ADHD

6 ADHD symptoms

- little attention to detail - careless mistakes - does not listen - loses things - distracted - forgetful

What brain region do people with ADHD struggle to activate? What do they do as a result?

-ACC -To compensate, they recruit other brain regions not normally involved in selective attention which allows them to perform task but inefficiently, slowly, with errors

6 functions of a2-A receptors?

-Anaesthesia -Analgesia -Sympatholysis -Sedation -Anxiolysis/Hypnosis -*Increased cognition*

Amphetamine is chemically similar to DA and NE

-Because of their similarity, all 3 compounds will be transported by both NET and DAT. -Amphetamine will therefore compete with DA and NE for transport into the neuron via these transporters.

What is the dopamine transfer theory?

-Cues that predict reward elicit anticipatory reward -Lack of DA response to cues that predict reward cause emotional distress and intolerance of delayed gradification

Describe the signal distribution in a dendritic spine?

-D1 receptors and α2A adrenoceptors may be on separate subsets of dendritic spines, allowing them to not only modulate different PFC networks simultaneously, but also modulate the same PFC networks with separate timing, i.e. NE and DA neurons may modulate the same PFC Glu neuron at different time points within the same experienced event.

Role of DA and NE in attention

-DA and NE fine-tune signal-to-noise ratio in PFC -NE increases sensitivity to relevant cues -DA reduces the sensitivity to irrelevant cues

What is information processing in ADHD like?

-Inefficient info processing during cognitive task -Tasks that involve selective attention specifically (like Stroop) that recruit ACC

Orbital Frontal Cortex Regulates Impulsivity. What does impulsivity look like?

-talks excessively -blurts out -not waiting turn -interrupts/intrudes

What are the 4 cortical networks regulating behavior?

1. DMN 2. DAN 3. VAN 4. SN- salience network involved in task preparation

Possible future treatments/other cognitive enhancers:

1. Histamine: H3 autoreceptor inhibition 2. Acetylcholine: Nicotinic receptor activation (agonist or PAMs) 3. AMPA receptor PAMs

Yerkes-Dodson's curve of arousal-performance relationship

1. Insufficient DA/NA levels: distracted, impulsive, poor judgement, and impaired working memory 2. Optimal physiological range: focused, attentive, and flexible 3. Excessive DA/NA levels: stressed, hyperactive, distractible, inattentive, excessively stimulus bound, mental inflexibility

Name 4 things about the diverse roles of mesolimbic dopamine?

1. Novelty/surprise 2. Pleasure/reward 3. Motivation/goal-directed behavior 4. Salience/importance

Stroop test is what?

A test of selective attention in a situation where several conflicting (relevant vs. distracting) cues are presented. Involves ACC activation

What is the traditional view:

ADHD= a cognitive disorder Anxiety/depression= affective disorders SWITCH THAT: ADHD= a affective disorder Anxiety/depression= a cognitive disorder

Brian activation to cues predicting inescapable delay in who?

Adolescents with ADHD

What agents allow patients to perform tasks accurately/activate ACC?

Agents that increase activation of DA 1 and/or a2A adrenergic receptors in PFC (stimulants, atomoxetine, guanfacine ER, modafinil) allow proper activation of the ACC

Norepinephrine/epinephrine receptors (adrenoceptors). What are the types of alpha receptors and types of beta receptors?

Alpha: a1 a2: endogenous agonist: noradrenaline and adrenaline Exogenous agonists: clonidine, guanfacine Beta: B1,B2,B3

Guanfacine

Also available as controlled/extended release, called guanfacine ER

Low limbic DA tone leads to

Anhedonia--> delay aversion--> low frustration threshold--> anger bursts--> regret/guilt/shame

Low limbic DA tone leads to what?

Anhedonia--> tendency to engage in too much activities--> stress--> emotional dysregulation

Optimal NE and DA levels do what?

Assist in goal-directed behavior by increasing the signal-to-noise ratio. Example: staying focused during a working memory task

High NE leads to

B1 and a1 activation--> inhibition of signal

What happens in ADHD?

Can't activate ACC + aberrant activation of attentional networks

Optimal DA leads to

D1 activation--> inhibition of noise

What is the nature of DA neurons?

DA neurons fire according to one's arousal state, attention and reward. -tonic firing reflects arousal state but phasic responses (bursts of action potentials) associated with , for example, during the presentation of a cue that predicts reward. 3) manyDAneuronsrespond phasically to reflect prediction error of rewards.

