Elsevier

NeuroImage

Volume 176, 1 August 2018, Pages 71-82
NeuroImage

Age-dependent effects of brain stimulation on network centrality

https://doi.org/10.1016/j.neuroimage.2018.04.038Get rights and content

Abstract

Functional magnetic resonance imaging (fMRI) studies have suggested that advanced age may mediate the effects of transcranial direct current stimulation (tDCS) on brain function. However, studies directly comparing neural tDCS effects between young and older adults are scarce and limited to task-related imaging paradigms. Resting-state (rs-) fMRI, that is independent of age-related differences in performance, is well suited to investigate age-associated differential neural tDCS effects. Three “online” tDCS conditions (anodal, cathodal, sham) were compared in a cross-over, within-subject design, in 30 young and 30 older adults. Active stimulation targeted the left sensorimotor network (active electrode over left sensorimotor cortex with right supraorbital reference electrode). A graph-based rs-fMRI data analysis approach (eigenvector centrality mapping) and complementary seed-based analyses characterized neural tDCS effects. An interaction between anodal tDCS and age group was observed. Specifically, centrality in bilateral paracentral and posterior regions (precuneus, superior parietal cortex) was increased in young, but decreased in older adults. Seed-based analyses revealed that these opposing patterns of tDCS-induced centrality modulation originated from differential effects of tDCS on functional coupling of the stimulated left paracentral lobule. Cathodal tDCS did not show significant effects. Our study provides first evidence for differential tDCS effects on neural network organization in young and older adults. Anodal stimulation mainly affected coupling of sensorimotor with ventromedial prefrontal areas in young and decoupling with posteromedial areas in older adults.

Introduction

Non-invasive brain stimulation techniques constitute promising approaches to investigate the relationship between brain structure and function and to develop cognitive enhancement strategies (Fertonani and Miniussi, 2016; Kuo and Nitsche, 2012; Nitsche et al., 2015). Importantly, such techniques have been discussed as a potential intervention to counteract age-related cognitive decline and reduced neural efficacy (Mameli et al., 2014; Perceval et al., 2016).

Here, transcranial direct current stimulation (tDCS) has proven to be the most feasible method, because of its relative low costs, few contraindications and adverse effects and its simplicity for concurrent application during task execution (Polania et al., 2018; Woods et al., 2016). When applied concurrent to cognitive training over multiple days, tDCS has been found to induce sustained performance improvement of trained and untrained functions (Antonenko et al., 2018; Berryhill, 2017; Kuo and Nitsche, 2012). In addition to its additive effect on training interventions, there is a large number of studies using single session tDCS to establish brain-behavior relationships and study underlying neural effects (Perceval et al., 2016; Polania et al., 2018). At the neural level, acute tDCS effects are modulation of cortical excitability by de- or hyperpolarizing resting membrane potentials (Nitsche and Paulus, 2000; Polania et al., 2018). Applied over a longer time interval, tDCS effects have been suggested to include synaptic mechanisms leading to long-term potentiation- (LTP) and depression-like plasticity (Monte-Silva et al., 2013; Nitsche and Paulus, 2001; Stagg and Nitsche, 2011). In particular, LTP-like effects induced by anodal tDCS can extend to interconnected brain areas, exerting network-based neurophysiological modulation that is evident during current application and can last up to an hour after the stimulation ends (Polania et al., 2018; Sehm et al., 2012; Stagg and Nitsche, 2011). Importantly, magnitude and direction of neurophysiological and behavioral effects of tDCS may not only depend on external methodological factors (e.g., stimulation parameters including electrode montage, current strength and stimulation duration), but also on inter-individual (e.g., genotype, baseline performance and education) and intra-individual factors (e.g., brain state) (Krause and Cohen Kadosh, 2014; Polania et al., 2018; Stephens et al., 2017).

