Professor Luis Rohde
Neurobiology across the life-course; brain development in ADHD
The opening session of Meeting of Minds IX was chaired by Professor Luis Rohde (Federal University of Rio Grande do Sul, Brazil), who highlighted the growth and ongoing success of the congress, which has evolved from a small, local meeting to a global congress, attended by more than 250 delegates from over 18 countries.
The opening session kicked off with an enlightening presentation by Dr Tomáš Paus (University of Toronto, Canada) entitled ‘The adolescent brain: its psychiatric risks’. Dr Paus introduced the integrated approach adopted by his research team to explore the interplay between epidemiology, genetics and neuroscience in the context of the adolescent brain. The importance of adolescent brain maturation was framed in the context of mental illnesses, many of which increase in incidence during this period.1,2 Particular focus was placed on ongoing international birth cohort studies, which present an opportunity to evaluate environmental and genetic influences on brain development and behavioural outcomes.
One example of an environmental factor highlighted by Dr Paus was maternal cigarette smoking during pregnancy, which has been associated with reduced cortical thickness in adolescent females, compared with non-exposed individuals.3 Furthermore, a genome-wide association study reported that this effect was modulated, at least in part, by the potassium channel tetramerisation domain 8 (KCTD8) gene.4 The potential links between maternal smoking during pregnancy and subsequent reward anticipation in adolescents were also explored. Reduced response to reward anticipation in the ventral striatum of prenatally-exposed adolescents may increase the risk of substance abuse and addiction in later life.5
Finally, the influence of maternal stress on white matter volume was discussed. Axonal diameter is known to increase during adolescence in males, but not females. Experiments in animals have indicated that testosterone is an important regulator of this process, and that in vitro, mibolerone can directly influence axonal transportation.6
In conclusion, Dr Paus reiterated that exploration of the processes underpinning brain maturation may aid the development of innovative therapies for mental health conditions.
The next speaker was Professor Joseph Sergeant (Vrije University, Amsterdam, The Netherlands). His presentation entitled ‘Transitioning from adolescence to adulthood’ highlighted key aspects of neurobiological development relevant to ADHD.
A prominent theme during the talk were the gaps in our knowledge and how these may impact our understanding of ADHD and other mental health conditions. In particular, the lack of data on longitudinal brain development was highlighted.
Although primarily identified with control of motor function, the cerebellum has additional roles in cognitive and emotional regulation. The particular importance of the cerebellum in ADHD was highlighted in a series of brain animations that showed the development of the cerebellum in normal subjects, in patients with persistent ADHD and in patients with remitted ADHD.
Similarly, the basal ganglia were highlighted as being of potential importance in the pathophysiology of ADHD. The caudate nucleus is reduced in adolescents with ADHD, this being one of the differential features between ADHD and non-ADHD patients,7 although it cannot be used as a diagnostic feature. The caudate nucleus is associated with the value system and executive functions, including inhibition control and task switching. Professor Sergeant also stated that potential differences between the striatum of ADHD and non-ADHD brains may have been underestimated due to MRI correction methods used during scans.
The development of the cortex is also an important area in the context of ADHD. Large-scale studies have identified differences in cortical thickness between ADHD and non-ADHD subjects.8,9 Animated visualisations of brain development were presented, showing a 2–5 year developmental delay in ADHD patients compared with controls. It is thought that such differences may result in later development of inhibitory controls in patients with ADHD.
Finally, the development of brain networks was explored. Differences in network development have been identified between persistent and remitted ADHD and controls.10-12 It has also been hypothesised that the fronto-parietal network may not exert the same level of control in individuals with ADHD compared with controls, and that inhibitory signals from the default mode network may not occur in the brains of ADHD patients.
In concluding his presentation, Professor Sergeant reinforced that, in this complex field, effects on emotional responses will require more studies that map changes in brain development with time.
Next, Professor Barbara Sahakian (University of Cambridge, Department of Psychiatry and Behavioural and Clinical Neuroscience Institute, UK) gave a thought-provoking overview of cognitive symptoms in ADHD entitled ‘The adult brain with ADHD; an update’.
