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Theta burst stimulation of the prefrontal cortex: Safety data and effects on cognition and resting EEG
Abstracts Benninger D, Lomarev M, Wassermann E, Lopez G, Dang N, Hallett M, NIH (Bethesda, US) Objective: Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in the treatment of Parkinson’s disease (PD). The best rTMS parameters remain yet unknown. 50 Hz rTMS may be superior to , 5 25 Hz rTMS investigated so far. Objective of this study is to determine the safe 50 Hz rTMS limit in PD as current safety limits are exceeded. Methods: 50 Hz rTMS is applied with a circular coil on the primary motor cortex (M1). Stimulation intensity is tested at 60% rest motor threshold [RMT] and 0.5 sec train duration, and stepwise increased by 0.5 to 2 sec and by 10% to 90% RMT. A multi-channel electromyography (EMG) is recorded to control for signs of increasing time-locked EMG activity, EMG correlates of the spread of excitation through M1, or an increase of M1 excitability. Pre- and post-50 Hz rTMS assessments include EEG, Unified PD Rating Scale (UPDRS), Grooved Pegboard Test, Serial Reaction Time Task (SRTT), Folstein Mini-Mental Status Examination (MMSE) and Verbal Fluency to control for side effects. Results: So far, 7 PD patients have been investigated. Multi-channel EMG showed no signs of increasing time-locked EMG activity, EMG correlates of the spread of excitation through M1, or an increase of M1 excitability. Pre- and post-50 Hz assessment showed no changes. No adverse events were observed. 50 Hz rTMS was well tolerated except by a patient who wished to terminate the study due to facial twitches. Conclusion: 50 Hz rTMS at an intensity of 90% RMT for 2 sec is safe in patients with PD.
TMS Poster Only 182
Corpus callosum and motor function I – Computer-based quantitative investigation of mirror movements
Koerte I1, Fuchs T1, Kirmess B1, Berweck S1, Henschel V2, Muench J1, Esslinger O3, Heinen F1, Danek A3, 1Dr. von Haunersches Kinderspital, LMU (Munich, DE); 2Institute for Epidemiology, LMU (Munich, DE); 3 Neurology, LMU (Munich, DE) Objective: Involuntary mirror movements (MM) of the contralateral hand, during unimanual voluntary movements, decrease with increasing maturation of the central nervous system. In order to indentify developmental changes we investigated MM of the dominant and the non-dominant hand quantitatively in three age-groups using a computer-based assessment. Methods: Healthy children (n 5 11; 8.3 6 1.5), adolescents (n 5 10;15.6 6 0.8) and adults (n 5 10; 25.9 6 2.6) held in each hand a force transducer in a precision grip between thumb and index finger. Grip forces were recorded (resolution: 0,1 N; sampling rate: 100 Hz) and the grip force maximum was determined for each hand. The subjects had to repeatedly increase and decrease their grip force of one hand for 15 s whilst the other (mirror) hand only had to prevent the force transducer from dropping. Experiments (E1, E2) were accomplished with 40 and 50% of subjects maximal force. E1: unimanual, slow grip force change (1/s). E2: unimanual grip force changes at maximum frequency. A monitor provided visual feedback about the grip force of the active hand. Mirror activity was quantified as the amplitude ratio of the mirror and active hand after the absolute values had been adjusted to the maximum grip force in each hand. For statistical analysis a mixed linear model for logarithmized values was applied. Results: All subjects showed mirror activity. In slow grip force changes MM ratio was higher in children than in adolescents and adults. During fast grip force changes MM ratio increased in children while it decreased in adolescents and adults. At highest frequency possible MM ratio was higher in the non-dominant compared to the dominant hand in all three age groups. At slow grip force
297 changes no differences were detected between dominant and non-dominant hand. Degree of grip force showed no additional effect on the MM ratio. Conclusion: The computer-based hand motor function test allows a precise assessment of MM. The data demonstrates a maturation of the neuronal network that is essential for lateralisation of movements. Relating to a demand of this network more challenging experiments caused an increase in mirror activity. In this case, frequency seemed to be the more difficult task compared to degree of grip force. Interhemispheric inhibition was pronounced when mediated by the dominant hemisphere.
