Basal ganglia - Anatomy, Neurochemistry, Connections, Disorders

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Anatomy and Physiology of the Basal Ganglia, Neuro-circuitry, Neurochemistry, Mathematical Models, Disorders, Deep Brain Stimulation

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  • Although techniques vary from center to center, the general aspects of the surgery will be described. DBS surgery uses stereotactic neurosurgical techniques to identify the brain targets of interest and to implant the DBS leads into them. Stereotaxis is typically performed by acquiring a brain image using magnetic resonance imaging (MRI) or computed tomography (CT) with a rigid stereotactic frame affixed to the patient’s skull. The surgeon is then able to calculate the three-dimensional targets of interest in the brain with relation to the x, y, and z coordinates marked on the stereotactic frame. This frame and the arc mounted to it then allows instruments and the DBS lead to be precisely guided to the brain target. This is accomplished, typically using local anesthesia, through an incision in the scalp and burr holes in the skull.
  • Basal ganglia - Anatomy, Neurochemistry, Connections, Disorders

    1. 1. Dr. Rahul Kumar, Senior Resident, Department of Neurology, M S Ramaiah Medical College and Hospitals
    2. 2. What are the basal ganglia?  Depends on target audience  Anatomical: Non-cortical nuclei in the forebrain  Caudate nucleus, putamen, nucleus accumbens, amygdala, septal nuclei, globus pallidus  Functional: Richly interconnected set of nuclei in the forebrain and midbrain
    3. 3. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    4. 4. Time Permitting ….  Introduction to Basal Ganglia Diseases  In Vivo assessment of disorders of basal ganglia – fMRI and PET  Recent advances in the neuropharmacology and interventional therapies in basal ganglia disorders
    5. 5. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    6. 6. The first anatomical identification of distinct subcortical structures, at the "base" of the brain, was carried out by Thomas Willis (1621 –1675) in his Cerebri Anatomi, published in 1664 and translated into English in 1681 as Anatomy of the Brain and Nerves. The term Corpus Striatum was used for the first time by Raymond de Vieussens (1641 – 1716) in his Neurographia Universalis, published in 1690, to describe the striped appearance which a section of its anterior part presents.
    7. 7. For many years the Basal Ganglia were considered formed by two structures: the caudate nucleus (Nucleus Caudatus), so called for the long characteristic tail, and the lenticular nucleus (or Nucleus Lenticularis).
    8. 8. The first systematic description of the Basal Ganglia was performed by the French anatomist and neurologist Joseph Jules Dejerine (1849-1917) in his Anatomie des Centres Nerveux, published in Paris in 1895. In this book there is the first use of the term Globus Pallidus to indicate the ventral part of the Nucleus Lenticularis which was separated by Dejerine from the Putamen, considered part of the Striatum.
    9. 9. MAIN STRUCTURES BELONGING TO THE BASAL GANGLIA: CLASSIC VISION
    10. 10. MAIN STRUCTURES BELONGING TO THE BASAL GANGLIA: MODERN VISION
    11. 11. THE EVOLUTION OF TELENCEPHALON During the phylogenesis the prefrontal cortex presents a disproportioned increase with respect to the other cerebral areas. The prefrontal cortex, in the homo sapiens, represents about 1/3 of the entire neocortical surface. Blinkov S.M., Glazer I.I., The human brain: a quantitative handbook. New York, Plenum Press, 1968.
