Motivation in ADHD - neurophysiological correlates

ADHD shows a deviant response to expected rewards as well as to rewards received.

The reward system of the human brain consists of two networks:¹

• Mesolimbic reward network consisting of VTA, nucleus accumbens, amygdala, striatum and septum
• Mesocorticolimbic reward network consisting of hippocampus, PFC and parahippocampal, entorhinal and motor cortical areas

The brain’s reward network includes the VTA, ventromedial PFC, orbitofrontal cortex, amygdala, hippocampus, nucleus accumbens, ACC, ventral pallidum and associated structures. Depending on the type of reward response, the following are also involved²
Consumption preference (in animals: sucrose uptake preference): NAc, ventral pallidum, OFC; µ opioid, GABA-A, endocannabinoid receptors
Anticipatory reward (in animals: positive/negative contrast): ACC, OFC, mPFC, basal ganglia, thalamus, hypothalamus
Motivational reward (in animals: response to effort): VTA to NAc dopamine; amygdala µ-opioid receptors; vmPFC to NAc glutamate; ACC; lateral hypothalamus
Learning: Dorsal basal ganglia (caudate); ACC

A particularly well-researched component of the brain reward network is the mesolimbic dopaminergic system, which leads from the VTA to the nucleus accumbens. The dopaminergic signaling pathway is involved in motivational aspects and the processing of reward-related stimuli. Rewarding stimuli such as food or drugs activate the mesolimbic dopaminergic system and release dopamine in the nucleus accumbens.³⁴⁵

ADHD is associated with an attenuated striatal response to the expectation of rewards⁶ and an enhanced prefrontal and striatal response to the receipt of rewards^{78 9 10} .¹¹

• 1. Neurophysiological correlates of reward expectation
  • 1.1. Striatum and reward expectation: underactivated in ADHD and stress
    • 1.1.1. Ventral striatum in reward anticipation: underactivated in ADHD
    • 1.1.2. Striatum for reward expectation and stress
      • 1.1.2.1. Striatum with reward expectation: increased activation during acute stress
      • 1.1.2.2. Striatum for reward expectation: underactivated in chronic stress
      • 1.1.2.3. Striatum with reward expectation: underactivated after early childhood stress
  • 1.2. ACC, PFC, cerebellum in reward anticipation: overactivated in ADHD
  • 1.3. Ventral anterior thalamus in reward anticipation: underactivated in ADHD
  • 1.4. OFC activity in reward anticipation: increased in ADHD
  • 1.5. Further changes during reward and loss expectation in early childhood stress
  • 1.6. Stress, anhedonia and the VTA-BLA-NAc pathway
• 2. Neurophysiological correlates of reward reception
  • 2.1. OFC for reward maintenance: overactivation in ADHD
  • 2.2. Caudate nucleus and frontal eye field in reward maintenance in ADHD
  • 2.3. Nucleus accumbens and reward response
  • 2.4. Connectivity of the ventral striatum during reward reception: increased in ADHD
• 3. Control of motivation through dopamine
  • 3.1. Phasic impulses from dopaminergic cells of the VTA
  • 3.2. Increase in tonic extracellular dopamine due to varicosities?

1. Neurophysiological correlates of reward expectation¶

The dopaminergic projections from the VTA to the ventral striatum (the nucleus accumbens) influence reward and motivation, while dopaminergic projections from the substantia nigra to the dorsal striatum influence voluntary movements and habit learning.¹²

Six components of reward processing were identified:¹³

• Association
• Differentiation
• Preference/rating
• Effort
• Expectation
• Reaction

These appear to develop in the first 6 months of life after birth.¹³

1.1. Striatum and reward expectation: underactivated in ADHD and stress¶

ADHD could be due to altered reward sensitivity. fMRI studies found that in ADHD

• For references to (monetary and affiliate) incentives
  • Hypoactivation in the bilateral ventral and dorsal striatum

• For food rewards, on the other hand, there was no difference between those with ADHD and those without.¹⁴
  Affiliate reactions are behaviors that signal a desire to make contact.

