Min-Fang Kuo

Partially non-linear stimulation intensity-dependent effects of direct current stimulation on motor cortex excitability in humans

•  Application of 2 mA cathodal transcranial direct current stimulation for 20 min results in cortical excitability enhancement instead of inhibition. •  Longer or more intensive stimulation does not necessarily increase its efficacy. •  Short intracortical inhibition and facilitation are shifted towards excitability enhancement after both 2 mA anodal and cathodal stimulation. •  I‐waves, input–output curves and cortical silent period are unaffected immediately after 2 mA stimulation.

Induction of Late LTP-Like Plasticity in the Human Motor Cortex by Repeated Non-Invasive Brain Stimulation

BACKGROUND Non-invasive brain stimulation enables the induction of neuroplasticity in humans, however, with so far restricted duration of the respective cortical excitability modifications. Conventional anodal transcranial direct current stimulation (tDCS) protocols including one stimulation session induce NMDA receptor-dependent excitability enhancements lasting for about 1 h. OBJECTIVE We aimed to extend the duration of tDCS effects by periodic stimulation, consisting of two stimulation sessions, since periodic stimulation protocols are able to induce neuroplastic excitability alterations stable for days or weeks, termed late phase long term potentiation (l-LTP), in animal slice preparations. Since both, l-LTP and long term memory formation, require gene expression and protein synthesis, and glutamatergic receptor activity modifications, l-LTP might be a candidate mechanism for the formation of long term memory. METHODS The impact of two consecutive tDCS sessions on cortical excitability was probed in the motor cortex of healthy humans, and compared to that of a single tDCS session. The second stimulation was applied without an interval (temporally contiguous tDCS), during the after-effects of the first stimulation (during after-effects; 3, or 20 min interval), or after the after-effects of the first stimulation had vanished (post after-effects; 3 or 24 h interval). RESULTS The during after-effects condition resulted in an initially reduced, but then relevantly prolonged excitability enhancement, which was blocked by an NMDA receptor antagonist. The other conditions resulted in an abolishment, or a calcium channel-dependent reversal of neuroplasticity. CONCLUSION Repeated tDCS within a specific time window is able to induce l-LTP-like plasticity in the human motor cortex.

Therapeutic effects of non-invasive brain stimulation with direct currents (tDCS) in neuropsychiatric diseases.

Neuroplasticity, which is the dynamic structural and functional reorganization of central nervous system connectivity due to environmental and internal demands, is recognized as a major physiological basis for adaption of cognition, and behavior, and thus of utmost importance for normal brain function. Pathological alterations of plasticity are increasingly explored as pathophysiological foundation of diverse neurological and psychiatric diseases. Non-invasive brain stimulation techniques (NIBS), such as repetitive transcranial magnetic stimulation (rTMS), and transcranial direct current stimulation (tDCS), are able to induce and modulate neuroplasticity in humans. Therefore, they have potential to alter pathological plasticity on the one hand, and foster physiological plasticity on the other, in neuropsychiatric diseases to reduce symptoms, and enhance rehabilitation. tDCS is an emerging NIBS tool, which induces glutamatergic plasticity via application of relatively weak currents through the scalp in humans. In the last years its efficacy to treat neuropsychiatric diseases has been explored increasingly. In this review, we will give an overview of pathological alterations of plasticity in neuropsychiatric diseases, gather clinical studies involving tDCS to ameliorate symptoms, and discuss future directions of application, with an emphasis on optimizing stimulation effects.

Shaping the Optimal Repetition Interval for Cathodal Transcranial Direct Current Stimulation (tDCS)

