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supported by studies that have noted a relationshipbetween frontal, temporal, caudate, andcerebellar volumes and ADHD symptom severity.63Furthermore, reduced thalamic and ventrostriatalvolumes have been found to significantly correlatewith measures of impulsivity, hyperactivity, andinattention in individuals with ADHD compared toindividuals without ADHD.64,65 Total brain volume isalso reduced, with studies reporting volumes 3% to5% smaller in individuals with ADHD compared toindividuals without ADHD.62,63Figure 2. Brain structures implicated in ADHD (adaptedfrom Faraone 2015). 52Prefrontal cortexLateral viewDorsolateralprefrontal entromedialprefrontal cortexCerebellumMedial viewAnterior cingulatecortexPutamenVentral anteriorcingulate cortexGlobuspallidusADHD, attention deficit/hyperactivity disorder.Figure 3. Reduced volume (in blue) in the dorsolateralprefrontal cortex and anterior cingulate gyrus (adaptedfrom Seidman 2006). 58CGa, anterior cingulate gyrus; DLPFC, dorsolateral prefrontal cortex.Figure 4. Reduced volume (green) in the globus pallidus,caudate, and thalamus. 57The Neurobiology of ADHD — April 2020Basal gangliaDoral anteriorcingulate cortexStriatumCaudatenucleusIn addition to decreased brain volume, delayedcortical development is also seen in children withADHD compared to children without.66 A landmarkstudy conducted in 2007 found that peak corticalthickness was achieved, on average, 3 years later inchildren with ADHD relative to controls.66 The delaywas longest in the PFC (approximately 5 years inthe middle PFC), an area important for executivefunctioning, reward, memory, suppression ofinappropriate responses, and motor control.66Extending these findings, a group of authorsreported “normalization” of caudate volume overthe course of extended maturation.63 Sophisticateddiffusion tensor imaging studies have discovereddelayed/reduced myelination of prefrontal-striataltracts, cortico-cortical connections, thalamocortical white matter tracts, and connectionswithin the default mode network (DMN; includingprefrontal, cingulate, and parietal corticesand temporal lobes) in individuals with ADHDcompared with controls.67-69 These differences maybe responsible for the delayed development ofcognitive-executive control observed in ADHD.67-69Cortical thinning, like cortical thickening, is anormal brain process.70 However, enhancedcortical thinning in children and adolescents withADHD vs controls has been found, with significantdifferences noted in areas important for attentionaland motor output (eg, prefrontal regions).71 Corticalthinning has also been reported in longitudinalstructural studies of adults with ADHD, with6

the rate of cortical thinning correlating with thenumber of ADHD symptoms.72,73 Furthermore,convergence toward normal brain dimensions wasonly observed in young adults whose symptomsremitted compared with individuals who remainedsymptomatic.73key takeaway: Individuals with ADHDexhibit reductions in gray mattervolume, delayed cortical maturation,and enhanced cortical thinning, whichhave been shown to be related to ADHDsymptomatology.BRAIN NETWORKS AND FUNCTIONALBRAIN CHANGESBrain networks involved in attention and, therefore,especially relevant to ADHD, include the cognitiveexecutive network, the cortico-striatal-thalamiccortical network, and the cortico-limbic network(Figure 5; Table 2).The cognitive-executive network (Figure 5A) iscomposed of interconnected cortical areas thathave a role in executive function and workingmemory and in selective and sustained attention.74,75Dorsal prefrontal cortical areas participate in“top-down” regulation of emotion.75-77 In addition,prefrontal cortical areas are connected to premotorcortices, where they participate in the planningof motoric activity, with abnormalities in theseconnections found in individuals with ADHD.15 Thecortico-striatal-thalamic-cortical network (Figure 5B)comprises parallel loops that connect the PFC withthe basal ganglia and thalamus.15,78 The network isrelevant in ADHD because it has a role in regulatingascending sensory information that reaches thePFC and assigning salience to this information(ie, selecting what information is important andwhat is not), as well as in motivation and inhibitinginappropriate actions.78 Interestingly, diminishedactivity of this network during tasks of motorinhibition and cognitive shifting have been shownto correlate with persistence and severity of ADHDTable 2. Brain Networks Involved in