1.1.1. Ventral striatum in reward anticipation: underactivated in ADHD¶

In rats that performed actions required to obtain a reward, dopamine levels continued to rise as the reward approached, peaking when the reward was received. Afterwards, when they consumed the reward, it quickly dropped again.¹⁵

ADHD correlates with reduced activity in response to anticipated rewards in the brain regions of the reward center (including the nucleus accumbens). Motivation triggered by (correspondingly high) personally interesting rewards reduces ADHD symptoms.

Adult males with ADHD-HI were found to have decreased activation of the ventral striatum during gain anticipation and increased activation of the orbitofrontal cortex in response to a gain. The lower the activation of the ventral striatum during prize anticipation, the higher the hyperactivity and impulsivity.¹⁰¹⁶ Children with ADHD-HI showed a significantly reduced volume of the ventral striatum bilaterally and a correlation of the reduction of the right ventral striatum with hyperactivity / impulsivity.¹⁷

Brain activity on reward anticipation and reward maintenance appears to be subtype-specific. ADHD-I showed bilateral underactivation of the ventral striatum during reward anticipation compared to ADHD-C and healthy controls. In contrast, ADHD-C showed underactivation of the OFC in response to reward compared to ADHD-I and controls.¹⁸

One study found underactivation of the striatum during reward anticipation in ADHD-C only in adults, but not in children.¹⁹

Another study found in ADHD-HI that hyperactivity/impulsivity correlated with (relatively) decreased ventral striatum activity during reward anticipation and increased ventral striatum activity as a reward response. In contrast, non-affected individuals showed increased activity of the ventral striatum during reward anticipation.²⁰

ADHD symptoms correlated with decreased activation of the striatum during reward anticipation in children, regardless of ADHD symptom severity.²¹

Dihydro-β-erythroidine (DHβE) is a plant-derived competitive antagonist of nicotinic receptors. It is an inhibitor of nicotinic acetylcholine receptors containing β2 units (β2* NAChRs; β2 nicotinic receptors). DHβE reduces the phasic release of dopamine in the dorsolateral striatum²²
Consequences are that reward anticipation, which is controlled by phasic dopamine in the striatum and even more so in the nucleus accumbens, is also increased by β2-nicotinic receptor agonists - such as nicotine - .

1.1.2. Striatum for reward expectation and stress¶

1.1.2.1. Striatum with reward expectation: increased activation during acute stress¶

Acute stress also increases dopamine, including in the nucleus accumbens, which triggers motivational expectancy. The increased expectation of motivation appears to be mediated by CRH release in the nucleus accumbens.²³ A CRH1 antagonist blocks this reinforcing effect of acute stress on reward motivation.²⁴ High chronic stress abolishes - up to 90 days after the cessation of the stressor - the ability of CRH to increase dopamine in the nucleus accumbens and at the same time causes a switch from appetitive to aversive motivation,²⁵ as is also observed in major depressive disorder MDD.²⁶

1.1.2.2. Striatum for reward expectation: underactivated in chronic stress¶

Chronic stress reduces the dopaminergic activity of the striatum in the long term. Institutional neglect, early childhood stress or maltreatment inhibit the striatal reward function, which is dopaminergically mediated.^27282930

More on this at ⇒ Changes in the dopaminergic system due to chronic stress

1.1.2.3. Striatum with reward expectation: underactivated after early childhood stress¶

Early childhood stress (e.g. postnatal deprivation, maternal separation) led to reduced mesolimbic dopamine levels in the striatum and reduced motivation to pursue rewards in adult rats and monkeys.³¹ Monkeys with early childhood stress experience showed reduced interest in rewards. However, reward consumption remained unchanged. Increased noradrenaline degradation substances were found in the urine.³²

In humans, early childhood stress is also associated with reduced reward-related activity in the ventral striatum³³, which is associated with increased symptoms of anhedonia,³⁴ although the data did not differentiate between reward expectation and reward receipt. It is conceivable that reduced reactivity to rewards received in particular correlates with anhedonia or depression.

