Compulsivity and impulsivity are linked to distinct aberrant developmental trajectories of fronto-striatal myelination

TLDR: This transition period is characterised by brain-wide growth in MT, within both gray matter and adjacent juxta-cortical white matter, highlighting a brain developmental linkage for emergent psychiatric risk features, evident in regionally specific perturbations in the expansion of MT-related myelination.

Abstract: The transition from adolescence into adulthood is a period where rapid brain development coincides with a greatly enhanced incidence of psychiatric disorder. The precise developmental brain changes that might account for this emergent psychiatric symptomatology remains obscure. Capitalising on a unique longitudinal dataset, that includes in-vivo myelin-sensitive magnetization transfer (MT) MRI, we show this transition period is characterised by brain-wide growth in MT, within both gray matter and adjacent juxta-cortical white matter. The expression of common developmental psychiatric risk symptomatology in this otherwise healthy population, namely compulsivity and impulsivity, was tied to regionally specific aberrant unfolding of these MT trajectories. This was most marked in superior frontal/cingulate cortex for compulsivity, and in inferior frontal/insular cortex for impulsivity. The findings highlight a brain developmental linkage for emergent psychiatric risk features, evident in regionally specific perturbations in the expansion of MT-related myelination.

Figures

Figure 1. Developmental growth of myelin-sensitive MT into early adulthood. Transitioning into adulthood is characterised by profound increases in a myelin marker within cortical gray (a), white (b) and subcortical gray matter (c). Statistical maps of MT saturation show growth with time/visit (longitudinal) or age (cross-sectional; for specific effects of covariates, e.g. time/visit, age, sex, interactions etc., see supplementary information). (a) Gray matter MT growth (top row; statistical zmaps, p<.05 FDR corrected) is strongest in posterior and middle cingulate, but also present in lateral temporal, prefrontal and parietal cortex. Longitudinal model in posterior cingulate peak voxel (coloured lines in left data plot; x-axis: relative time of scan) and data (uncoloured) show an MT growth in both sexes, with a greater MT in females indicating a maturational advantage (see Supplementary Fig. 2c for region-specific sex differences, Supplementary Fig. 2d for sexual dimorphism of age-trajectories). Corresponding cross-sectional model predictions in the same region show a similar increase with age (right data plot; x-axis: mean age over visits). (b) MT growth in adjacent cortical white matter is most pronounced in cingulate and parieto-temporal cortex with topographical correspondence to the gray matter MT effects. (c) Subcortical structures express MT growth in striatum, pallidum, thalamus and hippocampus (not shown). This growth is most pronounced in posterior striatum suggesting ongoing myelin-related growth in both cortical and subcortical brain structures.

Figure 2. The relation between macrostructural and microstructural brain development. (a) Coronal sections through prefrontal (left panels), striatal (middle) and thalamus (right; MNI: y=15, 12, -14) show more myelin-related MT in white than in gray matter with a clearly preserved whitegray matter boundary (top row). Developmental change in MT (second row) shows an increase in myelin marker in both tissues, with a stronger growth in gray matter areas. Developmental change in macrostructural brain volume (third row) shows a characteristic cortical shrinkage (blue colours) in gray, but an expansion in white matter (red colours; cf Supplementary Fig. 3). Only hippocampal gray matter shows an opposite effect with continuing gray matter growth on the verge of adulthood. (b) Association between microstructural myelin growth and macrostructural volume change. A positive association throughout white matter supports the notion that myelination contributes to white matter expansion. In gray matter, a predominantly negative association in deep layers advocates for partial volume effects at the tissue boundary and positive associations in superficial layers (correlation was obtained from posterior covariance of beta parameters in sandwich estimator model simultaneously including longitudinal observations of both imaging modalities). (c) Association as a function of Euclidean distance to GM/WM boundary. Microstructural growth (top row) shows consistent myelinrelated growth in both tissues, but opposite macrostructural volume change (middle row). Association between micro- and macrostructural growth is positive in white matter, independent of distance. In gray matter, the mean association changes from negative in deep layers (i.e. myelin MT change associated with reduced gray matter volume) to more positive associations in superficial layers (i.e. MT associated with a tendency to more gray matter volume).