    12. 12. Evolutionary conservatism “The basal ganglia in modern mammals, birds and reptiles (i.e. modern amniotes) are very similar in connections and neurotransmitters, suggesting that the evolution of the basal ganglia in amniotes has been very conservative.” Medina, L and Reiner, A. Neurotransmitter organization and connectivity of the basal ganglia in vertebrates: Implications for the evolution of basal ganglia. Brain Behaviour and Evolution (1995) 46, 235-258
    13. 13. The basal ganglia may have be conserved Human …. unlike cerebral cortex and cerebellum the basal ganglia have not increased in relative size with brain development Rat
    14. 14. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    15. 15. Spiny I neuron Spiny II neuron Aspiny I neuron Aspiny II neuron Aspiny III neuron Neurogliform cell
    16. 16. The Neostriatal Mosaic  Neostriatum divided into two compartments: patch (striosome) & matrix  First described by Ann Graybiel in 1978 using AChE stain  Not visible in Nissl stains (“hidden chemoarchitecture”)  Define input/output architecture of neostriatum From Holt et al., 1997, JCN
    17. 17. Basal Ganglia Basal Ganglia Components Components
    18. 18. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    19. 19. Basal Ganglia Basal Ganglia Connections Connections Input Portion STRIATUM (Caudate Nucleus and Putamen) Output Portion 1. PALLIDUM (Globus Pallidus) 2. SNr (Substantia Nigra, Pars Reticulata)
    20. 20. Connections of the Basal Ganglia Connections of the Basal Ganglia amygdaloid body amygdaloid body Cerebral Cerebral Cortex Cortex raphe raphe STRIATUM STRIATUM Thalamus Thalamus STN STN SNc SNc Pallidum Pallidum SNr SNr tectum tectum (superior colliculus) (superior colliculus) habenular habenular nucleus nucleus PPN PPN (pedunculopontine nucleus) (pedunculopontine nucleus)
    21. 21. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    22. 22. glutaminergic serotonergic dopaminergic glutaminergic
    23. 23. gabanergic Gpe – enkephalin, neurotensin Gpi - substance P, Dynorphin
    24. 24. Gpi and SNpr - GABA
    25. 25. Stn – Only excitatory output, Glutaminergic
    26. 26. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    27. 27. Functions of the Basal Ganglia
    28. 28. Recurrent loops  Motor loop  sensorimotor areas 1,2,3,4,5,6 -> putamen -> GP -> VA ->SMA  Oculomotor loop  prefrontal cortex & ppc 9,12, 7 -> caudate -> GP -> VA -> frontal eye fields & SC  Cognitive loop  prefrontal cortical areas 9,12 -> caudate -> GP -> VA -> prefrontal cortex  Limbic loop  cingulate -> caudate (striosomes)-> GP -> MD -> ant. cingulate. Topography is maintained within each loop!
    29. 29. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    30. 30. Cortex Neostriatum Gpi/SNpr “divergent-reconvergent processing” From Graybiel et al., The basal ganglia and adaptive motor control, Science, 265: 1826, 1994
    31. 31. Movement control via disnhibition From Chevalier and Deniau, TINS 13:277, 1990
    32. 32. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    33. 33. Initiation and control of voluntary movement
    34. 34. Motor loop Somatotopic subdivisions of the input remain segregated throughout the circuit. Adapted from Rothwell, 1994; from Alexander and Crutcher, 1990
    35. 35. Basal ganglia circuitry  two circuits important in cortex regulation of movement  direct pathway  indirect pathway putamen  direct pathway decreases inhibitory basal ganglia output  indirect pathway increases inhibitory basal ganglia output  balance of these two circuits underlies regulation of movements GPe STN VA/VL GPi/SNr
    36. 36. Direct pathway cortex putamen GPe VA/VL Glutamate (+) GABA (-) STN GPi/SNr
    37. 37. Direct pathway  DBStion of direct pathway reduces inhibitory output of basal ganglia  Consequence is to promote movement
    38. 38. Indirect pathway cortex Glutamate (+) putamen GABA (-) GPe STN VA/VL GPi/SNr
    39. 39. Indirect pathway  DBStion of indirect pathway increases inhibitory output of basal ganglia  Consequence is inhibition of movement
    40. 40. SN’s effects on direct and indirect pathways cortex putamen SNpc GPe VA/VL Glutamate (+) GABA (-) STN GPi/SNr
