A review of recent evidences for macroscopic reorganisation from in vivo imaging studies. This presentation focuses on the neuroplastic changes of white matter and the possible mechanisms behind this.

1. A review of evidences for macroscopic reorganisation
from in vivo imaging studies
Written by András Jakab
University of Debrecen / ETH Zürich
Contact: jakab@vision.ee.ethz.ch

2. Overview
 The recent advent of in vivo imaging
techniques like diffusion tensor or
functional magnetic resonance imaging
gave rise to studies that „reinvent”
classical or forgotten aspects of the human
macroscopic brain anatomy
 One such topic is to investigate the
structure of major white matter structures
and their connections („hodology”- Catani,
2007), this new-old aim was electrified by
the diffusion weighted and diffusion
tensor imaging (the former now An illustration of the arcuate fasciculus
celebrating 25th anniversary: Johansen- signifies the role of neuroimaging in
Berg et al., 2012) anatomical studies
Catani M (2007) From hodology to function. Brain 130: 602-605.
Le Bihan D, Johansen-Berg H (2012) Diffusion MRI at 25: Exploring brain tissue
structure and function. Neuroimage, in press

3. Overview
 The brain’s response to reinforced stimuli and adaptation to a changing
environment is considered the backbone of neuroplasticity, which is predominantly
understood as the synaptic reorganization within the cortex
 Significant effort is now carried out to reveal
macroscopic changes to the brain structure
after learning tasks, which vastly challenges
the classical views of neuroplasticity as a
phenomenon embedded in the electrical and
chemical milieu
 We aimed at reviewing studies that convey
evidence for the possible macroscopic change
after extensive learning tasks or challenging
environments. We focused on imaging studies
describing changes to white matter structure
and studies that try to elucidate the possible
mechanisms that realize and modulate such
an effect.
Illustration by H. Cushing

4. Plastic changes in grey matter thickness
 3 months of intensive juggling training is performed in a group of 12 people
whereas 12 controls are provided as „non-jugglers” (experiment: 3-ball cascade
juggling)
 Voxel-based morphometry is employed to reveal fine changes of grey matter
volume on anatomical MR images
 Transient changes take place in grey matter in specific motion-selective areas
 Though the microscopic
changes underlying dynamic
structural alterations remain
unclear
Figure by Draganski et al.
Draganski B, Gaser C, Busch V, Schuierer G, Bogdahn U, May A (2004): Neuroplasticity:
Changes in grey matter induced by training. Nature 427: 311-312.

5. Plastic changes in grey matter thickness
 Licensed London taxi drivers with
extensive navigation experience were
analyzed and compared with those of
control subjects who did not drive taxis
 Voxel-based morphometry is employed to
reveal fine changes of grey matter volume
on anatomical MR images
 Key findings included:
 The posterior hippocampi of taxi
drivers were significantly larger
 Hippocampal volume correlated with
the amount of time spent as a taxi
driver (positively in the posterior and
negatively in the anterior
hippocampus) Figure by Maguire et al.
Maguire EA, Gadian DG, Johnsrude IS, Good CD, Ashburner J, Frackowiak RSJ, Frith CD
(2000): Navigation-related structural change in the hippocampi of taxi drivers.
Proceedings of the National Academy of Sciences 97: 4398-4403.

6. Plastic changes in white matter properties
 Experience-dependent structural changes have been found in adult gray matter,
there is little evidence for such changes in white matter
 A longitudinal study with juggling training is conducted in a group of 24+24
human subjects, DTI is used to quantify the changes in diffusion anisotropy
 The anisotropy, i.e. the orderedness of diffusion is increased after training,
located in the parieto-occipital sulcus
Figure by Scholz et al.
Scholz J, Klein MC, Behrens TEJ, Johansen-Berg H (2009): Training induces changes in
white-matter architecture. Nat Neurosci 12: 1370-1371.

7. Plastic changes in white matter properties
 They examined whether 100 hr of intensive remedial instruction affected the
white matter of 8- to 10-year-old poor readers
 Prior to instruction, poor readers had significantly lower FA than good readers in a
region of the left anterior centrum semiovale
 Poor readers were given remedial instruction
which helps to improve reading skills
 The region where significant difference was
found between poor and normal readers
coincides with the region which showed FA
increase after the mediation
 FA increased, meaning an increased orderedness
of axonal diffusion (mechanism unkown)
Figure by Keller et al.
Keller TA, Just MA (2009): Altering Cortical Connectivity: Remediation-Induced Changes
in the White Matter of Poor Readers. Neuron 64: 624-631.

8. Learning-related white matter properties
 The following studies give indirect evidence that
long („lifelong”) conditioning induce macroscopic
changes in white matter structure or affect
development
 The time-dependency and timecourse of such
changes is not yet understood
 Diverse regions are reported to repond to these
stimuli by increased diffusion anisotropy values
Imfeld A, Oechslin MS, Meyer M, Loenneker T, Jancke L (2009): White matter plasticity in
the corticospinal tract of musicians: A diffusion tensor imaging study. Neuroimage 46: 600-
607.
Bengtsson SL, Nagy Z, Skare S, Forsman L, Forssberg H, Ullen F (2005): Extensive piano
practicing has regionally specific effects on white matter development. Nat Neurosci 8:
1148-1150.
Lee B, Park J, Jung WH, Kim HS, Oh JS, Choi C, Jang JH, Kang D, Kwon JS (2010): White
matter neuroplastic changes in long-term trained players of the game of “Baduk” (GO): A
voxel-based diffusion-tensor imaging study. Neuroimage 52: 9-19.

