Transcranial Magnetic Stimulation Scientific evidence in major depression and schizophrenia C.W. Slotema Parnassia Bavo Group The Hague, the Netherlands
Faraday s law (1831) Electrical current magnetic field D Arsonval 1896 head in magnetic field phosphenes, vertigo and syncope 1985 Anthony Barker first TMS-device
One flow pulse TMS Duration 1/4000 s Peakage voltage 2000 V Amount of electric charge 10.000 A Magnetic field 1,5-2,5 Tesla
Magnetic field rapid decline Range 2 (to 4) cm Effect on greater distance
Single pulse TMS Paired pulse TMS Repetitive TMS High-frequency 5Hz MEP Low-frequency 1Hz MEP
Effect Depolarization of neurons Effect longer than stimuli Long term depression / potentiation Change neurotransmitter level (NMDA, dopamine)
TMS indications Brain mapping Measuring cortical excitability Investigation of neural networks/connectivity Influence of brain functions
Variables of TMS Focus Type of coil Frequency Motor threshold Number of stimuli Number of sessions
TMS as treatment Major depressive disorder Negative symptoms Auditory verbal hallucinations
rtms for major depressive disorder Baxter 1989 left anterior hypoactivity in depressive patients (recovery balance left and right prefrontal cortex) George 1995 high-frequency rtms L DLPF 2008 FDA approval
Meta-analysis rtms for depression Slotema et al. J Clin Psych 2010 Total hg = 0.55 p 0.001 L DLPF hg = 0.53 p 0.001 R DLPF hg = 0.82 p 0.001 LR DLPF hg = 0.47 p = 0.03 Monotherapy hg = 0.96 p 0.001 Addition to AD hg = 0.51 p 0.001 Simultaneous onset AD hg = 0.37 p = 0.03 No psychosis vs t = 0.128 p = 0.04 Antidepressive agents hg = 0.17-0.46 (Moncrieff 2004, Joffe 1996) Psychotherapy d= 0.42 (Cuijpers 2010)
Variables Focus Type of coil Frequency Motor threshold Number of stimuli Number of sessions
Literature other rtms paradigms for depression Focus Parietal cortex 2Hz partial response (Schutter et al. 2009) Coil H coil, n = 65 open label, positive on depression and cogn functioning (Levkovitz 2009) Frequency Priming better than sham (Fitzgerald 2008) Theta burst open label (Chistyakov 2010)
rtms for negative symptoms of schizophrenia Activity & metabolism prefrontal cortex cognitive dysfunction in schizophrenia (Hill 2004 & Andreasen 1997) Low-frequency rtms R DLPF (Klein 1999)
rtms for negative symptoms
rtms for negative symptoms of schizophrenia d= 0.43; 95% CI, 0.05-0.80 (Dlabac-de Lange 2010) d = 0.39, p = 0.12 (Slotema 2010) d = 0.27, p = 0.42 (Freitas 2009) Antipsychotics 0.17-0.21 (Leucht 1999)
Variables Focus Type of coil Frequency Motor threshold Number of stimuli Number of sessions
Other paradigms for negative symptoms of schizophrenia Deep brain TMS 20 Hz prefrontal cx open label improvement of cognitive functioning and negative symptoms in 15 pts (Levkovitz 2011) Thetaburst TMS cerebellar vermis 8 pts open label decline of negative symptoms no change of positive symptoms (Demirtes- Tatlidede 2010)
rtms for auditory hallucinations rtms 1 hertz, 90%MT Left temporoparietal area (Hoffman 1999) Hyperactivity L TP (Silbersweig 1995, Shergill 2000)
Effect sizes 6 meta-analyses rtms for AVH 0.76 Aleman 2007 0.51 Tranulis 2008 1.0 Freitas 2009 0.54 Slotema 2010 0.42 Demeulemeester 2012 0.44 Slotema in press
RCT rtms for AVH Study Focus Frequency MT% Stimuli Sessions Blumberger L prim aud cx 1 115 1200 20 L prim aud cx priming 90 115 4200 20 Jesus 2010 T3P3 1 80 1200 20 Slotema 2011 T3P3 1 90 1200 20 fmri 1 90 1200 20 Vercammen 2009 T3P3 1 90 1200 12 T3P3 T4P4 1 90 1200 12 Rosa 2007 T3P3 1 90 960 10 Brunelin 2006 T3P3 1 90 1000 10 Chibbaro 2005 T3P3 1 90 900 4 Fitzgerald 2005 T3P3 1 90 900 10 Hoffman 2005 T3P3 1 90 900 10 Lee 2005 T3P3 1 100 1600 10 T4P4 1 100 1600 10 Saba 2004 T3P3 1 80 300 10