TMS Poster Only 183
Achieving faster reduction of depressive symptoms, with two rTMS sessions per day.
Sakkas P1, Theleritis CG2, Psarros C3, Masdrakis V4, Paparrigopoulos T2, Papadimitriou GN4, 1Athens University Medical School, Psychiatry Dpr., Eginition Hospital (Athens, GR); 2Athens University Medical School,Psychiatry Dept., Eginition Hospital (Athens, GR); 3Athens University Medical School, Psychiatry Dept., Eginition Hospital (Athens, GR); 4Athens University Medical School, Psychiatry Dept., Eginition Hospital (Athens, GR) During last seven years, we completed various pilot studies, using rTMS, trying to evaluate its efficiency. In this context we selected some patients suffering from drug resistant major depression, who wanted to be treated with rTMS and give them an intensive treatment. We raise the magnetic intensity to 110 - 120% of the motor threshold. We gave them about 40 trains of 20-25 Hz per session, using two electromagnetic coils. Also we extend the overall duration of the treatment to three weeks. Patients were evaluated with the Hamilton Depression Rating Scale at the baseline as well as in the end of every week thereafter. In addition, we extent our period of clinical assessment, to two more weeks, because we have an indication for some of our patients that rTMS sometimes produce a late effect. In the concept of enhance the antidepressant effect of the rTMS, we treat some of our patients (n 5 10) with two daily sessions (one in the morning, and another one in the afternoon) also for five days every week and for three consecutive weeks. Preliminary results indicate that patients who were treated with two daily sessions of rTMS, had show a faster reduction of depressive symptoms in HDRS scale, and for some of them faster remission of depressive symptoms, in comparison to patients treated with one rTMS session per day. Furthermore, two of our depressed patients, in the two daily schedule became manic, although these patients had never before experience manic symptoms (Sakkas et al., 2003). Finally, we have to note that although we apply generally very intensive magnetic stimulation to our patients, the only adverse effect observed was a short lasting Jacksonian epileptic clonic seizure in a bipolar patient (Sakkas et al., 2008). Further investigation in larger patient populations should verify this preliminary result. References: Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Masdrakis V, Politis A,et al. Induction of mania by rTMS: report of two cases. Eur Psychiatry 2003;18:196–8. Sakkas P, Theleritis CG, Psarros C, Papadimitriou GN, Soldatos CR. Jacksonian seizure in a manic patient treated with rTMS (letter). World Journal of Biological Psychiatry 2008; 9(2):159-60.
rTMS Poster Only 184
Theta burst stimulation of the prefrontal cortex: Safety data and effects on cognition and resting EEG
298
Abstracts
Grossheinrich N, Rau A, Pogarell O, Hennig-Fast K, Reinl M, Karch S, Dieler A, Leicht G, Mulert C, Sterr A, Padberg F, Ludwig-Maximilians University Munich (Munich, DE) Background: As standard rTMS protocols exhibit after-effects of short duration and show limited efficacy as therapeutic intervention in psychiatric and neurological disorders, novel protocols, e.g. theta burst stimulation (TBS), have been developed for motor cortex stimulation and are promising approaches to enhance the effectiveness of rTMS. However, little is known about the side effect profile of such protocols. Thus, the present study investigates whether TBS is safe in terms of side effects and has effects on cognition and EEG measurements. Methods: Within two exploratory placebo-controlled, cross-over studies, 24 healthy volunteers underwent continuous TBS (cTBS), intermittent TBS (iTBS) and sham TBS over the left dorsolateral prefrontal cortex (DLPFC, N 5 12) or the medial prefrontal cortices (mPFC, N 5 12) in random order. Side effects, resting EEG, performance in a neuropsychological test battery and mood were recorded. Results: All protocols proved to be safe in terms of seizure generation. The most prominent side effect was the occurrence of vasovagal reactions after TBS. Standardized low resolution brain electromagnetic tomography (sLORETA) showed changes in current source density of different frequency bands in the frontal lobe with simultaneous effects in neuropsychological data. Conclusions: Although TBS protocols of the human prefrontal cortex appear to be rather safe, future studies need to explain the occurrence of vasovagal reactions with TBS. The excitatory and inhibitory mechanisms of TBS reported for the motor cortex are not easily transferable to prefrontal sites. Moreover, TBS seems to exert long lasting effects after iTBS over the left DLPFC.
