Optimizing the neuroplastic effects of cathodal transcranial direct current stimulation over the primary motor cortex and transferability to prefrontal cortex

Die Behandlungsmöglichkeiten neurologischer und neuropsychiatrischer Erkrankungen haben sich in den letzten Jahrzehnten deutlich verbessert, sind aber immer noch eingeschränkt. Eine Dysregulation oder Störung der Neuroplastizität ist bei vielen psychischen und Hirnfunktionsstörungen beteiligt. Hier sind nicht-invasive Hirnstimulationstechniken relevant, die die Plastizität des Gehirns modulieren, ohne die physische Integrität des Schädels zu beeinträchtigen. Eine davon, die transkranielle Gleichstromstimulation (tDCS), hat in mehreren klinischen Pilotstudien vielversprechende Ergebnisse zur Verminderung von Symptomen auf der Grundlage von Störungen des Zentralnervensystems gezeigt. Diese Effekte sind jedoch häufig moderat, zeigen eine nichtlineare Dosisabhängigkeit und eine interindividuelle Variabilität. Um die Wirksamkeit dieses Verfahrens zu verbessern, sind länger anhaltende und homogenere Effekte erforderlich. Dies erfordert neuartige, verbesserte Interventionsstrategien. Darüber hinaus wurden die neuromodulatorischen Wirkungen von tDCS auf den primären motorischen Kortex bisher weitgehend als Grundlage für die Anwendung dieser Intervention auf andere Hirnregionen herangezogen, während eine direkte Untersuchung der physiologischen Wirkungen von tDCS auf nichtmotorische Regionen weitgehend fehlt. Die Arbeit zielt darauf ab, diese Herausforderungen durch den Einsatz innovativer neurophysiologischer und mathematischer Techniken anzugehen, um die Wirksamkeit des kathodalen tDCS über dem primären motorischen Kortex zu verbessern, aber auch die Übertragbarkeit der Ergebnisse auf den präfrontalen Kortex zu untersuchen. Zu diesem Zweck titrierten wir im ersten Schritt systematisch kathodale tDCS-Parameter für das humane motorische Kortexmodell mit unterschiedlichen Intensitäten (1, 2 und 3 mA) und Stimulationsdauern (15, 20 und 30 min). Die Ergebnisse zeigten intensitätsabhängige nichtlineare Effekte, bei denen die Stimulation mit 1 mA eine signifikante Verringerung der Amplitude der motorisch evozierten Potentiale (MEP) induzierte, während die Stimulation mit 2 mA zu einer signifikanten Erhöhung der kortikospinalen Erregbarkeit führte. Protokolle mit höherer Stimulationsintensität (insbesondere Stimulation mit 3 mA) induzierten erneut eine signifikante Verringerung der Erregbarkeit, die etwa eineinhalb Stunden nach der Stimulation andauerte, und waren daher effizienter als die anderen Protokolle. Im zweiten Schritt haben wir untersucht, ob wiederholte tDCS-Protokolle mit unterschiedlichen Intervallen die Nacheffekte verlängern können. Wir verglichen die Auswirkungen von Einzelinterventionen mit konventioneller (1 mA für 15 Minuten) und optimierter kathodaler tDCS (3 mA für 20 Minuten) mit den Auswirkungen einer wiederholten Anwendung in Intervallen von 20 Minuten und 24 Stunden auf die Erregbarkeit des primären motorischen Kortex, basierend auf tierexperimentellen Befunden, dass kurze, aber nicht lange Intervalle zwischen einzelnen Interventionen eine langanhaltende Plastizität erzeugen. Die Ergebnisse zeigten, dass die Dauer der Nacheffekte wiederholter konventioneller und optimierter Protokolle mit kurzen Intervallen im Vergleich zu den jeweiligen Einzelinterventionsprotokollen nahezu unverändert blieb. Für das lange Intervall (24 h) veränderte die Stimulation mit dem herkömmlichen Protokoll die jeweiligen Nachwirkungen nicht signifikant, während sie die Wirksamkeit des optimierten Protokolls im Vergleich zu den jeweiligen Einzelinterventionen verringerte. Ein wichtiges Ergebnis der ersten Studie waren die beobachteten nichtlinearen intensitätsabhängigen Effekte von tDCS, die eine Erklärung für teilweise heterogene Ergebnisse der kathodalen Stimulation bieten können, allerdings hinsichtlich ihrer neurophysiologischen Grundlagen bisher nur unzureichend untersucht waren. Im dritten Schritt haben wir daher die zugrunde liegenden Mechanismen dieser nonlinearen Effekte untersucht. Da tDCS eine NMDA-Rezeptor-abhängige Neuroplastizität erzeugt, die Kalzium-abhängig ist, kann eine solche Nichtlinearität möglicherweise durch unterschiedliche durch die Intervention induzierte Kalziumkonzentrationen erklärt werden, die die Richtung der Plastizität steuern. Wir verabreichten daher den Kalziumkanalblocker Flunarizin in niedrigen (2,5 mg), mittleren (5 mg) oder hohen (10 mg) Dosierungen vor der kathodalen tDCS des motorischen Kortex mit 3 mA für 20 Minuten. Die Ergebnisse zeigten, dass die durch kathodale tDCS hoher Intensität induzierten inhibitorischen Nachwirkungen bei niedrigen, mittleren bzw. hohen Dosierungen eines Kalziumblockers nicht verändert, verringert oder in eine Erregbarkeitserhöhung modifiziert wurden, was die Kalzium-abhängige Direktionalität von tDCS-induzierter Neuroplastizität bestätigt. Das Ergebnis der ersten und zweiten Studie zeigten eine relevante interindividuelle Variabilität der tDCS-Effekte, die eine weitere Quelle für die begrenzte Wirksamkeit dieser Intervention sein könnte. Jüngste In-vivo-Experimente und Computerstudien am Menschen zeigten, dass das tDCS-induzierte elektrische Feld (EF) stark von der individuellen Anatomie des Gehirns und den Leitfähigkeitseigenschaften des Gewebes abhängt. Die EF-Variabilität könnte daher ein wichtiger Faktor für heterogene Ergebnisse der tDCS sein. Im vierten Schritt, basierend auf neurophysiologischen Daten, die