Task positive networks:

DAN and VAN Dan: Top-down influence: Shows increased activation during cognitive or executive engagement. Van: Bottum-up influence: A 'circuit-breaker' that interrupts ongoing cognitive activity, by modulating dorsal network selection when an unexpected behaviourally relevant event happens.

What area regulates sustained attention and problem solving?

DLPFC -sustaining attention -follow through/ finish -organizing -avoids sustained mental effort

ADHD and stress-related affective disorders lead to what 2 things?

Depression and anxiety

CSTC circuit for selective attention

Dorsal ACC--> bottom of striatum--> thalamus--> ACC

NET endogenous substrate and false substrate

Endogenous substrate: NE False substrate: dopamine, epinephrine, amphetamine

SERT endogenous substrate and false substrate

Endogenous substrate: Serotonin Falso substrate: Ecstasy

Dopamine endogenous substrate and false substrate

Endogenous substrate: dopamine Falso substrate: NE, epinephrine, amphetamine

Hypofrontality in depression is the link to what?

Executive dysfunction and negative affective bias

In attention, DA and NE do what?

Fine-tune signal-to-noise ratio

Excessive DA suppress what?

Firing of preferred and non-preferred stimuli!!!

What is the role of DA and NE in executive functioning?

Has to do with the PFC

Prefrontal cortex

High NET expression Very low DAT expression

Aversion to delayed gratification can lead to what?

Hyperactivity and impulsivity

What is the effect of methylphenidate on anxiety and depressiomn n symptoms in patients with Asperger syndrome and comorbid ADHD?

IDK

Describe striatal activity during reward anticipation and reward delivery in ADHD

In depression, striatal activity is reduced during both anticipation and delivery, suggesting a more generalized anhedonia.

Low DA leads to

Insufficient D1 activation--> insufficient inhibition of noise

Low NE leads to

Insufficient a2A activation--> insufficient facilitation of signal

What is the main question of ADHD?

Is it a disorder or a mismatch?

What does the location of a2A and D1 receptors on dendritic spines of cortical pyramidal neurons in the PFC allow?

It allows them to gate incoming signals. Both a2A and D1 receptors are linked to the molecule cAMP. The effects on cAMP from NE and DA binding at their respective receptors are opposite (inhibitory effect on cAMP for NE and excitatory for DA)

Why is activity in DMN and task positive network NOT anti-correlated in ADHD?

It causes the DMN to randomly interrupt the TPN during attention tasks

What is challenging about delay discounting?

It challenges our ability to tolerate a delayed gratification

What happens during phasic firing?

Just a ton of high-frequency APs -large amount of vesicular DA released in synapse= the phasic pool that acts on postsynaptic receptors *Amount of DA released during phasic firing dependent on feedback inhibition provided by D2/D3 Tonic DA release

NE system has to do with what?

LC has to do with increase NE release -Mood -Arousal -Cognition -Vigilance -Wakefulness -Anxiety -Aggression

4 Core symptoms of ADHD and what is it linked to the malfunction of?

Linked to malfunctioning of PFC 1. selective attention 2. sustained attention problem solving 3. hyperactive symptoms 4. impulsive symptoms

What does the cAMP molecule do?

Links receptors to the hyper polarization-activiated HCN cation channels--> when those channels are open, incoming signals leak out before they can be passed along. When channels are closed, incoming signal survives and can be directed down the neuron.

What is a shared characteristic of ADHD and depression?

Low hedonic tone!

DAN is related to what?

Moderately high levels of tonic activity

Prefrontal Motor Cortex regulates what. What does hyperactivity look like?

Motor hyperactivity -fidgets -leaves seat -runs/climbs -on the go/driven -difficulty playing quietly

What is the nature of NE neurons?

NE neurons fire according to one's arousal state and attention! 1) silent during REM sleep 2) low, tonic firing during slow wave sleep and drowsiness 3) moderate, tonic firing with phasic responses (burst firing) to relevant stimuli during non- stressed waking 4) high tonic firing during stress. - High tonic NE firing during stress exposure requires activation from the amygdala.

What happens with tonic activity in ADHD?

NOT REGULATED Why? misbalanced DMN and distractibility due to a low threshold for phasic signaling which yields over activation of the VAN during task performance and short-term impulsivity

Atomoxetine or reboxetine

NRIs (NET)

If you increase amygdala reactivity in ADHD that leads to what?

Normalization by stimulants

Stimulant does what?

Normalizes mesolimbic DA transmission and reduces amygdala activation

DA vs NE in the PFC

PFC receives NE and DA input Clearance of DA and NE in the PFC occurs via NET Selective NET inhibitors (reboxetine, atomoxetine) enhance both NE and DA in the PFC. The NA and striatum receives almost no NE input and have less NET. Hence, selective NET inhibitors don't increase DA in these regions...

