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Chronic deep brain stimulation in the nucleus accumbens applied during adolescence: a positron emission tomography and behavioral study in the maternal immune stimulation animal model of schizophrenia
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Abstracts / Brain Stimulation 10 (2017) 346e540
[0797] DYNAMICS IN RESPONSE TO FOCAL STIMULATION IN A WHOLE-BRAIN NETWORK MODEL OF MICE e et de la A. Spiegler*1, M. Mohajerani 2, V.K. Jirsa 1. 1 Institut de la Sant Recherche M edical, Institut de Neurosciences des Syst emes UMR_S 1106, Aix-Marseille Universit e, France; 2 Department of Neuroscience, Canadian Centre for Behavioural Neuroscience (CCBN), University of Lethbridge, Canada Systematic exploration via stimulation of all cortical and subcortical brain areas can only be performed in silico. The pattern formation of brain activity after stimulation is constrained by the structural connectivity of the brain. The extent to which information is processed over short- and longrange connections is unclear. Here we use whole-brain models of mice to explain the brain activity following stimulation. The model bases on the structural brain connectivity data from the Allen Brain Atlas (http://connectivity.brain-map.org). Using The Virtual Brain (www.thevirtualbrain.org), the brain of the mice is modelled as a network of 14,400 nodes: 13,972 for both cortices and 428 for subcortical structures. A neural field approximated the cerebral surfaces, which is divided into 84 cortical regions. A reduced FitzHugh Nagumo model with a natural frequency in gamma range (~42 Hz) describes the dynamics of each node in the brain network. The dynamically responsive networks were extracted after stimulation by performing a principal component analysis. The in-silico exploration provides consistent activity patterns after stimulation, and a map indicating which brain areas need to be stimulated to place the brain in a particular state. The activity patterns were then compared to the voltagesensitive dye (VSD) imaging after stimulation and at rest (Mohajerani et al., 2013). The resulting catalogue contains the responsive patterns and moreover their stimulation sites that can be used for future experiments. The model does not only provide a mechanistic entry but also deeper insights. For instance, VSD can be used to measure activity in wide parts of the cortex, whereas electrophysiological signals such as local field potentials measure small volumes that, however, can lie deeper in the brain. The model can be
used to integrate and evaluate such diverse experimental data from mice. This approach can also be used for the human brain. Keywords: focal stimulation, network modeling, brain dynamics, mice
[0798] CHRONIC DEEP BRAIN STIMULATION IN THE NUCLEUS ACCUMBENS APPLIED DURING ADOLESCENCE: A POSITRON EMISSION TOMOGRAPHY AND BEHAVIORAL STUDY IN THE MATERNAL IMMUNE STIMULATION ANIMAL MODEL OF SCHIZOPHRENIA M. Casquero-Veiga*2,1, R. Hadar 4, C. Winter 4, M. Desco 3, 2, M.L. Soton Sanitaria Gregorio Maran ~o n, Montenegro 1, 2. 1 Instituto de Investigacio Spain; 2 CIBER de Salud Mental (CIBERSAM), Spain; 3 Universidad Carlos III €t Dresden, Germany de Madrid, Spain; 4 Technische Universita Introduction: A growing evidence suggests that schizophrenia is a progressive neurodevelopmental disorder. This is of particular interest in the development of preventive strategies to halt disease progression in schizophrenia. Among them, neuromodulatory interventions seem to be promising. Here, we evaluated deep brain stimulation (DBS) on nucleus accumbens (NAcc) of adolescent rats on brain glucose metabolism and behavior in the neurodevelopmental maternal immune stimulation (MIS) animal model of schizophrenia. Methods: Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (Poly I:C) or saline. At adolescence, animals underwent bilateral stereotaxic electrode implantation into the Nucleus accumbens [AP:+1.0 (from Bregma), ML:+1.2, DV:6.5 (from Dura)]. Rats were chronically stimulated during 15 days (24h/ day) of their adolescence period at a constant current of 130 Hz. Behavioral and PET imaging studies with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) were performed in adulthood. Differences in glucose uptake were assessed with Statistical Parametric Mapping software (SPM12). Animals were tested for deficits in sensorimotor gating as measured via prepulse inhibition (PPI) of the acoustic startle response.
