- Email: [email protected]
P19. The brain’s default mode is associated with executive oculomotor deficits in Parkinson’s disease
Society Proceedings / Clinical Neurophysiology 126 (2015) e63–e170
Methods: Thirty-five early HD subjects (TFC stage 1 and 2) and 32 age- and sex-matched healthy controls underwent3T-MRI (T1w, DTI and ifcMRI sequences). DTI and ifcMRI data analyses were performed using the Tensor Imaging and Fiber Tracking (TIFT) software (Müller et al., 2007) for complementary DTI fiber tracking (FT) and ifcMRI data analysis. For the motor ICN ifcMRI analyses, the dominant M1 was used as the seed, for the basal ganglia-thalamic ICN the thalamus was used. In addition, the cortico-spinal tract (CST) and the thalamocortical pathway were used for comparisons at the group level. Results: Structural connectivity measured by DTI at the group level showed an increase of FA values in the basal ganglia as well as FA reductions in the external and internal capsule, in parts of the thalamus, and in subcortical white matter. Intrinsic functional connectivity (brain function) showed hyper-connectivity in the motor ICN, i.e. the insula was less connected in HD than in controls. The basal ganglia-thalamic ICN connectivity differed between HD and controls in the insula and the basal ganglia in both hemispheres. Conclusion: At the group level, we confirmed microstructural changes identified in previous DTI studies in HD (e.g. (Rosas et al., 2006)). There is evidence that the insula becomes disconnected from the motor cortex. The caudatum seems to lose its functional integration with widely distributed cortical areas (basal ganglio-thalamic ICN). Abnormal connectivity of the insula and caudatum may be relevant in the emergence of clinical signs of HD. Acknowledgements: This work was partially supported by the European Union under the Seventh Framework programme PADDINGTON Project, Grant Agreement No.261358, and the European Huntington’s Disease Network (EHDN), project 070 PADDINGTON. References Müller H-P, Unrath A, Ludolph AC, Kassubek J. Preservation of diffusion tensor properties during spatial normalization by use of tensor imaging and fiber tracking on a normal brain database. Phys Med Biol 2007;52:N99–109. Rosas HD, Tuch DS, Hevelone ND, Zaleta AK, Vangel M, Hersch SM, et al. Diffusion tensor imaging in presymptomatic and early Huntington’s disease: selective white matter pathology and its relationship to clinical measures. Mov Disord 2006;21:1317–25. doi:10.1016/j.clinph.2015.04.136
P18. Pattern of ‘resting-state’ functional hyperconnectivity in Amyotrophic lateral sclerosis reflects neuropathological disease stages—I. Röll, M. Gorges, H.-P. Müller, D. Lulé, A.C. Ludolph, J. Kassubek (University of Ulm, Department of Neurology, Ulm, Germany) Background: Autopsy-controlled studies in Amyotrophic lateral sclerosis (ALS) proposed a 4-stage sequential spreading of the underlying TDP-43 pathology (Brettschneider et al., 2013). Recently the in vivo transfer of the neuropathological stages by use of tract of interest-based diffusion-tensor-imaging (DTI) has been performed (Kassubek et al., 2014). Based upon the DTI findings, we have expanded the imaging approach by complementary investigation of ifc-fMRI in order to trace the pathology spreading in well-defined intrinsic functional connectivity networks (ICNs). Methods: We used a 3.0T resting state-fMRI protocol for 76 ALS patients and 28 healthy controls. The preprocessing followed standardized procedures including motion correction, MNI normalization, spatial filtering, temporal linear detrending and bandpass filtering. ICNs were identified utilizing the seed-based approach (Gorges et al., 2014). These ICNs comprised the motor (neuropathological stage 1), frontoparietal, frontal executive and brainstem
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(stage 2), basal ganglia (stage 3), and hippocampal (stage 4) networks; we used the visual ICN as reference. Results: ALS patients compared with healthy controls demonstrated a large-scale pattern of increased functional connectivity (hyperconnectivity) in all networks with the exception of the reference network. More specifically, the hyperconnectivity pattern extended spatially into adjacent brain structures following the neuropathological spreading. The hyperconnectivity in stage 1 extended into frontal areas, in stage 2 into prefrontal and postcentral areas, in stage 3 into prefrontal and postcentral areas, and in stage 4 within the hippocampal formation. Moreover, the