TMS Poster Only 185
What is the role for the preSMA in the recognition of facial expressions? An event related TMS study
Rochas V1, Brunelin J2, Poulet E1, Saoud M2, d’Amato T1, Krolak P3, Bediou B4, 1EA 41 66 Vulne´rabilite´ a` la Schizophre´nie - CH Le Vinatier (Bron, FR); 2EA 41 66 Vulne´rabilite´ a` la Schizophre´nie - CH Le Vinatier (Bron, FR); 3Inserm U821 - Dynamique Ce´re´brale et Cognition (Bron, FR); 4CISA Centre Interfacultaire en Sciences Affectives, Universite´ de Gene`ve (Gene`ve, CH) Previous research suggests that the human preSMA is involved in the production and recognition of happy facial expression, suggesting an involvement in mirror mechanisms. However, the causal relationship between preSMA activation and happiness recognition has not yet been established We applied event-related TMS (trains of 5 pulses at 10 Hz synchronized with stimulus offset) to the preSMA in comparison to stimulation applied to the vertex (control condition, within subject crossover design) while healthy participants (n 5 10) judged facial expressions varying in both category (happiness, fear, anger) and intensity (7 levels) of emotion. There was a main effect of TMS (p , 0.05) and a borderline TMS x Emotion x Intensity interaction (p 5 0.057) reflecting reduced recognition of happy (overall, p , 0.05 and at 50% intensity, p , 0.01), fearful (at 60% and 70 % intensity, ps , 0.05) and angry facial expressions (overall, p , 0.05 and at 80%, p , 0.05) for TMS over the preSMA compared to TMS over the vertex (control). Though preliminary (N 5 6, preliminary results), these results suggest that TMS over the preSMA impairs the processing of emotional expressions of high but not full intensity (when performance under in the control condition is equal or above 85%).
Our results do not support the hypothesis that the preSMA is involved in the recognition of happiness exclusively. Rather, they suggest that its activity reflects the spontaneous facial mimicry that may participate to the recognition of high- but not full-intensity emotional facial expressions in general.
TMS Poster Only 186
TMS to the frontal operculum and supramarginal gyrus disrupts planning of outcome based hand-object interactions
Tunik E1, Lo OY1, Adamovich S2, 1New York University (New York, US); 2 New Jersey Institute of Technology (Newark, NJ, US) Behavioral data suggest that goal-based intentions, at least partially, inform the selection of appropriate motor commands even at the expense of an initially awkward movement (orienting the hand thumb-down when grasping an upside-down cup) if the final outcome is desirable (to drink from the cup). The neural correlates for selecting actions based on temporally-distant outcomes remain unknown. For this, 10 healthy righthanded subjects reached-to-grasp a cup placed upside-down on a table to use it for an unambiguous temporally-distant goal (grasp-to-pour water into it) or for no clear purpose (grasp-to-move it). This way, the temporally-distant goal constrained the grasp type to a thumb-down grasp in the former condition and an over-the-top grasp in the latter condition). We controlled for non-specific effects by including an arbitrary stimulusresponse association condition (lift-the-finger) and a rest condition (to ensure attention to the task). The four trial types were randomly interleaved throughout four blocks. In each block, single-pulse Transcranial Magnetic Stimulation (TMS) was applied (TMS trials) or not (noTMS trials) 100ms after the instruction cue. Four cortical sites were targeted in the contralateral hemisphere: inferior frontal gyrus pars opercularis (IFGo), pars triangularis (IFGt), supramarginal gyrus (SMG), and anterior intraparietal sulcus (aIPS). Our data suggest two novel findings (see Figure): 1) In no-TMS trials, reaction times were faster when acting toward temporally-distant, meaningful, goals (grasp-to-pour) than responses toward more ambiguous goals (grasp-to-move) and arbitrary stimulus-response mappings (lift finger). This finding suggested that biologically relevant and more used actions can be enacted quicker than actions arbitrarily associated with a stimulus. 2) TMS-induced virtual lesions to the IFGo and SMG caused delayed reaction times (relative to noTMS trials) in the grasp-to-pour condition only. No effects were noted when TMS was delivered to aIPS or IFGt or in the other conditions, when subjects grasped the object without a clear goal of how to use it. This suggests that IFGo and SMG are critical for planning well-learned and meaningful actions.
