1. Ascending Reticular Activating System & Diffuse Modulatory Systems

2. Objectives 1. Describe the anatomy of the reticular formation of the brainstem 2. Discuss the general and specific roles of the reticular formation in control of wakefulness, sleep, and motor 3. Describe the anatomy of the dopaminergic, cholinergic and monoamine systems of the CNS 4. Discuss the role of these systems in modulating forebrain areas involved in mood and executive functioning

3. Reticular Formation: What is it?  Archaic brain structure (so-called “reptilian brain”)  Conveniently located at the interface between spinal cord and higher brain structures  Consists of network of nuclei located throughout the brainstem; extending from the spinal cord to the hypothalamus  Active in both directions: ascending and descending pathways  Present in all vertebrates, including reptiles  Essential for survival

4. Where is it?

5. It is involved in a wide range of functions:  Alertness  Sleep/Wake cycle  Pain modulation  Motor regulation  Autonomic functions  Diffuse modulatory systems What does it do?

6. The reticular formation is anatomically organized  Longitudinally  Transversely

7. (Modified with permission from Barr ML, and Kiernan JA: The Human Nervous System,1993) in: Essential Neuroscience, Allan Siegel, Ph.D; Hreday N. Sapru PhD

8. From: Kmayer, W. and Pilleri, G.The Brainstem Reticular Formation and its Significance for Autonomicand Affective Behavior. Montreal: Hoffman-LaRoche Ltd., 1966. yellow Nucleus reticularis pontis caudalis (caudal pons) Light green Nucleus reticularis lateralis (lateral) Blue Nucleus reticularis gigantocellularis (magnocellular) Light blue Nucleus funiculi reticularis (lateral medulla) Red Nucleus reticularis pontis oralis (rostral pons) Pink Nucleus reticularis ventralis (ventral) Brown Nucleus reticularis tegmenti (tegmentum) Light brown Nucleus reticularis paramedianis (paramedian) Green Formation reticularis mesencephali (midbrain) Locus coeruleus (“nucleus pontis”) Raphe nucleus

9. RF: General functional considerations  RF is involved in a large array of functions including:  Long distance modulation  Intra-RF sensory and motor integration  Synchronization of downstream and upstream processes

10. Role in Alertness  ARAS - “Ascending Reticular Activating System”  Integrates afferents from all sensory systems:  Direct afferents from somatosensory, taste, auditory and vestibular  Indirect afferents from olfactory (via limbic structures) and visual (via colliculus superior).  In process, signals 1.Loses their specificity 2.Are summed 3.Projected to the thalamus 4.Modulate global level of alertness  Modulation influences:  Cortical excitability  Reaction to new stimuli  State of consciousness

11. In alertness modulation, RF  Scans & integrates multiple sensory information  filters out repetitive stimuli  accentuates new stimuli with impact for survival  projects to non-specific (intralaminar) nuclei of the thalamus  which in turn projects to wide cortical regions, especially to the frontal lobes

12. EEG features:  Absence of active sensory input: Quiet awake state and drowsiness: Alpha rhythm (synchronized cortical electrical pattern)  Active sensory input: Alertness: Beta rhythms (Low amplitude, with multiple/varying frequencies) in: Essential Neuroscience, Allan Siegel, Ph.D; Hreday N. Sapru PhD

13. © Dr. Gershon Leisman, 2009

14. Pathology: Coma  Lesions of the RF are associated with loss of consciousness

15.  “ARAS” was earlier believed to be the sole mechanism responsible of wake/sleep cycles:  activation associated with wakefulness  deactivation associated with sleep  Concept not supported by newer information  Sleep is now believed to be active process  depending on activation of a network involving RF and hypothalamus. Role in Sleep

16.  Five sleep stages corresponding to five patterns of brain waves (as measured by EEG):  REM sleep (rapid eye movement, dream stage)  Non-REM stage 1  Non-REM stage 2  Non-REM stage 3  Non-REM stage 4 (deep sleep)

