- Email: [email protected]
Optimization of multifocal transcranial current stimulation montages for specific targets using realistic models of electric fields
Abstracts / Brain Stimulation 8 (2015) 343e359
learning paradigms, C57Bl6/J mice receive daily iTBS immediately prior to undergoing a skilled pellet-reaching task for 10 days. In a separate group; Thy1-GFPM mice undergo cranial window insertion overlying the right motor cortex to enable visualisation of excitatory cortical neurons in the upper layers of the motor cortex. Images of synaptic structures are collected at regular intervals before and after iTBS and analysed for alterations in connectivity resulting from stimulation. Preliminary analysis suggests daily iTBS significantly increases accuracy but not speed of pellet reaching, relative to sham stimulation (handling control). Preliminary analysis of the imaging data suggests a single session of iTBS does not alter dendritic spine density. These results will help characterise the biological mechanisms underlying rTMS, which will undoubtedly pave the way forward in the therapeutic applications of non-invasive brain stimulation in health and disease.
137 Comparison of novel transcranial electrical stimulation montages using a computational modelling approach C.K. Loo , S. Bai , N.H. Lovell , S. Dokos Psychiatry & Biomedical Engineering, University of New South Wales, Sydney, Australia Introduction: Antidepressant efficacy has been demonstrated for both Electroconvulsive Therapy (ECT) and transcranial Direct Current Stimulation (tDCS). Both stimulation techniques involve passing an electrical current transcranially into the cerebrum. It has been hypothesised that antidepressant effects are related to stimulation of frontal and deep central structures (eg subgenual anterior cingulate, sgACC). Optimal electrode positioning (montage) may be important for maximising efficacy (tDCS, ECT) and minimising cognitive side effects (ECT). Indeed clinical studies have demonstrated that electrode montage affects these behavioural outcomes. This research examined the intensity of electric fields generated in key brain regions when electrode montage was varied for tDCS and ECT. Methods: Computational modelling in an anatomically accurate head model was used to examine outcomes of several stimulation montages for tDCS and ECT. Image segmentation and finite element mesh generation were carried out using MRI scans of a healthy 35year-old male subject. Existing and novel montages were modelled for tDCS (11 montages) and ECT (14 montages). Results: Wider spacing of electrodes led to less shunting of current over the scalp and a greater proportion of the stimulating current entering the cerebrum. For tDCS deep central structures were best activated using a fronto-occipital or fronto-extracephalic montage. Likewise, for ECT, compared to the bitemporal montage, a midline anterior-posterior montage led to more current reaching the cerebrum (80% vs 65%), greater stimulation of sgACC, similar stimulation of orbitofrontal cortices, and less stimulation of hippocampi. A 2cm error in placement of electrodes (displaced inferiorly) for bitemporal ECT led to significant differences in induced electric fields, including reduction of current entering the cerebrum to 55%. Conclusions: For both ECT and tDCS, novel montages may potentially lead to superior clinical outcomes compared with montages currently in use e this would need to be tested in clinical trials.
138 Non Invasive Brain Stimulation Therapy Restores Neuroplasticity in Depression C.K. Loo , M. Player , A. Alonzo , D. Martin , P.B. Mitchell , P.S. Sachdev , J.L. Taylor University of New South Wales; Black Dog Institute; Neuroscience Research Australia
349
Introduction: Clinical and preclinical evidence suggests that neuroplasticity is impaired in depression. However, prior clinical research testing functional plasticity has often been confounded by possible impacts of subject motivation and effort. We used a brain stimulation technique to test neuroplasticity independent of subject motivation and effort in a series of studies in depressed subjects and healthy controls. Methods: First, Paired Associative Stimulation (PAS) and Theta Burst Stimulation (TBS) were compared as tests of neuroplasticity in the motor cortex in healthy subjects. Then, PAS testing was used to compare functional neuroplasticity in 23 depressed subjects and age and gender matched controls. Lastly, 18 depressed subjects who received a 4-week treatment course of transcranial direct current stimulation (tDCS) were tested with the PAS protocol before and after treatment. Neuroplasticity is currently being assessed before and after 4 weeks of non-invasive brain stimulation treatment in a randomised, sham-controlled trial. Results: PAS induced neuroplastic changes more consistently than TBS. Neuroplasticity was significantly reduced in depressed subjects compared with healthy controls (p¼0.002). A four-week course of tDCS improved mood and normalised neuroplasticity (as tested by PAS) in depressed subjects, though these two outcomes were not correlated. Conclusions: Neuroplasticity was reduced in depression, as demonstrated by an objective test not confounded by subject effort and motivation. tDCS improved mood and restored neuroplasticity in depressed subjects.
