Changing Brain Networks Through Non-invasive Neuromodulation

“A generic property of a network is that dysfunction can spread easily between linked elements, leading to pathological cascades that include large parts of the system (Buldyrev et al., 2010; Huang et al., 2011).”

“…the (dorsolateral) prefrontal cortex with top-down prefrontal control, important in various disorder including tinnitus (Mitchell et al., 2005), substance use disorder (Bradshaw et al., 2017), pain (Martinez et al., 2017), depression (Ochsner and Gross, 2005) and schizophrenia (Mayer et al., 2015).”

“…been suggested as a mechanism underlying the preoccupation with self-referential processes related to DMN hyperactivity, and deficits in cognitive functioning, associated with CEN hypoconnectivity (Menon, 2011; Manoliu et al., 2013; Kaiser et al., 2015; Anderson et al., 2016; Wang et al., 2016).”

“…Mayberg, 2009; Fox et al., Frontiers in Human Neuroscience | www.frontiersin.org 8 April 2018 | Volume 12 | Article 128 2012a) to decrease hyperactivity in this brain region as this has been associated with antidepressant response in depressed patients (Mayberg et al., 2005; Drevets et al., 2008).”

“Connectivity in brain networks can indeed be assessed in different ways (Friston, 2011).”

“, 2005) might have important implications for understanding clinical brain disorders (Bullmore and Sporns, 2012; Menon, 2013; Rubinov and Bullmore, 2013; van den Heuvel and Sporns, 2013a; Crossley et al., 2014).”

“Conceptualizing the brain as a network (Sporns et al., 2005) might have important implications for understanding clinical brain disorders (Bullmore and Sporns, 2012; Menon, 2013; Rubinov and Bullmore, 2013; van den Heuvel and Sporns, 2013a; Crossley et al.”

“Another brain region that has been considered a key region in emotion regulation (Mayberg et al., 1999) and that has recently been investigated as a new rTMS target for depression is the dorsomedial prefrontal cortex (DMPFC; i.e., DMN node; Downar and Daskalakis, 2013; Anderson et al., 2016; Liu S.…”

“Moreover, the aberrant switching between the DMN and CEN in depression has been suggested as a mechanism underlying the preoccupation with self-referential processes related to DMN hyperactivity, and deficits in cognitive functioning, associated with CEN hypoconnectivity (Menon, 2011; Manoliu et al., 2013; Kaiser et a…”

“Abnormally increased DMN connectivity has been found in association with depression (Anand et al., 2005; Greicius et al., 2007; Broyd et al., 2009; Sheline et al., 2010; Liston et al., 2014; Kaiser et al., 2015), more specifically related to rumination and deficits in emotion regulation (Sheline et al.”

“In addition to the classification of hubs on the basis of anatomical or structural connectivity, numerous studies have also investigated the existence of ‘‘functional hubs’’ derived from networks of dynamic interactions between brain regions (van den Heuvel and Sporns, 2013a).”

“Lefaucheur et al. (2014), however, do not recommend of using this bilateral rTMS, because of contradictory results across studies.”

“…have mostly targeted the left DLPFC using the electrode montage where the anode is placed over the left DLPFC and the cathode over the right orbitofrontal cortex (for a review, see Lefaucheur et al., 2017; e.g., Boggio et al., 2008a; Loo et al., 2012; Palm et al., 2012; Bennabi et al., 2015).”

“…and decreased excitation (or LTD), depending on the previous history of neural activity is referred as ‘‘metaplasticity’’ or ‘‘homeostatic plasticity’’ (Abraham and Bear, 1996; Desai, 2003; Lang et al., 2004; Siebner et al., 2004; Abraham, 2008; Cosentino et al., 2012; Hulme et al., 2013;…”

“Fornito et al. (2015) have proposed different versions of a maladaptive response that can mediate the spread of pathology throughout the connectome, as well as the resources and processes that enable adaptation.”

“Bachtiar et al. (2015) replicated this tDCS experiment and confirmed the decreased GABA levels within M1 and increased resting motor network connectivity.”

“, 2015), more specifically related to rumination and deficits in emotion regulation (Sheline et al., 2009; Hamilton et al., 2011).”

“For example, a recent meta-analysis of structural and functional neuroimaging studies found a collective core of brain regions affected by most psychiatric disorders, centered on dorsal anterior cingulate cortex (dACC) and the insula (Goodkind et al., 2015; Downar et al., 2016).”

“These mechanisms involve the potentiation of synaptic glutamatergic receptors (Liebetanz et al., 2002; Nitsche et al., 2005) and decreased neurotransmission of GABA (Nitsche et al., 2004; Stagg et al., 2009; Stagg and Nitsche, 2011; Hunter et al., 2015; for a review, see Medeiros et al., 2012).”

“These techniques enable the perturbation of large-scale neural systems and may facilitate in testing whole brain models (Breakspear, 2017).”

“One of the first FDA-approved clinical uses of rTMS is HF stimulation to the left DLPFC for the treatment of depression (George et al., 1995; Pascual-Leone et al., 1996; O’Reardon et al., 2007; Padberg and George, 2009).”

“Abnormally increased DMN connectivity has been found in association with depression (Anand et al., 2005; Greicius et al., 2007; Broyd et al., 2009; Sheline et al., 2010; Liston et al., 2014; Kaiser et al., 2015), more specifically related to rumination and deficits in emotion regulation (Sheline et al.”

“This sliding of the modification threshold for increased excitation (or long-term potentiation, LTP) and decreased excitation (or LTD), depending on the previous history of neural activity is referred as ‘‘metaplasticity’’ or ‘‘homeostatic plasticity’’ (Abraham and Bear, 1996; Desai, 2003; Lang et al., 2004; Siebner e…”

“In general, it has been suggested that brain hubs are indeed involved in the anatomy of various brain disorders (Crossley et al., 2014).”

“Studies in healthy subjects targeting the DLPFC using anodal tDCS have reported to transiently improve working memory (e.g., Fregni et al., 2005) and attention in healthy subjects (e.g., Nelson et al., 2014).”

