Neurobiology of Attention Deficit Hyperactivity Disorder (ADHD) – A Primer

CLINICAL PRESENTATION OF ADHD

The main symptom domains in ADHD are inattention and hyperactivity-impulsivity. Below are the DSM – 5 criteria for ADHD. ([American Psychiatric Association, 2013]

ANATOMICAL BRAIN CHANGES IN ADHD

1. The most consistent finding in ADHD is an overall reduction in total brain size with specific changes in the caudate nucleus, prefrontal cortex white matter, corpus callosum and cerebellar vermis. [Tripp and Wickens, 2009]

2. Swanson in 2007 noted that the caudate nucleus and globus pallidus, parts of the basal ganglia which both contain a high density of dopamine receptors, are smaller in ADHD. [Swanson et al., 2007]

3. Ventral striatum, which is part of the reward pathway, tends to be reduced in ADHD and there is a negative correlation between ventral striatum and childhood hyperactivity and impulsivity. [Tripp and Wickens, 2009]

4. There is a reduction in cortical thickness which is associated with the DRD4 7-repeat allele.  This regional thinning resolves in adolescence and is associated with a better clinical outcome. [Shaw et al., 2007]

5. Diffusion transfer imaging shows alterations in frontal and cerebellar white matter in children and adolescents.

6. The frontostriatal circuit has been convincingly implicated in ADHD. Both DTI and functional MRI (fMRI) show abnormalities in the frontostriatal connectivity and function. [Faraone et al., 2015]

7. fMRI shows reduced activation of prefrontal cortex and striatal regions.

ROLE OF THE PREFRONTAL CORTEX IN ADHD

The prefrontal cortex is essential for executive functioning, allowing us to:

• Organise and plan for the future
• Inhibit responses to distraction to achieve a goal

The dorsal and lateral prefrontal cortex regulates attention and motor responses while the ventral and medial portion regulates emotion.

It is the last part of the brain to mature, and maturation only occurs in late adolescence.

The two key receptors that are situated in the prefrontal cortex are dopamine D1 receptor and alpha-2A adrenoreceptors.

The prefrontal cortex exhibits a Goldilocks phenomenon being highly dependent on a balanced neurochemical environment for proper functioning.

ADHD is associated with genetic changes that weaken catecholamine signalling and slow prefrontal cortex (PFC) maturation in some cases.

The following is from Arnsten’s excellent article. [Arnsten, 2009]

Functions of the PFC:

1.Regulation of Top-down attention

• Concentrate and sustain attention especially under boring conditions.
• Focus on material that is important but not salient by suppressing the processing of irrelevant stimuli and enhancing processing of relevant stimuli.
• Inhibits internal and external distractions.
• Divides and shift attention in multi-tasking.
• Responsible for attention regulation through its effect on the sensory cortices.

2. Regulation of Behaviour

• The prefrontal cortex is responsible for the inhibition of inappropriate behaviour
• Can guide behavioural output by projections to the motor and the premotor cortices along with the basal ganglia and cerebellum.

3. Regulation of emotions

• The ventromedial prefrontal cortex (VMPFC) has projections to amygdala, hypothalamus and nucleus accumbens and weakens reactions to disinhibited aggressive impulses and emotional dysregulation.
• Abnormalities of the VMPFC can lead to conduct disorder like symptoms

Functions of parietal and temporal lobes in the regulation of attention (Bottom-up processing of attention):

• The parietal and temporal lobes provide bottom-up processing, i.e., process stimuli according to inherent salience.
• The ventral and the dorsal temporal stream are responsible for visual features location of things
• The parietal lobe is responsible for orienting attention to parts of space and of time.

OTHER BRAIN PATHWAYS INVOLVED

1.Executive Network in ADHD: [Faraone et al., 2015]

2. Alerting network  

3. Default mode network (DMN) 

The DMN is a network of brain regions that are active when in a ‘resting state’ and tend to be negative correlated with attention networks.

Negative correlations between the DMN and the frontoparietal control network are weaker in patients with ADHD than in people who do not have the disorder.

A metanalysis of 55 MRI studies found that : [Cortese et al., 2012]

Children with ADHD have: 

• hypoactivation in frontoparietal and ventral attention networks
• hyperactivation in default mode networks, ventral attention and somatomotor areas

Adults with ADHD have:

• hypoactivation in the frontoparietal area.
• hyperactivation in the visual, dorsal attention, and default networks.

ROLE OF NEUROTRANSMITTERS IN ADHD - FOCUS ON DOPAMINE AND NORADRENALINE

The neurotransmitter dopamine is implicated as the main mediator of the brain’s reinforcement signal.

Dopamine cell bodies lie in the pars compacta of the substantia nigra (SN) and the ventral tegmental area (VTA).

We cover the dopamine pathways in more detail here.

The substantia nigra projects to the dorsolateral striatum and is responsible for motor control.

The ventromedial projections from the ventral tegmental area (VTA) are responsible for cognitive and affective function.

The Cellular Actions of Dopamine:
The physiological effects of dopamine transmission in the brain are mediated by G-protein coupled receptors.