139 Optimization of multifocal transcranial current stimulation montages for specific targets using realistic models of electric fields G. Ruffini a,b, M.D. Fox c,d, O. Ripolles b, A. Riera b, P. Cavaleiro b,e, A. Pascual-Leone d,f a Starlab Barcelona, Barcelona, Spain b Neuroelectrics Barcelona, Barcelona, Spain c Massachusetts General Hospital, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA c Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA e Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências da Universidade de Lisboa, Lisbon, Portugal f Institut Guttmann, Hospital de Neurorehabilitació, Institut Universitari adscrit a la Universitat Autònoma de Barcelona, Barcelona, Spain Recently, multifocal transcranial current stimulation (tCS) with several relatively small electrodes has been used to achieve more focal stimulation. However, it is becoming increasingly recognized that many behavioral manifestations of neurological and psychiatric diseases are not the result of abnormality in one isolated brain region. In this paper we propose a method for optimizing the configuration of multifocal tCS for stimulation of brain networks, represented by spatially extended cortical targets. The proposed method is very flexible, as using fMRI, PET, EEG or other data we can specify a target map on the cortical surface for excitatory, inhibitory or neutral stimulation, a solution can be produced with the optimal currents and locations of the electrodes. Based on the hypothesis that the effects of current stimulation are to first order due to the interaction of electric fields with populations of elongated cortical neurons, it is argued that the optimization problem for tCS stimulation can be defined in terms of the component of the electric field normal to the cortical surface. The method described here relies on a fast calculation of multifocal tCS electric fields using a five layer finite element model of a realistic head. Safety in protocol optimization is
350
Abstracts / Brain Stimulation 8 (2015) 343e359
addressed by limiting the current through each electrode and the total current injected into the brain. We demonstrate the approach both for localized and spatially extended targets defined using rs-fcMRI and PET data, with clinical applications in stroke and depression.
141 Higher current densities for transcranial direct current stimulation produce greater changes in cortical excitability e evidence from a pooled data study Kerrie-Anne Ho a,b,*, Janet L. Taylor b,c, Taariq Chew a,b, Veronica Galvez a,b, Angelo Alonzo a,b, Colleen K. Loo a,b,d a Black Dog Institute, Sydney, Australia b University of New South Wales, Sydney, Australia c Neuroscience Research Australia, Sydney, Australia c St George Hospital, South Eastern Sydney Health, Australia *E-mail: [email protected]. Transcranial direct current stimulation (tDCS) shows promise as a treatment for neurological and psychiatric disorders. Clinical attempts at increasing the therapeutic effect of tDCS have often increased the “dose” by increasing current density (stimulus amplitude divided by surface area of stimulating electrode) and stimulus duration. It is uncertain whether these higher stimulus parameters are more effective at increasing cortical excitability as previous studies with small sample sizes have produced mixed results. The present study examined the effect of different current densities on cortical excitability. Data was collated across five studies in healthy participants conducted in the same research laboratory. The effect of tDCS on motor cortical excitability was measured through motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation . The effect of different current densities (electric current per unit area) and stimulation durations were examined. A mixed effects model was conducted with fixed factors of current density (0.01 mA/cm2, 0.03 mA/cm2, 0.06 mA/cm2, 0.13 mA/cm2 and sham) and duration (10 min, 20 min) with participant as a random factor. Results from 88 participants across 229 sessions show a significant effect of current density with 0.13 mA/cm2 producing larger MEPs (0.65 mV greater) compared to sham, t(215) ¼ 3.35, p ¼ 0.01. There were no significant differences in MEP amplitudes for the other current densities compared to sham, p > 0.05. The duration of the stimulation also had a significant effect such that 20 min of stimulation produced larger MEPs (0.64 mV greater) than 10 min of stimulation, t(67) ¼ 5.89, p < 0.001. Results suggest that higher current densities do in fact produce a greater increase in excitability. This has important implications for the use of tDCS in clinical research applications and should be replicated in a clinical sample.