“…and functional abnormalities in distributed networks of cortical and limbic brain regions including the DLPFC, ventromedial prefrontal cortex, amygdala, hippocampus and subgenual cingulate amongst others (Campbell et al., 2004; Mayberg, 2007; Drevets et al., 2008; Koenigs and Grafman, 2009).”

“…regions such as the subgenual ACC have been targeted with invasive neuromodulation, such as deep brain stimulation (e.g., Mayberg et al., 2005; Drevets et al., 2008; Mayberg, 2009; Fox et al., Frontiers in Human Neuroscience | www.frontiersin.org 8 April 2018 | Volume 12 | Article 128 2012a)…”

“Loo et al. (2007), Bretlau et al. (2008), George et al. (2010) and Baeken et al. (2013, 2014) LF rTMS to the right DLPFC e.g., Klein et al. (1999), Januel et al. (2006), Fitzgerald et al. (2008), Bares et al. (2009) and Aguirre et al. (2011) Combined modulation of HF left DLPFC then LF right DLPFC…”

“The left DLPFC has been found to be hypoactive in patients with depression and an increase in activity is associated with antidepressant response (Fitzgerald et al., 2006b; Koenigs and Grafman, 2009).”

“One of the first FDA-approved clinical uses of rTMS is HF stimulation to the left DLPFC for the treatment of depression (George et al., 1995; Pascual-Leone et al., 1996; O’Reardon et al., 2007; Padberg and George, 2009).”

“Bachtiar et al. (2015) replicated this tDCS experiment and confirmed the decreased GABA levels within M1 and increased resting motor network connectivity.”

“In depressed individuals a dominance of DMN over CEN was found which correlated with maladaptive rumination (Hamilton et al., 2011; Wang et al., 2016).”

“…color tinnitus perception, but may efficiently switch the perceived Frontiers in Human Neuroscience | www.frontiersin.org 7 April 2018 | Volume 12 | Article 128 signal on and off (Rauschecker et al., 2010; Frank et al., 2012), therefore being able to influence both tinnitus distress and intensity.”

“Abnormally increased DMN connectivity has been found in association with depression (Anand et al., 2005; Greicius et al., 2007; Broyd et al., 2009; Sheline et al., 2010; Liston et al., 2014; Kaiser et al., 2015), more specifically related to rumination and deficits in emotion regulation (Sheline et…”

“Moreover, the aberrant switching between the DMN and CEN in depression has been suggested as a mechanism underlying the preoccupation with self-referential processes related to DMN hyperactivity, and deficits in cognitive functioning, associated with CEN hypoconnectivity (Menon, 2011; Manoliu et al., 2013; Kaiser et a…”

“Effective connectivity refers to the directional flow of information or the causal relationships between (Friston, 2011; Shafi et al., 2012; Fornito et al., 2013; Luft et al., 2014) nodes, whereas functional connectivity simply computes measures of statistical independence (correlation) between…”

“As opposed to rTMS, the electrical currents delivered by tDCS are not strong enough to fire an action potential (Radman et al., 2009).”

“This sliding of the modification threshold for increased excitation (or long-term potentiation, LTP) and decreased excitation (or LTD), depending on the previous history of neural activity is referred as ‘‘metaplasticity’’ or ‘‘homeostatic plasticity’’ (Abraham and Bear, 1996; Desai, 2003; Lang et al., 2004; Siebner e…”

“Increasing evidence points to the influence of neuromodulation on whole brain networks by stimulating just one brain region (or brain hub; Grefkes and Fink, 2011; Fox et al., 2012b).”

“…in attention in patients with traumatic brain injury (e.g., Kang et al., 2012), in working memory in patients with Parkinson’s disease (e.g., Boggio et al., 2006), in recognition memory in patients with Alzheimer disease (e.g., Ferrucci et al., 2008), in signs of consciousness in patients…”

“Most studies examined the effects of tDCS or rTMS on brain connectivity by analyzing changes in functional networks during task-independent (resting-state) or task-related neuroimaging (e.g., EEG, fMRI).”

“The auditory cortex has become a common stimulation target for tinnitus, as past neuroimaging studies have shown over-activation of the left auditory cortex in tinnitus patients (Arnold et al., 1996; Lockwood et al., 1998).”

“…has improved the spatial accuracy of conventional tDCS by using arrays of smaller ‘‘highdefinition’’ electrodes instead of two large pad electrodes (Datta et al., 2009; Dmochowski et al., 2011; Guleyupoglu et al., 2013; Villamar et al., 2013a; Heimrath et al., 2015; Shekhawat et al., 2016).”

“…have mostly targeted the left DLPFC using the electrode montage where the anode is placed over the left DLPFC and the cathode over the right orbitofrontal cortex (for a review, see Lefaucheur et al., 2017; e.g., Boggio et al., 2008a; Loo et al., 2012; Palm et al., 2012; Bennabi et al., 2015).”

“…subgenual ACC have been targeted with invasive neuromodulation, such as deep brain stimulation (e.g., Mayberg et al., 2005; Drevets et al., 2008; Mayberg, 2009; Fox et al., Frontiers in Human Neuroscience | www.frontiersin.org 8 April 2018 | Volume 12 | Article 128 2012a) to decrease…”

“It has been suggested that the stimulation can potentially interact with the prior state of the cortex (Filmer et al., 2014).”

“Loo et al. (2007), Bretlau et al. (2008), George et al. (2010) and Baeken et al. (2013, 2014) LF rTMS to the right DLPFC e.g., Klein et al. (1999), Januel et al. (2006), Fitzgerald et al. (2008), Bares et al. (2009) and Aguirre et al. (2011) Combined modulation of HF left DLPFC then LF right DLPFC…”

“A generic property of a network is that dysfunction can spread easily between linked elements, leading to pathological cascades that include large parts of the system (Buldyrev et al., 2010; Huang et al., 2011).”

