After-effects Of iTBS Research Articles

Effects of Priming Intermittent Theta Burst Stimulation With High-Definition tDCS on Upper Limb Function in Hemiparetic Patients With Stroke: A Randomized Controlled Study

Background Preconditioning with cathodal high-definition transcranial direct current stimulation (HD-tDCS) can potentiate cortical plasticity induced by intermittent theta burst stimulation (iTBS) and enhance the after-effects of iTBS in healthy people. However, it is unclear whether this multi-modal protocol can enhance upper limb function in patients with stroke. Objective The aim of this study was to investigate whether priming iTBS with cathodal HD-tDCS over the ipsilesional M1 can augment upper limb motor recovery in poststroke patients. Methods A total of 66 patients with subacute stroke were randomly allocated into 3 groups. Group 1 received priming iTBS with HD-tDCS (referred to as the tDCS + iTBS group), Group 2 received non-priming iTBS (the iTBS group), and Group 3 received sham stimulation applied to the ipsilesional M1. One session was performed per day, 5 days per week, for 3 consecutive weeks. In Group 1, iTBS was preceded by a 20-minute session of cathodal HD-tDCS at a 10-minute interval. The primary outcome measure was the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) score. Moreover, the secondary outcome measures for muscle strength and spasticity were the Motricity Index-Upper Extremity (MI-UE) and the Modified Ashworth Scale Upper-Extremity (MAS-UE), respectively, and the Hong Kong Version of the Functional Test for the Hemiplegic Upper Extremity (FTHUE-HK) and the Modified Barthel Index (MBI) for activity and participation. Results Significant differences were detected in the changes in FMA-UE, MI-UE, and MBI scores between the 3 groups from baseline to post-intervention (χ2FMA-UE = 10.856, P = .004; χ2MI-UE = 6.783, P = .034; χ2MBI = 9.608, P = .008). Post hoc comparisons revealed that the priming iTBS group demonstrated substantial improvements in FMA-UE (P = .004), MI-UE (P = .028), and MBI (P = 0.006) compared with those in the sham group. However, no significant difference was observed between the iTBS group and the sham group. Moreover, no significant differences were found in the changes in MAS-UE or FTHUE-HK between the groups. Conclusions Priming iTBS with HD-tDCS over the ipsilesional M1 cortex had beneficial effects on augmenting upper limb motor recovery and enhancing daily participation among subacute stroke patients.

Continuous, and not intermittent, theta-burst stimulation of the unlesioned hemisphere improved brain and hand function in chronic stroke: A case study

In chronic stroke, transcranial magnetic stimulation is used to investigate if the primary motor cortex (M1) of the unlesioned hemisphere (UH) optimizes or hampers the functional gains. Continuous and intermittent theta-burst stimulation (cTBS, iTBS) were used to decrease and increase UH-M1 excitability, respectively. However, the effects of these protocols were never compared in the same patients and studies remain controversial. Therefore, the present study first compared the two protocols in the same patient, a 60-yo male at a chronic stage post-stroke, then tested in the long-term the protocol with the largest after-effects. To this end, experiment 1 compared the after-effects of iTBS, cTBS, and sham over UH-M1 (one session each, one week apart): data showed that the paretic hand motricity and M1 excitability of the lesioned hemisphere (LH) were improved after cTBS only. cTBS was then administrated over 10 sessions in experiment 2 and the outcomes were tested at different timepoints: M1 excitability was improved in both hemispheres and the functional gains obtained during cTBS sessions were still present three months after the end of stimulation. In conclusion, our chronic case study showed that UH inhibition, and not activation, promoted the function in a patient with spared corticospinal control from LH. Group studies in chronic stroke should reproduce our experiments and determine if, to optimize the gains, UH should be inhibited in patients with spared LH function (our case) or activated in patients with lost LH function, as already hypothesized. This is of major interest in neurorehabilitation using TMS protocols.

Intermittent Theta Burst Stimulation Increases Natural Oscillatory Frequency in Ipsilesional Motor Cortex Post-Stroke: A Transcranial Magnetic Stimulation and Electroencephalography Study.