disease stages as observed in vivo by DTI significantly correlated with increasing functional connectivity in the ICNs. Conclusion: Ifc-fMRI provides a promising approach to functionally trace pathological spreading in ALS. As recently suggested (Douaud et al., 2011), the loss of the inhibitory influence may be most likely attributable to the pattern of hyperconnectivity in ALS. With increasing stages of disease, hyperconnectivity seems to spread sequentially into more frontal and postcentral regions following the neuropathological spreading. References Brettschneider et al. Ann Neurol 2013;74:20–38. Douaud et al. Brain 2011;134:3470–9. Gorges et al. Biomed Res Int 2014;2014:947252. Kassubek et al. Brain 2014;137:1733–40. doi:10.1016/j.clinph.2015.04.137
P19. The brain’s default mode is associated with executive oculomotor deficits in Parkinson’s disease—M. Gorges, H.-P. Müller, A.C. Ludolph, E. Pinkhardt, J. Kassubek (University of Ulm, Department of Neurology, Ulm, Germany) Introduction: Eye movements provide a valuable window into complex forms of human behavior. Impaired eye movement control in patients with Parkinson’s disease (PD) has been consistently demonstrated besides the well-known motor symptoms (Pinkhardt and Kassubek, 2011). Saccadic intrusions are a common oculomotor manifestation in PD and interrupt smooth pursuit and fixation during tracking a ’jumping’ target (visually guided reactive saccades) (Pinkhardt and Kassubek, 2011; Gorges et al., 2014). The default mode network (DMN) as observed with ’resting-state’ functional MRI is crucially involved in higher cognitive processes such as attention (Buckner et al., 2008). We hypothesized that prevalence of saccadic intrusions in patients with PD reflects executive deficits which are closely associated with intrinsic functional connectivity (iFC) within the DMN. Methods: The analysis was based on 31 patients with PD and 22 age-matched healthy controls. We acquired ’resting-state’ functional MRI (3 Tesla; BOLD-sensitive T2⁄-sequence) and video-oculographic recordings (VOG, Eye-Link I operating on 250 Hz sampling rate) of smooth pursuit eye movements and visually guided reactive saccades. ’Resting-state’ functional MRI analysis followed standardized procedures (Gorges et al., 2014) with the DMN computed by seeding the posterior cingulate cortex (Buckner et al., 2008). The posterior cingulate cortex is known to be both a major node of the DMN (Buckner et al., 2008) and to play a critical role in eye movement control (Olson et al., 1996). Both smooth pursuit gain as a measure for saccadic intrusions and the saccadic intrusion rate during reactive saccades were analyzed in patients vs. controls and correlated with iFC within the DMN. Results: VOG analysis revealed a significantly higher prevalence of saccadic intrusions during smooth pursuit (p < 0.001) and reactive
e96
Society Proceedings / Clinical Neurophysiology 126 (2015) e63–e170
saccades (p < 0.01) in PD patients compared with controls. Covariance analysis between the saccadic intrusion measures and the iFC in the DMN demonstrated significantly negative correlations (p < 0.001 for all clusters, corrected for multiple comparisons) in the sense that reduced iFC in almost all parts of the DMN was related to a higher prevalence of saccadic intrusions. Specifically, iFC between the posterior cingulate cortex and the (i) middle temporal lobe, (ii) thalamus, (iii) MST, (vi) precuneus (v), medial prefrontal cortex, and (vi) parietal lobule were significantly correlated with the saccadic intrusion rates. Conclusions: A high prevalence of saccadic intrusions in patients with PD appears to be closely related to a lack of attention, pointing towards an increased distractibility that might be associated with the neuroimaging correlate of a disrupted DMN. This supports the hypothesis that impaired oculomotor control in PD reflects a behavioral correlate of disturbed higher functions rather than impaired oculomotor circuits in the brainstem. References Buckner et al. Ann N Y Acad Sci 2008;1124:1–38. Gorges et al. J Ophthalmol 2014;2014:658243. Gorges et al. Biomed Res Int 2014;2014:947252. Olson et al. J Neurophysiol 1996;76:3285–300. Pinkhardt, Kassubek. Parkinsonism Relat Disord 2011;17:223–30. doi:10.1016/j.clinph.2015.04.138
P20. Deficit actual tool use in schizophrenia is linked to structural alterations in key regions of planning and executing of tool use and connecting fibers—P. Viher a, K. Stegmayer a, T. Vanbellingen b,c, A. Federspiel a, W. Strik a, R. Wiest d, S.
