Neuroscience and Biobehavioral Reviews 164 (2024) 105841

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Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

From neurons to brain networks, pharmacodynamics of stimulant

medication for ADHD
Valeria Parlatini a, b, c, d, e, f, * , Alessio Bellato a, b, c, f, g , Declan Murphy d, e, 1 ,
Samuele Cortese a, b, c, f, h, i, j, 1
a
School of Psychology, University of Southampton, Southampton, United Kingdom
b
Centre for Innovation in Mental Health, University of Southampton, Southampton, United Kingdom
c
Institute for Life Sciences, University of Southampton, Southampton, United Kingdom
d
Institute of Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s
College London, London SE5 8AF, United Kingdom
e
Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, United
Kingdom
f
Solent NHS Trust, Southampton, United Kingdom
g
School of Psychology, University of Nottingham, Semenyih, Malaysia
h
Mind and Neurodevelopment (MiND) Research Group, University of Nottingham, Semenyih, Malaysia
i
Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, United Kingdom
j
Hassenfeld Children’s Hospital at NYU Langone, New York University Child Study Center, New York, NY, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Stimulants represent the first line pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD)
Attention-deficit/hyperactivity disorder and are among the most prescribed psychopharmacological treatments. Their mechanism of action at synaptic
(ADHD) level has been extensively studied. However, it is less clear how their mechanism of action determines clinically
Stimulant
observed benefits. To help bridge this gap, we provide a comprehensive review of stimulant effects, with an
Methylphenidate
Amphetamine
emphasis on nuclear medicine and magnetic resonance imaging (MRI) findings. There is evidence that stimulant-
Pharmacodynamic induced modulation of dopamine and norepinephrine neurotransmission optimizes engagement of task-related
Brain networks brain networks, increases perceived saliency, and reduces interference from the default mode network. An
Magnetic resonance imaging (MRI) acute administration of stimulants may reduce brain alterations observed in untreated individuals in fronto-
Positron emission tomography (PET) striato-parieto-cerebellar networks during tasks or at rest. Potential effects of prolonged treatment remain
Single-photon emission computed tomography controversial. Overall, neuroimaging has fostered understanding on stimulant mechanism of action. However,
(SPECT) studies are often limited by small samples, short or no follow-up, and methodological heterogeneity. Future
studies should address age-related and longer-term effects, potential differences among stimulants, and pre-
dictors of treatment response.

1. Introduction present with neuropsychological deficits, mainly affecting executive

functions, such as attention, response inhibition, planning, and working
Attention-deficit/hyperactivity disorder (ADHD) is one of the most memory (Faraone et al., 2021). Co-occurrent conditions, such as affec-
common neurodevelopmental conditions and is characterized by age- tive, substance use or other neurodevelopmental disorders, are also
inappropriate inattentive and/or hyperactive-impulsive symptoms common (Gnanavel et al., 2019, Katzman et al., 2017). ADHD is asso-
(APA, 2022; Priya Ra 2023, WHO, 2019/2021). It is often diagnosed in ciated with educational and occupation failure, teenage pregnancies,
childhood, with a community prevalence between 2 % and 7 % (Cortese legal offences, road accidents, and increased mortality; as well as with
et al., 2023, Sayal et al., 2018). Impairing symptoms of ADHD persist in high costs related to income/health-related losses and educational
up to 75 % of adults (Sibley et al., 2016). Individuals with ADHD may support (Faraone et al., 2021). Pharmacological treatment has been

* Correspondence to: School of Psychology, University of Southampton, Southampton SO17 1PS, United Kingdom.
E-mail addresses: v.parlatini@soton.ac.uk, valeria.parlatini@kcl.ac.uk (V. Parlatini).
1
=equal contribution

https://doi.org/10.1016/j.neubiorev.2024.105841
Received 17 April 2024; Received in revised form 25 July 2024; Accepted 1 August 2024
Available online 2 August 2024
0149-7634/© 2024 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
V. Parlatini et al. Neuroscience and Biobehavioral Reviews 164 (2024) 105841