School years were identified as a critical period for young people with ADHD, potentially impacting on whole life trajectories. The importance of early detection and effective treatment of severe ADHD was stressed in order to improve outcomes and reduce direct and indirect costs.
During the presentation, psychiatric disorders were framed as disorders of neurodevelopmental origin, affecting cognition and motivation.1 Manifestations of cognitive defects included:
- attentional biases
- aberrant learning
- memory impairments
- dysfunctional reward systems
- lack of top-down cognitive control by prefrontal cortex.
Professor Sahakian also introduced the concepts of hot (visual and affective pathways) and cold (motor and spatial pathways) cognition,13,14 both of which are impaired in patients with ADHD.
A core cognitive deficit of ADHD is impairment in sustained attention, which can be assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB). Interestingly, problems in sustained attention were detected in patients with ADHD and their first-degree family members without ADHD; this was associated with decreased grey matter volume in the right inferior frontal gyrus compared with healthy controls.15 It was also shown that methylphenidate treatment improves sustained attention in patients with ADHD and in healthy controls.16
Spatial working memory is also impaired in childhood and adult ADHD. Methylphenidate treatment has been shown to be effective in improving working memory in adults with ADHD and healthy controls.17 The influence of the right inferior prefrontal cortex in impulse control was also highlighted.
It is hoped that a greater understanding of the core cognitive problems associated with ADHD and other neuropsychiatric disorders may lead to the development of more effective pharmacological and non-pharmacological treatments.
In the final talk of the morning session ‘From science to symptoms: a clinical perspective’, Professor Luis Rohde gave an overview of brain heterogeneity and how this relates to ADHD. A key message from this presentation was the advantage of adopting a developmental perspective when considering mental health disorders.
Sex differences in the brain were identified as being important with many studies reporting gender differences in adult ADHD outcomes,18 as were the gene-environment interactions that shape the brain during adolescence.
Professor Rohde highlighted the phenotypic heterogeneity of ADHD by showing that current diagnostic criteria permit a total of 116,220 possible combinations of symptoms. This means that ADHD cases are rarely identical between patients, presenting challenges to the clinician in optimising treatment.
Professor Sahakian: “Early detection and effective treatment will lead to better outcomes.”
Professor Rohde: “ADHD is much more complex than a simple list of symptoms.”
Professor Susan Young
The informative and engaging afternoon plenary session was opened by Professor Neill Epperson (Perelman School of Medicine, University of Pennsylvania, USA) with a presentation entitled ‘ADHD in girls and women’.
At the outset, Professor Epperson commented on the diversity of the audience and encouraged the attendees to embrace the opportunity for open discussion and collaboration.
The presentation focused on sex differences in the brain and how these affect neuropsychiatric risk over the lifespan: ‘from womb to tomb’. The sexual differentiation of the brain begins in utero on exposure to sex steroids; this process is thought to influence the risk of developing future mental health conditions.
Many differences have been identified in the likelihood of developing neuropsychiatric disorders between women and men. For example, women are more likely to be affected by affective disorders that develop in the post-pubescent period, such as major depression disorder, panic disorder or generalised anxiety disorder. In contrast, men are more commonly affected by conditions with an early onset, such as autism, ADHD, schizophrenia or oppositional defiant disorder.19,20
A key theme of the talk was the emerging view that intrauterine programming, modulated by maternal stress, plays a critical role in determining the risk of future psychopathology.21,22 It is thought that foetal exposure to glucocorticoids may drive epigenetic changes. Normally, the placenta effectively blocks foetal exposure to cortisol by enzymatic degradation by 11β-hydroxysteroid dehydrogenase (11β-HSD);23 however, under periods of stress, foetal exposure to maternal cortisol may increase.
