Organisation of the motor system Visual cortex Somatosensory cortex Cerebellum Basal ganglia Prefrontal cortex Supplementary motor cortex Pyramidal tract Premotor cortex Primary Motor nuclei of the thalamus Brainstem Extrapyramidal Motor pathways

Motor system includes Tracts Basal Ganglia (regulator) Corticospinal tract (Pyramidal tract ) Extra-pyramidal system Basal Ganglia (regulator) Cerebellum (regulator)

Motor regulators Motor control systems outside the cortex Cerebellum -controls neural ‘programs’ for the executionl of skilled movements Basal ganglia - a group of subcortical forebrain nuclei (caudate nucleus, putamen (= striatum), globus palludus, subthalamic nucleus) - modulate patterns of motor activity

MOVEMENT DISORDERS Parkinson disease Huntingtons disease

PARKINSONS DISEASE Effects dopaminergic neurons Neurons are lost from substantia nigra Rarely presents before 50 years Neurodegenerative disease

Neuropathology of Parkinson’s disease nigro-striatal pathway degeneration leading to a depletion of striatal dopamine some degeneration of other dopamine pathways too Striatum Dopamine Glutamate GABA X

CLINICAL FEATURES Characterized by: Tremors Rigidity bradykinesia

X Huntington’s disease Onset of symptoms usually at 30 to 45 years Genetically determined (single dominant gene) Causes degeneration of the output neurones from the striatum, reducing inhibitory modulation of motor function Progressive disease causing involuntary muscle jerks Striatum Dopamine Glutamate GABA X

HUNTINGTONS DISEASE Inherited disorder Autosomal dominant Males females equally affected Presents during the 4th decade Chorea which worsens with time Cognitive disorders Dementia

Motor control systems outside the cortex Cerebellum -controls neural ‘programs’ for the executionl of skilled movements Basal ganglia - a group of subcortical forebrain nuclei (caudate nucleus, putamen (= striatum), globus palludus, subthalamic nucleus) - modulate patterns of motor activity

GROSS STRUCTURE

Feed-back and feedback control circuits

Cerebellar connections Input: Sensory cortex (somato, visual) Vestibular system Spinocerebellar tract Output: Motor cortex Thalamus motor nuclei Extra-pyramidal tracts

The main functions of cerebellum: body equilibrium regulation of muscle tone coordination of movements

A t a x i a means disturbances of equilibrium of the body and coordination of movements. Cerebellum lesion produces cerebellar ataxia

Cerebellar ataxia Attactic gait – patient can’t to walk Disorders of equlibrium – patient can’t to stand Intention tremor – is dynamic tremor (it is more expressed while moving and disappears while rest) Nystagmus Dysmetria (disturbed ability to gauge distances)

Sleep

Why Do We Need Sleep? Adaptive Evolutionary Function safety energy conservation/ efficiency Restorative Function body rejuvenation & growth Brain Plasticity enhances synaptic connections memory consolidation

The ascending arousal system promotes wake B. A. (A) In the 1970s and 1980s, the neurochemistry of several brainstem ‘arousal’ centers was elaborated. In the contemporary view, the ascending arousal system consist of noradrenergic neurons of the ventrolateral medulla and locus coeruleus (LC), cholinergic neurons (ACh) in the pedunculopontine and laterodorsal tegmental (PPT/LDT) nuclei, serotoninergic neurons (5-HT) in the dorsal raphe nucleus (DR), dopaminergic neurons (DA) of the ventral periaqueductal gray matter (vPAG) and histaminergic neurons (His) of the tuberomammillary nucleus (TMN). These systems produce cortical arousal via two pathways: a dorsal route through the thalamus and a ventral route through the hypothalamus and basal forebrain (BF). The latter pathway receives contributions from the orexin and MCH neurons of the lateral hypothalamic area (LH) as well as from GABA-ergic or cholinergic neurons of the BF. Note that all of these ascending pathways traverse the region at the midbrain-diencephalic junction where von Economo observed that lesions caused hypersomnolence. Fuller, PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms 21(6):482-93 (2006) Slide by Patrick Fuller, PhD and Jun Lu, PhD Modified from Fuller et al., J Biol Rhythms, 2006

Hypocreatin (orexin)

Sleep/Waking “Flip-Flop” vlPOA= ventrolateral preoptic area ACh = acetylcholine NE = norepinephrine 5-HT = serotonin