“…2017), in mood in patients with depression (e.g., Blumberger et al., 2012b; Loo et al., 2012; Palm et al., 2012), in auditory hallucinations in patients with schizophrenia (e.g., Brunelin et al., 2012) and in craving in substance abusers (e.g., Boggio et al., 2008b, 2009; Fregni et al., 2008).”

“…and Bakker et al. (2015) Transcranial direct current stimulation Anode left DLPFC—cathode right supraorbital region e.g., Boggio et al. (2008a,b), Loo et al. (2012), Palm et al. (2012) and Bennabi et al. (2015) Anode left DLPFC—cathode right DLPFC e.g., Ferrucci et al. (2009), Brunoni et al.…”

“…in working memory in patients with Parkinson’s disease (e.g., Boggio et al., 2006), in recognition memory in patients with Alzheimer disease (e.g., Ferrucci et al., 2008), in signs of consciousness in patients in a minimally conscious state (e.g., Angelakis et al., 2014; Thibaut et al., 2014,…”

“, 2014), including the state of the brain during stimulation (at rest or paired with a task; Horvath et al., 2014), any intake of substances such as nicotine (Thirugnanasambandam et al.”

“…(i.e., cTBS) or an intermittent theta burst stimulation (i.e., iTBS) train. cTBS is suggested to be similar to 1 Hz-rTMS, mimicking the long-term depression (LTD) of synaptic plasticity, whereas iTBS is suggested to be excitatory (Di Lazzaro et al., 2005; Huang et al., 2005; Noh et al., 2015).”

“…between specific brain areas (e.g., intrahemispheric or interhemispheric connectivity changes; e.g., Polanía et al., 2011b; Sehm et al., 2013) or whether tDCS modulates functional connectivity of certain circuits (e.g., Alon et al., 2011; Polanía et al., 2012) in a non-clinical population.”

“Based on neuroimaging studies, a group of tinnitus researchers have proposed a tinnitus brain model consisting of multiple parallel, dynamic, and partially overlapping subnetworks each representing a specific aspect of tinnitus (see De Ridder et al., 2014).”

“Bachtiar et al. (2015) replicated this tDCS experiment and confirmed the decreased GABA levels within M1 and increased resting motor network connectivity.”

“Moreover, the aberrant switching between the DMN and CEN in depression has been suggested as a mechanism underlying the preoccupation with self-referential processes related to DMN hyperactivity, and deficits in cognitive functioning, associated with CEN hypoconnectivity (Menon, 2011; Manoliu et al., 2013; Kaiser et a…”

“…of consciousness, Alzheimer’s disease, tinnitus, schizophrenia, substance abuse, addiction and craving, amongst others (e.g., Fregni et al., 2008; Benninger et al., 2010; Van den Eynde et al., 2010; Zyss, 2010; Freitas et al., 2011; Avenanti et al., 2012; Borckardt et al., 2012; Brunelin et…”

“…have mostly targeted the left DLPFC using the electrode montage where the anode is placed over the left DLPFC and the cathode over the right orbitofrontal cortex (for a review, see Lefaucheur et al., 2017; e.g., Boggio et al., 2008a; Loo et al., 2012; Palm et al., 2012; Bennabi et al., 2015).”

“Studies have suggested that rTMS targeting the DMPFC could show similar antidepressant findings in patients with depression and is a safe procedure (e.g., Downar et al., 2014; Salomons et al., 2014; Bakker et al., 2015).”

“Conceptualizing the brain as a network (Sporns et al., 2005) might have important implications for understanding clinical brain disorders (Bullmore and Sporns, 2012; Menon, 2013; Rubinov and Bullmore, 2013; van den Heuvel and Sporns, 2013a; Crossley et al., 2014).”

“Besides the hypoactivity found in the left DLPFC, neuroimaging studies have also demonstrated hyperactivity in the right DLPFC in depressive disorder (Bench et al., 1995; Lefaucheur et al., 2014).”

“MACRO-Level: Assessing Network Connectivity With Task-Independent and Task-Related Neuroimaging Recent studies have shown that non-invasive neuromodulation techniques affect brain connectivity patterns both while performing tasks and while at rest (Grefkes et al., 2010; Alon et al., 2011; Keeser et al., 2011a; Polanía…”

“However, the revealed subnetworks encoding the different aspects of the tinnitus percept, e.g., the distress network, can be similar to other pathologies, such as pain (Moisset and Bouhassira, 2007; De Ridder et al., 2013, 2014).”

“This sliding of the modification threshold for increased excitation (or long-term potentiation, LTP) and decreased excitation (or LTD), depending on the previous history of neural activity is referred as ‘‘metaplasticity’’ or ‘‘homeostatic plasticity’’ (Abraham and Bear, 1996; Desai, 2003; Lang et al., 2004; Siebner e…”

“…Alzheimer disease (e.g., Ferrucci et al., 2008), in signs of consciousness in patients in a minimally conscious state (e.g., Angelakis et al., 2014; Thibaut et al., 2014, 2017), in mood in patients with depression (e.g., Blumberger et al., 2012b; Loo et al., 2012; Palm et al., 2012), in auditory…”

“…designs of non-invasive neuromodulation, studies have shown the possibility of targeting these deeper brain structures using, for example, double cone coil rTMS (Hayward et al., 2007; De Ridder et al., 2011; Deng et al., 2014; Kreuzer et al., 2015) or high definition tDCS (DaSilva et al., 2015).”

“Since there is evidence that the sum of glutamate and glutamine (Glx) levels are increased by tDCS (Clark et al., 2011) and that there is a strong relationship between Glx and functional connectivity (Horn et al., 2010; Kapogiannis et al., 2013), Frontiers in Human Neuroscience |…”

“, 2011) and even the time of the day (Sale et al., 2007).”

“…the left DLPFC in healthy subjects have been shown to influence regional electrical activity in both surface level and deeper structures using resting-state EEG (Keeser et al., 2011b) and resting-state fMRI (Keeser et al., 2011a; Peña-Gómez et al., 2012; Park et al., 2013; Stagg et al., 2013).”

