Attention-deficit/hyperactivity disorder (ADHD) is highly comorbid with substance use disorders, particularly cocaine. Preclinical studies using the well-validated Spontaneously Hypertensive Rat (SHR) model of ADHD suggest that adolescent treatment with the stimulant methylphenidate increases cocaine abuse risk in adulthood, highlighting the need to identify alternative medications for teenagers with ADHD. Experiments 1-4 tested the hypothesis that atomoxetine, a non-stimulant that improves prefrontal cortex functioning in adolescent SHR, would not increase cocaine abuse risk. The speed to acquire cocaine self-administration, the efficacy and motivating influence of cocaine reinforcement, and reactivity to cocaine cues in adulthood following discontinuation of adolescent atomoxetine treatment were examined in male SHR and two genetic control strains: inbred Wistar-Kyoto (WKY) and outbred Wistar (WIS). Because atomoxetine is not always as clinically efficacious as methylphenidate, Experiments 5-9 tested the hypothesis that an alternative stimulant, d-amphetamine, would improve cognitive performance in adolescent SHR during a strategy set-shifting task and not increase cocaine abuse risk in adult SHR after adolescent d-amphetamine was discontinued. Across experiments, adult SHR acquired cocaine self-administration faster than control strains and also were more sensitive to cocaine’s reinforcing and motivating influence and more reactive to cocaine cues. As hypothesized, adolescent atomoxetine did not increase any measure of cocaine abuse risk in adult SHR and modestly reduced SHR’s reactivity to cocaine cues. In WKY control, however, adolescent atomoxetine accelerated acquisition of cocaine self-administration. d-Amphetamine improved set-shifting deficits in adolescent SHR, demonstrating pro-cognitive effects as hypothesized. When self-administration was acquired, cocaine intake was lower in adult SHR that received adolescent d-amphetamine compared to vehicle-treated SHR, consistent with the hypothesis. Adolescent d-amphetamine slowed acquisition and reduced the efficacy and motivating influence of cocaine reinforcement in WIS control, but accelerated acquisition in WKY control. Collectively, these results highlight the heuristic value of SHR in evaluating comorbid ADHD and cocaine abuse risk, and suggest that atomoxetine and d-amphetamine may be safer medications than methylphenidate for teenagers with ADHD. However, findings in control strains emphasize the need for accurate ADHD diagnosis, as the long-term consequences of treatment could be favorable (d-amphetamine in WIS) or unfavorable (atomoxetine and d-amphetamine in WKY) in misdiagnosed individuals.

Attention reorienting is crucial to human survival in a constantly changing environment. In order to react and respond to novel and potentially threatening stimuli in the environment, we have to first reorient our attention to the stimuli themselves. While numerous studies in the past have attempted to uncover the principles of how our brain processes new stimuli and reorients our attention, they typically employed standardized paradigms such as an oddball or a cueing paradigm that do not represent how humans actually reorient attention in the real world. This dissertation seeks to directly address this issue by investigating the brain dynamics underlying attention reorienting in an immersive and naturalistic environment. We employ a virtual reality (VR)-based target detection paradigm that closely mimics how human would reorient their attention in real-world situations. During the experiments, subjects are instructed to reorient their attention between a primary visual task (driving simulation) and a secondary visual task (target detection) while their electroencephalography (EEG), eyetracking and behavioral inputs are being recorded. Each set of experiments and subsequent data analysis methods are tailored to answer different questions based on the three specific aims of this dissertation (1) how do eye movements affect attention reorienting signals? (2) how do we integrate the information obtained from the neural and ocular signals to decode reorienting? and (3) what is the relationship between attention reorienting and the arousal system? We found that while eye movements result in greater temporal variation of neural signals associated with attention reorienting, namely the P300 signal, time-locking the event-related potentials (ERPs) to image onset or saccade intersection still results in the best overall performance in classifying target vs. distractor stimuli. Similarly to eye movements, we also found that allowing for head movements results in greater temporal variations of both the neural (P300) and pupil-linked attention reorienting signals. However, by combining the EEG, pupil dilation and dwell time signals, a multi-modal hybrid classifier we developed using the hierarchical discriminant component analysis (HDCA) was able to capture and integrate the neural and ocular attention reorienting signals with similar performance both in the condition with and without head movements. In addition, the hybrid classifier outperformed single-modality classifiers (EEG-only, pupil dilation-only and dwell time-only) in all comparisons. Lastly, we reported a close-knit relationship between pupil-linked arousal and network-level EEG dynamics underlying attention reorienting. We observed improvements in overall performance as pupil-linked arousal increased. We also observed increased oscillatory activity across multiple frequency bands in regions associated with the dorsal and ventral attention networks as pupil-linked arousal increased. Additionally, we found a decrease in functional connectivity across nodes in the salience network and the ventral attention network as pupil-linked arousal increased. The findings of this dissertation have the potential to serve as the basis for the development of the next generation of non-invasive brain-computer interfaces (BCIs) that can function in real-world environments. Furthermore, these findings may also serve to help physicians and neuroscientists better understand the neurophysiology underlying attention-related disorders including attention-deficit disorder (ADD) or attention-deficit/hyperactivity disorder (ADHD).

