Interindividual variability and intraindividual reliability of intermittent theta burst stimulation-induced neuroplasticity mechanisms in the healthy brain

We combined patterned TMS with EMG in several sessions of a within-subject design to assess and characterize intraindividual reliability and interindividual variability of TMS-induced neuroplasticity mechanisms in the healthy brain. Intermittent theta burst stimulation (iTBS) was applied over M1 to induce long-term potentiation-like mechanisms as assessed by changes in corticospinal excitability. Furthermore, we investigated the association between the observed iTBS effects and individual differences in prolonged measures of corticospinal excitability. Our results show that iTBS-induced measures of neuroplasticity suffer from high variability between individuals within a single assessment visit and from low reliability within individuals across two assessment visits. This indicates that both group and individual effects of iTBS on corticospinal excitability cannot be assumed to be reliable and therefore need to be interpreted with caution, at least when measured by changes in the amplitudes of motor-evoked potentials.</p

Phase of beta-frequency tACS over primary motor cortex modulates corticospinal excitability

The assessment of corticospinal excitability by means of transcranial magnetic stimulation-induced motor evoked potentials is an established diagnostic tool in neurophysiology and a widely used procedure in fundamental brain research. However, concern about low reliability of these measures has grown recently. One possible cause of high variability of MEPs under identical acquisition conditions could be the influence of oscillatory neuronal activity on corticospinal excitability. Based on research showing that transcranial alternating current stimulation can entrain neuronal oscillations we here test whether alpha or beta frequency tACS can influence corticospinal excitability in a phase-dependent manner. We applied tACS at individually calibrated alpha- and beta-band oscillation frequencies, or we applied sham tACS. Simultaneous single TMS pulses time locked to eight equidistant phases of the ongoing tACS signal evoked MEPs. To evaluate offline effects of stimulation frequency, MEP amplitudes were measured before and after tACS. To evaluate whether tACS influences MEP amplitude, we fitted one-cycle sinusoids to the average MEPs elicited at the different phase conditions of each tACS frequency. We found no frequency-specific offline effects of tACS. However, beta-frequency tACS modulation of MEPs was phase-dependent. Post hoc analyses suggested that this effect was specific to participants with low (<19 Hz) intrinsic beta frequency. In conclusion, by showing that beta tACS influences MEP amplitude in a phase-dependent manner, our results support a potential role attributed to neuronal oscillations in regulating corticospinal excitability. Moreover, our findings may be useful for the development of TMS protocols that improve the reliability of MEPs as a meaningful tool for research applications or for clinical monitoring and diagnosis

Corticomotor Plasticity Predicts Clinical Efficacy of Combined Neuromodulation and Cognitive Training in Alzheimer’s Disease

Objective: To investigate the efficacy of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training for treatment of cognitive symptoms in patients with Alzheimer’s disease (AD). A secondary objective was to analyze associations between brain plasticity and cognitive effects of treatment. Methods: In this randomized, sham-controlled, multicenter clinical trial, 34 patients with AD were assigned to three experimental groups receiving 30 daily sessions of combinatory intervention. Participants in the real/real group (n = 16) received 10 Hz repetitive transcranial magnetic stimulation (rTMS) delivered separately to each of six cortical regions, interleaved with computerized cognitive training. Participants in the sham rTMS group (n = 18) received sham rTMS combined with either real (sham/real group, n = 10) or sham (sham/sham group, n = 8) cognitive training. Effects of treatment on neuropsychological (primary outcome) and neurophysiological function were compared between the 3 treatment groups. These, as well as imaging measures of brain atrophy, were compared at baseline to 14 healthy controls (HC). Results: At baseline, patients with AD had worse cognition, cerebral atrophy, and TMS measures of cortico-motor reactivity, excitability, and plasticity than HC. The real/real group showed significant cognitive improvement compared to the sham/sham, but not the real/sham group. TMS-induced plasticity at baseline was predictive of post-intervention changes in cognition, and was modified across treatment, in association with changes of cognition. Interpretation: Combined rTMS and cognitive training may improve the cognitive status of AD patients, with TMS-induced cortical plasticity at baseline serving as predictor of therapeutic outcome for this intervention, and potential mechanism of action. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01504958.publishersversionpublishe

Phase and power modulations on the amplitude of TMS-induced motor evoked potentials

