Exam 3 Flashcards
What do the main effector pathways from the basal ganglia arise from?
The main effector pathways from the basal ganglia arise from the cerebral cortex and include the corticospinal (pyramidal) tract as well as cortical projections to the brainstem.
What is the function of the basal ganglia?
This system is thought to be critical for the higher level behavioral planning that integrates cognitive, emotional and motivational information with sensorimotor signals in order to focus behavior on desired goals. The best-understood functions of the system include refinement of a motor plan for goal-directed actions, regulation of habit learning, regulation of action selection, and reward seeking.
What is the pallidum called?
Paleostriatum
What is in the dorsal striatum?
The dorsal (neo)striatum is comprised of the caudate nucleus (a C-shaped structure) and the putamen.
What is the lenticular nucleus?
The “lenticular nucleus” is comprised of the putamen and the globus pallidus. The term refers to the lentiform (wedge, lens) shape of this combined structure.
What are some diancephalic structures?
The diencephalic structures include the subthalamic nucleus and the habenula.
The most anterior part of the caudate nucleus is continuous with what?
The most anterior part of the caudate nucleus is continuous with the putamen and NAS. In fact, there are cells lodged between the fibers of the anterior limb of the internal capsule called the striatal cell bridges because they constitute a neuropil link between the caudate and putamen.
What do the limbs of the internal capsule separate?
The anterior limb of the internal capsule separates the caudate (which is medial) from the putamen (which is lateral), while the posterior limb of the internal capsule separates the thalamus (medial) from the lenticular nucleus (lateral).
What kind of neurons are striatal projection neurons?
Striatal projection neurons are called “medium spiny neurons” (MSNs) because their cell bodies are of medium size and their dendrites have spines. MSNs receive the major inputs to the BG system, and are the main output cells of the striatum. They are all GABAergic, but are subdivided into two important neurochemical classes: (i) those that co-localize substance P and have D1-like dopamine receptors, and (ii) those that co-localize enkephalin and have D2-like dopamine receptors.
What do the D1 receptors do?
The D1 family of receptors activates G-proteins that stimulate cAMP and thereby mediate postsynaptic excitation.
What do the D2 receptors do?
The D2 family inhibits cAMP and postsynaptic activity.
Where do MSN’s project?
MSNs project to the globus pallidus and substantia nigra.
Where is the globus pallidus located?
Globus pallidus is located lateral to the internal capsule and medial to the putamen.
What forms the dorsal pallidum?
The external (outer, lateral) GP (GPe) and the internal (inner, medial; GPi) segments are together referred to as the dorsal pallidum.
What are the output cells of the globus pallidus?
The output cells of all three parts of the GP are GABAergic (inhibitory).
What are the output cells of the subthalamic nucleus?
The output cells of STN are glutamatergic (excitatory).
What are the two parts of the substantia nigra?
The substantia nigra has two main parts: pars reticulata (SNpr) and pars compacta (SNpc).
What is the function of the SNpr?
SNpr is often considered a caudomedial extension of GPi. The output cells of both SNpr and GPi are GABAergic, and their target nuclei are similar (but not identical). However, SNpr has several unique projections, including one to the superior colliculus that is important for the coordination of eye, head and neck movements.
What is the function of the SNpc?
SNpc is one of the midbrain dopaminergic cell groups, and it provides an extremely important input to striatal MSNs.
What is the function of midbrain dopaminergic neurons?
Midbrain dopaminergic neurons, including those in SNpc and in the ventral tegmental area (VTA), modulate a broad range of behaviors from learning and working memory to motor control. They focus attention on significant and rewarding stimuli and thereby serve as an interface between cognitive, motor and limbic functional domains of the forebrain. VTA is located just medial and dorsal to SN. VTA provides dopaminergic input to the ventral striatum, as well as to limbic structures and the frontal lobes. These projections are thought to be abnormal in schizophrenia and other psychoses, and in drug addiction.