shown to reduce these risks, while improving outcomes and quality of circuits, and is well known for its role in movement regulation.
life (Bellato et al., 2024, Cortese et al., 2018, Faraone et al., 2021). Further, mesocortical and mesolimbic dopaminergic pathways are
Stimulants represent the first line pharmacological treatment and are involved in executive functions and affect regulation, as they project
generally effective in ameliorating symptoms (Cortese et al., 2018). from the SNc and the VTA directly to cortical regions, such as the mesial
Stimulants include methylphenidate (MPH) and various forms of am- frontal and anterior cingulate cortex (ACC), and to limbic structures,
phetamines, such as dexamfetamine and lisdexamfetamine (Cortese such as the amygdala and hippocampus (Moore and Bloom, 1978)
et al., 2018, Faraone et al., 2021). Stimulants are among the most pre- (Fig. 1). ADHD has been associated with dysfunction in all these three
scribed psychopharmacological treatments, and rates are increasing pathways (Del Campo et al., 2011, Mehta et al., 2019).
especially in adults, as highlighted by a recent data release of the UK The role of fronto-striatal pathways has been the most investigated in
NHS Business Services Authority (NHSBSA) (https://www.nhsbsa.nhs. ADHD research (da Silva et al., 2023, Del Campo et al., 2011, Mehta
uk/statistical-collections/medicines-used-mental-health-england et al., 2019, Parlatini et al., 2023b). These are GABA-glutamatergic
/medicines-used-mental-health-england-201516–202223). Stimulants circuits modulated by dopamine. They contribute to motor, cognitive
act by modulating dopamine and norepinephrine neurotransmission in and affective regulation by connecting different parts of the cortex to the
striato-cortical regions (Faraone, 2018). Although their mechanism of basal ganglia and thalamus, which then projects back to the cortex
action at synaptic level has been extensively studied, e.g. in vitro and in (Alexander and Crutcher, 1990, Alexander et al., 1986). Although there
animal models (Zimmer, 2017), it is less clear how these neurochemical is no consensus on their exact number, three major loops can be iden-
changes determine the beneficial clinical and behavioral effects. Neu- tified according to their main function and the cortical regions they
roimaging studies, such as positron emission tomography (PET), single originate from: 1) the sensorimotor loop originates from the sensori-
photon emission computed tomography (SPECT), and magnetic reso- motor cortex; 2) the cognitive circuit from the dorsolateral prefrontal
nance imaging (MRI), represent a powerful tool to address this gap by cortex (DLPFC); and 3) the affective (limbic) loop from the ACC and
investigating treatment effects on the brain at a macroscopic level. orbitofrontal cortex. Through these fronto-striatal loops, multiple
Given the lack of recent and comprehensive reviews in this fast- cortical inputs are integrated and conveyed to a specific single cortical
evolving field, here we present a timely overview of brain mechanisms area in order to modulate motor planning/initiation or to select and
underpinning stimulant mechanism of action, spanning from cellular to enable cognitive/emotional programs (Alexander et al., 1986, Allen and
brain network levels, with an emphasis on neurotransmission and novel Tsukahara, 1974, Kemp and Powell, 1971). Overall, these circuits
insight provided by neuroimaging research. This comprehensive narra- contribute to executive functions and affect regulation, which can be
tive review builds on evidence from relevant systematic and narrative impaired in ADHD.
reviews and meta-analyses and expands their findings by including Further, ADHD has been linked to noradrenergic dysfunction. In
updated evidence up to the 17th July 2024. We identified the studies via contrast to dopaminergic connections, noradrenergic pathways are
a systematic screening of publications in PubMed using the following highly distributed throughout the brain. These originate from the locus
search strategy: (ADHD [tiab] OR attention-deficit/hyperactivity dis- coeruleus (LC), which is in the brainstem and is reciprocally connected
order [tiab] OR attention-deficit [tiab] OR attention deficit [tiab] OR with cortical regions, such as the PFC (Gerfen and Clavier, 1979, Mor-
hyperkinetic syndrome [tiab] OR hyperkinetic disorder [tiab]) AND rison et al., 1982, Ramos and Arnsten, 2007) (Fig. 1). Animal studies
(separately for molecular mechanisms and each imaging modality) have demonstrated that these connections modulate neural functions
(pathogenesis [tiab] OR pathophysiology [tiab] OR molecular [tiab]); according to arousal state and attention (Aston-Jones and Cohen, 2005).
(PET [tiab] OR positron emission [tiab]); (SPECT [tiab] OR photon The LC shows a phasic activity when an animal is awake, characterized
emission [tiab]); (MRI [tiab] OR magnetic resonance imaging [tiab] OR by low levels of spontaneous firing alternated to bursts when a stimulus
fMRI [tiab] OR connectivity [tiab] OR diffusion [tiab]). We did not of interest is perceived. Conversely, when an animal is stressed or
include case reports and studies focusing on new methods development anxious, the LC enters a tonic phase, characterized by enhanced firing
instead of ADHD pathophysiology or treatment. and decreased cognitive performance. Once released, NE acts through
We will first describe neurotransmission systems involved in ADHD, three receptor families, including the α1, α2 and β receptors. NE has the
capitalizing on findings from nuclear medicine imaging techniques. We highest affinity for the α2 receptors, among which the α2A is the most
will then discuss stimulant mechanism of action and review current common in the PFC (Ramos and Arnsten, 2007). In summary, the bal-
evidence from structural and functional MRI studies, including ance between tonic and phasic NE release in the PFC is pivotal to
anatomical and functional connectivity analyses. Finally, we will discuss maintain performance in cognitive functions that are affected in ADHD
limitations of current research and suggest ways forward. Ultimately, (da Silva et al., 2023, Del Campo et al., 2011).
this work can provide clinicians and researchers working in the field DA and NE critically contribute to optimal PFC activity, and this
with a deeper understanding of the biological correlates of the most allows ‘top-down’ regulation of response inhibition, attention, and
prescribed pharmacological treatments for ADHD. motivation, through its connections with subcortical nuclei and poste-
rior cortical regions, such as the parietal cortex (Arnsten and Rubia,
2. Catecholaminergic neurotransmission 2012, Xing et al., 2016). As mentioned, this top-down regulatory PFC
function relies on local microcircuits of GABAergic inhibitory in-
ADHD research has traditionally focused on catecholaminergic terneurons and glutamatergic neurons. Neuronal excitability is dynam-
neurotransmission. Dopamine (DA) is predominantly synthesized from ically modulated by catecholamines, through cyclic adenosine
the amino acid L-tyrosine within the substantia nigra pars compacta monophosphate (cAMP) signaling. Whilst DA increases the production
(SNc) and the ventral tegmental area (VTA) (Blanchard et al., 1994, of cAMP within the target neurons through D1 receptors, and thus
Dahlstroem and Fuxe, 1964). This catecholamine directly acts as a weakens microcircuit inappropriate connections; NE inhibits cAMP
neurotransmitter or is converted into norepinephrine (NE) by the production through α2A receptors, and thus enhances the strength of
enzyme dopamine β-hydroxylase (DBH). DA and NE are the main cate- specific connections. Thus, DA and NE optimize PFC function by
cholamines in the brain and exert a predominant modulatory action on respectively reducing ‘noise’ and enhancing ‘signal’ within gluta-
other neurotransmitters. There are two main DA receptor families, D1 matergic circuits (Arnsten, 2009, Arnsten and Rubia, 2012, da Silva
(including D1 and D5) and D2 (including D2, D3, D4), which are et al., 2023). These microcircuits are very sensitive to their neuro-
differently distributed throughout the brain (Aston-Jones and Cohen, chemical environment. Therefore, unbalanced levels of catecholamines
2005, Beaulieu and Gainetdinov, 2011). DA acts through highly topo- may have a detrimental effect on PFC functions. Specifically, an inverted
graphically organized projections, such as the nigrostriatal pathway, U-shape relationship exists between catecholaminergic signaling in the
which connects the SNc to the striatum as part of the fronto-striatal PFC and cognitive performance, and both excessive and insufficient

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V. Parlatini et al. Neuroscience and Biobehavioral Reviews 164 (2024) 105841

Fig. 1. Catecholaminergic projections. Dopamine acts through highly topographically organised projections, such as the nigrostriatal pathway, which connects the
substantia nigra (SN) to the striatum (in yellow). Further, the mesocortical pathway (in green) and the mesolimbic pathway (in orange) are involved in executive
functions and affect regulation. They project from the SN and the ventral tegmental area (VTA) to cortical regions, such as the mesial frontal and anterior cingulate
cortex, and to limbic structures, such as the nucleus accumbens (NAcc), amygdala, and hippocampus (left panel). Conversely, noradrenergic projections originate
from the locus coeruleus (LC) in the brainstem, which directly connects to cortical areas, such as the prefrontal cortex, and the cerebellum (in blue) (right panel).

