- Email: [email protected]
Magnetic focusing by magnetic shielding for Non-Invasive Brain Stimulation
388
Abstracts / Brain Stimulation 10 (2017) 346e540
denoised data and calculated resting state networks in the two groups separately. We selected five networks of interest (1.bilateral-, 2.left- and 3.right frontoparietal network, 4.default mode network (DMN) and 5.bilateral basal ganglia and insula network) and performed regression analyses with severity of depression, as well as presence or non-presence of psychotic symptoms. Results: The functional connectivity (FC) pattern did not correlate with severity of depression. Depressed patients with psychotic symptoms (n¼14, 61%) compared with patients without psychotic symptoms (n¼9, 39%) from site one showed significantly decreased FC in the right part of the bilateral frontoparietal network (p¼0.002). This result was not replicated when comparing patients with (n¼9, 35%) and without (n¼17, 65%) psychotic symptoms from site two. Discussion: Psychotic depression may be associated with decreased FC of the frontoparietal network, which is involved in cognitive control processes, such as attention and emotion regulation. These findings suggest that FC in the frontoparietal network may be related to subtype of depression, i.e. presence of psychotic symptoms, rather than severity of depression. Since the findings could not be replicated in the 2nd sample, replication is needed before drawing definite conclusions. Keywords: ECT, resting state connectivity, psychotic depression [0208] GENOME-WIDE META-ANALYSIS OF DNA METHYLATION CHANGES ASSOCIATED WITH ANTIDEPRESSANT EFFECTS OF ELECTROCONVULSIVE THERAPY E. Pishva 1, 2, G. Kenis 1, E. Hannon 1, W. Viechtbauer 1, A. Jeffries 2, R. P. Sienaert 3, J. van Os 1, M.L. Stek 4, B.P.F. Lardenoije 1, Rutten*1. 1 Maastricht University Medical Centre, The Netherlands; 2 3 University of Exeter, UK; University Psychiatric Center KU Leuven, Belgium; 4 VU University Medical Center Amsterdam, The Netherlands Introduction: Electroconvulsive therapy (ECT) is a highly effective treatment, and is most frequently used for patients with treatment-resistant depression. Although it has been proposed that ECT induces alterations in the epigenome, and that these epigenomic alterations may act as a molecular mediator of the antidepressant effects of ECT, no epigenetic studies have been conducted on ECT in humans to date. Methods: Two prospectively followed, independent groups of patients treated with ECT, 12 from Maastricht University Medical Centre (Sample I), and 30 from GGZinGeest, Amsterdam (Sample II), were assessed for longitudinal changes of DNA methylation levels in peripheral blood samples before and one week following the last ECT. at the end of the period of ECT. The Infinium HumanMethylation450 BeadChip was used for measuring the levels of DNA methylation in a genome-wide manner. The MontgomeryeÅsberg Depression Rating Scale (MADRS) was administered before the first ECT treatment (baseline), and each week during the ECT course. A meta-analysis of the two datasets was performed, in order to identify CpG sites showing genome-wide, significant associations between changes in DNA methylation levels and improvement in clinical symptoms of depression across the period of ECT. Gene ontology and pathway analyses were subsequently employed in order to identify the related biological processes and functionally defined pathways for the genes that have been assigned to the top-ranked determined CpG sites. Results: Patients showed significant improvement in depressive symptomatology after ECT. The meta-analysis identified that 2 CpG sites in DNASE1L2 and 1 CpG site in RAD52 passed the highly conservative Bonferroni correction for genome-wide analyses, and that a total of 7 CpG sites in/near the genes DNASE1L2, RAD52, IKBKB and CHST8 passed the false discovery rate threshold of statistical significance. Discussion: This first study on longitudinal changes of DNA methylation and changes in depression score across the period of ECT has provided the first molecular evidence that DNA methylation may contribute to the mechanism of action of ECT. The study identified DNASE1L2, RAD52, IKBKB and CHST8 as candidate genes underlying the antidepressant effect of ECT. Keywords: ECT, Genome-wide meta analysis, DNA methylation changes