Figure 3. Compulsivity is related to altered fronto-striatal MT growth. Longitudinal developmental change of our myelin marker is reduced in high compulsive subjects. (a) Aggregate compulsivity score is related to decreased MT growth in superior frontal gyrus gray matter (upper panel; z-value=5.3, p<.0022, FDR corrected) and adjacent white matter including cingulate cortex (lower panel; blue colours depicting negative time by compulsivity interactions). Subjects with higher compulsivity scores (light yellow) compared to low scoring subjects (dark red) express significantly less MT growth over visits (coloured lines in right panel indicate the interaction effect; x-axis: time of scan in years relative to each subject’s mean age over visits). (b) The above slowing in cortical myelin-related growth is mirrored by a decreased developmental growth in subcortical ventral striatum (left panel) and the adjacent white matter (right panel). These findings indicate young people with high compulsive traits express slower maturational myelin-related change in a fronto-striatal network comprising cingulate cortex and ventral striatum. (c) More compulsive subjects showed locally increased baseline myelin marker (peak supplemental motor area, z-value=3.81, cluster FDR p<0.04,) in the medial wall. Right panel shows the plot of MT in this peak voxel over compulsivity (x-axis, z-scored) and with adjusted data (gray/black) and model predictions (red/orange, effects of interest: intercept, compulsivity, sex by compulsivity).

Figure 4. Decreased frontal growth in myelin-sensitive MT in impulsivity. Our myelin marker in frontal lobe is tied to impulsivity traits. (a) Impulsivity is associated with a reduced growth of MT in lateral (inferior and middle frontal gyrus), medial prefrontal areas (and motor/premotor and frontal pole) and anterior insula in both gray (top panel) and adjacent white matter (bottom panel) depicting negative time by impulsivity interactions (z maps, p<.05 FDR corrected). Plot shows that subjects with higher impulsivity (light yellow) compared to low scoring subjects (dark red) express significantly less MT growth over visits (coloured lines in right panel indicate the interaction effect; x-axis: time of scan in years relative to each subject’s mean age over visits). (b) More impulsive subjects showed locally decreased baseline myelin marker (peak middle frontal gyrus, z-value=4.33, p<0.027, FDR) in lateral frontal areas (fixed for other covariates, e.g. time/visits, mean age of subject, sex). Right panel shows the plot of MT in this peak voxel over impulsivity (x-axis, z-scored) and with adjusted data (gray/black) and model predictions (red/orange, effects of interest: intercept, impulsivity, sex by impulsivity). (c) Bilateral IFG not only shows a reduced myelination process for higher impulsivity (as shown in a, b), but this reduced growth rate is more strongly expressed in subjects who manifest an accentuated impulsivity growth over study visits, such that subjects who manifest an even more restricted growth in myelin become more impulsive.

Full text

1
Compulsivity and impulsivity are linked to distinct aberrant developmental trajectories
of fronto-striatal myelination
Gabriel Ziegler
1,2,3,4,*
, Tobias U. Hauser
1,2,*
, Michael Moutoussis
1,2
, Edward T.
Bullmore
5,6,7,8
, Ian M. Goodyer
5,6
, Peter Fonagy
9
, Peter B. Jones
5,6
, NSPN Consortium
10
,
Ulman Lindenberger
1,11
& Raymond J. Dolan
1,2
1
Max Planck University College London Centre for Computational Psychiatry and Ageing Research,
London WC1B 5EH, United Kingdom
2
Wellcome Centre for Human Neuroimaging, University College London, London WC1N 3BG,
United Kingdom
3
Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke-University
Magdeburg, 39120 Magdeburg, Germany
4
German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany
5
Department of Psychiatry, University of Cambridge, Cambridge CB2 0SZ, United Kingdom
6
Cambridgeshire and Peterborough National Health Service Foundation Trust, Cambridge CB21 5EF,
United Kingdom
7
Medical Research Council/Wellcome Trust Behavioural and Clinical Neuroscience Institute,
University of Cambridge, Cambridge CB2 3EB, United Kingdom
8
ImmunoPsychiatry, GlaxoSmithKline Research and Development, Stevenage SG1 2NY, United
Kingdom
9
Research Department of Clinical, Educational and Health Psychology, University College London,
London WC1E 6BT, United Kingdom
10
A complete list of the NSPN Consortium members can be found in the supplementary information
11
Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany
* These authors contributed equally to this work
Correspondence
Tobias U. Hauser
Max Planck UCL Centre for Computational Psychiatry and Ageing Research
University College London
10-12 Russell Square
London WC1B 5EH
United Kingdom
Phone: +44 / 207 679 5264
Email: t.hauser@ucl.ac.uk
Gabriel Ziegler
Institute of Cognitive Neurology and Dementia Research
German Center for Neurodegenerative Diseases (DZNE)
Otto-von-Guericke-University Magdeburg
Leipziger Str. 44
39120 Magdeburg
Germany
Phone: +49 / 391 67 250 54
Email: gabriel.ziegler@dzne.de
.CC-BY-NC-ND 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
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2
Abstract
The transition from adolescence into adulthood is a period where rapid brain
development coincides with an enhanced incidence of psychiatric disorder. The precise
developmental brain changes that account for this emergent psychiatric symptomatology
remain obscure. Capitalising on a unique longitudinal dataset, that includes in-vivo myelin-
sensitive magnetization transfer (MT) MRI, we show this transition period is characterised by
brain-wide growth in MT, within both gray matter and adjacent juxta-cortical white matter.
We show that an expression of common developmental psychiatric risk symptomatology in
this otherwise healthy population, specifically compulsivity and impulsivity, is tied to
regionally specific aberrant unfolding of these MT trajectories. This is most marked in frontal
midline structures for compulsivity, and in lateral frontal areas for impulsivity. The findings
highlight a brain developmental linkage for emergent psychiatric risk features, evident in
regionally specific perturbations in the expansion of MT-related myelination.
.CC-BY-NC-ND 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
The copyright holder for this preprint (which was notthis version posted July 26, 2018. ; https://doi.org/10.1101/328146doi: bioRxiv preprint