catecholamine release negatively impact on PFC functions (da Silva that the percentage of individuals receiving stimulant treatment was
et al., 2023, Granon et al., 2000, Robbins and Arnsten, 2009, Zahrt et al., positively associated with higher DAT levels (Fusar-Poli et al., 2012).
1997). In sum, DA and NE optimize PFC activity by both activating their Therefore, the studies reporting higher DAT density in ADHD were likely
respective receptors and favoring signaling integration within local biased by an adaptive response to chronic exposure to stimulants, which
circuitries (Xing et al., 2016). induces persistent DAT blockade (Fusar-Poli et al., 2012). Conversely, in
line with the dopaminergic dysfunction theory of ADHD, medication
3. Catecholaminergic dysfunction in ADHD naïve individuals were more likely characterized by lower striatal DAT
density. A more recent investigation pooling results from 20 studies
There is substantial evidence that catecholamine dysregulation plays confirmed increased striatal DAT binding but also highlighted an effect
an important role in ADHD pathophysiology. This is supported by of age, as no regional group differences were observed when the three
several pieces of evidence, such as candidate gene studies (Faraone studies in adolescents were excluded (Nikolaus et al., 2022). Additional
et al., 2021); animal models of the disorder (Rahi and Kumar, 2021); and evidence of reduced dopaminergic activity in individuals with ADHD
the efficacy of stimulants (Cortese et al., 2018). Evidence of altered came from studies targeting post-synaptic D2/D3 receptors, e.g. by
dopaminergic transmission, especially in fronto-striatal circuits, also injecting radiolabeled raclopride (Volkow et al., 2007b); or investi-
came from studies using nuclear medicine techniques, such as PET and gating DA synthesis, by using the radiolabeled DA precursor DOPA
SPECT (Weyandt et al., 2013, Yamamoto and Inada, 2023, Zimmer, (Ludolph et al., 2008). A recent investigation observed a significant
2017). In PET studies, active molecules, such as receptor or transporter reduction in D2 binding in the caudate and in DA synthesis in the frontal
ligands, are injected after being labelled with positron-emitting radio- cortex when pooling the existing studies in adults (5 each)(Nikolaus
nuclides. The emitted positron combines with an electron and generates et al., 2022). Taken together, PET/SPECT studies supported the sug-
two photons, which are then captured simultaneously by a camera, thus gestion that individuals with ADHD have altered striatal dopaminergic
allowing the localization of the original binding site of the tracer transmission (Weyandt et al., 2013).
(Zimmer, 2009). Similarly, a gamma camera detects gamma rays Initial studies focused on striatal DAT due to lack of radiotracers
emitted by the tracers used in SPECT studies (Accorsi, 2008). Of note, suitable to investigate cortical DAT and NET (Weyandt et al., 2013).
transporter and receptor density measured using specific radioligands is Indeed, DAT density is limited in the PFC (Piccini, 2003), where DA
considered an indirect measure of neurotransmitter binding and may reuptake is likely mainly mediated by NET (Moron et al., 2002). The
reflect altered neurotransmission (Weyandt et al., 2013). These tech- potential role of NET in ADHD has been supported by candidate gene
niques have allowed the investigation of catecholaminergic pathways studies (Faraone et al., 2021); by the involvement of the NE system in
dysfunction in ADHD (Zimmer, 2017), e.g. by measuring DA transporter cognitive processes affected in ADHD (Arnsten and Rubia, 2012,
(DAT) occupancy (Cheon et al., 2004, Spencer et al., 2007), DA synthesis Brennan and Arnsten, 2008); and by the effect of medications (Cortese
(Forssberg et al., 2006), and receptor density (Ilgin et al., 2001). et al., 2018). Thus, there have been increasing efforts to develop ra-
The DAT has been the main target of these studies. DAT is considered diotracers to target NET (Logan et al., 2007, Takano et al., 2008, Vanicek
a specific marker of DA neuronal integrity (Weyandt et al., 2013, Zim- et al., 2014). For example, analogues of the antidepressant reboxetine
mer, 2009), and modulates the magnitude and duration of the dopa- can be used to target NET but mainly in subcortical regions, such as the
minergic signal by reuptaking DA from the synaptic cleft. Radioligands LC and thalamus, or in the striatum, where it has the lowest concen-
targeting this transporter, such as substituted (nor)phenyltropanes, have tration (Logan et al., 2007, Takano et al., 2008). This limitation might
been primarily used to quantify DA binding in the striatum, which has explain why an initial study did not identify significant differences be-
the highest DAT density (Piccini, 2003). Studies of DAT binding have tween individuals with ADHD and controls in NET regional distribution
yielded inconsistent results - reporting higher or lower binding in ADHD or availability (Vanicek et al., 2014). However, a subsequent study from
or no group differences (Weyandt et al., 2013). However, a the same group identified genotype-dependent differences in the NET
meta-analysis including 9 PET/SPECT studies of striatal DA transporter binding potential between adults with ADHD and neurotypical controls
density highlighted that these inconsistencies may be related to the in the thalamus and cerebellum; as well as genotype-dependent associ-
confounding effect of previous treatment (Fusar-Poli et al., 2012). ations between cerebellar NET binding potential and hyper-
Although the ADHD group showed 14 % greater striatal DAT binding activity/impulsivity in the ADHD group (Sigurdardottir et al., 2016).
than controls, a meta-regression analysis on the same sample revealed Finally, a more recent epigenetic analysis has shown that the promoter

