L9 MedNeuro2 Sp25 Lec9 Basal Ganglia PDF

Basal Ganglia DO-SYS-725 Med Neuro II Lecture 9 Tony Harper, Ph.D Fri Jan 24 @9am READING: Young, Young and Tolbert (3rd ed): Ch 8 pgs 88-103 MOVIE: Awakenings (1990)...

Basal Ganglia DO-SYS-725 Med Neuro II Lecture 9 Tony Harper, Ph.D Fri Jan 24 @9am READING: Young, Young and Tolbert (3rd ed): Ch 8 pgs 88-103 MOVIE: Awakenings (1990) 1 Lecture Objectives Be able to recognize and predict the symptoms of the major hypo- and-hyperkinetic movement disorders mentioned in the lecture (Parkinson’s, Huntington’s, Cerebral Palsy, Tardive Dyskinesia) Be able to draw out the Direct Pathway and Indirect Pathway (not Hyperdirect Pathway), from the cerebral cortex, through the basal ganglia and thalamus, and back to the cerebral cortex. Predict the type of movement disorders resulting from lesions to specific basal ganglia, tracts and regions of cortex Identify the basal ganglia in cross sections 3  Moving Words Akathisia – uncontrollable urges to move Athetosis: Continuous writhing movement that interferes with posture, slower and longer term than chorea. Usually just in upper body Ballismus/Ballism: Large amplitude limb flailing movements, slightly slower than myoclonus Chorea: Slow or fast, but discrete involuntary movements Hyperkinesia: Excessive and/or abnormal movements Hypokinesia: Diminished motion, but not including weakness of muscle activity. Bradykinesia: Slower than normal movement, possible “start hesitation” when starting movements Akinesia: Inability to initiate or complete perceivable movements Tics: Repeated intermittent movements/vocalizations (always in same places). Tics can be briefly Bad pit in film suppressed with effort. “12 Monkeys” Cramps: involuntary painful contractions in a muscle/muscles demonstrating Dystonia: Hyperkinetic disorder causing painless, sustained, postural multi-muscle contractions. Dystonia Often causing cause repetitive twisting movements (includes BEB, Meige syndrome, and hemifacial spasm) Sometimes dystonia patients develop geste antagoniste to counteract unwanted contractions. Sometimes touching skin over spasming muscle prevents contractions. Can also respond to botox Paratonia: involuntary holding position of limbs ( e.g. when physician asks patient to drop weight of hands into theirs). AKA “waxy flexibility”. Can indicate frontal lobe cognitive decline. 4  Basal Ganglia Cerebrum can’t use the same muscles for different movements simultaneously Unlike the cerebellum, (which smoothly coordinates ongoing movements), the basal ganglia functions by permitting /inhibiting useful multi- joint/multi-muscle movements, out of a range of potential movements before they begin 5 Inhibitory Interneurons and Logic Most neurons have a spontaneous/tonic firing 5 APs/sec rate Excitation (e.g. glutamate) will increase rate of 8 APs/sec AP firing… …and inhibition( e.g. GABA) will decrease it Inhibition of an inhibitory neuron produces “disinhibition” 3 APs/sec +1 x -1 x +1 x -1 x +1 = 0 APs/sec Inhibitory neurons do not have to directly synapse on each other for disinhibition to occur Pathways with an odd number of inhibitory synapses will be inhibitory overall (negative feedback) 8 APs/sec Pathways with an even number of inhibitory synapses will be excitatory overall (positive feedback) 6  Your Brain is a Each of the lateral view of embryonic telencephalon Tortellini embryonic telencephalon OB = Olfactory Bulb vesicles develops as GE = Ganglionic an asymmetrically Eminence (bulge of thick tube, with a subpallium) thin outer Pallium and thicker basal Subpallium Pallium (becomes cortex, claustrum, and hippocampus) Subpallium Lateral Ventricle Thin Part Thick Part Empty Inside Coronal sections of telencephalon 7  Acb and OT are the Nucleus Accumbens and Olfactory The subpallial region forms Tubercle, parts of the concentric subdivisions along a “ventral striatum” that medio-lateral direction. These connect between the include the Striatum and putamen and caudate Pallidum(not Pallium) nucleus There is also a rostral-caudal “septoamygdaloid axis” but because of curvature of the telencephalon around the insula during development, Pal this axis becomes oblique and “C-Shaped” liu m Late in development, axons of cortical neurons (e.g. the corticospinal tract) grow through the striatum, splitting it into the caudate nucleus and putamen. The internal nucleus