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News Article | November 6, 2016
Site: www.sciencedaily.com

Philosophers have long struggled to define human consciousness. Now, a team of researchers led by neurologists at Beth Israel Deaconess Medical Center (BIDMC) has pinpointed the regions of the brain that may play a role maintaining it. Their finding were published today in journal Neurology. "For the first time, we have found a connection between the brainstem region involved in arousal and regions involved in awareness, two prerequisites for consciousness," said Michael D. Fox, MD, PhD, Director of the Laboratory for Brain Network Imaging and Modulation and the Associate Director of the Berenson-Allen Center for Noninvasive Brain Stimulation at BIDMC. "A lot of pieces of evidence all came together to point to this network playing a role in human consciousness." Classical neurology holds that arousal and awareness are two critical components of consciousness. Arousal is likely regulated by the brainstem -- the portion of the brain, contiguous with the spinal cord, that is responsible for the sleep/wake cycle and cardiac and respiratory rates. Awareness, another critical component of consciousness, has long been thought to reside somewhere in the cortex, the outer layer of the brain responsible for many of its higher functions. The researchers analyzed 36 patients with brainstem lesions, of which 12 led to coma and 24 did not. Mapping the injuries revealed that a small "coma-specific" area of the brainstem -- the rostral dorsolateral pontine tegmentum -- was significantly associated with coma. Ten out of the 12 coma-inducing brainstem lesions involved this area, while just one of the 24 control lesions did. Armed with that information, Fox and colleagues, including lead author David Fischer, MD, then a medical student at Harvard Medical School, used a wiring diagram of the healthy human brain -- based on a large, shared data set called the Human Connectome -- to identify which other parts of the brain were connected to these coma-causing lesions. Their analysis revealed two areas in the cortex of the brain that were significantly connected to the coma-specific region of the brainstem. One sat in the left, ventral, anterior insula (AI), the other in the pregenual anterior cingulate cortex (pACC). Both regions have been implicated previously in arousal and awareness. "We now have a great map of how the brain is wired up in the Human Connectome," said Fox, who is also an Assistant Professor of Neurology at Harvard Medical School. "We can look at not just the location of lesions, but also their connectivity. Over the past year, researchers in my lab have used this approach to understand visual and auditory hallucinations, impaired speech, and movement disorders. A collaborative team of neuroscientists and physicians had the insight and unique expertise needed to apply this approach to consciousness." The team included co-lead author, Aaron Boes, MD, PhD, and co-senior author, Joel Geerling, MD, PhD, both formerly of BIDMC and now of University of Iowa Carver College of Medicine. Finally, the team investigated whether this brainstem-cortex network was functioning in another subset of patients with disorders of consciousness, including coma. Using a special type of MRI scan, the scientists found that their newly identified "consciousness network" was disrupted in patients with impaired consciousness. The findings -- bolstered by data from rodent studies -- suggest the network between the brainstem and these two cortical regions plays a role maintaining human consciousness. "The added value of thinking about coma as a network disorder is it presents possible targets for therapy, such as using brain stimulation to augment recovery," Boes said. A next step, Fox notes, may be to investigate other data sets in which patients lost consciousness to find out if the same, different or overlapping neural networks are involved. "This is most relevant if we can use these networks as a target for brain stimulation for people with disorders of consciousness," said Fox. "If we zero in on the regions and network involved, can we someday wake someone up who is in a persistent vegetative state? That's the ultimate question." Study coauthors include David B. Fischer, MD, Aaron D. Boes, MD, PhD, Joel C. Geerling, MD, PhD, Clifford B. Saper, MD, PhD, and Alvaro Pascual-Leone, MD, PhD, of BIDMC; Athena Demertzi, PhD, of the Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM), Hôpital Pitié-Salpêtrière, Paris, France and the Coma Science Group, GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Steven Laureys, PhD, also of the Coma Science Group; Henry C. Evrard, PhD, of the Functional and Comparative Neuroanatomy Lab and the Centre for Integrative Neuroscience, Tübingen and the Max Planck Institute for Biological Cybernetics, Tübingen, Germany; Brian L. Edlow, MD, and Hesheng Liu, PhD. of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Charlestown, MA. This work was supported by the Howard Hughes Medical Institute, the Parkinson's Disease Foundation, the NIH (Shared Instrument Grant S10RR023043, K23NS083741, R01HD069776, R01NS073601, R01NS085477, R21MH099196, R21NS082870, R21NS085491, R21HD07616, R25NS065743, R25NS070682, T32 HL007901, P01HL095491), American Academy of Neurology/American Brain Foundation, Sidney R. Baer, Jr. Foundation, Harvard Catalyst, the Belgian National Funds for Scientific Research, the European Commission, the James McDonnell Foundation, the European Space Agency, Mind Science Foundation, the French Speaking Community Concerted Research Action (ARC-06/11-340), the Public Utility Foundation "Université Européenne du Travail," "Fondazione Europea di Ricerca Biomedica," the University and University Hospital of Liège, the Center for Integrative Neuroscience, and the Max Planck Society.


