A en ion-De ici
Hype ac i i y Diso de
Jan Bui elaa
Radboud Uni e si y Medical Cen e
Donde s Ins i u e o B ain, Cogni ion and Beha io
Depa men o Cogni i e Neu oscience, and
Ka ak e Child and Adolescen Psychia y Uni e si y Cen e
Nijmegen, The Ne he lands
Webina Se o onin &
Beyond, Feb ua y 7, 2023
Summa y
• ADHD has a s ong gene ic componen
• ADHD is e y he e ogeneous a he
cogni i e and neu al le el
• Bo h delayed and de ian b ain
de elopmen
• Abno mali ies o on o-s ia al, on o-
pa ie al and on o-ce ebella ci cui s
• Cogni ion: mul iple pa hway model
Ina en ion
Impulsi i y/Hype ac i i y
ADHD -Co e Symp om A eas
ADHD: DSM-5 C i e ia
• Ina en ion o de ails/ makes
ca eless mis akes
• Di icul y sus aining a en ion
• Seems no o lis en
• Fails o inish asks
Ina en ion
• Di icul y o ganizing
• A oids asks equi ing
sus ained a en ion
• Loses hings
• Easily dis ac ed
•Fo ge ul
Six o mo e o he ollowing -mani es ed o en:
DSM-IV, 1994
ADHD: DSM-5 C i e ia
Impulsi i y
• Blu s ou answe be o e ques ion is
inished
• Di icul y awai ing u n
• In e up s o in udes on o he s
Hype ac i i y
•Fidge s
• Unable o s ay sea ed
• Inapp op ia e unning/climbing
( es lessness)
• Di icul y in engaging in leisu e
ac i i ies quie ly
• “On he go”
• Talks excessi ely
Impulsi i y/Hype ac i i y
Six o mo e o he ollowing -mani es ed o en:
Neu ode elopmen al Diso de s
• Ex eme o no mal a ia ion
• Quan i a i e a ia ion
• Neu odi e si y
• Dimensional modal
4 D’s
•Disease,
•Diso de
•Disabili y
•Di e ence
• Disease
•Abno mali y
• Quali a i e di e ences
• Psychopa hology
•Ca ego ies
Figu e 1 The his o y o a en ion-de ici /hype ac i i y diso de
Fa aone, S. V. e al. (2015) A en ion-de ici /hype ac i i y diso de Na . Re . Dis. P ime s doi:10.1038/n dp.2015.20
ADHD -Diagnos ic Conside a ions
Ina en ion
Impulsi i y/Hype ac i i y
Como bidi y – he ull spec um
sleep
p oblems
mo o p oblems
(DCD)
lea ning
diso de s
ODD en CD
ics and OCD
bipola
diso de
subs ance
use/
gambling
obesi y
au ism
spec um
diso de
(ASD)
anxie y and
dep ession ADHD
NLZYA00380a
Genes En i onmen
B ain
Clinical symp oms
Ac i i y
dependen
de elopmen
Compensa o y
p ocesses may
mask p ima y
de ici s
These neu ode elopmen al diso de s a e
hough o esul om he dis up ion o no mal
b ain de elopmen and ela ed neu obiological
mechanisms du ing he p ena al and ea ly
pos na al pe iod
The de elopmen al “snowball” olls downhill o e ime……
“
Ou come
”
?
…….ga he ing speed and mass (loadings o psychopa hology and a ypicali y).
“
Ou come
”
?
…….ga he ing speed and mass (loadings o psychopa hology and a ypicali y).
En i onmen al
In luences
Gene ic
P edisposi ions
Ma u a ion
Time
Bi h
“
Ou come
”
Child
’
s Own
Beha io
The de elopmen al pa hway o an indi idual
child e lec s no only gene ic endowmen and
en i onmen al e ec s, bu also he in e ac ions
among hese and he child
’
s own ac i i y o e
ime.
Time
P o ec i e and Suppo i e
Condi ions and
Ad e se E en s
Risks and
P o ec i e
Fac o s
Beha io
Bi h
“
Ou come
”
Ma u a ion and
Ma u a ional
Vulne abili ies
Gene ic
P edisposi ions
En i onmen al
In luences
Adap i e and
Maladap i e
Beha io s
In luences on de elopmen a e bo h posi i e
and ad e se. Likewise, he indi idual
’
s
beha io s o e ime a e bo h adap i e and
maladap i e.
Is ADHD in Adul s a Valid Diagnosis?