What is the most fundamental connectivity of the BG?
The most fundamental connectivity involving the BG system is a loop from cerebral cortex to and through the BG to the thalamus and then back to cortex. This loop can be parsed into input structures, internal processing structures, and output structures.
What receives most of the input in the basal ganglia system?
The striatum receives most of the input to the basal ganglia system.
What are the 5 main sources of input to the striatum?
The five main sources of this input are (1) cerebral cortex (massive, topographical and glutamatergic); (2) glutamatergic thalamic nuclei including (a) parts of the ventral group (VA, VL, VM, with parts of these now referred to as Vop and Vim), (b) the intralaminar nuclei (such as the centromedian nucleus – CM), and (c) the medial dorsal (MD) nucleus; (3) dopaminergic cells of SNpc and VTA; (4) serotonergic neurons of the raphé nuclei, and (5) noradrenergic input from locus coeruleus.
What is the topographic organization of inputs and outputs in the BG system?
Cortical afferents terminate topographically: the putamen receives input from sensory-motor areas, central striatum gets input from association areas of cortex, and the ventromedial striatum receives limbic-related input. The striatum in turn projects topographically to the GP and SNpr. GABA/Substance P MSNs project primarily to GPi and SNr, whereas GABA/Enkephalin MSNs project primarily to GPe. Because of the precise topography of these projections, the system as a whole can mediate multiple functions through functionally-specific loops.
What differs about the inputs and what are the projections of the ventral striatum?
The ventral striatum: While the basic cortex-BG-thalamus-cortex loop is generally similar in all BG loops, the ventral striatum also receives inputs from the amygdala and the hippocampal formation, and most of the serotonergic input to the striatum is directed to the ventral striatum. The ventral striatum (which contains both types of medium spiny neurons) projects to the ventral pallidum, The ventral pallidum in turn projects to STN and thalamus.
What are the intrinsic nuclei of the Basal Ganglia?
The STN, the SNpc, the VTA, and the GPe.
What is the nigrostriatal pathway?
The “nigrostriatal pathway” is the dopaminergic projection from SNpc to the striatum. This pathway degenerates in Parkinson’s Disease. Similarly, there is a dopaminergic projection from VTA to the ventral striatum; this pathway does not usually degenerate in Parkinson’s Disease. (This is a good example of selective neuronal vulnerability in the CNS.)
Where do GPe neurons project to?
Primarily the STN.
Describe the inputs to the STN.
STN receives a massive input from GPe and parts of the ventral pallidum. These inputs are topographically organized and are GABAergic. STN also receives topographically organized, glutamatergic input from cerebral cortex, and dopaminergic input from SNpc. At least some of this dopaminergic input degenerates in Parkinson’s Disease, and in fact STN neurons are hyperactive in the disease. The STN projects topographically to both the pallidum and substantia nigra.
What are the output structures of the BG?
The output structures of the BG are GPi, SNpr and VP.
What is the difference in the functionality of the SNpr and the GPi?
Although GPi and SNpr are often considered as one entity (by analogy to the neostriatum), for motor control-related basal ganglia activity, SNpr participates primarily in eye, head and neck control while GPi exerts control over the rest of the body.
What is the prerubral field?
All GPi/SNr projection neurons are GABAergic. Their axons travel via 2 main routes: the ansa lenticularis and the lenticular fasciculus. These two fiber bundles join together in a region just rostral to the red nucleus called the prerubral field, where they form a fiber bundle called the thalamic fasiculus, which carries the fibers to the thalamus. All these projections are distributed topographically in the thalamic nuclei.
Where do the GPi/SNr project to?
In addition to the thalmus, GPi/SNr also project to cell groups in the pontine and medullary reticular formation. These fibers allow the system to influence the reticulospinal tracts. In addition, as noted above, SNpr projects to the superior colliculus and thereby influences the tectospinal tract. Thus, the basal ganglia system influences both the lateral (pyramidal) and medial (extrapyramidal) motor systems.