Prenatal programming can affect the duration of pregnancy and weight of the child at birth. Other effects on later life include externalising symptoms, behavioural dysregulation and decreased grey matter volume at age 6-9 years.24-26
Professor Epperson then provided some details of the genetic factors that can influence risk of psychiatric disorders and are modulated by sex hormones. One example she noted was the catechol-O-methyl transferase (COMT) gene, which is involved in the metabolism of dopamine and noradrenaline in the brain. People with the val/val genetic variant of COMT may be at increased risk of schizophrenia due to reduced prefrontal dopamine activity. Oestrogen has been shown to reduce COMT activity, potentially increasing the risk of psychiatric disorders in those with susceptible genetic profiles. Hormone cycles fluctuate more in females than males over the lifespan, and periods of change such as the menopause may result in deficits in executive functioning, particularly in response to stress. Interestingly, lisdexamfetamine in healthy adult women was seen to be effective at reducing menopause-onset executive function complaints.27
With respect to ADHD, Professor Epperson showed that, although ADHD is less prevalent in girls than boys, it is more likely to be under-recognised and therefore not treated in girls. No sex differences have been reported in long-term functional impairments or responses to treatment. She also presented some recent findings that suggest that use of antidepressant medication during pregnancy is not associated with an increased risk of ADHD in children.
The next speaker was Professor Susan Young (Imperial College London, UK), who presented a lively overview of the ‘Consequences of untreated ADHD’.
Drawing from her own clinical experience, Professor Young introduced some of the considerable number of obstacles facing young people with ADHD in their pathway to adulthood. These include the continuation of symptoms, a cycle of negative feedback and the consequential impact on personal resources, which can lead to personality problems and lack of self-esteem.
Highlighting the impact on academic outcomes, it was shown that ADHD is associated with problems with reading, written language and school exclusion.28 Studies in identical twins have demonstrated that the association is independent of genes and environmental factors. Life impairment for patients with ADHD often continues into adulthood, with results from one study showing 44% unemployment in adults with ADHD, compared with 3% unemployment in control subjects.
To illustrate the problems facing young people with ADHD, Professor Young presented job interview feedback obtained from a patient with ADHD from her clinic. The young person made several errors in protocol during the interview, including: arriving late, chewing gum, being argumentative and becoming distracted.
Incarcerated populations often have relatively high numbers of individuals with ADHD; recidivism was also greater in ADHD for total convictions, property offences and violent offences. Differences in motivation for initiating or maintaining substance use have been noted between offenders with ADHD and offenders with conduct disorder or other substance users. The ADHD group reported the main reason for drug use as ‘Coping’, whereas in the other groups ‘Sensation-seeking’, ‘Acceptance’, and ‘Dependency’ scored more highly. Furthermore, mortality rate ratios were significantly higher in patients with ADHD than non-ADHD controls, the most common cause of death being accidents.29
Another area of key concern is the drop-out from ADHD care that commonly occurs during adolescence; one study showed that by age 21, no patients were still taking ADHD medication.30 Recently published recommendations for effective transition from child to adult healthcare services aim to improve the continuity of care of treatment over this period.31,32
The possible consequences of ADHD non-treatment were also discussed, these include costs to the individual/family and to local and central government.33 A systematic review showed that, compared with people without ADHD, 74% of long-term (≥2 years) outcomes were worse for individuals with untreated ADHD. In total, 72% of long‑term outcomes showed benefit from treatment, and most outcomes improved with treatment regardless of age of initiation.34
In closing, Professor Young emphasised that in studies of people with ADHD, 28% of long-term outcome measures did not improve, even with treatment.34 She concluded that it was a priority to keep young people with persisting symptoms engaged with healthcare services and get them the treatment they need and to engage agencies to work together to identify, support and/or manage young people with ADHD (e.g. education, occupation, criminal justice).
Professor Young: “We need to develop much better occupational interventions and stop children moving from the classroom to the courtroom.”
- Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005; 62: 593-602.
- Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, Charlson FJ, Norman RE, Flaxman AD, Johns N, Burstein R, Murray CJ, Vos T. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet 2013; 382: 1575-1586.
- Toro R, Leonard G, Lerner JV, Lerner RM, Perron M, Pike GB, Richer L, Veillette S, Pausova Z, Paus T. Prenatal exposure to maternal cigarette smoking and the adolescent cerebral cortex. Neuropsychopharmacology 2008; 33: 1019-1027.
