L7 NEUROCLIN II:ADHD II

1. Understand Frontal Cortex + Dopamine theories of ADHD, 2. Critique Frontal Cortex + Dopamine Theories of ADHD, 3. Explain the clinical heterogeneity of ADHD, 4. Understand emerging symptom-based approaches for ADHD

ADHD: story so far

frontal issues (executive function)

• neuropsychological tests

• structural imaging

• functional imaging

dopamine issues (reward processing)

• mechanisms of drugs

• changes in dopamine receptors

• differences in reward processing

• some relevant genetic evidence

- DAT, D4, D5 receptors

- gene environment interactions?
- DAT1 gene + exposure to prenatal smoking (Kahn et al., 2003)

IOWA Gambling Task

• neuropsychological test of impulsivity

• ADHD and frontal cortex

ADHD and the frontal cortex: Iowa Gambling Task and Delay Aversion

• measures cognitive impulsivity

• advantageous (decks C+D) vs disadvantageous decks (decks A+B)

• ADHD groups typically ‘seduced’ by large immediate gains despite long term loss

• e.g. garon et al., 2006; miller et al., 2013

• similar changes seen following frontal lobe insult

• represents delay aversion

• adhd associated w strong preference for smaller soon vs larger late rewards → manipulating delay period can further increase preference for small-soon rewards

• characteristic of behavioural disinhibition

• also linked to dopamine systems

ADHD and the frontal cortex: Iowa Gambling Task and Delay Aversion → led to development of…

Barkley’s behavioural inhibition model

Barkley’s behavioural inhibition model- foundation

• model of ADHD (1997)

• posits ADHD symptoms present as a failure to inhibit behaviour:

• attention problems- distractibility

• kinetic symptoms- movement

• i.e. executive function deficits (neural basis = frontal cortex)

Barkley’s behavioural inhibition model of ADHD, 1997

behavioural inhibition (inhibit prepotent response, stop an ongoing response, interference control) (1)

arrows to:

(2)

a) working memory

b) self-regulation of affect/ motivation/ arousal

c) internalisation of speech

d) reconstruction- facilitate the response fluence

(3)

motor control/fluency/syntax

a) inhibition taks-irrelevant responses

b) executing goal-directed responses

c) execution of novel/complex motor sequence

d) goal-directed persistence

e) sensitivity to response feedback

f) task re-engagement following disruption

g) control of behaviour by internally represented information

adhd and the frontal cortex- evidence of frontal cortex insult and behaviour change

• classic case = phineas gage

• post injury- impulsive, impatient, rude

• introduced link between frontal lobe damage/ changes and executive control

also:

• neurocognitive disorders (NCDs) - Huntington’s disease, Alzheimer’s, etc; post-concussive syndrome; TBIs

• schizophrenia

• lesion studies in animal models- risk aversion, impulsivity, response inhibition

ADHD and the frontal cortex- structural evidence

• Lin et al., (2023) analysis of 1798 ADHD brains vs 6007 without ADHD

• range of targets, but consistent reductions in frontal lobe compared to age matched controls

• but..

• may be a developmental delay , rather than chronic underdevelopment, e.g. Shaw et al., (2007)

• effect sizes quite small, and with high variance

• purely correlational

ADHD and the frontal cortex: function evidence

• evidence of frontal hypoactivity in ADHD groups during cognitive tasks of attention

• PET/fMRI: Dickstein et al., (2006), Weyandt et al., (2013)

but…

• reviews show areas where ADHD patients have greater levels of activation → compensatory recruitment of other regions?

• limited research on adults → delayed maturation?

• real world deficits, or task performance?