What is the direct pathway of BG motor function?
The direct pathway includes projections from cerebral cortex to MSNs containing GABA/Substance P and D1 dopamine receptors. These MSNs project primarily to GPi, inhibiting it. Since GPi projects to thalamus, thalamus is disinhibited, resulting in cortical excitation. This is a positive feedback pathway that serves to reinforce and retain cortico-BG activity and facilitate movement. This can be further reinforced by the dopaminergic input, mediated by D1 receptors.
What are the 4 cardinal motor signs of parkinsonism?
Bradykinesia, tremor, rigidity, and postural instability. Among these, only bradykinesia (slowness) is required to make the diagnosis – patients must have this and at least one of the other three features.
What are the premotor signs of parkinsonism?
The four commonly accepted pre-motor signs are hyposmia, constipation, anxiety and/or depression, and REM sleep behavior disorder. Other non-motor findings include excessive saliva; rhinorrhea; erectile dysfunction in men; urinary urgency; excessive daytime sleepiness; impaired discrimination of colors; cognitive slowing; and apathy.
What does PD usually present with?
Parkinson disease typically presents with a unilateral onset and a persistent asymmetry (a “good side” and a “bad side”); rest tremor (as opposed to postural or kinetic tremor), excellent response to levodopa for at least 5 years with later development of levodopa-induced dyskinesias; and a clinical course of 10 years or longer.
Discuss the YES/NO movement signals in PD.
Recall the anatomy and physiology of the direct and indirect pathways that you have just learned. Think of the thalamus as the regulator of the cortex – the cortex by default wants to cause movement, and the thalamus sends a yes or no signal. Simplistically, the direct pathway is the YES signal that tells the cortex to move (complicated because it’s a double-negative: the striatum inhibits the GPi, which is trying to inhibit the thalamus and cortex). The indirect pathway is the NO signal (think of it as a triple-negative, with the striatum inhibiting the GPe, which inhibits the STN, which excites the GPi, which inhibits the thalamus and cortex). Dopaminergic signals from the substantia nigra pars compacta regulate this – dopamine reinforces the direct pathway and promotes movement (think of giving levodopa to a patient with PD), and inhibits the indirect pathway.
Discuss the differences between PD and MSA-P
MSA-P may present with classic motor signs of parkinsonism, but may be more symmetric than PD, and often patients have poor postural reflexes (and hence falls) very early in disease. Symptoms overlap and converge, so that patients who present with dysautonomia can (and often do) develop cerebellar signs, and vice versa. Cervical dystonia and camptocormia occur in MSA more than in PD.
What is Progressive Supranuclear Palsy (PSP)?
Sometimes called the “toppling disease” because of severely impaired postural reflexes, often at the onset of the illness. Deepened nasolabial folds, a ‘growly’ guttural voice, severe blepharospasm, freezing of gait, and relative extension of the neck (compared to the flexed posture seen in PD) are characteristic. The supranuclear vertical gaze palsy and square-wave jerks may not occur until later in the disease, but if present, are diagnostically helpful. This is the most axial and symmetric of the parkinsonisms. Minimal response to levodopa.
What is Corticobasal Syndrome/Degeneration (CBS/CBD)?
Like PSP, pathologically characterized by inclusions of hyperphosphorylated tau protein in neurons – and patients usually have poor postural reflexes and oculomotor abnormalities (impaired saccades and square-wave jerks). However, usually a markedly asymmetric clinical picture, with dystonia, myoclonus, and impaired praxis in the initially affected arm. The arm may also levitate or even become an “alien limb”, with purposeless movements. Initially may present as primary progressive aphasia or frontal lobe dementia. Essentially untreatable, although botulinum toxin injections may help with painful dystonia of the arm.
Discuss Secondary Parkinsonisms.