The purpose of this study was to determine if attention-deficit/hyperactivity disorder (ADHD) subtypes (predominantly hyperactive/impulsive, ADHD-HI; predominantly inattentive, ADHD-IA; combined, ADHD-C) exhibit distinct neuropsychological profiles, using the Attention and Executive Function subtests of the Developmental Neuropsychological Assessment, (NEPSY) and the omission and commission scores obtained on the Conners' Continuous Performance Test-II (CPT-II), a test that assesses attention processes. The sample was selected using archival data collected in a neurodevelopmental clinic over the past decade and consisted of 138 children between the ages of 6 and 12 years old. Using the Diagnostic and Statistical Manual of Mental Disorders (4th ed.) (DSM-IV) criteria, the children were placed in either the ADHD-HI (n = 40), ADHD-IA (n = 35), or ADHD-C (n = 36) group, or a symptom free comparison group (n = 27). It was hypothesized that children with elevations on the impulsivity/ hyperactivity (ADHD-HI and ADHD-C) scale would be impaired on measures of inhibition and those with elevations on the inattention scale (ADHD-IA and ADHD-C) would be impaired on tests of attention, vigilance, and other executive functions. A one-way multivariate analyses of variance (MANOVA) was conducted (Group X Task), with significant results for overall main effect for group on the 7 dependent variables post hoc tests using the Tukey's honestly significant difference (HSD) revealed the following: the ADHD-HI group scored significantly lower on tests that require behavioral inhibition processes (Knock and Tap, Statue and CPT-Commission errors). The ADHD-IA group scored significantly lower on tests of problem-solving and planning (Tower) but not on tests of attention as was expected. The ADHD-C group scored significantly lower on tests of inhibition, attention, and other executive functions (Auditory Attention Response Set, Visual Attention, Tower, Knock and Tap, Statue, and CPT-Omission and CPT-Commission errors). Overall results suggest that the NEPSY Attention and Executive Function subtests are able to differentiate ADHD subtypes. Recommendations for future research are discussed.

Bakgrund: Attention deficit/hyperactivity disorder (ADHD) hos barn är en av världens vanligaste neuropsykiatriska funktionsnedsättningar (NPF). Många människor har förutfattade meningar angående vad ADHD är, men att få lära sig och förstå hur det är att vara förälder till ett barn med ADHD och förstå vad dessa föräldrar går igenom varje dag, finns det inte tillräckligt mycket forskning om. Syfte: Att beskriva föräldrarnas upplevelse av att vara förälder till ett barn med ADHD. Metod: En litteraturstudie med kvalitativ design. För att få fram det kvalitativa materialet till studien användes tre databaser, PubMed, Cinahl och PsychInfo. En litteraturstudie med en kvalitativ innehållsanalys med induktiv ansats valdes för att kunna fördjupa sig i upplevelsen från ett inifrånperspektiv från föräldrar till barn med ADHD och deras vardag. Under innehållsanalysen användes ett manifest förhållningssätt för att analysera de utvalda artiklarna innehåll. Innehållsanalysen utfördes genom att de utvalda artiklarna lästes igenom och sedan extraherades textenheter, som är meningar, stycken eller citat som har relevans för det utvalda syftet. Efter kondensering och kategorisering av textenheter resulterade i fyra kategorier. Resultat: De fyra kategorierna som framkom i analysen var; Att hantera och uppleva stress i vardagslivet, Att känna press och krav från skolan, Att känna brist på stöd och resurser och Att bli socialt isolerad och stigmatiserad. I helhet kunde de ses i denna litteraturstudie att den generella upplevelsen av att vara förälder till ett barn med ADHD var den konstanta stressen. Stressen över deras framtid, stress för att de inte ska klara av skolan, stress över att de inte kommer ha några vänner och stressen över att inte veta när nästa utbrott kommer ske. Det som även kunde ses var att föräldrarna inte bara blev påverkade av barnets sjukdom, men även att syskonen påverkades. Slutsats: Att leva med ett barn som har ADHD resulterar i stor stress hos föräldrarna. Barnets beteende påverkar familjen i och utanför hemmet, samt hur skola och samhället uppfattar dem som familj och som föräldrar. Nyckelord: ADHD, Attention deficit/hyperactivity disorder, parents, lived experience, nursing, stress.