Figure 1. Voxel-based SPM results in T-maps overlaid on a MR image, showing the metabolic changes after DBS in salines (left) and Poly I:C (middle) offspring; and the phenotype difference between saline and Poly I:C offspring after DBS (right). The color bars represent the T values corresponding to lower and higher FDG uptake.
Abstracts / Brain Stimulation 10 (2017) 346e540
Results: In saline animals, DBS induced a decreased glucose metabolism in the striatum and increased it in subiculum. However, in Poly I:C offspring, DBS induced a lower FDG uptake in cerebellum, subiculum and striatum and higher FDG uptake in cortex, mainly in PFC. DBS increased metabolism in the hippocampus and cortex and decreased it in the cerebellum in the Poly I:C- compared to Saline-offspring. We found significant interactions between the factors phenotype and stimulation. NAcc-DBS significantly decreased PPI deficits in Poly I:C offspring and induced a PPI deficit in saline offspring. Conclusion: DBS induced different behavioral and brain metabolic changes depending on the phenotype. This study indicates that early neuro-modulation might halt schizophrenia-progression and calls for the development of early non-pervasive neuromodulatory interventions for individuals at risk for schizophrenia. Acknowledgements: We thank de Francisco A and Sierra Y for their support in experimental procedures. This work was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants (PI14/00860, CPII/00005), cofinanced by ERDF (FEDER) Funds from the European Commission, “A way n Mapfre and Comunidad de Madrid. of making Europe”, Fundacio Supplementary data Keywords: Deep brain stimulation, FDG-PET, Schizophrenia, Nucleus accumbens [0801] STIMULATION ACTIVATES FUNCTIONALLY RELEVANT NETWORKS IN A NETWORK MODEL OF THE HUMAN BRAIN A. Spiegler*1, E.C.A. Hansen 1, C. Bernard 1, A.R. McIntosh 2, V.K. e et de la Recherche M edical, Institut de Jirsa 1. 1 Institut de la Sant Neurosciences des Syst emes UMR_S 1106, Aix-Marseille Universit e, France; 2 2Rotman Research Institute of Baycrest Center, University of Toronto, Canada When the brain is stimulated, for example, by sensory inputs or goal-oriented tasks, the brain initially responds with activities in specific areas. The subsequent pattern formation of functional networks is constrained by the structural connectivity (SC) of the brain. The extent to which information is processed over short- or long-range SC is unclear. The present study investigates the effects of SC on the network response to stimulation. A human whole-brain network model comprising long- and short-range connections is used. The brain comprises a network of 16,500 nodes: 8,192 per hemisphere and 116 for thalamic nuclei. Each node holds a reduced FitzHugh Nagumo model performing an oscillation at 42 Hz. A neural field approximates the folded cortical surfaces, where nodes are connected over short-ranges. Following a functional brain atlas, the cortex is divided into 74 areas, which are interconnected over long-ranges with a finite transmission speed of 7 m/s (also with the thalamus). Each cortical and thalamic area was systematically activated by stimulation. When the model was operating at the edge of criticality, stimulation caused a cascade of network recruitments, collapsing onto a smaller space that is partly constrained by SC. Both short- and long-range SC were found to be essential to reproduce experimental results. In particular, the stimulation of specific areas results in the activation of one or more restingstate networks. The model explains the emergence of functional networks by (stimulus-) induced brain activity, which may indicate information and cognitive processing, that follows specific routes imposed by structural networks. The resulting lookup table links stimulation targets and functional network activations, which potentially can be useful in diagnostics and treatments with brain stimulation. Keywords: network modeling, focal stimulation, resting state, criticality [0802] EFFECTS OF LOW-FREQUENCY RTMS OF THE UNAFFECTED HEMISPHERE IN CHRONIC STROKE: A CONCOMITANT TMS AND FMRI STUDY A. Salatino*1, R. Morese 1,2, M. Daniele 1, A. Berti 1, P. Perozzo 3, M.T. Molo 3, P. Cerrato 1, M. Nobili 4, C. Valentini 5, R. Ricci 1. 1 University of della Svizzera Italiana, Switzerland; 3 Carlo Molo Turin, Italy; 2 Universita