143 Effects of repeated trains of theta burst stimulation to human primary motor cortex - evidence of homeostatic corticospinal plasticity Mark R. Hinder a, Emily L. Goss a, Rohan Puri a, Hakuei Fujiyama a,b, Alison J. Canty a,c, Michael I. Garry a, Alexander D. Tang d, Jennifer Rodger d, Jeffery J. Summers a,e a Human Motor Control Laboratory, School of Medicine, Faculty of Health, University of Tasmania, Australia b Movement Control and Neuroplasticity Research Group, Department of Kinesiology KU Leuven, Belgium c Wicking Dementia Research and Education Centre, University of Tasmania, Australia d Experimental and Regenerative Neuroscience, School of Animal Biology, University of Western Australia, Australia
e
Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, UK
Introduction: Homeostatic plasticity is an important concept for the use of non-invasive brain stimulation (NBS) in rehabilitative settings. We aimed to determine the extent to which homeostatic plasticity was evident following administration of two trains of intermittent theta burst stimulation (iTBS; 600 pulses per train). Of particular interest was the degree of homeostatic effects evident across the whole experimental cohort, and at the level of individual participants. Methods: Two trains of iTBS were applied 35 min apart to twentytwo participants. Motor evoked potentials (MEPs), elicited via transcranial magnetic stimulation (TMS) were used as a measure of corticospinal excitability prior to, and every 10 min for 30 min following each iTBS train. Results: Both iTBS trains evoked increases in corticospinal excitability for the duration of the post-iTBS assessment period, relative to the excitability observed immediately prior to that train (train 1: 10.4%; train 2: 7.6%; p¼0.017). However, the extent of this potentiation did not vary significantly between trains (p ¼ 0.818) suggesting that, at the group level, homeostatic plasticity effects were not apparent. However, examination of data at the individual level reflected a differing view. Specifically, a strong and statistically significant negative correlation (r ¼ -0.496, p ¼ 0.018) between the extent of plastic changes exhibited by each individual following the first and second trains. Discussion: The findings suggest that homeostatic effects at the group level may be masked by the inherent intra-participant variability in responses to iTBS. We discuss the implications for use of NBS for rehabilitation purposes.
144 Noradrenaline and Brain Stimulation; a preliminary evaluation D.J. Doudet a,*, S. Jakobsen b, S. Dyve b, A. Gjedde c, P. Videbech b, L. Boyd a, A.M. Landau b a University of British Columbia, Vancouver, BC, Canada b Aarhus University Hospital, Denmark c University of Copenhagen, Copenhagen, Denmark *E-mail: [email protected]. Non pharmacologic brain stimulation has become an increasingly attractive alternative to drugs in many psychiatric and neurological disorders. Most stimulation techniques include direct or indirect electrical or magnetic activation of the entire brain or localized areas. Aside from Deep Brain Stimulation (DBS) and Vagal Nerve Stimulation (VNS), electroconvulsive therapy (ECT) and several variants of magnetic stimulation, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), or magnetic seizure therapy (MST) are relatively non invasive. Yet, the mechanism of action of most of the stimulation therapies remains unclear. Taking their antidepressant action as an example, we hypothesized that stimulation induces noradrenergic (NA) activation. We took advantage of a new NA tracer that is sensitive to NA release to assess the abilities of ECT, VNS and theta burst stimulation (TBS), a form of TMS, to induce NA release in large animals, minipigs (ECT and VNS) and rhesus monkeys (TBS). For all 3 stimulation therapies, the stimulation procedures were applied to the animals using clinical parameters and criteria. All the animals were scanned prior to stimulation with 11C-yohimbine, a selective tracer of the alpha2 adrenoceptors which is also sensitive to acute changes in synaptic NA. Minipigs were scanned 24-48 hrs after a clinical course of ECT, or were scanned immediately after turning a VNS stimulator (implanted several weeks prior) ON for the first time and 2 rhesus monkeys were scanned immediately following a sequence of continuous TBS over the left frontal areas. VNS and ECT induced brain wide decrease in yohimbine binding
learning paradigms, C57Bl6/J mice receive daily iTBS immediately prior to undergoing a skilled pellet-reaching task for 10 days. In a separate group; Thy1-GFPM mice undergo cranial window insertion overlying the right motor cortex to enable visualisation of excitatory cortical neurons in the upper layers of the motor cortex. Images of synaptic structures are collected at regular intervals before and after iTBS and analysed for alterations in connectivity resulting from stimulation. Preliminary analysis suggests daily iTBS significantly increases accuracy but not speed of pellet reaching, relative to sham stimulation (handling control). Preliminary analysis of the imaging data suggests a single session of iTBS does not alter dendritic spine density. These results will help characterise the biological mechanisms underlying rTMS, which will undoubtedly pave the way forward in the therapeutic applications of non-invasive brain stimulation in health and disease.
