TMS: BASIC MECHANISM OF ACTION...• TMS affects various neuronal processes such as neurotransmitter levels, circuit -level patterns and network oscillations • TMS appears to act

© 2018 American Psychiatric Association. All rights reserved.

TMS: BASIC MECHANISM OF ACTIONAPA MASTER COURSE

Karl I. Lanocha, MD | May 20, 2019

TMS Health Solutions

© 2018 American Psychiatric Association. All rights reserved.2

DISCLOSURE INFORMATION

• RoyaltiesAPPI Press

• Stock/PatentsNone

• Speakers BureauNone

• Organizations/AffiliationsClinical TMS Society


LEARNING OBJECTIVES

• Explain the mechanism of action of TMS

• Review the historical development of TMS

• Understand the effects of different TMS stimulation parameters

• Consider the ways in which TMS can modulate brain circuitry


WHAT IS TMS?

Transcranial magnetic stimulation (TMS) is a non-invasive,safe, neuromodulation procedure that uses high strengthpulsed magnetic fields to induce a depolarizing current in alocalized area of the cerebral cortex.


IMPORTANT ASPECTS OF TMS

• TMS is effective for patients who do not respond to antidepressant medications

• Unlike ECT, TMS is an office-based procedure that requires no anesthesia or sedation

• Unlike ECT, TMS causes no cognitive side effects

• Unlike medications, TMS causes no systemic side effects

• TMS is an observed procedure


NEUROMODULATION TREATMENTS FOR DEPRESSION

• Phototherapy

• ECT (electroconvulsive therapy)

• VNS (vagus nerve stimulation)

• TNS (trigeminal nerve stimulation)

• DBS (deep brain stimulation)

• tDCS (transcranial direct current stimulation

• TMS (transcranial magnetic stimulation)


GENERAL ATTRIBUTES OF NEUROMODULATION TREATMENTS FOR DEPRESSION

• Invasive vs. non-invasive

• Depolarizing vs. non-depolarizing

• Convulsive vs. non-convulsive

• Electrical vs. magnetic stimulus


ELECTRICAL AND MAGNETIC STIMULATION

• Alternative to pharmacologic interventions

• Allow stimulation of CNS without systemic side effects of medications

• Electrical current is applied directly with electrodes

• Magnetic stimulation induces an electrical current withoutelectrodes

• Electrical current cannot be focused

• Magnetic field can be spatially focused


BASIC PRINCIPLES OF MAGNETIC STIMULATION

Two Electromagnetic Principles

• Ampere’s LawAn alternating electrical current generates a magnetic field

• Faraday’s LawAn alternating magnetic field generates an electrical current


BASIC PARTS OF A TMS DEVICE

Transcranial Magnetic Stimulation : Clinical Applications forPsychiatric Practice, Edited by Bermudes, Lanocha, Janicak 2018


ELECTRICAL FIELD INDUCTION

Lanocha, 2018


EARLY EXPERIMENTS

Sylvanus P. Thompson 1851-1916


FIRST MODERN TMS DEVICE

Lancet 11;1 (8437):1106-7. 1985

Anthony Barker

Non-invasive Magnetic Stimulation of Human Motor Cortex


TMS STIMULATION OF MOTOR CORTEX

Loporto et al. 2011


3 TYPES OF TMS PULSES

• Single Pulse• Always excitatory• May or may not cause depolarization depending on strength

• Paired Pulses• Excitatory or inhibitory depending on inter stimulus interval (ISI)

• Repetitive Pulses (rTMS)• Low frequency (< 1 Hz)—Inhibitory• High Frequency (> 1 Hz)—Excitatory


3 TYPES OF TMS PULSES

>>

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Valero-Cabré et al. 2017


PERSISTENT NEUROMODULATION

>

Valero-Cabré et al. 2017


REPETITIVE TMS (RTMS)

• Slow: 5 HzExcitatoryPyramidal cells (Glu)