Meta-analysis left temporoparietal cortex Slotema et al. in press Schizophr Res Study name Subgroup within study Hedges's g and 95% CI Hedges's g p-value Slotema b T3P3 0,000 1,000 Brunelin T3P3 1,158 0,008 Vercammen b T3P3-0,175 0,613 de Jesus T3P3 0,464 0,321 Hoffman T3P3 0,552 0,052 Rosa PANSS pos T3P3-0,084 0,880 Chibbaro SAH T3P3 1,283 0,014 Saba PANSS pos T3P3-0,053 0,910 Lee b frequency T3P3 0,498 0,189 Fitzgerald HCS T3P3 0,329 0,344 Jandl c PSYRATS T3P3 0,534 0,154 Loo c T3P3 0,034 0,916 Poulet c T3P3 1,350 0,005 McIntoshc PANSS pos T3P3 0,195 0,573 Hoffman c hcs T3P3 1,219 0,005 0,437 0,000-2,00-1,00 0,00 1,00 2,00 sham rtms Meta Analysis
Low-frequency rtms at the L temporoparietal cortex for auditory verbal hallucinations
Meta-analysis rtms left temporoparietal area: effect after one month Slotema et al. in press Schizophrenia Res Study name Subgroup within study Hedges's g and 95% CI Hedges's g p-value de Jesus T3P3 0,359 0,441 Rosa frequency T3P3 0,770 0,182 Slotema b T3P3 0,018 0,953 Bais b T3P3-0,327 0,346 Chibbaro T3P3 1,713 0,002 0,396 0,215-2,00-1,00 0,00 1,00 2,00 sham rtms
Variables Focus Type of coil Frequency Motor threshold Number of stimuli Number of sessions
Focus of rtms for AVH + T3P3 TP cortex & L supramarginal gyrus T4P4 1 RCT (+), 1 RCT (-) T4P4 & T3P3 (-) - Broca s area or homologue Primary auditory cortex or homologue L superior temporal gyrus fmri-targeted L primary auditory cortex Area with maximal hallucinatory activation fmri
fmri during AVH > 50% hallucinatory activation in the right hemisphere! Sommer et al. Brain 2008
Neural Nagivator Neggers et al. Neuroimage 2004
Figuur AHRS total score Slotema et al. Biol Psych 2011
Coil Deep brain TMS LTP RCT sham no differences, 18pts, dropouts 8 (Rosenberg 2012) LTP, open label (n = 8) (Rosenberg 2011)
Frequency 1 Hz Priming TMS (n = 23, RCT) Slotema et al. Accepted Brain Stimulation 20 Hz (open label, n = 11, 2 days, L sup temp sulcus) (Montagne-Larmurier 2009) 50 Hz case reports
Motor threshold & total number of stimuli No studies MT 100% LTP Blumberger 115% no effect primary auditory cortex Total number of stimuli til maximum of 24,000 High vs low number of stimuli no better effect
Discussion Sham condition Therapy resistance in majority of participants Studies were underpowered? Neuroimaging guidance (Herwig 2001) Duration of effect weeks? Other treatment paradigms have not been (fully) investigated until now
Conclusions rtms for major depressive disorder TMS for major depressive disorder Many RCT s Moderate mean weighted effect size Monotherapy? No psychosis Low-frequency R DLPF?
Conclusions rtms for schizophrenia TMS for auditory hallucinations Small number of studies Decreasing, moderate mean weighted effect size Duration effect might be less than 1 month TMS for negative symptoms Small number of studies Promising as other treatment options are poor
Conclusions, side effects Mild High-frequency more than lowfrequency Frontal labe more than temporal lobe
Main issue: does rtms work? Is there a future for therapeutic use of transcranial magnetic stimulation (Ridding and Rothwell Nature 2007) Duration after-effects: 30-60 min 5 to 6 times more current needed to stimulate language areas versus motor cortex (Pouratian 2004 J Neurosurg, Lesser 1987 J Clin Neurophysiol, Lesser 1984 Epilepsia)
Future directions Working mechanism of rtms Other paradigms of rtms