of the globus pallidus is also split from the substantia nigra pars reticulata in a similar way Striat = Stiriatum (putamen and caudate nucleus) Pall = Pallidum (globus pallidus) Diag = “Diagonal Band of Broca” region Preopt = Preoptic area (of hypothalamus) Sept = Septal area Parasept = Paraseptal area Amygd = Amygdala 8 Basal Ganglia Anatomy Caudate Nucleus Putamen Globus Pallidus 9  The basal ganglia includes: Telencephalon: Corpus striatum Diencephalon: Subthalamic Nucleus Midbrain: Substantia Nigra 10 Coronal Section Axial (Transverse) Section 11 Basal Ganglia Lenticular/Lentiform nucleus = Globus pallidus + Putamen ROSTRAL Striatum = Globus pallidus + Putamen + Caudate CAUDAL Caudate Putamen Nucleus accumbens Subthalamic nucleus (STN) Globus pallidus, externa (GPe) Substantia nigra - pars reticulata (SNpr) Globus pallidus, interna (GPi) - pars compacta (SNpc) Amydala (part of lymbic system) 12 Inputs to Basal Ganglia Areas of cortex that project to basal ganglia Major input to the striatum (caudate and putamen) is excitatory(glutamate) from layer 5 of cerebral cortex 13  Classification of Nuclei Separated by Basal Ganglia have GABA-ergic projection Corticospinal fibers neurons, and Cholinergic (but inhibitory) (internal capsule) interneurons Input Nuclei: Caudate Nucleus + Putamen = Striatum (functional unit) Subthalamus (not shown) These nuclei receive significant afferent information from non-basal ganglia sources and project their output to intrinsic nuclei. Caudate has intrinsic cholinergic interneurons that counteract nigrostriatal Intrinsic Nuclei: Substantia Nigra Pars Compacta (SNpc; not shown) Separated by Corticospinal fibers Lateral/External segment of Globus Pallidus (cerebral crus) (GPL) These nuclei have connections with both input and output nuclei. Output: Substantia Nigra pars Reticulata (SNpr) Medial/Internal Segment Globus Pallidus (GPm) These project out of the Basal Ganglia. Spontaneous discharge at a rate ~50-100 Hz. 14  A Typical Basal Ganglia Scenario 0) without outside stimulation, basal ganglia output nuclei inhibit motor cortex and thalamus (e.g. no movement by default). Chewing Amount of Movement Walking Bubble Gum 1) Activation of Basal Ganglia allows for the coordination of actions that use different muscles/joints, and the prevention of simultaneous actions that use the same muscles and joints differently. So minimally active basal ganglia prevent all action, while a high level of basal ganglia activity allows for multitasking (not necessarily faster or wider movements) Possible Movements 15 Basal Ganglia PRE -MOTOR CORTEX The output nuclei of the basal ganglia can be considered as the “brake” Output for self-generated movements + Input Nuclei - GABA Caudate/Putamen Lateral Globus (Striatum) Pallidus Tonic GABAergic activity of the basal ganglia output Indirect Path Direct Path nuclei causes motor GABA - GABA - thalamus and cortex to be inhibited most of the time Medial Globus Pallidus Subthalamus + Substantia Nigra pars Ret. Output Nuclei e.g. doing nothing is - GABA default state Thalamus (VA/VL) + Glutamate + Spinal Motor Cortex Cord 16  While walking and chewing bubble gum, you notice something that causes you to reprioritize your actions. F REE t It turns out that instead of transforming one motor r Swif Taylo s!! Hug nly) pattern into a new one, the basal ganglia send a “global o (tod a y inhibition” signal that inhibits all basal ganglia controlled movements in order to initiate a new motor pattern from a simpler starting point. Chewing The basal ganglia pathway that causes this “global Amount of Movement Bubble Gum Walking inhibition” signal is called the Hyperdirect Pathway 1) There you are, walking along and chewing bubble gum 2) Sudden unexpected stimulus causes you to reprioritize your future actions. To initiate a new motor pattern the Hyperdirect Pathway causes a sudden (“phasic”) increase in inhibition of the motor thalamus and cortex Possible Movements 17  MOTOR Axons connecting CORTEX motor cortex to subthalamus are large and myelinated (unlike + Input Nuclei in the direct pathway), - GABA so it is called the Caudate/Putamen Hyperdirect Pathway Lateral Globus Pallidus (Striatum) Indirect Path Direct Path The global inhibition GABA signal reaches the GABA - - motor thalamus and Medial Globus Pallidus cortex before any + Subthalamus + Substantia Nigra pars