News Article | November 4, 2016
Site: www.eurekalert.org

BOSTON - Philosophers have long struggled to define human consciousness. Now, a team of researchers led by neurologists at Beth Israel Deaconess Medical Center (BIDMC) has pinpointed the regions of the brain that may play a role maintaining it. Their findings, which have already garnered multiple awards from the American Academy of Neurology, were published today in that society's journal, Neurology. "For the first time, we have found a connection between the brainstem region involved in arousal and regions involved in awareness, two prerequisites for consciousness," said Michael D. Fox, MD, PhD, Director of the Laboratory for Brain Network Imaging and Modulation and the Associate Director of the Berenson-Allen Center for Noninvasive Brain Stimulation at BIDMC. "A lot of pieces of evidence all came together to point to this network playing a role in human consciousness." Classical neurology holds that arousal and awareness are two critical components of consciousness. Arousal is likely regulated by the brainstem - the portion of the brain, contiguous with the spinal cord, that is responsible for the sleep/wake cycle and cardiac and respiratory rates. Awareness, another critical component of consciousness, has long been thought to reside somewhere in the cortex, the outer layer of the brain responsible for many of its higher functions. The researchers analyzed 36 patients with brainstem lesions, of which 12 led to coma and 24 did not. Mapping the injuries revealed that a small "coma-specific" area of the brainstem - the rostral dorsolateral pontine tegmentum - was significantly associated with coma. Ten out of the 12 coma-inducing brainstem lesions involved this area, while just one of the 24 control lesions did. Armed with that information, Fox and colleagues, including lead author David Fischer, MD, then a medical student at Harvard Medical School, used a wiring diagram of the healthy human brain - based on a large, shared data set called the Human Connectome - to identify which other parts of the brain were connected to these coma-causing lesions. Their analysis revealed two areas in the cortex of the brain that were significantly connected to the coma-specific region of the brainstem. One sat in the left, ventral, anterior insula (AI), the other in the pregenual anterior cingulate cortex (pACC). Both regions have been implicated previously in arousal and awareness. "We now have a great map of how the brain is wired up in the Human Connectome," said Fox, who is also an Assistant Professor of Neurology at Harvard Medical School. "We can look at not just the location of lesions, but also their connectivity. Over the past year, researchers in my lab have used this approach to understand visual and auditory hallucinations, impaired speech, and movement disorders. A collaborative team of neuroscientists and physicians had the insight and unique expertise needed to apply this approach to consciousness." The team included co-lead author, Aaron Boes, MD, PhD, and co-senior author, Joel Geerling, MD, PhD, both formerly of BIDMC and now of University of Iowa Carver College of Medicine. Finally, the team investigated whether this brainstem-cortex network was functioning in another subset of patients with disorders of consciousness, including coma. Using a special type of MRI scan, the scientists found that their newly identified "consciousness network" was disrupted in patients with impaired consciousness. The findings - bolstered by data from rodent studies - suggest the network between the brainstem and these two cortical regions plays a role maintaining human consciousness. "The added value of thinking about coma as a network disorder is it presents possible targets for therapy, such as using brain stimulation to augment recovery," Boes said. A next step, Fox notes, may be to investigate other data sets in which patients lost consciousness to find out if the same, different or overlapping neural networks are involved. "This is most relevant if we can use these networks as a target for brain stimulation for people with disorders of consciousness," said Fox. "If we zero in on the regions and network involved, can we someday wake someone up who is in a persistent vegetative state? That's the ultimate question." Study coauthors include David B. Fischer, MD, Aaron D. Boes, MD, PhD, Joel C. Geerling, MD, PhD, Clifford B. Saper, MD, PhD, and Alvaro Pascual-Leone, MD, PhD, of BIDMC; Athena Demertzi, PhD, of the Brain and Spine Institute (Institut du Cerveau et de la Moelle épinière-ICM), Hôpital Pitié-Salpêtrière, Paris, France and the Coma Science Group, GIGA-Research & Cyclotron Research Centre, University and University Hospital of Liège, Belgium; Steven Laureys, PhD, also of the Coma Science Group; Henry C. Evrard, PhD, of the Functional and Comparative Neuroanatomy Lab and the Centre for Integrative Neuroscience, Tübingen and the Max Planck Institute for Biological Cybernetics, Tübingen, Germany; Brian L. Edlow, MD, and Hesheng Liu, PhD. of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Charlestown, MA. This work was supported by the Howard Hughes Medical Institute, the Parkinson's Disease Foundation, the NIH (Shared Instrument Grant S10RR023043, K23NS083741, R01HD069776, R01NS073601, R01NS085477, R21MH099196, R21NS082870, R21NS085491, R21HD07616, R25NS065743, R25NS070682, T32 HL007901, P01HL095491), American Academy of Neurology/American Brain Foundation, Sidney R. Baer, Jr. Foundation, Harvard Catalyst, the Belgian National Funds for Scientific Research, the European Commission, the James McDonnell Foundation, the European Space Agency, Mind Science Foundation, the French Speaking Community Concerted Research Action (ARC-06/11-340), the Public Utility Foundation "Université Européenne du Travail," "Fondazione Europea di Ricerca Biomedica," the University and University Hospital of Liège, the Center for Integrative Neuroscience, and the Max Planck Society. Beth Israel Deaconess Medical Center is a patient care, teaching and research affiliate of Harvard Medical School and consistently ranks as a national leader among independent hospitals in National Institutes of Health funding. BIDMC is in the community with Beth Israel Deaconess Hospital-Milton, Beth Israel Deaconess Hospital-Needham, Beth Israel Deaconess Hospital-Plymouth, Anna Jaques Hospital, Cambridge Health Alliance, Lawrence General Hospital, MetroWest Medical Center, Signature Healthcare, Beth Israel Deaconess HealthCare, Community Care Alliance and Atrius Health. BIDMC is also clinically affiliated with the Joslin Diabetes Center and Hebrew Rehabilitation Center and is a research partner of Dana-Farber/Harvard Cancer Center and the Jackson Laboratory. BIDMC is the official hospital of the Boston Red Sox. For more information, visit http://www. .