Huerta 2009


3 BROAD CATEGORIES OF RTMS

• Conventional rTMSFigure 8 coil

• Deep TMS (dTMS)• H-coil

• Theta burst stimulation (TBS)• Continuous theta burst (cTBS)

• Inhibitory• Intermittent theta burst (iTBS)

• Excitatory


THE DEPRESSED BRAIN


R-TMS FOR DEPRESSION


TMS PARAMETERS

• Location• Brain region stimulated

• Intensity• Magnetic field strength (induced electrical field

strength) relative to motor threshold• Frequency

• Number or pulses per second and frequency of treatment sessions

• Duration• Number of pulses per treatment session and total

number of treatment sessionsTranscranial Magnetic Stimulation : Clinical ApplicationsFor Psychiatric Practice, Edited by Bermudes, Lanocha, Janicak 2018


STIMULUS LOCATION

• Left Dorsolateral Prefrontal Cortex (LDLPFC)

• High frequency• (most common)

• Right Dorsolateral Prefrontal Cortex (RDLPFC)

• Low frequency• (less common)

• Sequential LDLPFC and RDLPFC

Transcranial Magnetic Stimulation : Clinical ApplicationsFor Psychiatric Practice, Edited by Bermudes, Lanocha, Janicak 2018


STIMULUS INTENSITY AND PULSE FREQUENCY

• Intensity• 100-120% of motor threshold (MT)

• Frequency• High frequency:

• 10 Hz @ 120% MT• 20 Hz @ 100% MT

• Low frequency• 1 Hz @ 110% MT



PULSE TRAIN DURATION AND INTERVAL

Lanocha, 2018


NUMBER OF PULSES

• High Frequency• 2000-6,000 per session (average: 3000)• Up to 216,000 per course

• Low Frequency• 300-1560 per session (average: 900)• Up to 56,160 per course



PULSE TRAIN DURATION AND INTERVAL

• Pulse Train Duration• High frequency

• 10 Hz 4 seconds • 20 Hz 2 seconds

• Low frequency• 1 Hz for 5-26 minutes

• Pulse Train Interval• High frequency: 10-28 seconds • Low Frequency: 0 seconds



TYPICAL TMS TREATMENT PARAMETERS

• Target: left dorsolateral prefrontal cortex• Pulse frequency: 10 Hz• Pulse train duration: 4 seconds• Pulse train interval: 26 seconds• Pulse trains per treatment: 75 (total 3000 pulses)• Stimulus intensity: 120% MT• Treatment frequency: Once a day, 5 days per week• Total treatment number: 30+



TRANS-SYNAPTIC—CIRCUIT—NETWORK EFFECTS

Williams LM 2016

Courtesy of Stanford Miller, Neuronetics, Inc.

Left Premotor Cortex Right Premotor Cortex


Stern AP, Cohen D. Repetitive Transcranial Magnetic Stimulation for Treatment Resistant Depression. Neuropsychiatry (2013) 3 (1), 107-115

DEPRESSION CIRCUIT


DEPRESSION CIRCUIT



KEY BRAIN EFFECTS

• Gene expression• Neurotransmitter effects• Neuro-plasticity• Cerebral metabolism• Electrophysiologic changes• Neuroendocrine function• Neural network effects

Lanocha, Transcranial Magnetic Stimulation : Clinical ApplicationsFor Psychiatric Practice, Edited by Bermudes, Lanocha, Janicak 2018


GENE EXPRESSION

• c-FOS and DUSP1: ↓ post-LFR rTMS (Teyssier et al. 2013)

• BDNF Val/Val and Val66Met predict response (Bocchio-Chiavetto et al., 2008)

• SERTPR and 5-HT(1A) predict response (Zanardini et al., 2006)

• LL variant of the 5-HTTLPR gene predicts response(Bocchio-Chiavetto et al., 2008)

rTMS down-regulates expression of stress response genes while certain polymorphisms may affect response