[0209] HOME-BASED NEUROMODULATORY TECHNOLOGIES FOR MIGRAINE AND OROFACIAL PAIN DISORDERS A. DaSilva*. University of Michigan, USA Introduction: Migraine is a debilitating chronic condition that affects most of the patient’s life, from childhood to late adulthood. Unfortunately, current medicinal and non-pharmacological treatments for migraine are quite often inadequate for successfully preventing and aborting the attacks that go beyond the headache, including aura, nausea, vomiting and inhibitory behavior. Neuromodulation is a promising, novel approach for the treatment of migraine, other primary headaches and orofacial pain disorders. It offers a new option in the treatment that is easily reversible, tends to be highly tolerated by the patients, and allows for their combination with drug therapies. Mechanisms: There is also growing scientific evidence from neuroimaging studies that neuromodulation has the ability to change endogenous central mechanisms related to migraine suffering, pain perception and persistence, including the mu-opioid system. The positive outcome will depend on several factors, for instance the brain target(s), electric current level used, and also number of sessions. Results: For prophylactic treatment of primary headaches and facial pain disorders, frequent visits to a clinic or hospital for the neuromodulatory sessions are needed to produce meaningful pain relief, which makes the treatment regimen a burdensome for patients; especially when they are incapacitated by their ongoing pain and attacks. Hence, their application in clinical practice will depend on the recent industry's capacity to develop portable and more user-friendly devices. Discussion: This presentation will focus on the most recent advances in home-therapy based neuromodulation for migraine and orofacial pain disorders, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation, transcutaneous supraorbital stimulation, and so forth. In addition, we will discuss current and future suitable platforms for home use, their feasibility, evidence from most recent clinical trials, and potential neuromechanisms for their therapeutic effects. Keywords: Pain, Migraine, Neuroimaging, Home therapy [0210] MAGNETIC FOCUSING BY MAGNETIC SHIELDING FOR NON-INVASIVE BRAIN STIMULATION Q. Meng 1, 2, M. Cherry 1, X. Du 1, H. Lu 2, E. Hong 1, Y. Yang 2, F.-S. Choa*1. 1 University of Maryland, USA; 2 National Institutes of Health, USA Instruction: Transcranial magnetic stimulation (TMS) is one of the most widely used methods for brain stimulation. It is utilized in diagnosis and treatment for many neural diseases, such as neuropathic pain and loss of function caused by stroke. Current commercial TMS stimulators cannot provide well targeted stimulation. Due to fast field divergence, the effective distance in TMS is limited to around 1.5 cm. A breakthrough is needed to achieve non-invasive, focused brain stimulation. Methods: We demonstrated using magnetic shield to achieve magnetic focusing without sacrificing significant amount of throughput. The shield is composed of multiple layers of copper ring arrays, which utilize induced current in the ring to generate counter magnetic fields. We experimentally set up a two pole stimulator system designed for animals (rats). A transient magnetic field probe was used for field measurements. Results: The shield effect depends on not only the design of shield structure but also the intensity of original magnetic field from the stimulator. A higher original magnetic field can produce stronger counter field and achieve smaller size focal point. A tight focal spot with a diameter of 0.5cm was achieved by using 4 layers of copper ring arrays when data was measured at mid plane of the stimulator and 3cm away from iron surface as figure 1a illustrated. Discussion: With proper designing and arrangement of array structures and rings locations, the combined original and counter fields can produce a final focused field distribution. Such a multilayer copper ring array made shield structure will be useful for future targeted non-invasive stimulation applications.
Abstracts / Brain Stimulation 10 (2017) 346e540
389
Figure 1a. Experimental setup of animal TMS stimulator; b. Four layers of shield in the TMS; c. Magnetic field distribution in the central plane without using shield; d. Magnetic field distribution in the central plane with shield.