There are five key receptors:  D1 to D5.  Each of these is situated in different parts of the brain and perform different functions.

Dopamine receptors and the role of the D1 receptor:

The D1 receptor is the most abundant of the dopamine receptors. D1 and D2 are uniformly expressed throughout the striatum and play an important part in the reward pathway. [Arnsten, 2009]

• The D1 receptor is an important regulator of cognitive functions, including spatial learning, working memory, executive function, and visuospatial functions. [Jones-Tabah et al, 2022].
• D4 and D5 receptors are found at lower levels in the striatum and moderate levels in the prefrontal cortex.
• Low to moderate levels of D1 receptor stimulation can improve prefrontal cortex functioning.
• Stimulation of D1 receptors weakens the neuronal signal and is responsible for decreasing ‘noise’ by pruning inappropriate connections.
• Excessive D1 receptor stimulation (such as occurs during stress) impairs PFC function by weakening too many network connections.

The dopamine cells tend to have two firing modes:

• clock-like rhythmic firing
• burst-like firing in response to events connected with reward.

Normally, cells tend to respond approximately 200 ms after the delivery of an unexpected reward.

Individuals with ADHD tend to have altered dopamine signalling which leads to altered reinforcement sensitivity. [Luman et al., 2010]

The DAT1 gene variable number tandem repeat (VNTR) is known to be associated with ADHD and may explain the delayed, altered reinforcement sensitivity. [Tripp and Wickens, 2009] (See Dopamine transfer deficit theory later)

The Cellular Actions of Noradrenaline (NA): [Arnsten, 2009]

• At moderate levels, noradrenaline can improve prefrontal cortex functioning by stimulating postsynaptic α2A receptors
• NA activation of the α2A receptor strengthens the neuronal signal and hence strengthens network connectivity
• Higher levels of NA can impair prefrontal cortex function by stimulating α1 receptors

Thus, DA and NE have complementary beneficial actions with NA increasing the signal and DA reducing noise, and an optimal balance of both neurotransmitters is required for proper PFC functioning.

The Connection to Pyramidal Glutamate Neurons:

The prefrontal cortex has pyramidal glutamate neurons.  These neurons can “keep in mind” information to help guide attention and behaviour in a thoughtful manner. [Arnsten, 2009]

The neurons in these networks interact with other pyramidal cells through synapses on dendritic spines which contain NA alpha-2A receptors or D1 receptors.

These pyramidal glutamate neurons are inhibited by GABA, which in turn is suppressed by the D4 receptor.

Thus, activation of the D4 receptors suppresses GABA, which in turn activates the pyramidal glutamate neurons.

Not much research has been carried out on the D4 receptor; however the D4 receptor can be stimulated by NA and DA and deficient stimulation of the D4 receptor can impair PFC functioning by weakening glutamate release.

ADHD PATHOPHYSIOLOGY - NEUROCHEMICAL DEFICIT THEORIES

The reward network underpins two key dopamine related neurochemical deficit theories.

1. Dynamic Developmental Theory:
The dynamic developmental theory hypothesises that there is a dysfunction of dopamine transmission in the frontal-limbic circuits, which is responsible for a steeper delay-of-reinforcement gradient and slower effects of extinction. [Sagvolden et al., 2005]

The model proposes that due to the steep delay of reinforcement there is a critical window during which reinforcement of behaviour can occur in individuals with ADHD. The steep and shorter delay of reinforcement is caused due to lower levels of tonic dopamine.

Thus, a reinforcer loses its value relatively quickly, which makes it difficult to change behaviour. Only short sequences of responses can be reinforced due to the short critical window in which behaviour can be reinforced.

Children therefore, tend to respond better to immediate rewards over delayed rewards and only show learning when rewards are received immediately and frequently.

Furthermore, due to the lower tonic dopamine levels, there is only a blunted dip in the phasic dopamine after the omission of the reward. Thus, there is a slower extinction of behaviour.

In normal children, the gradient is not as steep and is gradual, thus allowing a greater window of opportunity where children can obtain adequate reinforcement from delayed rewards.

2. Dopamine Transfer Deficit Theory:

The dopamine system uses previous instances of reinforcement to produce anticipatory dopamine release. [Tripp and Wickens, 2008]

According to the dopamine transfer deficit, this assumes that there is a normal tonic level of dopamine but the phasic dopamine response to reinforcement is altered.

The model proposes that the anticipatory dopamine cell firing is disturbed whereby the dopamine response does not transfer to earlier and earlier predictors of response requiring actual instances of reinforcement for control of behaviour rather than predicted behaviour.

In children with ADHD the phasic dopamine cell response to cues that predict reinforcement is reduced in amplitude to the point of being ineffective and similarly when the reward is taken away there is a blunting of the phasic dopamine decrease response leading to slower extinction of behaviour.

The dopamine transfer deficit explains the symptoms of inattention as the child fails to give close attention to details and makes careless mistakes and cannot maintain on-task behaviour as there is an absence of the continuous reinforcement of attending by anticipation of dopamine release.

Similarly, it also explains hyperactivity and impulsivity, where the child leaves the seat in the classroom where remaining seated is expected due to lack of effective reinforcement, i.e., lowered phasic dopamine response to rewards.

