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1. Presenter: Dr. Amrindar Jeet Kour JR 2 Psychiatry AFMC, Pune Moderator: Col V S Chauhan Prof (Psychiatry) AFMC, Pune Functional Neural Networks

2. Overview Introduction History Functional neural networks Implication in Psychiatric disorders 2 Other networks Therapeutic implication Future aspects Summary Take home message

3. Introduction H uman brain 100 billion (10 11 ) neurons 100 trillion (10 14 ) synapses B rain functions are determined N ot only by a single neuron or a single brain region independently A lso b y C lusters of neurons N eural circuits within a function block Gr oup of interactions between brain regions 3 F. A. C. Azevedo, L. R. B. Carvalho, L. T. Grinberg et al., “Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain,” Journal of Comparative Neurology,vol.513, p532,2009.

4. Introduction Specific regions of brain are specialized for different functions Role of particular brain region in production of specific behaviors cannot be viewed in isolation Speech a complex faculty Role to be considered within context of neural circuits connecting neurons with other brain regions 4 Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17.

5. History 1943 , Warren Mcculloch and Walter Pitts describe how neurons in the brain work M odeled a simple neural network using electrical circuits 1949, Donald Hebb wrote  The Organization of Behavior N eural pathways are strengthened each time they are used 1950's, simulation of hypothetical neural network by Nathanial Rochester 5

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7. Functional neural networks Gordon EM, Laumann TO, Adeyemo B, Huckins JF, Kelley WM, Petersen SE. Generation and evaluation of a cortical area parcellation from resting-state correlations. Cereb Cortex. 2016;26(1):288–303 7

8. Default mode network 8 McCormick, E.M., Telzer , E.H. Contributions of default mode network stability and deactivation to adolescent task engagement.  Sci Rep   8,  18049 (2018).

9. 9 Default mode network

10. Default Mode Network: Functions N eurological basis for the self: Autobiographical information :  Memories of collection of events and facts about one's self Self-reference :  Referring to traits and descriptions of one's self Remembering the past and thinking about the future : Remembering the past :  Recalling events that happened in the past Imagining the future :  Envisioning events that might happen in the future 10 Andrews-Hanna JR. The brain’s default network and its adaptive role in internal mentation. The Neuroscientist. 2012 Jun;18(3):251-70 .

11. Default Mode Network: Functions Thinking about others: Theory of mind :  Thinking about the thoughts of others and what they might or might not know Emotions of other :  Understanding the emotions of other people and empathizing with their feelings Moral reasoning :  Determining just and unjust result of an action Social evaluations :  Good-bad attitude judgments about social concepts 11 Andrews-Hanna JR. The brain’s default network and its adaptive role in internal mentation. The Neuroscientist. 2012 Jun;18(3):251-70.

12. Default mode Network: Task related behavior Down-regulated in order to perform goal-directed behaviours. Default Mode N etwork shows marked suppression during task engagement visual attention or cognitive tasks T hus network labelled as   task negative network A ctivation in DMN regions : inverse relationship with “task-active” regions 12 Andrews-Hanna JR. The brain’s default network and its adaptive role in internal mentation. The Neuroscientist. 2012 Jun;18(3):251-70.

13. Central Executive Network: Anatomy Network gets activated during functional MRI tasks T erm equivalent to the frontoparietal network 13 D orsolateral prefrontal cortex P osterior parietal cortex Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17.

14. E xecutive functions T ask s which need cognitive control and working memory T arget -directed activities C ontrol of intellectual activities Activ e during task condition Exhibits a nticorrelated network during resting condition 14 Central Executive Network: Function Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17.

15. Salience network Anatomy Dorsal anterior cingulate cortex Bilateral insula Presupplementary motor area 15 Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17 .

16. Salience network: Functions S witching between other large-scale networks to facilitate access to attention and working memory resources when a salient event occurs S trong functional coupling with Anterior Cingulate cortex to facilitate rapid access to motor system 16 Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17.

17. Switching in Functional networks 17 Bressler SL, Menon V. Large-scale brain networks in cognition: emerging methods and principles. Trends in cognitive sciences. 2018 Jun 1;14(6):277-90.