17. From Bear MF, et al.: Neuroscience: Exploring the Brain, 2001 EEG characteristics of sleep stages

18. Looking at Sleep - Awake

19. Looking at Sleep – REM

20. Looking at Sleep – Stage 1

21. Looking at Sleep – Stage 2

22. Looking at Sleep – Stage 3

23. Looking at Sleep – Stage 4

24. Physiological Changes During non-REM and REM sleep

25. Characteristics of Three Functional States of the Brain

26. Sleep and Learning Learn A 8 Hrs. Sleep Relearn A % Savings Learn A 8 Hrs. Waking Activity Relearn A Learn A 8 Hrs. Sleep 8 Hrs. Waking Activity Learn A 8 Hrs. Sleep 8 Hrs. Waking Activity Relearn A 79 49 81 51

27. LEARNING AND ECS

28. Homeostatic Decline in Recall

29. Grades as a Function of Hours of Wakefulness

30. Neonatal and Infant Sleep Patterns  Sleep +/-17 hrs with 50% of this time in REM.  Adult NREM/REM pattern does not emerge for several months after birth.  At 32 weeks REM/NREM cycles distinguished When infants “sleep through he night.”  Brainstem reaches developmental high btwn 28- 31 wks. FLink between these neural systems & control of REM/NREM ultradian cycles.

31. Neonatal and Infant Sleep Patterns Similarities  Both newborn & near-term fetuses (as young as 36-38 weeks) display high arousal sleep states accompanied by REM.  Neonates and the fetus display similar wake-sleep cycles and,  REM & non-REM periods similar to adults.

32. Differences Neonates & Fetuses  Immediately enter REM & demonstrate ↑ voltage fast activity (deep"paradoxical" sleep)  Initially have 2 sleep cycles, REM & non-REM (active/quiet sleep). Only +/- 3-4 months does adult sleep pattern appear. Neonatal and Adult Sleep Patterns

33. Adults  Adult sleep onset characterized by slow wave, non-REM (light sleep) cycle.  Sleep cycle followed by intermediate sleep stages culminating (+/- 90 min.) in deep sleep demonstrated by REM and irregular fast EEG activity (as if the brain were highly aroused: hence, the term "paradoxical sleep"). Neonatal and Adult Sleep Patterns

34. TMS, Sleep, and Functional Connectivity Sleeping subject undergoes TMS. Tononi found why consciousness fades when we fall into deep sleep.

35. TMS, Sleep, and Functional Connectivity Awake TMS of awake subject. Cells in a specific region of brain can relay signals to critical regions mediating perception, thought and action. Asleep TMS of subject asleep. Stimulation quickly extinguishes & activity does not propagate far. Fading consciousness in sleep result of functional disconnections.

36. WE POSSESS, ESPECIALLY AS ADULTS, LOCALIATION OF FUNCTION, BUT THAT IS NOT ENOUGH TO EXPALIN THE CAPCITY FOR PLASTICITY, REGENERATION, SPONTANEOUS RECOVERY, AND OPTIMIZATION

37. (L)CT of normal brain; (R) Schiavo's 2002 CT showing hydrocephalus & loss of brain tissue. CT of congenitally hydrocephalic female aged 18. FS IQ= 118. Plastic Brain Development in Childhood

38. Pictorial History of Adult with Congenital Hydrocephalus: A Case for Plasticity

39. Image of rCBF of congenitally hydrocephalic female aged 18 CT of congenitally hydrocephalic female aged 18

40. ↑CMRGlc during 3-10 yrs. corresponds to era of exuberant connectivity needed for energy needs of neuronal processes. > by a factor of 2 compared to adults. PET shows relative glucose metabolic rate. We see the complexity of dendritic structures of cortical neurons consistent with expansion of synaptic connectivities and increases in capillary density in frontal cortex.