    41. 41. Dopamine’s effects on direct and indirect pathways  Dopamine release by SNpc DBStes direct pathway via D1 receptor  Dopamine release by SNpc inhibits indirect pathway via D2 receptor  Dopamine promotes movement
    42. 42. Direct vs. indirect pathways •Different populations of spiny neurons •Neuromodulators/co-transmitters •Striosomes vs. matrix •Dopamine receptor subtypes From Graybiel, A. Neural Networks, Am J Psychiatry 158:21, January 2001
    43. 43. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    44. 44. Dorso-lateral prefrontal circuit “Executive functions”: attention, concentration, multi-tasking, set-shifting, problem solving, planning and organisation of tasks
    45. 45. Orbito-frontal circuit Irritability, emotional lability, failure to respond to social cues, lack of empathy, obsessive-compulsive behaviours
    46. 46. “Limbic” circuit Input also from hippocampus, amygdala and entorhinal cortex Motivation and emotional behaviour
    47. 47. Oculomotor Loop
    48. 48. Dr. Rahul Kumar, Senior Resident, Department of Neurology, M S Ramaiah Medical College and Hospitals
    49. 49. To Recapitulate……  Subcortical structures and circuits  No direct projections, act via pyramidal pathways  Control movements, cognition, emotions, eye movements  Work on the Disinhibition Model  Circuits work in parallel, not in isolation
    50. 50. Outline for the Session  History and evolution of knowledge base  Gross and microscopic anatomy of basal ganglia  Connections of basal ganglia – input and output  Neurochemistry  Functional Subsystems in basal ganglia  Processing of information  Skeletomotor Circuit  Other important circuits  Mathematical Models of Basal Ganglia functioning
    51. 51. General Thoughts on Mathematical Modeling  What is being modeled – Math at the mercy of the biology  Anatomy and neurochemsitry does not reveal dynamics, rather leads to misconceptions  Radically different concept of the BG-Th-Ctx network
    52. 52. Serial Selection in the Basal Ganglia Inputs 1) Up-down states (Cortex/Thalamus) of medium spiny neurones Striatum 2) Local inhibition Up-state/down-state filtering in striatum 3) Diffuse/focused projection onto output nuclei 4) Recurrent inhibition in output nuclei Subthalamus Local inhibitory circuits Focused inhibition Diffuse excitation Output Nuclei Local recurrent circuits
    53. 53. Resonance Effect Time = cycle (0) Time = cycle (1/2) Time = cycle (1)
    54. 54. Multiple Circuits of Different Resonant Frequencies SMA Motor Cortex Putamen VL Thalamus GPe GPi STN
    55. 55. Specialization by Learning Algorithms (Doya, 2009) output Cortex Basal Ganglia: TD vs Reinforcement Learning ? Inbuilt vs reward Basalthalamus Ganglia SN IO input output Cerebellum target + -
    56. 56. Temporal Dispersion Model of Basal Ganglia(Houk et al. 1995, Montague et al. 1996, Schultz et al. 2007,...) sensory input action output Cerebral cortex state representation Ach? Striatum evaluation 5-HT? Thalamus TD signal a V(s) Dopamine neurons reward SNr, GP action selection DA neurons: TD error δ SNr/GPi: action selection: Q(s,a) → a NA?
    57. 57. before learning after learning omit reward (Schultz et al. 2007) Dopamine Neurons and TD Error δ(t) = r(t) + γV(s(t+1)) - V(s(t))
    58. 58. RL Model of Basal Ganglia (…, Doya 2000)  Striatum: value functions V(s) and Q(s,a) sensory input Cerebral cortex state representation s action output Striatum evaluation TD signal δ V(s) Thalamus Q(s,a) Dopam ine neurons r reward SNr, GP action selection Dopamine neurons: TD error δ SNr/GPi: action selection: Q(s,a) → a
    59. 59. Enhancement of response by dopamine
    60. 60. Likely learning rule in the Probably 3 factors in striatum striatum pre post Glu depolarize dopamine reward NMDA LTP consolidates
    61. 61. Outline for the Session  Introduction to Basal Ganglia Diseases  In Vivo assessment of disorders of basal ganglia – fMRI and PET  Recent advances in the interventional therapies in basal ganglia disorders
    62. 62. Cortex + + Substantia Nigra + Parkinson’s Disease Putamen X SMA - Globus Pallidus (GPi) VLo - + Subthalamic Nucleus