ObjectiveIntermittent theta burst stimulation (iTBS) has been widely used as a neural modulation approach in stroke rehabilitation. Concurrent use of transcranial magnetic stimulation and electroencephalography (TMS-EEG) offers a chance to directly measure cortical reactivity and oscillatory dynamics and allows for investigating neural effects induced by iTBS in all stroke survivors including individuals without recordable MEPs. Here, we used TMS-EEG to investigate aftereffects of iTBS following stroke.MethodsWe studied 22 stroke survivors (age: 65.2 ± 11.4 years; chronicity: 4.1 ± 3.5 months) with upper limb motor deficits. Upper-extremity component of Fugl-Meyer motor function assessment and action research arm test were used to measure motor function of stroke survivors. Stroke survivors were randomly divided into two groups receiving either Active or Sham iTBS applied over the ipsilesional primary motor cortex. TMS-EEG recordings were performed at baseline and immediately after Active or Sham iTBS. Time and time-frequency domain analyses were performed for quantifying TMS-evoked EEG responses.ResultsAt baseline, natural frequency was slower in the ipsilesional compared with the contralesional hemisphere (P = 0.006). Baseline natural frequency in the ipsilesional hemisphere was positively correlated with upper limb motor function following stroke (P = 0.007). After iTBS, natural frequency in the ipsilesional hemisphere was significantly increased (P < 0.001).ConclusionsThis is the first study to investigate the acute neural adaptations after iTBS in stroke survivors using TMS-EEG. Our results revealed that natural frequency is altered following stroke which is related to motor impairments. iTBS increases natural frequency in the ipsilesional motor cortex in stroke survivors. Our findings implicate that iTBS holds the potential to normalize natural frequency in stroke survivors, which can be utilized in stroke rehabilitation.

After-Effects of Intermittent Theta-Burst Stimulation Are Differentially and Phase-Dependently Suppressed by α- and β-Frequency Transcranial Alternating Current Stimulation.

Intermittent theta-burst stimulation (iTBS) using transcranial magnetic stimulation (TMS) is known to produce excitatory after-effects over the primary motor cortex (M1). Recently, transcranial alternating current stimulation (tACS) at 10 Hz (α) and 20 Hz (β) have been shown to modulate M1 excitability in a phase-dependent manner. Therefore, we hypothesized that tACS would modulate the after-effects of iTBS depending on the stimulation frequency and phase. To test our hypothesis, we examined the effects of α- and β-tACS on iTBS using motor evoked potentials (MEPs). Eighteen and thirteen healthy participants were recruited for α and β tACS conditions, respectively. tACS electrodes were attached over the left M1 and Pz. iTBS over left M1 was performed concurrently with tACS. The first pulse of the triple-pulse burst of iTBS was controlled to match the peak (90°) or trough (270°) phase of the tACS. A sham tACS condition was used as a control in which iTBS was administered without tACS. Thus, each participant was tested in three conditions: the peak and trough of the tACS phases and sham tACS. As a result, MEPs were enhanced after iTBS without tACS (sham condition), as observed in previous studies. α-tACS suppressed iTBS effects at the peak phase but not at the trough phase, while β-tACS suppressed the effects at both phases. Thus, although both types of tACS inhibited the facilitatory effects of iTBS, only α-tACS did so in a phase-dependent manner. Phase-dependent inhibition by α-tACS is analogous to our previous finding in which α-tACS inhibited MEPs online at the peak condition. Conversely, β-tACS reduced the effects of iTBS irrespective of its phase. The coupling of brain oscillations and tACS rhythms is considered important in the generation of spike-timing-dependent plasticity. Additionally, the coupling of θ and γ oscillations is assumed to be important for iTBS induction through long-term potentiation (LTP). Therefore, excessive coupling between β oscillations induced by tACS and γ or θ oscillations induced by iTBS might disturb the coupling of θ and γ oscillations during iTBS. To conclude, the action of iTBS is differentially modulated by neuronal oscillations depending on whether α- or β-tACS is applied.