in früheren Studien unserer Gruppe erhoben wurden, die tDCS-induzierte MEP- (induziert durch transkranielle Magnetstimulation (TMS)) und zerebrale Blutfluss-Veränderungen (CBF; gemessen durch funktionelle Magnetresonanztomographie (MRT) über arterielles Spin-Labelling) erfaßten, untersuchten wir den Zusammenhang zwischen einzelnen anatomischen Faktoren, tDCS-induziertem EF und den jeweiligen physiologischen Parametern auf der Ebene des Individuums. Zu diesem Zweck wurde für jeden Teilnehmer ein MRT-basiertes realistisches Kopfmodell entworfen, um 1) anatomische Faktoren zu berechnen und 2) die tDCS- und TMS-induzierten elektrischen Felder (EF) zu simulieren. Anschließend untersuchten wir auf regionaler Ebene, welche einzelnen anatomischen Faktoren die simulierten EFs erklären. Schließlich untersuchten wir, welche spezifischen anatomischen und / oder EF-Faktoren die neurophysiologischen Ergebnisse der tDCS vorhersagten. Die Ergebnisse zeigten, dass von den untersuchten anatomischen Faktoren höhere EF-Werte mit einem geringeren Abstand zwischen Elektrode und Kortex (ECD) und einer geringeren Dicke des Liquor cerebrospinalis (CSF) verbunden waren. Zusätzlich waren CSF-Dicke und ECD negativ korreliert, während EFs positiv mit tDCS-induzierten physiologischen Veränderungen korreliert waren. Schließlich untersuchten wir im fünften Schritt die Übertragbarkeit der durch kathodale tDCS induzierten Neuroplastizität vom motorischen auf den präfrontalen Kortex. Die neurophysiologischen Wirkungen von tDCS auf den primärmotorischen Kortex wurden bereits in einer vielzahl von Studien untersucht. Viel weniger ist jedoch hinsichtlich physiologischer Effekte der tDCS auf nichtmotorische Bereiche wie den präfrontalen Kortex bekannt, der eine wichtige Basis für vielfältige kognitive Funktionen darstellt und dessen Dysfunktionen an neuropsychiatrischen Störungen beteiligt sind. Zu diesem Zweck wurde kathodale tDCS mit niedrigen, mittleren und hohen Dosierungen oder eine Placebo-Stimulation über dem primärmotorischen und dorsolateralen präfrontalen Kortex appliziert. Die Nacheffekte der tDCS wurden mittels TMS-Elektroenzephalographie (EEG) und TMS-MEP auf regionaler Ebene für die Ergebnisparameter TMS-evozierte Potentiale (TEP), TMS-evozierte Oszillationen und MEP-Amplitudenänderungen bewertet. Die Ergebnisse zeigten eine dosisabhängige nichtlineare neurophysiologische Wirkung der tDCS über dem motorischen Kortex, die nicht vollständig auf die Ergebnisse der tDCS über dem präfrontalen tDCS übertragbar war. Niedrige und hohe Dosierungen der tDCS über dem motorischen Kortex reduzierten frühe positive TEP-Peaks und MEP-Amplituden, während eine Erhöhung der Amplituden dieser Potentiale für primärmotorische tDCS mit mittlerer Dosierung beobachtet wurde. Im Gegensatz dazu reduzierte präfrontale tDCS mit niedriger, mittlerer und hoher Dosierung die frühen positiven TEP-Amplituden gleichermaßen. Darüber hinaus wurden für beide kortikalen Bereiche keine tDCS-induzierten neuromodulatorischen Effekte auf späte TEP-Amplituden (mit Ausnahme präfrontaler tDCS mit niedriger Dosierung) oder TMS-evozierte Oszillationen beobachtet. Zusammengenommen hat diese Arbeit unter Verwendung innovativer neurophysiologischer, Computergestützter und bildgebender Verfahren wichtige Aspekte in Bezug auf tDCS-induzierte neuroplastische Effekte untersucht, und liefert neue Erkenntnisse für zukünftige Anwendungen von tDCS in Grundlagen- und klinischen Studien.Major advances have been made in treatment of neurological and neuropsychiatric disorders; they have however still significant limitations. A vast body of evidence shows a dysregulation or disruption of neuroplasticity in mental and brain disorders. Here, non-invasive brain stimulation techniques come into play, which modulate brain plasticity without disrupting the integrity of the skull. One of those, transcranial direct current stimulation (tDCS), has shown promising results in several pilot clinical studies to improve symptoms of central nervous system disorders; but, in general, effects are often moderate, show nonlinear dosage-dependency, and interindividual variability. For improving the efficacy of this tool, more sustained, and homogeneous effects are required. This requires novel, improved intervention strategies. In addition, neuromodulatory effects of tDCS over the primary motor cortex were largely taken as a template so far for the use of this intervention over other brain regions, whereas a direct exploration of the physiological effects of tDCS on non-motor regions is largely missing. The thesis aims to address these challenges, by utilizing advanced neurophysiological and computational techniques, aiming to improve the efficacy of cathodal tDCS over the primary motor cortex, but also to explore the transferability of the results to the prefrontal cortex. To this end, we at the first step systematically titrated cathodal tDCS parameters for the human motor cortex model with different intensities (1, 2, and 3mA) and durations (15, 20 and 30 min). The results revealed intensity-dependent nonlinear effects, in which stimulation with 1 mA induced a significant motor evoked potentials (MEP) amplitude diminution, while stimulation with 2 mA resulted in a significant corticospinal excitability enhancement. Protocols with higher stimulation intensity (specifically stimulation with 3 mA) induced again a significant excitability diminution lasting for about one and half hour after stimulation, and thus were more efficient