“These mechanisms involve the potentiation of synaptic glutamatergic receptors (Liebetanz et al., 2002; Nitsche et al., 2005) and decreased neurotransmission of GABA (Nitsche et al., 2004; Stagg et al., 2009; Stagg and Nitsche, 2011; Hunter et al., 2015; for a review, see Medeiros et al., 2012).”

“Studies in healthy subjects targeting the DLPFC using anodal tDCS have reported to transiently improve working memory (e.g., Fregni et al., 2005) and attention in healthy subjects (e.g., Nelson et al., 2014).”

“Task-related neuroimaging studies have also examined short-term reorganization in healthy subjects (e.g., O’Shea et al., 2007; Andoh and Paus, 2011; Chib et al., 2013; Weber et al., 2014) after non-invasive neuromodulation.”

“…over the DMPFC demonstrated increased anticorrelation between the DMPFC (DMN node) and the insula (SN node), and increased connectivity with the thalamus (CEN node) to be associated with a greater clinical response in patients with depression (Salomons et al., 2014; Anderson et al., 2016).”

“Interestingly, studies have also combined non-invasive neuromodulation with simultaneous task-based neuroimaging (e.g., Meinzer et al., 2012, 2013).”

“Most studies examined the effects of tDCS or rTMS on brain connectivity by analyzing changes in functional networks during task-independent (resting-state) or task-related neuroimaging (e.g., EEG, fMRI).”

“Interestingly, studies have also combined non-invasive neuromodulation with simultaneous task-based neuroimaging (e.g., Meinzer et al., 2012, 2013).”

“…2017), in mood in patients with depression (e.g., Blumberger et al., 2012b; Loo et al., 2012; Palm et al., 2012), in auditory hallucinations in patients with schizophrenia (e.g., Brunelin et al., 2012) and in craving in substance abusers (e.g., Boggio et al., 2008b, 2009; Fregni et al., 2008).”

“…efficacy of HF rTMS to the left DLPFC using a variety of parameters has been established (For review, see Lefaucheur et al., 2014; e.g., Pascual-Leone et al., 1996; Berman et al., 2000; Rossini et al., 2005; Loo et al., 2007; Bretlau et al., 2008; George et al., 2010; Baeken et al., 2013, 2014).”

“Interestingly, Stagg et al. (2013) focused on brain perfusion changes during left DLPFC tDCS (using wholebrain arterial spin labeling) and found decreased functional connectivity between the left DLPFC and the bilateral thalami after tDCS, possibly offering a mechanistic explanation for the…”

“…others (e.g., Fregni et al., 2008; Benninger et al., 2010; Van den Eynde et al., 2010; Zyss, 2010; Freitas et al., 2011; Avenanti et al., 2012; Borckardt et al., 2012; Brunelin et al., 2012; Frontiers in Human Neuroscience | www.frontiersin.org 1 April 2018 | Volume 12 | Article 128 Brunoni…”

“Bachtiar et al. (2015) replicated this tDCS experiment and confirmed the decreased GABA levels within M1 and increased resting motor network connectivity.”

“…a key region in emotion regulation (Mayberg et al., 1999) and that has recently been investigated as a new rTMS target for depression is the dorsomedial prefrontal cortex (DMPFC; i.e., DMN node; Downar and Daskalakis, 2013; Anderson et al., 2016; Liu S. et al., 2017; Liu W. et al., 2017).”

“…in depression (e.g., George et al., 2010; Triggs et al., 2010; Ray et al., 2011; Baeken et al., 2013, 2014), post-traumatic stress disorder (e.g., Boggio et al., 2010; Watts et al., 2012), panic disorder (e.g., Mantovani et al., 2013), schizophrenia targeting the negative symptoms (e.g., Rollnik…”

“…(e.g., Rollnik et al., 2000; Hajak et al., 2004; Cordes et al., 2010; Prikryl et al., 2013) and in addiction disorders—more specifically food (e.g., Van den Eynde et al., 2010; Barth et al., 2011), alcohol (e.g., Mishra et al., 2010) and cigarettes (e.g., Li et al., 2013; Prikryl et al., 2014).”

“Currently, behavioral manifestations of neurological and psychiatric diseases are seen as a result of alterations in a brain network and its connectivity as opposed to an abnormality in one isolated brain region (Fox et al., 2012b; Shafi et al., 2012; Luft et al., 2014; Fornito and Bullmore, 2015).”

“…and craving, amongst others (e.g., Fregni et al., 2008; Benninger et al., 2010; Van den Eynde et al., 2010; Zyss, 2010; Freitas et al., 2011; Avenanti et al., 2012; Borckardt et al., 2012; Brunelin et al., 2012; Frontiers in Human Neuroscience | www.frontiersin.org 1 April 2018 | Volume 12…”

“A recent study by Tik et al. (2017) further demonstrated that stimulation of the left DLFPC modulates ACC connectivity in a specific meso-cortico-limbic network, which might explain the treatment mechanism of psychiatric disorders such as depression.”

“More recently, the introduction of High-Definition tDCS (HD-tDCS) has improved the spatial accuracy of conventional tDCS by using arrays of smaller ‘‘highdefinition’’ electrodes instead of two large pad electrodes (Datta et al., 2009; Dmochowski et al., 2011; Guleyupoglu et al., 2013; Villamar et al., 2013a; Heimrath…”

“Tremblay et al. (2014) have concluded that prefrontal tDCS targeting the DLFPC has the potential to modulate numerous cognitive functions simultaneously and that the effect of prefrontal tDCS on a given task is probably associated with the extensive modulation of a wide range of cognitive functions.”

“…have mostly targeted the left DLPFC using the electrode montage where the anode is placed over the left DLPFC and the cathode over the right orbitofrontal cortex (for a review, see Lefaucheur et al., 2017; e.g., Boggio et al., 2008a; Loo et al., 2012; Palm et al., 2012; Bennabi et al., 2015).”