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region of the gene encoding for NET was hypermethylated in adults with adults with ADHD as compared to 44 controls. Authors concluded that a
ADHD as compared to neurotypicals. This resulted in a reduced tran- glutamatergic imbalance in this key region of the default mode network
scriptional activity and NET binding potential in subcortical regions (DMN) may contribute to dysfunctional activation and interaction with
only in the ADHD group (Sigurdardottir et al., 2021). Taken together, task-based networks (Vidor et al., 2024). This finding contradicts an
these results point to genetic and epigenetic influences leading to altered earlier study in a mixed sample of children and adults (Arcos-Burgos et al.,
NET expression in ADHD. 2012), although this inconsistency might be driven by age-related dif-
In summary, PET and SPECT studies support the role of catechol- ferences. Further evidence for glutamatergic alterations in ADHD has
aminergic systems in ADHD pathogenesis. been provided by genetic, animal model, and post-mortem studies (Huang
et al., 2019, Kus et al., 2023, Sudre et al., 2023). Glutamate acts through
4. Beyond catecholaminergic neurotransmission fast ionic receptors, i.e., the N-methyl-D-aspartate (NMDA), α-amino-3--
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate re-
Although ADHD research has primarily focused on catecholamines, ceptors; and through slower metabotropic (protein G-coupled) receptors,
there is increasing evidence that other neurotransmitter systems are part of the mGluR family. The NMDA receptors are well known for their
involved in its pathophysiology. Among these, the role of serotonin (5- role in long term-potentiation and are involved in learning and memory.
HT) has been supported by animal models as well as candidate gene and As reviewed by Huang et al. (2018), association studies have primarily
imaging studies (Banerjee and Nandagopal, 2015, Quintero et al., 2022). supported the involvement of inotropic receptors in ADHD, with kainate
5-HT is known to influence activity levels, impulsivity, aggression, receptors potentially more associated with hyperactive-impulsive symp-
attention, mood, and appetite (Banerjee and Nandagopal, 2015, Quin- toms (Naaijen et al., 2017) and NMDA receptors with inattention (Huang
tero et al., 2022). Seminal animal studies showed that the administra- et al., 2019, Kim et al., 2020). Further, copy number variations in
tion of 5-HT precursors, selective serotonin re-uptake inhibitors (SSRI), metabotropic receptors have been implicated in ADHD and the
or an antagonist of the 5-HTR2A receptor (excitatory) reduced hyper- often-associated low intelligent quotient or anxiety (Akutagava-Martins
activity in DAT knock-out mice. Conversely, stimulation of the et al., 2014, Huang et al., 2019). Human post-mortem studies also high-
pre-synaptic receptor 5-HT1B (inhibitory) increased anxiety and loco- lighted significant downregulation of neurotransmitter gene pathways,
motion. These findings suggest that serotoninergic stimulation affects particularly glutamatergic, especially in the ACC of individuals with
hyperactivity by modulating striatal dopaminergic neurotransmission ADHD (Sudre et al., 2023). These findings are in line with the known
(Banerjee and Nandagopal, 2015, Barr et al., 2004, Gainetdinov et al., reciprocal interaction between glutamatergic and dopaminergic systems.
1999). Similarly, genetic studies have suggested associations between For instance, stimulation of D2 and D4 receptors respectively inhibits
specific polymorphisms of the serotonin transporter gene (SERT) and the NMDA and AMPA receptors (Kotecha et al., 2002, Yuen and Yan, 2009,
5-HT1B and 5-HTR2A receptors and ADHD, although associations were Yuen et al., 2010). Further, animal studies have revealed that the hy-
not confirmed in all samples (Banerjee and Nandagopal, 2015, Hawi peractivity of DAT knock-out mice could be reduced by stimulation of
et al., 2002, Kent et al., 2002). Finally, nuclear medicine studies have NMDA receptors (Gainetdinov et al., 2001), and that of AMPA GluR1
provided evidence of altered serotoninergic neurotransmission in knock-out mice by an D2 receptor antagonist (Boerner et al., 2017). Taken
ADHD. A recent work pooling the results of three adult studies reported together, these findings indicate that several neurotransmitter systems
reduced SERT binding in the striatum and thalamus, irrespective of may be affected in ADHD. It is important to notice that these systems have
medication-status, and in the striatum and midbrain of medi- also been implicated in other neurodevelopmental and mental health
cation-naïve individuals (Nikolaus et al., 2022). disorders, from autism to schizophrenia and depression, which supports
Emerging evidence also highlights an altered balance between excit- the suggestions that transdiagnostic neurobiological features underlie
atory/inhibitory neurotransmission, i.e., between glutamatergic and these conditions (Lawn et al., 2024, Nguyen et al., 2024).
GABAergic signaling, in individuals with ADHD, although with some in- Finally, although in our review we primarily focused on neuro-
consistencies. Magnetic resonance spectroscopy (MRS) has been used to transmitters and related neuroimaging findings, it is important to
quantify metabolites in specific brain areas, which can be interpreted as highlight that there is increasing evidence that ADHD is also associated
surrogate markers for cellular mechanisms, from neurotransmission to with alterations in genes encoding for transcription factors, synaptic
neuronal integrity (Vidor et al., 2022). Considering GABAergic neuro- adhesion molecules, and micro-RNAs (Demontis et al., 2023, Demontis
transmission, an initial meta-analysis including only three MRS studies et al., 2019, Ferranti et al., 2024, Parlatini et al., 2024c). It has been
did not find significant differences between individuals with ADHD and noted that there is little/no convergence between candidate gene or
controls in fronto-striatal GABA levels (Schur et al., 2016). However, as linkage studies and Genome-Wide Association Studies (GWAS) findings
recently reviewed by Ferranti et al. (2024), other studies have shown that (Poelmans et al., 2011). Meta-analyses of candidate gene studies yielded
lower GABA levels in the anterior cingulate cortex were significantly significant associations primarily with genes involved in dopaminergic
associated with inattention and impulsivity in individuals with ADHD and serotoninergic pathways (i.e., DAT, SERT, D4, D5, HTR1B), in
(Ferranti et al., 2024, Mamiya et al., 2022, Silveri et al., 2013). Further, addition to SNAP25, encoding for synaptosome associated protein 25
specific single nucleotide polymorphisms (SNPs) in the glutamic acid involved in vesicular release during neurotransmission (Gizer et al.,
decarboxylase (GAD1) gene, encoding for an enzyme involved in GABA 2009, Li et al., 2006, Parlatini et al., 2024c). However, the only iden-
synthesis, were found to increase susceptibility to ADHD (Bruxel et al., tified overlap between these studies and GWAS is represented by the
2016). Thus, it has been suggested that inefficient GABAergic trans- cadherin-13 (CDH13) gene, which encodes for a cell adhesion molecule
mission may favor neuronal stimulation and contribute to hyperactivity that has been implicated in several conditions, from ADHD to autism and
and reduced focus in at least some ADHD subpopulations, although this depression. Although the exact mechanism remains unclear, it has been
warrants further investigation (Ferranti et al., 2024, Quintero et al., suggested that CDH13 affects GABAergic neurons and thus excitator-
2022). Considering glutamate, a meta-analysis of 6 MRS studies revealed y/inhibitory balance (Rivero et al., 2015). Finally, a recent work inte-
increased glutamate/glutamine levels, a marker of excitatory neuro- grating results from the 5 GWAS in ADHD highlighted that, among the
transmission, in the right medial frontal cortex of children with ADHD as 85 top-ranked ADHD-related genes, 45 encoded for proteins involved in
compared to neurotypical controls (Vidor et al., 2022). As gluta- neurite outgrowth especially during neurodevelopment (Poelmans
mate/glutamine were measured together, authors suggested that both et al., 2011). These findings are in line with previous reports both in
glutamate neurotoxicity or depletion could underlie these findings and ADHD and other neurodevelopmental disorders suggesting an imbal-
potentially contribute to the cortical thinning observed in ADHD. ance between synaptic proliferation and pruning (Quintero et al., 2022,
Extending these results, a more recent work from the same authors Ugarte et al., 2023). For instance, a review highlighted the potential role
indicated lower glutamate levels in the posterior cingulate cortex in 88 of neurotrophins in ADHD pathophysiology, especially the