Transcranial DC stimulation (tDCS) is a plasticity-inducing noninvasive brain stimulation tool with various potential therapeutic applications in neurological and psychiatric diseases. Currently, the duration of the aftereffects of stimulation is restricted. For future clinical applications, stimulation protocols are required that produce aftereffects lasting for days or weeks. Options to prolong the effects of tDCS are further prolongation or repetition of tDCS. Nothing is known thus far about optimal protocols in this behalf, although repetitive stimulation is already performed in clinical applications. Thus we explored the effects of different break durations on cathodal tDCS-induced cortical excitability alterations. In 12 subjects, two identical periods of cathodal tDCS (9-min duration; 1 mA) with an interstimulation interval of 0 (no break), 3, or 20 min or 3 or 24 h were performed. The results indicate that doubling stimulation duration without a break prolongs the aftereffects from 60 to 90 min after tDCS. When the second stimulation was performed during the aftereffects of the first, a prolongation and enhancement of tDCS-induced effects for ≤ 120 min after stimulation was observed. In contrast, when the second stimulation followed the first one after 3 or 24 h, the aftereffects were initially attenuated, or abolished, but afterwards re-established for up to 120 min after tDCS in the 24-h condition. These results suggest that, for prolonging the aftereffects of cathodal tDCS, stimulation interval might be important.

Timing-Dependent Modulation of Associative Plasticity by General Network Excitability in the Human Motor Cortex

Associative neuroplasticity, which encompasses the modification of synaptic strength by coactivation of two synaptic inputs, has been linked to learning processes. Because unlimited plasticity destabilizes neuronal networks, homeostatic rules were proposed and experimentally proven that control for the amount and direction of plasticity dependent on background network activity. Accordingly, low background activity would enhance facilitatory plasticity, whereas high background activity would inhibit it. However, the impact of background excitability on associative plasticity has not been studied so far in humans. Facilitatory associative plasticity was induced by paired associative stimulation (PAS) in the human motor cortex, whereas background activity was enhanced or diminished by transcranial direct current stimulation (tDCS). When applied before PAS, excitability-enhancing tDCS also boosted the efficacy of PAS, whereas excitability-diminishing tDCS turned it into inhibition. Thus, previous background activity does not influence associative plasticity homeostatically. When tDCS and PAS were applied simultaneously, now in accordance with homeostatic rules of neuroplasticity, reduced background activity resulted in a prolonged excitability enhancement by PAS, whereas enhanced background activity turned it into inhibition. We conclude that background network activity can influence associative plasticity homeostatically. However, only simultaneous modulation of both parameters is in accordance with homeostatic concepts. These findings might be of importance for the development of plasticity-inducing stimulation protocols supporting information processing in humans.

Effects of Transcranial Electrical Stimulation on Cognition

Alterations of cortical excitability, oscillatory as well as non-oscillatory, are physiological derivates of cognitive processes, such as perception, working memory, learning, and long-term memory formation. Since noninvasive electrical brain stimulation is capable of inducing alterations in the human brain, these stimulation approaches might be attractive tools to modulate cognition. Transcranial direct current stimulation (tDCS) alters spontaneous cortical activity, while transcranial alternating current stimulation (tACS) and transcranial random noise stimulation (tRNS) are presumed to induce or interfere with oscillations of cortical networks. Via these mechanisms, the respective stimulation techniques have indeed been shown to modulate cognitive processes in a multitude of studies conducted during the last years. In this review, we will gather knowledge about the potential of noninvasive electrical brain stimulation to study and modify cognitive processes in healthy humans and discuss directions of future research.

Serotonin Affects Transcranial Direct Current–Induced Neuroplasticity in Humans

BACKGROUND Modulation of the serotonergic system affects long-term potentiation (LTP) and long-term depression (LTD), the likely neurophysiologic derivates of learning and memory formation, in animals and slice preparations. Serotonin-dependent modulation of plasticity has been proposed as an underlying mechanism for depression. However, direct knowledge about the impact of serotonin on neuroplasticity in humans is missing. Here we explore the impact of the serotonin reuptake blocker citalopram on plasticity induced by transcranial direct current stimulation (tDCS) in humans in a single-blinded, placebo-controlled, randomized crossover study. METHODS In 12 healthy subjects, anodal excitability-enhancing or cathodal excitability-diminishing tDCS was applied to the motor cortex under a single dose of 20-mg citalopram or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation (TMS). RESULTS Under placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for about 60-120 min. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS, whereas it turned cathodal tDCS-induced inhibition into facilitation. CONCLUSIONS Serotonin has a prominent impact on neuroplasticity in humans, which is in favor for facilitatory plasticity. Taking into account serotonergic hypoactivity in depression, this might explain deficits of learning and memory formation. Moreover, the results suggest that for therapeutic brain stimulation in depression and other neuropsychiatric diseases (e.g., in neurorehabilitation), serotonergic reinforcement may enhance facilitatory aftereffects and thereby increase the efficacy of these tools.