Qi Y.,Center for Integrative Neuroscience | Andolfi L.,CNR Institute of Materials | Frattini F.,Center for Integrative Neuroscience | Mayer F.,Center for Integrative Neuroscience | And 2 more authors.
Nature Communications | Year: 2015

Sensing force is crucial to maintain the viability of all living cells. Despite its fundamental importance, how force is sensed at the molecular level remains largely unknown. Here we show that stomatin-like protein-3 (STOML3) controls membrane mechanics by binding cholesterol and thus facilitates force transfer and tunes the sensitivity of mechano-gated channels, including Piezo channels. STOML3 is detected in cholesterol-rich lipid rafts. In mouse sensory neurons, depletion of cholesterol and deficiency of STOML3 similarly and interdependently attenuate mechanosensitivity while modulating membrane mechanics. In heterologous systems, intact STOML3 is required to maintain membrane mechanics to sensitize Piezo1 and Piezo2 channels. In C57BL/6N, but not STOML3 a '/a' mice, tactile allodynia is attenuated by cholesterol depletion, suggesting that membrane stiffening by STOML3 is essential for mechanical sensitivity. Targeting the STOML3-cholesterol association might offer an alternative strategy for control of chronic pain. © 2015 Macmillan Publishers Limited. All rights reserved.


PubMed | Center for Integrative Neuroscience, Ecole Polytechnique Federale de Lausanne, National Research Council Italy, CNR Institute of Materials and 2 more.
Type: | Journal: eLife | Year: 2016

At its most fundamental level, touch sensation requires the translation of mechanical energy into mechanosensitive ion channel opening, thereby generating electro-chemical signals. Our understanding of this process, especially how the cytoskeleton influences it, remains unknown. Here we demonstrate that mice lacking the -tubulin acetyltransferase Atat1 in sensory neurons display profound deficits in their ability to detect mechanical stimuli. We show that all cutaneous afferent subtypes, including nociceptors have strongly reduced mechanosensitivity upon Atat1 deletion, and that consequently, mice are largely insensitive to mechanical touch and pain. We establish that this broad loss of mechanosensitivity is dependent upon the acetyltransferase activity of Atat1, which when absent leads to a decrease in cellular elasticity. By mimicking -tubulin acetylation genetically, we show both cellular rigidity and mechanosensitivity can be restored in Atat1 deficient sensory neurons. Hence, our results indicate that by influencing cellular stiffness, -tubulin acetylation sets the force required for touch.