137 Comparison of novel transcranial electrical stimulation montages using a computational modelling approach C.K. Loo , S. Bai , N.H. Lovell , S. Dokos Psychiatry & Biomedical Engineering, University of New South Wales, Sydney, Australia Introduction: Antidepressant efficacy has been demonstrated for both Electroconvulsive Therapy (ECT) and transcranial Direct Current Stimulation (tDCS). Both stimulation techniques involve passing an electrical current transcranially into the cerebrum. It has been hypothesised that antidepressant effects are related to stimulation of frontal and deep central structures (eg subgenual anterior cingulate, sgACC). Optimal electrode positioning (montage) may be important for maximising efficacy (tDCS, ECT) and minimising cognitive side effects (ECT). Indeed clinical studies have demonstrated that electrode montage affects these behavioural outcomes. This research examined the intensity of electric fields generated in key brain regions when electrode montage was varied for tDCS and ECT. Methods: Computational modelling in an anatomically accurate head model was used to examine outcomes of several stimulation montages for tDCS and ECT. Image segmentation and finite element mesh generation were carried out using MRI scans of a healthy 35year-old male subject. Existing and novel montages were modelled for tDCS (11 montages) and ECT (14 montages). Results: Wider spacing of electrodes led to less shunting of current over the scalp and a greater proportion of the stimulating current entering the cerebrum. For tDCS deep central structures were best activated using a fronto-occipital or fronto-extracephalic montage. Likewise, for ECT, compared to the bitemporal montage, a midline anterior-posterior montage led to more current reaching the cerebrum (80% vs 65%), greater stimulation of sgACC, similar stimulation of orbitofrontal cortices, and less stimulation of hippocampi. A 2cm error in placement of electrodes (displaced inferiorly) for bitemporal ECT led to significant differences in induced electric fields, including reduction of current entering the cerebrum to 55%. Conclusions: For both ECT and tDCS, novel montages may potentially lead to superior clinical outcomes compared with montages currently in use e this would need to be tested in clinical trials.
138 Non Invasive Brain Stimulation Therapy Restores Neuroplasticity in Depression C.K. Loo , M. Player , A. Alonzo , D. Martin , P.B. Mitchell , P.S. Sachdev , J.L. Taylor University of New South Wales; Black Dog Institute; Neuroscience Research Australia
349
Introduction: Clinical and preclinical evidence suggests that neuroplasticity is impaired in depression. However, prior clinical research testing functional plasticity has often been confounded by possible impacts of subject motivation and effort. We used a brain stimulation technique to test neuroplasticity independent of subject motivation and effort in a series of studies in depressed subjects and healthy controls. Methods: First, Paired Associative Stimulation (PAS) and Theta Burst Stimulation (TBS) were compared as tests of neuroplasticity in the motor cortex in healthy subjects. Then, PAS testing was used to compare functional neuroplasticity in 23 depressed subjects and age and gender matched controls. Lastly, 18 depressed subjects who received a 4-week treatment course of transcranial direct current stimulation (tDCS) were tested with the PAS protocol before and after treatment. Neuroplasticity is currently being assessed before and after 4 weeks of non-invasive brain stimulation treatment in a randomised, sham-controlled trial. Results: PAS induced neuroplastic changes more consistently than TBS. Neuroplasticity was significantly reduced in depressed subjects compared with healthy controls (p¼0.002). A four-week course of tDCS improved mood and normalised neuroplasticity (as tested by PAS) in depressed subjects, though these two outcomes were not correlated. Conclusions: Neuroplasticity was reduced in depression, as demonstrated by an objective test not confounded by subject effort and motivation. tDCS improved mood and restored neuroplasticity in depressed subjects.