Dose-Dependent Inverted U-Shaped Effect of Dopamine (D2-Like) Receptor Activation on Focal and Nonfocal Plasticity in Humans

The neuromodulator dopamine (DA) has multiple modes of action on neuroplasticity induction and modulation, depending on subreceptor specificity, concentration level, and the kind of stimulation-induced plasticity. To determine the dosage-dependent effects of D2-like receptor activation on nonfocal and focal neuroplasticity in the human motor cortex, different doses of ropinirole (0.125, 0.25, 0.5, and 1.0 mg), a D2/D3 dopamine agonist, or placebo medication were combined with anodal and cathodal transcranial direct current stimulation (tDCS) protocols, which induce nonfocal plasticity, or paired associative stimulation (PAS, ISI of 10 or 25 ms), which generates focal plasticity, in healthy volunteers. D2-like receptor activation produced an inverted “U”-shaped dose–response curve on plasticity for facilitatory tDCS and PAS and for inhibitory tDCS. Here, high or low dosages of ropinirole impaired plasticity. However, no dose-dependent response effect of D2-like receptor activation was evident for focal inhibitory plasticity. In general, our study supports the assumption that modulation of D2-like receptor activity exerts dose-dependent inhibitory or facilitatory effects on neuroplasticity in the human motor cortex depending on the topographic specificity of plasticity.

Focusing Effect of Acetylcholine on Neuroplasticity in the Human Motor Cortex

Cholinergic neuromodulation is pivotal for arousal, attention, and cognitive processes. Loss or dysregulation of cholinergic inputs leads to cognitive impairments like those manifested in Alzheimers disease. Such dysfunction can be at least partially restored by an increase of acetylcholine (ACh). In animal studies, ACh selectively facilitates long-term excitability changes induced by feed-forward afferent input. Consequently, it has been hypothesized that ACh enhances the signal-to-noise ratio of input processing. However, the neurophysiological foundation for its ability to enhance cognition in humans is not well documented. In this study we explore the effects of rivastigmine, a cholinesterase inhibitor, on global and synapse-specific forms of cortical plasticity induced by transcranial direct current stimulation (tDCS) and paired associative stimulation (PAS) on 10–12 healthy subjects, respectively. Rivastigmine essentially blocked the induction of the global excitability enhancement elicited by anodal tDCS and revealed a tendency to first reduce and then stabilize cathodal tDCS-induced inhibitory aftereffects. However, ACh enhanced the synapse-specific excitability enhancement produced by facilitatory PAS and consolidated the inhibitory PAS-induced excitability diminution. These findings are in line with a cholinergic focusing effect that optimizes the detection of relevant signals during information processing in humans.

Limited impact of homeostatic plasticity on motor learning in humans

Neuroplasticity is the adaptive modification of network connectivity in response to environmental demands and has been identified as a major physiological correlate of learning. Since unrestricted neuroplastic modifications of network connectivity will result in a de-stabilization of the system, metaplastic modification rules have been proposed for keeping plastic connectivity changes within a useful dynamic range. In this connection, the modification threshold to achieve synaptic strengthening is thought to correlate negatively with the history of activity of the respective neurons, i.e. high previous activity enhances the threshold for synaptic strengthening and vice versa. However, the relevance of metaplasticity for actual learning processes has not been tested so far. We reduced or enhanced motor cortex excitability before performance of the serial reaction time task (SRTT), a sequential motor learning paradigm, and a reaction time task (RTT) by transcranial direct current stimulation (tDCS). If homeostatic rules apply, excitability-diminishing cathodal tDCS should improve subsequent motor learning, especially if combined with the partial NMDA receptor-agonist d-cycloserine, which selectively enhances efficacy of active receptors, while excitability-enhancing anodal tDCS should reduce it. Only the results for anodal tDCS, when combined with d-cycloserine, were in accordance with the rules of homeostatic plasticity. We conclude that homeostatic plasticity, as tested here, has a limited influence on implicit sequential motor learning.