3
Introduction
Structural brain development extends into adulthood, particularly so in regions that
mediate higher cognition such as prefrontal cortex
1
. A canonical view is that this maturation
is characterised by regional shrinkage in gray matter coupled to an expansion of white
matter
2
. However, the underlying microstructural processes remain obscure. Two candidate
mechanisms have been proposed
3
namely synaptic loss (pruning) to reduce supernumerary
connections, and an increase in myelination to enhance communication efficiency. Both
accounts receive some support from cross-sectional and ex-vivo studies
4–7
. There are
substantial inter-individual differences in these growth trajectories
8
, and the most marked
changes occur within an age window where the emergence of psychiatric disorder becomes
increasingly common
9,10
. This raises a possibility that psychiatric risk is tied to altered
maturational brain trajectories during this critical developmental period
11,12
.
Compulsivity and impulsivity are two fundamental psychiatric dimensions
13
and
show a substantial variation in expression within a ‘healthy’ population (Supplementary Fig.
1a-e). At their extreme these features manifest as obsessive-compulsive disorder (OCD) and
attention-deficit/hyperactivity disorder (ADHD) respectively. Macrostructural and cross-
sectional studies suggest a link to deficits in fronto-striatal regions
14–17
, but leave unanswered
the question of whether compulsivity and impulsivity reflect consequences of aberrant
developmental microstructural processes.
Here, we used semi-quantitative structural MRI
18
to investigate how microstructural
brain development unfolds during a transition into adulthood, and how individual variability
in these developmental trajectories is linked to compulsive and impulsive traits
(Supplementary Fig. 1f-g). We used a novel magnetic transfer saturation (MT) imaging
protocol to provide an in-vivo marker for macromolecules, in particular myelin
19,20
.
Importantly, MT saturation has been shown to be a more direct reflection of myelin
.CC-BY-NC-ND 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
The copyright holder for this preprint (which was notthis version posted July 26, 2018. ; https://doi.org/10.1101/328146doi: bioRxiv preprint

4
compared to other imaging protocols, such as magnetization transfer ratio
21,22
. It also is
sensitive to developmental effects
7
which renders it ideal for tracking patterns of brain
maturation within longitudinal studies involving repeated scanning of participants, a crucial
feature for characterising development
23
. Using such a protocol, we show that during late
adolescence and early adulthood cingulate cortex expresses the strongest myelin-related
growth, both within gray and adjacent white matter. Individual differences in compulsivity
are reflected in the rate of this growth in cingulate and superior frontal regions. This
contrasts with impulsivity, which was associated with reduced myelin-related growth in
lateral prefrontal cortex. Our results suggest that compulsivity and impulsivity traits within
the healthy population may reflect a regionally specific consequence of differential unfolding
of myelin growth trajectories.
.CC-BY-NC-ND 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
The copyright holder for this preprint (which was notthis version posted July 26, 2018. ; https://doi.org/10.1101/328146doi: bioRxiv preprint

