Modulation of I-wave generating pathways by TBS: a model of plasticity induction

KEY POINTS: • Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta-burst stimulation (iTBS) remain poorly understood. • Individual response to iTBS is associated with recruitment of late indirect wave (I-wave) generating pathways that can be probed by the onset latency of TMS applied to primary motor cortex (M1) at different coil orientations. • We found an association between late I-wave recruitment (reflected by AP-LM latency, i.e. the excess latency of motor evoked potentials (MEPs) generated by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation) and changes in cortical excitability following iTBS, confirming previous studies. •AP-LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS-induced increase in cortical excitability across subjects. •Plasticity in the motor network may in part derive from a modulation of excitability and recruitment of late I-wave generating cortical pathways. ABSTRACT: Plasticity-induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I-waves) can be probed by the excess latency of motor evoked potentials (MEPs) elicited by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation, referred to as "AP-LM latency" difference. Importantly, AP-LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I-wave generating pathways. We investigated in 20 healthy subjects whether intermittent TBS (iTBS) modulates I-wave recruitment as reflected by changes in the AP-LM latency. As expected, we found that AP-LM latencies before iTBS were associated with iTBS-induced excitability changes. A novel finding was that iTBS reduced the AP-LM latency, and that this correlated significantly with changes in cortical excitability observed following iTBS: subjects with the largest reductions in AP-LM latencies had the largest increases in cortical excitability following iTBS. Our findings suggest that plasticity-induction by iTBS may derive from the modulation of I-wave generating pathways projecting onto M1, accounting for the predictive potential of I-wave recruitment. The excitability of I-wave generating may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel rTMS protocols

Saccadic Eye Movement Abnormalities in Children with Epilepsy

Childhood onset epilepsy is associated with disrupted developmental integration of sensorimotor and cognitive functions that contribute to persistent neurobehavioural comorbidities. The role of epilepsy and its treatment on the development of functional integration of motor and cognitive domains is unclear. Oculomotor tasks can probe neurophysiological and neurocognitive mechanisms vulnerable to developmental disruptions by epilepsy-related factors. The study involved 26 patients and 48 typically developing children aged 8–18 years old who performed a prosaccade and an antisaccade task. Analyses compared medicated chronic epilepsy patients and unmedicated controlled epilepsy patients to healthy control children on saccade latency, accuracy and dynamics, errors and correction rate, and express saccades. Patients with medicated chronic epilepsy had impaired and more variable processing speed, reduced accuracy, increased peak velocity and a greater number of inhibitory errors, younger unmedicated patients also showed deficits in error monitoring. Deficits were related to reported behavioural problems in patients. Epilepsy factors were significant predictors of oculomotor functions. An earlier age at onset predicted reduced latency of prosaccades and increased express saccades, and the typical relationship between express saccades and inhibitory errors was absent in chronic patients, indicating a persistent reduction in tonic cortical inhibition and aberrant cortical connectivity. In contrast, onset in later childhood predicted altered antisaccade dynamics indicating disrupted neurotransmission in frontoparietal and oculomotor networks with greater demand on inhibitory control. The observed saccadic abnormalities are consistent with a dysmaturation of subcortical-cortical functional connectivity and aberrant neurotransmission. Eye movements could be used to monitor the impact of epilepsy on neurocognitive development and help assess the risk for poor neurobehavioural outcomes

Modulation of I-wave generating pathways by theta-burst stimulation: a model of plasticity induction