SYNDROMATIC
CONTINUITY
Family-Gene ic
S udies
T ea men
E ec i eness
Como bidi y and
Neu opsych
De ici s
Impai men s
Imaging
S udies
Causes o gene ic disease
(adap ed om McCa hy e al., 2008)
Ve y a e Ra e Uncommon Common
High
In e media e
Modes
Low Allele
equency
P ene ance
Monogenic
Diseases
Mul i-
ac o ial
diseases
0.10.010.001
Oligogenic
Diseases
Majo Ra e Va ian
Abou 5-10% o ADHD?
Figu e 1 The his o y o a en ion-de ici /hype ac i i y diso de
Fa aone, S. V. e al. (2015) A en ion-de ici /hype ac i i y diso de
Na . Re . Dis. P ime s doi:10.1038/n dp.2015.20
Fa aone e al. (2015). Na . Re . Dis. P ime s
doi:10.1038/n dp.2015.20
Twin s udies
Fa aone & La sson (2019) Molecula Psychia y, 24(4):562-575575
P e alence o ADHD in a e gene ic
condi ions
Fa aone & La sson (2019) Molecula Psychia y, 24(4):562-575575
Gize e al., 2009
3-5% o gene ic con ibu ion explained
by known isk alleles
XXXX
Ea ly de elopmen – ole o empe amen
Nigg e al. (2021) Annu Re De Psychol
Gene ics o ADHD –La es GWAS
Demon is (2019). Na u e Gene ics, 51, 63-75
Gene ics o ADHD –PRS-ADHD
Demon is (2019).
Na u e Gene ics, 51, 63-75
ADHD sha es gene ic ac o s wi h many o he ai s
Demon is (2019). Na u e Gene ics, 51, 63-75
Figu e 1 The his o y o a en ion-de ici /hype ac i i y diso de
Fa aone, S. V. e al. (2015) A en ion-de ici /hype ac i i y diso de
Na . Re . Dis. P ime s doi:10.1038/n dp.2015.20
Fa aone, S. V. e al. (2015) A en ion-de ici /hype ac i i y
diso de . Na . Re . Dis. P ime s doi:10.1038/n dp.2015.20
Do sola e al
PFC – wo king
memo y
Figu e 1 The his o y o a en ion-de ici /hype ac i i y diso de
Fa aone, S. V. e al. (2015) A en ion-de ici /hype ac i i y diso de
Na . Re . Dis. P ime s doi:10.1038/n dp.2015.20
Fa aone, S. V. e al. (2015) A en ion-de ici /hype ac i i y
diso de . Na . Re . Dis. P ime s doi:10.1038/n dp.2015.20
Rewa d sys em
Figu e 1 The his o y o a en ion-de ici /hype ac i i y diso de
Fa aone, S. V. e al. (2015) A en ion-de ici /hype ac i i y diso de
Na . Re . Dis. P ime s doi:10.1038/n dp.2015.20
Fa aone, S. V. e al. (2015) A en ion-de ici /hype ac i i y
diso de . Na . Re . Dis. P ime s doi:10.1038/n dp.2015.20
De aul mode
ne wo k
S uc u al MRI: subco ical and co ical di e ences
Hoogman e al. (2019). Am J Psychia y 176(7):531-542
S uc u al MRI
S op-signal ask
Van Rooij e al. Ame ican Jou nal o Psychia y 2015, 172(7):674-83
Van Rooij e al. Neu oimage Clinical 2015, 13;7:325-35.
S op-signal ask
Func ional connec i i y, ask pe o mance and ADHD
se e i y
Conclusions
•Longe S op Signal Reac ion Time (SSRT)
•Hypoac i a ion in Le IFG, node o inhibi ion ne wo k
•Al e ed neu al connec i i y in ADHD:
-hypo-connec i i y wi hin Response Inhibi ion Ne wo k
-hype -connec i i y wi hin De aul Node Ne wo k
•Le els o connec i i y a e ela ed o bo h esponse
inhibi ion pe o mance and ADHD pheno ype
•Neu al connec i i y p o ides impo an complemen a y
insigh in o he neu obiological unde pinnings o
esponse inhibi ion de ici s
Neu ophysiology
Co ela ions be ween diso de s in b ain abno mali ies
(7 subco ical and 34 co ical egions)
Radonjić e al, T ansla ional Psychia y, 2020
G ea e simila i y in b ain abno mali ies (7 subco ical and
34 co ical egions) be ween diso de s co ela es wi h
s onge gene ic co ela ion be ween diso de s
Radonjić e al, T ansla ional Psychia y, 2020
ADHD and S ess
Gene ics and Imaging
Gene ics
“
Gene ic sensi i i y o he en i onmen
”
Caspi e al. Science; 301:386–389 (2003).