In order to investigate effects on neural processing, brain stimulation can be combined with brain imaging techniques (for an overview, see Bergmann et al., 2016; Siebner et al., 2009). These include electroencephalography, magnetoencephalography, functional near-infrared spectroscopy and functional magnetic resonance imaging (fMRI) – each having its advantages, limits and technical challenges regarding the temporal and spatial resolution with which they can map certain neural patterns (Bolognini and Miniussi, 2016; Jones et al., 2015; Miniussi et al., 2012). The main advantage of fMRI over other techniques is that it can provide whole-brain information of stimulation effects on both local activity and large scale functional network with high spatial and sufficient temporal resolution (Antal et al., 2011; Johnstone et al., 2016; Siebner et al., 2009; Woods et al., 2016).

Using fMRI assessment, several studies have described tDCS-induced modulations of functional brain networks comprising effects in areas proximal and distant to the stimulation electrodes using both task-dependent and resting-state fMRI assessments in young adults (Bachtiar et al., 2015; Lindenberg et al., 2016; Martin et al., 2017; Meinzer et al., 2012; Sehm et al., 2012). Investigations of tDCS-induced functional modulation in older adults are scarce but essential, given differential effects in young versus older cohorts due to prominent age-related reorganization (cf. Perceval et al., 2016; Summers et al., 2016). Studies with older participants, in fact, allow to anticipate age-specific patterns of tDCS-induced modulations (Antonenko et al., 2017; Lindenberg et al., 2013). For instance, in a recent study we found that functional connectivity in the sensorimotor network is reduced due to anodal tDCS in older participants (Antonenko et al., 2017), as compared to an increase previously reported in young adults (Bachtiar et al., 2015).

Only one study to date included both older and young adults and compared the effects of tDCS on underlying functional connectivity during a semantic word generation task (Martin et al., 2017). The authors found performance improvements during tDCS administered to the left sensorimotor cortex and overlapping functional network modulations as assessed by independent component analysis during the task in both age groups. Only older adults showed increased lateralization of language related networks during anodal tDCS. Thus, tDCS resulted in partially different effects in both age groups. Effects on blood-oxygenated level-dependent (BOLD) task fMRI were related to the experimental paradigm, stimulus input and behavioral output. Here, task-independent resting-state BOLD fMRI not only offers a promising approach avoiding confounds related to the interaction of brain activity during task performance, but may also facilitate the understanding of complex network organization and stimulation-induced neuromodulation in aging (Ferreira and Busatto, 2013; Fox and Raichle, 2007).

The present study compared brain stimulation response in groups of older and young participants during task-free resting-state fMRI. Specifically, we administered anodal, cathodal and sham tDCS over the left sensorimotor cortex (SM1) with a right supraorbital (SO) reference electrode using a within-subjects design. Resting-state fMRI was acquired in all tDCS conditions during stimulation. For connectivity analysis, we chose the established graph theory-based eigenvector centrality mapping (ECM) approach, because it is purely data-driven and allows characterization of whole-brain functional connectivity without requiring a priori assumptions about anatomical or functional network organization or regions-of-interest specification (Bonacich, 2007; Lohmann et al., 2010; Nierhaus et al., 2012; Zuo et al., 2012). In addition, this approach has successfully been used to map tDCS-induced modulations of resting-state functional connectivity in several previous studies in young or older adults (Lindenberg et al., 2013, 2016; Meinzer et al., 2012, 2015; Sehm et al., 2012).

Based on substantial evidence of age-related brain network reorganization (Ferreira and Busatto, 2013; Geerligs et al., 2015; Sala-Llonch et al., 2015) and previous fMRI studies that pointed towards age group-specific patterns of neural tDCS effects on brain activity and connectivity (Lindenberg et al., 2013; Martin et al., 2017; Meinzer et al., 2012), we aimed to investigate the interaction between stimulation condition and age group. Thus, we focused on differences in whole-brain spatial distribution of tDCS-induced neural effects with the aim to explore which regions showed modulatory patterns in different directions in older and young adults. Based on available preliminary data described above, we expected differential large-scale network modulations in both age groups with inter-regional connectivity of areas surrounding the targeted sensorimotor cortex to be increased during anodal stimulation in young adults (Bachtiar et al., 2015; Lindenberg et al., 2016) and to be decreased in older adults (Antonenko et al., 2017).