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brain-derived neurotrophic factor (BDNF), which is involved in neuro- The ability of stimulants to act as DA and NE reuptake inhibitors has
plasticity (Tsai, 2017). Its involvement is supported by animal models been demonstrated in vitro and later in animal models, before being
but results from human genetic and blood level studies have been confirmed in vivo in humans through nuclear medicine studies (Zimmer,
inconsistent (El-Saied et al., 2024, Quintero et al., 2022, Tsai, 2017). 2017). Considering animal models, it is worth mentioning that early
Taken together, these findings suggest that several molecular and studies in rats used high doses of stimulants, generally administered
cellular mechanisms contribute to ADHD pathophysiology, although intraperitoneally, and reported a positive association between the
variably according to clinical profiles, associated cognitive deficits, and release of striatal DA and activity levels (Segal and Kuczenski, 1987).
comorbidities. Given the substantial heterogeneity of ADHD, future These findings contributed to the misleading interpretation that the
studies are needed to map the underlying alterations according to the calming effect observed in individuals with ADHD was paradoxical.
specific clinical profile. Clarifying these mechanisms can also provide a Later studies reported that lower doses, more comparable to therapeutic
more solid base to understand stimulant mechanisms of action, as dis- doses and administered orally, were associated with reduced locomotor
cussed in the following section. activity in animals (Kuczenski and Segal, 2002) as in neurotypical
humans (Rapoport and Inoff-Germain, 2002). Further, lower doses
5. Stimulant mechanisms of action mainly modulate PFC catecholamine levels, and especially those of NE
(Berridge et al., 2006). In line with these findings, stimulant beneficial
Stimulants used for the treatment of ADHD include MPH and am- effects have also been observed in DAT knock-out mice, further sup-
phetamines (Cortese et al., 2018, Faraone et al., 2021). MPH exists as porting the role of the NE system in mediating treatment response (Rahi
two enantiomers (i.e. two compounds with mirrored chemical struc- and Kumar, 2021). In sum, animal studies have revealed that stimulants
ture), respectively called d-threo and l-threo-MPH, but its therapeutic mainly affect DA in the striatum and NE/DA in the PFC, in line with their
effects are primarily due to the d-enantiomer (Kimko et al., 1999). MPH distinct transporter density (Hannestad et al., 2010, Madras et al., 2005,
blocks both DA and NE transporters through allosteric binding (i.e. on a Rahi and Kumar, 2021).
different site from that of the endogenous neurotransmitter), inhibiting By acting on the catecholamine transporters, stimulants increase the
both catecholamines reuptake and increasing their availability (Arnsten endogenous DA stimulation of D1-receptors, and the NE-dependent
and Pliszka, 2011, Kuczenski and Segal, 2002, Seu et al., 2009) (Fig. 2). activation of post-synaptic α2A-receptors (Arnsten and Dudley, 2005,
Conversely, amphetamines block DAT and NET by binding on the same Gamo et al., 2010). As discussed above, an optimal stimulation of these
site of the endogenous neurotransmitter, thus they act as a competitive receptors enhances PFC function, by respectively reducing ‘noise’ and
inhibitor (Fig. 2). At higher than therapeutic doses, such as those taken enhancing ‘signal’ within glutamatergic circuits (Arnsten, 2006, Arns-
for abuse, they may also induce the release of DA from intrasynaptic ten, 2009, Arnsten and Rubia, 2012). However, PET studies in humans
vesicles into the cytoplasm, and then into the synaptic cleft through DAT suggest that the ultimate effect of stimulant treatment is more complex
reversal, a phenomenon which is linked to euphoria and addiction than a simple increase in catecholaminergic transmission (Swanson
(Calipari and Ferris, 2013). Amphetamines also exist as D- and l-isomers et al., 1999, Volkow et al., 1999), and likely involve the optimization of
but, although the former is more potent for DAT binding, they are the balance between tonic and phasic catecholamine release (Grace,
equally potent for NET binding. Notably, lisdexamfetamine is a long- 1995). Catecholaminergic modulation may in turn support the engage-
acting d-amphetamine prodrug. It is hydrolyzed into d-amphetamine in ment of task-related brain networks, such as the dorsal frontoparietal
the blood and has a different pharmacokinetic profile than short-acting attentive network, and reduce (i.e., focus) attentional resources that are
amphetamines, offering the longest therapeutic action among stimulants needed to ensure cognitive performance (Volkow et al., 2008). It might
(up to 13–14 hours)(Ermer et al., 2016). also reduce the activation of the DMN, which connects medial brain

Fig. 2. Mechanism of action of stimulants at synaptic level. The function of dopamine (DA) and norepinephrine (NE) transporters (DAT and NET) is to reuptake
DA and NE after they have been released in the synaptic cleft (left panel). Methylphenidate (MPH) acts by blocking both DAT and NET through allosteric binding (i.e.
it binds them on a different site from that of the endogenous neurotransmitter). Conversely, amphetamines (AMP) block DAT and NET by binding on the same site of
the endogenous neurotransmitter, thus acting as a competitive inhibitor. As a result, they both inhibit catecholamines reuptake and increase their availability in the
synaptic cleft. However, at high doses, AMPs also induce more complex changes within catecholaminergic neurons (see main text)(right panel).

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V. Parlatini et al. Neuroscience and Biobehavioral Reviews 164 (2024) 105841