Foundation onlus, Italy; 4 Koelliker Hospital, Italy; Salute e della Scienza di Torino, Italy
537 5
della Hospital-Citta
Recent evidence shows that repetitive Transcranial Magnetic Stimulation (rTMS) over primary motor cortex (M1) ameliorates motor symptoms in stroke patients. However, little is known about the putative effects of other sites of stimulation and rTMS induced neuroplasticity. In this study, we compared the effects of a novel rTMS protocol over dorsolateral prefrontal cortex (DLPFC) with those of a canonical rTMS protocol over M1, on motor disorders in five chronic patients with right or left hemisphere lesions and upper and lower limb motor impairments. One Hz rTMS was applied to the unaffected M1 (APB muscle) in two patients (T-M1) and the unaffected DLPFC (F3/F4, according to the 10-20 EEG system) in three patients (TDLPFC). Six-hundred pulses of rTMS were applied at 30% of the machine output, for 3 days in a week (every other day). Before and after intervention, patients underwent extensive motor and neuropsychological assessment. A Follow-Up evaluation was administered after one week. FMRI measures (i.e. left and right hand and foot motor tasks), were also obtained before and after treatment. Post treatment evaluation indicated reduction of spasticity, maintained at the Follow-Up, in one out of two patients assigned to T-M1 and in three out of three patients assigned to TDLPFC. In two patients (one per type of treatment) a mild improvement was also observed on other motor scales. Interestingly, in the above patients, neuroimaging data indicated opposite patterns of neuroplastic changes following treatments: decreased activity of contralesional hemisphere after T-M1, and increased activity of contralesional hemisphere after T-DLPFC. These preliminary findings suggest that DLPFC might provide an effective site of stimulation for the treatment of motor disorders after stroke through rTMS. We are currently increasing the sample size of the present study to better understand neuroplastic effects by rTMS of DLPFC and associated motor recovery. [0803] CATHODAL/ANODAL TECHNIQUE USE OF REPETITIVE TRANSCRAINAL MAGNETIC STIMULATION IN TREATMENT OF AUTISM SPECTRUM DISORDER (ASD) A. Marei*, H. Rashed, R. Magdy. Brains' Clinic Maadi, Egypt Objective: To investigate the possible effect of rTMS in ASD, using multiple alternative frequencies (both stimulatory and inhibitory protocols) over multiple brain areas within the same session. Hypothesis: To further understand ASD, we compared it to other disorders mainly depression, obsessive compulsive disorder (OCD) and movement related disorders. There are many recent which correlates ASD to OCD in the stereotype of movements. It was also established that there is over activation of the right orbitofrontal area in OCD. There is also evidence that the orbitofrontal area has a role in facial recognition. Thus the idea of performing 1 pulse per second, 100 pulses per train with 10 second inter train interval for 10 trains was used at 50% intensity of the used machine. New theories of the involvement of the cerebellum have evolved in the pathology of ASD. There are also theories that state that the cerebellum is stimulated when the motor areas are being stimulated. We used these theories alongside the theory that we could actually inhibit movement using the same protocol stated above but at a 10-20% increase (i.e. at 60-70%) depending on the severity of hyperactivity and repetition rate of the movements. ASD enjoys a great deal of emotional dysregulation. It is established that the left Dorsolateral Prefrontal Cortex has a hypofunction in depression and thus the use of high frequency stimulation has been recognized. We used the same European protocol (5pps,100 pulse per train, 20 trains, 20 seconds inter train interval, at 50 % intensity). This protocol sometimes worsened the condition as it cause symptoms of hypomania with few cases. Conclusions: Multiple brain area stimulation using an alteration between stimulatory and inhibitory rTMS protocols in same the session may improve treatment outcome of ASD. Further researches are needed to confirm our hypothesis. Keywords: rTMS, ASD, Multiple brain areas, Cathodal/Anodal rTMS