than the other protocols. At the second step, we explored if repeated tDCS protocols with different intervals can prolong the after-effects. We compared the impact of single interventions of conventional (1mA for 15min) and optimized cathodal tDCS (3mA for 20min) with the effects of repeated application with intervals of 20 min and 24 hours on primary motor cortex excitability, based on the assumption derived from animal models that short, but not long intervals induce late phase plasticity. The results revealed that the duration of after-effects of repeated conventional and optimized protocols with short intervals remained nearly unchanged, as compared to the respective single intervention protocols. For the long interval (24 h), stimulation with the conventional protocol did not significantly alter respective after-effects, while it reduced the efficacy of the optimized protocol, as compared with respective single interventions. One important outcome of the first study were the observed nonlinear intensity-dependent effects of tDCS, which might be an explanation for sometimes heterogeneous outcomes of cathodal stimulation, and are not well explained at the neurophysiological level. At the third step we therefore explored the underlaying mechanisms of this nonlinearity. Since tDCS generates NMDA receptor-dependent neuroplasticity, which has calcium channel properties, such non-linearity can likely be explained by different levels of calcium concentration induced by the intervention, which control for the directionality of plasticity. We therefore administrated the calcium channel blocker flunarizine in low (2.5 mg), medium (5 mg) or high (10 mg) dosages before cathodal motor cortex tDCS of 3mA for 20min. The results revealed that the inhibitory after-effects induced by high intensity cathodal tDCS were unchanged, diminished, or converted to excitability enhancement with low, medium and high dosages of a calcium blocker, respectively, which confirms the calcium-dependent directionality of tDCS-induced neuroplasticity. The outcome of the first and second studies showed also relevant inter-individual variability of tDCS effects, which could be another source of limited efficacy of this intervention. Recent human in-vivo experiments and computational studies indicated that the tDCS-induced electrical field (EF) depends strongly on individual brain anatomy and tissue conductivity properties. EF variability might thus be an important factor for heterogeneous outcomes of tDCS. At the fourth step, based on neurophysiological data obtained in former studies of our group, which explored tDCS-altered MEP (induced by transcranial magnetic stimulation (TMS)) and cerebral blood flow (CBF; measured by functional magnetic resonance imaging (MRI) via arterial spin labeling), we investigated the association between individual anatomical factors and tDCS-induced EF, and the respective physiological outcomes at the level of the individual. To this end, for each participant, a MRI-based realistic head model was designed to 1) calculate anatomical factors and 2) simulate the tDCS- and TMS-induced electrical fields (EF). We then investigated at the regional level which individual anatomical factors explain the simulated EFs. Finally, we explored which specific anatomical and/or EF factors predicted the neurophysiological outcomes of tDCS. The results indicated that, of the included anatomical factors, higher EF values were associated with lower electrode to cortex distance (ECD), and cerebrospinal fluid (CSF) thickness. In addition, CSF thickness, and ECD were negatively correlated, whereas EFs were positively correlated with tDCS-induced physiological changes. Finally, at the fifth step, we explored the transferability of cathodal tDCS-induced neuroplasticity from the motor to the prefrontal cortex. Neurophysiological effects of tDCS have been extensively studied over the primary motor cortex. Much less is however known for its effects over non-motor areas, such as the prefrontal cortex, which is the neuronal foundation for many high-level cognitive functions, and involved in neuropsychiatric disorders. To this end, cathodal tDCS was applied with low, medium, and high dosages, or as sham stimulation, and applied over the primary motor and dorsolateral prefrontal cortex. After-effects of tDCS were evaluated via TMS-electroencephalography (EEG), and TMS-MEP at the regional level, for the outcome parameters TMS-evoked potentials (TEP), TMS-evoked oscillations, and MEP amplitude alterations. The results indicated a dosage-dependent nonlinear neurophysiological effect of motor cortex tDCS, which was not one-to-one transferable to the results of prefrontal tDCS. Low and high dosages of motor cortex tDCS reduced early positive TEP peaks, and MEP amplitudes, while an enhancement was observed for medium dosage motor cortex tDCS (early positive TEP peak and MEP amplitudes). In contrast, prefrontal low, medium and high dosage tDCS uniformly reduced the early positive TEP peak amplitudes. Furthermore, for both cortical areas, tDCS-induced neuromodulatory effects were not observed for late TEP peaks (with the exception of low-dosage prefrontal tDCS), nor TMS-evoked oscillations. Taken together, using advanced neurophysiological, computational and neuroimaging techniques, this thesis has addressed important challenges regarding tDCS-induced neuroplastic effects, and thus provides new insight for future applications of tDCS in basic and clinical studies

