15- cerebellum (anatomy, nerve paths, histoanatomy).pdf

Writer: Heseong Chang Proofreader: Diego Garcia Guerra Neuroanatomy 15 Prof. Emmi 28/03/2023 MACROSCOPIC AND MICROSCOPIC ANATOMY OF THE CEREBELLUM AND CLINICAL CASES Information regarding the exam Generally, during the last years, students had the opportunity to earn an extra point for the final gra...

Writer: Heseong Chang Proofreader: Diego Garcia Guerra Neuroanatomy 15 Prof. Emmi 28/03/2023 MACROSCOPIC AND MICROSCOPIC ANATOMY OF THE CEREBELLUM AND CLINICAL CASES Information regarding the exam Generally, during the last years, students had the opportunity to earn an extra point for the final grade by doing a practical examination on a brain specimen. So, what we generally did with your colleagues was examining a brain and I would ask you general questions about the anatomy of the brain and if you pass this part of the examination, you get one extra point at the end of the exam. It never happened that someone did not pass the practical examination. The practical examination is made to give you an extra point. Macroscopic Anatomy of the Cerebellum The cerebellum occupies most of the posterior cranial fossa and is in strict relationship with the brainstem. The cerebellum derives from the rhombencephalon, from the metencephalic vesicle. The term meta in Greek refers to a structure lying beyond the brain, referring in this case to the position of the cerebellum with respect to the brainstem. In fact, the cerebellum is located posteriorly to the brainstem and together they delimit the fourth ventricle, the ventricular cavity of the rhombencephalon. In order to examine the morphology of the cerebellum properly, we must consider its strict relationship with the brainstem, particularly the anatomical connections between both structures. Cerebellar Peduncles Fig 1 On Fig 1, cerebellar peduncles are white matter bundles that connect the brainstem to the cerebellum. There are three pairs of cerebellar peduncles that give rise to the white matter projections. The first pair is the inferior cerebellar peduncle that connects the medulla to the cerebellum and is also known as the restiform bodies. The second pair is the middle cerebellar peduncle, which are the largest peduncles with the largest quantity of axons connecting the pons to the cerebellum and are also known as brachia pontis (i.e., the arms of the pons). The third pair of cerebellar peduncles connects the midbrain to the cerebellum and is also known as brachium conjunctivum (Superior Cerebellar Peduncles). This refers to the conjoining of different types of fibers at the level of this peduncle, i.e., both afferent and efferent fibers are joined together to form a single bundle. Specifically, while the inferior and middle cerebellar peduncles contain only afferent fibers, the superior cerebellar peduncle contains both afferent fibers (going from the brainstem and the brain to the cerebellum) as well as efferent fibers (projections from the cerebellum to other brainstem regions). 1 By performing a section of the cerebellum at the level of the cerebellar peduncles, we separate it from the anteriorly located brainstem and expose ventrally the floor of the 4th ventricle and dorsally the medial aspect of the cerebellum. The cerebellum has an ovoidal shape with a lateral-to-lateral transverse diameter of around 10 cm, an anterior to posterior axis of 5 cm and a mean height from top to bottom of 5 cm. Cerebellar notches, lobes, and vermis fig2 Once separated from the brainstem, we can macroscopically identify two incisions/notches in the cerebellum. An anterior cerebellar notch and a posterior cerebellar notch. These helps define two important parts of the macroscopic anatomy of the cerebellum. The anterior cerebellar notch indicates the ventral surface of the cerebellum and the cerebellar hilum (generic anatomical term that refers to the opening of a structure). At the level of the hilum of the cerebellum the connections between cerebellum and brainstem (i.e., the cerebellar peduncles) are found (see inferior surface view). This is where afferent fibers enter the cerebellum and where efferent fibers from the cerebellum exit the structure to reach the brainstem and other targets. The posterior cerebellar notch separates the cerebellum into two distinct lobes/cerebellar hemispheres. 2 fig3 On fig3, along the midline between both lobes can be identified an asymmetrical structure known as the cerebellar vermis (from Latin, it means the worm, due to its metameric/segmented structure). The superior surface of the cerebellum is separated from the occipital lobes by the tentorium cerebelli and displays the primary fissure of the cerebellum. The primary fissure divides the cerebellum into a smaller anterior lobe and a larger posterior lobe that takes on most of the superior and inferior surface of the cerebellum. The two lobes are phylogenetically distinct and have different functions. The vermis is continuous beyond the primary fissure, bending backwards and downwards and returning anteriorly, leading to the anterior extremity of the vermis being in close relationship to its posterior extremity, forming a C-like shape. This bending of the vermis gives rise to the ovoidal shape of the cerebellum, as the cerebellar hemispheres develop laterally from the vermis. Tonsils of cerebellum & herniation fig4 In the inferior surface of the cerebellum, we can appreciate the hilum and the part of the cerebellum that lies inferiorly on the bony surface of the posterior cranial fossa. Most of the inferior