Intermittent Theta Burst Stimulation to the Primary Motor Cortex Reduces Cortical Inhibition: A TMS-EEG Study.

Introduction: The aim of this study was to reveal the effects of intermittent theta burst stimulation (iTBS) in modulating cortical networks using transcranial magnetic stimulation and electroencephalography (TMS-EEG) recording. Methods: Eighteen young adults participated in our study and received iTBS to the primary motor cortex (M1), supplementary motor area, and the primary visual cortex in three separate sessions. A finger tapping task and ipsilateral single-pulse TMS-EEG recording for the M1 were administrated before and after iTBS in each session. The effects of iTBS in motor performance and TMS-evoked potentials (TEPs) were investigated. Results: The results showed that iTBS to the M1, but not supplementary motor area or the primary visual cortex, significantly reduced the N100 amplitude of M1 TEPs in bilateral hemispheres (p = 0.019), with a more prominent effect in the contralateral hemisphere than in the stimulated hemisphere. Moreover, only iTBS to the M1 decreased global mean field power (corrected ps < 0.05), interhemispheric signal propagation (t = 2.53, p = 0.030), and TMS-induced early α-band synchronization (p = 0.020). Conclusion: Our study confirmed the local and remote after-effects of iTBS in reducing cortical inhibition in the M1. TMS-induced oscillations after iTBS for changed cortical excitability in patients with various neurological and psychiatric conditions are worth further exploration.

Cortical mechanisms underlying variability in intermittent theta-burst stimulation-induced plasticity: A TMS-EEG study

ObjectiveTo test the hypothesis that intermittent theta burst stimulation (iTBS) variability depends on the ability to engage specific neurons in the primary motor cortex (M1). MethodsIn a sham-controlled interventional study on 31 healthy volunteers, we used concomitant transcranial magnetic stimulation (TMS) and electroencephalography (EEG). We compared baseline motor evoked potentials (MEPs), M1 iTBS-evoked EEG oscillations, and resting-state EEG (rsEEG) between subjects who did and did not show MEP facilitation following iTBS. We also investigated whether baseline MEP and iTBS-evoked EEG oscillations could explain inter and intraindividual variability in iTBS aftereffects. ResultsThe facilitation group had smaller baseline MEPs than the no-facilitation group and showed more iTBS-evoked EEG oscillation synchronization in the alpha and beta frequency bands. Resting-state EEG power was similar between groups and iTBS had a similar non-significant effect on rsEEG in both groups. Baseline MEP amplitude and beta iTBS-evoked EEG oscillation power explained both inter and intraindividual variability in MEP modulation following iTBS. ConclusionsThe results show that variability in iTBS-associated plasticity depends on baseline corticospinal excitability and on the ability of iTBS to engage M1 beta oscillations. SignificanceThese observations can be used to optimize iTBS investigational and therapeutic applications.

FV 8. The effect of repeated blocks of intermittant theta burst stimulation (iTBS) over the dorsolateral prefrontal cortex (dlPFC) on fronto-striatal connectivity. A 18F-DesmethoxyFallypride (DMFP) Positron Emission Tomography study (PET)

