Downloaded 17 times
More Related Content
Neuro circuit
- 1.
- 2. Overview • Introduction • History •Importance • Basics of Neuro Circuits • Default mode Network • Salience Network • Neuro circuits of psychiatric illness • Latest Researches • Summery • Take Home Message • References
- 3. Introduction • A neuralcircuit is a population of neurons interconnected by synapses to carry out a specific function when activated.* • Interconnected to form large scale brain network • Basic kind of connections between neurons are synapses are chemical and electrical synapses * Purves, Dale (2011). Neuroscience (5th ed.). Sunderland, Mass.: Sinauer. p. 507. `
- 4. Why it wasimportant? • The practice of human cadaveric dissection during its inception in ancient Greece in 3rd century BC • Italy at the beginning of 14th century and subsequent evolution in Europe and the United States of America over the centuries. • Microscopic examinations ( Around 1620 Europe ) –Striking resemblance in structural motifs in animal to animal • Most of the diseases found to have some molecular / biochemical basis • For brain treatment is based on complaints/behaviour. • Equivalent motifs unknown
- 5. Challenges Vast array ofcell types
- 6. Knowing about onepart is not enough
- 7.
- 8. Challanges •Complex structure andfunction of nervous system GENE STRUCTURE FUNCTION
- 9. Gene –Structure -Function
- 10. Challanges •Complex structure andfunction of nervous system GENE STRUCTURE FUNCTION
- 11. Challanges •Complex structure andfunction of nervous system GENE STRUCTURE FUNCTION Experiences
- 12. H Sapiens IrisOrtoria • Slow development • Experience based neural development • Obligate learner • Culture based behavior
- 13. What we arelooking for Map out the atomic structure at a resolution at which they function • To determine • Etiology • Pathogenesis • Course • Treatment • Prognosis
- 14. History • Golgi's methodis a silver staining technique that is used to visualize nervous tissue under light microscopy. • The method was discovered by Camillo Golgi, an Italian physician and scientis t, who published the first picture made with the technique in 1873.
- 15. History • Santiago Ramóny Cajal was a Spanish neuroscientist, path ologist, and histologist specializing in neuroanatomy . • Camillo Golgi received the Nobel Prize in Physiology or Medicine in 1906.
- 16.
- 17. History • Brodmann areaswere originally defined and numbered by the German anatomist Korbinian Brodmann • Based on the cytoarchitectural organization of neurons he observed in the cerebral cortex using the Nissl method of cell staining. • Brodmann published his maps of cortical areas in humans, monkeys, and other species in 1909
- 18. Concept of Connectomics •Branch of biotechnology • Computer assisted image acquisition and analysis • Structural mapping of sets of neural circuits or complete organism • Using high speed methods and organizing the results in Database • Application of dada base in neurology, psychiatry or fundamental neurosciences ** Kasthuri, N. & Lichtman, J. W. The role of neuronal identity in synaptic competition. Nature 424, 426–430 (2003).
- 19. The Pioneer workby Cajal • Gave the basic concept • Sparse network • Black & White • Difficult to trace • Inadequate information • Could not explain the detailed structure
- 20. YFP-16 Transgenic mouseNeural Structures
- 21. Labelling Neural Architecturewith Fluorescent Proteins
- 22. Labelling Neural Architecturewith Fluorescent Proteins (BRAIN BOW)
- 24. Decreased Convergence with compensatorysynaptic takeover
- 25. Concept of CircuitRecognition
- 26.
- 28.
- 29.
- 30.
