Functional Connectivity of Substantia Nigra and Ventral Tegmental Area: Maturation During Adolescence and Effects of ADHD
Cerebral Cortex April 2014;24:935–944
doi:10.1093/cercor/bhs382
Advance Access publication December 12, 2012
Functional Connectivity of Substantia Nigra and Ventral Tegmental Area: Maturation
During Adolescence and Effects of ADHD
Dardo Tomasi1,2 and Nora D. Volkow1,2,3
1
National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA, 2Medical Department, Laboratory of Neuroimaging
(LNI/NIAAA), Brookhaven National Laboratory, Upton, NY 11973, USA and 3National Institute on Drug Abuse, Bethesda, MD
20892, USA
Address correspondence to Dardo Tomasi, PhD, Medical Department, Laboratory of Neuroimaging (LNI/NIAAA), Bldg 490, Brookhaven National
Laboratory, 30 Bell Ave., Upton, NY 11973, USA. Email:
Keywords: addiction, attention-deficit/hyperactivity disorder, connectivity,
dopamine, maturation
Introduction
The transition from childhood into adolescence is characterized by a dramatic increase in risk-taking behaviors (Steinberg
2008) and the emergence of various psychiatric disorders
(Paus et al. 2008). Developmental changes in brain dopamine
(DA) networks are likely contributing factors since they
modulate both risk-taking behaviors and some of the neuropsychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and addiction (Lewis 1997;
Volkow et al. 2009).
Whereas aging is associated with a significant decline in
markers of DA neurotransmission in the human brain (receptors, transporters, and DA synthesis), most of the studies
focused on adult subjects whether from imaging (Volkow
et al. 2000) or from postmortem brains (Scherman et al.
1989), and few studies have assessed the effect of age in the
transition from childhood to adulthood. Nevertheless, there is
evidence of an age-related decrease in cortical DA D1 receptors in adolescence (Jucaite et al. 2010), of abnormalities in
markers of DA neurotransmission (Swanson et al. 2000), and
of functional connectivity in limbic DA pathways in adolescents with ADHD (Tomasi and Volkow 2012a). However, our
knowledge regarding the maturation of DA pathways in the
Published by Oxford University Press 2012.
human brain from childhood into adulthood is still very
limited.
Studies that combined resting-state functional connectivity
(RSFC), a technique based on spontaneous brain activity captured during brief (3–6 min) magnetic resonance imaging
(MRI) scanning that is extensively used to evaluate functional
coupling between brain regions, with positron emission tomography (PET), a technique that allows to measure molecular
targets involved in DA signaling, have corroborated a role of
DA in brain functional connectivity across striatocortical pathways (Kelly et al. 2009; Cole et al. 2011; Rieckmann et al.
2011). Recent studies have shown that RSFC can predict individuals’ brain maturity across development (Dosenbach et al.
2010) and that RSFC is sensitive to aging effects during adulthood (Tomasi and Volkow 2011a). The functional connectivity of striatocortical pathways was recently reported using
RSFC (Di Martino et al. 2008), but the connectivity patterns of
DA midbrain nuclei have not been mapped nor have the
effects of development on DArgic networks been evaluated in
the human brain.
Here, we aimed to evaluate the maturation of functional
connectivity of the ventral tegmental area (VTA; midbrain DA
neurons that give rise to the mesocorticolimbic pathway) and
the substantia nigra (SN; midbrain DA neurons that give rise
to the nigrostriatal pathway) using RSFC datasets from typically developing healthy children (TDC) and healthy adults.
We hypothesized that the VTA would show functional connectivity with the ventral striatum (including nucleus accumbens,
NAc) and limbic (amygdala and hippocampus) and prefrontal
regions and that the SN would show connectivity with dorsal
striatum (caudate and putamen) and motor cortex. We further
hypothesized that RSFC patterns with VTA and SN would be
highly reproducible across research institutions and that their
strength in childhood would differ from those in young adulthood. To assess the sensitivity of these pathways to disruption
by developmental psychiatric disorders, we also evaluated the
RSFC of VTA and SN in ADHD children. We expected more
accentuated RSFC differences between ADHD children and
young adults than those observed for TDC.
Materials and Methods
Datasets
A total of 1420 “resting-state” functional scans that corresponded to
714 healthy young adults (321 males and 393 females; age = 23 ± 5;
mean ± SD) from 15 research sites of the 1000 functional connectomes
project (FCP) (http://www.nitrc.org/projects/fcon_1000/; research
Dopaminergic (DArgic) pathways play crucial roles in brain function
and their disruption is implicated in various neuropsychiatric diseases. Here, we demonstrate in 402 healthy children/adolescents
(12 ± 3 years) and 704 healthy young adults (23 ± 5 years) that the
functional connectivity of DA pathways matures significantly from
childhood to adulthood and is different for healthy children and children with attention-deficit/hyperactivity disorder (ADHD; N = 203;
12 ± 3 years). This transition is characterized by age-related increases in the functional connectivity of the ventral tegmental area
(VTA) with limbic regions and with the default mode network and
by decreases in the connectivity of the substantia nigra (SN) with
motor and medial temporal cortices. The changes from a predominant influence of SN in childhood/adolescence to a combined influence of SN and VTA in young adulthood might explain the
increased vulnerability to psychiatric disorders, such as ADHD,
early in life. We also show that VTA and SN connectivity networks
were highly reproducible, which highlights their potential value as
biomarkers for evaluating DArgic dysfunction in neuropsychiatric
disorders.
Table 1
Demographic data and imaging parameters for all 714 healthy subjects from the 1000 FCP image
repository (321 males, M and 393 females, F), 459 TDC (244 males and 215 females), and 247
children with ADHD (197 males and 50 females) from the ADHD-200 image repository
Dataset
Males
Females
Age
B (T)
Tp
TR (s)
19
8
20
75
13
75
22
16
17
9
8
12
2
11
14
2
15
0
122
13
123
8
21
18
10
12
10
15
7
17
15–41
20–40
19–38
18–26
23–44
18–30
20–27
20–42
20–32
21–39
18–46
20–35
22–46
21–34
21–29
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
295
127
265
225
195
119
215
195
145
135
175
175
235
190
127
2.0
2.5
2.0
2.0
2.3
3.0
2.2
2.3
2.0
2.0
2.0
2.0
2.0
2.1
2.5
34
45
17
71
45
32
27
51
25
45
40
27
8–13
7–18
7–12
8–15
10–20
7–22
3.0
3.0
3.0
3.0
3.0
3.0
124
176
78
195
200
135
2.5
2.0
2.5
2.5
1.5
2.5
10
92
24
71
12
23
10
5
8–13
7–18
7–12
8–15
3.0
3.0
3.0
3.0
124
176
78
195
2.5
2.0
2.5
2.5
B: magnetic field strength; Tp: number of imaging time points; TR: MRI repetition time.
sites that included 46 years/older participants were excluded from the
study) and 459 TDC (244 males and 215 females; age = 12 ± 3), and
247 ADHD children ( (...truncated)