Background. Frontostriatal networks are neural pathways formed between frontal lobe regions and striatum that is involved in cognitive and behavioural processes. Transcranial Magnetic Stimulation (TMS) is able to modulate connectivity in the human brain and it is widely used for clinical purposes to treat depression patients. This exploratory PET and TMS multimodal study would contribute to better understand the role of striatal dopaminergic neurotransmission in the fronto-striatal area. Objective. The main objective of the study is to investigate the fronto-striatal connectivity by measuring the release of dopamine in the striatum in response to an excitatory intermittent theta burst stimulation (iTBS) of the left-dlPFC. A PET measurement was performed by using the 18F-DesmethoxyFallypride (DMFP) radioligand, that is a high affinity receptor-antagonist which competes with endogenous Dopamine neurotransmitters for D2/D3 receptor binding. Methods. The study was conducted on 23 healthy participants, who underwent iTBS sham (control) and verum stimulations on separate days. The PET scan lasted 120 mins, consisting of 4 iTBS stimulations delivered to the left-DLPFC at 30 mins interval. In verum stimulation, 90% of resting motor threshold (rMT) was used as the stimulation intensity. The excitatory iTBS protocol is delivered in a sequence of trains (burst of 10 pulses in 2 secs having inter train interval of 8 secs), with a total duration of 190 secs. PET dynamic data was analysed using reference region method in which cerebellum was used as the reference region (due to lack of D2-D3 receptors). Binding Potentials (BP) are the main outcome measure representing the ligand binding which is inversely proportional to the Dopamine (DA) levels.Mean Binding Potentials in the sub-regions of the striatum (Nucleus Caudate and Putamen) were compared between the sham and verum stimulation using analysis of variance (ANOVA). Results. iTBS stimulation of the left DLPFC increased the dopamine release (as reflected by BPs) in the striatum areas (putamen and nucleus caudate) in the verum stimulation, as compared to sham stimulation.Although the increase in dopamine release did not differ between the first block of stimulation, we observed significant increase after two, three and fourth blocks of stimulation. Conclusion. Our data suggest that the efficiency of iTBS protocol can effectively enhance fronto-striatal connectivity by applying a higher number of stimuli (i.e., 3rd & 4th TMS block but not 1st-& 2nd block). This minimal time stimulation protocol can be used as a therapy for treating Depression patients by presenting it in the repeated blocks of short intervals. This scheme could prevent the long stimulation protocols, and be less painful. Fig. 1. Figure represents the statistically significant main effect of TMS . The verum stimulation shows a reduction of 8.6% [18F]DMFP Binding Potential as compared to the sham stimulation. Fig. 2. Percentage reduction in [18F] desmethoxyfallypride-binding potentials extracted from the difference of sham and verum stimulation in healthy subjects. Dose-dependent iTBS aftereffects seem to be more pronounced at 3rd block and 4th block respectively as compared to 1st and 2nd block of TMS.

New Horizons in Early Dementia Diagnosis: Can Cerebellar Stimulation Untangle the Knot?

Differentiating Mild Cognitive Impairment (MCI) from dementia and estimating the risk of MCI-to-dementia conversion (MDC) are challenging tasks. Thus, objective tools are mandatory to get early diagnosis and prognosis. About that, there is a growing interest on the role of cerebellum-cerebrum connectivity (CCC). The aim of this study was to differentiate patients with an early diagnosis of dementia and MCI depending on the effects of a transcranial magnetic stimulation protocol (intermittent theta-burst stimulation -iTBS) delivered on the cerebellum able to modify cortico-cortical connectivity. Indeed, the risk of MDC is related to the response to iTBS, being higher in non-responder individuals. All patients with MCI, but eight (labelled as MCI-), showed preserved iTBS aftereffect. Contrariwise, none of the patients with dementia showed iTBS aftereffects. None of the patients showed EEG aftereffects following a sham TBS protocol. Five among the MCI- patients converted to dementia at 6-month follow-up. Our data suggest that cerebellar stimulation by means of iTBS may support the differential diagnosis between MCI and dementia and potentially identify the individuals with MCI who may be at risk of MDC. These findings may help clinicians to adopt a better prevention/follow-up strategy in such patients.

Intermittent Theta-Burst Stimulation Reverses the After-Effects of Contralateral Virtual Lesion on the Suprahyoid Muscle Cortex: Evidence From Dynamic Functional Connectivity Analysis.