Plasticity-induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and the underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I-waves) can be probed by the excess latency of motor-evoked potentials elicited by transcranial magnetic stimulation with an anterior-posterior (AP) orientation over the latency of motor-evoked potentials evoked by direct activation of corticospinal axons using lateromedial (LM) stimulation, referred to as the 'AP-LM latency' difference. Importantly, AP-LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I-wave generating pathways. In 20 healthy subjects, we investigated whether intermittent TBS (iTBS) modulates I-wave recruitment as reflected by changes in the AP-LM latency. As expected, we found that AP-LM latencies before iTBS were associated with iTBS-induced excitability changes. A novel finding was that iTBS reduced AP-LM latency, and that this reduction significantly correlated with changes in cortical excitability observed following iTBS: subjects with larger reductions in AP-LM latencies featured larger increases in cortical excitability following iTBS. Our findings suggest that plasticity-induction by iTBS may derive from the modulation of I-wave generating pathways projecting onto M1, accounting for the predictive potential of I-wave recruitment. The excitability of I-wave generating pathways may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel repetitive transcranial magnetic stimulation protocols

Modulation of I‐wave generating pathways by TBS: a model of plasticity induction

Plasticity‐induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and the underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I‐waves) can be probed by the excess latency of motor‐evoked potentials elicited by transcranial magnetic stimulation with an anterior–posterior (AP) orientation over the latency of motor‐evoked potentials evoked by direct activation of corticospinal axons using lateromedial (LM) stimulation, referred to as the ‘AP‐LM latency’ difference. Importantly, AP‐LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I‐wave generating pathways. In 20 healthy subjects, we investigated whether intermittent TBS (iTBS) modulates I‐wave recruitment as reflected by changes in the AP‐LM latency. As expected, we found that AP‐LM latencies before iTBS were associated with iTBS‐induced excitability changes. A novel finding was that iTBS reduced AP‐LM latency, and that this reduction significantly correlated with changes in cortical excitability observed following iTBS: subjects with larger reductions in AP‐LM latencies featured larger increases in cortical excitability following iTBS. Our findings suggest that plasticity‐induction by iTBS may derive from the modulation of I‐wave generating pathways projecting onto M1, accounting for the predictive potential of I‐wave recruitment. The excitability of I‐wave generating pathways may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel repetitive transcranial magnetic stimulation protocols

Polymorphisms in vascular endothelial growth factor receptor 2 are associated with better response rates to Ranibizumab treatment in age-related macular degeneration.

Item does not contain fulltextPURPOSE: Intravitreal anti-vascular endothelial growth factor (VEGF) injections are currently the standard treatment for neovascular age-related macular degeneration (AMD), but a broad range of response rates has been observed. We evaluated the association of single nucleotide polymorphisms (SNPs) in VEGF genes and their receptors (VEGFR) with the response rate to ranibizumab in 366 patients with neovascular AMD. DESIGN: Case series study. PARTICIPANTS: A total of 366 eyes of 366 patients with neovascular AMD. METHODS: Visual acuity (VA) was determined at baseline, after 3 monthly ranibizumab injections, and after 1 year of treatment. Genotyping of 126 SNPs in the genes encoding VEGF family members VEGFA, VEGFB, VEGFC, VEGFD (FIGF), and placental growth factor (PGF); VEGF receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4); and the gene encoding pigment epithelium-derived factor (PEDF) (SERPINF1) was performed. MAIN OUTCOME MEASURES: The changes in VA after 3 injections and after 1 year of treatment and their association with VEGF and VEGFR genotypes. RESULTS: Univariate analyses of variance (ANOVAs) revealed a significant effect of SNP rs4576072 in the VEGFR2 gene on VA change after 12 months (F[1,235] = 14.05; P = 0.02). A stepwise linear regression analysis returned a model (P = 0.01) with SNPs rs4576072 and rs6828477 in the VEGFR2 gene as independent predictors for VA change after 12 months, with a mean increase in VA of 0.26 on the logarithm of the minimum angle of resolution (logMAR) scale in patients with 3 contributing minor alleles compared with a loss of 0.03 logMAR in patients with no minor allele. CONCLUSIONS: Polymorphisms in the VEGFR2/KDR gene significantly influence visual outcome in patients receiving ranibizumab treatment for neovascular AMD. This study shows that genetic variation partially explains the wide range of response to ranibizumab treatment, which in the future might help clinicians tailoring medical interventions to individual needs