NEUROTRANSMITTER EFFECTS

• DA: ↑ PFC, striatum (Pogarell et al. 2006)

• NE: ↑ locus ceruleus (Yukimasa et al. 2006)

• 5-HT: ↑ PFC, ↓ hippocampus (Baeken et al. 2011)

• Ach: ↑ basal forebrain, striatum (Luborzewski et al. 2007)

• GABA: ↑ PFC, hippocampus and striatum (Bajbouj 2005)

• Glu: ↑ PFC, striatum, hippocampus (Luborzewski et al. 2007)

rTMS alters neurotransmitter levels


NEURO-PLASTICITY

• Brain derived neurotrophic factor (BDNF): ↑ (Lang et al. 2006)

• Long term potentiation: HF rTMS (Hallett 2007)

• Long term depression: LF rTMS (Hallett 2007)

• Neurogenesis: ↑ dentate gyrus (Crupi et al. 2008)

rTMS alters synaptic plasticity and promotes neurogenesis


CEREBRAL METABOLISM

• Single-proton emission computed tomography (SPECT)• HF rTMS: ↑ rCBF (Catafau et al., 2001) • LF rTMS: ↓ rCBF (Loo et al., 2003)

• Positron emission tomography (PET)• rCBF changes in regions distal to stimulation site

• OFC, VLPFC, ACC, sgACC (Speer et al. 2000)• Functional magnetic resonance imaging (fMRI)

• ↑ BOLD responses following HF rTMS (Cardoso 2008)• Functional near-infrared spectroscopy (fNIRS)

• LF rTMS: ↓ HbO2 (Kozel et al. 2009)

rTMS increases LDLPFC activity and decreases RDLPFC activity


ELECTROPHYSIOLOGIC CHANGES

• Alpha band: ↑ frontal, central, parietal (Valiulis et al. 2012) • Beta band: ↑ frontal, central, temporal (García-Anaya et al. 2011) • Theta band: ↑ prefrontal, central, occipital (Noda et al. 2013) • Delta band: ↑ central, parietal (Noda et al. 2013) • Sigma band: no change (Saeki et al. 2013) • Event-related potentials (ERPs): ↑ P2, ↓ N2 (Spronk et al. 2008)• Resting motor threashold (RMT): ↓ (Zarkowski et al. 2009) or ↑

(Shajahan et al. 2002)

rTMS increases power in multiple EEG frequencies


NEUROENDOCRINE FUNCTION

• ↓ CRH, ↓ ACTH (Mingli 2009)

• ↓ ACTH cortisol (Baeken 2009)

• ↑ parasympathetic, ↓ sympathetic activity (Udupa 2007)

rTMS normalizes the hypothalamic-pituitary-adrenal axis


NEURAL NETWORK EFFECTS

DLPFC hypoactivity ←→ sgACC hyperactivity

• rTMS increases functional connectivity in the dorsolateral frontal loop, i.e. DLPFC, caudate and GP (Shajahan et al. 2002)

• rTMS increases functional connectivity in the limbic loop, i.e. PFC, ventral striatum (Shajahan et al. 2002)

• rTMS modulates functional connectivity within and between the central executive network (CEN) and default mode network (DMN), decreasing abnormal hyperactivity in the DMN (Liston et al. 2014)

rTMS produces top-down modulation of cortico-limbic activity (Leuchter et al. 2013)


OVERVIEW OF RTMS MECHANISM OF ACTION

Adapted from Brunelin 2015


SUMMARY

• TMS is a non-invasive form of targeted brain stimulation• TMS is a clinical application of electromagnetic induction• Dosage is described in terms of stimulus parameters

• Location• Intensity• Frequency• Duration

• Stimulus parameters determine clinical effect


SUMMARY

• High frequency = excitatory• Low frequency = inhibitory• Effective stimulus parameters for depression

• High frequency (10-20 Hz) LDLPFC• Low frequency (1 Hz) RDLPFC• Combined high and low frequency