- continuous performance task = sustained attention

- go-no go = response inhibition

- ADHD associated w periods of hyperfocus (Ashinoff & Abu-Akel, 2019)

structural and functional evidence suggests…

1. insult to frontal regions can produce ADHD-like behaviours

2. frontal regions are undeveloped in ADHD-kids relative to age matched controls

3. frontal regions show hypoactivation during cog tasks of attention in ADHD-kids relative to age matched controls

ADHD and dopamine

• ADHD associated with increased dopamine clearance:

• dopamine vacuuming- DA does not hang around long enough to have an effect

• consistent evidence that ADHD drugs increase DA levels in murine forebrain

• microdialysis

• invasive technique that enables sampling of neurotransmitters

• allows us to monitor drug-induced changes

ADHD and dopamine: effects of stimulants on dopamine levels

• both d-Amphetamine and Methylphenidate significantly increase DA levels

• d-Amphetamine more potent

• methlyphenidate longer lasting

ADHD and dopamine: stimulant mechanisms

• both drugs primarily interfere with dopamine support

• methlyphenidate - antagonises dopamine transporters → blocks reuptake of DA

• amphetamine - enters pre-synaptic neuron → reverses transporters DA out

ADHD and dopmaine: DAT and the Dopamine ‘ Vacuum’

Cheon et al., (2002):

• drug-naive ADHD kids have more dopamine transporters

• dopamine cleared too quickly, creating low dopamine state

Spencer et al., (2006):

• PET evidence that methylphenidate occupies DAT

• suggests thereapeutic benefits are achieved thru impeding DA reuptake

ADHD and dopmaine: reward and reinforcement

• robust evidence that dopamine is released during reward- food,water,sex,etc

• evidence disrupted in ADHD

• how? historically mixed findings. some increases, some decreases

• may be due to tonic vs phasic activity- phasic DA response signals rewards

ADHD and dopmaine: tonic vs phasic dopamine

• dopamine activity in striatum (basal ganglia) are key to efficient reward processing

• Badagaiyan et al., (2015)

• PET study looking at DA receptors in striatum during reward

• ADHD vs non ADHD

• higher binding = reduced DA activity

• findings

• higher binding at rest → reduced tonic DA activity

• lower binding during rewards → enhanced phasic da

level of extracellular dopamine modulated by two mechanisms…

tonic and phasic transmission

tonic DA transmission

occurs when small amounts of dopamine are released without being preceded by presynaptic action potentials.

regulated by a variety of factors, including the activity of other neurons and neurotransmitter reuptake.

→ sustsained

phasic DA transmission

release

like most neurotransmitter release in the nervous system, is driven directly by action potentials in the dopamine-containing cells

→ momentary

drugs used to target adhd

• have mechanisms targeting dopamine transportation

• increases dopamine levels in various regions

ADHD kids + dopamine

appear to have increased availability of dopamine transports (DAT)

reward processing + ADHD

• disrupted

• may be due to decreased tonic and increased phasic DA activity

frontal processing vs dopamine models

• not likely to be one or the other

• integrate models

• dopamine- the engine- altered responses to reward

• frontal processing- the brakes- executive control

classical conceptualisation of ADHD

differences in top down executive control and bottom up reward processing

issues with classic adhd theories

• classic theories alone cannot explain all cases of ADHD

critiquing frontal theories

• lack of diagnostic specificity → frontal dysfunction found in almost all conditions (E.g. Hoogman et al., 2022)

• other non-frontal areas implicated in symptoms

• inconsistent findings in frontal research (hypo vs hyper activity and connectivity)

• evidence of deficits in experimental EF tasks but: high variability; only 50-60% of ADHD patients show deficits in most sensitive EF tasks (Luo et al., 2019)

critiquing dopamine theories

• stimulants not always effective in treating adhd

• newer drugs do not target DA

• atomoxetine, viloxazine → selective noradrenaline (norephinephrine) reuptake inhibitor

• guanfacine → selective alpha 2a adrenergic agonist

• d-amphetamine also has affinity for NA and (to lesser extent) 5-HT receptor transporters

• recent evidence of 5-HT differences in DHD (Jackson et al., 2025)

→ suggests of diff neurotransmitters mediating different ADHD symptoms

what we know about ADHD

• primary behavioural features are inattention and/or hyperactivity/impulsivity → but presentation varies across patients

• most common treatments are methylphenidate, amphetamines, and non-stimulants (e.g. atomoxetine, viloxazine, guanfacine) → but responses to treatment and side effect presentation varies across patients