Induction of long-term potentiation-like plasticity in the primary motor cortex with repeated anodal transcranial direct current stimulation - better effects with intensified protocols?

Background: A single session of anodal tDCS induces LTP-like plasticity which lasts for about 1 h, while repetition of stimulation within a time interval of 30 min results in late-phase effects lasting for at least 24 h with standard stimulation protocols. Objective: In this pilot study, we explored if the after-effects of a recently developed intensified single session stimulation protocol are relevantly prolonged in the motor cortex by repetition of this intervention. Methods: 16 healthy right-handed subjects participated in this study. The effects of an intensified (3 mA-20min) and a standard anodal tDCS protocol (1 mA-15min) with short (20 min) and long (3 h) repetition intervals were compared with the effects of respective single session tDCS protocols (3 mA-20min, 1 mA-15min, and Sham). Cortical excitability alterations were monitored by single-pulse TMS-elicited MEPs. Results: Compared to sham, both single session tDCS protocols (1 mA-15min, and 3 mA-20min) resulted in cortical excitability enhancements lasting for about 30 min after stimulation. The short repetition interval (20 min) resulted in a prolongation of after-effects for the standard protocol, which lasted for more than 24 h after stimulation. For the intensified protocol, the prolongation of after-effects was limited to 120 min after stimulation. The long repetition interval (3 h) resulted in no excitabilityenhancing after-effects for the intensified, and only minor excitability enhancement within the first 30 min after the intervention for the standard protocol. Conclusion: These results suggest a non-linearity of late-phase LTP-like plasticity induction, which was dependent not only on the interval of intervention repetition, but also on other protocol characteristics, including intensity, and duration of tDCS. Further studies in larger samples are needed to confirm these results