41. COMPUTATIONAL NEUROSCIENCE SUPPORTS THE UNDERSTANDING OF PLASTICITY

42. Characterization, Organization & Development of Large-Scale Brain Networks in Children Using Graph-Theoretical Metrics

43. Functional connectivity along the posterior-anterior & ventral- dorsal axes showing ↑ subcortical connectivity ( ● ), ↓ paralimbic connectivity ( ● ) in children, compared to young-adults. Brain regions plotted using y and z coordinates of centroids (in mm), 430 pairs of regions show ↑ r’s in children & 321 pairs showed significantly ↑ r’s in young-adults Characterization, Organization & Development of Large-Scale Brain Networks in Children Using Graph-Theoretical Metrics

44. RF nuclei implicated in sleep  Initiation of the REM state:  pedunculopontine nucleus and lateral dorsal nucleus  cholinergic pontine nucleus of the RF  project to other parts of the RF, hypothalamus, basal forebrain and thalamus  Modulation of sleep:  Locus coeruleus (noradrenaline)  Raphe (serotonin)

45. Pathology: Sleep Lesion or neurochemical imbalance in the sleep associated RF nuclei produce sleep pathology:  Narcolepsy  Sleep apnea  Sleep impairments in depression and post- traumatic disorder

46.  RF receives and filters pain and temperature afferents from the spinoreticulothalamic pathway  Transmits pain information to the thalamus  Top-down feedback from the midbrain periaqueductal gray (PAG) to the raphe nucleus of the midbrain  PAG produce enkephalin that stimulates serotonin neurons from the raphe, which in turn modulate (inhibition) the nociceptive pathway at the level of the spinal cord Role in Pain modulation

47. Reticular formation (precerebellar & lateral groups):  Receives extensive afferents from sensorimotor cortex  Generates feedback loop with cerebellum  Input from the cortex is integrated in that loop  Projects to the spinal cord (via reticulospinal fibers)  Modulates motorneuron activity of the extensor muscles (e.g. modulation of postural reflex in reaction to a fall)  Influences both voluntary and reflex motor functions, as well as posture Role in Motor activity

48.  RF nuclei use two (2) descending pathways (medial and lateral reticulospinal tracts) to influence alpha and gamma motoneurons of extensors in the spinal cord  Excitatory (facilitatory) output arising from RF nucleus located in the pons  Inhibitory output arising from RF nuclei located in the medulla  Combined together, they modulate muscle tone and regulate posture

49. Reticular formation also modulates eye movements  Influences oculomotor saccade and gaze:  integrates inputs from the cortex (frontal eye field) and the vestibular nuclei  controls horizontal gaze  refines posture with position of head in space  Must be inhibited to allow saccades

50. Pathology: Motor Disruption of RF-cerebello-cortical network results in significant motor deficits such as:  spasticity  rigidity  hypertonicity

51. Reticular formation  Receives inputs from cranial nerves (glossopharyngeal IX and Vagus X)  Modulates blood pressure, heart rate and respiration  Via two descending pathways: inhibitory and excitatory  Additional inputs from hypothalamus, midbrain PAG, amygdala and prefrontal cortex, participate in regulation of blood pressure Role in Autonomic functions

52. Summary of organization and roles of the Reticular Formation

53. SENSORY INPUTS R.F. OUTPUTS Spinal cord [Pain/temperature signal] Spinal cord [Ascending pain modulation fibers] Cranial nerves [Direct sensory signal] Limbic structures [secondary sensory signal] Colliculus superior [secondary sensory signal] Parvocellular nuclei of pons and medulla Magnocellular nuclei of pons and medulla Thalamus Peri Aqueductal Gray (enkephalinergic inhibition) Cerebral cortex Spinal cord [Descending pain modulation fibers] Diffuse modulatory systems

54. MOTOR INPUTS R.F. OUTPUTS Motor cerebral cortex Cerebellum Magnocellular nuclei (a) of the pons [excitatory] (b) of the medulla [inhibitory] Spinal cord [descending fibers] Alpha & Gamma Motor neurons [extensor muscles]

