Motivation in ADHD - Neurophysiological correlates

ADHD shows an aberrant response to expected reward as well as to received reward.

• 1. Neurophysiological correlates of reward expectancy
  • 1.1. Striatum and reward expectancy: underactivated in ADHD and stress
    • 1.1.1. Striatum in reward expectancy: underactivated in ADHD
    • 1.1.2. Striatum in reward expectation and stress
      • 1.1.2.1. Striatum during reward anticipation: increased activation during acute stress
      • 1.1.2.2. Striatum in reward expectation: underactivated in chronic stress
      • 1.1.2.3. Striatum in reward expectation: underactivated after early childhood stress
  • 1.2. ACC, PFC, cerebellum in reward expectancy: overactivated in ADHD
  • 1.3. Ventral anterior thalamus in reward expectancy: underactivated in ADHD
  • 1.4. OFC activity in reward expectancy: increased in ADHD
  • 1.5. Further changes during reward and loss expectancy in early childhood stress
  • 1.6. Stress, anhedonia and the VTA-BLA-NAc pathway
• 2. Neurophysiological correlates of reward reception
  • 2.1. OFC in 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 by dopamine
  • 3.1. Phasic pulses from dopaminergic cells of the VTA
  • 3.2. Increase tonic extracellular dopamine by varicosities?

1. Neurophysiological correlates of reward expectancy¶

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 .¹

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

1.1.1. Striatum in reward expectancy: underactivated in ADHD¶

In rats that performed actions required to obtain a reward, dopamine levels continued to rise as the reward approached and peaked with the receipt of the reward. Afterwards, when they consumed the reward, it quickly dropped again.²

ADHD correlates with reduced activity on expected rewards in brain regions of the reward center (including nucleus accumbens). Motivation triggered by (appropriately 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 gain. The lower activation of the ventral striatum during gain anticipation, the higher hyperactivity and impulsivity were.³⁴ Children with ADHD-HI showed significantly decreased ventral striatum volume bilaterally and a correlation of right ventral striatum reduction with hyperactivity/impulsivity.⁵

Brain activity on reward expectancy and reward maintenance appears to be subtype specific. ADHD-I showed bilateral underactivation of the ventral striatum during reward expectancy compared to ADHD-C and healthy controls. In contrast, ADHD-C showed underactivation of the OFC in response to reward compared with ADHD-I and controls.⁶

One study found underactivation of the striatum during reward anticipation in ADHD-C only in adults but not in children.⁷

Another study found in ADHD-HI that hyperactivity/impulsivity correlated with (relatively) decreased ventral striatum activity during reward expectancy and increased ventral striatum activity as a reward response. In contrast, unaffected subjects showed increased activity of the ventral striatum during reward expectancy.⁸

ADHD symptoms correlated with decreased striatum activation in reward expectancy in children, independent of ADHD symptom severity.⁹

Dihydro-β-erythroidine (DHβE) is a herbal competetive antagonist of nicotinic receptors. It is an inhibitor of nicotinic acetylcholine receptors containing β2-units (β2* NAChRs; β2-nicotinic receptors). DHβE decreases phasic dopamine release in the dorsolateral striatum¹⁰
It follows 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 in reward expectation and stress¶

1.1.2.1. Striatum during reward anticipation: increased activation during acute stress¶

Acute stress also increases dopamine, including in the nucleus accumbens, which triggers motivational expectancy. Mediation of the increased motivational expectancy appears to occur through CRH release in the nucleus accumbens.¹¹ A CRH1 antagonist blocks this reinforcing effect of acute stress on reward motivation.¹² High chronic stress abolishes - after up to 90 days after cessation of the stressor - the ability of CRH to increase dopamine in the nucleus accumbens and at the same time caused a switch from appetitive to aversive motivation,¹³ as is also observed in major depression MDD.¹⁴

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

Chronic stress reduces striatal dopaminergic activity over the long term. Institutional neglect, early childhood stress, or maltreatment inhibit striatal reward function, which is dopaminergically mediated.^15161718

See more at ⇒ Alteration of the dopaminergic system by chronic stress

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

Early childhood stress (e.g., postnatal deprivation, maternal separation) resulted in decreased mesolimbic dopamine levels in the striatum and decreased motivation to pursue rewards in adult rats and monkeys.¹⁹ Monkeys with early childhood stress experience showed decreased interest in rewards. However, reward consumption remained unchanged. Increased urinary norepinephrine depletion was found.²⁰

In humans, early childhood stress is also associated with decreased activity in relation to reward in the ventral striatum²¹, which is associated with increased symptoms of anhedonia²², although the data did not differentiate between reward expectation and reward receipt. It would be conceivable that reduced reactivity to received rewards in particular correlates with anhedonia or depression.

Adolescents who were maltreated as children showed reduced dopaminergic activation of the pallidum (part of the striatum) in reward expectancy concomitant with more severe depression symptoms.²³

Further studies confirm that early childhood stress (with no direct link to depression) correlates with decreased activation of the striatum during reward expectancy but not during reward maintenance.²⁴¹⁷ This is consistent with changes in ADHD in both reward expectancy and reward maintenance.