- 31. In situ SynapticAchitecture
- 32. In situ SynapticArchitecture
- 33. In situ SynapticArchitecture 1 2 3
- 34. Challenges Of theStudy
- 35. Neuro-imaging • Historically functionalneuro imaging works were focused on 1. SPECT /PET 2. f MRI • Indirect estimation of neural activity through the measurement of 1.Oxygen Metabolism- PET 2.Blood flow- SPECT 3.Blood oxygen level dependent activity- BOLD-f MRI
- 36. F-MRI studies Convert Convert measuredRF data to image Receive Receive radio waves re transmitted by subject Turn off Turn off radio wave transmitter Transmit Transmit radio waves into subject (2-10 ms) Put Put subject in big magnetic field
- 37. Neuro-imaging • Primarily TASKBASED studies were done- PET / fMRI • To assess diffential activation of brain regions during • Cognitive • Affective • Social task • Ambition was to develop testing hypothesis • By seeing abnormal BOLD activity • Identify probable regions effected in different manifestations of mental illness
- 38. Neuro-imaging DLPFC Amygda la Insula Stiatum Depression Cognitive dysfunction in psychosis AnxietyDisorder Addictive Disorder
- 39. Later Understanding • Rarelydoes one specific activity activity activates any specific brain region • Rarely particular psychopathology associated with abnormal activation only a single brain region • Both Input and Output changes the activity of brain region
- 40. Change in thefocus of the study Specific Brain Region Neural Circuit
- 41. Later Understanding Normal Relationshipbetween the brain regions Successful cognitive and affective functioning
- 42. Not Regions butConnections DLPFC SCHIZOPHRENIA Input Output Cognitive Control task ! Abnormality in the DLPFC
- 43. Advent Of StudyingFunctional Connectivity • The Main inference of functional connectivity is • If two regions have high correlated neuronal activity • Then they are more likely to engage in a common set of processing mechanism • May provide a tool for understanding the brain regions • Different areas and circuit for cognitive and effective demands • Cognitive/emotional /social processing
- 44. Resting State FunctionalConnectivity • A major breakthrough in 1995 ( Biswal et al) • Spontaneous activity from regions in the Right &Left motor cortices at resting state • This was suggestive of functional connectivity between these brain regions • Spontaneous low frequency fluctuations of the BOLD signal (0.01 to .010 Hz) • These signals were previously discarded as noise in task-based studies • This resting state activity consumes a major portion of body’s energy ( aprox 20%) • Robust studies demonstrated that the fluctuations in brain activity are coherent
- 45. Resting State FunctionalConnectivity Networks • Resting state functional connectivity revealed • Intrinsically organized networks of brain regions that are consistently functionally connected. • Present even in the absence of task induced perturbations in ongoing brain activity • Default Mode Network • Fronto-Parietal Network • Cingulo-Opercular Network • Dorsal Attention Network
- 46. Resting State FunctionalConnectivity Networks • In a recent study, 356 regions (Parcels) with homogenous activity, at resting state were identified • They grouped into 12 resting state network that map nicely to networks identified in previous resting state study • These maps closely /partially matches with the maps identified task-based studies
- 47. Resting State Network •Mapping of resting state network to known task networks led to the following hypothesis • Resting State Network reflect in part organized interactions that arise from a history of coactivation over development • Not Dependent on Task Performance • Present even at rest • Relatively consistent across tasks and environmental states • These are referred as “intrinsic connectivity network”
- 48.
- 49. Human Connectome Project •5 years Project • Sponsored by National Institute of Health • Launched in July 2009 • University of Southern California and 6 other universities participating in the study • Goal- Is to build up a “Network Map” (Connectome) • Which will shed light on anatomical and functional connectivity within healthy human brain • Produce a body of DATA which will facilitate research into brain disorders • Dyslexia • Autism • Alzheimer’s Disease • Schizophrenia
- 50. Human Connectome Project •Wu Minn Oxford Consortium • Developed improved MRI machine , image acquisition and image analysis methods for mapping the connectivity • Collected behavioral and MRI DATA of 1200 healthy individuals • Twin pairs and their siblings from 300 families • Used 3 Tesla MRI machine (Also took 184 subjects scan using 7 Tesla MRI) • Understanding anatomical & functional connection of brain region • Related to behavioral DATA / Genetic DATA (From Identical Twins)
- 51. Human Connectome Project •Wu Minn Oxford Consortium • Understanding relative contribution of Genes and environment in shaping brain circuitry • Pinpoint relevant genetic variation • Methods: • Resting state fMRI • Task based f MRI • MEG • Diffuse Tensor Imaging
- 52. Human Connectome Project •Wu Minn Oxford Consortium • Mapping connectomes in macroscale • Large brain system divided in anatomical and functionally distinct areas • Not mapping individual neurons • Data available in public domain as open accessible neuro-formatics platform
- 53. Human Connectome Project •MGH/ Harvard- UCLA Consortium • Work on spatial resolution of Diffusion MRI for brain mapping • Diffusion MRI is employed to map brain’s fibrous long-distance connections by tracking motion of water • Water diffusion pattern in different types of cells allow detection of different types of tissues • To understand relationship between brain connectivity and behavior • Neurological & behavioral functions measured by NIH toolbox (Cognition/sensation/Motor/Emotions)
- 54. Human Connectome Project •MGH/ Harvard- UCLA Consortium • The Study fall into 3 categories • Healthy adult connectomes • Life span connectome DATA • Connectomes related to human diseases
- 55. Human Connectome Project •The results of the project confirmed and extended the current knowledge about • The critical relationship between individual variations in functional brain connectivity • Individual variation in a range of behaviors relevant to mental health and both negative and positive outcome.