areas and is associated with mind wondering, and thus decrease SERT promoter region were associated with varying degree of response
distractibility (Tomasi et al., 2009, Volkow et al., 2008). Finally, cate- to MPH in children - but not in adults (Banerjee and Nandagopal, 2015,
cholamine modulation may increase the perception of events as salient. Contini et al., 2012, Thakur et al., 2010). Further, stimulants have been
This in turn improves attention and performance, as revealed by studies shown to increase GABA levels in animal models; however, a more
using academic tasks and appetitive stimuli (Volkow et al., 2002, Vol- recent study in humans has shown that MPH effects may be
kow et al., 2004). Stimulant-induced catecholaminergic increases in age-dependent (Ferranti et al., 2024). In fact, an MPH challenge
both cortical regions (e.g., fronto-temporal) and subcortical structures increased GABA levels in the medial prefrontal cortex only in adult
(e.g., ventral striatum) have been associated with long-term symptom- participants treated since childhood, which had lower levels of GABA
atic improvement in adults with ADHD (Volkow et al., 2012). However, compared to those treated in adulthood only (Solleveld et al., 2017).
MPH induced a comparable increase in striatal DA levels in individuals Considering glutamatergic neurotransmission, animal studies have
with/without ADHD and improved attention irrespective of diagnosis suggested that low and high doses of MPH respectively enhance and
(del Campo et al., 2013). Notably, the effect of stimulant treatment reduce NMDA receptor response, possibly through α1 receptor stimu-
appeared to depend on both the degree of transporter blockade and on lation (Cheng et al., 2014, Zhang et al., 2012). Pharmacogenetic studies
the baseline rate of DA release (Volkow et al., 2001). This has been noted in humans have reported that genetic variants of the GRIN2B gene,
to be reduced in individuals with ADHD (Forssberg et al., 2006, Volkow encoding for an NMDA subunit, and the SNAP-25 gene, linked to NMDA
et al., 2001, Volkow et al., 2007a), although this was not confirmed by receptor trafficking, were associated with better response to MPH in
all studies (Cherkasova et al., 2014). Further, higher baseline DAT children (Kim et al., 2017, Song et al., 2014). Overall, these findings
availability has been associated with increase probability of responding indicate that stimulants may affect several neurotransmitter systems,
to MPH in adults with ADHD (Krause et al., 2005, la Fougere et al., although they may partly differ in their effects (Quintero et al., 2022).
2006). Treatment effects appear to be task-dependent, as DA release is For instance, studies in vitro have shown that amphetamines may also
higher during a rewarded task than during a neutral one (Volkow et al., affect monoaminergic neurotransmission through inhibition of the
2005) and distinct tasks have different dose–response associations synaptic vesicular amine transporter (VMAT2) and a weak inhibition of
(Arnsten and Rubia, 2012). In sum, as described in a comprehensive the monoaminoxidase (MAO), rather than 5-HTR1A stimulation (Hut-
systematic review of preclinical and imaging studies in humans (not son et al., 2014). Further, they can stimulate the trace amine-associated
specifically with ADHD), MPH and amphetamines increase catechol- receptor 1 (TAAR1), which is highly expressed in monoaminergic brain
aminergic availability in cortico-striatal regions that are altered in regions and may contribute to modulation of activity and motivated
ADHD, and positively affect executive functions, decision making, behavior (Sotnikova et al., 2009). These differences may contribute to
emotion and reward processing (Faraone, 2018). There is substantial individual variation in the response to MPH and amphetamines, as well
evidence that stimulants increase endogenous catecholaminergic as the beneficial effects of medications such as lisdexamfetamine in
transmission in proportion to transporter blockade and basal DA levels. binge eating disorder (Guerdjikova et al., 2016).
However, the final effect depends on the task at hand and its saliency. Beyond neurotransmitter systems, stimulants have been shown to
Further, the basal activity of catecholaminergic neurons and the modulate neurotropic factors, such as BDNF (Quintero et al., 2022). For
U-shaped relationship between neurotransmission and cognitive per- instance, as reviewed in Tsai et al. (2017), MPH increases BDNF
formance may account for individual variability in response to treat- expression and alleviates hyperactivity in the spontaneously hyperten-
ment (Swanson et al., 2011, Volkow et al., 2005, Zimmer, 2017). sive rats, a model of ADHD (Kim et al., 2011b). However, other studies
Neuropharmacological studies using PET and SPECT in ADHD have reported that MPH and amphetamines both increased and decreased
been dependent on the development of radioligands, thus they have BDNF brain levels and suggested reduced or opposite findings in adult as
primarily focused on dopaminergic transmission (Yamamoto and Inada, compared to juvenile animals (Banerjee et al., 2009, Tsai, 2017).
2023). Their use has also been limited due to the risks concerning Pharmacogenetic studies in children with ADHD highlighted that BDNF
exposure to ionizing radiations. As a result, most studies included a and neurotrophin-3 gene variants were associated with better response to
small sample and were in adults. Nevertheless, there is some recent MPH or side effects respectively (Kim et al., 2011a, Park et al., 2014).
evidence of similar effects in adolescents. For instance, a recent SPECT Further, MPH-related increased blood BDNF levels were associated with
study comparing striatal DAT binding on/off MPH reported that treat- improvement in hyperactive-impulsive symptoms in children with
ment was associated with a ~30 % reduction of DAT binding potential, ADHD (Amiri et al., 2013, Tsai, 2017). Finally, there is preliminary
especially in those with higher baseline symptom severity (Aster et al., evidence that stimulants may indirectly affect other cellular processes,
2022). Further, another SPECT study showed that decreased DAT such as genetic transcription, apoptosis, and release of proinflammatory
availability was observed after two months of MPH treatment in the cytokines (Quintero et al., 2022). Of note, a recent systematic review of
basal ganglia, especially in adolescents with more robust clinical neuroimaging studies reported that two out of the three identified
response (Akay et al., 2018). In sum, PET/SPECT studies have been studies found that stimulants increased brain iron levels in children with
pivotal to clarify the effects of stimulants on catecholaminergic ADHD. However, the underlying mechanisms remains unclear (Mor-
neurotransmission. andini et al., 2024).
Nevertheless, there is increasing evidence that other neurotrans- In sum, multiple molecular and cellular mechanisms may contribute
mitter systems are involved in their mechanisms of action. Considering to stimulant mechanisms of action. However, it is less clear how these
serotonin, as reviewed in Banerjee et al. (2015), preclinical studies have changes at microscopic level translate into beneficial clinical effects.
suggested that MPH also acts as an agonist to the 5-HTR1A receptor and MRI represents a powerful tool to address this gap by investigating
has low affinity for SERT, thus might balance serotoninergic and stimulant effects on the brain at a macroscopic level. Importantly, as
dopaminergic signaling (Banerjee and Nandagopal, 2015, Gatley et al., they do not involve ionizing radiation, they have become the main in-
1996, Markowitz et al., 2009). Studies in rats have shown that MPH strument to investigate stimulant mechanism of action in children and
administration leads to increased SERT density (Daniali et al., 2013), adults with ADHD in recent years.
whilst a 5-HTR1B agonist potentiates MPH effects on activity levels
(Borycz et al., 2008). Further, MPH can reduce hyperactivity levels in 6. Stimulant effects on brain regional structure and function
DAT knock-out mice without affecting DA levels (thus may act through
NET or SERT)(Gainetdinov et al., 1999). However, other studies have MRI studies have suggested that stimulants may reduce some of the
suggested that the activity on SERT is more typical of amphetamines structural and functional brain alterations observed in untreated in-
(Quintero et al., 2022). Pharmacogenetic studies in humans corrobo- dividuals with ADHD (Albajara Saenz et al., 2019, Firouzabadi et al.,
rated serotoninergic involvement, by highlighting that variants of the 2022, Frodl and Skokauskas, 2012, Nakao et al., 2011, Pereira-Sanchez

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V. Parlatini et al. Neuroscience and Biobehavioral Reviews 164 (2024) 105841