tive-executivenetworkDLPFC, posterior parietal cortexInvolved in executive function, working memory, selectiveand sustained attention; regulating emotion; planning ofmotor activityCortico-limbic networkVLPFC, amygdala, hypothalamus, brainstemRegulating level of , basal ganglia, thalamusRegulating and assigning salience to sensory information;inhibiting inappropriate actions, motivationDefault mode networkMPFC, posterior cingulate cortex, lateral parietal Involved in self-reflection, planning future activities,cortex, precuneus, medial temporal lobemonitoring environmentDorsal attentionalnetworkPrecentral and parietal regionsMediating goal-directed, executive control processes,including reorienting attention during visual attentionalfunctioningMotor networkPrimary and secondary motor cortices,supplementary motor area, putamen,thalamus, cerebellumInvolved in motor activityVentral attentionalnetworkTemporoparietal junction, frontal operculum,anterior insulaMonitoring environment for emergence of salient stimuliand interrupting ongoing activity when necessaryVisual networkOccipital visual cortex and temporalstructuresInteracting with dorsal attentional network to maintainattention and suppress attention to irrelevant stimuliADHD, attention deficit/hyperactivity disorder; DLPFC, dorsolateral prefrontal cortex; MPFC, medial prefrontal cortex; PFC, prefrontal cortex; VLPC,ventrolateral prefrontal cortex.The Neurobiology of ADHD — April 20207

Figure 5. Select brain networks involved in attention.15A. Cognitive-executive networkTop-Down Guidance ofAttention and ThoughtDorsalSensoryCorticesPrefrontalCortexBasal l/RewardSystemsB. Cortico-striatal-thalamic-cortical and corticothalamic-cerebellar ActionsPrefrontalCortexBasal l/RewardSystemsC. Cortico-limbic networkDorsalBasal toms.84,85 Connections in the cortico-limbicnetwork (Figure 5C) originate from the ventral PFCand link to limbic areas, such as the amygdala andhypothalamus, as well as with brainstem NE nucleithat regulate level of arousal.76,81,86 Dysfunction ofthese connections in ADHD may result in emotionallability and deficits in impulsivity and motivation.80The Neurobiology of ADHD — April 2020More recent understanding of the neurobiologicalunderpinnings of ADHD is based on restingfunctional network imaging. Altered activity infunctional brain networks involved in ADHD ishypothetically linked to compromised responseinhibition and impulsivity, difficulty sustaining andappropriately shifting attention, altered arousaland vigilance, deficits in working memory andexecutive function, and impairment of socialcognition.53-55,87-89 Functional imaging studieshave also looked at fronto-amygdalar connectionsand the ventral attentional network. Atypicalfronto-amygdalar connectivity and reducedVLPFC‑amygdalar connectivity in ADHD hasbeen linked to inadequate emotional control andemotional reactivity (behaviors that sometimesaccompany ADHD),90 while malfunction of ventralattentional pathways has been associated withmotivational deficits and difficulty delayinggratification (common symptoms of ADHD).2Moreover, VMPFC functional deficits have beenlinked not only to impaired motivational control, butalso to conduct disorder in individuals with ADHD.91Resting functional network imaging is also usedto support more contemporary elaborations ofADHD underpinnings. The frontoparietal networkincludes the DLPFC, VLPFC, anterior PFC, ACC,and the inferior parietal lobes (these regions arealso described as the cognitive executive network[CEN]), as well as the lateral cerebellum, caudate,and anterior insula. Its main role is to exerciseexecutive control and participate in decisionmaking. Most of the components of this networkdemonstrate reduced activity in individualswith ADHD, except the dorsal ACC, which hasdemonstrated heightened activity (possibly acompensatory adaptation) in some studies.1,92,93The previously mentioned ventral attentionalnetwork shares components with the saliencenetwork and includes the temporoparietal junction,operculum, and anterior insula. It is tasked withmonitoring the environment for emergence ofsalient stimuli and interrupting ongoing activity8

