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Neuroscience- Hilary term 2014
Vestibular system/posture:???Though NYSTAGMUS can be demonstrated physiologically as part of the VOR in an experiment whereby a subject is rotated in a chair and their eyes movements are tracked, it can also happen PATHOLOGICALLY ? In unilateral vestibular hypofunction, there is a pattern of afferent vestibular signalling analogous to that stemming from rotation away from that side: there is a strong feeling of SPINNING (vertigo) and the VOR responds by generating the pathological nystagmus. If lesion is PERIPHERAL, nystagmus can be suppressed by vision and will recover over time (relies on calibration by cerebellum). If lesion is central in VESTIBULAR NUCLEI, there is little suppression and less recovery. Bilateral vestibular hypofunction (e.g. from OTOTOXICITY caused by antibiotics) can be devastating. Patients appear normal but cannot read street signs or recognise friends' faces whilst walking in the street (lack of VOR; they have to stop to see). They can ever 'see' their own HEARTBEAT ? no VOR compensating for the tiny head movements caused by one's own pulse. ? Lack of orientation whilst SWIMMIMG; marked LOSS of STABILITY when subject asked to stand and CLOSE one's EYES. The CEREBELLAR FLOCCULUS is essential for the ADAPTIVE CHANGES in the VOR. ? It normally learns to correlate visual input with the vestibular input through experience. This is important as the VOR has to be constantly CALIBRATED to maintain its accuracy in the face of changes such as INJURY or AGEING to vestibular and visual organs or pathways (or indeed in patients who wear glasses). Patients with LESIONS in the lateral part of the vestibulocerebellum DO NOT undergo these adaptive changes. SINGLE-CELL RECORDINGS in the "vestibular cortex" (S-1, parietal association cortex, area near S-2) show that these areas receive visual AND somatosensory inputs, in addition to the vestibular ones. ? Site of integration of these modalities so that a UNIFYING PERCEPTION of position and movement in space can be experienced? ? A few patients with LESIONS in the PARIETAL CORTEX perceive their visual environments to be rotated by 90-180 degrees. (Primarily probably an interference with otolithic processing). ZEBRAFISH KNOCKOUTS for the gene "starmaker" causes malformation of the OTOCONIA (calcium carbonate crystals in the otolithic organs) and loss of otolithic function. BENIGN PAROXYSMAL POSITIONAL VERTIGO is where pieces of the otolithic membrane BREAK OFF and fall into the semicircular canal, displacing fluid. Common in elderly. ? The EPLEY MANOEUVRE is used to treat this, and works by allowing the free floating particles from the affected semicircular canal to be relocated back to the utricle using gravity, where they can no longer stimulate the cupula. MENIERE'S DISEASE is where there is mild to severe vertigo due to IMPROPER DRAINAGE of the endolymphatic duct and thus DILATION of the endolymph system. Sometimes this is treated SURGICALLY to reduce this buildup; however as a last-resort STREPTOMYCIN can be injected to KILL the vestibular hair cells.
???Generally DAMAGE to the vestibulospinal system results in ATAXIA and POSTURAL INSTABILITY. For example, if unilateral damage occurs to the lateral vestibulospinal tract, the person will likely sway to that side and fall when walking. This occurs because the healthy side "over powers" the weak side in a way that will cause the person to veer and fall towards the injured side. Potential early onset of damage can be witnessed through a positive ROMBERG'S TEST. Patients will likely regain postural stability over weeks and months through a process called VESTIBULAR COMPENSATION, related to a greater reliance on OTHER sensory information (nevertheless there may still be residual deficits during COMPLEX movements). Nevertheless, SHERRINGTON showed that interrupting the pathway from brain/midbrain to spinal cord through using the DECEREBRATE CAT model (whilst keeping the MEDULLA connections intact) still resulted in a RIGID ANTIGRAVITY STANCE; presumably this represents the residual importance of the CUTAENOUS MECHANORECEPTORS on the soles of the feet. When visual info DOESN'T MATCH vestibular info, MOTION SICKNESS occurs. (E.g. travelling in a car and reading; microgravity). As above though, over time this RECTIFIES due to vestibular compensation. ? Most common hypothesis for the cause is that it functions as a DEFENSE mechanism against NEUROTOXINS. As a result of the discordance, the brain will come to the conclusion