Chen J.T.-C.,Center for Integrative Neuroscience | Guo D.,Center for Integrative Neuroscience | Campanelli D.,Center for Integrative Neuroscience | Campanelli D.,Hearing Research Center | And 7 more authors.
Nature Communications | Year: 2014

The gate control theory proposes the importance of both pre- and post-synaptic inhibition in processing pain signal in the spinal cord. However, although postsynaptic disinhibition caused by brain-derived neurotrophic factor (BDNF) has been proved as a crucial mechanism underlying neuropathic pain, the function of presynaptic inhibition in acute and neuropathic pain remains elusive. Here we show that a transient shift in the reversal potential (E GABA) together with a decline in the conductance of presynaptic GABA A receptor result in a reduction of presynaptic inhibition after nerve injury. BDNF mimics, whereas blockade of BDNF signalling reverses, the alteration in GABA A receptor function and the neuropathic pain syndrome. Finally, genetic disruption of presynaptic inhibition leads to spontaneous development of behavioural hypersensitivity, which cannot be further sensitized by nerve lesions or BDNF. Our results reveal a novel effect of BDNF on presynaptic GABAergic inhibition after nerve injury and may represent new strategy for treating neuropathic pain. © 2014 Macmillan Publishers Limited. All rights reserved.


Piryankova I.V.,Max Planck Institute for Biological Cybernetics | Piryankova I.V.,Center for Integrative Neuroscience | De La Rosa S.,Max Planck Institute for Biological Cybernetics | Kloos U.,Reutlingen University | And 3 more authors.
Displays | Year: 2013

Many scientists have demonstrated that compared to the real world egocentric distances in head-mounted display virtual environments are underestimated. However, distance perception in large screen immersive displays has received less attention. We investigate egocentric distance perception in a virtual office room projected using a semi-spherical, a Max Planck Institute CyberMotion Simulator cabin and a flat large screen immersive display. The goal of our research is to systematically investigate distance perception in large screen immersive displays with commonly used technical specifications. We specifically investigate the role of distance to the target, stereoscopic projection and motion parallax on distance perception. We use verbal reports and blind walking as response measures for the real world experiment. Due to the limited space in the three large screen immersive displays we use only verbal reports as the response measure for the experiments in the virtual environment. Our results show an overall underestimation of distance perception in the large screen immersive displays, while verbal estimates of distances are nearly veridical in the real world. We find that even when providing motion parallax and stereoscopic depth cues to the observer in the flat large screen immersive display, participants estimate the distances to be smaller than intended. Although stereo cues in the flat large screen immersive display do increase distance estimates for the nearest distance, the impact of the stereoscopic depth cues is not enough to result in veridical distance perception. Further, we demonstrate that the distance to the target significantly influences the percent error of verbal estimates in both the real and virtual world. The impact of the distance to the target on the distance judgments is the same in the real world and in two of the used large screen displays, namely, the MPI CyberMotion Simulator cabin and the flat displays. However, in the semi-spherical display we observe a significantly different influence of distance to the target on verbal estimates of egocentric distances. Finally, we discuss potential reasons for our results. Based on the findings from our research we give general suggestions that could serve as methods for improving the LSIDs in terms of the accuracy of depth perception and suggest methods to compensate for the underestimation of verbal distance estimates in large screen immersive displays. © 2013 Elsevier B.V. All rights reserved.


Hu J.,Molecular Physiology of Somatic Sensation | Hu J.,Center for Integrative Neuroscience | Chiang L.-Y.,Molecular Physiology of Somatic Sensation | Koch M.,University of Cologne | Lewin G.R.,Molecular Physiology of Somatic Sensation
EMBO Journal | Year: 2010

The gating of ion channels by mechanical force underlies the sense of touch and pain. The mode of gating of mechanosensitive ion channels in vertebrate touch receptors is unknown. Here we show that the presence of a protein link is necessary for the gating of mechanosensitive currents in all low-threshold mechanoreceptors and some nociceptors of the dorsal root ganglia (DRG). Using TEM, we demonstrate that a protein filament with of length 100 nm is synthesized by sensory neurons and may link mechanosensitive ion channels in sensory neurons to the extracellular matrix. Brief treatment of sensory neurons with non-specific and site-specific endopeptidases destroys the protein tether and abolishes mechanosensitive currents in sensory neurons without affecting electrical excitability. Protease-sensitive tethers are also required for touch-receptor function in vivo. Thus, unlike the majority of nociceptors, cutaneous mechanoreceptors require a distinct protein tether to transduce mechanical stimuli. © 2010 European Molecular Biology Organization.