- 56. Most Commonly IdentifiedRelevant Networks • Cingulo-Opercular Network• Fronto Parietal Network DLPFC Parietal Cortex Dorsal Anterior Cingulate cortex Thaluma s Anterior prefrontal cortex Dorsal Anterior insula
- 57. • Cingulo-Opercular Network •Fronto Parietal Network DLPFC Pariet al Cortex Dorsal Anterior Cingulate cortex Thalum as Anterior prefrontal cortex Dorsal Anterior insula Anomalies seen in these networks: • Schizophrenia-cognition • Mood Disorder- emotional contro
- 58. Dorsal Attention Network DLPFC ParietalCortex Eye Field Area Dorsal Supplementary Motor Area
- 59. Dorsal Attention Network DLPFC ParietalCortex Eye Field Area Dorsal Supplementary Motor Area
- 60. Dorsal Attention Network DLPFC ParietalCortex Eye Field Area Dorsal Supplementary Motor Area
- 61. Dorsal Attention Network DLPFC ParietalCortex Eye Field Area Dorsal Supplementary Motor Area Top-down guided voluntary allocation of attention
- 62. Ventral Attention Network Temporo- Parietal Junction VLPFCSalient event in the environment
- 63. Dorsal And VentralAttention Network on f MRI • Dorsal fronto parietal system was proposed to mediate the top down guided voluntary allocation of attention to location or features • Ventral fronto parietal system was assumed to be involved in detecting unattended or unexpected stimuli triggering shift of attention **Simone Vossel, Joy J. Geng, Gereon R. Fink, Neuroscientist. 2014 Apr; 20(2): 150–159
- 64. Default Mode Network Medial Prefrontal Cortex Medial Posterior Cingulate Cortex Precuneus •The default mode network (DMN) is active when a person is not focused on the outside world • Brain is at wakeful rest, such as during daydreaming and mind-wandering. • Thinking about others, thinking about themselves, remembering the past, and planning. • The network activates “by default” when a person is not involved in a task.
- 65.