• TMS produces persistent changes akin to long-term potentiation and long-term depression of synaptic transmission

• Effects can occur distant from the site of stimulation


SUMMARY

• TMS affects various neuronal processes such as neurotransmitter levels, circuit-level patterns and network oscillations

• TMS appears to act in a top down manner to modulate activity in cortical-limbic circuits with specific effects in the subgenual anterior cingulate cortex

• TMS produces non-neuronal effects, such as changes in blood flow, and genetic and protein regulation which are still poorly understood


REFERENCES 1

Transcranial Magnetic Stimulation: Clinical Applications for Psychiatric Practice, Edited by Bermudes, Lanocha, Janicak 2018

Baeken C, De Raedt R, Leyman L, Schiettecatte J, Kaufman L, Poppe K, Vanderhasselt MA, Anckaert E, Bossuyt A (2009). The impact of one HF-rTMS session on mood and salivary cortisol in treatment resistant unipolar melancholic depressed patients. Journal of Affective Disorders 113, 100–108

Baeken C , De Raedt R, Bossuyt A, Vanhove C, Mertens J et al. (2011) The impact of HF-rTMStreatment on serotonin 2A receptors in unipolar melancholic depression. Brain Stimulation. 4(2). p.104-111

Bajbouj M, Brakemeier EL, Schubert F, Lang UE, Neu P, Schindowski C, Danker-Hopfe H (2005). Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder. Experimental Neurology 196, 332–338

Bickford RG, Guidi M, Fortesque P, Swenson M. Magnetic stimulation of human peripheral nerve and brain: response enhancement by combined magnetoelectrical technique. Neurosurgery. 1987 Jan;20(1):110-6

https://biblio.ugent.be/publication?q=year+exact+2011https://www.ncbi.nlm.nih.gov/pubmed/?term=Bickford%20RG%5bAuthor%5d&cauthor=true&cauthor_uid=3808250https://www.ncbi.nlm.nih.gov/pubmed/?term=Guidi%20M%5bAuthor%5d&cauthor=true&cauthor_uid=3808250https://www.ncbi.nlm.nih.gov/pubmed/?term=Fortesque%20P%5bAuthor%5d&cauthor=true&cauthor_uid=3808250https://www.ncbi.nlm.nih.gov/pubmed/?term=Swenson%20M%5bAuthor%5d&cauthor=true&cauthor_uid=3808250


REFERENCES 2

Bocchio-Chiavetto L, Miniussi C, Zanardini R, Gazzoli A, Bignotti S, Specchia C, Gennarelli M. 5-HTTLPR and BDNF Val66Met polymorphisms and response to rTMS treatment in drug resistant depression. Neurosci Lett. 2008 May 30;437(2):130-4.

Cardoso EF, Fregni F, Maia FM, Boggio PS, Myczkowski ML. rTMS treatment for depression in Parkinson's disease increases BOLD responses in the left prefrontal cortex. International Journal of Neuropsychopharmacology, Volume 11, Issue 2, 1 March 2008, Pages 173–183

Catafau AM, Perez Sola V, Gironell A, Raya Álvarez. SPECT mapping of cerebral activity changes induced by repetitive transcranial magnetic stimulation in depressed patients. A pilot study Psychiatry Research 106(3):151-60. 2001

R. Crupi, M. Cambiaghi, H. Wang, R. Hen, F. Battaglia, R. Crupi (2008). rTMS, neurogenesis and synaptic plasticity Brain Stimulation Volume 1, Issue 3, Page 309

García-Anaya M, González–Olvera J, Ricardo–Garcell J, Armas G, Miranda E, Reyes E, Adelina Otero G (2011). Clinical and electophysiological effect of right and left repetitive transcranial magnetic stimulation in patients with major depressive disorder. Salud Mental 34, 291–299


REFERENCES 3

Hallett M (2007). Transcranial magnetic stimulation: a primer. Neuron 55, 187–199.