Adolescents who were maltreated as children showed reduced dopaminergic activation of the pallidum (part of the striatum) during reward anticipation with simultaneously stronger symptoms of depression.³⁵

Further studies confirm that early childhood stress (without a direct link to depression) correlates with reduced activation of the striatum during reward anticipation, but not during reward maintenance.³⁶²⁹ This is consistent with the changes in ADHD with respect to both reward anticipation and reward maintenance.

More on this at ⇒ Early childhood stress permanently alters the dopaminergic system

1.2. ACC, PFC, cerebellum in reward anticipation: overactivated in ADHD¶

A larger study found increased responses during reward anticipation in adolescents and young adults with ADHD in the³⁷

• Anterior cingulate cortex (ACC)
• PFC
• Cerebellum

The results were identical in the siblings who were not people with ADHD, with the exception of the cerebellum.

1.3. Ventral anterior thalamus in reward anticipation: underactivated in ADHD¶

In the control group, cues that predicted a reward caused greater activation in the ventral anterior thalamus than cues that did not predict a reward, while, conversely, in ADHD, cues that predicted a reward caused less activation than cues that did not predict a reward.³⁸

1.4. OFC activity in reward anticipation: increased in ADHD¶

An fMRI study found a significant signal increase in the OFC to large compared to small expected rewards in all test subjects. In ADHD, the responses were significantly stronger and also correlated with hyperactivity / impulsivity. High cognitive abilities normalized the OFC responses.³⁹

1.5. Further changes during reward and loss expectation in early childhood stress¶

A study that re-examined children with high and low early childhood stress after 10 years found:⁴⁰

Early childhood stress correlated with

• With expectation of loss
  • Reduced activation of the putamen
  • Reduced activation of the insula
• When suffering losses
  • Increased activation of the left lower frontal gyrus
• With reward expectation
  • Reduced activation of the posterior cingulate cortex
  • Reduced activation of the precuneus
  • Reduced activation of the middle temporal gyrus
  • Reduced activation of the upper occipital cortex

1.6. Stress, anhedonia and the VTA-BLA-NAc pathway¶

A signaling pathway between the ventral tegmentum, basolateral amygdala and nucleus accumbens appears to be activated by (sexual) reward. Blockade of this pathway caused anhedonic behavior. Chronic stress (by movement restriction in rats) inhibited the responsiveness of dopaminergic VTA neurons to sexual reward. Reactivation of ventral tegmental area cells associated with sexual reward experience acutely counteracted stress-induced impairment of reward-seeking behavior (anhedonia).⁴¹

(Severe) one-off stress can cause long-lasting neuro-adaptive changes in VTA dopamine neurons. Thus, even a single acute stress can alter the responsiveness of VTA dopamine neurons to future stressors or rewards.⁴²

2. Neurophysiological correlates of reward reception¶

2.1. OFC for reward maintenance: overactivation in ADHD¶

A larger study found increased responses in adolescents and young adults with ADHD during the receipt of rewards in the³⁷

• OFC
• Occipital lobe
• Ventral striatum

In the unaffected siblings, the results were identical, with the exception of the ventral striatum.

ADHD-HI symptom severity predicted higher orbitofrontal activity in response to an immediate reward.⁴³

2.2. Caudate nucleus and frontal eye field in reward maintenance in ADHD¶

In the control group, feedback that no reward was given resulted in stronger activation in the left caudate nucleus and in the frontal eye field than feedback about rewards received, while in the ADHD-HI group, feedback that no reward was given resulted in weaker activation in the left caudate nucleus and in the frontal eye field than feedback about rewards received.³⁸

2.3. Nucleus accumbens and reward response¶

Mice in which dopamine was chemically reduced in the nucleus accumbens showed a reduced response to offered rewards. The nucleus accumbens appears to dopaminergically moderate the response to rewards and aversive stimuli.⁴⁴ Motivational control by the nucleus accumbens appears to be stimulated by the mPFC via noradrenaline. Noradrenaline deficiency in the mPFC leads to dopamine deficiency in the nucleus accumbens with the resulting changes in motivational control.⁴⁵