TMS Poster Only 182
Corpus callosum and motor function I – Computer-based quantitative investigation of mirror movements
Koerte I1, Fuchs T1, Kirmess B1, Berweck S1, Henschel V2, Muench J1, Esslinger O3, Heinen F1, Danek A3, 1Dr. von Haunersches Kinderspital, LMU (Munich, DE); 2Institute for Epidemiology, LMU (Munich, DE); 3 Neurology, LMU (Munich, DE) Objective: Involuntary mirror movements (MM) of the contralateral hand, during unimanual voluntary movements, decrease with increasing maturation of the central nervous system. In order to indentify developmental changes we investigated MM of the dominant and the non-dominant hand quantitatively in three age-groups using a computer-based assessment. Methods: Healthy children (n 5 11; 8.3 6 1.5), adolescents (n 5 10;15.6 6 0.8) and adults (n 5 10; 25.9 6 2.6) held in each hand a force transducer in a precision grip between thumb and index finger. Grip forces were recorded (resolution: 0,1 N; sampling rate: 100 Hz) and the grip force maximum was determined for each hand. The subjects had to repeatedly increase and decrease their grip force of one hand for 15 s whilst the other (mirror) hand only had to prevent the force transducer from dropping. Experiments (E1, E2) were accomplished with 40 and 50% of subjects maximal force. E1: unimanual, slow grip force change (1/s). E2: unimanual grip force changes at maximum frequency. A monitor provided visual feedback about the grip force of the active hand. Mirror activity was quantified as the amplitude ratio of the mirror and active hand after the absolute values had been adjusted to the maximum grip force in each hand. For statistical analysis a mixed linear model for logarithmized values was applied. Results: All subjects showed mirror activity. In slow grip force changes MM ratio was higher in children than in adolescents and adults. During fast grip force changes MM ratio increased in children while it decreased in adolescents and adults. At highest frequency possible MM ratio was higher in the non-dominant compared to the dominant hand in all three age groups. At slow grip force
297 changes no differences were detected between dominant and non-dominant hand. Degree of grip force showed no additional effect on the MM ratio. Conclusion: The computer-based hand motor function test allows a precise assessment of MM. The data demonstrates a maturation of the neuronal network that is essential for lateralisation of movements. Relating to a demand of this network more challenging experiments caused an increase in mirror activity. In this case, frequency seemed to be the more difficult task compared to degree of grip force. Interhemispheric inhibition was pronounced when mediated by the dominant hemisphere.
TMS Poster Only 183
Achieving faster reduction of depressive symptoms, with two rTMS sessions per day.