surface of the cerebellum is constituted by the posterior lobe. Here we find two folding of the cerebellar hemispheres close to the midline and close to the point where the two extremities of the vermis join, called tonsils of the cerebellum. They are not related to the functionality of the cerebellum but are pathologically relevant. The tonsils of the cerebellum are right behind the inferior parts of the brainstem such as the medulla. When an increase of intracranial pressure leads to the displacement of structures, i.e. a herniation, (herniation or hernia referring to an anatomical structure leaving its boundaries) the cerebellum can be displaced anteriorly with herniation of the cerebellar tonsils. This causes the tonsils to start pushing on the brainstem and enter the foramen magnum, leading to compression of the brainstem, the outcome of which is often fatal (due to damage to the cardiovascular center of the medulla). 3 Increased intracranial pressure can be caused by numerous conditions, such as hemorrhages, tumors or any mass forming lesions that create additional mass within the cranial cavity. Flocculonodular lobe (Vestibulocerebellum) The third lobe of the cerebellum is called the flocculonodular lobe (fig4 left highlighted in light blue) and is found medially, close to the hilum at the level of the inferior surface and the posterior most part of the cerebellum and the vermis. It is one of the phylogenetically most ancient parts of the cerebellum and is formed by a central nodular structure at the level of the vermis and two lateral floccules at the level of the hemispheres (resembling a knot with two laces). White and grey matter morphology of the cerebellum By performing a transverse section at the level of the hilum (see picture) we can appreciate the internal organization of the cerebellum. The morphology in terms of white and grey matter is different from that of the spinal cord and the brainstem. We can distinguish between three parts: the deep cerebellar nuclei, the medullary core of the cerebellum and the cerebellar cortex. Deep cerebellar nuclei Deep within the cerebellum are found grey matter nuclei called deep cerebellar nuclei that represent the primordial mantle layer. From an embryological point of view the mantle layer is the first layer of grey matter that develops laterally from the lumen of the cavity of the neural tube. These cerebellar nuclei receive all the information elaborated by the cerebellum and project it towards the brainstem, the spinal cord and the brain, thus they can be considered the final output station of all cerebellar signals. fig5 On fig5, there are four paired, distinct nuclei found on each side in medial to lateral positions and each of them relates to a distinct part of the cerebellum. The fastigial nuclei are found the most medially, their name (Latin for roof) referring to their position closest to the roof of the fourth ventricle in the ventral part of the cerebellum. The fastigial nuclei are phylogenetically related to the flocculonodular lobe and receive information from it that they relay to the brainstem. Together with the flocculonodular lobe, the fastigial nuclei are among the oldest structures of the cerebellum. Laterally to the fastigial nuclei are two nuclei per side that are jointly known as interposed nuclei. Individually they are known as globose (more medially positioned) and emboliform (more laterally 4 positioned) nuclei. Globose refers to the spherical shape of the nucleus, while emboliform refers to the plug-like shape of this nucleus that is similar to that of a small embolism of the heart. They are phylogenetically related to the anterior lobe of the cerebellum. The most lateral of the cerebellar nuclei is called the dentate nucleus, composed of a convoluted lamina of neurons with a medial hilum (dentate referring to the toothed pattern of protuberances). The dentate nucleus is the phylogenetically most recent of the deep cerebellar nuclei and is related mostly to the posterior lobe and the lateral parts of the cerebellar hemispheres. The shape of the dentate nucleus is practically identical to that of the inferior olivary nuclei of the medulla, due to these structures being related; the olives of the medulla originate from a migration of neurons coming from the cerebellum. This is important for two reasons: first for physiological reasons, as they are interrelated structures and convey similar signals. The olivary nuclei are afferent, projecting very refined information concerning motor commands to the cerebellum; the dentate nuclei are efferent, projecting from the cerebellum to the brainstem. Secondly, this matters because in some degenerative conditions we see that there is a similar degeneration of the olivary and dentate nuclei that affects both structures, generally called olivopontocerebellar dentate dysplasia, that is a consequence of the same embryological origin of these structures. Medullary body of the cerebellum Aside from the masses of grey matter of the deep cerebellar nuclei, there is also the deep white matter of the cerebellum known as the medullary body/core of the cerebellum. This refers to the marginal layer that is always found around the mantle layer. The mantle layer forms the deep cerebellar nuclei, while the marginal layer forms the medullary body of the cerebellum. In contrast to the spinal cord and the brain stem, in the cerebellum there is another superficial layer of grey matter outside of the marginal layer called the cerebellar cortex (fig5 highlighted in green). It is