Bohlhalter b,c, S. Walther a (a University Hospital of Psychiatry, Department of Psychiatric Neurophysiology, Bern, Switzerland, b Inselspital, Department of Clinical Research, Bern, Switzerland, c Luzerner Kantonsspital, Neurology and Neurorehabilitation Center, Luzern, Switzerland, d Inselspital, Support Center of Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, Bern, Switzerland) Introduction: Schizophrenia patients frequently suffer from complex motor abnormalities including fine and gross motor disturbances, abnormal involuntary movements, neurological soft signs and parkinsonism. These symptoms occur early in the course of the disease, continue in chronic patients and may deteriorate with antipsychotic medication (Walther and Strik, 2012). Furthermore gesture performance is impaired in patients, including the pantomime of tool use. Whether schizophrenia patients would show difficulties of actual tool use has not yet been investigated. Human tool use is complex and relies on a network of distinct and distant brain areas. We therefore aim to test if schizophrenia patients had difficulties in tool use and to assess associations with structural brain imaging using voxel based morphometry (VBM) and tract based spatial statistics (TBSS). Methods: In total, 44 patients with schizophrenia (DSM-5 criteria; 59% men, mean age 38) underwent structural MR imaging and performed the Tool-Use test (Randerath et al., 2011). The test examines the use of a scoop and a hammer in three conditions: pantomime (without the tool), demonstration (with the tool) and actual use (with a recipient object). T1-weighted images were processed using SPM8 and DTI-data using FSL TBSS routines. To assess structural alterations of impaired tool use we first compared gray matter (GM) volume in VBM and white matter (WM) integrity in TBSS data of patients with and without difficulties of actual tool use. Next we explored correlations of Tool use scores and VBM and TBSS data.
Fig. 1. A Gray matter volume reduction and B reduced white matter associated with deficit tool use in schizophrenia patients.
Methods: Thirty-five early HD subjects (TFC stage 1 and 2) and 32 age- and sex-matched healthy controls underwent3T-MRI (T1w, DTI and ifcMRI sequences). DTI and ifcMRI data analyses were performed using the Tensor Imaging and Fiber Tracking (TIFT) software (Müller et al., 2007) for complementary DTI fiber tracking (FT) and ifcMRI data analysis. For the motor ICN ifcMRI analyses, the dominant M1 was used as the seed, for the basal ganglia-thalamic ICN the thalamus was used. In addition, the cortico-spinal tract (CST) and the thalamocortical pathway were used for comparisons at the group level. Results: Structural connectivity measured by DTI at the group level showed an increase of FA values in the basal ganglia as well as FA reductions in the external and internal capsule, in parts of the thalamus, and in subcortical white matter. Intrinsic functional connectivity (brain function) showed hyper-connectivity in the motor ICN, i.e. the insula was less connected in HD than in controls. The basal ganglia-thalamic ICN connectivity differed between HD and controls in the insula and the basal ganglia in both hemispheres. Conclusion: At the group level, we confirmed microstructural changes identified in previous DTI studies in HD (e.g. (Rosas et al., 2006)). There is evidence that the insula becomes disconnected from the motor cortex. The caudatum seems to lose its functional integration with widely distributed cortical areas (basal ganglio-thalamic ICN). Abnormal connectivity of the insula and caudatum may be relevant in the emergence of clinical signs of HD. Acknowledgements: This work was partially supported by the European Union under the Seventh Framework programme PADDINGTON Project, Grant Agreement No.261358, and the European Huntington’s Disease Network (EHDN), project 070 PADDINGTON. References Müller H-P, Unrath A, Ludolph AC, Kassubek J. Preservation of diffusion tensor properties during spatial normalization by use of tensor imaging and fiber tracking on a normal brain database. Phys Med Biol 2007;52:N99–109. Rosas HD, Tuch DS, Hevelone ND, Zaleta AK, Vangel M, Hersch SM, et al. Diffusion tensor imaging in presymptomatic and early Huntington’s disease: selective white matter pathology and its relationship to clinical measures. Mov Disord 2006;21:1317–25. doi:10.1016/j.clinph.2015.04.136