- 66. Salience Network • Thesalience network (SN) is a large-scale brain network of the human brain • Aanterior insula (AI) and • Dorsal anterior cingulate cortex (dACC). • It is involved in detecting and filtering salient stimuli, as well as in recruiting relevant functional networks. • Contributes to communication, social behaviour, and self-awareness through the integration of sensory, emotional, and cognitive information
- 67. Methods For AnalysingResting State Functional Connectivity • Region of Interest or a priori network based analysis • Seed /ROI to whole brain connectivity analysis • Independent Component analysis
- 68. Functional Connectivity Abnormalitiesin Schizophrenia • More than 200 studies done • Functional connectivity in schizhophrenia spectrum Disorder (as DSM IV) • Altered thalamic connectivity • Among multiple hypotheses , Andersen et al , suggested that schizophrenia involves a disruption in the integration of cortical - sub cortical – cerebellar circuits • Hypotheses termed as “Cognitive Dysmetria”
- 69. Functional Connectivity Abnormalitiesin Schizophrenia • Large body of studies shown connectivity • Bilateral thalamic region (Medial Dorsal &Anterior neclei) • Bilateral DLPFC • Dorsal Anterior Cingulate Cortex (dACC) • Parts of striatum • Bilateral cerebellum
- 70. Functional Connectivity Abnormalities in Schizophrenia • Reducedthalamic connectivity (Depicted in Blue) 1. Bilateral prefrontal and parietal cortex 2. ACC 3. Bilateral Stiatum and Cerebellum
- 71. Functional Connectivity Abnormalities in Schizophrenia • Increasedthalamic connectivity (Depicted in Red) 1. Motor Cortex 2. Somatosensory cortex 3. Visual cortex
- 72. Functional Connectivity Abnormalitiesin Schizophrenia • Similar pattern of altered connectivity is seen in individuals at clinical and genetic risk for schizophrenia • Other disorders characterized by psychosis as Bipolar Disorder • The pattern of altered thalamic connectivity are most pronounced among those who subsequently converted to full blown psychosis • Importantly , reduced connectivity between thalamus and DLPFC predicts cognitive impairment • Thalamic connectivity is a potential bio marker for risk of psychosis • Along with increased presynaptic dopamine availability in the striatum • Altered glutamate levels in the thalamus
- 73. Schizophrenia-Altered Default Mode Connectivity •One of the major functions ascribes to the default mode network is attention to internal emotional states • A number of researches hypothesized that the attention to internal states must be dampened when individuals need to engage in specific tasks or attend to external world • It was hypothesized that in schizophrenia enhanced attention to internal thoughts , feelings and experiences, , due to altered connectivity as well as activity of the Default Mode Network • It has been Hypothesized that a failure to suppress default mode network activity during cognitive task performance leading to disruptive cognitive function in schizophrenia
- 74. Schizophrenia-Altered Default Mode Connectivity •The empirical literature on abnormalities in default mode network connectivity is quite mixed (Narr et al) • Evidence of Hyper-connectivity and Hypo-connectivity both are present • One of the challenges in this literature may be that many of the studies focused on comparing individuals with schizophrenia, regardless of symptom profile to healthy controls • Results found to be variable with the same diagnosis and across time in the same individuals • It may be critical to examine default mode connectivity in relationship to variation in the severity of specific symptoms (eg. Hallucination, delusion and cognitive impairment)
- 75. Graph Theory Analysisof Functional Brain Connectivity in Schizophrenia • Individuals with schizophrenia show reduction in both global and local efficiency, particularly when examining specific networks • Most reduced global/local efficiency tend to involve the anterior cingulate and cingula • Cingulo-opercular network • Fronto-parietal network • These findings are backed by ROI based and ICA based analysis • Impaired cognition and reduction in global and local connectivity are consistent finding in patients with schizophrenia.
- 76. Graph Theory Analysisof Functional Brain Connectivity in Schizophrenia • Individuals with schizophrenia show reductions in both global and local efficiency • Specially “Hub” regions in the brain, which are highly interconnected • Individuals with schizophrenia show significant reductions in the connections among hubs eg • insula, • superior frontal cortex, • precuneus, • superior parietal lobe • They do not show reduction in connection between these hub regions and non hub regions
- 77. Graph Theory Analysisof Functional Brain Connectivity in Schizophrenia
- 78. Graph Theory Analysisof Functional Brain Connectivity in Schizophrenia Loss of connectivity in between ” Hubs”
- 79. Summery of SchizophreniaFunctional Connectivity Literature • Reduced thalamic connectivity with frontal, cingulate, striatal and cerebellar region • Reduced global and local efficiency in fronto-parietal, cingulo-opercular networks • Reduced Connectivity in HUB regions. • Large scale dysconnectivity may result reduced efficiency in information transfer, causing cognitive impairment • These impairments are present at the start or even before start of the illness • More prominent among those who develop full blown psychosis