et al., 2021, Santos et al., 2019). have been reported for working memory - with some studies reporting
Structural MRI studies using a cross-sectional design suggested that no effect of medication on the brain regions involved in this function
stimulant treatment is associated with attenuation or absence of some (Cubillo et al., 2014a, Kobel et al., 2009, Rubia et al., 2014). Notably,
gray matter volumetric reductions often observed in untreated children stimulants also improve suppression of regions belonging to the DMN,
with ADHD, e.g. in the ACC (Semrud-Clikeman et al., 2006), middle such as the ACC, during working memory tasks (Cubillo et al., 2014a)
frontal and precentral gyri (Villemonteix et al., 2015), pulvinar of the and interference inhibition (Peterson et al., 2009). Beyond executive
thalamus (Ivanov et al., 2010), posterior inferior vermis and functions, treatment effects on brain activation have been observed
executive/non-motor portions of the cerebellum (Bledsoe et al., 2009, during reward processing, with an attenuation of the baseline increased
Fernandez et al., 2023), splenium of the corpus callosum (Schnoebelen orbitofrontal activation (Rubia et al., 2009); and during time estimation
et al., 2010), or whole gray matter volume (Priya 2023). Several studies tasks, with the upregulation of the underlying fronto-striato-cerebellar
reported no differences in overall caudate volume (Castellanos et al., network (Noreika et al., 2013, Smith et al., 2013). A meta-analysis
2002, Semrud-Clikeman et al., 2006, Sobel et al., 2010). However, fewer including 14 whole brain fMRI studies reported that
basal ganglia morphological alterations were observed in medicated as treatment-enhanced activation of the right inferior frontal cortex and
compared to unmedicated children (Sobel et al., 2010). Similarly, a insula was the most consistent finding across a range of cognitive
positive association was reported between the duration of stimulant functions. In addition, a ‘normalization’ of putamen activity was
treatment and the volume of the left nucleus accumbens (Villemonteix observed (although at a less restrictive significance threshold) (Rubia
et al., 2015). Volumetric differences between treated and treatment-- et al., 2014). Taken together, these studies suggest that stimulants
naïve individuals have also been detected in adults with ADHD (Onnink modulate brain activity levels in individuals with ADHD towards those
et al., 2014, Seidman et al., 2011), although not in all studies (Maier of their neurotypical peers (Schweren et al., 2013, Spencer et al., 2013).
et al., 2015). A treatment-related attenuation of gray matter volumetric Importantly, there is preliminary evidence that early rather than late
alterations was further supported by two meta-analyses (Frodl and treatment may be associated with more evident beneficial effects on
Skokauskas, 2012, Nakao et al., 2011). The former conducted a brain activity in youths with ADHD (Schweren et al., 2017).
meta-regression analysis on a pool of 14 voxel-based morphometry Conversely, the few studies that investigated the effect of chronic
(VBM) studies in children and adults with ADHD and reported that the treatment with MPH reported scarce, inconclusive, or no evidence of
percentage of individuals on stimulants was associated with larger (thus improvement on brain function after wash-out (Kobel et al., 2009,
more similar to controls) volumes of the right caudate (Nakao et al., Konrad et al., 2007, Pliszka et al., 2006). Thus, stimulant treatment
2011). Similarly, the latter reported more prominent volumetric might not translate into long-lasting changes of brain activity (Schweren
reduction in the ACC (children and adults) and in the caudate (children) et al., 2013). However, two studies have shown that adults with ADHD
in studies with more untreated individuals (Frodl and Skokauskas, treated with MPH during childhood did not show the pattern of altered
2012). Only few longitudinal studies have explored this further. A small activation observed in treatment-naïve individuals compared to neuro-
longitudinal volumetric study in adults suggested that typical controls during reward and emotional processing
medication-induced volumetric changes in the ventral striatum might be (Schlochtermeier et al., 2011, Stoy et al., 2011). This finding was in line
transient (Hoekzema et al., 2014). However, a small longitudinal study with that of two meta-regressions conducted in a mixed pediatric-adult
in a pediatric sample reported that 4 years’ stimulant treatment was sample, which showed that prolonged stimulant treatment was signifi-
associated with a lower rate of cortical thinning, and thus with cortical cantly associated with a pattern of activation similar to controls in the
thickness more similar to controls in frontal and parieto-occipital re- right DLPFC during timing tasks (Hart et al., 2012) and in the right
gions, compared to untreated individuals (Shaw et al., 2009). Gray caudate during attention tasks (Hart et al., 2013). The effect on striatal
matter changes, either transient or persistent, have been suggested to activation was remarkably similar to that observed for striatal volumes
reflect an activity-induced neuronal plasticity, since catecholaminergic in two meta-analyses of structural MRI studies (Frodl and Skokauskas,
transmission may affect neuronal morphology (Robinson and Kolb, 2012, Nakao et al., 2011). Taken together, fMRI studies suggest that an
2004, Schweren et al., 2013). Nevertheless, more recent studies do not acute stimulant administration may improve the function of brain areas
appear to support this treatment-related effect (Greven et al., 2015). For affected in individuals with ADHD. However, potential longer-term ef-
instance, two large multi-center studies reported no effect of current fects need further investigation. Further, as reviewed in the following
stimulant treatment on ADHD versus controls differences in total section, brain regions do not operate in isolation, but are part of circuits
intracranial and subcortical structures volumes, as well as in cortical whose ‘connectivity’ is crucial to cognitive functions.
thickness (Hoogman et al., 2017, Hoogman et al., 2019). However, those
on medication had lower surface area in two frontal regions as compared 7. Stimulant effects on brain structural and functional
to those not on medication (Hoogman et al., 2019). In sum, the potential connectivity
long-term effects of stimulant treatment on brain anatomy remain
controversial. Moving forward, it would help to account for the potential MRI studies have revealed that the effects of stimulants extend to
effect of treatment duration, as well as the pre-treatment differences brain anatomical and functional connections, especially in fronto-
between responders and non-responders to treatment. In fact, it has been striato-parieto-cerebellar circuits (Bouziane et al., 2019, de
suggested that the proposed ‘normalizing’ effect of treatment with time Luis-Garcia et al., 2015, Kowalczyk et al., 2022, Pereira-Sanchez et al.,
may partly depend on a selection bias, as those that respond to (and thus 2021). An early structural MRI study showed that total white matter
continue) stimulants have less evident pre-treatment brain alterations volume was reduced in unmedicated ADHD children compared to both
(Parlatini et al., 2024a). medicated and neurotypical individuals (Castellanos et al., 2002). Since
fMRI studies reported that an acute administration of stimulants then, the study of anatomical (white matter) connectivity in ADHD has
upregulate the under-activation observed at baseline in key regions grown, thanks to the increasing use of diffusion-weighted imaging
involved in cognitive functions implicated in ADHD, such as in fronto- (DWI). The most recent systematic review of DWI studies in ADHD
parietal, subcortical, and cerebellar regions during attentive tasks included 129 studies, however, they mostly focused on ADHD versus
(Kowalczyk et al., 2019, Rubia et al., 2009, Shafritz et al., 2004, Shang controls comparisons (Parlatini et al., 2023a). Among the included
et al., 2016); in fronto-striatal areas during inhibition (Chou et al., 2015, studies, only two investigated the potential effect of treatment in chil-
Cubillo et al., 2014b, Epstein et al., 2007, Rubia et al., 2014, Rubia et al., dren with ADHD. The first, a tractography study, found no differences in
2011, Schulz et al., 2017, Shang et al., 2022, Vaidya et al., 1998); and in fractional anisotropy (FA), a measure of white matter microstructural
frontal and subcortical (caudate, putamen) areas involved in reward organization, between treated and untreated children with ADHD.
processing (Newcorn et al., 2024). More conflicting results, however, However, the former had a reduced mean diffusivity (MD) in the inferior