P18. Pattern of ‘resting-state’ functional hyperconnectivity in Amyotrophic lateral sclerosis reflects neuropathological disease stages—I. Röll, M. Gorges, H.-P. Müller, D. Lulé, A.C. Ludolph, J. Kassubek (University of Ulm, Department of Neurology, Ulm, Germany) Background: Autopsy-controlled studies in Amyotrophic lateral sclerosis (ALS) proposed a 4-stage sequential spreading of the underlying TDP-43 pathology (Brettschneider et al., 2013). Recently the in vivo transfer of the neuropathological stages by use of tract of interest-based diffusion-tensor-imaging (DTI) has been performed (Kassubek et al., 2014). Based upon the DTI findings, we have expanded the imaging approach by complementary investigation of ifc-fMRI in order to trace the pathology spreading in well-defined intrinsic functional connectivity networks (ICNs). Methods: We used a 3.0T resting state-fMRI protocol for 76 ALS patients and 28 healthy controls. The preprocessing followed standardized procedures including motion correction, MNI normalization, spatial filtering, temporal linear detrending and bandpass filtering. ICNs were identified utilizing the seed-based approach (Gorges et al., 2014). These ICNs comprised the motor (neuropathological stage 1), frontoparietal, frontal executive and brainstem
e95
(stage 2), basal ganglia (stage 3), and hippocampal (stage 4) networks; we used the visual ICN as reference. Results: ALS patients compared with healthy controls demonstrated a large-scale pattern of increased functional connectivity (hyperconnectivity) in all networks with the exception of the reference network. More specifically, the hyperconnectivity pattern extended spatially into adjacent brain structures following the neuropathological spreading. The hyperconnectivity in stage 1 extended into frontal areas, in stage 2 into prefrontal and postcentral areas, in stage 3 into prefrontal and postcentral areas, and in stage 4 within the hippocampal formation. Moreover, the disease stages as observed in vivo by DTI significantly correlated with increasing functional connectivity in the ICNs. Conclusion: Ifc-fMRI provides a promising approach to functionally trace pathological spreading in ALS. As recently suggested (Douaud et al., 2011), the loss of the inhibitory influence may be most likely attributable to the pattern of hyperconnectivity in ALS. With increasing stages of disease, hyperconnectivity seems to spread sequentially into more frontal and postcentral regions following the neuropathological spreading. References Brettschneider et al. Ann Neurol 2013;74:20–38. Douaud et al. Brain 2011;134:3470–9. Gorges et al. Biomed Res Int 2014;2014:947252. Kassubek et al. Brain 2014;137:1733–40. doi:10.1016/j.clinph.2015.04.137
P19. The brain’s default mode is associated with executive oculomotor deficits in Parkinson’s disease—M. Gorges, H.-P. Müller, A.C. Ludolph, E. Pinkhardt, J. Kassubek (University of Ulm, Department of Neurology, Ulm, Germany) Introduction: Eye movements provide a valuable window into complex forms of human behavior. Impaired eye movement control in patients with Parkinson’s disease (PD) has been consistently demonstrated besides the well-known motor symptoms (Pinkhardt and Kassubek, 2011). Saccadic intrusions are a common oculomotor manifestation in PD and interrupt smooth pursuit and fixation during tracking a ’jumping’ target (visually guided reactive saccades) (Pinkhardt and Kassubek, 2011; Gorges et al., 2014). The default mode network (DMN) as observed with ’resting-state’ functional MRI is crucially involved in higher cognitive processes such as attention (Buckner et al., 2008). We hypothesized that prevalence of saccadic intrusions in patients with PD reflects executive deficits which are closely associated with intrinsic functional connectivity (iFC) within the DMN. Methods: The analysis was based on 31 patients with PD and 22 age-matched healthy controls. We acquired ’resting-state’ functional MRI (3 Tesla; BOLD-sensitive T2⁄-sequence) and video-oculographic recordings (VOG, Eye-Link I operating on 250 Hz sampling rate) of smooth pursuit eye movements and visually guided reactive saccades. ’Resting-state’ functional MRI analysis followed standardized procedures (Gorges et al., 2014) with the DMN computed by seeding the posterior cingulate cortex (Buckner et al., 2008). The posterior cingulate cortex is known to be both a major node of the DMN (Buckner et al., 2008) and to play a critical role in eye movement control (Olson et al., 1996). Both smooth pursuit gain as a measure for saccadic intrusions and the saccadic intrusion rate during reactive saccades were analyzed in patients vs. controls and correlated with iFC within the DMN. Results: VOG analysis revealed a significantly higher prevalence of saccadic intrusions during smooth pursuit (p < 0.001) and reactive