Ret. other signal. Output Nuclei - GABA Thalamus (VA/VL) + Glutamate + Spinal Motor Cortex Cord 18  F REE t r Swif Taylo s!! Hug nly) a y o (tod 3) From the reset initial state, the basal ganglia Amount of Movement Uncoordinated use the Direct Pathway Running which causes disinhibition of the motor thalamus and motor cortex in order to release the newly selected action from inhibition. Possible Movements 19  MOTOR Somatosensory, primary CORTEX motor, supplemental motor and premotor cortex make excitatory synapses with the + Input Nuclei putamen through - GABA unmyelinated corticostriatal Caudate/Putamen Lateral Globus (Striatum) axons. Pallidus Indirect Path Direct Path GABA - GABA - Medial Globus Pallidus Subthalamus + + Substantia Nigra pars Ret. Output Nuclei - GABA The Direct pathway has an even Connections from the number of inhibitory synapses, Thalamus (VA/VL) making the whole pathway striatum send GABAergic Excitatory (positive feedback) (inhibitory) signals to the Glutamate + basal ganglia output nuclei. + Spinal Motor Cortex Cord 20  F REE t r Swif Taylo s!! Hug nly) a y o (tod The newly disinhibited motor pattern is initially uncoordinated, and needs to “outcompete” similar but Amount of Movement Coordinated Running unwanted motor patterns. 4) The Indirect Pathway provides selective inhibition of similar but unwanted actions to the selected action Possible Movements 21  MOTOR There are a few CORTEX different “indirect paths” but we only + Input Nuclei cover the main - GABA Caudate/Putamen skeletomotor one Lateral Globus Pallidus (Striatum) Indirect Path Direct Path GABA - GABA - Medial Globus Pallidus Subthalamus + + Substantia Nigra pars Ret. Output Nuclei - GABA Thalamus (VA/VL) The Indirect Pathway has an odd number of inhibitory synapses, Glutamate making the whole pathway + + Inhibitory (negative feedback) Spinal Motor Cortex Cord 22 Pallidofugal PRE -MOTOR Pathways CORTEX Motor Thalamus + Input Nuclei - GABA Caudate/Putamen Lateral Globus (Striatum) Pallidus Indirect Path Direct Path GABA - - GABA Subthalamus Medial Globus Pallidus Substantia Nigra pars Ret. + - GABA Output Nuclei Both axons of Thalamus indirect pathway in Coronal View Axial View “Subthalamic Fasciculus” + Glutamate + Spinal Basal Ganglia output pathway Motor Cortex Cord AL = Ansa lenticualris. LF = Lenticular fascicle called “Thalamic (H2 field of Forel). MD = Mediodorsal nucleus Fasciculus” of Thalamus. SF = Subthalamic Fasciculus. Sth = Really two tracts, Subthalamuic Nucleus. TF = Thalamic the Lenticular Fasciculus (H1 field of Forel). VA-VL = Motor Fasciculus and Ansa Lenticularis Thalamus. ZI = Zona Incerta. 23 Problems in the Pathways Hemiballismus: Unilateral basal ganglia lesion causing contralateral ballism. Often (40% of the time) caused by lesion of subthalamus (hyperdirect pathway). Huntington's Chorea: Autosomal dominant disease, causing degeneration of caudate nucleus neurons that project to external globus pallidus. Causes less inhibition of external globus pallidus, and indirect pathway is underactive. Eventually pallidum and substantia nigra cells die, and ventricles expand. Akinesia eventually replaces hyperkinesia, and usually death after ~15 years from first symptoms 24  Huntington Disease Gross morphology: Small brain with striking atrophy of caudate (putamen also has atrophy but less in early stages) Globus pallidus also becomes atrophied with lateral and 3rd ventricle dilation Atrophy of frontal lobe and sometimes the entire cortex Intranuclear protein inclusions (containing huntingtin) in striatum and cortex 25  What about Dopamine? (Substantia Nigra) Tonic dopaminergic activity in the nigrostriatal tract SNpc dopaminergic SNpr GABAergic is like “motor oil” for the corticospinal tract Dopamine receptors in striatum modulate E.g. needed to balance of direct and counteract tonic indirect pathways inhibitory output D1 receptors excite of medial globus the Direct Pathway pallidus and sub D2 receptors inhibit nigra reticulata. the Indirect Pathway 26 Basal Ganglia PRE -MOTOR CORTEX Circuits + Input Nuclei - GABA Striatum Lateral Globus Pallidus D2 - +D1 Indirect Path Direct Path Substantia GABA - GABA - Nigra pars Comp Medial Globus Pallidus Subthalamus + Substantia Nigra pars Ret. Dopamine Output Nuclei - GABA Thalamus + Glutamate + Spinal Motor Cortex Cord 27  Normal (Left) and Parkinson Disease (Right) Midbrain