“More recently, studies have applied bilateral tDCS, placing the anode electrode over the left DLPFC and the cathode over the right DLPFC instead of the right supraorbital region (e.g., Ferrucci et al., 2009; Brunoni et al., 2013, 2014; Valiengo et al., 2013, 2016, 2017).”

“Thus, modulation of any part of this network may interfere with tinnitus perception (Vanneste and De Ridder, 2012).”

“Even in a recent reappraisal of historic cases, such as Phineas Gage, Louis Victor Leborgne, and Henry Gustave Molaison, researchers indicated that the disruptions extended to areas far from the site of the lesions themselves (Thiebaut de Schotten et al., 2015).”

“, 2005) might have important implications for understanding clinical brain disorders (Bullmore and Sporns, 2012; Menon, 2013; Rubinov and Bullmore, 2013; van den Heuvel and Sporns, 2013a; Crossley et al., 2014).”

“Stagg et al. (2014) showed that tDCS on M1 decreased GABA levels within M1 and increased resting motor network connectivity.”

“…and craving, amongst others (e.g., Fregni et al., 2008; Benninger et al., 2010; Van den Eynde et al., 2010; Zyss, 2010; Freitas et al., 2011; Avenanti et al., 2012; Borckardt et al., 2012; Brunelin et al., 2012; Frontiers in Human Neuroscience | www.frontiersin.org 1 April 2018 | Volume 12…”

“…are increased by tDCS (Clark et al., 2011) and that there is a strong relationship between Glx and functional connectivity (Horn et al., 2010; Kapogiannis et al., 2013), Frontiers in Human Neuroscience | www.frontiersin.org 5 April 2018 | Volume 12 | Article 128 studies have been…”

“Transcranial direct current stimulation Anode left auditory cortex—cathode contralateral supraorbital region e.g., Fregni et al. (2006), Garin et al. (2011), Shekhawat et al. (2013) and Forogh et al. (2016) Anode right DLPFC—cathode right DLPFC e.g., Vanneste et al. (2010), Vanneste and De Ridder…”

“This sliding of the modification threshold for increased excitation (or long-term potentiation, LTP) and decreased excitation (or LTD), depending on the previous history of neural activity is referred as ‘‘metaplasticity’’ or ‘‘homeostatic plasticity’’ (Abraham and Bear, 1996; Desai, 2003; Lang et al., 2004; Siebner e…”

“NIBS has been proposed to normalize the interhemispheric imbalance of neuronal activity by excitatory stimulation of the left DLPFC and inhibitory stimulation over the right DLPFC (Palm et al., 2016; Lefaucheur et al., 2017).”

“…al., 2012; Frontiers in Human Neuroscience | www.frontiersin.org 1 April 2018 | Volume 12 | Article 128 Brunoni et al., 2012; Sun et al., 2012; Berlim et al., 2013; Li et al., 2013;Marangolo et al., 2013; Villamar et al., 2013b; Donnell et al., 2015; Douglas et al., 2015; Shekhawat et al., 2016).”

“…et al., 2012; Frontiers in Human Neuroscience | www.frontiersin.org 1 April 2018 | Volume 12 | Article 128 Brunoni et al., 2012; Sun et al., 2012; Berlim et al., 2013; Li et al., 2013;Marangolo et al., 2013; Villamar et al., 2013b; Donnell et al., 2015; Douglas et al., 2015; Shekhawat et al.,…”

“Loo et al. (2007), Bretlau et al. (2008), George et al. (2010) and Baeken et al. (2013, 2014) LF rTMS to the right DLPFC e.g., Klein et al. (1999), Januel et al. (2006), Fitzgerald et al. (2008), Bares et al. (2009) and Aguirre et al. (2011) Combined modulation of HF left DLPFC then LF right DLPFC…”

“…2017), in mood in patients with depression (e.g., Blumberger et al., 2012b; Loo et al., 2012; Palm et al., 2012), in auditory hallucinations in patients with schizophrenia (e.g., Brunelin et al., 2012) and in craving in substance abusers (e.g., Boggio et al., 2008b, 2009; Fregni et al., 2008).”

“Later on, HF rTMS was applied to the left auditory cortex with the belief that a virtual temporary lesion of this area can induce a transient reduction in tinnitus (Plewnia et al., 2003).”

“Task-related neuroimaging studies have also examined short-term reorganization in healthy subjects (e.g., O’Shea et al., 2007; Andoh and Paus, 2011; Chib et al., 2013; Weber et al., 2014) after non-invasive neuromodulation.”

“…memory in patients with Alzheimer disease (e.g., Ferrucci et al., 2008), in signs of consciousness in patients in a minimally conscious state (e.g., Angelakis et al., 2014; Thibaut et al., 2014, 2017), in mood in patients with depression (e.g., Blumberger et al., 2012b; Loo et al., 2012; Palm et…”

“…designs of non-invasive neuromodulation, studies have shown the possibility of targeting these deeper brain structures using, for example, double cone coil rTMS (Hayward et al., 2007; De Ridder et al., 2011; Deng et al., 2014; Kreuzer et al., 2015) or high definition tDCS (DaSilva et al., 2015).”

“Effective connectivity refers to the directional flow of information or the causal relationships between (Friston, 2011; Shafi et al., 2012; Fornito et al., 2013; Luft et al., 2014) nodes, whereas functional connectivity simply computes measures of statistical independence (correlation) between…”

“…substance abuse, addiction and craving, amongst others (e.g., Fregni et al., 2008; Benninger et al., 2010; Van den Eynde et al., 2010; Zyss, 2010; Freitas et al., 2011; Avenanti et al., 2012; Borckardt et al., 2012; Brunelin et al., 2012; Frontiers in Human Neuroscience | www.frontiersin.org 1…”

“…George et al., 2010; Triggs et al., 2010; Ray et al., 2011; Baeken et al., 2013, 2014), post-traumatic stress disorder (e.g., Boggio et al., 2010; Watts et al., 2012), panic disorder (e.g., Mantovani et al., 2013), schizophrenia targeting the negative symptoms (e.g., Rollnik et al., 2000; Hajak…”

“This sliding of the modification threshold for increased excitation (or long-term potentiation, LTP) and decreased excitation (or LTD), depending on the previous history of neural activity is referred as ‘‘metaplasticity’’ or ‘‘homeostatic plasticity’’ (Abraham and Bear, 1996; Desai, 2003; Lang et al., 2004; Siebner e…”

“For example, a recent meta-analysis of structural and functional neuroimaging studies found a collective core of brain regions affected by most psychiatric disorders, centered on dorsal anterior cingulate cortex (dACC) and the insula (Goodkind et al., 2015; Downar et al., 2016).”

