Transcranial Magnetic Stimulation in Metabolic Disease John M. Schreiber, MD March 31, 2016

Disclosures None relevant

Objectives Explain TMS methods Discuss applications of TMS Review TMS data in various metabolic and neurologic diseases Discuss TMS data in SSADH deficiency and implications for disease pathophysiology and treatment Understand limitations of TMS Limitations – primarily, that there are multiple factors influencing a single TMS measure; also intra- and inter-subject variability, changes related to motor activation, attention, etc.

TMS Applications Central motor conduction time (MEP latency – peripheral motor conduction time [F wave]) Motor mapping Research into disease states and cognition Low Hz 0.5-2 Hz rTMS tends to focally decrease cortical excitability, while ≥5 Hz increases excitability Treatment Biomarker studies

TMS concepts Electromagnetic induction – electric current in stimulation coil produces a magnetic field -> this changing magnetic field induces flow of electric current in adjacent brain tissue TMS can stimulate cortical inhibitory and excitatory interneurons (indirect) in addition to corticospinal output neurons (direct) (Rothwell 1997; Hallett 2000) Subthreshold pulse only excites cortical interneurons Measure activity in contralateral muscle(s) Can examine effects of medications, disease states, etc. Important distinction between acute and chronic effects, the latter which may be subject to pharmacodynamic tolerance and sensitization – chronic application of CBZ and LTG result in trend toward increased SICI (not seen in acute experiments), which may be due to suppression of SICF by decreased glutamate release (Lee et al. 2005)

TMS Methods

Resting motor threshold Minimum stimulus intensity required to produce a MEP of at least 50 µV in the contralateral FDI in ≥ 5/10 consecutive trials 30 ms Scale here should be mV

Recruitment Curve Measure of Excitatory Neurotransmission (Glutamate) MEPs recorded at increasing stimulus intensities – 90% RMT to 160% RMT

90% RMT

110% RMT

130% RMT

Cortical Silent Period (CSP) Voluntary motor activity is inhibited for up to 100-300 ms following a suprathreshold TMS pulse Spinal inhibition plays a role during the first 50 ms Otherwise, the CSP is due to reduced cortical excitability GABA-B – CSP is facilitated by tiagabine (GABA reuptake inhibitor) and baclofen (GABA-B agonist) (Siebner et al. 1998) May also be due to disruption of access of voluntary motor drive to primary motor cortex Pathology: Shortened – Parkinson’s Disease (Cantello et al. 1991, etc) but can be normalized with DAergic medication (LeFauchuer 2005); schizophrenia (Daskalakis et al. 2002) Lengthened – Stroke, except with focal seizures (Kessler et al. 2002) Epilepsy – may be longer or shorter, but generally shorter on affected hemisphere (Cincotta et al, 1998) Tergau et al, 1999 – no difference between RMT and AMT during CSP Inibitory/ excitatory balance thought to play significant role in movement disorders like PD Stroke – changes postulated due to decreased thalamocortical and cortico-cortical excitatory input

110% RMT Nearly 100 ms

120% RMT

130% RMT

Paired-Pulse Stimuli Short Interval Intracortical Inhibition (SICI) Subthreshold (70% RMT) -> 2 ms -> suprathreshold (120%) Intracortical Facilitation (ICF) Subthreshold (70% RMT) -> 10 ms -> suprathreshold (120%) Long Interval Intracortical Inhibition (LICI) Suprathreshold (120%) -> 10 ms -> suprathreshold (120%) There is a balance between facilitation and inhibition, and therefore interventions designed to influence one process often exert the opposite effect on the other E.g. medications that reduce inhibition may enhance excitation Ilic et al. 2002 - Facilitation may occur at short interstimulus intervals when the intensity of the conditioning stimulus is increased

Short Interval Intracortical Inhibition (SICI) Subthreshold pulse precedes the test pulse by 1-5 ms MEP typically inhibited by 50-90% Mediated through synaptic inhibitory mechanisms of local interneurons in the primary motor cortex GABA-A (ionotropic) (Ziemann et al. 1996; Kujirai et al. 1993; Ilic et al., 2002) – benzodiazepines increase SICI SICI duration consistent with GABA-A mediated IPSPs Pathology Reduced – schizophrenia, corrected by antipsychotics (Daskalakis et al. 2002), Parkinsonian syndromes, OCD, Tourette’s syndrome (Bunse et al. 2014) Normal in DYT1 (Segawa disease) (Hanajima et al. 2007) SICI is controlled by presynaptic GABA-B receptor-mediated auto-inhibition on inhibitory interneurons (Sanger et al. 2001) – Tiagabine and baclofen decrease SICI Additionally, SICI is reduced in the presence of LICI

SICI

Long Interval Intracortical Inhibition (LICI) Suprathreshold conditioning stimulus precedes the test pulse by 50-200 ms GABA-B (metabotropic) (McDonnell et al. 2006) Facilitated by tiagabine (GABA reuptake inhibitor) (Werhahn et al. 1999) and baclofen (GABA-B agonist) (McDonnell et al. 2006) Pathology Increased in Parkinson’s Disease, felt to correlate with bradykinesia (Berardelli et al. 1996) Reduced in generalized epilepsies (Badawy et al, 2013) Interstingly, LGS has the opposite findings with reduced excitation and increased inhibition, though it is certainly difficult to separate out medication effects