found on the surface of the cerebellum and most of the cerebellar signals arrive here and cerebellar information is processed. Histologically, the cerebellar cortex is formed by three layers of neurons that receive different types of information and process them in a complex manner. The cerebellum, particularly the cerebellar cortex, is the structure that contains the most neurons of the brain, more than the entire rest of the brain which allows for a very fine elaboration of incoming signals. Similarly, to the brain, in order to achieve a higher surface-tovolume ratio the cerebellum forms convolutions called folia (fig6 on right). Macroscopically, the folia of the cerebellar cortex give rise to the laminar appearance of the cerebellar hemispheres and vermis, that are collectively known as lamellae or laminae of the cerebellum. fig6 Here is the representation of the sectional anatomy of the cerebellum and the brainstem that shows a peculiar appearance. The brainstem is positioned anteriorly, we find the fourth ventricle interposed between the two structures and there is a midline sagittal section at the level of the vermis. This allows us to appreciate a 5 typical morphology that is found only at the level of the midline section of the vermis that takes on the name of arbor vitae (fig6 on left). The deep white matter of the cerebellum forms a tree-like pattern with branches going to the periphery surrounded by the convoluted grey matter giving rise to the folia. They are called folia because their appearance is very similar to that of a tree: with a trunk given by the white matter, branches that separate from the main trunk and the branches covered by smaller leaves (the cerebellar folia) forming the cerebellar cortex and the cerebellar convolutions. In this case you do not see deep cerebellar nuclei because they are found more laterally at the level of the cerebellar hemispheres, not at the level of the vermis. This typical appearance of the arbor vitae can be seen only when performing a midline sagittal section of the vermis of the cerebellum. fig7 The next images (fig7) show a transverse view of the cerebellum. Dentate nucleus, the white matter marginal layer (i.e., the medullary core) and the cerebellar cortex with its convoluted pattern of cerebellar foliage are visible. Anteriorly is the pons and the large bundle of axons of white matter is the middle cerebellar peduncle, that is the junction between the pons and the cerebellum; between them is the 4th ventricle with its lumen and floor. At this level we are at the level of the facial colliculus, at the upper triangle of the 4th ventricle while posteriorly we find the roof of the 4th ventricle given by the ventral surface of the cerebellum. This is the nodulus of the cerebellum, part of the flocculonodular lobe. Functions of the Cerebellum To examine functionality, the cerebellum is divided into parts based on their phylogenetic order of appearance and origin. We can distinguish three main components that mostly reflect the organization of the cerebellar lobes. fig8 Fig8 explains the structures of cerebellum 6 The first is an older part of the cerebellum called the archicerebellum; functionally, this region is also termed vestibulocerebellar. It is the first part of the cerebellum to develop in phylogenesis and corresponds macroscopically to the flocculonodular lobe. This is an opening of the cerebellum that instead of being bent in the C-like shape determined by the vermis, has been opened and flattened. This is why we see the nodule and the flocculus in this posterior position. This part of the cerebellum receives and operates mostly on vestibular information. The vestibular nuclei of the brainstem receive vestibular information from the eight cranial nerve (vestibulocochlear nerve) that come from the vestibular structures of the inner ear. These structures provide information about acceleration, deceleration, and angular movement of the head, which is fundamental for balance and the ability to move; the vestibular system gives us special information about the position of our head in the three-dimensional space regarding our body. The second component is the paleocerebellum which developed later, forming mostly the vermis and part of the anterior lobe. Functionally, this part is called spinocerebellar because it mostly receives proprioceptive information from the spinal cord that conveys sensory inputs concerning the status of relaxation and contraction of the muscles. When a muscle is contracted or relaxed, sensory information called proprioception (i.e., perception of your own body) is sent from the periphery to the spinal cord and from the spinal cord to the cerebellum, through a series of pathways known as spinocerebellar pathways. These pathways convey this information mostly to the vermis and the anterior lobe of the cerebellum, i.e. to the spinocerebellar. This is what allows us to perform coordinated movements through a joint and congruent activity of muscle groups. The third component is the phylogenetically most recent part of the cerebellum and is called the pontocerebellar/neocerebellum. It corresponds mostly to the lateral parts of the cerebellar hemispheres and to the posterior lobe of the cerebellum. The neocerebellum receives many projections from the pons. The term pontocerebellar refers to the part of the extrapyramidal system that we generally call esopyramidal. The corticopontocerebellar pathway goes from the cerebral cortex to the pons and from the pons to the cerebellum, specifically the