Corrigendum to "Repeated stimulation of the dorsolateral-prefrontal cortex improves executive dysfunctions and craving in drug addiction: A randomized, double-blind, parallel-group study" [Brain Stimul 13 (3) (2020) 582-593].

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An Arbitrary Waveform Wearable Neuro-stimulator System for Neurophysiology Research on Freely Behaving Animals

Portable wireless neuro-stimulators have been developed to facilitate long-term cognitive and behavioral studies on the central nervous system in freely moving animals. These stimulators can provide precisely controllable input(s) to the nervous system, without distracting the animal attention with cables connected to its body. In this study, a low power backpack neuro-stimulator was developed for animal brain researches that can provides arbitrary stimulus waveforms for the stimulation, while it is small and light weight to be used for small animals including rats. The system consists of a controller that uses an RF link to program and activate a small and light microprocessor-based stimulator. A Howland current source was implemented to produce precise current controlled arbitrary waveform stimulations. The system was optimized for ultra-low power consumption and small size. The stimulator was first tested for its electrical specifications. Then its performance was evaluated in a rat experiment when electrical stimulation of medial longitudinal fasciculus induced circling behavior. The stimulator is capable of delivering programmed stimulations up to ± 2 mA with adjusting steps of 1 μA, accuracy of 0.7% and compliance of 6 V. The stimulator is 15 mm × 20 mm × 40 mm in size, weights 13.5 g without battery and consumes a total power of only 5.l mW. In the experiment, the rat could easily carry the stimulator and demonstrated the circling behavior for 0.1 ms current pulses of above 400 μA. The developed system has a competitive size and weight, whereas providing a wide range of operation and the flexibility of generating arbitrary stimulation patterns ideal for long-term experiments in the field of cognitive and neuroscience research