Abstracts / Brain Stimulation 10 (2017) 346e540
[0797] DYNAMICS IN RESPONSE TO FOCAL STIMULATION IN A WHOLE-BRAIN NETWORK MODEL OF MICE e et de la A. Spiegler*1, M. Mohajerani 2, V.K. Jirsa 1. 1 Institut de la Sant Recherche M edical, Institut de Neurosciences des Syst emes UMR_S 1106, Aix-Marseille Universit e, France; 2 Department of Neuroscience, Canadian Centre for Behavioural Neuroscience (CCBN), University of Lethbridge, Canada Systematic exploration via stimulation of all cortical and subcortical brain areas can only be performed in silico. The pattern formation of brain activity after stimulation is constrained by the structural connectivity of the brain. The extent to which information is processed over short- and longrange connections is unclear. Here we use whole-brain models of mice to explain the brain activity following stimulation. The model bases on the structural brain connectivity data from the Allen Brain Atlas (http://connectivity.brain-map.org). Using The Virtual Brain (www.thevirtualbrain.org), the brain of the mice is modelled as a network of 14,400 nodes: 13,972 for both cortices and 428 for subcortical structures. A neural field approximated the cerebral surfaces, which is divided into 84 cortical regions. A reduced FitzHugh Nagumo model with a natural frequency in gamma range (~42 Hz) describes the dynamics of each node in the brain network. The dynamically responsive networks were extracted after stimulation by performing a principal component analysis. The in-silico exploration provides consistent activity patterns after stimulation, and a map indicating which brain areas need to be stimulated to place the brain in a particular state. The activity patterns were then compared to the voltagesensitive dye (VSD) imaging after stimulation and at rest (Mohajerani et al., 2013). The resulting catalogue contains the responsive patterns and moreover their stimulation sites that can be used for future experiments. The model does not only provide a mechanistic entry but also deeper insights. For instance, VSD can be used to measure activity in wide parts of the cortex, whereas electrophysiological signals such as local field potentials measure small volumes that, however, can lie deeper in the brain. The model can be
used to integrate and evaluate such diverse experimental data from mice. This approach can also be used for the human brain. Keywords: focal stimulation, network modeling, brain dynamics, mice
[0798] CHRONIC DEEP BRAIN STIMULATION IN THE NUCLEUS ACCUMBENS APPLIED DURING ADOLESCENCE: A POSITRON EMISSION TOMOGRAPHY AND BEHAVIORAL STUDY IN THE MATERNAL IMMUNE STIMULATION ANIMAL MODEL OF SCHIZOPHRENIA M. Casquero-Veiga*2,1, R. Hadar 4, C. Winter 4, M. Desco 3, 2, M.L. Soton Sanitaria Gregorio Maran ~o n, Montenegro 1, 2. 1 Instituto de Investigacio Spain; 2 CIBER de Salud Mental (CIBERSAM), Spain; 3 Universidad Carlos III €t Dresden, Germany de Madrid, Spain; 4 Technische Universita Introduction: A growing evidence suggests that schizophrenia is a progressive neurodevelopmental disorder. This is of particular interest in the development of preventive strategies to halt disease progression in schizophrenia. Among them, neuromodulatory interventions seem to be promising. Here, we evaluated deep brain stimulation (DBS) on nucleus accumbens (NAcc) of adolescent rats on brain glucose metabolism and behavior in the neurodevelopmental maternal immune stimulation (MIS) animal model of schizophrenia. Methods: Pregnant rats were injected on gestational day 15 with the viral mimic polyriboinosinic-polyribocytidylic acid (Poly I:C) or saline. At adolescence, animals underwent bilateral stereotaxic electrode implantation into the Nucleus accumbens [AP:+1.0 (from Bregma), ML:+1.2, DV:6.5 (from Dura)]. Rats were chronically stimulated during 15 days (24h/ day) of their adolescence period at a constant current of 130 Hz. Behavioral and PET imaging studies with 2-deoxy-2-[18F]fluoro-D-glucose (FDG) were performed in adulthood. Differences in glucose uptake were assessed with Statistical Parametric Mapping software (SPM12). Animals were tested for deficits in sensorimotor gating as measured via prepulse inhibition (PPI) of the acoustic startle response.