Kozel FA, Tian F, Dhamne S, Croarkin PE, McClintock SM, et al. Using simultaneous repetitive Transcranial Magnetic Stimulation/functional Near Infrared Spectroscopy (rTMS/fNIRS) to measure brain activation and connectivity. NeuroImage 47 (2009) 1177–1184

Lang UE, Bajbouj M, Gallinat J, Hellweg R. Brain-derived neurotrophic factor serum concentrations in depressive patients during vagus nerve stimulation and repetitive transcranial magnetic stimulation. Psychopharmacology. 2006; 187(1): 56-59

Leuchter AF, Cook IA, Jin Y, Phillips B (2013). The relationship between brain oscillatory activity and therapeutic effectiveness of transcranial magnetic stimulation in the treatment of major depressive disorder. Frontiers in Human Neuroscience 7, 37.

Liston C, Chen AC, Zebley BD, Drysdale AT, Gordon R, Leuchter B, Voss HU, Casey BJ, Etkin A, Dubin MJ (2014). Default mode network mechanisms of transcranial magnetic stimulation in depression. Biological Psychiatry 76, 517–526.

Loporto M, McAllister C, Williams J, Hardwick R, Holmes P. Investigating Central Mechanisms Underlying the Effects of Action Observation and Imagery Through Transcranial Magnetic Stimulation Journal of Motor Behavior, Vol. 43, No. 5, 2011


REFERENCES 4

Luborzewski A, Schubert F, Seifert F, Danker-Hopfe H, Brakemeier EL, Schlattmann P, Anghelescu I, Colla M Bajbouj M (2007). Metabolic alterations in the dorsolateral prefrontal cortex after treatment with high-frequency repetitive transcranial magnetic stimulation in patients with unipolar major depression. Journal of Psychiatric Research 41, 606–615

Mingli H, Zhengtian G, Xinyi W, Xiaoping T (2009). Effects of repetitive transcranial magnetic stimulation on hypothalamic–pituitary–adrenal axis of patients with depression. Journal of Medical Colleges of PLA 24, 337–345

Noda Y, Nakamura M, Saeki T, Inoue M, Iwanari H, Kasai K (2013). Potentiation of quantitative electroencephalograms following prefrontal repetitive transcranial magnetic stimulation in patients with major depression. Neuroscience Research 77, 70–77

Pogarell O, Koch W, Pöpperl G, Tatsch K, Jakob F, Zwanzger P, Mulert C, Rupprecht R, MöllerHJ, Hegerl U, Padberg F (2006). Striatal dopamine release after prefrontal repetitive transcranial magnetic stimulation in major depression: preliminary results of a dynamic.Journal of Psychiatric Research 40, 307–31

Saeki T, Nakamura M, Hirai N, Noda Y, Hayasaka S, Iwanari H, Hirayasu Y (2013). Localized potentiation of sleep slow-wave activity induced by prefrontal repetitive transcranial magnetic stimulation in patients with a major depressive episode. Brain Stimulation 6, 390–396


REFERENCES 5

Shajahan PM, Glabus MF, Steele JD, Doris AB, Anderson K, Jenkins JA, Gooding PA, EbmeierKP (2002). Left dorso-lateral repetitive transcranial magnetic stimulation affects cortical excitability and functional connectivity, but does not impair cognition in major depression.Progress in Neuro-Psychopharmacology and Biological Psychiatry 26, 945–954.

Speer AM, Kimbrell TA, Wassermann EM, Repella JD, Willis MW et al. Opposite Effects of High and Low Frequency rTMS on Regional Brain Activity in Depressed Patients. BiolPsychiatry 2000;48:1133–1141

Spronk D, Arns M, Bootsma A, van Ruth R, Fitzgerald PB (2008). Long-term effects of left frontal rTMS on EEG and ERPs in patients with depression. Clinical EEG and Neuroscience: Official Journal of the EEG and Clinical Neuroscience Society (ENCS) 39, 118–124

Stern AP, Cohen D. Repetitive Transcranial Magnetic Stimulation for Treatment Resistant Depression. Neuropsychiatry (2013) 3 (1), 107-115

Teyssier JR, Trojak B, Chauvet-Gelinier JC, Bonin B (2013). Low frequency transcranial magnetic stimulation downregulates expression of stress genes in blood leucocytes: preliminary evidence. Journal of Psychiatric Research 47, 935–936.