[0211] ASSESSING AND STABILIZING ABERRANT NEUROPLASTICITY IN AUTISM SPECTRUM DISORDER USING TRANSCRANIAL MAGNETIC STIMULATION: PRELIMINARY FINDINGS FROM A PROOF-OF-PRINCIPLE STUDY P. Desarkar*1, 3, T.K. Rajji 1, 3, S.H. Ameis 1, 2, M.C. Lai 1, 2, D. Blumberger 1, 3, Z.J. Daskalakis 1, 3. 1 University of Toronto, Canada; 2 The Hospital for Sick Children, Canada; 3 Temerty Centre for Therapeutic Brain Intervention, Canada Purpose: To gather evidence to support aberrant hyperplasticity in the brain in adults with Autism Spectrum Disorder (ASD), and to study if hyperplasticity can be reversed with a 'mechanism-driven' inhibitory repetitive Transcranial Magnetic Stimulation (rTMS). Methods: Using a randomized cross-over design, we so far assessed neuroplasticity in the motor cortex in 7 right-handed ASD subjects and compared them to 7 sex and age matched controls. We further randomized the ASD subjects (1:1) to receive a single session of active or sham rTMS (6000 pulses at 20Hz, inter-train interval of 30s) and then reassessed neuroplasticity on the next day following rTMS. To calculate neuroplasticity, Theta burst stimulation (TBS), which comprises of 2 paradigmsintermittent TBS or iTBS and continuous TBS or cTBS, was applied. cTBS results in long lasting suppression of cortical activity that is analogous to Long Term Depression (LTD) and iTBS results in long lasting enhancement that is analogous to Long Term Potentiation (LTP). The LTD- and LTP-like
activities were calculated by measuring the duration of suppression (to cTBS) and enhancement (to iTBS) of TBS-induced cortico-spinal excitability (primary outcome measure). Results: iTBS-induced LTP-like neuroplasticity is already significantly excessive in the ASD group (mean + SD : 99.28+26.9 min), compared to controls (mean + SD: 47+19.8min) (p¼0.004). Active rTMS attenuated both LTP (n¼2;duration reduced by 80min) and LTD-like (n¼2;duration reduced by 50min) neuroplasticity (n¼2), but the same wasn't observed in the sham group (n¼5). Conclusion: To our knowledge, this is the first study attempting to stabilize aberrant hyperplasticity in ASD using rTMS. Since aberrant neuroplasticity has been linked with autistic behaviours, If successful, this information will pave the way for treatments based on etio-pathogenetic mechanism. Given that successful treatment of ASD is still elusive, a novel and effective treatment for ASD will be transformative for the field. Keywords: Autism Spectrum Disorder, Neuroplasticity, Transcranial Magnetic Stimulation [0212] NOVEL TREATMENT RTMS STRATEGIES TO COUNTERACT NEGLECT. G. Koch*. Santa Lucia Foundation, Italy Introduction: The human brain is characterized by the lateralization of cognitive functions. Multiple lines of evidence suggest the deployment of visuospatial attention is controlled by a frontoparietal network, with a
Abstracts / Brain Stimulation 10 (2017) 346e540
denoised data and calculated resting state networks in the two groups separately. We selected five networks of interest (1.bilateral-, 2.left- and 3.right frontoparietal network, 4.default mode network (DMN) and 5.bilateral basal ganglia and insula network) and performed regression analyses with severity of depression, as well as presence or non-presence of psychotic symptoms. Results: The functional connectivity (FC) pattern did not correlate with severity of depression. Depressed patients with psychotic symptoms (n¼14, 61%) compared with patients without psychotic symptoms (n¼9, 39%) from site one showed significantly decreased FC in the right part of the bilateral frontoparietal network (p¼0.002). This result was not replicated when comparing patients with (n¼9, 35%) and without (n¼17, 65%) psychotic symptoms from site two. Discussion: Psychotic depression may be associated with decreased FC of the frontoparietal network, which is involved in cognitive control processes, such as attention and emotion regulation. These findings suggest that FC in the frontoparietal network may be related to subtype of depression, i.e. presence of psychotic symptoms, rather than severity of depression. Since the findings could not be replicated in the 2nd sample, replication is needed before drawing definite conclusions. Keywords: ECT, resting state connectivity, psychotic depression [0208] GENOME-WIDE META-ANALYSIS OF DNA METHYLATION CHANGES ASSOCIATED WITH ANTIDEPRESSANT EFFECTS OF ELECTROCONVULSIVE THERAPY E. Pishva 1, 2, G. Kenis 1, E. Hannon 1, W. Viechtbauer 1, A. Jeffries 2, R. P. Sienaert 3, J. van Os 1, M.L. Stek 4, B.P.F. Lardenoije 1, Rutten*1. 1 Maastricht University Medical Centre, The Netherlands; 2 3 University of Exeter, UK; University Psychiatric Center KU Leuven, Belgium; 4 VU University Medical Center Amsterdam, The Netherlands Introduction: Electroconvulsive therapy (ECT) is a highly effective treatment, and is most frequently used for patients with treatment-resistant depression. Although it has been proposed that ECT induces alterations in the epigenome, and that these epigenomic alterations may act as a molecular mediator of the antidepressant effects of ECT, no epigenetic studies have been conducted on ECT in humans to date. Methods: Two prospectively followed, independent groups of patients treated with ECT, 12 from Maastricht University Medical Centre (Sample I), and 30 from GGZinGeest, Amsterdam (Sample II), were assessed for longitudinal changes of DNA methylation levels in peripheral blood samples before and one week following the last ECT. at the end of the period of ECT. The Infinium HumanMethylation450 BeadChip was used for measuring the levels of DNA methylation