ADHD är en vanligt förekommande neuropsykiatrisk funktionsnedsättning som kan leda till stigmatisering på arbetsplatsen. Syftet med föreliggande studie var att genom en kvalitativ intervjustudie studera hur en grupp personer med ADHD upplever denna stigmatisering på arbetsplatsen utifrån ett inifrånperspektiv. Studien syftade även till att undersöka vilka faktorer i arbetslivet som kan vara faciliterande och hindrande för personer med ADHD. Tio personer med ADHD intervjuades med hjälp av en semistrukturerad intervjuguide. Intervjuerna analyserades därefter utifrån ett hermeneutiskt synsätt. Analysen resulterade i fem teman; Upplevelser av och förhållningssätt till sin ADHD diagnos på arbetsplatsen, Identitet och självbild på arbetsplatsen, Deltagarnas uppfattning av allmänhetens uppfattning- stigmatisering, Öppet eller dolt stigma och Faciliterande och hindrande faktorer i arbetsmiljön. Deltagarna hade både individuella och gemensamma upplevelser av stigmatisering på arbetsplatsen kopplat till ADHD. I intervjuerna framkommer bland annat en önskan om ökad kunskap och förståelse, och det framkommer en oro bland deltagarna över hur diagnosen ska tas emot av andra. Det fanns en koppling mellan att vilja berätta om sin diagnos och tilliten till den man ska berätta det för. Deltagarna önskar också stöd kring rutiner och arbetsmiljö för att kunna vara så effektiva som möjligt.  Studier som undersöker ADHD hos vuxna är få och denna studie bidrar till att öka kunskapen kring gruppen.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that affects academic, social, and health functioning. The psychometric properties of measures commonly used in diagnostic settings to assess the constructs of attention, hyperactivity, and executive functioning, including concurrent and incremental validity with other commonly used measures, are not well-established. Additionally, these specific psychometric properties within ecological samples of children and adolescents presenting to community-based clinics is infrequent. The purpose of this dissertation was to describe a sample of children and adolescents presenting to a community-based mental health clinic and to test the concurrent and incremental validity of parent- and teacher-report questionnaires and neuropsychological measures of inattention, hyperactivity, and executive functioning. Participants included a consecutive sample of 597 youth aged six to eighteen years presenting to a community-based mental health clinic for a psychological assessment between 2010 and 2019. Measures included the BASC (2nd and 3rd editions), Conners 3 (long and short forms), BRIEF (1st and 2nd editions), D-KEFS, NEPSY-II, and CPT (2nd and 3rd editions). Approximately 50% of individuals were diagnosed with ADHD. Correlations between attention, hyperactivity, and executive function constructs on questionnaires were significantly and moderately-to-strongly correlated (Spearman’s  = .27-.82) to each other (e.g., BASC Hyperactivity and Conners Hyperactivity/Impulsivity subscales) and across parent and teacher forms (e.g., Conners Parent Inattention and Conners Teacher Inattention subscales). Constructs measured by neuropsychological tests were not significantly correlated to similar constructs measured by other neuropsychological measures or questionnaires (e.g., inhibition measured by NEPSY-II Response Set and BRIEF Inhibition subscale; Spearman’s  = .02-.38). Logistic regression analyses suggested that measures such as the BASC, BRIEF, NEPSY-II, and CPT do not clinically significantly increase prediction of ADHD diagnosis above and beyond the Conners 3. Results indicate convergence of information with potential redundancy in the assessment and diagnosis of ADHD across questionnaire measures and informants. Questionnaires and neuropsychological measures were not correlated, suggesting they measure different constructs or different aspects of the same construct. Results indicate that clinicians may sufficiently rely on questionnaires and reduce the number of other neuropsychological measures administered during a diagnostic assessment without significantly reducing diagnostic accuracy. However, the value of evidence of symptoms in multiple settings and converging information should still be considered.