when necessary.1 The dorsal attentional network iscomposed of precentral and parietal regions (alsoshares components with the CEN) and appears tohave diminished activity in ADHD, which coincideswith inattentiveness, working memory deficits, andinadequate response inhibition.1The motor network includes the primary motorcortex, secondary motor cortex (ie, the premotorcortex and supplementary motor area), primaryand secondary sensory cortices, putamen,thalamus, and cerebellum.1,94 Individuals withADHD have been shown to manifest decreasedactivation of the primary and premotor corticescompared with controls. Substantially reducedcortical inhibition in ADHD has been correlatedwith deficient motor performance.1The visual network includes the occipital visualcortex and temporal structures. It interacts with thedorsal attentional network to maintain attentionand suppress attention to irrelevant stimuli.1Decreased cortical and gray matter volume in theoccipital cortex has been reported in individualswith ADHD.1,95 Interestingly, a 33-year follow-upstudy of childhood-diagnosed ADHD found anassociation between persistence of an ADHD anddecreased occipital cortical thickness.1Main hubs of the DMN are the medial prefrontalcortices, posterior cingulate cortex, precuneus,and medial temporal lobe.1,82 Increased DMNactivity coincides with self-reflection, rumination,reminiscing, processing social information, andplanning future activities.96 Typically, the DMNis not active when an individual is engaged incognitive-executive tasks.96 Convergent imagingevidence suggests that individuals with ADHDhave diminished recruitment of DMN activity whenengaged in tasks requiring focus and sustainedattention.97 Daydreaming and distractibilitycommonly described in children with ADHDmay be a consequence of inadequate DMNsuppression during cognitive tasks.1 ProperThe Neurobiology of ADHD — April 2020deactivation of DMN in ADHD occurs only incircumstances of elevated salience or withstimulant use.1,98 One can wonder whether thetendency to procrastinate in individuals withADHD may be a pseudo-adaptive maneuverdirected toward increasing salience andsuppressing distracting DMN activity. Furthersupporting these findings, newer studies havefound decreased connectivity between the dorsaland ventral attentional networks and increasedconnectivity within the DMN in individuals withADHD relative to controls.99,100Due to the high rate of comorbid depression andanxiety in ADHD,7 one may question whetherthese 3 disorders share common neurobiologicalalterations. A recently published paper looking atmood and anxiety disorders evaluated whethertheir shared clinical features are reflected inshared neurobiological substrates.101 Basedon a meta-analyses of 226 relevant studiesin mood and anxiety disorders, alterations inbrain functioning were found to be similar andcorrelated with cognitive deficits and negativeemotions (ie, transdiagnostic convergence).These results suggest that the symptoms ofmood and anxiety disorders are associatedwith similar neurobiological patterns.101 Ofnote, although ADHD was not included inthis meta-analysis, many of the ADHD-relatedneurobiological alterations discussed aboveare consistent with those observed for moodand anxiety disorders, lending support for thepathophysiological overlap between ADHD andthese comorbidities.41,102key takeaway: Multiple brain networksare involved in attention, with reducedfunction of these networks associated withsymptoms and characteristics of ADHD,including deficits in sustained attention,response inhibition, executive function,and emotional control.9

ALTERED NEUROTRANSMISSION IN ADHDIn addition to studies implicating candidate genesregulating NE and DA synthesis and breakdownin ADHD, imaging studies have provided furthersupportive evidence of catecholamine and otherneurotransmitter dysregulations in ADHD (Table 3).Table 3. Potential Neurotransmitters Involved in ADHD52,103-107NeurotransmitterAttention-related functionsDAPlanning and initiation of motorresponse, reaction to novelty,processing of rewardNEArousal modulation, cognitiveprocessing5-HTManagement of depression, anxiety,and sleep; emotional regulationGABAMotor control, behavioral inhibitionGluLearning, memory5-HT, serotonin; ADHD, attention deficit/hyperactivity disorder; DA,dopamine; GABA, gamma-aminobutyric acid; Glu, glutamate; NE,norepinephrine.Functional imaging studies, such as positronemission tomography and single-photon emissioncomputed tomography, which use selective ligandsfor the dopamine transporter (DAT), have reportedincreased DAT binding in up to 70% of children andadults diagnosed with ADHD, indicating a higherdensity of DAT in the brains of these individualsthan in controls.2,108 It is important to mention thatthis is not conclusive, as a number of studies havenot found altered DAT binding in ADHD, and it ispossible that medication status may explain