18. Psychiatric disorders 18

19. Substance use disorder 19 Zhang R, Volkow ND. Brain defaultmode network dysfunction in addiction. Neuroimage. 2019 Oct 15;200:313-31. Substance use disorder Aberrant patterns of brain functional connectivity in Default Mode Network Resting State Functional Connectivity anterior region decreased posterior region increased Associated with craving and relapse Prominence decreased during intoxication phases Disruption of the Default Mode Network in addiction reflects in changes in dopaminergic, glutamatergic and others Neuro transmitters

20. Schizophrenia S ignificant hypoconnectivities were observed between seed regions and A reas in auditory network (left insula) C ore network (right superior temporal cortex) Default mode network S elf-referential network (right superior temporal cortex) S omatomotor network (right precentral gyrus) 20 Lewis DA, Curley AA, Glausier JR, Volk DW. Cortical parvalbumin interneurons and cognitive dysfunction in schizophrenia. Trends Neurosci . 2012;35;57–67

21. Obsessive Compulsive Disorder Intrinsic functional connectivity in Salience Network D ecreased intrinsic functional connectivity strength within Salience Network subregions D ecreased intrinsic functional connectivity strength between left thalamus and left cerebellum B etween left insula and right thalamus B etween right cerebellum and bilateral insula, and right Ant Cingulate Cortex 21 Yun JY, Boedhoe PS, Vriend C, Jahanshad N, Abe Y, Ameis SH, Anticevic A, Arnold PD, Batistuzzo MC, Benedetti F, Beucke JC. Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium. Brain. 2020 Feb 1;143(2):684-700.

22. Obsessive Compulsive Disorder Functional Connectivity Between the SN and Other Networks E xhibited decreased intrinsic Functional Connectivity strength between the Salience Network and Default Mode Network Intrinsic Functional Connectivity strength between Salience Network and Central Executive Network was significantly decreased in patients with OCD Specifically between Salience Network subregions (left insula) and ventral lateral prefrontal cortex (VLPFC) 22 Yun JY, Boedhoe PS, Vriend C, Jahanshad N, Abe Y, Ameis SH, Anticevic A, Arnold PD, Batistuzzo MC, Benedetti F, Beucke JC. Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium. Brain. 2020 Feb 1;143(2):684-700.

23. Depression 23 Rive MM, van Rooijen G, Veltman DJ, Phillips ML, Schene AH, Ruhé HG. Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies. Neuroscience & Biobehavioral Reviews. 2013 Dec 1;37(10):2529-53 Amygdala connectivity and emotion regulation Positive functional connectivity with amygdala Hippocampus Ventro Medial Pre Frontal Cortex Anterior temporal poles Negative functional connectivity with amygdala DorsoLateral Prefrontal Cortex Parietal regions Dorsal Anterior Cingulate Also seen in early life stress, or at risk for depression ( eg , family history)

24. Depression 24 Rive MM, van Rooijen G, Veltman DJ, Phillips ML, Schene AH, Ruhé HG. Neural correlates of dysfunctional emotion regulation in major depressive disorder. A systematic review of neuroimaging studies. Neuroscience & Biobehavioral Reviews. 2013 Dec 1;37(10):2529-53. Default Mode Network connectivity and rumination Increase in Default Mode Network connectivity (Intra-network) Preoccupation with negative mood, negative self-evaluation and rumination Increased connectivity of Default Mode Network with salience network Dominance of Default Mode Network over Salience Network Negative evaluation bias to salient information in environment Degree of hyperconnectivity between sub genual Prefrontal Cortex and Default Mode Network predicts the level of rumination

25. Stroke Damage to the attention network and symptoms of spatial neglect F unctional connectivity correlates with severity of symptoms A lterations in default-mode network associated with post stroke depression and episodic memory dysfunction 25 Ovadia-Caro S, Margulies DS, Villringer A. The value of resting-state functional magnetic resonance imaging in stroke. Stroke. 2014 Sep;45(9):2818-24.