Udupa K, Sathyaprabha TN, Thirthalli J, Kishore KR, Raju TR, Gangadhar BN (2007). Modulation of cardiac autonomic functions in patients with major depression treated with repetitive transcranial magnetic stimulation. Journal of Affective Disorders 104, 231–236


REFERENCES 6

Valero-Cabré A, Amengual JL, Stengel C, Pascual-Leone A, Coubard OA. Transcranial magnetic stimulation in basic and clinical neuroscience: A comprehensive review of fundamental principles and novel insights Neuroscience and Behavioral Reviews 83 (2017)

Valiulis V, Gerulskis G, Dapšys K, Vištartaite G, Šiurkute A, Mačiulis V (2012). Electrophysiological differences between high and low frequency rTMS protocols in depression treatment. Acta Neurobiologiae Experimentalis (Warsaw) 72, 283–295

Williams LM. Precision psychiatry: a neural circuit taxonomy for depression and anxiety Lancet Psychiatry 2016; 3:472-80

Yukimasa T, Yoshimura R, Tamagawa A, Uozumi T, Shinkai K, Ueda N, Tsuji S, Nakamura J (2006). High-frequency repetitive transcranial magnetic stimulation improves refractory depression by influencing catecholamine and brain-derived neurotrophic factors.Pharmacopsychiatry 39, 52–59

Zanardini R, Gazzoli A, Ventriglia M, et al. Effect of repetitive transcranial magnetic stimulation on serum brain derived neurotrophic factor in drug resistant depressed patients. J Affect Disord. 2006;91:83-86.

Zarkowski P, Navarro R, Pavlicova M, George MS, Avery D (2009). The effect of daily prefrontal repetitive transcranial magnetic stimulation over several weeks on resting motor threshold. Brain Stimulation 2, 163–167.

© 2018 American Psychiatric Association. All rights reserved.

TMS: BASIC MECHANISM OF ACTIONAPA MASTER COURSE

Karl I. Lanocha, MD | May 2019

TMS Health Solutions

TMS: BASIC Mechanism of ActionDisclosure INFORMATIONLEARNING OBJECTIVESWhat is tms?important aspects of tmsNEUROMODULATION TREATMENTS FOR DEPRESSIONGeneral attributes of NEUROMODULATION TREATMENTS FOR DEPRESSIONELECTRICAL AND MAGNETIC STIMULATIONBasic principles of magnetic stimulationBASIC PARTS OF A TMS DEVICEELECTRICAL FIELD INDUCTIONEarly experimentsFIRST modern TMS DEVICETMS stimulation of motor cortex3 TYPES OF TMS PULSES3 TYPES OF TMS PULSESPersistent neuromodulationRepetitive TMS (rTMS)3 broad categories of RTMSThe depressed brainR-TMS for depressionTMS PARAMETERSstimulus LOCATIONstimulus intensity and pulse frequencyPulse train duration and intervalNumber of pulsesPulse train duration and intervalTypical tms treatment parameterstrans-synaptic—circuit—network effectsSlide Number 30depression circuitdepression circuitKey BRAIN EFFECTSGene expressionNeurotransmitter effectsNeuro-plasticityCerebral metabolismelectrophysiologic changesneuroendocrine functionNeural network effectsOverview of rTMS Mechanism of actionsummarysummarysummaryReferences 1References 2References 3References 4References 5References 6TMS: BASIC Mechanism of Action

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TMS: BASIC MECHANISM OF ACTION...• TMS affects various neuronal processes such as neurotransmitter levels, circuit -level patterns and network oscillations • TMS appears to act