- Paus T, Bernard M, Chakravarty MM, Davey Smith G, Gillis J, Lourdusamy A, Melka MG, Leonard G, Pavlidis P, Perron M, Pike GB, Richer L, Schumann G, Timpson N, Toro R, Veillette S, Pausova Z. KCTD8 gene and brain growth in adverse intrauterine environment: a genome-wide association study. Cereb Cortex 2012; 22: 2634-2642.
- Muller KU, Mennigen E, Ripke S, Banaschewski T, Barker GJ, Buchel C, Conrod P, Fauth-Buhler M, Flor H, Garavan H, Heinz A, Lawrence C, Loth E, Mann K, Martinot JL, Pausova Z, Rietschel M, Strohle A, Struve M, Walaszek B et al. Altered reward processing in adolescents with prenatal exposure to maternal cigarette smoking. JAMA Psychiatry 2013; 70: 847-856.
- Pesaresi M, Soon-Shiong R, French L, Kaplan DR, Miller FD, Paus T. Axon diameter and axonal transport: In vivo and in vitro effects of androgens. Neuroimage 2015; 115: 191-201.
- Shaw P, de Rossi P, Watson B, Wharton A, Greenstein D, Raznahan A, Sharp W, Lerch JP, Chakravarty MM. Mapping the development of the basal ganglia in children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2014; 53: 780-789.
- Shaw P, Lerch J, Greenstein D, Sharp W, Clasen L, Evans A, Giedd J, Castellanos FX, Rapoport J. Longitudinal mapping of cortical thickness and clinical outcome in children and adolescents with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2006; 63: 540-549.
- Mous SE, Muetzel RL, El Marroun H, Polderman TJ, van der Lugt A, Jaddoe VW, Hofman A, Verhulst FC, Tiemeier H, Posthuma D, White T. Cortical thickness and inattention/hyperactivity symptoms in young children: a population-based study. Psychol Med 2014; 44: 3203-3213.
- Schulz KP, Li X, Clerkin SM, Fan J, Berwid OG, Newcorn JH, Halperin JM. Prefrontal and parietal correlates of cognitive control related to the adult outcome of attention-deficit/hyperactivity disorder diagnosed in childhood. Cortex 2017; 90: 1-11.
- McCarthy H, Skokauskas N, Mulligan A, Donohoe G, Mullins D, Kelly J, Johnson K, Fagan A, Gill M, Meaney J, Frodl T. Attention network hypoconnectivity with default and affective network hyperconnectivity in adults diagnosed with attention-deficit/hyperactivity disorder in childhood. JAMA Psychiatry 2013; 70: 1329-1337.
- Kessler D, Angstadt M, Welsh RC, Sripada C. Modality-spanning deficits in attention-deficit/hyperactivity disorder in functional networks, gray matter, and white matter. J Neurosci 2014; 34: 16555-16566.
- Roiser JP, Sahakian BJ. Hot and cold cognition in depression. CNS Spectr 2013; 18: 139-149.
- Roiser JP, Cannon DM, Gandhi SK, Taylor Tavares J, Erickson K, Wood S, Klaver JM, Clark L, Zarate CA, Jr., Sahakian BJ, Drevets WC. Hot and cold cognition in unmedicated depressed subjects with bipolar disorder. Bipolar Disord 2009; 11: 178-189.
- Pironti VA, Lai MC, Muller U, Dodds CM, Suckling J, Bullmore ET, Sahakian BJ. Neuroanatomical abnormalities and cognitive impairments are shared by adults with attention-deficit/hyperactivity disorder and their unaffected first-degree relatives. Biol Psychiatry 2014; 76: 639-647.
- del Campo N, Fryer TD, Hong YT, Smith R, Brichard L, Acosta-Cabronero J, Chamberlain SR, Tait R, Izquierdo D, Regenthal R, Dowson J, Suckling J, Baron JC, Aigbirhio FI, Robbins TW, Sahakian BJ, Muller U. A positron emission tomography study of nigro-striatal dopaminergic mechanisms underlying attention: implications for ADHD and its treatment. Brain 2013; 136: 3252-3270.