• classically believed to be deficit of frontal cortex and DA activity → but extent of differences varies across patients and does not explain all cases

• genetic/familial component → but each candidate gene has small effect, meaning genetic impact varies across patients

key characteristic in adhd

heterogeneity

• in symptoms

• in treatment response

• in underlying neural changes

• in causes/genetic basis

problem: classical theories alone cannot explain all cases of ADHD

proposed solution….

move towards conceptualising ADHD as a heterogenous disorder, try to understand homogenous subgroups as targets for novel interventions (Luo et al., 2019) → looking at smaller symptom clusters

benefits to new proposed solution

• more effective/personalised treatment options

• accelerated genetic/biomarker research

• improved developmental prognosis

is there evidence for focussing on individual symptoms/ homogenous subgroups?

• evidence from latent analyses shows diff trajectories even when accounting for DSM presentations → suggests more than 3 presentations?

• is it likely can all be explained by single theory/pathological loci , or focus on individual symptoms?

ADHD symptom networks (Liu et al., 2022)

• network analysis of ADHD symptoms

thicker lines - stronger correlation

blue- positive relationship, red - negative rls

blue ring - extent a node predicted by neighbours

more lines - more central

• distractibility and fidgeting = most common and connected symptoms

• inferences:

• some symptoms v unlikely to present together, some v likely to → different pathological loci?

latent class ADHD trajectories: Murray et al., (2021)

• tracked H-I latent trajectories of ADHD symptoms over 11 years in UK Millenium Cohort Study

6 clusters identified:

• Pre-school onset persistent (6.4%): Classical ADHD trajectory

• Developmentally increasing (7.6%): Later onset group that starts with moderate symptoms

• Pre-school onset partially remitting (14.1%): Borderline symptoms that decline into the non-clinical range

• Subclinical remitting (12.8%): Elevated sub-clinical symptoms that decrease over time.

• Mildly affected (24.1%): Constant slightly elevated but sub-clinical symptoms.

• Unaffected (34.9%): Consistently low levels of symptoms

latent class ADHD trajectories: Arnold et al., (2014)

• tracked latent class ADHD symptoms over 36 months in sub-clinical ADHD cohort

• 3 inattentive trajectories: mild, intermediate, severe

• 4 H-I trajectories: consistently mild, consistently severe, improving dramatically, worsening over time

example of symptom-based approach to adhd

distractibility

distractibility

• core ft of adhd since 40/50s

• central node in adhd symptom network analysis (Liu et al., 2022)

• most common symptom in ADHD (Wilens et al., 2009) and most persistent with age

• importantly- neural substrate mediating distractibility well known

ADHD, distractibility- neural substrate

superior colliculus (SC)

ADHD, distractibility, superior colliculus

• SC associated w D

• SC key role in diversion of attentional and motor resources towards novel stimuli

• tasks relying on SC input are impaired in ADHD → projection from SC to substania nigra- influence over DA response?

• SC has necessary architecture for psychostimulant action

• → visual activity in SC depressed by d-amphetamine and methylphenidate (Gowan et al., 2008; Dommett et al., 2005) → effects of ADHD drug mimicked by 5-HT

• potential to develop drugs to improve distractibility in ADHD by targeting SC

rats, superior colliculus

lesions on bilateral SC → ignore distraction and go straight to task

serotonin + distractibility

• effects of stimulants in SC mediated by 5-HT and SSRIs mimic effects of stimulants in SC

• converging research suggests 5-HT more relevant in ADHD than thought- Jackson et al., (2025)

• pharma and/or dietary targets

tectonigral projection

superior colliculus → substantia nigra

summary

• ADHD traditionally viewed as a deficit in frontal ‘Brakes’ (executive functions) and dopamine ‘engines’ (reward processing).

• But these theories cannot explain all cases of ADHD

• Contemporary approaches view ADHD as not a single condition but a cluster of varying trajectories

• Research is shifting away from applying a one-size-fits-all approach to focusing on addressing symptom clusters

• Focusing on specific symptoms like distractibility may be a fruitful approach to more personalised drug interventions for ADHD