pontocerebellum. This is very important because it receives information concerning ongoing motor activity at the level of the cortex; as we plan a movement this information is received by the cerebellum, which allows us to adjust a series of parameters concerning our posture, balance, and the contraction of other supporting muscles, in order for us to be able to execute the movements and eventually put them in sequence. This is called motor coordination, the ability to perform different movements one after the other. From the vestibular nuclei to the spinal cord to the cerebral cortex, we have three different phylogenetic stages, from the most ancient to the most recent one, that elaborate progressively more complex types of information. All of this is integrated in the cerebellar cortex, giving rise to an output from the cerebellum, i.e., the efferent pathways. 7 Sensory pathways of the cerebellum Next, we will examine the different sensory pathways joining the cerebellum and define the microscopical organization of the cerebellar hemispheres that allow the complex processing of this type of information. The cerebellum receives a multitude of sensory information that must be integrated in order to generate a complex response. Therefore, we need a series of afferent pathways that bring information to the cerebellum, for this information to be elaborated in the cerebellar cortex and to generate an integrated response through what we call cerebellar efferences; in short, input, elaboration, output. Cerebellar afferences represent incoming axons carrying sensory information to the cerebellum and can be of different types, mostly reflecting the phylogenetic division and functional representation of the cerebellum. There are: Fig9 vestibulocerebellar afferences that reach the cerebellum from the vestibular nuclei spinocerebellar afferences that reach the cerebellum from the spinal cord corticopontocerebellar afferences that reach the cerebellum from the cortex. These types of afferences have in common that they give rise to a type of fibers that end at the cerebellar cortex, forming a peculiar synaptic formation called mossy fiber. The function of these pathways is to convey information to numerous cells in the cerebellum, as this is rougher information that still requires integration. Another afference, called the olivocerebellar afference, is different because it is a more refined, direct pathway between the olivary nuclei in the medulla and the cerebellum. The olives act as a pre-integration center for cerebellar information and have a privileged relationship with cerebellar neurons, forming a small ratio of projections. This means that each of the olivocerebellar fibers generally contacts a single neuron, which allows for the very fine tuning of signals, forming what are known as climbing fibers. There are also cerebellar efferences, which go from the cerebellar cortex to the deep cerebellar nuclei and then project to structures of the brainstem, in order to give feedback to the rest of the nervous system. At this point, the cerebellar output often splits into different pathways that either go to the spinal cord to directly modulate movement (i.e., performing adjustments as we perform a movement) or to the cerebral cortex giving higher centers feedback on the adjustments that are being performed. All of this requires a complex type of integration of signals that occurs at the level of the cerebellar cortex. 8 Vestibulocerebellar pathway fig10 The vestibulocerebellar afferences reflect a system of fibers that from the vestibular system, project to the vestibular nuclei of the medulla. From there (or directly from the 8th cranial nerve) they reach the cerebellum at the level of the flocculonodular lobe. This type of information is essential for mediating balance, i.e., the ability to move in the three-dimensional space without falling. Lesions of the vestibulocerebellum and vestibulocerebellar afferences typically manifest clinically in the form of ataxia, characterized by unsteady gait and frequent loss of balance. You see here this representation of the vestibular nuclei at the level of the medulla. These are the four distinct nuclei at the level of the brainstem that project to the nodulus and the two floccules in order to provide the cerebellum information concerning the vestibular system. This is fundamental to be able to execute complex motor patterns without losing balance. Spinocerebellar pathway fig11 Phylogenetically next are the spinocerebellar pathways (fig11, green), that deal with the type of information that is elaborated by the cerebellum through a series of ascending pathways going through the brainstem. This type of sensory pathway originates at the level of the muscles, particularly at the level of specific sensory receptors found within the muscles called Golgi tendon organs (fig11, orange) and neuromuscular spindles. These are devices found within muscle fibers that provide proprioceptive information concerning the status of contraction and relaxation of a muscle. In this pathway we can identify a first order neuron, found at the level of the dorsal root ganglion. The dorsal root ganglion is the site where we find all the first order sensory neurons that from the periphery convey sensory information to the spinal cord. These neurons are called pseudounipolar neurons as they are characterized by axonal branching with a T-like shape. The neuronal body has an axon that splits into a peripheral branch, going to the sensory receptors found in the muscles, e.g., neuromuscular