Acute and chronic effects of noradrenergic enhancement on transcranial direct current stimulation‐induced neuroplasticity in humans

Abstract

Noradrenaline affects cognition and motor learning processes via its impact on long-term potentiation (LTP) and depression (LTD). We aimed to explore the impact of single dose and chronic administration of the selective noradrenaline reuptake inhibitor (NRI) reboxetine (RBX) on plasticity induced by transcranial direct current stimulation (tDCS) in healthy humans via a double-blinded, placebo-controlled, randomized crossover study. Sixteen healthy volunteers received placebo or single dose RBX (8 mg) before anodal or cathodal tDCS of the primary motor cortex. Afterwards, the same subjects took RBX (8 mg day ) consecutively for 21 days. During this period, two additional interventions were performed (RBX with anodal or cathodal tDCS), to explore the impact of chronic RBX treatment on plasticity. Plasticity was monitored by motor-evoked potential amplitudes elicited by transcranial magnetic stimulation. Chronic administration of RBX increased and prolonged the LTP-like plasticity induced by anodal tDCS for over 24 h. Chronic RBX significantly converted cathodal tDCS-induced LTD-like plasticity into facilitation, as compared to the single dose condition, for 120 min after stimulation. The results show a prominent impact of chronic noradrenergic enhancement on plasticity of the human brain that might partially explain the delayed therapeutic impact of selective NRIs in depression and other neuropsychiatric diseases.

Does transcranial electrical stimulation enhance corticospinal excitability of the motor cortex in healthy individuals? A systematic review and meta‐analysis

“…Seven studies provided data on a‐tDCS in their placebo arms (Nitsche et al ., , , ; Grundey et al ., ; Batsikadze et al ., ; Lugon et al ., ; Kuo et al ., ). Pooled data from these studies showed a significant effect on CSE (SMD 0.31, 95% CI 0.19 to 0.42, P < 0.00001) and non‐significant heterogeneity ( I 2 = 2%, P = 0.42) (Fig.…”

Therapeutic interventions in patients with prolonged disorders of consciousness

“…Physiologically, the establishment of the long-lasting after-effects depends on membrane potential changes as well as modulations of N-methyl-D-aspartate (NMDA) receptor efficacy, which can induce long-term potentiation and long-term depression like effects. [85][86][87] However, more mechanistic and in vivo studies need to be performed to better understand how tDCS can influence cortical activity and act on neuroplasticity.…”

The application of tDCS for the treatment of psychiatric diseases

“…Stronger stimulation, more stimulation sessions, and tDCS in less severely affected patients might generate larger effects, as implied by the results of the study by Brunoni, Valiengo, et al (2013). Moreover this study is in favor of a superior efficacy of combined tDCS and pharmacological intervention, which makes sense, given the deficient LTP hypothesis of depression, the positive impact of both agents alone on symptoms, and the strengthening of tDCS-induced LTP-like plasticity by application of serotonin or noradrenaline reuptake-inhibitors (Kuo et al, 2016;Nitsche, Boggio, et al, 2009). tDCS seems to be relatively well tolerated; however, hypomania, and manifest mania were described in relatively rare cases, which might hint to the importance of 'dosed' stimulation.…”

“…Future studies should be designed to identify optimally suited stimulation protocols with regard to the abovementioned parameters, and, given the positive results of the studies by Brunoni, Valiengo, et al (2013) and Valiengo et al (2013), it would make sense to conduct large multi-centre double-blinded sham-controlled trials. Apart from this, it might, furthermore, make sense to explore the potential of tDCS by elucidating the interaction of tDCS with antidepressant medication or medication known to improve the efficacy of anodal tDCS, such as D-cycloserine and reboxetine (Kuo et al, 2016;Nitsche, Jaussi, et al, 2004), combining tDCS with cognitive training of prefrontal functions, comparing the efficacy of different electrode positions directly, testing the impact of remote 'boosting' sessions of tDCS on the maintenance of therapeutic effects, broadening the application of tDCS to specific depression syndromes, such as post-stroke depression, and exploring the cognitive effect of tDCS in more detail. The results of these studies might help to identify optimized stimulation protocols, to learn more about the cognitive impact of tDCS in depression, and suitable patient groups.…”

“…Another option to prolong and strengthen the aftereffects of tDCS is the combination of stimulation with pharmacological interventions. The partial NMDA receptor agonist D-cycloserine, amphetamine, serotonin, and reboxetine all have been demonstrated to enhance the efficacy of anodal tDCS (Kuo et al, 2016;Nitsche, Jaussi, et al, 2004, Nitsche, Grundey, et al, 2004, whereas application of L-dopa, as well as dopamine agonists extend the after-effects of cathodal stimulation (Fresnoza et al, 2014;Kuo, Paulus, & Nitsche, 2008;Monte-Silva et al, 2009Nitsche et al, 2006). The latter effects have been shown to be non-linearly dosage-dependent.…”