    63. 63. + SMA Putamen X- Huntington’s Disease VLo - ++ GPe GPi - Subthalamic Nucleus
    64. 64. SMA + Hyperkinesia (e.g. ballism) Striatum - VLo - Globus Pallidus + X Subthalamic Nucleus
    65. 65. Outline for the Session  Introduction to Basal Ganglia Diseases  In Vivo assessment of disorders of basal ganglia – fMRI and PET  Recent advances in the interventional therapies in basal ganglia disorders
    66. 66. Functional Imaging with ß-CIT: Dopamine Transporter Healthy subject PD patient – Hoehn-Yahr Stage 1
    67. 67. Longitudinal DAT Imaging in PD
    68. 68. Outline for the Session  Introduction to Basal Ganglia Diseases  In Vivo assessment of disorders of basal ganglia – fMRI and PET  Neuroimaging in Diseases of Basal Ganglia  Recent advances in the interventional therapies in basal ganglia disorders
    69. 69. Outline for the Session  Introduction to Basal Ganglia Diseases  In Vivo assessment of disorders of basal ganglia – fMRI and PET  Recent advances in the interventional therapies in basal ganglia disorders
    70. 70. Approved Indications  DBS Therapy is approved for the treatment of symptoms due to:  Essential Tremor  FDA approved in 1997  Parkinson’s disease  FDA approved in 2002  Dystonia  FDA approved (HDE*) in 2003
    71. 71. Target Sites for DBS Therapy Vim Thalamus: Essential Tremor Subthalamic Nucleus: Parkinson’s disease and Dystonia Globus Pallidus: Parkinson’s disease and Dystonia
    72. 72. DBS Therapy: Implantable Components  Lead  Extension  Neurostimulator (implantable pulse generator) Soletra™ Single Channel Output Kinetra® Dual Channel Output
    73. 73. Parkinson’s Disease Treatment: Continuum of Interventions Disease Severity Patient Symptoms Mild Moderate Signs of levodopa “wearing-off” Severe Dyskinesia, “On-Off” Motor Fluctuations Treatment DBS Modified from Giroux, ML and Farris, SF. Cleveland Clinic Foundation 2005 Cleveland Clinic Foundation Center for Neurological Restoration Postural Instability, Freezing, Falls, Dementia
    74. 74. Efficacy: Benefits of DBS Therapy Impact on Mobility Dyskinesia Before “On” Time After “Off” Time
    75. 75. Additional Benefits of DBS  Bilateral, reversible, and adjustable  Non-destructive versus ablative procedures  Can be non-invasively fine-tuned to each patient’s individual needs
    76. 76. DBS Therapy: Potential Complications and Risks  Surgery related  Hemorrhage (inherent in any stereotactic procedure); may be silent or symptomatic  Transient confusion  Infection (typically occurs at neurostimulator site in chest when it does occur)  Stimulation related  Usually can be minimized or eliminated by adjusting stimulation settings  Reversible paresthesia, dysarthria, muscle contraction
    77. 77. Surgical Technique  Stereotactic frame placement or frameless stereotaxy  Targeting  Imaging  Stereotactic targeting  Physiologic targeting (microelectrode recording and stimulation)  Electrode placement  Pulse generator implantation
    78. 78. Surgical Technique: Targeting  Sophisticated imaging and software enables precise targeting for optimal outcomes and minimal risk  Microelectrode recording (MER) offers additional levels of verification of lead location
    79. 79. Surgical Technique: Microelectrode Recording Border Sagittal Section Through the Thalamus 80ms STN 10sec 80ms Border/SN 10sec 80ms
    80. 80. Surgical Technique: DBS Lead Placement  Leads placed in motor territory of nucleus  Leads have four electrodes  Multiple electrode configurations possible during postoperative programming
    81. 81. Target Sites for DBS Therapy Vim Thalamus: Essential Tremor Subthalamic Nucleus: Parkinson’s disease and Dystonia Globus Pallidus: Parkinson’s disease and Dystonia
    82. 82. Surgical Technique: Neurostimulator Placement  Can be done immediately or days/weeks later  Typically placed below clavicle  Connected to lead using extension
    83. 83. To Summarize …….  Mathematical models antedate the major discoveries in basal ganglia circuitry  Neuroimaging abnormalities are being described, functional neuroimaging possible but little discriminatory value  DBS promising, replicates tonic activity.

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