“…al., 2012; Frontiers in Human Neuroscience | www.frontiersin.org 1 April 2018 | Volume 12 | Article 128 Brunoni et al., 2012; Sun et al., 2012; Berlim et al., 2013; Li et al., 2013;Marangolo et al., 2013; Villamar et al., 2013b; Donnell et al., 2015; Douglas et al., 2015; Shekhawat et al., 2016).”

“These studies all combined tDCS with either resting-state EEG or resting-state fMRI to examine for example whether tDCS induces increased or decreased functional connectivity between specific brain areas (e.g., intrahemispheric or interhemispheric connectivity changes; e.g., Polanía et al., 2011b; Sehm et al., 2013) o…”

“Furthermore, the positive clinical effects of non-invasive neuromodulation in various disorders are presumably caused by the complex interactions between the associated brain network and the stimulation target (Kunze et al., 2016).”

“Eichhammer et al. (2003) found considerable improvement in tinnitus in two out of three patients after 1 week (five consecutive days) with LF (1 Hz) rTMS with 2000 stimuli per day, measured by the Tinnitus Questionnaire (assessing different tinnitus complaints e.g., distress, auditory perceptual…”

“…a combined modulation of HF left DLPFC rTMS and LF right DLPFC rTMS during the same sessions in the same patients (e.g., Hausmann et al., 2004; Fitzgerald et al., 2006a; Garcia-Toro et al., 2006; McDonald et al., 2006; Pallanti et al., 2010; Blumberger et al., 2012a; Fitzgerald et al., 2012).”

“…Alzheimer disease (e.g., Ferrucci et al., 2008), in signs of consciousness in patients in a minimally conscious state (e.g., Angelakis et al., 2014; Thibaut et al., 2014, 2017), in mood in patients with depression (e.g., Blumberger et al., 2012b; Loo et al., 2012; Palm et al., 2012), in auditory…”

“For these responders, a significant reduction was found for both tinnitus intensity and tinnitus-related distress (Vanneste et al., 2010).”

“…and functional abnormalities in distributed networks of cortical and limbic brain regions including the DLPFC, ventromedial prefrontal cortex, amygdala, hippocampus and subgenual cingulate amongst others (Campbell et al., 2004; Mayberg, 2007; Drevets et al., 2008; Koenigs and Grafman, 2009).”

“Neuromodulation research has also shifted its approach from targeting individual brain regions to targeting entire brain networks (Sale et al., 2015).”

“A study by Kleinjung et al. (2008) combined HF prefrontal and LF temporal rTMS. Patients received either LF temporal rTMS or a combination of HF prefrontal and LF temporal rTMS. Directly after therapy they found an improvement for both groups, but no differences between the groups.”

“…2012; Borckardt et al., 2012; Brunelin et al., 2012; Frontiers in Human Neuroscience | www.frontiersin.org 1 April 2018 | Volume 12 | Article 128 Brunoni et al., 2012; Sun et al., 2012; Berlim et al., 2013; Li et al., 2013;Marangolo et al., 2013; Villamar et al., 2013b; Donnell et al., 2015;…”

“Bachtiar et al. (2015) replicated this tDCS experiment and confirmed the decreased GABA levels within M1 and increased resting motor network connectivity.”

“In general, the efficacy of HF rTMS to the left DLPFC using a variety of parameters has been established (For review, see Lefaucheur et al., 2014; e.g., Pascual-Leone et al., 1996; Berman et al., 2000; Rossini et al., 2005; Loo et al., 2007; Bretlau et al., 2008; George et al., 2010; Baeken et al., 2013, 2014).”

“For example, studies targeting the left DLPFC in healthy subjects using TBS have demonstrated influence on regional and more remote functions using resting-state fMRI (e.g., Gratton et al., 2013; Iwabuchi et al., 2017).”

“…have mostly targeted the left DLPFC using the electrode montage where the anode is placed over the left DLPFC and the cathode over the right orbitofrontal cortex (for a review, see Lefaucheur et al., 2017; e.g., Boggio et al., 2008a; Loo et al., 2012; Palm et al., 2012; Bennabi et al., 2015).”

“…designs of non-invasive neuromodulation, studies have shown the possibility of targeting these deeper brain structures using, for example, double cone coil rTMS (Hayward et al., 2007; De Ridder et al., 2011; Deng et al., 2014; Kreuzer et al., 2015) or high definition tDCS (DaSilva et al., 2015).”

“…et al., 2011; Keeser et al., 2011a; Polanía et al., 2011a, 2012; Vanneste and De Ridder, 2011; Meinzer et al., 2012, 2013; Peña-Gómez et al., 2012; Chib et al., 2013; Park et al., 2013; Stagg et al., 2013; Ding et al., 2014; Weber et al., 2014), suggesting that stimulation is not influencing the…”

“…color tinnitus perception, but may efficiently switch the perceived Frontiers in Human Neuroscience | www.frontiersin.org 7 April 2018 | Volume 12 | Article 128 signal on and off (Rauschecker et al., 2010; Frank et al., 2012), therefore being able to influence both tinnitus distress and intensity.”

“…tDCS or rTMS on short term reorganization in functional networks in healthy subjects (for review see Luft et al., 2014) and in patients (e.g., tinnitus patients, Vanneste and De Ridder, 2011) using fMRI (for review see Luft et al., 2014) or EEG (Polanía et al., 2011a; Vanneste and De Ridder, 2011).”