- 80. Functional Connectivity Abnormalities InMajor Depression • Amygdala Connectivity and Emotional Regulation • Fear Conditioning • Threat sensitivity • General response to salient events in the environment
- 81. Amygdala and earlylife experience Poverty Stress trauma Amygdal a Development Functioning Structure
- 82. Amygdala Positive AndNegative Functional Connectivity DMPFC dACC Amygdala VMPFC Hippocampu s
- 83. Amygdala Positive AndNegative Functional Connectivity DLPFC dACC VMPFC Hippocampu s Amygdala
- 84. Amygdala Positive AndNegative Functional Connectivity DLPFC dACC Amygdala VMPFC Hippocampu s PositiveNegetive Important for effective emotion regulation
- 85. Amygdala Positive AndNegative Functional Connectivity DLPFC dACC VMPFC Hippocampu s Negetive Important for effective emotion regulation
- 86. Amygdala Positive FunctionalConnectivity • Amygdala shows positive and negative connections with other regions of the brain • Positive resting state functional connectivity • Hippocampus • Ventral Medial Prefrontal cortex • Amygdala also found to couple with other regions of salience network • Ventral anterior cingulate cortex • Ventral region Insula • Anterior Temporal Poles • Responsible for emotion and stress response
- 87. Amygdala Negative FunctionalConnectivity • Negative resting state functional connectivity (Anti correlations) • Parietal Region • Dorsal Prefrontal cortex • Dorsal Anterior Cingulate • Amygdala also found to couple with other regions of salience network • Ventral anterior cingulate cortex • Ventral region Insula • Anterior Temporal Poles • Responsible for emotion and stress response
- 88. Implication in DepressiveDisorder • These anti-correlations are thought to indicate top down regulation of emotion and stress responsivity • This suggest a critical role for integrity of these connections between amygdala and fronto-parietal and cingulo-opercular network in mood and effective functioning • Early life stress/ maternal deprivation results altered connectivity between amygdala/ VMPFC/ Anterior Cingulate cortex important for effective emotion regulation • Altered amygdala connectivity has been found with these regions and with components of Salience network /Fronto-Parietal/Cingulo-opercular network in MDD
- 89. Implication in DepressiveDisorder • One hypothesis states that reduced amygdala to prefrontal / Cingulate connectivity reflects impaired top down regulation of emotion processing • This contributes to psychopathology • These pattern of altered connectivity have been found across the life span /at risk groups • Connectivity disruption precedes the onset of manifest illness
- 90. Default Mode NetworkConnectivity and Rumination • Consistent findings of altered connectivity associated with major depressive disorder in the domain of Default Mode Network (DMN) • DMN modulate attention to internal emotional state and govern self referential processing • Phenomenologically in MDD the following are seen • Preoccupation with negative mood • Negative self evaluation • Ruminative style of coping with negative events Increase connectivity among Default Mode Network regions and Salience Network regions
- 91. Default Mode NetworkConnectivity and MDD Increase connectivity among Default Mode Network regions and Salience Network regions Over activity of DMN+ Salience Network = Negative evaluation of salient events Negative Mood & Negative self evaluation
- 92. Default Mode NetworkConnectivity and MDD • Increased connectivity between (In MDD) • Sub Genual Prefrontal Cortex • Default Mode Network • Responsible for • Behavioral withdrawal • Negative effective appraisal • Experiencing Guilt • Promoting safety oriented behaviour
- 93. Conclusion • Brief overviewof the current state of field in Human Functional Connectome • Functional Connection abnormalities relevant for understanding pathophysiology of Major Mental Illness • Due to the advancement of imaging technologies multiple Functional Brain Networks has been identified • Human connectome Project confirmed individual variations in the intrinsic network connectivity responsible for positive and negative traits • Robust evidences demonstrated altered thalamic connectivity connectivity associated with psychosis • In MDD altered amygdala to prefrontal –cingulate connectivity relevant for understanding emotional regulation • In MDD increased default mode connectivity implicated in increased rumination
- 94. References • Kaplan andSaddock Comprehensive Text Book Of Psychiatry 10th Edition
Editor's Notes
- #21 Fluorescent protein from Jelly Fish
- #23 Promontory Gene Identified (CRE-cause recombination)
- #49 5 years Project Sponsored by National Institute of Health Launched in July 2009 University of Southern California and 6 other universities participating in the study Goal- Is to build up a “Network Map” (Connectome) Which will shed light on anatomical and functional connectivity within healthy human brain Produce a body of DATA which will facilitate research into brain disorders Dyslexia Autism Alzheimer’s Disease Schizophrenia