5
Results
Ongoing myelin-related growth at the edge of adulthood
To assess developmental trajectories of myelin-sensitive MT, we carried out repeat
scanning in 299 adolescents and young adults aged 14–24 years, up to three times in all,
with an average follow-up time of 1.3±0.32 years (mean±SD) in an accelerated longitudinal
design (1 scan: N=103, 2 scans: N=172, 3 scans: N=24. The sample was gender balanced and
consisted otherwise healthy subjects (excluding self-reported illness a priori to avoid illness-
related confounds, such as medication effects) selected to be approximately representative of
the population (cf online methods for details).
Examining whole-brain maturation in gray matter revealed a brain-wide increase in
myelin-related MT, with a focus within cingulate, prefrontal and temporo-parietal areas (Fig.
1a, p<.05 false-discovery rate [FDR] peak corrected; merging cross-sectional and
longitudinal effects, separate effects shown in Supplementary Fig. 2a-b; mean±SD:
0.55±0.19% per year; max z-value voxel in posterior cingulate: 0.98% per year;
Supplementary Table 1). This change was accompanied by increased MT in adjacent (juxta-
cortical) superficial white matter, most pronounced in the exact same areas (Fig. 1b,
mean±SD: 0.45±0.15% per year; max z-value voxel in posterior cingulate with 0.95% per
year), consistent with the idea that connections within gray and white matter are myelinated
in concert. Similar, albeit less pronounced, microstructural maturation was observed in
subcortical areas such as posterior striatum, pallidum and dorsal thalamus (Fig. 1c). These
findings highlight that myelin-related development in both cortical and subcortical areas is a
marked feature of a transition from adolescence into adulthood, and is likely to involve both
local and inter-regional fibre projections.
.CC-BY-NC-ND 4.0 International licensea
certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under
The copyright holder for this preprint (which was notthis version posted July 26, 2018. ; https://doi.org/10.1101/328146doi: bioRxiv preprint

Frequently asked questions

Q1. What have the authors contributed in "Compulsivity and impulsivity are linked to distinct aberrant developmental trajectories of fronto-striatal myelination" ?

These authors contributed equally to this work 

Q2. What are the two mechanisms proposed to reduce supernumerary connections?

Two candidate mechanisms have been proposed3 namely synaptic loss (pruning) to reduce supernumerary connections, and an increase in myelination to enhance communication efficiency. 

Q3. What is the effect of a different trajectories on myelin growth?

Their results suggest that compulsivity and impulsivity traits within the healthy population may reflect a regionally specific consequence of differential unfolding of myelin growth trajectories. 

Q4. What is the effect of myelination on the volume of gray matter?

In deeper layers, close to the gray-white matter boundary, ongoing myelination appears to contribute to an inflated estimate of volume reduction, where a myelin-induced ‘whitening’ of gray matter can result in a misclassification of gray matter voxels (i.e. partial volume effects24), leading to an apparent volume reduction. 

Q5. What are the main characteristics of compulsivity and impulsivity?

As compulsivity and impulsivity are primarily associated with deficits in frontal and striatal networks14, the authors constrained the analyses of these psychiatric dimensions to striatal and prefrontal regions (cf supplementary information). 

Q6. What is the positive association between these measures in white matter?

The positive association between these measures in white matter suggests that macrostructural volume change is, at least in part, driven by myelination. 

Q7. What is the effect of adolescence on myelin-sensitive growth?

These findings highlight that myelin-related development in both cortical and subcortical areas is a marked feature of a transition from adolescence into adulthood, and is likely to involve both local and inter-regional fibre projections. 

Q8. What was the correlation between compulsivity and impulsivity?

Compulsivity and impulsivity trait measures showed a very minor correlation r=0.119 in the large behaviouralsample, supporting a notion of rather independent dimensions (less than 1.4% shared variance). 

Q9. What metric allows to assess how a trait relates to a trait?

The latter metric allows to assess how MT growth is associated with compulsivity and impulsivity trait (e.g. lower MT growth in high compulsives), whereas the former indicates how a trait relates to overall MT differences across individuals, independent of all other covariates (time, mean age of a subject over all scans, sex, etc.). 

Q10. What is the link between compulsivity and developmental trajectories?

This suggests that compulsivity might be linked to distinct developmental trajectories, with a pre-adolescent hypermyelination in motor-related areas and a decreased myelination during adolescence in cingulate and frontopolar regions. 

Q11. What is the relationship between the depth and the volume of gray matter?

In gray matter, depth-dependent associations suggest that macrostructural volume reduction in adolescence is the result of multiple microstructural processes.