Figure 1. Voxel-based SPM results in T-maps overlaid on a MR image, showing the metabolic changes after DBS in salines (left) and Poly I:C (middle) offspring; and the phenotype difference between saline and Poly I:C offspring after DBS (right). The color bars represent the T values corresponding to lower and higher FDG uptake.
Abstracts / Brain Stimulation 10 (2017) 346e540
Results: In saline animals, DBS induced a decreased glucose metabolism in the striatum and increased it in subiculum. However, in Poly I:C offspring, DBS induced a lower FDG uptake in cerebellum, subiculum and striatum and higher FDG uptake in cortex, mainly in PFC. DBS increased metabolism in the hippocampus and cortex and decreased it in the cerebellum in the Poly I:C- compared to Saline-offspring. We found significant interactions between the factors phenotype and stimulation. NAcc-DBS significantly decreased PPI deficits in Poly I:C offspring and induced a PPI deficit in saline offspring. Conclusion: DBS induced different behavioral and brain metabolic changes depending on the phenotype. This study indicates that early neuro-modulation might halt schizophrenia-progression and calls for the development of early non-pervasive neuromodulatory interventions for individuals at risk for schizophrenia. Acknowledgements: We thank de Francisco A and Sierra Y for their support in experimental procedures. This work was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants (PI14/00860, CPII/00005), cofinanced by ERDF (FEDER) Funds from the European Commission, “A way n Mapfre and Comunidad de Madrid. of making Europe”, Fundacio Supplementary data Keywords: Deep brain stimulation, FDG-PET, Schizophrenia, Nucleus accumbens [0801] STIMULATION ACTIVATES FUNCTIONALLY RELEVANT NETWORKS IN A NETWORK MODEL OF THE HUMAN BRAIN A. Spiegler*1, E.C.A. Hansen 1, C. Bernard 1, A.R. McIntosh 2, V.K. e et de la Recherche M edical, Institut de Jirsa 1. 1 Institut de la Sant Neurosciences des Syst emes UMR_S 1106, Aix-Marseille Universit e, France; 2 2Rotman Research Institute of Baycrest Center, University of Toronto, Canada When the brain is stimulated, for example, by sensory inputs or goal-oriented tasks, the brain initially responds with activities in specific areas. The subsequent pattern formation of functional networks is constrained by the structural connectivity (SC) of the brain. The extent to which information is processed over short- or long-range SC is unclear. The present study investigates the effects of SC on the network response to stimulation. A human whole-brain network model comprising long- and short-range connections is used. The brain comprises a network of 16,500 nodes: 8,192 per hemisphere and 116 for thalamic nuclei. Each node holds a reduced FitzHugh Nagumo model performing an oscillation at 42 Hz. A neural field approximates the folded cortical surfaces, where nodes are connected over short-ranges. Following a functional brain atlas, the cortex is divided into 74 areas, which are interconnected over long-ranges with a finite transmission speed of 7 m/s (also with the thalamus). Each cortical and thalamic area was systematically activated by stimulation. When the model was operating at the edge of criticality, stimulation caused a cascade of network recruitments, collapsing onto a smaller space that is partly constrained by SC. Both short- and long-range SC were found to be essential to reproduce experimental results. In particular, the stimulation of specific areas results in the activation of one or more restingstate networks. The model explains the emergence of functional networks by (stimulus-) induced brain activity, which may indicate information and cognitive processing, that follows specific routes imposed by structural networks. The resulting lookup table links stimulation targets and functional network activations, which potentially can be useful in diagnostics and treatments with brain stimulation. Keywords: network modeling, focal stimulation, resting state, criticality [0802] EFFECTS OF LOW-FREQUENCY RTMS OF THE UNAFFECTED HEMISPHERE IN CHRONIC STROKE: A CONCOMITANT TMS AND FMRI STUDY A. Salatino*1, R. Morese 1,2, M. Daniele 1, A. Berti 1, P. Perozzo 3, M.T. Molo 3, P. Cerrato 1, M. Nobili 4, C. Valentini 5, R. Ricci 1. 1 University of della Svizzera Italiana, Switzerland; 3 Carlo Molo Turin, Italy; 2 Universita