Which end of the curve does ADHD represent?

Probably both!

Shared neurobiological changes in depression, anxiety and ADHD

Reduced DLPFC functioning: impaired executive function. • ADHD: inability to top-down control impulsivity and hyperactivity reduced mesocortical DA transmission • Depression: inability to disengage from negativity (lack of cognitive flexibility) reduced mesocortical DA transmission • Anxiety: inability to correct an inflated estimate of the probability and consequenses of adverse events Deficient mesolimbic DA transmission: anhedonia • ADHD: lack of ability to attribute salience to reward-predicting cues -> inability to tolerate delayed gradification. • Depression: anhedonia, lack of ability to attribute salience to pleasurable events -> lack of interest and drive to pursue pleasure Increased amygdala reactivity: emotional dysregulation • ADHD: emotional lability, frustration/anxiety during delayed gradification • Depression: ruminative thoughts, irritability, default-mode network hyperactivity • Anxiety: panic, excessive worrying, default-mode network hyperactivity

Amygdala is more than a 'fear center'...it is closely related to what?

Reward anticipation

What is tonic firing?

Small amount of DA continuously released by presynaptic terminal -DA is released from D2/D3 presynaptic receptors that provide feedback inhibition to limit release of DA *reduced tonic activity leads to larger phasic release of DA

Optimal DA levels enhance what?

Spatial tuning by suppressing delay- related firing for the non-preferred direction.

What activates VAN?

Stimulus-related phasic catecholaminergic signaling, inducing attentional shifts in focused states and transitions between DAN and the DMN

Anhedonia is what?

The loss of interest and enjoyment in all activities that you once liked; the feeling of not caring anymore

Why are other brain regions activated in ADHD patients?

To compensate (VLPFC helps with stimulus selection) or because of frustration over the difficulty of the task (insular cortex)

Blocking DAT/NET enhances what?

Tonic pool and therefore leads to larger phasic release of DA (this might lead to ADHD)

High DA leads to

Too much D1 activation--> inhibition of both signal and noise

NE and DA show inverted what?

U dose-response effects on attention / working memory related DLPFC activity

Monoamine transporters involved in ADHD

VMAT = vesicular monoamine transporter 5-HT = 5-hydroxy-tryptamine = serotonin NE = norepinephrine = noradrenaline DA = dopamine DA is also transported into NE neurons via NET and NE is also transported into DA neurons via DAT

N.Accumbens and striatum:

Very low NET expression High DAT expression

What is delay discounting?

a decay of the subjective experience of reward value if the reward delivery is delayed (Now-later)- reward value decays faster in impulsive individuals

Optimal NE leads to

a2A activation--> facilitation of signal

Describe optimal NE levels (hold info online, stay focused)

activation of α2A adrenoceptors --> facilitation of signal (inhibition of HCN channel--> disinhibition of the 'delay neurons' (glutamate ner), enhancing delay activity for the preferred direction

Activity in DMN and task positive network is what?

anti-correlated but NOT in ADHD!

Treatment options for ADHD

d,l-methylphenidate = more potent NET; available as immediate and controlled release formulation d,l-amphetamine: more potent on the DAT, similar potency on NET Lisdexamphetamine= lysine-coupled d-amphetamine, lysine keeps d-amphetamine inactivate, but is slowly cleaved off, thereby releasing d-amphetamine

What do high NE levels cause? (info lost, no more goal-directed behavior)

excessive α1 and β1 adrenoceptor stimulation -->activation of HCN channel activity -->inhibition of the 'delay neurons' (glutamate neuron) reducing delay-related activity for the preferred direction

What is the MESOCORTICAL brain dopamine (DA) pathway responsible for?

executive function, response inhibition, emotion regulation

ADHD is a flip-flopping between what?

hypo and hyper arousal

DMN is associated with what?

low tonic catecholaminergic activity

What is deficient in ADHD?

mesolimbic and mesocortical DA activity

What is the NIGROSTRIATAL brain dopamine (DA) pathway responsible for?

motor function, habitual responses

What activates the SN?

phasic signaling, which is associated with a buildup of DA activity related to expectation and task preparation

What is the MESOLIMBIC brain dopamine (DA) pathway responsible for?

reward, motivation, hedonic tone

DLPFC

• Problem solving • Abstract thinking • Sustained attention • Working memory • Cognitive flexibility • Disengagement from negativity