The evaluation of transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) promises valuable information about fundamental brain related mechanisms and may serve as a diagnostic tool for clinical monitoring of therapeutic progress or surgery procedures. However, reports about spontaneous fluctuations of MEP amplitudes causing high intra-individual variability have led to increased concerns about the reliability of this measure. One possible cause for high variability of MEPs could be neuronal oscillatory activity, which reflects fluctuations of membrane potentials that systematically increase and decrease the excitability of neuronal networks. Here, we investigate the dependence of MEP amplitude on oscillation power and phase by combining the application of single pulse TMS over the primary motor cortex with concurrent recordings of electromyography and electroencephalography. Our results show that MEP amplitude is correlated to alpha phase, alpha power as well as beta phase. These findings may help explain corticospinal excitability fluctuations by highlighting the modulatory effect of alpha and beta phase on MEPs. In the future, controlling for such a causal relationship may allow for the development of new protocols, improve this method as a (diagnostic) tool and increase the specificity and efficacy of general TMS applications

Action–effect congruence during observational learning leads to faster action sequence learning

Common coding theory suggests that any action (pressing a piano key) is intimately linked with its resultant sensory effect (an auditory musical tone). We conducted two experiments to explore the effect of varying auditory action-effect patterns during complex action learning. In Experiment 1, participants were assigned to 1 of 4 groups, watched a silent video of a hand playing a sequence on a piano keyboard with no auditory action effect (observation) and were asked to practise and perform the sequence on an identical keyboard with varying action effects (reproduction). During reproduction, Group 1 heard no auditory tones (identical to observed video), Group 2 heard typical scale-ascending piano tones with each key press, Group 3 heard fixed but out-of-sequence piano tones with each key press, and Group 4 heard random piano tones with each key press. In Experiment two, new participants were assigned to 1 of 2 groups and watched an identical video; however, the video in this experiment contained typical, scale-ascending piano sounds. During reproduction, Group 1 heard no auditory tones while Group 2 heard typical, scale-ascending piano tones with each key press (identical to observed video). Our results showed that participants whose action-effect patterns during reproduction matched those in the observed video learned the action sequence faster than participants whose action-effect patterns during reproduction differed from those in the observed video. Additionally, our results suggest that adding an effect during reproduction (when one is absent during observation) is somewhat more detrimental to action sequence learning than removing an effect during reproduction (when one is present during observation

Phase and power modulations on the amplitude of TMS-induced motor evoked potentials

The evaluation of transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) promises valuable information about fundamental brain related mechanisms and may serve as a diagnostic tool for clinical monitoring of therapeutic progress or surgery procedures. However, reports about spontaneous fluctuations of MEP amplitudes causing high intra-individual variability have led to increased concerns about the reliability of this measure. One possible cause for high variability of MEPs could be neuronal oscillatory activity, which reflects fluctuations of membrane potentials that systematically increase and decrease the excitability of neuronal networks. Here, we investigate the dependence of MEP amplitude on oscillation power and phase by combining the application of single pulse TMS over the primary motor cortex with concurrent recordings of electromyography and electroencephalography. Our results show that MEP amplitude is correlated to alpha phase, alpha power as well as beta phase. These findings may help explain corticospinal excitability fluctuations by highlighting the modulatory effect of alpha and beta phase on MEPs. In the future, controlling for such a causal relationship may allow for the development of new protocols, improve this method as a (diagnostic) tool and increase the specificity and efficacy of general TMS applications

Humans with Type-2 Diabetes Show Abnormal Long-Term Potentiation-Like Cortical Plasticity Associated with Verbal Learning Deficits

BACKGROUND: Type-2 diabetes mellitus (T2DM) accelerates cognitive aging and increases risk of Alzheimer’s disease. Rodent models of T2DM show altered synaptic plasticity associated with reduced learning and memory. Humans with T2DM also show cognitive deficits, including reduced learning and memory, but the relationship of these impairments to the efficacy of neuroplastic mechanisms has never been assessed. OBJECTIVE: Our primary objective was to compare mechanisms of cortical plasticity in humans with and without T2DM. Our secondary objective was to relate plasticity measures to standard measures of cognition. METHODS: A prospective cross-sectional cohort study was conducted on 21 adults with T2DM and 15 demographically-similar non-diabetic controls. Long-term potentiation-like plasticity was assessed in primary motor cortex by comparing the amplitude of motor evoked potentials (MEPs) from single-pulse transcranial magnetic stimulation before and after intermittent theta-burst stimulation (iTBS). Plasticity measures were compared between groups and related to neuropsychological scores. RESULTS: In T2DM, iTBS-induced modulation of MEPs was significantly less than controls, even after controlling for potential confounds. Furthermore, in T2DM, modulation of MEPs 10-min post-iTBS was significantly correlated with Rey Auditory Verbal Learning Task (RAVLT) performance. CONCLUSION: Humans with T2DM show abnormal cortico-motor plasticity that is correlated with reduced verbal learning. Since iTBS after-effects and the RAVLT are both NMDA receptor-dependent measures, their relationship in T2DM may reflect brain-wide alterations in the efficacy of NMDA receptors. These findings offer novel mechanistic insights into the brain consequences of T2DM and provide a reliable means to monitor brain health and evaluate the efficacy of clinical interventions