Contralateral intermittent theta burst stimulation (iTBS) can potentially improve swallowing disorders with unilateral lesion of the swallowing cortex. However, the after-effects of iTBS on brain excitability remain largely unknown. Here, we investigated the alterations of temporal dynamics of inter-regional connectivity induced by iTBS following continuous TBS (cTBS) in the contralateral suprahyoid muscle cortex. A total of 20 right-handed healthy subjects underwent cTBS over the left suprahyoid muscle motor cortex and then immediately afterward, iTBS was applied to the contralateral homologous area. All of the subjects underwent resting-state functional magnetic resonance imaging (Rs-fMRI) pre- and post-TBS implemented on a different day. We compared the static and dynamic functional connectivity (FC) between the post-TBS and the baseline. The whole-cortical time series and a sliding-window correlation approach were used to quantify the dynamic characteristics of FC. Compared with the baseline, for static FC measurement, increased FC was found in the precuneus (BA 19), left fusiform gyrus (BA 37), and right pre/post-central gyrus (BA 4/3), and decreased FC was observed in the posterior cingulate gyrus (PCC) (BA 29) and left inferior parietal lobule (BA 39). However, in the dynamic FC analysis, post-TBS showed reduced FC in the left angular and PCC in the early windows, and in the following windows, increased FC in multiple cortical areas including bilateral pre- and postcentral gyri and paracentral lobule and non-sensorimotor areas including the prefrontal, temporal and occipital gyrus, and brain stem. Our results indicate that iTBS reverses the aftereffects induced by cTBS on the contralateral suprahyoid muscle cortex. Dynamic FC analysis displayed a different pattern of alteration compared with the static FC approach in brain excitability induced by TBS. Our results provide novel evidence for us in understanding the topographical and temporal aftereffects linked to brain excitability induced by different TBS protocols and might be valuable information for their application in the rehabilitation of deglutition.

Effects of iTBS on TMS-evoked potentials and spectral perturbations over dorsolateral prefrontal cortex, posterior parietal cortex, and primary motor cortex

Purpose. Intermittent theta-burst stimulation (iTBS) enables modulation of cortical reactivity in humans. iTBS aftereffects have been well-characterized in primary motor cortex (M1) using single-pulse transcranial magnetic stimulation (TMS) coupled with electromyography. Combining TMS with electroencephalography (EEG) allows for characterization of iTBS-induced modulation of non-motor brain regions, which remains poorly understood.

The effect of repeated iTBS on brain activities during hand movements

Theta burst stimulation (TBS) is proved to be the most efficient protocol of rTMS inducing neuroplasticity-like aftereffects. TBS-induced aftereffects depend on the pattern of stimulation. The aim of the study was to investigate the aftereffects of iTBS repeated every 5 min for 3 times (repeated iTBS) over the left primary motor cortex (LM1) by means of the amplitudes of motor evoked potential (MEP) evoked from the left (LMEP) and right (RMEP) M1 and their correlation with the brain oscillation. Each subject came for two sessions to have EEG with auditory-triggered shoulder flexion and extension action and MEPs measurements before and after repeated iTBS. Results showed that repeated iTBS suppressed LMEPs (mean change = -26.26%; range from -4.8 to -49.64%, p

Similar effect of intermittent theta burst and sham stimulation on corticospinal excitability: A 5‐day repeated sessions study

Despite accumulating evidence of inter and intraindividual variability in response to theta burst stimulation, it is widely believed that in therapeutic applications, repeated sessions can have a "build-up" effect that increases the response over and above that seen in a single session. However, strong evidence for this is lacking. Therefore, we examined whether daily administration of intermittent theta burst stimulation (iTBS) over the primary motor cortex induces cumulative changes in transcranial magnetic stimulation measures of cortical excitability, above the changes induced by sham stimulation. Over five consecutive days, 20 healthy participants received either active iTBS or sham stimulation. Each day, baseline measures of cortical excitability were assessed before and up to 30min after the intervention. There was no significant difference in the rate of response between iTBS and sham stimulation on any of the 5days. There was no iTBS specific cumulative increase of corticospinal excitability. The likelihood that an individual would remain a responder from day-to-day was low in both groups, implying high within-subject variability of both active and sham iTBS after-effects. In contrast, we found a high within-subject repeatability of resting and active motor threshold, and baseline motor-evoked potential amplitude. In summary, sham stimulation has similar effect to active iTBS on corticospinal excitability, even when applied repeatedly for 5days. Our results might be relevant to research and clinical applications of theta burst stimulation protocols.

Reproducibility of Single-Pulse, Paired-Pulse, and Intermittent Theta-Burst TMS Measures in Healthy Aging, Type-2 Diabetes, and Alzheimer's Disease.