- Turner DC, Blackwell AD, Dowson JH, McLean A, Sahakian BJ. Neurocognitive effects of methylphenidate in adult attention-deficit/hyperactivity disorder. Psychopharmacology (Berl) 2005; 178: 286-295.
- Williamson D, Johnston C. Gender differences in adults with attention-deficit/hyperactivity disorder: A narrative review. Clin Psychol Rev 2015; 40: 15-27.
- Bale TL, Epperson CN. Sex as a Biological Variable: Who, What, When, Why, and How. Neuropsychopharmacology 2017; 42: 386-396.
- Bale TL, Epperson CN. Sex differences and stress across the lifespan. Nat Neurosci 2015; 18: 1413-1420.
- Gluckman PD, Hanson MA, Beedle AS. Early life events and their consequences for later disease: a life history and evolutionary perspective. Am J Hum Biol 2007; 19: 1-19.
- Barker ED, Maughan B. Differentiating early-onset persistent versus childhood-limited conduct problem youth. Am J Psychiatry 2009; 166: 900-908.
- Chapman K, Holmes M, Seckl J. 11beta-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev 2013; 93: 1139-1206.
- Glover V. Annual Research Review: Prenatal stress and the origins of psychopathology: an evolutionary perspective. J Child Psychol Psychiatry 2011; 52: 356-367.
- Buss C, Davis EP, Muftuler LT, Head K, Sandman CA. High pregnancy anxiety during mid-gestation is associated with decreased gray matter density in 6-9-year-old children. Psychoneuroendocrinology 2010; 35: 141-153.
- Sarkar P, Bergman K, O’Connor TG, Glover V. Maternal antenatal anxiety and amniotic fluid cortisol and testosterone: possible implications for foetal programming. J Neuroendocrinol 2008; 20: 489-496.
- Epperson CN, Shanmugan S, Kim DR, Mathews S, Czarkowski KA, Bradley J, Appleby DH, Iannelli C, Sammel MD, Brown TE. New onset executive function difficulties at menopause: a possible role for lisdexamfetamine. Psychopharmacology (Berl) 2015; 232: 3091-3100.
- Yoshimasu K, Barbaresi WJ, Colligan RC, Killian JM, Voigt RG, Weaver AL, Katusic SK. Written-language disorder among children with and without ADHD in a population-based birth cohort. Pediatrics 2011; 128: e605-e612.
- Dalsgaard S, Ostergaard SD, Leckman JF, Mortensen PB, Pedersen MG. Mortality in children, adolescents, and adults with attention deficit hyperactivity disorder: a nationwide cohort study. Lancet 2015; 385: 2190-2196.
- McCarthy S, Asherson P, Coghill D, Hollis C, Murray M, Potts L, Sayal K, de Soysa R, Taylor E, Williams T, Wong IC. Attention-deficit hyperactivity disorder: treatment discontinuation in adolescents and young adults. Br J Psychiatry 2009; 194: 273-277.
- Young S, Murphy CM, Coghill D. Avoiding the ‘twilight zone’: recommendations for the transition of services from adolescence to adulthood for young people with ADHD. BMC Psychiatry 2011; 11: 174.
- Young S, Adamou M, Asherson P, Coghill D, Colley B, Gudjonsson G, Hollis C, McCarthy J, Muller U, Paul M, Pitts M, Arif M. Recommendations for the transition of patients with ADHD from child to adult healthcare services: a consensus statement from the UK adult ADHD network. BMC Psychiatry 2016; 16: 301.
- Daley D, Jacobsen RH, Lange AM, Sorensen A. Costing adult attention deficit hyperactivity disorder. Oxford: Oxford University Press. 2015.
- Shaw M, Hodgkins P, Caci H, Young S, Kahle J, Woods AG, Arnold LE. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. BMC Med 2012; 10: 99.