Section snippets

Participants and study design

The study sample comprised sixty participants, 30 older (16 f, mean/SD age: 63/7, mean/SD education: 16/3 years) and 30 young adults (16 f, mean/SD age: 24/4, mean/SD education: 16/3 years). All were native German speakers and had no history of neurological or psychiatric disorders. Intake of medication affecting the central nervous-system was treated as an exclusion criterion. Smoking was not an exclusion criterion, but the proportion of smokers in the study sample was low (n = 2 in each age

Electric field simulations

The modeling results indicate that this conventional electrode montage induced electric fields with maximum intensity between the two electrodes, but also high intensities around the intended target area. More specifically, in both age groups, high electric field intensities occurred in the vicinity of the left-hemispheric paracentral lobe, at the precentral gyrus and central sulcus (Fig. 1A). On average, the spatial distribution of the electric field strength is highly similar between age

Discussion

The present study explored the difference in tDCS effects on functional connectivity between older and young adults. We used a counterbalanced, cross-over design with anodal, cathodal and sham stimulation targeting the sensorimotor network. Functional network analysis revealed neuromodulatory effects of tDCS in brain regions under the anode, but also distant to the stimulation site. We observed differential effects of anodal stimulation on centrality in left paracentral, right superior parietal

Conclusions

This is the first systematic investigation of age-related differences in tDCS-induced modulation of resting-state functional network connectivity. We confirm and extend previous evidence for neuromodulatory effects in the aging brain by providing a detailed picture of distinct stimulation-induced global brain network reorganization. Importantly, we observed an interaction between the effect of anodal stimulation and age group, reflecting opposite patterns of network centrality modulation in

Acknowledgements

The authors thank Semiha Aydin, Florian Bohm, and Angelica Sousa for help with data acquisition and Dr. Ulrike Grittner for statistical assistance. This work was supported by the “Bundesministerium für Bildung und Forschung” [01GQ1424A]. Conflicts of interest: none.

References (77)

  • S.C. Johnson et al.

    The relationship between fMRI activation and cerebral atrophy: comparison of normal aging and alzheimer disease

    Neuroimage

    (2000)
  • K.T. Jones et al.

    The strategy and motivational influences on the beneficial effect of neurostimulation: a tDCS and fNIRS study

    Neuroimage

    (2015)
  • J.H. Kim et al.

    Inconsistent outcomes of transcranial direct current stimulation may originate from anatomical differences among individuals: electric field simulation using individual MRI data

    Neurosci. Lett.

    (2014)
  • I. Laakso et al.

    Inter-subject variability in electric fields of motor cortical tDCS

    Brain Stimul.

    (2015)
  • R. Lindenberg et al.

    Neural correlates of unihemispheric and bihemispheric motor cortex stimulation in healthy young adults

    Neuroimage

    (2016)
  • S. Mahdavi et al.

    Computational human head models of tDCS: influence of brain atrophy on current density distribution

    Brain Stimul.

    (2018)
  • F. Mameli et al.

    Transcranial direct current stimulation and cognition in the elderly

  • M. Meinzer et al.

    Transcranial direct current stimulation in mild cognitive impairment: behavioral effects and neural mechanisms

    Alzheimers Dement.

    (2015)
  • K. Monte-Silva et al.

    Induction of late LTP-like plasticity in the human motor cortex by repeated non-invasive brain stimulation

    Brain Stimul.

    (2013)
  • A. Opitz et al.

    Determinants of the electric field during transcranial direct current stimulation

    Neuroimage

    (2015)
  • G. Perceval et al.

    Can transcranial direct current stimulation counteract age-associated functional impairment?

    Neurosci. Biobehav Rev.

    (2016)
  • R. Polanía et al.

    Introducing graph theory to track for neuroplastic alterations in the resting human brain: a transcranial direct current stimulation study

    Neuroimage

    (2011)
  • C. Poreisz et al.

    Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients

    Brain Res. Bull.

    (2007)
  • G.B. Saturnino et al.