Background: Transcranial magnetic stimulation (TMS) can be used to assess neurophysiology and the mechanisms of cortical brain plasticity in humans in vivo. As the use of these measures in specific populations (e.g., Alzheimer’s disease; AD) increases, it is critical to understand their reproducibility (i.e., test–retest reliability) in the populations of interest.Objective: Reproducibility of TMS measures was evaluated in older adults, including healthy, AD, and Type-2 diabetes mellitus (T2DM) groups.Methods: Participants received two identical neurophysiological assessments within a year including motor thresholds, baseline motor evoked potentials (MEPs), short- and long-interval intracortical inhibition (SICI, LICI) and intracortical facilitation (ICF), and MEP changes following intermittent theta-burst stimulation (iTBS). Cronbach’s α coefficients were calculated to assess reproducibility. Multiple linear regression analyses were used to investigate factors related to intraindividual variability.Results: Reproducibility was highest for motor thresholds, followed by baseline MEPs, SICI and LICI, and was lowest for ICF and iTBS aftereffects. The AD group tended to show higher reproducibility than T2DM or controls. Intraindividual variability of baseline MEPs was related to age and variability of RMT, while the intraindividual variability in post-iTBS measures was related to baseline MEP variability, intervisit duration, and Brain-derived neurotrophic factor (BDNF) polymorphism.Conclusion: Increased reproducibility in AD may reflect pathophysiological declines in the efficacy of neuroplastic mechanisms. Reproducibility of iTBS aftereffects can be improved by keeping baseline MEPs consistent, controlling for BDNF genotype, and waiting at least a week between visits.Significance: These findings provide the first direct assessment of reproducibility of TMS measures in older clinical populations. Reproducibility coefficients may be used to adjust effect- and sample size calculations for future studies.

Current direction-dependent modulation of human hand motor function by intermittent theta burst stimulation (iTBS)

BackgroundTranscranial magnetic stimulation (TMS) with different current directions can activate different sets of neurons. Current direction can also affect the results of repetitive TMS. Objective: To test the influence of uni-directional intermittent theta burst stimulation (iTBS) using different current directions, namely posteroanterior (PA) and anteroposterior (AP), on motor behaviour. MethodsIn a cross-over design, PA- and AP-iTBS was applied over the left primary motor cortex in 19 healthy, right-handed volunteers. Performance of a finger-tapping task was recorded before and 0, 10, 20, and 30min after the iTBS. The task was conducted with the right and left hands separately at each time point. As a control, AP-iTBS with reduced intensity was applied to 14 participants in a separate session (APweak condition). ResultsThe finger-tapping count with the left hand was decreased after PA-iTBS. Neither AP- nor APweak-iTBS altered the performance. ConclusionsCurrent direction had a significant impact on the after-effects of iTBS.

Modulation of iTBS after-effects via concurrent directional TDCS: A proof of principle study

BackgroundPolarising currents can modulate membrane potentials in animals, affecting the after-effect of theta burst stimulation (TBS) on synaptic strength. ObjectiveWe examined whether a similar phenomenon could also be observed in human motor cortex (M1) using transcranial direct current stimulation (TDCS) during monophasic intermittent TBS (iTBS). MethodsTDCS was applied during posterior-anterior iTBS using three different conditions: posterior-anterior TDCS (anode 3.5 cm posterior to M1, cathode 3.5 cm anterior to M1), anterior-posterior TDCS (cathode 3.5 cm posterior to M1, anode 3.5 cm anterior to M1), and sham TDCS. ResultsWhen the direction of TDCS (posterior-anterior) matched the direction of the electrical field induced by iTBS, we found a 19% non-significant increase in excitability changes in comparison with iTBS combined with sham TDCS. When the TDCS was reversed (anterior-posterior), the excitatory effect of iTBS was abolished. ConclusionOur findings suggest that excitatory after-effects of iTBS can be modulated by directionally-specific TDCS.