that one of the inputs is hallucinating and further conclude that the hallucination is due to poison ingestion. The brain responds by inducing vomiting, to clear the supposed toxin. VISION strongly influences posture: place a subject on a tilted chair in a dummy room tilted the other way and they report the height to be between the apparent height and actual height ? Static visual and vestibular contributions. The STATIC visual contributions are from the LEARNT horizontal and vertical elements of the environment around us in modern society (though were they important in more natural environments from which we evolved?) Moreover OPTOKINETIC REFLEXES can compensate for VORs once the semicircular canals ADAPT. Movements of the eyes, or visual info moving across the retina, informs about movement of head because of EFFERENCE COPY of oculomotor output (eyes not subject to same external influence as limbs so proprioceptive input not necessary). Visual and vestibular info are weighted about equally: RECORDINGS from vestibular nuclei show they receive info from both ? as mentioned the CEREBELLUM is needed to calibrate both inputs. The POSITIVE SUPPORTING REACTION: is a decerebrate animal is suspended in the air with its legs hanging down, PUSHING UP on the sole of one of its feet will elicit an EXTENSOR RESPONSE in that limb. Variations include STEPPING and HOPPING reactions. NECK REFLEXES: before info can be used about the position of the head in space to inform about body position in space, we need to know the POSITION OF THE HEAD RELATIVE TO THE BODY. ? Comes from proprioceptors in the neck (mostly joint receptors in the vertebrae). This reflex can be demonstrated in animals by moving the body whilst keeping the head still ? Causing DORSIFLEXION of the neck by tilting the BODY up results in FRONT-LEG EXTENSION and REAR-LEG RETRACTION. Cerebellum:
?DISORDERS of the cerebellum are in marked contrast to the PARALYSIS caused by damage to the cerebral cortex. Generally, movements are DISRUPTED rather than abolished. There are five major symptomatic manifestations: Hypotonia- diminished resistance to passive limb displacements. For example, a leg may OSCILLATE like a pendulum in response to the knee jerk reflex rather than immediately coming to rest. Astasia-abasia- an inability to stand or walk. ? Many cerebellar patients compensate when sitting or standing by SPREADING their feet in an attempt to stabilise balance. Ataxia- the abnormal execution of multi-jointed voluntary movements; characterised by a lack of co-ordination. Patients have difficulty in controlling the SIZE of a movement (dysmetria) and the RATE and REGULARITY of repeated movements. (Dysdiadochokinesia). The latter can be shown by asking a patient to pronate and supinate rapidly; the patient is unable to do so, presumably because he cannot issue the command to REVERSE a movement SUFFICIENTLY SOON after having sent the command to start it. Action/intention tremor: form of tremor both DURING and at the END of movement- but not seen at rest- (usually 3-4Hz oscillations) when the patients attempt to stop the movement using antagonist muscles: this is a series of ERRONEOUS CORRECTIONS of the movement. Suggests that the cerebellum is important in the PROPERLY TIMED SEQUENCE of activation in agonist and antagonist muscles. ? When the dentate and interposed nuclei are EXPERIMENTALLY INACTIVATED in animals, contraction of the antagonist muscle that terminates a rapid single-joint movement (which normally starts early, well before there is any time for sensory feedback, so must be programmed with the movement) is DELAYED until the limb has OVERSHOT its target. ? Programmed contraction is thus replaced by a feedback correction driven by SENSORY INPUT, and results in another error, which in turn needs a new adjustment. Loss of automatic movements: this is especially true for motor acts made up of MULTIPLE SEQUENTIAL MOVEMENTS. E.g. a patient with a LESION of the RIGHT cerebellar hemisphere reports that he has to THINK OUT each movement of the right arm. ? Suggests that normally motor programmes are STORED within the cerebellum and thus movement is seamlessly controlled by cerebellar inputs and outputs; when this MALFUNCTIONS it seems that the CEREBRAL CORTEX has to play a more active role in programming the motor actions, which is a much SLOWER PROCESS.
? These symptoms can be replicated in a healthy subject during the execution of any genuinely NEW tast (e.g. drawing whilst looking in a mirror). In this case dysmetria and intention tremor are seen.
