UofR : Neural Basis of Cognition

1. UofR: Neural Basis of Cognition Lecture 4 Motor Control, Part II Motor Disorders

2. Motor Disorders • As we saw in the last lecture, motor control is a complex system • There are many ways in which motor control can be disrupted or damaged • We will go over some of these ways • First, a brief review of basic synaptic transmission

3. Synaptic Transmission

4. Synaptic Transmission

5. Parkinson’s Disease • Damage to dopaminergic neurons of the substantianigra • May result from • Encephalitis • Example: encephalitis lethargica(aka von Economo’s encephalitis) of the 1910s and 1920s • Toxins • Example: adults in their twenties and thirties in the mid 1980s developed Parkinson’s due to use of a synthetic heroin, MPTP, which the body converts into methylphenylpyridinum MPP+, which is toxic to dopaminergic neurons (“frozen addicts”) • Trauma • Neural degradation

6. Parkinson’s Disease

7. Parkinson’s Disease • Symptoms are not evident until 60% of nerve cells and 80% of dopamine has been lost • This is due to the brain’s high ability to compensate through upregulation of dopamine production and other mechanisms • Generally around 60-70 years of age, compensation mechanisms fail and behavioral effects are observed

8. Parkinson’s Disease • Usually observed bilaterally (unilateral Parkinson’s is called “hemi-Parkisonism”) • Symptoms: • Tremors • Generally of the arms and hands, at rest (“pill rolling”) • Rarely seen during deliberate movements • Cogwheel rigidity • Increased muscle tone in the extensor and flexor muscles • Term refers to mechanical nature of movements

9. Parkinson’s Disease • Symptoms: • Akinesia or bradykinesia • Akinesia: poverty of movement • Bradykinesia: slowness of movement • “Parkinsonian mask” • Disturbances of posture • Affects muscle groups throughout the body • Occurs due to difficulty counteracting force of gravity • Walking, recovering from loss of balance, postural transitions, &c. become difficult • Patients tend to shuffle

10. Parkinson’s Disease • Not all symptoms are typically observed in each person • Rigid-bradykinetic-predominant form versus tremor predominant form • Forms also differ in degree of intellectual impairment and clinical course of disease • These may be less severe in patients with the tremor predominant form

11. Parkinson’s Disease • Overactivation of the cholinergic system is associated • How would one treat Parkinson’s? • First, dopamine synthesis

12. Dopamine Synthesis

13. Dopamine Synthesis

14. Parkinson’s Disease • DA cannot be administered orally because it does not pass the blood-brain barrier • Tyrosine is before the slow step in DA synthesis (and is already plentiful in a normal diet) • L-DOPA is therefore used • Anticholinergic compounds help alleviate overactivity of the cholinergic system

15. Parkinson’s Disease • Experimental (and controversial) treatments: • Grafting of fetal tissue with dopamine-producing cells to the substantianigra • Demonstrated in monkeys • Varying success in human trials • Pallidotomy (destruction of globuspallidus) to reduce tremors • Implantation of electrodes to artificially produce simulation in the subthalamic nuclei (which inhibit the GP)

16. Huntington’s Disease • Caused by degeneration of the striatum • Symptoms: • Difficulty initiating movements • Abnormal speed, initiation of voluntary eye movements • Abnormal movements (chorea) • Cognitive deficits (eventually dementia) • Psychiatric symptoms • Inherited • Gene remains dormant until 30-45 years of age, followed by slow decline of 10-15 years and ending in death • No cure or established treatment of symptoms

17. Huntington’s Disease • Degree of atrophy of caudate has been directly linked to eye-movement abnormalities, disruptions on tests requiring writing speed, tests of complex psychomotor processing, severity of cognitive empairment, but not with the severity of chorea • Starkstein, S. E., J. Brandt, et al. (1988). "Neuropsychological and neuroradiological correlates in Huntington's disease." J NeurolNeurosurg Psychiatry 51(10): 1259-63.

18. Tourette’s Syndrome • Symptoms: • Tics: typically involve face and head, can affect limbs and the entire body • Complex movements such as touching, hitting, jumping, can occur • More severe symptoms: • Cries and vocalizations • Echolalia: repeating what was just said • Coprolalia: obscene speech • Seen in childhood, usually before age of 11

19. Tourette’s Syndrome • Much more common in males • Also associated with obsessive-compulsive behavior (50% of children show some symptoms, 25% have full-blown OCD) • People with Tourette’s say that trying to suppress a tic makes the urge to do it become stronger and stronger until carried out • Some association with ADHD as well

20. Tourette’s Syndrome • Cause isn’t known • Evidence: • Linked to ADHD and OCD • Drugs that increase DA levels aggravate symptoms • Drugs that block DA receptors ameliorate symptoms • Homovanillic acid (HVA), a metabolite of DA, found at lower levels • Therefore it is believed that Tourette’s is caused by dysfunction of the dopaminergic system, largely comprised of the basal ganglia, specifically by hypersensitivity to DA • Treatment usually involves blocking of D2 receptors with drugs such as haloperidol, which reduces vocal tics in 85% of patients • Few patients stay on haloperidol due to unpleasant side effects • Treatments: • Leckman, J. F. and M. A. Riddle (2000). "Tourette's syndrome: when habit-forming systems form habits of their own?" Neuron 28(2): 349-54.

