Continuous Theta-burst rTMS Research Articles

Theta-burst transcranial magnetic stimulation promotes stroke recovery by vascular protection and neovascularization.

Rationale: The integrity and function of the blood-brain barrier (BBB) is compromised after stroke. The current study was performed to examine potential beneficial effects and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) on angiogenesis and vascular protection, function, and repair following stroke, which are largely unknown.Methods: Using a rat photothrombotic (PT) stroke model, continuous theta-burst rTMS was administered once daily to the infarcted hemisphere for 5 min, beginning 3 h after PT stroke. This treatment was applied for 6 days. BBB integrity, blood flow, vascular associated proteins, angiogenesis, integrity of neuronal morphology and structure, and behavioral outcome were measured and analyzed at 6 and/or 22 days after PT stroke.Results: We report that rTMS significantly mitigated BBB permeabilization and preserved important BBB components ZO-1, claudin-5, occludin, and caveolin-1 from PT-induced degradation. Damage to vascular structure, morphology, and perfusion was ameliorated by rTMS, resulting in improved local tissue oxygenation. This was accompanied with robust protection of critical vascular components and upregulation of regulatory factors. A complex cytokine response was induced by PT, particularly at the late phase. Application of rTMS modulated this response, ameliorating levels of cytokines related to peripheral immune cell infiltration. Further investigation revealed that rTMS promoted and sustained post-ischemic angiogenesis long-term and reduced apoptosis of newborn and existing vascular endothelial cells. Application of rTMS also inhibited PT-induced excessive astrocyte-vasculature interactions and stimulated an A1 to A2 shift in vessel-associated astrocytes. Mechanistic studies revealed that rTMS dramatically increased levels of PDGFRβ associated with A2 astrocytes and their adjacent vasculature. As well, A2 astrocytes displayed marked amplification of the angiogenesis-related factors VEGF and TGFβ. PT induced a rise in vessel-associated expression of HIF-1α that was starkly intensified by rTMS treatment. Finally, rTMS preserved neuronal morphology, synaptic structure integrity and behavioral outcome.Conclusions: These results indicate that rTMS can exert powerful protective and restorative effects on the peri-infarct microvasculature after PT stroke by, in part, promoting HIF-1α signaling and shifting vessel-associated astrocytic polarization to the A2 phenotype. This study provides further support for the potent protective effects of rTMS in the context of ischemic stroke, and these findings implicate vascular repair and protection as an important underlying phenomenon.

Beneficial Effects of Theta-Burst Transcranial Magnetic Stimulation on Stroke Injury via Improving Neuronal Microenvironment and Mitochondrial Integrity.

Recent work suggests that repetitive transcranial magnetic stimulation (rTMS) may beneficially alter the pathological status of several neurological disorders, although the mechanism remains unclear. The current study was designed to investigate the effects of rTMS on behavioral deficits and potential underlying mechanisms in a rat photothrombotic (PT) stroke model. From day 0 (3h) to day 5 after the establishment of PT stroke, 5-min daily continuous theta-burst rTMS (3 pulses of 50Hz repeated every 200ms, intensity at 200G) was applied on the infarct hemisphere. We report that rTMS significantly attenuated behavioral deficits and infarct volume after PT stroke. Further investigation demonstrated that rTMS remarkably reduced synaptic loss and neuronal degeneration in the peri-infarct cortical region. Mechanistic studies displayed that beneficial effects of rTMS were associated with robust suppression of reactive micro/astrogliosis and the overproduction of pro-inflammatory cytokines, as well as oxidative stress and oxidative neuronal damage especially at the late stage following PT stroke. Intriguingly, rTMS could effectively induce a shift in microglial M1/M2 phenotype activation and an A1 to A2 switch in astrocytic phenotypes. In addition, the release of anti-inflammatory cytokines and mitochondrial MnSOD in peri-infarct regions were elevated following rTMS treatment. Finally, rTMS treatment efficaciously preserved mitochondrial membrane integrity and suppressed the intrinsic mitochondrial caspase-9/3 apoptotic pathway within the peri-infarct cortex. Our novel findings indicate that rTMS treatment exerted robust neuroprotection when applied at least 3h after ischemic stroke. The underlying mechanisms are partially associated with improvement of the local neuronal microenvironment by altering inflammatory and oxidative status and preserving mitochondrial integrity in the peri-infarct zone. These findings provide strong support for the promising therapeutic effect of rTMS against ischemic neuronal injury and functional deficits following stroke.