In e ac ion be ween se o onin anspo e and
s ess / li e e en s
5-HTTLPR
S ess
B ain co ela es o he in e ac ion e ec
be ween he se o onin anspo e gene and
s ess exposu e media ing ADHD
Dennis an de Mee , Pie e J. Hoeks a, Ma cel Zwie s, Maa en Mennes, Lizanne J. Schwe en, Ba ba a F anke,
Di k J. Heslen eld, Jaap Oos e laan, S ephen V. Fa aone, Jan K. Bui elaa # & Ca ha ina A. Ha man #
Jou nal o Child Psychology Psychia y, 2014, Dec;55(12):1363-71
Ame ican Jou nal o Psychia y, 2015, Aug 1;172(8):768-75
Van de Mee e al. JCPP (2014).
Van de Mee e al. JCPP (2014).
ØAge
ØGende
ØSocio-economic s a us
ØScanning loca ion
Reg ession o s ess on he an e io cingula e olume
Conclusions
1. 5-HTTLPR mode a es he e ec s o s ess on GMV in se e al
on al egions in ol ed in social-cogni i e p ocesses and
cogni i e con ol1.
2. GMV o a eas in ol ed in cogni i e con ol media e he e ec
o he GxE on ADHD symp om coun .
1 Olson e al. B ain 2007, 130:1718-1731; Pessoa Na Re Neu osci.
2008, 9(2):148-58.
Summa y
• ADHD has a s ong gene ic componen
• ADHD is e y he e ogeneous a he
cogni i e and neu al le el
• Bo h delayed and de ian b ain
de elopmen
• Abno mali ies o on o-s ia al, on o-
pa ie al and on o-ce ebella ci cui s
• Cogni ion: mul iple pa hway model
Aims and objec i es o ea men
– Reduce co e symp oms o ADHD and au ism
– Reduce como bid symp oms
– Reduce isk o u he complica ions
– Educa e he pa ien and he en i onmen abou he
diso de
– Adap he en i onmen o he pa ien ’s needs
– Enhance pa ien , pa en , eache e al’s coping skills
– Change maladap i e iews
Mo e ca e han cu e
88
CAADRA pha macological ea men
ecommenda ions: child en (≥ 6 yea s),
adolescen s and adul s
• A combina ion o medica ion and psychosocial in e en ions is
ecommended
• Recommended pha macological ea men s a e unchanged om he
2011 Clinical P ac ice Guideline:
− 1s line: long-ac ing psychos imulan s (AMP, MPH and LDX)
− 2nd line/adjunc i e: non-s imulan s (ATX) and sho /in e media e
ac ing psychos imulan s (MPH and DEX)
−The non-s imulan GXR is a ailable o child en and
adolescen s only (6-17 yea s old)
− 3 d line: exceeding ecommended maximum doses o ea men
wi h o -label d ugs bup opion, clonidine, imip amine and
moda inil
AMP, amphe amine; ATX, a omoxe ine; DEX, dex oamphe amine; GXR, guan acine; LDX, lisdexam e amine; MPH, me hylphenida e
Canadian ADHD Resou ce Alliance (CADDRA): Canadian ADHD P ac ice Guidelines, 4 h Edi ion, To on o, ON; CADDRA, 2018. A ailable a :
h ps://www.cadd a.ca/canadian-adhd-p ac ice-guidelines/
In he 2018 guidelines, gene ic long-ac ing psychos imulan s a e conside ed 2nd line
agen s because o he unp edic abili y o esponse
Compa ison o du a ion o clinical e ec
be ween ADHD ea men s
Adap ed om Hazell. CNS D ugs. 2007;21(1):37-46.
School ac i i ies Ex acu icula , homewo k,
d i ing, pa - ime wo k
IR s imulan plus SR s imulan
SR s imulan plus IR s imulan
OROS me hylphenida e
A omoxe ine
0800 1000 1200 1400 1600 1800 2000 2200 2400
Time (h)
Guan acine
Non-s imulan s
• A omoxe ine
• Guan acine
• Bo h ac on he no ad ene gic
sys em