21. Tourette’s Syndrome

22. Tourette’sSyndome

23. Tardive Dyskinesia • Occurs in 20-40% of long-term conventional antipsychotic drugs that act to block dopamine • Symptoms: Increased motor movements that affect the face, especially the mouth and lips, sometimes the trunk and limbs, including: • Chorea • Tics • Akathisia (compulsive, hyperactive, “fidgety” movements of the legs) • Dystonia (painful, sustained muscle spasms of the same muscle groups, frequently causing twisting and repetitive movements or abnormal postures)

24. Tardive Dyskinesia • Identifying which individuals on anti-psychotic medications will exhibit tardive dyskinesia is nearly impossible because the symptoms appear after at least three months of drug use • Lowering dosage completely eliminates the problem in only ~30% of patients (and lower dosages may not be enough to treat psychotic behavior) • New antipsychotic treatments that do not block D2 receptors like traditional antipsychotics

25. Cortical Motor Disorders • Most subcortical disorders involve bradykinesia , akinesia, or some form in increased movement • Cortical motor disorders have a different effect, tending to disrupt the ability to pursue specific plans of motor action or to relate motor action to meaning

26. Alien Limb Syndrome • Symptoms: • Patients feel as if one of their limbs is “alien” –it seems to move on its own, seems as though it doesn’t “belong” to its owner, or seems to have its own “personality” • Patients commonly complain that their limbs do not obey them or that they make involuntaryand complex movements, typically groping and grasping • Competition between hands or difficulty in bimanual control • For more examples: • Leckman, J. F. and M. A. Riddle (2000). "Tourette's syndrome: when habit-forming systems form habits of their own?" Neuron 28(2): 349-54. • In almost all cases, only one limb, contralateral to a site of lesion, is affected

27. Alien Limb Syndrome • No consensus on what type of damage causes alien limb syndrome • Usually observed after infarction (blockage of blood vessel) in territory of the anterior cerebral artery, the anterior two thirds of the corpus callosum, and the anterior cingulate cortex • Damaged areas of the frontal cortex tend to invlude the SMA

28. Alien Limb Syndrome • No cure • Treatments: • Keeping the limb “busy” with repetitive action or with holding an object • Muscle relaxation • Warm water to “calm” the limb • Issuing verbal commands to the limb

29. Apraxia • Apraxia: an inability to perform a skilled, sequential, purposeful movement, that cannot be accounted for by disruptions in more basic motor processes such as muscle weakness, abnormal posture or tone, or movement disorders • Evidence that apraxias are a higher-order motor deficit: • Usually bilateral • Low-level motor processes are intact • Complex movements can be performed spontaneously but not purposefully • Classification of apraxias is a subject of debate; one approach is by the part of the body affected

30. Apraxia • Oral apraxia • difficulty performing voluntary movements with the tongue, lips, cheek, larynx (clearing one’s throat, yawning, sticking out one’s tongue, sucking on a straw can be impaired) • Limb apraxia • Difficulty manipulating items and tools • When asked to imitate manipulation of an object, a patient may use a limb to represent that object, e.g. stirring a cup of water with a finger when asked to imitate using a spoon

31. Apraxia • Alternative classification scheme, due to Lipemann in 1905: • Ideational (conceptual) apraxia: inability to form an “idea” of a movement, so a person cannot determine which actions would be necessary and in what order they should occur. • Example: cannot light a candle due to inability to sequence the necessary events • Ideomotor apraxia: disconnection between the idea of a movement and its execution • Abstract though simple actions such as waving “hello” would be impaired • Complex sequences of moves can still be performed • There is debate on how, exactly to differentiate between these two classifications

32. Apraxia • Underlying cause is unclear • Sequencing of motor acts? • Understanding of abstract meanings of motor acts? • Linkage between visual/kinesthetic cues with motor plan?

33. Apraxia • Other varieties of apraxia, related to spatial understanding • Constructional apraxia: items cannot be correctly manipulated in regard to their spatial relations, e.g. wooden blocks cannot be manipulated to copy an arrangement created by someone else • Dressing apraxia: difficulty manipulating and orienting both clothes and limbs so that clothes cannot be put on correctly • Generally observed after right hemisphere lesions and often associated with spatial-processing difficulties and hemineglect; thus, often considered to be motor manifestations of visuoconstructive disorders

34. Apraxia • Other apraxias can occur from disconnection syndrome • Callosal apraxia: inability to perform movements or manipulate objects with the left hand in response to verbal commands due to damage to the corpus callosum • Verbal instructions are understood via Wernicke’s area and translated into a motor plan in the left hemisphere, but the motor plan cannot be relayed to the right hemisphere to control the left hand

35. Motor control • Neural control of motor actions is a very complex system that is highly regulated and integrates many different areas of the brain • There are many ways in which normal motor control can be disrupted, sometimes in very strange and unusual ways • As our understanding of motor control increases, treatments improve • Motor control also involves a huge amount of work done by other portions of the brain, especially relating to the various sensory modalities and our understanding of the world; these will be subjects for further discussion.