2.4. Connectivity of the ventral striatum during reward reception: increased in ADHD¶

People with ADHD show increased activity in the ventral striatum and superior frontal gyrus and increased connectivity between the ventral striatum and motor control regions when receiving rewards.⁴⁶

Increased activation in the ventral striatum was also shown in ADHD when receiving affiliative rewards.
For food rewards, on the other hand, there was no difference between those with ADHD and those without.¹⁴

3. Control of motivation through dopamine¶

Motivation is controlled by increased dopamine in the ventral striatum (nucleus accumbens).
The increase in dopamine levels can be triggered by various mechanisms.

3.1. Phasic impulses from dopaminergic cells of the VTA¶

The mesolimbic dopamine projection from the VTA to the nucleus accumbens is a central element for reward-driven learning and for the motivation to be active for more reward.

The dorsolateral striatum, the nucleus accumbens core and the nucleus accumbens shell responded in vitro with different dopamine releases to electrical stimulation of different numbers (single pulse (tonic), 5 pulses, 20 pulses (phasic) each at 20 Hz and 0.5 to 1 ms in length):⁴⁷

• Single pulse (tonic signal)
  • Dorsolateral striatum: high dopaminergic response
  • Nucleus accumbens core: intermediate dopaminergic response
  • Nucleus accumbens shell: low dopaminergic response
• 5 Impulses
  • Dorsolateral striatum: high dopaminergic response
  • Nucleus accumbens core: intermediate dopaminergic response
  • Nucleus accumbens shell: intermediate dopaminergic response
• 20 pulses (phasic signal)
  • Dorsolateral striatum: smallest increase in dopaminergic response
  • Nucleus accumbens core: mean increase in dopaminergic response
  • Nucleus accumbens shell: largest increase in dopaminergic response

The dorsolateral striatum responded to tonic stimuli with an amplification of the dopaminergic signal and to phasic stimuli with an attenuation, while the nucleus accumbens shell responded to tonic stimulation with a weak dopamine signal and to phasic stimulation with a strong dopamine signal.

With a very slow tonic stimulation at 0.2 Hz followed by a 5-pulse burst at 20 Hz, the dopamine amplitude is higher in the dorsolateral striatum than in the nucleus accumbens shell, and the dopamine release to the phasic stimulus is higher in both regions than to the preceding tonic stimulation. In the nucleus accumbens shell, the increase in dopamine release from the tonic to the phasic stimulus is higher than in the striatum.

The usual tonic firing frequency of dopaminergic neurons is around 4 Hz^{22 48}

• Continuous single pulses of 3.3 Hz (tonic signal)
  • Dopamine response began to blur
  • Static dopaminergic background level
• 5 pulses at 20 Hz
  • Dorsolateral striatum: only slightly increased dopaminergic response
  • Nucleus accumbens core: significantly increased dopaminergic response
  • Nucleus accumbens shell: very clearly increased dopaminergic response

A strong phasic dopamine response is a representative of an unexpected positive perception that is better than the expectation, e.g. for a surprising reward. Expected rewards do not correlate with phasic dopamine bursts in the striatum.⁴⁹

3.2. Increase in tonic extracellular dopamine due to varicosities?¶

There is evidence that motivational dopamine dynamics do not result from the firing of VTA dopamine cells, but may reflect local influences on forebrain dopamine varicosities:⁵⁰

The mesolimbic dopamine projection sent from the VTA to the nucleus accumbens encodes reward prediction errors. These are important as learning signals for behavioral adaptation.
However, the actual release of dopamine in the nucleus accumbens corresponds more to the value of reward anticipation, a motivational signal that promotes approach behavior.
This discrepancy could be due to changes in the tonic firing of the dopamine neurons, or to a fundamental separation between firing and release.

Dopamine release in the nucleus accumbens core and the ventral prelimbic cortex correlates with reward anticipation.
In contrast, the firing rate of dopamine neurons in the VTA does not correlate with reward expectancy, but with transient, error-like responses to unexpected cues, thus encoding reward prediction errors.