Sakkas P1, Theleritis CG2, Psarros C3, Masdrakis V4, Paparrigopoulos T2, Papadimitriou GN4, 1Athens University Medical School, Psychiatry Dpr., Eginition Hospital (Athens, GR); 2Athens University Medical School,Psychiatry Dept., Eginition Hospital (Athens, GR); 3Athens University Medical School, Psychiatry Dept., Eginition Hospital (Athens, GR); 4Athens University Medical School, Psychiatry Dept., Eginition Hospital (Athens, GR) During last seven years, we completed various pilot studies, using rTMS, trying to evaluate its efficiency. In this context we selected some patients suffering from drug resistant major depression, who wanted to be treated with rTMS and give them an intensive treatment. We raise the magnetic intensity to 110 - 120% of the motor threshold. We gave them about 40 trains of 20-25 Hz per session, using two electromagnetic coils. Also we extend the overall duration of the treatment to three weeks. Patients were evaluated with the Hamilton Depression Rating Scale at the baseline as well as in the end of every week thereafter. In addition, we extent our period of clinical assessment, to two more weeks, because we have an indication for some of our patients that rTMS sometimes produce a late effect. In the concept of enhance the antidepressant effect of the rTMS, we treat some of our patients (n 5 10) with two daily sessions (one in the morning, and another one in the afternoon) also for five days every week and for three consecutive weeks. Preliminary results indicate that patients who were treated with two daily sessions of rTMS, had show a faster reduction of depressive symptoms in HDRS scale, and for some of them faster remission of depressive symptoms, in comparison to patients treated with one rTMS session per day. Furthermore, two of our depressed patients, in the two daily schedule became manic, although these patients had never before experience manic symptoms (Sakkas et al., 2003). Finally, we have to note that although we apply generally very intensive magnetic stimulation to our patients, the only adverse effect observed was a short lasting Jacksonian epileptic clonic seizure in a bipolar patient (Sakkas et al., 2008). Further investigation in larger patient populations should verify this preliminary result. References: Sakkas P, Mihalopoulou P, Mourtzouhou P, Psarros C, Masdrakis V, Politis A,et al. Induction of mania by rTMS: report of two cases. Eur Psychiatry 2003;18:196–8. Sakkas P, Theleritis CG, Psarros C, Papadimitriou GN, Soldatos CR. Jacksonian seizure in a manic patient treated with rTMS (letter). World Journal of Biological Psychiatry 2008; 9(2):159-60.
rTMS Poster Only 184
Theta burst stimulation of the prefrontal cortex: Safety data and effects on cognition and resting EEG
298
Abstracts
Grossheinrich N, Rau A, Pogarell O, Hennig-Fast K, Reinl M, Karch S, Dieler A, Leicht G, Mulert C, Sterr A, Padberg F, Ludwig-Maximilians University Munich (Munich, DE) Background: As standard rTMS protocols exhibit after-effects of short duration and show limited efficacy as therapeutic intervention in psychiatric and neurological disorders, novel protocols, e.g. theta burst stimulation (TBS), have been developed for motor cortex stimulation and are promising approaches to enhance the effectiveness of rTMS. However, little is known about the side effect profile of such protocols. Thus, the present study investigates whether TBS is safe in terms of side effects and has effects on cognition and EEG measurements. Methods: Within two exploratory placebo-controlled, cross-over studies, 24 healthy volunteers underwent continuous TBS (cTBS), intermittent TBS (iTBS) and sham TBS over the left dorsolateral prefrontal cortex (DLPFC, N 5 12) or the medial prefrontal cortices (mPFC, N 5 12) in random order. Side effects, resting EEG, performance in a neuropsychological test battery and mood were recorded. Results: All protocols proved to be safe in terms of seizure generation. The most prominent side effect was the occurrence of vasovagal reactions after TBS. Standardized low resolution brain electromagnetic tomography (sLORETA) showed changes in current source density of different frequency bands in the frontal lobe with simultaneous effects in neuropsychological data. Conclusions: Although TBS protocols of the human prefrontal cortex appear to be rather safe, future studies need to explain the occurrence of vasovagal reactions with TBS. The excitatory and inhibitory mechanisms of TBS reported for the motor cortex are not easily transferable to prefrontal sites. Moreover, TBS seems to exert long lasting effects after iTBS over the left DLPFC.