    On the importance of electrode parameters for shaping electric field patterns generated by tDCS

    Neuroimage

    (2015)
  • H.R. Siebner et al.

    Consensus paper: combining transcranial stimulation with neuroimaging

    Brain Stimul.

    (2009)
  • J.J. Summers et al.

    Does transcranial direct current stimulation enhance cognitive and motor functions in the ageing brain? A systematic review and meta- analysis

    Ageing Res. Rev.

    (2016)
  • M. Taubert et al.

    Long-term effects of motor training on resting-state networks and underlying brain structure

    Neuroimage

    (2011)
  • C. Thomas et al.

    Effect of aging on current flow due to transcranial direct current stimulation

    Brain Stimul. Basic, Transl. Clin. Res. Neuromodulation

    (2017)
  • D.A. Wiepert et al.

    A robust biomarker of large-scale network failure in Alzheimer's disease

    Alzheimers Dement. (Amst)

    (2017)
  • A.J. Woods et al.

    A technical guide to tDCS, and related non-invasive brain stimulation tools

    Clin. Neurophysiol.

    (2016)
  • S.M. Adriaanse et al.

    The association of glucose metabolism and eigenvector centrality in Alzheimer's disease

    Brain Connect.

    (2016)
  • D. Antonenko et al.

    Tdcs-induced modulation of GABA levels and resting-state functional connectivity in older adults

    J. Neurosci.

    (2017)
  • V. Bachtiar et al.

    Modulation of GABA and resting state functional connectivity by transcranial direct current stimulation

    Elife

    (2015)
  • M.E. Berryhill

    Longitudinal tDCS: consistency across working memory training studies

    AIMS Neurosci.

    (2017)
  • M.A. Binnewijzend et al.

    Brain network alterations in Alzheimer's disease measured by eigenvector centrality in fMRI are related to cognition and CSF biomarkers

    Hum. Brain Mapp.

    (2014)
  • N. Bolognini et al.

    Multimodal association of tDCS with electroencephalography

  • E. Bullmore et al.

    Complex brain networks: graph theoretical analysis of structural and functional systems

    Nat. Rev. Neurosci.

    (2009)
  • A. Bungert et al.

    Where does TMS stimulate the motor Cortex? Combining electrophysiological measurements and realistic field estimates to reveal the affected cortex position

    Cereb. Cortex

    (2017)
  • Cited by (40)

    • Age-dependent non-linear neuroplastic effects of cathodal tDCS in the elderly population: a titration study

      2022, Brain Stimulation
      Citation Excerpt :

      Thirty-nine healthy, non-smoking participants of two age groups were recruited: 20 Pre-Elderly participants (11 females; mean age (years ± SD) 58.65 ± 3.86) and 19 Elderly participants (10 females; mean age (years ± SD) 72.68 ± 5.12). These age ranges were selected based on previous findings looking at the impact of age on tDCS-generated plasticity [37,38], and is in line with the assumed course of plasticity alteration in advanced age (see these also for further details: [39,40]. All participants were right-handed according to the Edinburgh Handedness Inventory [41].

    • Inter-individual and age-dependent variability in simulated electric fields induced by conventional transcranial electrical stimulation

      2021, NeuroImage
      Citation Excerpt :

      However, anatomical variations are mostly neglected in brain stimulation research with healthy participants and patients, but can be a core factor causing the variability in empirical findings (Kim et al., 2014; Laakso et al., 2015; Liu et al., 2018). Given that age-related brain atrophy affects tissue volumes in an inter-individually variable extent (Grady, 2012; Reuter-Lorenz and Park, 2014), its effects on altered current distribution induced by brain stimulation may be particularly relevant in studies with older populations (Antonenko et al., 2018; Mahdavi et al., 2018; Thomas et al., 2017). The development of accessible computational modeling approaches has advanced the understanding of physical principles and neurophysiological effects of electrical current on the human brain (Hartwigsen et al., 2015; Peterchev, 2017; Thielscher et al., 2015).

    View all citing articles on Scopus
    View full text