26. Autism spectrum disorder Salience Network is decisive for identifying salient stimuli Builds central interface between sensory information processing, attention, motor function and cognition Alterations in social cognition is characteristic Alterations in the Salience Network is characteristically seen 26 Neufeld J, Kuja-Halkola R, Mevel K, Cauvet É, Fransson P, Bölte S. Alterations in resting state connectivity along the autism trait continuum: a twin study. Molecular psychiatry. 2018 Jul;23(7):1659-65 .

27. Autism spectrum disorder Early hyperconnectivity followed by decreased connectivity in adulthood Negative within-pair correlation between autistic traits and connectivity between rt Ant Insula and ventromedial Prefrontal Cortex only in adults Default Mode Network under-active owing to dysfunctional regulatory mechanisms depending on other networks Reduced connectivity of Default Mode Network at different ages 27 Neufeld J, Kuja-Halkola R, Mevel K, Cauvet É, Fransson P, Bölte S. Alterations in resting state connectivity along the autism trait continuum: a twin study. Molecular psychiatry. 2018 Jul;23(7):1659-65.

28. Attention Deficit Hyperactivity Disorder Higher local efficiency and decreased global efficiency Indicating a developmental delay of whole-brain functional networks Medial prefrontal, temporal, and occipital cortices Regional loss of efficiency Inferior frontal gyrus Increased nodal efficiency D efault mode network connectivity Delayed maturation De creased anterior-posterior connectivity 28

29. Stress Impact of early life stress associated Decreased default network connectivity Changes in structure and function in medial prefrontal cortex Increases in connectivity between amygdala and medial prefrontal cortex 29 Philip NS, Sweet LH, Tyrka AR, Price LH, Bloom RF, Carpenter LL. Decreased default network connectivity is associated with early life stress in medication-free healthy adults. European Neuropsychopharmacology. 2013 Jan 1;23(1):24-32.

30. Other networks 30

31. Dorsal and Ventral Attention Networks 24 Vossel S, Geng JJ, Fink GR. Dorsal and ventral attention systems: distinct neural circuits but collaborative roles. The Neuroscientist. 2014 Apr;20(2):150-9.

32. Dorsal and Ventral Attention Networks: Function Top-down, goal-driven attention Orienting after symbolic predictive cues Visual search Visual short-term maintenance Stimulus-driven attention to salient behaviorally relevant events Orienting to exogenous cues Reorienting to unexpected events Response to contextual cues 32 Vossel S, Geng JJ, Fink GR. Dorsal and ventral attention systems: distinct neural circuits but collaborative roles. The Neuroscientist. 2014 Apr;20(2):150-9.

33. Post Traumatic Stress Disorder G reater cross-network connectivity involving Salience Network (dorsal Ant Cingulate Cortex) and default mode network (ventromedial Prefrontal cortex) associated with impairments in disengagement and orienting of attention, processes B oth attentional orienting processes and balance observed to be disrupted in veterans with Post Traumatic Stress Disorder Interventions that utilize attention training, such as mindfulness might be useful for alleviating attentional impairments in Post Traumatic Stress Disorder 33 Block SR, King AP, Sripada RK, Weissman DH, Welsh R, Liberzon I. Behavioral and neural correlates of disrupted orienting attention in posttraumatic stress disorder. Cognitive, Affective, & Behavioral Neuroscience. 2017 Apr;17(2):422-36.

34. Cingulo-Opercular Network: Function F unction has been particularly difficult to characterize N etwork's pervasive activity F requent co-activation with other control-related networks Functions S ustaining alertness Cognitive control functions 34 Coste CP, Kleinschmidt A. Cingulo-opercular network activity maintains alertness. Neuroimage. 2016 Mar 1;128:264-72.

35. Precuneus network Core of default mode network High metabolic rate compared to other networks Part of superior Parietal lobule Located in front of Cuneus Functions Autobiographical memory retrieval, Emotional stimulus processing Reward outcome monitoring Assists behavioral function 35 Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17.