See more at ⇒ Early childhood stress permanently alters the dopaminergic system

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

A larger study found increased responses in adolescents and young adults with ADHD during reward expectancy in the²⁵

• Anterior cingulate cortex (ACC)
• PFC
• Cerebellum

In the unaffected siblings, the results were identical, except for the cerebellum.

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

Cues that predicted reward caused greater activation in the ventral anterior thalamus in the control group than cues that did not predict reward, whereas in ADHD, just the opposite, cues that predicted reward caused less activation than cues that did not predict reward.²⁶

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

An fMRI study found a significant signal increase in OFC to large versus small expected rewards in all subjects. Responses were significantly stronger in ADHD and also correlated with hyperactivity/impulsivity. High cognitive ability normalized OFC responses.²⁷

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

A study that reexamined children with high and low early childhood stress after 10 years found:²⁸

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 inferior 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 superior occipital cortex

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

A signaling pathway between ventral tegmentum, basolateral amygdala, and nucleus accumbens seems to be activated by (sexual) reward. Blockade of this signaling pathway caused anhedonic behavior. Chronic stress (from exercise restriction in rats) inhibited the responsiveness of VTA dopaminergic neurons to sexual reward. Reactivation of ventral tegmentum cells associated with sexual reward experience acutely counteracted stress-induced impairment of reward-seeking behavior (anhedonia).²⁹

(Severe) one-time stress can cause long-lasting neuroadaptive changes in VTA dopamine neurons. Thus, even one-time acute stress can alter the responsiveness of VTA dopamine neurons to future stressors or rewards.³⁰

2. Neurophysiological correlates of reward reception¶

2.1. OFC in reward maintenance: overactivation in ADHD¶

A larger study found increased responses in adolescents and young adults with ADHD during receipt of reward in the²⁵

• OFC
• Occipital lobe
• Ventral striatum

In the unaffected siblings, the results were identical except for the ventral striatum.

ADHD-HI symptom severity predicted higher orbitofrontal activity in response to immediate reward.³¹

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

Feedback that no reward was received caused stronger activation in the left caudate nucleus and frontal eye field than feedback about rewards received in the control group, whereas in the ADHD-HI group, exactly the opposite, feedback that no reward was received caused weaker activation in the left caudate nucleus and frontal eye field than feedback about rewards received.²⁶

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.³² In this context, motivational control by the nucleus accumbens appears to be stimulated by the mPFC via norepinephrine. Norepinephrine deficiency in the mPFC leads to dopamine deficiency in the nucleus accumbens with resultant changes in motivational control.³³

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

ADHD sufferers show increased activity in the ventral striatum and superior frontal gyrus when receiving rewards, as well as increased connectivity between the ventral striatum and regions of motor control.³⁴

3. Control of motivation by 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 pulses from dopaminergic cells of the VTA¶

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

The dorsolateral striatum, nucleus accumbens nucleus, and nucleus accumbens shell responded in vitro with different dopamine releases to electrical stimulation of different numbers (single pulse (tonic), 5 pulses, 20 pulses (phasic) at 20 Hz each and 0.5 to 1 ms in length):³⁵

• Single pulse (tonic signal)
  • Dorsolateral striatum: high dopaminergic response
  • Nucleus accumbens nucleus: medium dopaminergic response
  • Nucleus accumbens shell: low dopaminergic response
• 5 Impulses
  • Dorsolateral striatum: high dopaminergic response
  • Nucleus accumbens nucleus: medium dopaminergic response
  • Nucleus accumbens shell: medium dopaminergic response
• 20 pulses (phasic signal)
  • Dorsolateral striatum: smallest increase of the dopaminergic response
  • Nucleus accumbens nucleus: mean increase in dopaminergic response
  • Nucleus accumbens shell: greatest increase in dopaminergic response

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

During very slow tonic stimulation at 0.2 Hz followed by a 5-pulse burst at 20 Hz, dopamine amplitude is higher in the dorsolateral striatum than in the nucleus accumbens shell, and 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 dl striatum.

The usual tonic firing frequency of dopaminergic neurons is about 4 Hz^{10 36}

• Running 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 nucleus: markedly increased dopaminergic response
  • Nucleus accumbens shell: very marked increased dopaminergic response

A strong phasic dopamine response is a respresentative of an unexpected positive perception that turns out better than expected, e.g., for a surprising reward. Expected rewards do not correlate with phasic dopamine bursts in the striatum.³⁷

3.2. Increase tonic extracellular dopamine by varicosities?¶

There is evidence that motivation-related dopamine dynamics do not result from firing of VTA dopamine cells but may reflect local influences on forebrain dopamine varicosities:³⁸

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 is more consistent with the value of reward expectancy, a motivational signal that promotes approach behavior.
This discrepancy could be due to changes in tonic firing of dopamine neurons, or a fundamental disconnect between firing and release.

Dopamine release in the nucleus accumbens nucleus and ventral prelimbic cortex correlates with reward expectancy.
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.