Synofzik M.,University of Tübingen | Synofzik M.,German Center for Neurodegenerative Diseases | Ilg W.,Hertie Institute for Clinical Brain Research | Ilg W.,Center for Integrative Neuroscience
BioMed Research International | Year: 2014

The cerebellum is essentially involved in movement control and plays a critical role in motor learning. It has remained controversial whether patients with degenerative cerebellar disease benefit from high-intensity coordinative training. Moreover, it remains unclear by which training methods and mechanisms these patients might improve their motor performance. Here, we review evidence from different high-intensity training studies in patients with degenerative spinocerebellar disease. These studies demonstrate that high-intensity coordinative training might lead to a significant benefit in patients with degenerative ataxia. This training might be based either on physiotherapy or on whole-body controlled videogames ("exergames"). The benefit shown in these studies is equal to regaining one or more years of natural disease progression. In addition, first case studies indicate that even subjects with advanced neurodegeneration might benefit from such training programs. For both types of training, the observed clinical improvements are paralleled by recoveries in ataxia-specific dysfunctions (e.g., multijoint coordination and dynamic stability). Importantly, for both types of training, the retention of the effects seems to depend on the frequency and continuity of training. Based on these studies, we here present preliminary recommendations for clinical practice, and articulate open questions that might guide future studies on neurorehabilitation in degenerative spinocerebellar disease. © 2014 Matthis Synofzik and Winfried Ilg.


Ilg W.,Hertie Institute for Clinical Brain Research | Ilg W.,Center for Integrative Neuroscience | Schatton C.,Hertie Institute for Clinical Brain Research | Schatton C.,Center for Integrative Neuroscience | And 8 more authors.
Neurology | Year: 2012

Objective: Degenerative ataxias in children present a rare condition where effective treatments are lacking. Intensive coordinative training based on physiotherapeutic exercises improves degenerative ataxia in adults, but such exercises have drawbacks for children, often including a lack of motivation for high-frequent physiotherapy. Recently developed whole-body controlled video game technology might present a novel treatment strategy for highly interactive and motivational coordinative training for children with degenerative ataxias. Methods: We examined the effectiveness of an 8-week coordinative training for 10 children with progressive spinocerebellar ataxia. Training was based on 3 Microsoft Xbox Kinect video games particularly suitable to exercise whole-body coordination and dynamic balance. Training was started with a laboratory-based 2-week training phase and followed by 6 weeks training in children's home environment. Rater-blinded assessments were performed 2 weeks before laboratorybased training, immediately prior to and after the laboratory-based training period, as well as after home training. These assessments allowed for an intraindividual control design, where performance changes with and without training were compared. Results: Ataxia symptoms were significantly reduced (decrease in Scale for the Assessment and Rating of Ataxia score, p = 0.0078) and balance capacities improved (dynamic gait index, p = 0.04) after intervention. Quantitative movement analysis revealed improvements in gait (lateral sway: p = 0.01; step length variability: p = 0.01) and in goal-directed leg placement (p 5 0.03). Conclusions: Despite progressive cerebellar degeneration, children are able to improvemotor performance by intensive coordination training. Directed training of whole-body controlled video games might present a highly motivational, cost-efficient, and home-based rehabilitation strategy to train dynamic balance and interaction with dynamic environments in a large variety of youngonset neurologic conditions. Classification of evidence: This study provides Class III evidence that directed training with Xbox Kinect video games can improve several signs of ataxia in adolescents with progressive ataxia as measured by SARA score, Dynamic Gait Index, and Activity-specific Balance Confidence Scale at 8 weeks of training. © 2012 American Academy of Neurology.


Theis L.,Center for Integrative Neuroscience | Hoffman M.D.,Adobe Systems
32nd International Conference on Machine Learning, ICML 2015 | Year: 2015

Stochastic variational inference allows for fast posterior inference in complex Bayesian models. However, the algorithm is prone to local optima which can make the quality of the posterior approximation sensitive to the choice of hyperparameters and initialization. We address this problem by replacing the natural gradient step of stochastic varitional inference with a trust-region update. We show that this leads to generally better results and reduced sensitivity to hyperparameters. We also describe a new strategy for variational inference on streaming data and show that here our trust-region method is crucial for getting good performance. © Copyright 2015 by International Machine Learning Society (IMLS). All rights reserved.

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