Bakgrund: Fysioterapeutiska interventioner som exempelvis fysisk aktivitet har positiv effekt på flertalet symptom hos personer med ADHD. Dessa personer har även påvisad nedsatt motorisk kontroll och motorisk färdighet jämfört med neurotypiska personer. Trots påvisade positiva effekter nyttjas inte fysioterapeuters kompetens vid rehabilitering av ADHD. Syfte: Syftet var att kartlägga det aktuella kunskapsläget angående fysisk träning som fysioterapeutisk intervention för ökad motorisk färdighet och ökad motorisk kontroll hos personer med ADHD. Metod: En artikelsökning utfördes i databaserna Pubmed, PEDro, Cinahl, Web of Science och Scopus. Sökningen resulterade i elva relevanta artiklar varav fyra av dessa inkluderades. Referenslistor på inkluderade artiklar och review-studier granskades, vilket resulterade i ytterligare två inkluderade artiklar. Alla artiklar kvalitetsgranskades och sammanställdes i en resultattabell. Resultat: Fem artiklar, varav fyra av dessa med högt bevisvärde, visar att fysisk träning har signifikant effekt på motorisk färdighet. En artikel med högt bevisvärde indikerar att fysisk träning har signifikant effekt på motorisk kontroll. Effekten verkar inte bero på vilken typ av träning som utfördes, däremot visar en studie att högintensiv träning verkar ha bättre effekt på motorisk färdighet än lågintensiv. Konklusion: Fysisk träning verkar ha effekt på motorisk färdighet och motorisk kontroll hos personer med ADHD oavsett typ av träningsform. Högintensiv träning verkar ge bättre effekt på motorisk färdighet än lågintensiv. Brist på forskning inom området leder till svårigheter att dra tydliga slutsatser utifrån dessa resultat, därav behöver fler studier utföras.

Adhesion G-protein coupled receptors (GPCRs) are the second largest class of GPCRs, yet their functions and ligands remain predominantly unidentified. Polymorphisms in the gene encoding the adhesion GPCR latrophilin 3 (ADGRL3) have been associated with an increased risk for attention deficit hyperactivity disorder (ADHD) and substance use disorder (SUD) in various linkage and association studies. Disrupting the function of ADGRL3 homologs across mammalian and invertebrate model systems leads to changes in various dopaminergic phenotypes such as hyperactivity, sleep impairment, and changes in sensitivity to psychostimulants, suggesting that ADGRL3 contributes to behavior by modulating dopamine signaling. Here, I use behavioral and imaging studies to delineate an important role for Cirl, the Drosophila homolog of ADGRL3, in a recently characterized dopaminergic sleep circuit. Sleep impairment is a common symptom in both SUD and ADHD, and sleep studies are well established in Drosophila. Our work shows that fruit flies that carry a null mutation for Cirl are hyperactive and display a deficit in sleep that is enhanced by adult thermogenetic activation of dopamine neurons. Though Cirl displays high expression within dopamine neurons, conditional knockout of Cirl in dopamine neurons does not recapitulate sleep deficits seen in Cirl null flies, and specific rescue of Cirl in a knockout background does not ameliorate them. Intriguingly, activating dopamine neurons in Cirl null flies throughout development rescued the sleep deficits, indicating that this dopaminergic intervention induces lasting changes that can ameliorate lack of Cirl function. Imaging studies reveal that Cirl shows high expression in the central complex, which is involved in sleep and receives dense dopaminergic input. I demonstrate that Cirl functions within different populations of the central complex downstream of dopaminergic innervation to differentially affect night and daytime sleep through both dopaminergic and non-dopaminergic mechanisms. This work delineates a novel role for an adhesion GPCR in modulating sleep behavior, and further characterizes ADGRL3 as a potential therapeutic target for disorders characterized by dysregulation of dopaminergic neurotransmission.