139 Optimization of multifocal transcranial current stimulation montages for specific targets using realistic models of electric fields G. Ruffini a,b, M.D. Fox c,d, O. Ripolles b, A. Riera b, P. Cavaleiro b,e, A. Pascual-Leone d,f a Starlab Barcelona, Barcelona, Spain b Neuroelectrics Barcelona, Barcelona, Spain c Massachusetts General Hospital, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA c Berenson-Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA e Instituto de Biofísica e Engenharia Biomédica, Faculdade de Ciências da Universidade de Lisboa, Lisbon, Portugal f Institut Guttmann, Hospital de Neurorehabilitació, Institut Universitari adscrit a la Universitat Autònoma de Barcelona, Barcelona, Spain Recently, multifocal transcranial current stimulation (tCS) with several relatively small electrodes has been used to achieve more focal stimulation. However, it is becoming increasingly recognized that many behavioral manifestations of neurological and psychiatric diseases are not the result of abnormality in one isolated brain region. In this paper we propose a method for optimizing the configuration of multifocal tCS for stimulation of brain networks, represented by spatially extended cortical targets. The proposed method is very flexible, as using fMRI, PET, EEG or other data we can specify a target map on the cortical surface for excitatory, inhibitory or neutral stimulation, a solution can be produced with the optimal currents and locations of the electrodes. Based on the hypothesis that the effects of current stimulation are to first order due to the interaction of electric fields with populations of elongated cortical neurons, it is argued that the optimization problem for tCS stimulation can be defined in terms of the component of the electric field normal to the cortical surface. The method described here relies on a fast calculation of multifocal tCS electric fields using a five layer finite element model of a realistic head. Safety in protocol optimization is
350
Abstracts / Brain Stimulation 8 (2015) 343e359
addressed by limiting the current through each electrode and the total current injected into the brain. We demonstrate the approach both for localized and spatially extended targets defined using rs-fcMRI and PET data, with clinical applications in stroke and depression.
141 Higher current densities for transcranial direct current stimulation produce greater changes in cortical excitability e evidence from a pooled data study Kerrie-Anne Ho a,b,*, Janet L. Taylor b,c, Taariq Chew a,b, Veronica Galvez a,b, Angelo Alonzo a,b, Colleen K. Loo a,b,d a Black Dog Institute, Sydney, Australia b University of New South Wales, Sydney, Australia c Neuroscience Research Australia, Sydney, Australia c St George Hospital, South Eastern Sydney Health, Australia *E-mail: [email protected]. Transcranial direct current stimulation (tDCS) shows promise as a treatment for neurological and psychiatric disorders. Clinical attempts at increasing the therapeutic effect of tDCS have often increased the “dose” by increasing current density (stimulus amplitude divided by surface area of stimulating electrode) and stimulus duration. It is uncertain whether these higher stimulus parameters are more effective at increasing cortical excitability as previous studies with small sample sizes have produced mixed results. The present study examined the effect of different current densities on cortical excitability. Data was collated across five studies in healthy participants conducted in the same research laboratory. The effect of tDCS on motor cortical excitability was measured through motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation . The effect of different current densities (electric current per unit area) and stimulation durations were examined. A mixed effects model was conducted with fixed factors of current density (0.01 mA/cm2, 0.03 mA/cm2, 0.06 mA/cm2, 0.13 mA/cm2 and sham) and duration (10 min, 20 min) with participant as a random factor. Results from 88 participants across 229 sessions show a significant effect of current density with 0.13 mA/cm2 producing larger MEPs (0.65 mV greater) compared to sham, t(215) ¼ 3.35, p ¼ 0.01. There were no significant differences in MEP amplitudes for the other current densities compared to sham, p > 0.05. The duration of the stimulation also had a significant effect such that 20 min of stimulation produced larger MEPs (0.64 mV greater) than 10 min of stimulation, t(67) ¼ 5.89, p < 0.001. Results suggest that higher current densities do in fact produce a greater increase in excitability. This has important implications for the use of tDCS in clinical research applications and should be replicated in a clinical sample.