Impulsivity may also be explained as there is a delay between the target behaviour and actual reinforcement.

The fidgetiness may be due to activating effects of dopamine due to excitability of striatal neurons.

Hence, specific abnormalities in reward sensitivity include: [Luman et al., 2010]

1. Greater emphasis on immediate rewards than delayed rewards.
2. Poorer performance under partial or discontinuous reinforcement schedules.
3. Impaired reinforcement learning and acquisition of behaviour.
4. Impaired integration of earlier reinforcers.
5. Impaired ability to change behaviour in response to changes in reinforcement contingencies.
6. Impaired response to conditioned than to actual reinforcement.
7. Problems with adding new contingency information in the working memory.
8. Behavioural inhibition less under the influence of cues of aversive stimuli.
9. Lower level of tonic dopamine in frontal-limbic circuitry in the brain and hypodopaminergic state.
10. Smaller phasic dopamine response to actual rewards.
11. Slower shift in dopamine from actual reward to reward cues.
12. Reduced phasic anticipatory dopamine release in striatum to reward cues.
13. Slower rate of extinction.

ALTERNATE NEUROBIOLOGICAL MODELS

The observed clinical variability of ADHD may indicate the possibility of multiple developmental pathways. Since Barkley theorised in 1997 [Barkley, 1997] that normal behavioural inhibition was necessary for attention and executive function, there have been a number of subsequent neurobiological models proposed.

Most of these models have been attributed to delayed development within the later maturing areas of the brain that affect attention, decision-making, and reinforcement learning.

1.Behavioural neuroenergetics model: [Killeen, 2013]

This model involves the inadequate production of lactate by astrocytes in the brain.

Astrocytes take up glucose from blood vessels and convert it to glycogen and lactate, with the latter being released for the neurons to metabolise into energy (ATP). Therefore, the insufficient provision of neuronal energy creates a state of hypo-energy.

There is an approximate loss of 15-25% of neurocognitive energy that can be applied to any one task, which results in attention drifting and mental fatigue.

2. The state regulation model: [Hegerl and Hensch, 2014]

This model postulates that there is a dysregulation in the regulation of vigilance (brain arousal), which underlies the attention deficits in ADHD.

This model has pathogenetic relevance to both ADHD and mania whereby unstable or low vigilance can induce an excessive autoregulatory attempt to stabilise vigilance. This is how periods of hyperactivity are proposed to occur.

3. Executive dysfunction theory: [Baroni and Castellanos, 2014]

Advances in MRI techniques have shown researchers that the observed phenotypic variations in ADHD are a result of impairments to top-down cognitive processes that are important for organising behaviour. The executive control network is implicated here.

The implications of disrupted executive processes and functions affect reward-related processing, inhibition, vigilance, reaction time variability, and emotional lability.

4.Delay Aversion Theory: [Sonuga-Barke et al., 1992]

This model proposes that escape from delay is a key reinforcer for children with ADHD, as the delay appears to have a negative association.

When delay cannot be reduced, children will engage in behaviours that reduce the perception of the length of delay or engage in behaviours that act as immediate reinforcers such as fidgeting and attending to alternative stimuli.

In terms of neurobiological mechanisms, the delay aversion is due to a reduced efficiency of dopamine in reward circuits signalling future rewards and a steeper and shorter delay-of-reinforcement gradient in children with ADHD.

5. Dual Pathway model: [Sonuga-Barke, 2003]

Sonuga-Barke incorporated the delay aversion model within the dual pathway model.

According to the dual pathway model, it proposes there are two independent neurocircuitries linked to ADHD, namely the ventrolateral and dorsolateral corticostriatal circuitry subserving executive and inhibitory processes and mesolimbic-ventrostriatal circuitry subserving motivational and reward processes, so there are abnormalities in executive processes and motivational processes.

6. Tripartite Pathway Model: [Sonuga-Barke et al., 2010]

This model is a refinement of the dual pathway theory and explains the neuropsychological heterogeneity of ADHD as a combination of one or more deficits in inhibitory control, motivational control, and temporal processing.

Three pathways are involved indicating ADHD subtypes:

1. Dysfunction of the prefrontal cortex is likely to result in a reduced ability to exert control.

2. Dysfunction in dorsal striatum might lead to differences in the ability to predict what events are going to occur, whereas dysfunction in ventral striatum is more likely to lead to deficits in motivation and reward processing.

3. Dysfunction of the cerebellum is likely associated with problems in the ability to predict when events are going to occur and other problems with timing. The fronto-cerebellar circuit may be involved in temporal processing.  The cerebellum has outputs to both the prefrontal cortex and the basal ganglia. [Durston et al., 2011]

THE FUTURE

The neurobiology of ADHD is complex and involves multiple brain pathways. Two key neurotransmitters highlighted in the pathogenesis of ADHD are dopamine and noradrenaline.

As neuroimaging advances, different subtypes of ADHD may emerge involving distinct pathways giving rise to a specific set of symptoms. By combining this with an understanding of the neurotransmitters we may be able to develop and target treatments for better outcomes.

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