Attention Deficit Hyperactivity Disorder, eller ADHD, är en neuropsykiatrisk funktionsnedsättning som kan ha stor inverkan på elevers skolgång. Den svenska skolans kompensatoriska uppdrag syftar dock till att bland annat minska diagnosernas påverkan på elevers skolgång med hjälp av olika stödinsatser så att elever ska kunna ta till sig utbildningen på bästa sätt. Detta kan ske på olika vis, men en faktor är de anpassningar som görs av lärare i undervisningen. Syftet med denna studie är att undersöka vilka anpassningar gymnasielärare har erfarenhet av att använda i sin undervisning i relation till ADHD, samt deras attityd till detta arbete. Data samlades in via inspelade semistrukturerade intervjuer som sedan transkriberades och analyserades med reflexiv tematisk analys. Samtliga moment genomfördes av båda författarna. I analysen framkom det att lärare genomför anpassningar som vi delade in i två huvudteman:individanpassningar och klassövergripande anpassningar. Detta beroende på om anpassningen endast var till nytta för individen eller om hela klassen kunde dra nytta av anpassningen. Det uppmärksammades även att lärarnas attityder formas av deras olika infallsvinklar och upplevelser till arbetet med anpassningar för elever med diagnoser som ADHD. Några av slutsatserna som framkom i studien är bland annat att gymnasielärare har erfarenhet av attanvända sig av en rad olika anpassningar, både för specifika individer men även anpassningar som gynnar hela klassen. Lärarnas attityd till arbetet med anpassningar är både komplext och varierande i relation till deras upplevelser och infallsvinklar till anpassningar.

Diverse clinical presentation in neurodevelopmental disorders (NDDs) leads to difficulty in matching individuals with effective treatments. Autism spectrum disorders (ASD) and attention deficit hyperactivity disorder (ADHD) are the two most prevalent neurodevelopmental disorders (NDDs), characterized by deficits in communication, social interactions, and behaviours. There is high within-diagnosis heterogeneity and striking overlap between diagnoses. The literature suggests that current diagnostic criteria do not align well with behaviour metrics. Therefore, identifying novel biomarkers underlying behaviour in NDDs may provide a reliable way to group individuals with similar behavioural phenotypes. This thesis examines how gut-immune biology is linked to clinical heterogeneity in children with NDDs. The first study used unsupervised machine learning to cluster typically developing (TD), ADHD, and ASD participants by their behaviour metrics in a diagnosis-agnostic approach. The results produced a six-cluster solution, five of which were a mix of all diagnostic categories. Further, gastrointestinal (GI) symptoms were mapped to the clusters, revealing a link between constipation, social communication deficits and restrictive-repetitive behaviours. The second study used hierarchical clustering to group TD and NDD participants based on a profile of gut and inflammatory markers. Participants clustered into two biotypes, both containing TD and NDD participants. Additionally, using regression analysis, novel markers were linked to anxiety. The third study evaluated the multisite biospecimen collection protocol of the Province of Ontario Neurodevelopmental Disorders (POND) Network. The final study used biospecimens collected from the POND network to phenotype peripheral blood mononuclear cells in TD and NDD participants. In NDD groups, monocyte and B cell activation markers were differentially expressed compared to TD. Overall, this thesis demonstrates that gut-immune mechanisms contribute to clinical heterogeneity in a subset of people and contribute to the search for biomarkers in NDDs. / Thesis / Doctor of Philosophy (PhD) / Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are diagnosed based on behavioural symptoms. However, symptoms can vary a lot from person to person, and some symptoms are shared between ASD and ADHD. Understanding the biological reasons for symptom differences between people can help pinpoint treatments which work best for an individual. This thesis looks at the role of the gut and immune system in ASD and ADHD. Blood samples and behaviour questionnaires were collected to study how immune cells, inflammation, and intestinal permeability shape behaviour symptoms. The results show that diagnosis is not the most accurate way to group people. Anxiety symptoms were different when people were grouped based on their inflammation levels. Also, specific immune cells appear to work differently in people with ASD and ADHD. These findings clarify some of the biology that affects behavioural symptoms in ASD and ADHD.