? Other symptoms may include DYSARTHRIA (slurred speech- whilst normal people don't have to think about the sequence of mouth and tongue actions that one makes when speaking, cerebellar patients have to think about the formation of each phoneme- related to above) and NYSTAGMUS. LESIONS of the CEREBROCEREBELLAR lateral hemispheres have delays in INITIATING MULTI-JOINT MOVEMENTS, and have irregularities in the TIMING of the individual movement components. ( Same defects seen in primates with lesions of the DENTATE NUCLEUS). Some neurons in the dentate nucleus fire 100ms BEFORE a movement begins, and even before the discharge of neurons in the PRIMARY
???MOTOR CORTEX or INTERPOSED NUCLEI (which are more concerned with the EXECUTION of movement). Moreover, the onset of firing in the primary motor cortex (and thus the onset of movement) can be DELAYED experimentally by INACTIVATING the dentate nucleus. MULTIPLE SCLEROSIS seems to regularly involve the cerebellum ? patients can become ataxic and 25-60% develop tremor of some sort. LATERAL MEDULLARY SYNDROME- due to occlusion of the posterior inferior cerebellar artery, results in infarct of the INFERIOR CEREBELLAR PEDUNCLE. Amongst a whole host of other neuronal deficits, this results in the cerebellar symptoms of ataxia, dysmetria (past pointing), and dysdiadokokinesia. Studies of the movements of patients with CEREBELLAR ATAXIA suggest that the INTERACTION TORQUES of a multi-segment limb are represented by an INTERNAL MODEL in the cerebellum. Because of the structure of the arm and the momentum it develops when moving, movement of the FOREARM ALONE causes a force that moves the UPPER ARM. Thus in order to flex one's elbow without simultaneously moving the shoulder, muscles acting at the shoulder must contract to prevent this movement. In control subjects, these STABILIZING CONTRACTIONS occur almost perfectly to counter the very specific and personal forces that the subject generates with the initial movement. However patients with cerebellar ataxia are unable to compensate for the interaction torques; they thus experience greater difficulty with MULTIJOINT vs single-joint movements. It is generally suggested that the cerebellum uses an INTERNAL MODEL to anticipate these forces, and this is generated through LEARNING, which also enables the model to be customised in the light of change ? E.g. ADAPTING to a CHANGING IN GAIT after a HIP REPLACEMENT. CEREBELLAR COGNITIVE AFFECTIVE SYNDROME ? a constellation of deficits in the cognitive domains of executive function, spatial cognition, language, and affect resulting from damage to the cerebro-cerebellum. Impairments of EXECUTIVE FUNCTION include problems with planning, set-shifting, abstract reasoning, verbal fluency, and working memory. Deficits in SPATIAL COGNITION produce visual-spatial disorganization and impaired visual-spatial memory. PERSONALITY CHANGES manifest as blunting of affect or disinhibited and inappropriate behavior. These cognitive impairments result in an overall lowering of INTELLECTUAL FUNCTION. Overall this CHALLENGES the traditional view of the cerebellum being responsible solely for regulation of motor functions; it is now thought it is responsible for monitoring both motor and non-motor functions.
? DYSMETRIA OF THOUGHT HYPOTHESIS proposes that the non-motor deficits are caused by a DEREGULATION of the cognitive and emotional behaviours, in a COMPARABLE way to the dysmetria of movement that describes the motor malfunctions. These ideas build upon earlier OBSERVATIONS from TRACING STUDIES that the cerebellum is linked with the prefrontal cortex, limbic system, and reticular structures. Analyses of LTD in SLICES and CULTURES of cerebellum, whereby the postsynaptic potentials of Purkinje cells are recorded, show that following CONCURRENT stimulation of climbing fibres and parallel fibres there is a DEPRESSION in Purkinje cell responses to subsequent stimulation of the SAME parallel fibres but NOT to stimulation of parallel fibres that had not been
?stimulated earlier with the climbing fibres. ? According to Marr's theory, the climbing fibres respond to SPECIFIC MOVEMENT ERRORS during an inaccurate movement and depress the synaptic strength of those parallel fibres on the Purkinje cell that were involved in that error. ? Such synaptic PLASTICITY could be the mechanism could be the mechanism that creates and maintains accurate INTERNAL MODELS of the dynamics and kinematics of body parts that the cerebellum uses to AUTOMATE motor (and cognitive skills). HOWEVER, evidence has recently been provided that CONTRADICTS with this hypothesis. ? Researchers used PICK KNOCKOUT MICE that were unable to undergo PKC-mediated AMPA receptor INTERNALISATION (and thus unable to undergo LTD), and using three different cerebellar coordination tasks (adaptation of the vestibulo-ocular reflex, eyeblink conditioning, and locomotion learning on the Erasmus Ladder), showed that there was NO motor learning impairment in these mutant mice. ? Suggests that PF-PC LTD is not essential for cerebellar motor learning; however, the experiment cannot account for any redundant compensatory mechanisms of plasticity. Perhaps is telling of the fact that there could be many other types of plasticity other than LTD involved?