Theta Burst Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations: Negative Findings From a Double-Blind-Randomized Trial.

Auditory verbal hallucinations (AVH) in schizophrenia are resistant to antipsychotic medication in approximately 25% of patients. Treatment with repetitive transcranial magnetic stimulation (rTMS) for refractory AVH has shown varying results. A stimulation protocol using continuous theta burst rTMS (TB-rTMS) showed high efficacy in open label studies. We tested TB-rTMS as a treatment strategy for refractory AVH in a double-blind, placebo-controlled trial. Seventy-one patients with AVH were randomly allocated to TB-rTMS or placebo treatment. They received 10 TB-rTMS or sham treatments over the left temporoparietal cortex in consecutive days. AVH severity was assessed at baseline, end of treatment and follow-up using the Psychotic Symptom Rating Scale (PSYRATS) and the Auditory Hallucinations Rating Scale (AHRS). Other schizophrenia-related symptoms were assessed with the Positive and Negative Syndrome Scale (PANSS). Seven patients dropped out before completing the study. In the remaining 64, AVH improved significantly after treatment in both groups as measured with both PSYRATS and AHRS. PANSS positive and general subscores also decreased, but the negative subscores did not. However, improvement did not differ significantly between the TB-rTMS and the placebo group on any outcome measure. Symptom reduction could be achieved in patients with medication-resistant hallucinations, even within 1 week time. However, as both groups showed similar improvement, effects were general (ie, placebo-effects) rather than specific to treatment with continuous TB-rTMS. Our findings highlight the importance of double-blind trials including a sham-control condition to assess efficacy of new treatments such as TMS.

EPA-0228 - Non invasive brain stimulation in the treatment of schizophrenia

Auditory verbal hallucinations (AVH) are a characteristic symptom of schizophrenia. Previous studies have investigated 1-Hz repetitive transcranial magnetic stimulation (rTMS) to the left temporoparietal region as a non-invasive treatment option for treatment-resistant patients, with several studies with large sample sizes not demonstrating efficacy of rTMS compared to sham stimulation. A new stimulation protocol using continuous theta-burst rTMS could provide a more effective therapeutic option. In a double-blind study, forty-one patients with AVH were randomly allocated to either continuous theta-burst rTMS or sham treatment. The theta-burst TMS group received 10 treatments over left temporoparietal cortex distributed over five consecutive days. The placebo group received 10 treatments of sham stimulation following the same procedures as the theta-burst group. Severity of AVH was assessed using the psychotic symptom rating scales (PSYRATS), the auditory hallucinations rating scale (AHRS) and item P3 of the positive and negative syndrome scale (PANSS) before treatment, after five days of treatment, and during follow-up one month later. Data were analyzed using repeated measures ANOVA. Significant main effects of treatment were observed for the PSYRATS (p=0.017) and a trend was observed for the AHRS (p=0.053), indicating lower hallucination severity scores after treatment. No significant interaction effects were observed for any of the hallucination severity scales, indicating that AVH did not significantly improve after theta-burst stimulation compared to sham stimulation. These results suggest a placebo effect of continuous theta-burst rTMS on the left temporoparietal region.

Continuous theta-burst rTMS over primary somatosensory cortex modulates tactile perception on the hand

ObjectiveTheta-burst stimulation (TBS) over the primary somatosensory cortex (SI) alters cortical excitability, and in its intermittent form (iTBS) improves tactile spatial acuity. The effects of continuous TBS (cTBS) on tactile acuity remain unknown. The present study examined the influence of cTBS over SI on temporal and spatial tactile acuity on the contralateral hand. MethodsIn separate experiments, temporal discrimination threshold (TDT) and spatial amplitude discrimination threshold (SDT) were obtained from the right hand before and for up to 34min following real and sham cTBS (600 pulses) over left-hemisphere SI. ResultsCTBS reduced temporal and spatial tactile acuity for up to 18min following real cTBS. Tactile acuity was unaltered in the groups receiving sham cTBS. ConclusionsCTBS over SI impairs both temporal and spatial domains of tactile acuity for a similar duration. SignificanceCTBS over SI appears to decrease neural activity within targeted cortex and has potential utility in reducing excessive sensory processing.