TMS Poster Only 185
What is the role for the preSMA in the recognition of facial expressions? An event related TMS study
Rochas V1, Brunelin J2, Poulet E1, Saoud M2, d’Amato T1, Krolak P3, Bediou B4, 1EA 41 66 Vulne´rabilite´ a` la Schizophre´nie - CH Le Vinatier (Bron, FR); 2EA 41 66 Vulne´rabilite´ a` la Schizophre´nie - CH Le Vinatier (Bron, FR); 3Inserm U821 - Dynamique Ce´re´brale et Cognition (Bron, FR); 4CISA Centre Interfacultaire en Sciences Affectives, Universite´ de Gene`ve (Gene`ve, CH) Previous research suggests that the human preSMA is involved in the production and recognition of happy facial expression, suggesting an involvement in mirror mechanisms. However, the causal relationship between preSMA activation and happiness recognition has not yet been established We applied event-related TMS (trains of 5 pulses at 10 Hz synchronized with stimulus offset) to the preSMA in comparison to stimulation applied to the vertex (control condition, within subject crossover design) while healthy participants (n 5 10) judged facial expressions varying in both category (happiness, fear, anger) and intensity (7 levels) of emotion. There was a main effect of TMS (p , 0.05) and a borderline TMS x Emotion x Intensity interaction (p 5 0.057) reflecting reduced recognition of happy (overall, p , 0.05 and at 50% intensity, p , 0.01), fearful (at 60% and 70 % intensity, ps , 0.05) and angry facial expressions (overall, p , 0.05 and at 80%, p , 0.05) for TMS over the preSMA compared to TMS over the vertex (control). Though preliminary (N 5 6, preliminary results), these results suggest that TMS over the preSMA impairs the processing of emotional expressions of high but not full intensity (when performance under in the control condition is equal or above 85%).
Our results do not support the hypothesis that the preSMA is involved in the recognition of happiness exclusively. Rather, they suggest that its activity reflects the spontaneous facial mimicry that may participate to the recognition of high- but not full-intensity emotional facial expressions in general.
TMS Poster Only 186
TMS to the frontal operculum and supramarginal gyrus disrupts planning of outcome based hand-object interactions
Tunik E1, Lo OY1, Adamovich S2, 1New York University (New York, US); 2 New Jersey Institute of Technology (Newark, NJ, US) Behavioral data suggest that goal-based intentions, at least partially, inform the selection of appropriate motor commands even at the expense of an initially awkward movement (orienting the hand thumb-down when grasping an upside-down cup) if the final outcome is desirable (to drink from the cup). The neural correlates for selecting actions based on temporally-distant outcomes remain unknown. For this, 10 healthy righthanded subjects reached-to-grasp a cup placed upside-down on a table to use it for an unambiguous temporally-distant goal (grasp-to-pour water into it) or for no clear purpose (grasp-to-move it). This way, the temporally-distant goal constrained the grasp type to a thumb-down grasp in the former condition and an over-the-top grasp in the latter condition). We controlled for non-specific effects by including an arbitrary stimulusresponse association condition (lift-the-finger) and a rest condition (to ensure attention to the task). The four trial types were randomly interleaved throughout four blocks. In each block, single-pulse Transcranial Magnetic Stimulation (TMS) was applied (TMS trials) or not (noTMS trials) 100ms after the instruction cue. Four cortical sites were targeted in the contralateral hemisphere: inferior frontal gyrus pars opercularis (IFGo), pars triangularis (IFGt), supramarginal gyrus (SMG), and anterior intraparietal sulcus (aIPS). Our data suggest two novel findings (see Figure): 1) In no-TMS trials, reaction times were faster when acting toward temporally-distant, meaningful, goals (grasp-to-pour) than responses toward more ambiguous goals (grasp-to-move) and arbitrary stimulus-response mappings (lift finger). This finding suggested that biologically relevant and more used actions can be enacted quicker than actions arbitrarily associated with a stimulus. 2) TMS-induced virtual lesions to the IFGo and SMG caused delayed reaction times (relative to noTMS trials) in the grasp-to-pour condition only. No effects were noted when TMS was delivered to aIPS or IFGt or in the other conditions, when subjects grasped the object without a clear goal of how to use it. This suggests that IFGo and SMG are critical for planning well-learned and meaningful actions.