaminergic
The attention shift consists of three sub-processes:
- Detachment of the focus of attention (“disengagement”)
- Shifting the focus of attention (“shifting”)
- Focusing on the new object of attention (“engagement”).
Three areas of the brain are apparently involved in the spatial attention network:
-
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¶
Generation and maintenance of a basic activation level or a basic readiness to react.
- Reacts when behaviorally relevant stimuli occur unexpectedly
- Predominantly subcortical
- Mesencephalic structures
- Right hemispheric cortical areas
-
Noradrenergic
2.3. Salience network¶
- Monitors the meaning of external inputs and internal brain events
- Components
- 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 primarily associated with inattention
- Somatomotor network
- SM mouth network
- SM manual network
2.8. Cerebellar network¶
In the past, the cerebellum was associated exclusively with motor control. It is now clear that the cerebellum plays an important role in the regulation of cognitive and affective processes, primarily through communication between the posterior lobe of the cerebellum and the superior and associative cortices.
Inhibition of the right crus I and the posterior vermis overrides their inhibition of the mPFC. Dysfunction of the posterior cerebellum impairs social and cognitive functions. Perinatal cerebellar injuries in preterm infants correlated with cognitive deficits, language deficits and externalizing behaviors in almost every second child at the age of two years.
2.9. Language network¶
2.10. Temporal network¶
2.11. Limbic network¶
2.12. Cortical network¶
The cortical network is described as a network of
-
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 influence the functional connectivity of certain brain regions. According to one study, amisulpride (a D2/D3 antagonist) increased functional connectivity from the putamen to the precuneus and from the ventral striatum to the precentral gyrus. 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.
3.2. Noradrenaline and connectivity of brain networks¶
The pupil diameter at rest, which correlates with tonic noradrenal firing, also reflects the connectivity between frontoparietal, striatal and thalamic brain regions.