9. Plastic changes in white matter properties
 Using voxel-based analysis (VBA) of
fractional anisotropy (FA) measures
of fiber tracts, the authors
investigated the effect of working
memory training on structural
connectivity in an interventional
study
 The amount of working memory
training correlated with increased
FA in the white matter regions
adjacent to the intraparietal sulcus
and the anterior part of the body of
the corpus callosum after training.
Figure by Takeuchi et al.
Takeuchi H, Sekiguchi A, Taki Y, Yokoyama S, Yomogida Y, Komuro N, Yamanouchi T,
Suzuki S, Kawashima R (2010): Training of Working Memory Impacts Structural
Connectivity. The Journal of Neuroscience 30: 3297-3303.

10. White matter plasticity in adults and the elderly?
 If the hypothesis is justifiable that anisotropy (FA)
increase is the sign of plastic changes in white
matter, it still remains unclear if this ability is
available through the entire lifespan
 Over a period of 180 days training, Lövdén and
colleagues revealed that white matter changes
were presend in older subjects as well (indicated
by a slight increase in axial diffusivities (i.e.
diffusion magnitude along the axonal direction)
 The potential application relying on such basic
knowledge is of vast importance for the
rehabilitation science
Figure by Lövdén et al.
Lövdén M, Bodammer NC, Kühn S, Kaufmann J, Schütze H, Tempelmann C, Heinze H,
Düzel E, Schmiedek F, Lindenberger U (2010): Experience-dependent plasticity of
white-matter microstructure extends into old age. Neuropsychologia 48: 3878-3883.

11. Plastic changes affected diffusion anisotropy.
Where does anisotropy originate from?
 Two major mechanisms were found to affect
anisotropy:
 The dense packaging of axons where the
cell membranes delimit diffusion (90%
effect)
 Myelin sheet: myelin layers affect
diffusion anisotropy (approx. 10% effect)
 Neither neurofilaments nor intracellular
organella affects anisotropy according to
experimental studies
Figures by Beaulieu et al.
Beaulieu C (2002): The basis of anisotropic water diffusion in the nervous system ? a
technical review. NMR Biomed 15: 435-455.

12. Age related changes of white matter anisotropy
 White matter anisotropy changes during development until adulthood
 Different regions follow different myelination patterns relative to each other, some areas
continuing changes in the 20s
 However, the potential to dynamically change myelination in the adulthood is
questionable
Figure by Jakab et al.
Schmithorst VJ, Wilke M, Dardzinski BJ, Holland SK (2002) Correlation of white matter
diffusivity and anisotropy with age during childhood and adolescence: a cross-sectional
diffusion-tensor MR imaging study. Radiology. 222(1):212-8.

13. Possible mechanisms for white matter
neuroplastic chages
 Significant changes in the axonal membrane structure
or new growth of axons are not viable and unproven
mechanisms for neuroplastic changes in white
matter
 It has been proposed that learning-associated
myelination could be responsible for the
observations
 Synaptic efficiency could be regulated by changing
the transmission speed of axons by modifying myelin Figure by Bengtsson et al.: piano
content; „wiring together” could therefore mean a practice improves FA values in
commissural pathways.
more efficient synchronization of remote connections
Fields RD (2005): Myelination: An Overlooked Mechanism of Synaptic Plasticity? The
Neuroscientist 11: 528-531.
Ishibashi T, Dakin KA, Stevens B, Lee PR, Kozlov SV, Stewart CL, Fields RD (2006):
Astrocytes Promote Myelination in Response to Electrical Impulses. Neuron 49: 823-
832.

14. Possible mechanisms for white matter
neuroplastic chages
 Oligodendrocytes mediate the myelin production in response to electrical signals,
insulating the axon
Electrically active axons signal adjacent
oligodendrocytes, triggering local cellular
signaling pathways that promote specific
myelination of active axons. Vesicular
glutamate released from axons signals
neighboring oligodendrocytes to form
cholesterol-rich signaling domains and locally
produce myelin basic protein.
Araque A, Navarrete M (2011): Electrically Driven Insulation in the Central Nervous
System. Science 333: 1587-1588.
H. Wake, P. R. Lee, R. D. Fields (2011) Control of Local Protein Synthesis and Initial
Events in Myelination by Action Potentials Science 333, 1647.

15. Perspectives
 In vivo imaging delivered interesting
but contradictory results on the
possible changes of white matter
during neuroplasticity
 It is not yet obvious which
mechanisms are most responsible for
this effect
 Myelination is potentially modulated
in the adulthood representing a
meaningful way to retune and
synchronize brain circuits
 Still far from the practical application
of this knowledge, there is no mean to
intervene into this mechanism to
facilitate better brain regeneration
after neuronal (axonal) loss
Horacio Salinas: „Brain Repair” for
the New York Time Magazine