in a genome-wide manner. The MontgomeryeÅsberg Depression Rating Scale (MADRS) was administered before the first ECT treatment (baseline), and each week during the ECT course. A meta-analysis of the two datasets was performed, in order to identify CpG sites showing genome-wide, significant associations between changes in DNA methylation levels and improvement in clinical symptoms of depression across the period of ECT. Gene ontology and pathway analyses were subsequently employed in order to identify the related biological processes and functionally defined pathways for the genes that have been assigned to the top-ranked determined CpG sites. Results: Patients showed significant improvement in depressive symptomatology after ECT. The meta-analysis identified that 2 CpG sites in DNASE1L2 and 1 CpG site in RAD52 passed the highly conservative Bonferroni correction for genome-wide analyses, and that a total of 7 CpG sites in/near the genes DNASE1L2, RAD52, IKBKB and CHST8 passed the false discovery rate threshold of statistical significance. Discussion: This first study on longitudinal changes of DNA methylation and changes in depression score across the period of ECT has provided the first molecular evidence that DNA methylation may contribute to the mechanism of action of ECT. The study identified DNASE1L2, RAD52, IKBKB and CHST8 as candidate genes underlying the antidepressant effect of ECT. Keywords: ECT, Genome-wide meta analysis, DNA methylation changes
[0209] HOME-BASED NEUROMODULATORY TECHNOLOGIES FOR MIGRAINE AND OROFACIAL PAIN DISORDERS A. DaSilva*. University of Michigan, USA Introduction: Migraine is a debilitating chronic condition that affects most of the patient’s life, from childhood to late adulthood. Unfortunately, current medicinal and non-pharmacological treatments for migraine are quite often inadequate for successfully preventing and aborting the attacks that go beyond the headache, including aura, nausea, vomiting and inhibitory behavior. Neuromodulation is a promising, novel approach for the treatment of migraine, other primary headaches and orofacial pain disorders. It offers a new option in the treatment that is easily reversible, tends to be highly tolerated by the patients, and allows for their combination with drug therapies. Mechanisms: There is also growing scientific evidence from neuroimaging studies that neuromodulation has the ability to change endogenous central mechanisms related to migraine suffering, pain perception and persistence, including the mu-opioid system. The positive outcome will depend on several factors, for instance the brain target(s), electric current level used, and also number of sessions. Results: For prophylactic treatment of primary headaches and facial pain disorders, frequent visits to a clinic or hospital for the neuromodulatory sessions are needed to produce meaningful pain relief, which makes the treatment regimen a burdensome for patients; especially when they are incapacitated by their ongoing pain and attacks. Hence, their application in clinical practice will depend on the recent industry's capacity to develop portable and more user-friendly devices. Discussion: This presentation will focus on the most recent advances in home-therapy based neuromodulation for migraine and orofacial pain disorders, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), vagus nerve stimulation, transcutaneous supraorbital stimulation, and so forth. In addition, we will discuss current and future suitable platforms for home use, their feasibility, evidence from most recent clinical trials, and potential neuromechanisms for their therapeutic effects. Keywords: Pain, Migraine, Neuroimaging, Home therapy [0210] MAGNETIC FOCUSING BY MAGNETIC SHIELDING FOR NON-INVASIVE BRAIN STIMULATION Q. Meng 1, 2, M. Cherry 1, X. Du 1, H. Lu 2, E. Hong 1, Y. Yang 2, F.-S. Choa*1. 1 University of Maryland, USA; 2 National Institutes of Health, USA Instruction: Transcranial magnetic stimulation (TMS) is one of the most widely used methods for brain stimulation. It is utilized in diagnosis and treatment for many neural diseases, such as neuropathic pain and loss of function caused by stroke. Current commercial TMS stimulators cannot provide well targeted stimulation. Due to fast field divergence, the effective distance in TMS is limited to around 1.5 cm. A breakthrough is needed to achieve non-invasive, focused brain stimulation. Methods: We demonstrated using magnetic shield to achieve magnetic focusing without sacrificing significant amount of throughput. The shield is composed of multiple layers of copper ring arrays, which utilize induced current in the ring to generate counter magnetic fields. We experimentally set up a two pole stimulator system designed for animals (rats). A transient magnetic field probe was used for field measurements. Results: The shield effect depends on not only the design of shield structure but also the intensity of original magnetic field from the stimulator. A higher original magnetic field can produce stronger counter field and achieve smaller size focal point. A tight focal spot with a diameter of 0.5cm was achieved by using 4 layers of copper ring arrays when data was measured at mid plane of the stimulator and 3cm away from iron surface as figure 1a illustrated. Discussion: With proper designing and arrangement of array structures and rings locations, the combined original and counter fields can produce a final focused field distribution. Such a multilayer copper ring array made shield structure will be useful for future targeted non-invasive stimulation applications.