P295 APOE polymorphism and cortical plasticity are independently associated with cognitive decline in Alzheimer’s disease

Introduction APOE E4 allele associates not only with AD risk and a lower age onset, but also with faster cognitive decline and greater cerebral atrophy, suggesting a key role of this polymorphism in modulating both disease risk and clinical outcome. Objectives In this study we investigated the correlation between cognitive decline, motor cortical plasticity and cerebrospinal fluid (CSF) biomarkers profile of AD patients divided by APOE polymorphism in E4 allele carriers (E4) and homozygous E3 carriers. Materials and methods A monophasic Magstim 200 device was used to deliver intermitted/continuous theta burst stimulation (iTBS/cTBS) protocols. ELISA was used for determination of CSF biomarkers level. Forty-one AD patients underwent lumbar puncture for CSF withdrawal, blood screening for APOE polymorphism, stimulation protocols applied over the primary motor cortex and mini mental state examination (MMSE) at baseline and at 6-, 12- and 18-months. Results No difference was found in CSF biomarkers profile within the APOE variants group. I-TBS after-effects were significantly reduced in E3 in comparison with E4 AD patients. Correlation analyses revealed that the individual amount of iTBS induced plasticity correlated with delta-MMSE and total Tau showing that a less pronounced LTP-like plasticity and higher total-Tau CSF levels were associated with a higher delta-MMSE. Only in apoE4 patients Tau pathology correlates with cortical plasticity impairment and cognitive decline. A multivariate analysis showed that APOE polymorphism and LTP-like plasticity, but not t-Tau levels, are independently able to predict delta-MMSE in AD patients. Conclusions APOE variants show different level of cortical plasticity and are independently associated with clinical progression in AD patients. Tau pathology is specific for ApoE4 group driving cortical plasticity impairment and cognitive decline. ApoE4 patients represent a pure model of TAU-driven AD pathology. ApoE3 patients are characterized by different mechanisms of cortical plasticity impairment and clinical symptoms. LTP impairment is a marker of pathophysiological dysfunction in AD and, as such, it should be taken in account also for the adoption of new pharmacological strategies, considering AD as a disorder of synaptic plasticity.

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

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. 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. 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. 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. 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.

P82. Motor network connectivity predicts responsiveness to theta-burst stimulation

Introduction Intermittent theta-burst stimulation (iTBS) effectively increases cortical excitability within the human brain (Huang et al., 2005). However, individual after-effects of iTBS vary between subjects, with a large proportion not responding at all in terms of changes in excitability (Ridding and Ziemann, 2010; Hamada et al., 2013). We here investigated whether subjects responding to iTBS show differential changes in resting-state functional connectivity (rsFC) within the cortical motor system compared to subjects with no response and whether the application of multiple iTBS-blocks can alter responsiveness. Methods We used a sham-stimulation controlled, single-blinded within-subject design to test for iTBS after-effects on (i) motor evoked potentials (MEPs) and (ii) resting-state functional connectivity (rsFC) in 16 healthy, right-handed subjects ( m =7, 27±3years). iTBS was applied over the left primary motor cortex (M1-iTBS) and over the parieto-occipital vertex (sham-iTBS) in separate sessions. In each stimulation session three iTBS blocks were applied, separated by 15min. Seed-based whole-brain rsFC was computed for the stimulated M1. Results Subjects were divided into groups of responders ( n =7) and non-responders ( n =9) according to iTBS-induced changes in MEPs (criterion: increase of at least 10% compared to baseline; Hinder et al., 2014). Increases in MEP-amplitudes following all three M1-iTBS blocks compared to sham-iTBS could exclusively be found for responders. Likewise, rsFC between M1 and premotor areas was significantly higher in responders after all three iTBS blocks ( p ⩽0.05, cluster-level FWE-corrected), whereas no significant increases could be found for the non-responder group. Dose-dependent increases in MEP-amplitudes and rsFC could also only be found for responders. Importantly, non-responders featured higher levels of pre-interventional rsFC compared to responders ( p ⩽0.01, cluster-level FWE-corrected). Individual changes in MEPs and rsFC did not correlate. Discussion Significant iTBS-induced modulations of rsFC and MEP-amplitudes were exclusively found for the responder group, suggesting that responsiveness to iTBS is paralleled by differential changes in motor network connectivity. However, there was no linear correlation between changes in MEP-amplitudes and rsFC. Additional iTBS blocks did not cause a conversion from non-responders to responders, but rather enhanced cortical excitability and rsFC in responders. Furthermore, lower levels of pre-interventional rsFC might contribute to better effectiveness of iTBS.