55. AUTONOMIC: Respiration INPUTS R.F. OUTPUTS Cranial nerves IX & X Hypothalamus Solitary nucleus (a) ventral part [expiration] (b) dorsal part [inspiration] Spinal cord [descending fibers] Limbic system Medial parabrachial nucleus [modulatory]

56. AUTONOMIC pathway: blood pressure and heart rate INPUTS R.F. OUTPUTS Cranial nerves IX & X Hypothalamus Solitary nucleus Spinal cord [descending fibers] Amygdala Periaqueductal Gray Ventrolateral Medulla

57. AUTONOMIC pathway: top-down modulation INPUTS R.F. OUTPUTS Prefrontal cortex Spinal cord [descending fibers] Hypothalamus Amygdala Periaqueductal Gray Tegmental nucleus Solitary nucleus

58. Learning objectives  Describe the anatomy of the reticular formation of the brainstem  Discuss the general and specific roles of the reticular formation in control of wakefulness, sleep, pain, motor and autonomic activities  Describe in detail the anatomy of the dopaminergic, cholinergic and monoamine systems of the CNS  Discuss the role of these systems in modulating forebrain areas involved in mood and executive functioning  Describe the role of these transmitter systems in reward pathways and in models of addiction

59. Diffuse modulatory systems of the reticular formation – what is it?  Consists of small groups of neurons that diffuse neurotransmitters throughout large brain areas (by “volume transmission”)  These groups of special RF nuclei regulate diverse populations of neurons  Process of diffuse modulation differs from direct synaptic transmission:  Neurotransmitter is not quickly reabsorbed by the neuron  Neurotransmitters is released in the space between neurons (not necessarily at the synapse level)

60. Noradrenergic DMS: Synopsis SystemOriginTargetsEffects Noradrenaline system Locus coeruleus adrenergic receptors in: * spinal cord * thalamus * hypothalamus * striatum * neocortex * cingulate gyrus * hippocampus * amygdala * arousal * reward system * sleep * mood Lateral tegmental field * hypothalamus

61. Norepinephrine system Cells of origin located in pons/upper medulla, mainly in:  N. Locus Ceruleus (NLC)  Lateral tegmental field J. Nolte: The Human Brain, p. 281

62. Sends extensive efferents to:  Spinal Cord and Cerebellum  Midbrain (VTA)  Diencephalon  Limbic system  Basal Forebrain nuclei  Somatosensory cortex Barr’s, 2005: The Human Nervous System. P. 165 Receives afferents from:  Brain stem  Hypothalamus Locus ceruleus

63. Key functional associations :  Arousal: Most active in awake, attentive animals  Sleep:  Less active in non-REM sleep  Non-active in REM sleep  Mood:  High activity associated with Mania  Low activity associated with depression  PCP (Phencyclidine) and Amphetamine potentiate activity of NLC (probably mediated via Dopamine) Lesions damaging N. Locus Ceruleus (NLC) and related nuclei produce arousal difficulties, somnolence and has been associated with depressive disorders)

64.  Where is the largest collection of Norepinephrine (NE) projecting cells located in the human brain? Test your knowledge

65. SystemOriginTargetsEffects Serotonin system Caudal dorsal raphe nucleus Serotonin receptors in: * deep cerebellar nuclei * cerebellar cortex * spinal cord Increase mood, satiety, body temperature and sleep, while decreasing nociception. Rostral dorsal raphe nucleus Serotonin receptors in: * thalamus * striatum * hypothalamus * nucleus accumbens * neocortex * cingulate gyrus * hippocampus * amygdala Serotonergic DMS: Synopsis

66. Serotonergic system Origin in:  Raphe nuclei complex of medulla, Pons and midbrain From: J. Nolte, 2002. The Human Brain, p. 284