Consideration of Individual Brain Geometry and Anisotropy on the Effect of tDCS

Introduction: The response variability between subjects, which is one of the fundamental challenges facing transcranial direct current stimulation (tDCS), can be investigated by understanding how the current is distributed through the brain. This understanding can be obtained by means of computational methods utilizing finite element (FE) models. Materials and Methods: In this study, the effect of realistic geometry and white matter anisotropy on the head electrical current density intensity (CDI) distribution was measured using a magnetic resonance imaging (MRI)-derived FE model at the whole brain, below electrodes, and cellular levels. Results: The results revealed that on average, the real geometry changes the CDI in gray matter and the WM by 29% and 55%, respectively. In addition, WM anisotropy led to an 8% and 36% change of CDI across GM and WM, respectively. The results indicated that for this electrode configuration, the maximum CDI occurs not below the electrode, but somewhere between the electrodes, and its locus varies greatly between individuals.  In addition, by investigating the effect of current density components on cellular excitability, significant individual differences in the level of excitability were detected. Conclusion: Accordingly, consideration of the real geometry in computational modeling is vital. In addition, WM anisotropy does not significantly influence the CDI on the gray matter surface, however, it alters the CDI inside the brain; therefore, it can be taken into account, especially, when stimulation of brain’s internal regions is proposed. Finally, to predict the outcome result of tDCS, the examination of its effect at the cellular level is of great importance

Probing the relevance of repeated cathodal transcranial direct current stimulation over the primary motor cortex for prolongation of after‐effects

Transcranial direct current stimulation (tDCS) has shown promising results in pilot studies as a therapeutic intervention in disorders of the central nervous system, but more sustained effects are required for clinical application. To address this issue, one possible solution is the use of repeated stimulation protocols. Previous studies indicated the possibility of extending the after‐effects of single intervention cathodal tDCS by repeating the tDCS, with relatively short intervals between repetitions being most effective. In this study, we thus investigated the effects of repeated stimulation protocols at short and long intervals, for a conventional tDCS protocol (1 mA for 15 min) and a newly developed optimized protocol (3 mA for 20 min). In 16 healthy participants, we compared single interventions of conventional and optimized protocols, repeated application of these protocols at intervals of 20 min and 24 h, and a sham tDCS session. tDCS‐induced neuroplastic after‐effects were then monitored with transcranial magnetic stimulation (TMS)‐induced motor evoked potentials (MEPs) until the following evening after stimulation. The results revealed that the duration of the after‐effects of repeated conventional and optimized protocols with short intervals remained nearly unchanged compared to the respective single intervention protocols. For the long‐interval (24 h) protocol, stimulation with the conventional protocol did not significantly alter respective after‐effects, while it reduced the efficacy of the optimized protocol, compared with respective single interventions. Thus late‐phase plasticity could not be induced by a single repetition of stimulation in this study, but repetition reduced the efficacy of stimulation protocols with higher intensities. This study provides further insights into the dependency of tDCS‐induced neuroplasticity on stimulation parameters, and therefore delivers crucial information for future tDCS applications

Expanding the parameter space of anodal transcranial direct current stimulation of the primary motor cortex

Size and duration of the neuroplastic effects of tDCS depend on stimulation parameters, including stimulation duration and intensity of current. The impact of stimulation parameters on physiological effects is partially non-linear. To improve the utility of this intervention, it is critical to gather information about the impact of stimulation duration and intensity on neuroplasticity, while expanding the parameter space to improve efficacy. Anodal tDCS of 1–3 mA current intensity was applied for 15–30 minutes to study motor cortex plasticity. Sixteen healthy right-handed non-smoking volunteers participated in 10 sessions (intensity-duration pairs) of stimulation in a randomized cross-over design. Transcranial magnetic stimulation (TMS)-induced motor-evoked potentials (MEP) were recorded as outcome measures of tDCS effects until next evening after tDCS. All active stimulation conditions enhanced motor cortex excitability within the first 2 hours after stimulation. We observed no significant differences between the three stimulation intensities and durations on cortical excitability. A trend for larger cortical excitability enhancements was however observed for higher current intensities (1 vs 3 mA). These results add information about intensified tDCS protocols and suggest that the impact of anodal tDCS on neuroplasticity is relatively robust with respect to gradual alterations of stimulation intensity, and duration