“…a combined modulation of HF left DLPFC rTMS and LF right DLPFC rTMS during the same sessions in the same patients (e.g., Hausmann et al., 2004; Fitzgerald et al., 2006a; Garcia-Toro et al., 2006; McDonald et al., 2006; Pallanti et al., 2010; Blumberger et al., 2012a; Fitzgerald et al., 2012).”

“…studies suggest that tinnitus occurs as a result of dysfunctional top-down inhibitory mechanisms originating in the prefrontal lobe (Norena et al., 1999), indicating that the prefrontal cortex does not only color tinnitus perception, but may efficiently switch the…”

“…(e.g., Boggio et al., 2010; Watts et al., 2012), panic disorder (e.g., Mantovani et al., 2013), schizophrenia targeting the negative symptoms (e.g., Rollnik et al., 2000; Hajak et al., 2004; Cordes et al., 2010; Prikryl et al., 2013) and in addiction disorders—more specifically food (e.g., Van den…”

“…Forogh et al. (2016) Anode right DLPFC—cathode right DLPFC e.g., Vanneste et al. (2010), Vanneste and De Ridder (2011), De Ridder and Vanneste (2012), Faber et al. (2012) and Frank et al. (2012) Simultaneuos 1 anode prefrontal cortex—2 cathode left and right auditory cortex e.g., Pal et al.…”

“Loo et al. (2007), Bretlau et al. (2008), George et al. (2010) and Baeken et al. (2013, 2014) LF rTMS to the right DLPFC e.g., Klein et al. (1999), Januel et al. (2006), Fitzgerald et al. (2008), Bares et al. (2009) and Aguirre et al. (2011) Combined modulation of HF left DLPFC then LF right DLPFC…”

“…DLPFC has also been found effective in several studies (for a review, see Lefaucheur et al., 2014; e.g., Klein et al., 1999; Januel et al., 2006; Fitzgerald et al., 2008; Bares et al., 2009; Aguirre et al., 2011) and there seems to be no difference in antidepressant effect between HF of the…”

“, 2013), schizophrenia targeting the negative symptoms (e.g., Rollnik et al., 2000; Hajak et al., 2004; Cordes et al., 2010; Prikryl et al., 2013) and in addiction disorders—more specifically food (e.”

“For example, studies targeting the left DLPFC in healthy subjects using TBS have demonstrated influence on regional and more remote functions using resting-state fMRI (e.g., Gratton et al., 2013; Iwabuchi et al., 2017).”

“For rTMS, brief high-current pulses are produced in a coil of wire, called the magnetic coil (Shapira-Lichter et al., 2013).”

“With more advanced designs of non-invasive neuromodulation, studies have shown the possibility of targeting these deeper brain structures using, for example, double cone coil rTMS (Hayward et al., 2007; De Ridder et al., 2011; Deng et al., 2014; Kreuzer et al., 2015) or high definition tDCS (DaSilva et al.”

“…et al. (2009) and Aguirre et al. (2011) Combined modulation of HF left DLPFC then LF right DLPFC during same session e.g., Hausmann et al. (2004), Fitzgerald et al. (2006a, 2012), Garcia-Toro et al. (2006), McDonald et al. (2006), Pallanti et al. (2010) and Blumberger et al. (2012a) Combined…”

“…a combined modulation of HF left DLPFC rTMS and LF right DLPFC rTMS during the same sessions in the same patients (e.g., Hausmann et al., 2004; Fitzgerald et al., 2006a; Garcia-Toro et al., 2006; McDonald et al., 2006; Pallanti et al., 2010; Blumberger et al., 2012a; Fitzgerald et al., 2012).”

“In general, the efficacy of HF rTMS to the left DLPFC using a variety of parameters has been established (For review, see Lefaucheur et al., 2014; e.g., Pascual-Leone et al., 1996; Berman et al., 2000; Rossini et al., 2005; Loo et al., 2007; Bretlau et al., 2008; George et al., 2010; Baeken et al., 2013, 2014).”

“…Ray et al., 2011; Baeken et al., 2013, 2014), post-traumatic stress disorder (e.g., Boggio et al., 2010; Watts et al., 2012), panic disorder (e.g., Mantovani et al., 2013), schizophrenia targeting the negative symptoms (e.g., Rollnik et al., 2000; Hajak et al., 2004; Cordes et al., 2010; Prikryl…”

“More recently, studies have applied bilateral tDCS, placing the anode electrode over the left DLPFC and the cathode over the right DLPFC instead of the right supraorbital region (e.g., Ferrucci et al., 2009; Brunoni et al., 2013, 2014; Valiengo et al., 2013, 2016, 2017).”

“…over the DMPFC demonstrated increased anticorrelation between the DMPFC (DMN node) and the insula (SN node), and increased connectivity with the thalamus (CEN node) to be associated with a greater clinical response in patients with depression (Salomons et al., 2014; Anderson et al., 2016).”

“Loo et al. (2007), Bretlau et al. (2008), George et al. (2010) and Baeken et al. (2013, 2014) LF rTMS to the right DLPFC e.g., Klein et al. (1999), Januel et al. (2006), Fitzgerald et al. (2008), Bares et al. (2009) and Aguirre et al. (2011) Combined modulation of HF left DLPFC then LF right DLPFC…”

“According to the ‘‘valence hypothesis’’ the affective processing exhibits hemispheric lateralization, with the right hemisphere specializing in negative emotional processing and the left hemisphere specializing in positive emotional processing (Prete et al., 2015; Liu S. et al., 2017).”

“Repetitive TMS (Fregni et al., 2006), as well as anodal tDCS to the auditory cortex (left temporal or temporoparietal cortices areas; Fregni et al., 2006; Garin et al., 2011), were found to suppress tinnitus.”

“In depressed individuals a dominance of DMN over CEN was found which correlated with maladaptive rumination (Hamilton et al., 2011; Wang et al., 2016).”