e96
Society Proceedings / Clinical Neurophysiology 126 (2015) e63–e170
saccades (p < 0.01) in PD patients compared with controls. Covariance analysis between the saccadic intrusion measures and the iFC in the DMN demonstrated significantly negative correlations (p < 0.001 for all clusters, corrected for multiple comparisons) in the sense that reduced iFC in almost all parts of the DMN was related to a higher prevalence of saccadic intrusions. Specifically, iFC between the posterior cingulate cortex and the (i) middle temporal lobe, (ii) thalamus, (iii) MST, (vi) precuneus (v), medial prefrontal cortex, and (vi) parietal lobule were significantly correlated with the saccadic intrusion rates. Conclusions: A high prevalence of saccadic intrusions in patients with PD appears to be closely related to a lack of attention, pointing towards an increased distractibility that might be associated with the neuroimaging correlate of a disrupted DMN. This supports the hypothesis that impaired oculomotor control in PD reflects a behavioral correlate of disturbed higher functions rather than impaired oculomotor circuits in the brainstem. References Buckner et al. Ann N Y Acad Sci 2008;1124:1–38. Gorges et al. J Ophthalmol 2014;2014:658243. Gorges et al. Biomed Res Int 2014;2014:947252. Olson et al. J Neurophysiol 1996;76:3285–300. Pinkhardt, Kassubek. Parkinsonism Relat Disord 2011;17:223–30. doi:10.1016/j.clinph.2015.04.138
P20. Deficit actual tool use in schizophrenia is linked to structural alterations in key regions of planning and executing of tool use and connecting fibers—P. Viher a, K. Stegmayer a, T. Vanbellingen b,c, A. Federspiel a, W. Strik a, R. Wiest d, S.
Bohlhalter b,c, S. Walther a (a University Hospital of Psychiatry, Department of Psychiatric Neurophysiology, Bern, Switzerland, b Inselspital, Department of Clinical Research, Bern, Switzerland, c Luzerner Kantonsspital, Neurology and Neurorehabilitation Center, Luzern, Switzerland, d Inselspital, Support Center of Advanced Neuroimaging (SCAN), University Institute of Diagnostic and Interventional Neuroradiology, Bern, Switzerland) Introduction: Schizophrenia patients frequently suffer from complex motor abnormalities including fine and gross motor disturbances, abnormal involuntary movements, neurological soft signs and parkinsonism. These symptoms occur early in the course of the disease, continue in chronic patients and may deteriorate with antipsychotic medication (Walther and Strik, 2012). Furthermore gesture performance is impaired in patients, including the pantomime of tool use. Whether schizophrenia patients would show difficulties of actual tool use has not yet been investigated. Human tool use is complex and relies on a network of distinct and distant brain areas. We therefore aim to test if schizophrenia patients had difficulties in tool use and to assess associations with structural brain imaging using voxel based morphometry (VBM) and tract based spatial statistics (TBSS). Methods: In total, 44 patients with schizophrenia (DSM-5 criteria; 59% men, mean age 38) underwent structural MR imaging and performed the Tool-Use test (Randerath et al., 2011). The test examines the use of a scoop and a hammer in three conditions: pantomime (without the tool), demonstration (with the tool) and actual use (with a recipient object). T1-weighted images were processed using SPM8 and DTI-data using FSL TBSS routines. To assess structural alterations of impaired tool use we first compared gray matter (GM) volume in VBM and white matter (WM) integrity in TBSS data of patients with and without difficulties of actual tool use. Next we explored correlations of Tool use scores and VBM and TBSS data.
Fig. 1. A Gray matter volume reduction and B reduced white matter associated with deficit tool use in schizophrenia patients.