Neat example of cerebellar learning: make a subject wear PRISMS that deflect the light path sideways. When a person plays darts with the prisms that deflect light to the right, the initial dart throw lands to the LEFT side of the target. However the subject gradually ADAPTS to the distortion through practice, such that the darts land on target within 30 throws. However, if at this stage the prisms are removed, the adaptation PERSISTS, and the darts hit the right side of the target by the same distance as the prism-induced error. ? Patients with a cerebellar damage are unable to adapt in this task. Basal ganglia:?In CLINICAL DISORDERS of the basal ganglia, there is still an intact motor apparatus (e.g. though their movements are slowed, Parkinsonian patients can transiently show flawless movement during KINESIA PARADOXICA) --> basal ganglia clearly is instead nestled within the complex realms of HIGHER MOTOR CONTROL. Though the classical model of the BG circuitry has been DISPUTED, recent research re-affirmed the DIRECT/INDIRECT pathway dogma. ? OPTOGENETIC control (the insertion of light-sensitive proteins into neurons to control welldefined events within specific cells of living tissue) was used to selectively target the medium-spiny neurons involved in either pathway: Cre-dependent viral expression of CHANNELRHODOPSIN-2 in transgenic mice expressing Cre recombinase under the control of the regulatory elements for either the D1 (excitatory) or D2 receptor. ? This in vivo activation of direct or indirect pathways generated pathway-specific regulation of movement: turning on the laser bilaterally activating the indirect pathway inhibited movement in these mice; it induced a PARKINSONIAN-LIKE STATE that was REVERSED upon activation of the direct pathway. In a broad sense, nigrostriatal dopamine input leads to the ACQUISITION and REINFORCEMENT of behaviours that are tuned to BOTH respond to SALIENT STIMULI and those that lead to REWARD (or conversely to the latter case, enable the avoidance of behaviours that lead to adverse outcomes.) In the FORMER, dopamine sets the "effort threshold" for initiating behaviours ? the
??higher the level of dopamine activity, the lower the impetus required to evoke a given behavior. This is highlighted PATHOLOGICALLY: in PD patients there is stiffness and greatly reduced movement---only when people with the disease are confronted with strong stimuli such as a serious threat can their reactions be as vigorous as those of a healthy person. In the opposite direction, heightened levels of dopamine caused by L-DOPA therapy cam produce psychomotor agitation and stereotyped movements (dyskinesias). The second important effect of dopamine is as a "TEACHING" signal. ?
MICROELECTRODE RECORDINGS show that a nigrostriatal dopaminergic neuron responds each time a reward is given at RANDOM TIMES; these responses DECREASE as the association between a novel stimulus and reward is made; once the reward is PREDICTABLE, there is no dopaminergic firing. ?
This suggests that there is a "reward prediction error" being encoded. Ultimately, dopamine is altering the circuitry such that it enables the selection of a given motor programme if it is appropriate for the context. The fact that this 'selection' has a LONG-TERM EFFECT means it is presumably not solely affecting transmission at the level of current flow but rather inducing NEUROPLASTIC CHANGES in the basal ganglia circuitry. PATHOLOGICAL effects include a LACK of MOTIVATION in PD patients, or on the opposite side of the spectrum, ADDICTIVE BEHAVIOUR after prolonged L-DOPA therapy (dopamine dysregulation syndrome). HOWEVER, there are thought to be OTHER CIRCUITS operating in parallel that are NON-MOTOR, however the circuitry still adopts the SAME FUNDAMENTAL CONNECTIVITY as seen in the above circuit, so ultimately the BG is thought to still be implementing a 'selecting function' in each case. ? Prefrontal circuits have a role in COGNITION: involved in organising the correct behavioural responses to complex problems (originating in dorsolateral prefrontal cortex) and in selecting empathetic and socially appropriate behaviour (originating in orbitofrontal prefrontal cortex). ? Limbic circuit originating from the amygdala, hippocampus, and other areas, with main projections to the VENTRAL STRIATUM and thence to the ventral pallidum (e.g. the nucleus accumbens): SELECTION and control of expression of EMOTIONS just like motor programmes. (Can use anatomical staining evidence here too). ? Disturbances to these circuits may contribute to the development of COGNITIVE and BEHAVIOURAL disturbances that accompany the movement disorders, but also in themselves manifest as primary disorders, for example OCD. ?