LICI

Intracortical Facilitation (ICF) Subthreshold pulse precedes the test pulse by 7-20 ms NMDA – glutamatergic Decrease in ICF with NMDAR antagonists (Ziemann et al. 1998) NMDA EPSP onset latency is ~10 ms (Kujirai et al. 1993, Ziemann et al. 1996) GABA-A receptor agonists also decrease ICF (Inghilleri et al. 1996, etc)

ICF

TMS in SSADH Deficiency (Reis) Lack of LICI Reduced CSP duration

Chronic taurine in SSADH deficiency Open label crossover design Performed TMS in 6 subjects after 3 months on and 3 months off taurine 200 mg/kg/day (up to 10 grams daily) No change in CSF GABA levels Significant increase in CSF taurine

Short interval intracortical inhibition Mean SICI (short interval intracortical inhibition), expressed as percent of baseline MEP (motor evoked potential), off and on taurine for each subject, showing a treatment-related decrease in inhibition (p < 0.05) This is likely due to a shift to more facilitation This may be due to an increase in activity of pre-synaptic GABAB receptors Tiagabine and baclofen may reduce SICI due to increased auto-inhibition of inhibitory interneurons (Sanger et al, 2001) Chronic treatment likely results in sensitization of certain pathways/ receptors (presynaptic GABA-B receptors on inhibitory interneurons that remain more active due to taurine’s effects; excitatory neurotransmitters) and pharmacodynamic tolerance at others (pyramidal post-synaptic GABA-B receptors resulting in decreased IPSPs) due to changes in gene expression, receptor downregulation, etc.

Cortical Silent Period Box plot (with 25-75% quartiles, range, and outliers) of individual cortical silent period (CSP) measures (expressed in seconds) at different stimulus intensities off and on taurine; data combined from all subjects. Taurine treatment was associated with decreased cortical silent period values at the 140% MT (p < 0.05). Presumably due to decreased GABA-B receptor-mediated inhibition on pyramidal neurons

Cortical silent period Mean CSP off and on taurine for each subject at the highest stimulus intensity, 140% MT, showing a decreased CSP in all but one subject after chronic taurine administration (p < 0.047).

Summary of TMS results on and off taurine “Off” mean ± SD “On” mean ± SD P value RC slope 0.028 ± 0.015 0.022 ± 0.006 0.40 SICI 69% ± 26 159% ± 93 <0.05 ICF 129% ± 27 141% ± 72% 0.917 LICI 96% ± 107 93% ± 98 0.753 CSP at 140% MT (ms) 128 ± 50 96 ± 48 < 0.05 MT (motor threshold) 53.67% ± 11 55.17% ± 12 0.586

TMS as Treatment rTMS of the pre-frontal cortex in patients with treatment-resistant depression approved by FDA Epilepsy Low frequency rTMS reduces cortical excitability and has been employed in focal epilepsy (with seizure focus located near the scalp) (Fregni et al. 2006, Bae et al. 2007, Bae et al. 2011, Rotenberg 2013, Sun et al. 2012) Enhancement of cognition – working memory, motor learning tasks, language, visuospatial Pain Tinnitus

Low‐frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: A controlled clinical study  The trend of average seizures frequency per week during 14 weeks. The seizure frequency per week had further reduction after the 2‐week “90% rMT” rTMS and showed a significant difference compared with baseline and follow‐up data in group 2. The effect continued to the last week of follow‐up period. © IF THIS IMAGE HAS BEEN PROVIDED BY OR IS OWNED BY A THIRD PARTY, AS INDICATED IN THE CAPTION LINE, THEN FURTHER PERMISSION MAY BE NEEDED BEFORE ANY FURTHER USE. PLEASE CONTACT WILEY'S PERMISSIONS DEPARTMENT ON PERMISSIONS@WILEY.COM OR USE THE RIGHTSLINK SERVICE BY CLICKING ON THE 'REQUEST PERMISSION' LINK ACCOMPANYING THIS ARTICLE. WILEY OR AUTHOR OWNED IMAGES MAY BE USED FOR NON-COMMERCIAL PURPOSES, SUBJECT TO PROPER CITATION OF THE ARTICLE, AUTHOR, AND PUBLISHER. Epilepsia Volume 53, Issue 10, pages 1782-1789, 5 SEP 2012 DOI: 10.1111/j.1528-1167.2012.03626.x http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1167.2012.03626.x/full#f4

New Directions SGS-742 trial Biomarker studies Seizure localization SCN1A splice-site polymorphism affects pharmacoresponse to CBZ as measured by CSP duration (Menzler et al. 2014) Seizure localization Epilepsy treatment

Acknowledgements NIH Children’s National Boston Children’s William H. Theodore, MD Irene Dustin, CRNP, PhD Xianping Zhou, MD Tamika Mason Eric M. Wassermann, MD Pat Reeves-Tyer Allison Austermuehle David Kalikman Edythe Wiggs, PhD Children’s National Robert McCarter, ScD Joe Yu Emily Barrios Boston Children’s Phillip L. Pearl, MD Washington State University K. Michael Gibson, PhD

And finally. . . Thank you to the many individuals and families affected with SSADH deficiency who have been so eager and willing to participate!