Abstracts / Brain Stimulation 10 (2017) 346e540
389
Figure 1a. Experimental setup of animal TMS stimulator; b. Four layers of shield in the TMS; c. Magnetic field distribution in the central plane without using shield; d. Magnetic field distribution in the central plane with shield.
[0211] ASSESSING AND STABILIZING ABERRANT NEUROPLASTICITY IN AUTISM SPECTRUM DISORDER USING TRANSCRANIAL MAGNETIC STIMULATION: PRELIMINARY FINDINGS FROM A PROOF-OF-PRINCIPLE STUDY P. Desarkar*1, 3, T.K. Rajji 1, 3, S.H. Ameis 1, 2, M.C. Lai 1, 2, D. Blumberger 1, 3, Z.J. Daskalakis 1, 3. 1 University of Toronto, Canada; 2 The Hospital for Sick Children, Canada; 3 Temerty Centre for Therapeutic Brain Intervention, Canada Purpose: To gather evidence to support aberrant hyperplasticity in the brain in adults with Autism Spectrum Disorder (ASD), and to study if hyperplasticity can be reversed with a 'mechanism-driven' inhibitory repetitive Transcranial Magnetic Stimulation (rTMS). Methods: Using a randomized cross-over design, we so far assessed neuroplasticity in the motor cortex in 7 right-handed ASD subjects and compared them to 7 sex and age matched controls. We further randomized the ASD subjects (1:1) to receive a single session of active or sham rTMS (6000 pulses at 20Hz, inter-train interval of 30s) and then reassessed neuroplasticity on the next day following rTMS. To calculate neuroplasticity, Theta burst stimulation (TBS), which comprises of 2 paradigmsintermittent TBS or iTBS and continuous TBS or cTBS, was applied. cTBS results in long lasting suppression of cortical activity that is analogous to Long Term Depression (LTD) and iTBS results in long lasting enhancement that is analogous to Long Term Potentiation (LTP). The LTD- and LTP-like
activities were calculated by measuring the duration of suppression (to cTBS) and enhancement (to iTBS) of TBS-induced cortico-spinal excitability (primary outcome measure). Results: iTBS-induced LTP-like neuroplasticity is already significantly excessive in the ASD group (mean + SD : 99.28+26.9 min), compared to controls (mean + SD: 47+19.8min) (p¼0.004). Active rTMS attenuated both LTP (n¼2;duration reduced by 80min) and LTD-like (n¼2;duration reduced by 50min) neuroplasticity (n¼2), but the same wasn't observed in the sham group (n¼5). Conclusion: To our knowledge, this is the first study attempting to stabilize aberrant hyperplasticity in ASD using rTMS. Since aberrant neuroplasticity has been linked with autistic behaviours, If successful, this information will pave the way for treatments based on etio-pathogenetic mechanism. Given that successful treatment of ASD is still elusive, a novel and effective treatment for ASD will be transformative for the field. Keywords: Autism Spectrum Disorder, Neuroplasticity, Transcranial Magnetic Stimulation [0212] NOVEL TREATMENT RTMS STRATEGIES TO COUNTERACT NEGLECT. G. Koch*. Santa Lucia Foundation, Italy Introduction: The human brain is characterized by the lateralization of cognitive functions. Multiple lines of evidence suggest the deployment of visuospatial attention is controlled by a frontoparietal network, with a