36. Visual Network: Anatomy & Function Primary visual areas Lateral occipital gyrus Superior occipital gyrus Function Perception of visual stimuli 36 Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17.

37. Visuo-spatial Network: Anatomy & Function P osterior parietal cortex of the occipitoparietal junction M idline of the precuneus P osterior cingulate cortex F rontal pole 37 Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17. Functions Spatial attention O rienting to salient visuospatial cues

38. Language Network: Anatomy 38 Broca’s areas Wernicke’s areas Additional regions P refrontal T empor o- parietal S ubcortical regions Wernick area Broca s area Auditory cortex Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17.

39. Language Network: Function 39 S peech C omprehension R eading I nterpreting M imicking

40. Sensorimotor Network: Anatomy & Functions 40 Smitha KA, Akhil Raja K, Arun KM, Rajesh PG, Thomas B, Kapilamoorthy TR, Kesavadas C. Resting state fMRI: A review on methods in resting state connectivity analysis and resting state networks. The neuroradiology journal. 2017 Aug;30(4):305-17. Primary motor cortex Pre-central gyrus Somatosensory motor cortex Post-central gyrus Function Performing and co-ordinating motor tasks

41. Therapeutic Implications 41

42. Therapeutic Implications Mindfulness Repetitive Trans cranial Magnetic Stimulation Transcranial Direct Current Stimulation 42

43. Mindfulness Associated with brain activity in areas overlapping with default mode, salience, and central executive networks (DMN, SN, CEN) Four different mental states during meditation Focus on the present experience was most strongly related to dorso -lateral prefrontal cortex activation of central executive network (CEN) Mind wandering was associated with default mode network (DMN), Awareness of mind wandering linked with activation salience network (SN) Shift of attention back towards focus on the present experience was again linked with of central executive network (CEN) 43 Doll A, Hölzel BK, Boucard CC, Wohlschläger AM, Sorg C. Mindfulness is associated with intrinsic functional connectivity between default mode and salience networks. Frontiers in human neuroscience. 2015 Aug 25;9:461.

44. Mindfulness Mindfulness is correlated with inter-intrinsic Functional Connectivity of subnetworks of Default Mode network Show decreased correlation between anterior and posterior-dorsal Default Mode Network Stronger negative correlation between the insula Salience N etwork and posterior ventral Default M ode N etwork 44

45. Mindfulness 45

46. Repetitive Trans cranial Magnetic Stimulation Applied over left dorso -lateral prefrontal cortex (DLPFC) Treatment response mechanism based on modulations in functional networks, particularly the meso-cortico-limbic reward circuit. Stimulation of left Dorsol-ateral Prefrontal Cortex modulates anterior cingulate cortex connectivity in one specific meso-cortico-limbic network 46 Tik M, Hoffmann A, Sladky R, Tomova L, Hummer A, de Lara LN, Bukowski H, Pripfl J, Biswal B, Lamm C, Windischberger C. Towards understanding rTMS mechanism of action: stimulation of the DLPFC causes network-specific increase in functional connectivity. N euroimage . 2017 Nov 15;162:289-96.

47. Transcranial Direct Current Stimulation Psychiatric disorders demonstrate disrupted functional and structural neural networks, tDCS application modulate functional connectivity and induce synchronization changes Active tDCS enhanced functional connectivity in frontal and fronto -parietal regions regions known to play important underlying role in depression tDCS results in increase in cortical excitability within DLPFC leads to a subsequent disturbance of the integrity of DMN tDCS -induced deactivations of Default Mode N facilitate reallocation of cerebral resources to support task performance 47 Baeken C, Brunelin J, Duprat R, Vanderhasselt MA. The application of tDCS in psychiatric disorders: a brain imaging view. Socioaffective neuroscience & psychology. 2016 Jan 1;6(1):29588.

48. Future Aspects Recent advances should focus on persistent needs to identify neural networks involved in biologic process of psychiatric illness and aid in drug discovery process N on invasive Interventions targeting various networks can be utilized for benefits in whom drugs are not indicated Networks can act as potential biomarker for predicting clinical outcomes and intervention at appropriate time 48

49. Summary 49

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