Inter-individual variability in cortical excitability and motor network connectivity following multiple blocks of rTMS

The responsiveness to non-invasive neuromodulation protocols shows high inter-individual variability, the reasons of which remain poorly understood. We here tested whether the response to intermittent theta-burst stimulation (iTBS) – an effective repetitive transcranial magnetic stimulation (rTMS) protocol for increasing cortical excitability – depends on network properties of the cortical motor system. We furthermore investigated whether the responsiveness to iTBS is dose-dependent.To this end, we used a sham-stimulation controlled, single-blinded within-subject design testing for the relationship between iTBS aftereffects and (i) motor-evoked potentials (MEPs) as well as (ii) resting-state functional connectivity (rsFC) in 16 healthy subjects. In each session, three blocks of iTBS were applied, separated by 15min.We found that non-responders (subjects not showing an MEP increase of ≥10% after one iTBS block) featured stronger rsFC between the stimulated primary motor cortex (M1) and premotor areas before stimulation compared to responders. However, only the group of responders showed increases in rsFC and MEPs, while most non-responders remained close to baseline levels after all three blocks of iTBS. Importantly, there was still a large amount of variability in both groups.Our data suggest that responsiveness to iTBS at the local level (i.e., M1 excitability) depends upon the pre-interventional network connectivity of the stimulated region. Of note, increasing iTBS dose did not turn non-responders into responders. The finding that higher levels of pre-interventional connectivity precluded a response to iTBS could reflect a ceiling effect underlying non-responsiveness to iTBS at the systems level.

P 82. Dose-dependent effects of theta-burst rTMS on the cortical excitability and fMRI-connectivity of the primary motor cortex

Introduction Theta Burst Stimulation (TBS) is an effective rTMS-protocol to modulate the excitability of cortical motor regions (Huang et al., 2005). However, the effects between subjects are rather variable (Hamda et al., 2012). The reason for this variability is still unclear (Thickbroom, 2007). Recently, animal studies showed that there are dose-dependent effects of TBS on the expression of cellular proteins (Volz et al., 2010). In contrast, studies with human subjects did not find a consistent dose–effect after applying two TBS sessions serially at different intersession intervals (Gamboa et al., 2010, 2011). Objectives The aim of our study was to investigate the effect of a triple TBS session on the cortical excitability compared to a control-stimulation. By combining TBS with functional magnetic resonance imaging (fMRI) measurements we sought to reveal stimulation effects on cortical connectivity. Methods 15 healthy subjects received three stimulations according to the iTBS-protocol (600 pulses per stimulation, (Huang et al., 2005)). iTBS sessions were applied in a serial fashion spaced by intervals of 15min. Two different stimulation sites were tested at different days: primary motor cortex (M1) and the parieto-occipital cortex (control). Stimulation after-effects on cortical excitability were tested via stimulus–response curves. In separate stimulation sessions, the iTBS effects on fMRI-connectivity were tested for two conditions: (i) resting-state measurements and (ii) during thumb movements. The following motor areas were included in the network analysis: M1, supplementary motor area (SMA), dorsal and ventral premotor cortex (dPMC, vPMC), anterior intraparietal cortex, putamen, thalamus and cerebellum. Results We found a dose-dependent effect of iTBS on the height of the stimulus–response-curve with significantly higher MEPs after applying iTBS over M1 compared to the control-stimulation. The connectivity-analyses revealed that after M1 stimulation with 1800 pulses the effective connectivity of the ipsilateral dPMC to the stimulated M1 was significantly enhanced while the control-stimulation had no differential effect on cortical connectivity ( p Conclusions Our results suggest that the after-effects of iTBS are dose-dependent. Furthermore, our data show that iTBS of M1 leads to a higher integration of the stimulated area with premotor areas.