Narcolepsy VS Insomnia

Melatonin: Produced by pineal gland, released at night-inhibited during the day (circadian regulation); initiates and maintain sleep; treat symptoms of jet lag and insomnia Melatonin, ramelteon, and agomelatine are all agonists for melatonin 1 (MT1) and melatonin 2 (MT2) receptors [87]. Ramelteon has an affinity for both receptors that is 3–16 times greater than melatonin, and it has a longer half-life. Agomelatine also has a high affinity for melatonin receptors, in addition to acting as an antagonist at serotonin 5-HT2C receptors to decrease anxiety as well as promote sleep. Both MT1 and MT2 play a role in sleep induction; MT1 activation suppresses firing of SCN neurons, and MT2 receptors are involved in entraining circadian rhythms. Melatonin and the SCN impact sleep and wake in several ways. The SCN receives light signals from the retina, which are transmitted to the dorsal medial hypothalamus (DMH). The DMH acts as a relay center for signals to regions involved in sleep and wake maintenance, including inhibitory inputs to the VLPO and excitatory inputs to the LC [14, 95]. Melatonin acts through MT1 receptors to suppress firing of SCN neurons, thereby disinhibiting the sleep-promoting neurons in the VLPO, suppressing excitatory signals to wake-promoting regions, and increasing sleepiness [87].

Biological Clocks Suprachiasmatic nucleus Pineal gland A nucleus situated atop the optic chiasm responsible for organizing circadian rhythms. Pineal gland A gland attached to the dorsal tectum; produces melatonin and plays a role in circadian and seasonal rhythms.

SCN and sleep Wild type animal with period of ~24h Tau mutant Basics of Sleep Guide: Chronobiology SCN and sleep 5/18/2018 5/18/2018 Wild type animal with period of ~24h Tau mutant with period of ~20h A SCN lesioning B Transplanting SCN of donor with ~20-h period C SCN lesioning abolishes circadian rhythm Wild type animal acquires period of donor (~20h) Modified from Ralph and Lehman, Trends Neuro 1991 Scheer-Shea Set #8 34 34

Coffee

Coffee During waking, brain consume ATP

Coffee During waking, brain consume ATP adenosine

Coffee During waking, brain consume ATP adenosine Adenosine bind to A1 receptor Inhibit acetylcholine neurons

Coffee During waking, brain consume ATP adenosine Adenosine bind to A1 receptor Inhibit acetylcholine neurons Caffeine and Theophylline are A1 antagonist

Sleep stages Awake Stage 1 Stage 2 Stage 3 Stage 4 Slow wave sleep

Sleep stages Awake Stage 1 Stage 2 Stage 3 Stage 4 Rapid eye movement sleep (REM) Slow wave sleep (NREM)

Types and Stages of Sleep: NREM Stage 1 – eyes are closed and relaxation begins; the EEG shows alpha waves; one can be easily aroused Stage 2 – EEG pattern is irregular with sleep spindles (high-voltage wave bursts); arousal is more difficult

Stage 3 – sleep deepens;; theta and delta waves appear; vital signs decline; dreaming is common Stage 4 – EEG pattern is dominated by delta waves; skeletal muscles are relaxed; arousal is difficult

REM Sleep Presence of beta activity (desynchronized EEG pattern) Physiological arousal threshold increases Heart-rate quickens Breathing more irregular and rapid Brainwave activity resembles wakefulness Genital arousal Loss of muscle tone (paralysis) Vivid, emotional dreams May be involved in memory consolidation

REM Dreaming NREM Dreaming “vivid and exciting” “just thinking” ~3 per night Longer, more detailed Fantasy world nightmares “just thinking” Shorter, less active Logical, realistic

Dream theories Activation synthesis theory Continual activation theory Sensory experiences are fabricated by the cortex as a means of interpreting signals from the PGO activity. Continual activation theory Encoding of short term into long-term memories. NREM sleep processes the conscious-related memory (declarative memory), REM sleep processes the unconscious related memory (procedural memory). Dream theories

Sleep Disorders insomnia sleep walking, talking, and eating nightmares and night terrors narcolepsy sleep apnea IM: Activity Handout 6.2: Which Sleep Disorder Is It? 49

Sleep Disorders Insomnia: persistent problems in falling asleep, staying asleep, or awakening too early Sleep Apnea: repeated interruption of breathing during sleep Narcolepsy: sudden and irresistible onsets of sleep during normal waking hours

Sleep disorders Nightmares: anxiety-arousing dreams occurring near the end of sleep, during REM sleep Night Terrors: abrupt awakenings from NREM sleep accompanied by intense physiological arousal and feelings of panic

Sleep Disorders Somnambulism…sleepwalking 40% of children will have an episode, peaking at between 11-12 years of age; Can be induced if arouse children during NREM; associated with complete amnesia, Occurs within 2 hours of falling asleep.. EEG..reveals both waking and sleep signals. Considered benign.

Coma & Brain death Definition: Greek in origin – “deep sleep or trance” It refers to an unconscious state characterised by a lack of both arousal and responsiveness

language

Broca Aphasia (Expressive aphasia) Left hemisphere Broca's aphasia - Sarah Scott - teenage stroke http://www.youtube.com/watch?v=1aplTvEQ6ew

Wernicke Aphasia (Receptive aphasia) Left hemisphere Wernicke's Aphasia Interview with Amelia Carter http://www.youtube.com/watch?v=UtadyCc_ybo

(right hemisphere)

Prosody of speech (right hemisphere)