sections: Destruction of melanin- Parkinson’s Disease Symptoms: containing DA- Masked faces: Loss of ergic pars emotional expressions compacta Resting tremor: e.g. Pill neurons rolling with thumb and fingers, usually asymmetric, not effected by emotion Dopamine Parkinson’s Disease Festinating Gait: Shuffling Transporter gait, hard to change angles 19/100,000 prevalence scan Cogwheel Rigidity: UMN (DATscan): CT 1-2% of all individuals > 65 sign scan that Myerson’s Sign (Glabellar Loss of pars compacta dopaminergic neurons. Indirect Tap Reflex): Unable to detects pathway is disinhibited (D2), Direct pathway is resist blinking when radioactive tapped between eyebrows disfacilitated(D1) Ioflupane 18 gene locations (e.g. PARK18) related to PD; genetic bound to causes are more common in young onset Dopamine Transporters Mutation in alpha-synuclein gene, mutant protein in aggregates to form insoluble fibrils (“Lewy bodies”) nigrostriatal Commonly associated with other neurons “ synucleinopathies ” (e.g. Lewy Body Dementia) 28 Differential Diagnosis of “parkinsonism” Parkinson disease (idiopathic or genetic) Parkinson-plus degenerations (dementia with ? Lewy bodies, progressive supranuclear palsy, corticobasal degeneration, multiple system atrophy) Drug-induced parkinsonism (anti-dopaminergics) Rare but treatable diseases in young people: Wilson disease and Dopa-responsive dystonia Other: “vascular” parkinsonism (often only in legs), brain trauma, CNS infection 29 Warning Signs of “Parkinson’s Plus” Conditions Marked cerebellar dysfunction Early vertical gaze palsy Profound autonomic dysfunction within the first 5 yrs Parkinsonism restricted to the lower limbs Rapid progression of gait impairment to wheelchair in 5 yrs Profound & severe bulbar symptoms in 5 yrs Recurrent falls within first 3 yrs Bilateral symptoms at onset Absence of response to levodopa in a patient with at least moderate disease level 30  Side Effects of Dopamine Replacement Drugs Just increasing dopamine in brain will increase DA signaling in all dopamine pathways Too much DA in mesolimbic pathway (D2 receptors on the nucleus accumbens) causes positive symptoms of psychosis (e.g.delusions hallucinations) Too little DA in mesocortical pathway (D1 receptors in prefrontal cortex) worsens negative symptoms of psychosis (e.g. alogia, avolition, flat affect) Blocking DA (D2 antagonist) in nigrostriatal(mesostriatal) pathway worsens “extrapyramidal” hypokinetic symptoms (e.g. parkinsonism) Schizophrenia-like psychosis is from too little DA in mesocortical pathway or too much DA in mesolimbic pathway Too little DA in mesocortical pathway also causes too much DA mesolimbic pathway. So long term use of DA Antagonist antipsychotic drugs can lead to new problems: Tardive Dyskinesia: Frog-like licking and mouth movements caused by dopamine receptor super-sensitivity. Can be permanent. “Tardive” means late appearing, Punding: Complex, prolonged, purposeless, and stereotyped behaviors (such as arranging froot loops) from excessive phasic dopamine 31  Methanol Poisoning Methanol – Found in windshield washer fluid, paint removers, cleaners, solvents, antifreeze, bad moonshine. Metabolized to formaldehyde Decreased vision within days of exposure Longer term leads to blindness and hypertensive bilateral putaminal hemorrhages – with motor symptoms Flame test for bootleg moonshine: “red means dead” - is bunk 32 Cerebral Palsy Non-progressive motor disorder caused by dysregulation of cerebral cortex Usually from exposure to hypoxia or toxins during pregnancy ~1/3 cases involve only unilateral (contralateral) paralysis/paresis Very similar to UMN lesions talked about in Corticospinal lecture Spastic Gait: is result of Scissors Gait: is from UMN Lesion causing long term contractures hemiplegia/paresis and (e.g. in calf muscles a foot-dragging gait (leg and hip adductors) is posterior to hip) due to cerebral palsy 33  Practice Question 1 What symptoms would be seen in the patient with the MRI shown in the image? A) Athetosis B) Ballism C) Punding D) Hyperreflexia What is the name of the disease? Normal Brain for Comparison 34  Practice Question 2 What type of slice is this? What is the red structure? A lesion represented by the red blob would interfere with which pathway? A) Direct Pathway B) Indirect Pathway C) Hyperdirect Pathway D) Corticospinal Pathway E) No Symptoms 35