143 Effects of repeated trains of theta burst stimulation to human primary motor cortex - evidence of homeostatic corticospinal plasticity Mark R. Hinder a, Emily L. Goss a, Rohan Puri a, Hakuei Fujiyama a,b, Alison J. Canty a,c, Michael I. Garry a, Alexander D. Tang d, Jennifer Rodger d, Jeffery J. Summers a,e a Human Motor Control Laboratory, School of Medicine, Faculty of Health, University of Tasmania, Australia b Movement Control and Neuroplasticity Research Group, Department of Kinesiology KU Leuven, Belgium c Wicking Dementia Research and Education Centre, University of Tasmania, Australia d Experimental and Regenerative Neuroscience, School of Animal Biology, University of Western Australia, Australia
e
Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, UK
Introduction: Homeostatic plasticity is an important concept for the use of non-invasive brain stimulation (NBS) in rehabilitative settings. We aimed to determine the extent to which homeostatic plasticity was evident following administration of two trains of intermittent theta burst stimulation (iTBS; 600 pulses per train). Of particular interest was the degree of homeostatic effects evident across the whole experimental cohort, and at the level of individual participants. Methods: Two trains of iTBS were applied 35 min apart to twentytwo participants. Motor evoked potentials (MEPs), elicited via transcranial magnetic stimulation (TMS) were used as a measure of corticospinal excitability prior to, and every 10 min for 30 min following each iTBS train. Results: Both iTBS trains evoked increases in corticospinal excitability for the duration of the post-iTBS assessment period, relative to the excitability observed immediately prior to that train (train 1: 10.4%; train 2: 7.6%; p¼0.017). However, the extent of this potentiation did not vary significantly between trains (p ¼ 0.818) suggesting that, at the group level, homeostatic plasticity effects were not apparent. However, examination of data at the individual level reflected a differing view. Specifically, a strong and statistically significant negative correlation (r ¼ -0.496, p ¼ 0.018) between the extent of plastic changes exhibited by each individual following the first and second trains. Discussion: The findings suggest that homeostatic effects at the group level may be masked by the inherent intra-participant variability in responses to iTBS. We discuss the implications for use of NBS for rehabilitation purposes.
144 Noradrenaline and Brain Stimulation; a preliminary evaluation D.J. Doudet a,*, S. Jakobsen b, S. Dyve b, A. Gjedde c, P. Videbech b, L. Boyd a, A.M. Landau b a University of British Columbia, Vancouver, BC, Canada b Aarhus University Hospital, Denmark c University of Copenhagen, Copenhagen, Denmark *E-mail: [email protected]. Non pharmacologic brain stimulation has become an increasingly attractive alternative to drugs in many psychiatric and neurological disorders. Most stimulation techniques include direct or indirect electrical or magnetic activation of the entire brain or localized areas. Aside from Deep Brain Stimulation (DBS) and Vagal Nerve Stimulation (VNS), electroconvulsive therapy (ECT) and several variants of magnetic stimulation, including transcranial magnetic stimulation (TMS), transcranial direct current stimulation (tDCS), or magnetic seizure therapy (MST) are relatively non invasive. Yet, the mechanism of action of most of the stimulation therapies remains unclear. Taking their antidepressant action as an example, we hypothesized that stimulation induces noradrenergic (NA) activation. We took advantage of a new NA tracer that is sensitive to NA release to assess the abilities of ECT, VNS and theta burst stimulation (TBS), a form of TMS, to induce NA release in large animals, minipigs (ECT and VNS) and rhesus monkeys (TBS). For all 3 stimulation therapies, the stimulation procedures were applied to the animals using clinical parameters and criteria. All the animals were scanned prior to stimulation with 11C-yohimbine, a selective tracer of the alpha2 adrenoceptors which is also sensitive to acute changes in synaptic NA. Minipigs were scanned 24-48 hrs after a clinical course of ECT, or were scanned immediately after turning a VNS stimulator (implanted several weeks prior) ON for the first time and 2 rhesus monkeys were scanned immediately following a sequence of continuous TBS over the left frontal areas. VNS and ECT induced brain wide decrease in yohimbine binding