Tremor, bradykinesia, rigidity, and gait disorders can arise in the context of systemic diseases, toxins, or other insults to the appropriate regions of the brain. Often (but not always!) more symmetric than idiopathic PD, so a patient with symmetric symptoms and poor response to levodopa should have an MRI and further investigations. Of course, a meticulous history is always the most important tool to reach the diagnosis, and may reveal exposure to dopamine-blocking medications (including the so-called ‘atypical’ agents such as aripiprazole and olanzapine), exposure to environmental toxins (MPTP, carbon monoxide), recent infections, and family history of brain diseases (e.g., Huntington disease, Fragile X Syndrome, or Dopa-Responsive Dystonia). Any pharmacologic derangement of the dopamine system or structural insult to the substantia nigra or basal ganglia may produce parkinsonism.
What are Carbidopa and benserazide and why are they given?
Carbidopa and benserazide are peripheral dopa-decarboxylase inhibitors that do not cross the BBB; they are administered along with levodopa to inhibit peripheral conversion of levodopa and prevent side effects such as nausea/vomiting (“Sinemet”).
What are some dopamine agonists?
Pramipexole, ropinirole, rotigotine, apomorphine, and bromocriptine. Agonists can be delivered orally (pramipexole, ropinirole, bromocriptine), transdermally (rotigotine), and by subcutaneous injection (apomorphine). Agonist side effects include sudden episodes of extreme sleepiness (“sleep attacks”), impulse control disorders (gambling, shopping, hypersexuality), hypotension, hallucinations, nausea, and vomiting.
What is amantadine?
The antiviral drug amantadine serendipitously emerged as a treatment for the symptoms of PD in patients taking it to treat influenza. It may be particularly helpful in treating tremor and certain gait disorders, but is most often used to treat levodopa-induced dyskinesias. Side effects include constipation, leg edema, livedo reticularis, hallucinations, and hypotension.
What do MAO-B inhibitors do?
Dopamine is metabolized by enzymes that include monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT). Selective MAO-B inhibitors (selegiline and rasagiline), prolong the presence of endogenous and exogenous (from oral levodopa) and can be used alone in early disease, or later as adjunctive agents when levodopa begins to ‘wear off’ too quickly. They have a mild symptomatic benefit, but are very well tolerated. The COMT inhibitors (entacapone and tolcapone) are administered with levodopa and prolong its effects; tolcapone is rarely used due to incidents of chemical hepatitis caused by the drug.
What are the MAO-B inhibitors used to treat PD?
selegiline and rasagiline
What are the COMT inhibitors used to treat PD?
The COMT inhibitors (entacapone and tolcapone) are administered with levodopa and prolong its effects; tolcapone is rarely used due to incidents of chemical hepatitis caused by the drug.
Discuss anticholinergic drugs in PD.
Anticholinergic drugs (trihexyphenidyl, benztropine) can ameliorate tremor and dystonia in PD, but have significant side effects (dry eyes, constipation, urinary retention, cognitive impairment) and are poorly tolerated in elderly patients.
What to acetylcholinesterase inhibitors do in PD?
Acetylcholinesterase inhibitors (rivastigmine, donepezil, and galantamine) may improve concentration and memory in patients with PD. Their use is correlated with a lower risk of falling as well, perhaps due to increased attention to gait and obstacles. These drugs may improve hallucinations and other psychiatric symptoms in PD and DLB, and may obviate the need to treat with antipsychotics. Among the antipsychotics, only quetiapine and clozapine are considered useful in treating patients with PD and LBD without worsening the motor features of the illnesses, although there is little robust evidence for their use.
What does Botulin Toxin do in PD?
Botulinum toxin acts at the axonal terminal to prevent the release of vesicles of acetylcholine and other neurotransmitters. Intramuscular injections of toxin may help to relieve dystonia in patients with PD and other forms of parkinsonism, such as CBS. Injections of toxin into the parotid and submandibular saliva glands can improve sialorrhea.