Exploring and optimizing the neuroplastic effects of anodal transcranial direct current stimulation over the primary motor cortex of older humans

BACKGROUND: tDCS modulates cortical plasticity and has shown potential to improve cognitive/motor functions in healthy young humans. However, age-related alterations of brain structure and functions might require an adaptation of tDCS-parameters to achieve a targeted plasticity effect in older humans and conclusions obtained from young adults might not be directly transferable to older adults. Thus, our study aimed to systematically explore the association between tDCS-parameters and induced aftereffects on motor cortical excitability to determine optimal stimulation protocols for older individuals, as well as to investigate age-related differences of motor cortex plasticity in two different age groups of older adults. METHODS: 32 healthy, volunteers from two different age groups of Young-Old (50–65 years, n = 16) and Old-Old (66–80 years, n = 16) participated in this study. Anodal tDCS was applied over the primary motor cortex, with respective combinations of three intensities (1, 2, and 3 mA) and durations (15, 20, and 30 min), in a sham-controlled cross-over design. Cortical excitability alterations were monitored by single-pulse TMS-induced MEPs until the next day morning after stimulation. RESULTS: All active stimulation conditions resulted in a significant enhancement of motor cortical excitability in both age groups. The facilitatory aftereffects of anodal tDCS did not significantly differ between age groups. We observed prolonged plasticity in the late-phase range for two protocols with the highest stimulation intensity (i.e., 3 mA-20 min, 3 mA-30 min). CONCLUSIONS: Our study highlights the role of stimulation dosage in tDCS-induced neuroplastic aftereffects in the motor cortex of healthy older adults and delivers crucial information about optimized tDCS protocols in the domain of the primary motor cortex. Our findings might set the grounds for the development of optimal stimulation protocols to reinstate neuroplasticity in different cortical areas and induce long-lasting, functionally relevant plasticity in normal aging and in pathological conditions, which would require however systematic tDCS titration studies over respective target areas

The impact of individual electrical fields and anatomical factors on the neurophysiological outcomes of tDCS: A TMS-MEP and MRI study

BACKGROUND: Transcranial direct current stimulation (tDCS), a neuromodulatory non-invasive brain stimulation technique, has shown promising results in basic and clinical studies. The known interindividual variability of the effects, however, limits the efficacy of the technique. Recently we reported neurophysiological effects of tDCS applied over the primary motor cortex at the group level, based on data from twenty-nine participants who received 15min of either sham, 0.5, 1.0, 1.5 or 2.0 mA anodal, or cathodal tDCS. The neurophysiological effects were evaluated via changes in: 1) transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEP), and 2) cerebral blood flow (CBF) measured by functional magnetic resonance imaging (MRI) via arterial spin labeling (ASL). At the group level, dose-dependent effects of the intervention were obtained, which however displayed interindividual variability. METHOD: In the present study, we investigated the cause of the observed inter-individual variability. To this end, for each participant, a MRI-based realistic head model was designed to 1) calculate anatomical factors and 2) simulate the tDCS- and TMS-induced electrical fields (EFs). We first investigated at the regional level which individual anatomical factors explained the simulated EFs (magnitude and normal component). Then, we explored which specific anatomical and/or EF factors predicted the neurophysiological outcomes of tDCS. RESULTS: The results highlight a significant negative correlation between regional electrode-to-cortex distance (rECD) as well as regional CSF (rCSF) thickness, and the individual EF characteristics. In addition, while both rCSF thickness and rECD anticorrelated with tDCS-induced physiological changes, EFs positively correlated with the effects. CONCLUSION: These results provide novel insights into the dependency of the neuromodulatory effects of tDCS on individual physical factors