Foundation onlus, Italy; 4 Koelliker Hospital, Italy; Salute e della Scienza di Torino, Italy
537 5
della Hospital-Citta
Recent evidence shows that repetitive Transcranial Magnetic Stimulation (rTMS) over primary motor cortex (M1) ameliorates motor symptoms in stroke patients. However, little is known about the putative effects of other sites of stimulation and rTMS induced neuroplasticity. In this study, we compared the effects of a novel rTMS protocol over dorsolateral prefrontal cortex (DLPFC) with those of a canonical rTMS protocol over M1, on motor disorders in five chronic patients with right or left hemisphere lesions and upper and lower limb motor impairments. One Hz rTMS was applied to the unaffected M1 (APB muscle) in two patients (T-M1) and the unaffected DLPFC (F3/F4, according to the 10-20 EEG system) in three patients (TDLPFC). Six-hundred pulses of rTMS were applied at 30% of the machine output, for 3 days in a week (every other day). Before and after intervention, patients underwent extensive motor and neuropsychological assessment. A Follow-Up evaluation was administered after one week. FMRI measures (i.e. left and right hand and foot motor tasks), were also obtained before and after treatment. Post treatment evaluation indicated reduction of spasticity, maintained at the Follow-Up, in one out of two patients assigned to T-M1 and in three out of three patients assigned to TDLPFC. In two patients (one per type of treatment) a mild improvement was also observed on other motor scales. Interestingly, in the above patients, neuroimaging data indicated opposite patterns of neuroplastic changes following treatments: decreased activity of contralesional hemisphere after T-M1, and increased activity of contralesional hemisphere after T-DLPFC. These preliminary findings suggest that DLPFC might provide an effective site of stimulation for the treatment of motor disorders after stroke through rTMS. We are currently increasing the sample size of the present study to better understand neuroplastic effects by rTMS of DLPFC and associated motor recovery. [0803] CATHODAL/ANODAL TECHNIQUE USE OF REPETITIVE TRANSCRAINAL MAGNETIC STIMULATION IN TREATMENT OF AUTISM SPECTRUM DISORDER (ASD) A. Marei*, H. Rashed, R. Magdy. Brains' Clinic Maadi, Egypt Objective: To investigate the possible effect of rTMS in ASD, using multiple alternative frequencies (both stimulatory and inhibitory protocols) over multiple brain areas within the same session. Hypothesis: To further understand ASD, we compared it to other disorders mainly depression, obsessive compulsive disorder (OCD) and movement related disorders. There are many recent which correlates ASD to OCD in the stereotype of movements. It was also established that there is over activation of the right orbitofrontal area in OCD. There is also evidence that the orbitofrontal area has a role in facial recognition. Thus the idea of performing 1 pulse per second, 100 pulses per train with 10 second inter train interval for 10 trains was used at 50% intensity of the used machine. New theories of the involvement of the cerebellum have evolved in the pathology of ASD. There are also theories that state that the cerebellum is stimulated when the motor areas are being stimulated. We used these theories alongside the theory that we could actually inhibit movement using the same protocol stated above but at a 10-20% increase (i.e. at 60-70%) depending on the severity of hyperactivity and repetition rate of the movements. ASD enjoys a great deal of emotional dysregulation. It is established that the left Dorsolateral Prefrontal Cortex has a hypofunction in depression and thus the use of high frequency stimulation has been recognized. We used the same European protocol (5pps,100 pulse per train, 20 trains, 20 seconds inter train interval, at 50 % intensity). This protocol sometimes worsened the condition as it cause symptoms of hypomania with few cases. Conclusions: Multiple brain area stimulation using an alteration between stimulatory and inhibitory rTMS protocols in same the session may improve treatment outcome of ASD. Further researches are needed to confirm our hypothesis. Keywords: rTMS, ASD, Multiple brain areas, Cathodal/Anodal rTMS