Brain Imaging and Behavior

, Volume 12, Issue 6, pp 1730–1741 | Cite as

Motor and extra-motor gray matter integrity may underlie neurophysiologic parameters of motor function in amyotrophic lateral sclerosis: a combined voxel-based morphometry and transcranial stimulation study

  • Foteini ChristidiEmail author
  • Efstratios Karavasilis
  • Georgios Velonakis
  • Michail Rentzos
  • Thomas Zambelis
  • Vasiliki Zouvelou
  • Sophia Xirou
  • Panagiotis Ferentinos
  • Efstathios Efstathopoulos
  • Nikolaos Kelekis
  • Ioannis Evdokimidis
  • Nikolaos Karandreas


The association between gray matter (GM) density and neurophysiologic changes is still unclear in amyotrophic lateral sclerosis (ALS). We evaluated the relationship between GM density and motor system integrity combining voxel-based morphometry (VBM) and transcranial magnetic stimulation (TMS) in ALS. We included 17 ALS patients and 22 healthy controls (HC) who underwent 3D-T1-weighted imaging. Among the ALS group, we applied left motor cortex single-pulse TMS. We used whole-brain VBM comparing ALS and HC in GM density. We also conducted regression analysis to examine correlations between GM density and the following TMS parameters: motor evoked potential (MEP)/M ratio and central motor conduction time (CMCT). We found significantly decreased GM density in ALS patients in several frontal, temporal, parietal/occipital and cerebellar regions (p < 0.001 uncorrected; cluster-extent threshold k = 100 voxels per cluster). With regards to TMS parameters, ALS patients showed mostly increased MEP/M ratio and modest prolongation of CMCT. MEP/M ratio was associated with GM density in (a) rolandic operculum/inferior frontal gyrus/precentral gyrus; anterior cingulate gyrus; inferior temporal gyrus; superior parietal lobule; cuneus; superior occipital gyrus and cerebellum (positive association) and (b) paracentral lobule/supplementary motor area (negative association). CMCT was associated with GM density in (a) inferior frontal gyrus and middle cingulated gyrus (positive association) and (b) superior parietal lobule; cuneus and cerebellum (negative association). Our findings support a significant interaction between motor and extra-motor structural and functional changes and highlight that motor and extra-motor GM integrity may underlie TMS parameters of motor function in ALS patients.


Amyotrophic lateral sclerosis Voxel-based morphometry Gray matter density Transcranial magnetic stimulation Motor Action 



Amyotrophic lateral sclerosis


Revised Amyotrophic Lateral Sclerosis Functional Rating Scale


Abductor pollicis brevis


Behavioral variant of frontotemporal dementia


Central motor conduction time


Cerebrospinal fluid


Continuous theta burst stimulation




Functional magnetic resonance imaging


Family-wise error




Gray matter


Healthy control


High resolution 3D–T1-weighted


Lower motor neuron


Motor evoked potentials


Montreal Neurological Institute


Magnetic resonance imaging


Motor threshold


Resting motor threshold


Supplementary motor area


Statistical Parametric Mapping


T2-Fluid attenuation inversion recovery


Echo time


Total intracranial volume


Transcranial magnetic stimulation


Time of repetition


Triple-stimulation technique


Upper motor neuron


Voxel-based morphometry


White matter



The study did not receive any funding. F.C. was supported by the IKY FELLOWSHIPS OF EXCELLENCE FOR POSTGRADUATE STUDIES IN GREECE - SIEMENS PROGRAM (SPHA:11118/13a) and IKY SHORT TERMS PROGRAM (2013-ΠΕ2-SHORT TERMS-18671). We acknowledge Odysseas Benekos, Giannis Spandonis and the Philips Medical System for providing all necessary research keys for MRI sequence acquisition. We also acknowledge the radiologists-technologists of Research Radiology & Medical Imaging Department (Ioannis Gkerles, Christos Lioulios, Anestis Passalis, Efstathios Xenos) for conducting participants’ MR scanning. Finally, we would like to thank patients with ALS and their families, as well as healthy volunteers for their willingness to participate to the present study.

Compliance with ethical standards

Ethical publication statement

We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Conflict of interest

The authors declare no conflicts of interest.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Foteini Christidi
    • 1
    Email author
  • Efstratios Karavasilis
    • 2
  • Georgios Velonakis
    • 2
  • Michail Rentzos
    • 1
  • Thomas Zambelis
    • 1
  • Vasiliki Zouvelou
    • 1
  • Sophia Xirou
    • 1
  • Panagiotis Ferentinos
    • 3
  • Efstathios Efstathopoulos
    • 2
  • Nikolaos Kelekis
    • 2
  • Ioannis Evdokimidis
    • 1
  • Nikolaos Karandreas
    • 1
  1. 1.First Department of Neurology, Aeginition Hospital, Medical SchoolNational & Kapodistrian University of AthensAthensGreece
  2. 2.Radiology and Medical Imaging Research Unit, Second Department of Radiology, Medical SchoolNational & Kapodistrian University of AthensAthensGreece
  3. 3.Second Department of Psychiatry, Attikon University Hospital, Medical SchoolNational & Kapodistrian University of AthensAthensGreece

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