67. Serotonergic system Receives afferents from:  Spinal cord  Midbrain (PAG)  Limbic system  Hypothalamus  Prefrontal cortex Sends efferents to:  Cerebral cortex  Limbic system  Diencephalon  Cerebellum  Locus ceruleus  Spinal cord From: J. Nolte, 2002. The Human Brain, p. 284

68. Serotonergic system Key functional associations:  Inhibitory to thalamic and cortical neurons (regulate affect and sensory perception)  Active in deep sleep, Less active in REM sleep  Regulate sleep-wake cycle  Regulate motor tone and pain perception  Thermoregulation, food intake, sexual behaviors  High activity associated with mania, narcolepsy  Low activity associated with depression, anxiety and insomnia

69.  Where is the largest collection of Serotonergic (5HT) projecting cells located in the human brain? Test your knowledge

70. Originate in cells of:  Upper pontine tegmentum  Basal forebrain (nucleus basalis of Meynert) From: J. Nolte, 2002. The Human Brain, p. 285 Afferents are from:  Brain stem  Diencephalon  Striatum Efferents go to:  Brain stem  Diencephalon  Striatum  Limbic system  Cerebral cortex Cholinergic system

71. Key functional associations:  Implicated in sleep/wakefulness cycle  Active in awake states  Active in REM sleep  Non-active in non-REM sleep  Enhance cortical responses to incoming sensory stimuli  High activity associated with psychosis, insomnia, hypertonia, hyper-reflexia, muscle rigidity, and severe movement disorders  Low activity associated with flat affect, dystonia, lack of interest, somnolence

72.  Where is the largest collection of Acetylcholine (Ach) projecting cells located in the human brain? Test your knowledge

73. SystemOriginTargetsEffects Dopamine system * Substantia nigra (midbrain-cortical pathway) * Ventral Tegmental Area (midbrain-limbic pathway) *frontal lobes *basal ganglia *nucleus accumbens motor system, reward system, cognition, endocrine system, nausea Dopaminergic DMS: Synopsis

74. Dopaminergic system Origin in:  Substantia nigra (pars compacta)  Ventral Tegmental Area of midbrain, (VTA)  Retrorubral field  Dorsal hypothalamus  Tubero-infundibular nuclei of hypothalamus From: J. Nolte, 2002. The Human Brain, p. 283

75. Dopaminergic system Receives afferents from:  Brain stem  Diencephalon  Striatum  Limbic system  Cerebral cortex Sends efferents to :  Somatosensory cortex  Striatum  Limbic system  Hypothalamus  Spinal cord

76. Dopaminergic system Key functional associations:  Emotion and behavioral response (Motivation, Drive states, Satiety, Sleep- wakefulness cycle)  Thought and thought disorders (e.g. as in Schizophrenia), Memory  Movement and disorders of affect (e.g., in Parkinson’s disease)  Autonomic and endocrine regulation (Pleasure and Reward seeking)  High activity associated with obsessive-compulsive activity, agitation, catatonia, psychosis, hypersexuality, loss of inhibition  Low activity associated with apathy, withdrawal  Cocaine related addictive behaviors and psychosis

77.  Where is the largest collection of Dopamine (DA) projecting cells located in the human brain? Test your knowledge

78. Drugs targeting the neurotransmitter of DMS affect the whole system Mode of action of some drugs  Prozac :  selective serotonin reuptake inhibitor (SSRI)  potentiates naturally released serotonin  Cocaine:  blocks the reuptake of dopamine  leaves neurotransmitter in the synaptic gap longer  Deprenyl:  inhibits monoamine oxidase (MAO)-B  increases dopamine levels. Drugs and the DMS

79. Pathology DMS: Depression & Mania  Serotonin modulatory system arising from Raphe  Noradrenaline modulatory system arising from locus coeruleus Associated with low levels of neurotransmitters: NE, DA and 5HT Associated with high levels of neurotransmitters: NE, DA and 5HT