someof the discrepancy.2,108 Both reduced and elevatedDA receptor D2 availability, as well as reducedD2 and D3 binding in the striatum and nucleusaccumbens, have also been noted, differentiatingADHD from control groups.2,108,109Absence of appropriate radioligands for NEhas limited imaging research into NE function inADHD,2 however, non-imaging evidence for NEdysfunction in ADHD comes from multiple othersources. Neurobiological evidence includes theabundance of the α2A adrenoceptor subtype in theThe Neurobiology of ADHD — April 2020PFC110 and enhanced PFC functioning followingstimulation of postsynaptic α2A receptors by NE.111Genetic studies have found an association betweena variation in the gene encoding for dopamine ßhydroxylase, resulting in reduced NE synthesis112and deficits in sustained attention.113,114 The roleof NE dysfunction in the pathogenesis of ADHDis also supported by the fact that all US Food andDrug Administration–approved medications forADHD have either direct or indirect effects onNE, presumably leading to improvement of PFCfunction.114 Peripheral levels of NE, monoamineoxidase, and the NE metabolite, 3-methoxy4-hydroxyphenyl-ethylene glycol, are beingstudied as biomarkers that could differentiateindividuals with ADHD from controls, as well asreflect symptom severity and predict treatmentresponse.115Evidence of catecholamine dysfunction in ADHDlends further credibility to the pathophysiologicalhypothesis implicating prefrontal cortical, caudate,and cerebellar dysfunction. Studies have found thatthe PFC is especially sensitive to its neurochemicalenvironment, particularly DA and NE signaling.111These catecholamines are so critical to the functionof the PFC that either too little or too muchneurotransmitter results in impaired functioning.15,116In fact, DA and NE regulate the activity of prefrontalpathways in an inverted u-shaped dose-responsemanner (Figure 6).111 Namely, hypoactive andhyperactive catecholamine signaling in thesecircuits (including excessive DA signaling dueto stress or an excessive dose of a stimulantmedication) can cause disruption in attention,impulse control, and executive function.15,111 Thishas ramifications for ADHD treatment, as currentlyapproved pharmacotherapies (both stimulantsand nonstimulants) correct for catecholamineimbalance in the PFC.116As was the case with catecholamines, studies havepointed to involvement of variations of genes in theregulation of Glu signaling.42 Further supporting10

Figure 6. Catecholamine levels and PFC function (adapted from Arnsten 2009).111,117OptimalFocusedOrganizedResponsiblePFC AbilitiesEngage NE α 2(mostly α 2A, α 2C)Moderate DA edAnxiousIrritable“Brain freeze”ExcessiveInadequateEngage NE α1, ß1(mostly α1B and α 2C?)Too much DA D1Too littleNE and DALevels of Catecholamine ReleaseIncrease With Arousal StateDA, dopamine; NE, norepinephrine; PFC, prefrontal cortex.Note: Optimal NE levels also engage α1, associated with wakefulness and alertness.118these findings, a proton magnetic resonancespectroscopic (MRS) study reported reduced Gluglutamine (Glx) concentrations in the striatumof participants with ADHD relative to controls.Interestingly, lower basal ganglia Glx was significantlycorrelated with greater symptom severity in theADHD group.119 Gamma-aminobutyric acid (GABA)has also been implicated in ADHD, with an MRSstudy reporting reduced GABA concentrations insomatosensory and motor cortices of participantswith ADHD compared with controls, possiblyreflecting deficient intracortical inhibition in ADHD.104Serotonin also appears to play a role in ADHD.Functional brain imaging of 5-HT binding andplatelet 5-HT binding in individuals with ADHD haveyielded inconsistent results,109 most likely supportingthe biological heterogeneity of ADHD. Furthermore,we previously mentioned that α2A adrenoceptorsare implicated in the pathophysiology of ADHD: notonly are α2A adrenoceptors in the PFC involved inregulation of NE release, but they are also involvedin the modulation of 5-HT synthesis and release.120Moreover, data suggest that 5-HT signalingincreases DMN activity, a known imaging finding inThe Neurobiology of ADHD — April 2020ADHD.121 Studies of the 5-HT transporter (SERT) andthe

relationship problems/divorce in adolescents and adults.3,13,17-23 ADHD also imparts a higher mortality rate. Studies show up to a 3-times greater risk of premature death and up to a 4-times greater risk of death from all causes in individuals with ADHD compared to individuals without ADHD, often due to accidents and