FUNCTIONAL IMAGING STUDIES demonstrate abnormalities in the VENTRAL STRIATUM (ventromedial caudate nucleus and nucleus accumbens) are involved in OCD. When OCD symptoms are accompanied with MOTOR or VOCAL TICS, the same abnormalities are seen, and what is informative is that DOPAMINE-BLOCKING DRUGS SUPPRESS THE TICS. EVIDENCE from SONGBIRDS that basal ganglia are involved in MOTOR LEARNING: lesions of the basal ganglia-forebrain circuitry equivalent in birds ABOLISHES their ABILITY to LEARN species-specific SONGS during their critical period for learning. Lesioning AFTER the critical period does not interfere with song production but DOES prevent adaptive changes that can shape the bird's song in different acoustic environments. This model is too simplistic to account for the particular SUBTLETIES of symptoms in PARKINSON'S DISEASE: rather than just disinhibiting the indirect
??pathway, and preventing movement in a CRUDE way, patients specifically exhibit a DIMINSHED ABILITY to acquire and express the AUTOMATIC and HABITUAL components of motor behaviour, despite repeated practice (they require a much higher triggering sensory input). For example, during WALKING, patients require a CONSCIOUS decision to INITIATE each step, and STOP abruptly if they become DISTRACTED by a new external stimulus, idea or another behaviour like talking. ? They lose the fast computational benefits of automated behaviour, and remain trapped in that which is GOAL-DIRECTED. ?
This suggests that the BG circuitry is responsible for 'allowing' different TYPES of movement through different 'sub-circuits', and that in PD one is being selectively impaired. Early evidence that smaller "SUB-CIRCUITS" are involved in motor control came primarily from ANATOMICAL STUDIES whereby SMALL INTRACEREBRAL INJECTIONS of herpes and rabies viruses are done into different areas of the cortex- e.g. the primary motor cortex, SMA and PMA- and these are taken up by neurons are transported TRANS-SYNAPTICALLY, with the virus particles carrying a MAKRER GENE that can be stained in slides. ? The result is RETROGRADE labelling of SEPARATE populations of neurons in specific areas of the THALAMUS and INTERNAL PALLIDAL SEGMENT: separate cortical domains remain segregated and run in parallel through the BG circuitry.
? MICROSTIMULATION and MICROELECTRODE recordings have furthered this discovery, and shown that there is a "sensorimotor" input (involved in habitual behaviour) to the DORSOLATERAL ZONES of the striatum and an associative- mainly prefrontal- input (involved in goal-directed behaviour) more medially. ? It appears that the NIGROSTRIATAL NEURONS that project mostly to the dorsolateral zones of the striatum are specifically affected by the neurodegenerative process in PD: clearly shown in PET IMAGING which reveals a disproportionately reduced level of 18fluorodopa uptake in this area. ?
Correlates neatly with experiments whereby LOCAL INACTIVATION of this area of the striatum in monkeys reproduced Parkinsonian-like symptoms, but as predicted the animals were STILL ABLE to LEARN new motor sequences (through 'goal-directed' behaviour). However, this still does not adequately explain the TREMOR and MUSCLE TONE observed in PD patients at rest. ? Whilst imaging studies expectedly show (according the above model) increased inhibitory firing from the BG output neurons in the STN and GPi, closer observation using MICROELECTRODE RECORDINGS show that this consists of ABNORMAL OSCILLATORY PATTERNS that are ACTIVELY DISTORTING. Evidence which causally links the two is that UNILATERAL SURGICAL LESIONS of the SUBTHALAMIC NUCLEUS in animals eliminates these Parkinsonian symptoms without leading to other motor problems in the short-term. ? Thus, it appears that having NO OUTPUT from this malfunctioning sensorimotor sub-circuit is BETTER than producing Parkinsonian "NOISE".
? The ROOT of these distortions in TEMPORAL CODING are in my opinion likely to be COMPENSATORY NEUROPLASTIC CHANGES from the prolonged absence of dopamine in those affected parts of the striatum. By the same token, the DYSKINESIAS (importantly this is a feature of the disease that quickly becomes one of the most debilitating) experienced by patients after a certain time that L-DOPA
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