“…(2011) Combined modulation of HF left DLPFC then LF right DLPFC during same session e.g., Hausmann et al. (2004), Fitzgerald et al. (2006a, 2012), Garcia-Toro et al. (2006), McDonald et al. (2006), Pallanti et al. (2010) and Blumberger et al. (2012a) Combined modulation of HF left than right…”

“The first rTMS case studies (shamcontrolled) in tinnitus mostly investigated LF rTMS targeting the left auditory cortex in an attempt to inhibit the hyperactivity in this area (Eichhammer et al., 2003; Langguth et al., 2003).”

“…populations, tDCS targeting the DLPFC has been found to show transient improvement in attention in patients with traumatic brain injury (e.g., Kang et al., 2012), in working memory in patients with Parkinson’s disease (e.g., Boggio et al., 2006), in recognition memory in patients with…”

“…al., 2012; Frontiers in Human Neuroscience | www.frontiersin.org 1 April 2018 | Volume 12 | Article 128 Brunoni et al., 2012; Sun et al., 2012; Berlim et al., 2013; Li et al., 2013;Marangolo et al., 2013; Villamar et al., 2013b; Donnell et al., 2015; Douglas et al., 2015; Shekhawat et al., 2016).”

“…of bifrontal tDCS elicited a larger reduction in tinnitus intensity and distress compared to EEG driven tDCS. TACS targeting the DLPFC has also been investigated (Vanneste et al., 2013b), as it could theoretically normalize alpha power, which is known to decrease in tinnitus (Lorenz et al., 2009).”

“However, the revealed subnetworks encoding the different aspects of the tinnitus percept, e.g., the distress network, can be similar to other pathologies, such as pain (Moisset and Bouhassira, 2007; De Ridder et al., 2013, 2014).”

“…changes of brain stimulations (Filmer et al., 2014), including the state of the brain during stimulation (at rest or paired with a task; Horvath et al., 2014), any intake of substances such as nicotine (Thirugnanasambandam et al., 2011) and even the time of the day (Sale et al., 2007).”

“Tinnitus Tinnitus is a common and distressing disorder that is characterized by the perceived sensation of a sound in the absence of an external sound source (Langguth et al., 2012; De Ridder et al., 2014).”

“More recently, studies have applied bilateral tDCS, placing the anode electrode over the left DLPFC and the cathode over the right DLPFC instead of the right supraorbital region (e.g., Ferrucci et al., 2009; Brunoni et al., 2013, 2014; Valiengo et al., 2013, 2016, 2017).”

“…(e.g., Rollnik et al., 2000; Hajak et al., 2004; Cordes et al., 2010; Prikryl et al., 2013) and in addiction disorders—more specifically food (e.g., Van den Eynde et al., 2010; Barth et al., 2011), alcohol (e.g., Mishra et al., 2010) and cigarettes (e.g., Li et al., 2013; Prikryl et al., 2014).”

“These flexible hubs play an important role in switching from one state to the other in order to attend to the necessary task demands (Luft et al., 2014).”

“…et al. (2010) and Baeken et al. (2013, 2014) LF rTMS to the right DLPFC e.g., Klein et al. (1999), Januel et al. (2006), Fitzgerald et al. (2008), Bares et al. (2009) and Aguirre et al. (2011) Combined modulation of HF left DLPFC then LF right DLPFC during same session e.g., Hausmann et al.…”

“A subset of nodes (brain regions) with strong internal interaction and relatively weak external associations are represented as modules (van denHeuvel and Sporns, 2013b; Cocchi et al., 2015).”

“…the left DLPFC in healthy subjects have been shown to influence regional electrical activity in both surface level and deeper structures using resting-state EEG (Keeser et al., 2011b) and resting-state fMRI (Keeser et al., 2011a; Peña-Gómez et al., 2012; Park et al., 2013; Stagg et al., 2013).”

“…direct current stimulation Anode left auditory cortex—cathode contralateral supraorbital region e.g., Fregni et al. (2006), Garin et al. (2011), Shekhawat et al. (2013) and Forogh et al. (2016) Anode right DLPFC—cathode right DLPFC e.g., Vanneste et al. (2010), Vanneste and De Ridder (2011),…”

“, 2017), pain (Martinez et al., 2017), depression (Ochsner and Gross, 2005) and schizophrenia (Mayer et al.”

“…fMRI to investigate whether TBS can induce increased or decreased functional connectivity between specific brain areas (e.g., intrahemispheric or interhemispheric connectivity changes; e.g., Rahnev et al., 2013; Noh et al., 2015; Valchev et al., 2015; Mancini et al., 2017) in healthy subjects.”

“…have also investigated a combined modulation of HF left DLPFC rTMS and LF right DLPFC rTMS during the same sessions in the same patients (e.g., Hausmann et al., 2004; Fitzgerald et al., 2006a; Garcia-Toro et al., 2006; McDonald et al., 2006; Pallanti et al., 2010; Blumberger et al., 2012a;…”

“Task-related neuroimaging studies have also examined short-term reorganization in healthy subjects (e.g., O’Shea et al., 2007; Andoh and Paus, 2011; Chib et al., 2013; Weber et al., 2014) after non-invasive neuromodulation.”

“According to the rehabilitation potentiality of the Non Invasive Brain stimulation (NIBS) techniques [256, 257], further research in the future could be crucial to evaluate neuromodulation approaches to improve functions mediated by the cerebellum [233].”

“This change in oscillations may rapidly spread through brain networks to related brain regions [3,4].”

“For instance, focus on dysfunctional sensorimotor networks or limbic salience via non-invasive brain stimulation techniques like transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) may provide a therapeutic advantage for FND individuals [171,172].”

“There is increasing evidence that regional stimulation might improve tinnitus, but the optimal target (or multiple targets) of stimulation is still under debate (Chung et al., 2012; Lehner et al., 2016; Lehner et al., 2013; To et al., 2018; Wang et al., 2015).”

“The relatively strong prediction based upon spectral similarity is consistent with the observation that frequency spectrum coupling shapes brain network connectivity (To et al., 2018).”