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V. Parlatini et al. Neuroscience and Biobehavioral Reviews 164 (2024) 105841

longitudinal fasciculus, uncinate fasciculus, and posterior corpus cal- they were mostly in small samples and greatly differed in study design
losum (de Luis-Garcia et al., 2015). The second study reported no sig- and analytic approach (Pereira-Sanchez et al., 2021). For instance, most
nificant differences in asymmetry of brain networks between treated and included individuals already on medication, after a short wash-out
medication-naïve children but greater interhemispheric asymmetry of period, and only two investigated the effects of an acute challenge of
the uncinate fasciculus, inferior longitudinal fasciculus, superior longi- MPH on rs-fc in children/adolescents. The former reported that a single
tudinal fasciculus, and cortico-spinal tract in those treated compared to dose of MPH ‘normalized’ case-control differences in
controls (Douglas et al., 2018). Of note, the meta-regression analysis fronto-cerebellar-parietal regional homogeneity (a measure of local
testing the effect of previous exposure to stimulant medication, did not functional connectivity), and that the treatment-induced change in pa-
yield significant results (Parlatini et al., 2023a). Another study including rietal areas was associated with symptom improvement at two months in
172 children and young adults (mean age: 17 years), showed that higher the 7 followed-up participants (An et al., 2013). The latter only included
cumulative stimulant intake was associated with lower MD, but no dif- 16 adolescents and reported that a single dose of MPH ‘normalized’ rs-fc
ferences in FA, in orbitofrontal-striatal white matter (Schweren et al., in several brain networks (Silk et al., 2017). Two more recent studies
2016). Further, a study suggested an age-dependent effect, since an in- showed that MPH enhanced rs-fc in the reward network, including the
crease in FA was observed after 16 weeks of MPH treatment in several nucleus accumbens, both in children and adults with ADHD (Mizuno
association tracts of the left hemisphere and lateral aspect of the body of et al., 2023, Rode et al., 2023). Increased rs-fc within the DMN has also
the corpus callosum in boys (but not men) with ADHD (Bouziane et al., been reported in both adolescents (Kim et al., 2021) and adults with
2019). Although preliminary, these findings suggest that protracted ADHD (Picon et al., 2020). A more recent study showed that
stimulant use might be associated with microscopic changes in white MPH-induced changes in latent brain dynamics and functional connec-
matter brain connections, although longitudinal studies controlling for tivity between the salience and DMN networks at rest were associated
treatment parameters are needed. with behavioural improvement (Cai et al., 2023). Considering
A few studies have investigated stimulant effects on functional con- longer-term effects, a graph theory study reported that treated children
nectivity in ADHD youths. A recent systematic review identified 8 task- with ADHD had increased connectivity between sensory and higher
based studies investigating the impact of stimulants in ADHD (among order brain regions subserving executive functions and attention as
which only two were in adults)(Kowalczyk et al., 2022). These studies compared to untreated individuals (Carmona et al., 2015). This suggests
showed that stimulants significantly improved fronto-striatal and that stimulants may support a more effective balance between internal
fronto-cerebellar connectivity in children with ADHD during vigilant and external sources of information. Studies in adults have been more
and sustained attention (Rubia et al., 2009), as well as fronto-parietal limited. A recent study in 53 medication-naïve adults and 50 controls
and fronto-striatal connectivity during working memory showed that 6-week MPH treatment increased functional connectivity
(Abi-Dargham and Horga, 2016, Wong and Stevens, 2012, Wu et al., between the precentral gyrus (salience network) and the precuneus to-
2017). The observed changes in brain functional connectivity might wards that of neurotypical controls (Ulrich et al., 2022). Further, there is
represent the mechanisms underlying the beneficial effects of stimulants some preliminary evidence that the beneficial effects of amphetamines
on task performance. Beyond ‘cold’ executive functions, stimulants and MHP on symptom improvement are related to changes in
might also affect emotion processing, as they have been reported to fronto-limbic or fronto-cerebellar rs-fc (Yang et al., 2016)(Pretzsch,
reduce the increased functional connectivity between the amygdala and Parlatini et al., under review). Taken together, these findings suggest
the lateral PFC observed in ADHD adolescents during the subliminal that stimulants may exert their effects through shifting functional con-
presentation of fearful faces (Posner et al., 2011). A later study showed nectivity within the affected networks in both children and adults with
that lisdexamfetamine increased the activation of the right amygdala ADHD.
and reduced its connectivity with the orbitofrontal cortex in response to
sad faces in adults with ADHD. Changes in amygdala activation were 8. Conclusion
associated with symptom improvement (Schulz et al., 2018). MPH may
also reduce functional fronto-striatal connectivity during reward pro- Nuclear medicine approaches have primarily documented the cate-
cessing in adults with ADHD (Furukawa et al., 2020). Further, treatment cholaminergic dysregulation that underlies ADHD pathophysiology, and
has been shown to optimize suppression of the DMN network during helped clarify the molecular targets of stimulants, their pharmacoki-
cognitive tasks, such as the Stroop and the flanker test, and to decrease netics, and their effects on brain networks. They elucidated how stim-
the associated response time variability typical of individuals with ulants fine tune catecholaminergic transmission, which in turn
ADHD (Peterson et al., 2009, Querne et al., 2014). These findings are in optimizes attention and executive control by engaging task-related brain
line with those of a recent systematic review of 12 studies investigating networks and deactivating the DMN. However, their use has been
treatment-related changes on the DMN using different techniques in limited by the available radioligands and concerns related to ionizing
children or adults with ADHD. The most consistent result was an radiations, especially in children. MRI studies have been more widely
increased deactivation of the DMN during tasks (Santos et al., 2019). used in recent years, especially in pediatric samples. They showed that
However, this was not confirmed by all studies. For instance, a study an acute administration of stimulants may reduce or abolish brain
including 20 adults with ADHD on and off MPH and 27 controls showed regional or functional connectivity alterations observed in untreated
that MPH shifted within-network connectivity of the DMN, but not individuals during tasks or at rest. However, potential longer-term ef-
between-network connectivity, during a reward based decision-making fects of stimulant treatment remain unclear.
task (Mowinckel et al., 2017). Taken together, these findings suggest Overall, nuclear medicine and MRI studies have shed light on stim-
that acute treatment may produce functional changes within ulant neuropharmacology. However, they are often limited by small and
task-related brain networks and/or reduce DMN-mediated interference, heterogenous samples. This unfortunately does not allow them to
perhaps especially during ‘cool’ executive function tasks. robustly account for the effects of clinicodemographic characteristics,
In recent years, there has been a greater emphasis on functional such as ADHD presentation, age, sex, and comorbidities, on treatment-
connectivity at rest. Resting-state functional connectivity (rs-fc) is based related brain effects. Most anatomical studies have adopted a cross-
on the observation that brain networks functionally activated at rest sectional design, thus limiting our understanding of longer-term treat-
correspond to those activated during cognitive and motor tasks (Smith ment effects. Longitudinal studies or meta-regression analyses often
et al., 2009). Thus, rs-fc MRI offers the opportunity to investigate controlled for present versus absent previous exposure to stimulants, but
functional networks in a task-independent manner and at a whole brain did not have more fine grained available data on treatment character-
level. A recent systematic-review identified only 9 studies (5 in children istics (Hoogman et al., 2017, Hoogman et al., 2019, Parlatini et al.,
and 4 in adults) investigating effects of ADHD medications on rs-fc, and 2023a). Thus, although subtle differences have been reported in both

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Bellato, A., Perrott, N.J., Marzulli, L., Parlatini, V., Coghill, D., Cortese, S., 2024.
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Adolescent Central Health (ACAMH), Canadian ADHD Alliance Blanchard, V., Raisman-Vozari, R., Vyas, S., Michel, P.P., Javoy-Agid, F., et al., 1994.
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