spindles, Golgi tendon organs etc., and a centripetal branch that goes from the periphery towards the 9 spinal cord. These are the first order neurons found in the dorsal root ganglion. These fibers form synapses within the spinal cord at the level of the posterior horn. The posterior horn is mainly for sensory information where we find the nuclei responsible for receiving the information coming from the first order neurons. At this level we can identify two main groups of neurons that receive proprioceptive information going to the cerebellum: the nucleus dorsalis of Clarke (fig11, light blue) and another group of neurons found around the nucleus dorsalis called border cells. (fig11, purple) They are almost in the same position; however, we have to differentiate between the nucleus dorsalis and the border cells because they give rise to two distinct spinocerebellar pathways. First spinocerebellar pathway fig12 The first spinocerebellar pathway forms synapses with the nucleus dorsalis of Clarke. The second order neuron receives this proprioceptive information from the first order neurons located in the ganglia. The second order neurons project their axon laterally towards the lateral funiculus of the spinal cord of the same side. The axons that arise from the second order neurons in the nucleus of Clarke go towards the lateral funiculus of the spinal cord (the lateral bundle of white matter found at the level of the spinal cord) and take on a very superficial positions close to the external limit of the white matter of the spinal cord, in a quite dorsal position within the lateral funiculus. This is why this pathway is called posterior or dorsal spinocerebellar (fig12, orange) pathway/tract, since it goes to the same side of the nucleus of origin in the lateral funiculus of the spinal cord and takes on an external and dorsal position within the white matter. These fibers ascend within the spinal cord in this position and the dorsal and most external part of the lateral funiculus is occupied by the fibers of the posterior or dorsal spinocerebellar tract. They ascend all the way through the spinal cord and at the level of the medulla join the inferior cerebellar peduncle (fig12, orange) to reach the homolateral cerebellar cortex, particularly the spinocerebellum (i.e., the vermis and the anterior lobe of the cerebellum). They convey proprioceptive information coming from the periphery. Second spinocerebellar pathway The second spinocerebellar pathway arises from the border cells found around the nucleus dorsalis and has a distinct course. Unlike the previous one, the fibers deriving from the second order neurons found at the level of the border cells, decussate the midline, crossing over to the contralateral side and end up in the lateral funiculus of the spinal cord but in a more ventral position than the other pathway. Thus, it is called the anterior or ventral spinocerebellar tract (fig12, green). 10 At the level of the spinal cord, they have a peculiar path because they travel all the way up the lateral funiculus of the spinal cord, ascend through the brain stem, the medulla and the pons and arrive at the midbrain. Here they cross the midline again, performing a second decussation. This way they enter the superior cerebellar peduncle (fig12, green) found at the level of the midbrain. The dorsal or posterior spinocerebellar tract does not decussate, instead remaining homolateral. By decussating twice, the ventral spinocerebellar tract returns homolaterally. This means that the left side of the cerebellum receives sensory information coming from the left side of the body and vice versa. There is no cross information in the cerebellum as in the end each pathway projects to the same side of origin. The following mnemonic helps in remembering which of the pathways decussates and which does not: the posterior or dorsal spinocerebellar tract is also called the direct tract (dorsal-direct). This matters because it means that a lesion at the level of the cerebellum affects the homolateral side of the body (i.e., a lesion of the left cerebellum affects the left side of the body and v.v.) Corticopontocerebellar pathway The most phylogenetically recent part is the one belonging to the neocerebellum. This third type of afferences belong to the so-called esopyramidal system. There are motor pathways in the brain that do not pass at the level of the pyramids of the medulla and they are known as extrapyramidal and esopyramidal system. The esopyramidal system is the system of motor fibers that projects towards the cerebellum, specifically the neocerebellum. We can distinguish an afferent pathway of the esopyramidal system, called the corticopontocerebellar pathway, that from the brain targets the cerebellum and an efferent pathway that represents the main output source of all cerebellar information. fig13 Fig13 shows the parallel representation of the esopyramidal system (corticopontine neuron) and the pyramidal system (corticospinal neuron). The corticospinal neuron descends with its axon throughout the brain, arriving at the medulla in the brainstem and forming the pyramidal decussation, from which point it goes downwards to the spinal cord, bringing motor commands to the lower motor neurons in the anterior horn. Whenever this pathway is activated, a parallel activation of the esopyramidal system occurs, bringing information concerning the ongoing motor command to the cerebellum. 11 The corticopontine neuronal body is found at the level of the cortex, near that of the corticospinal neuron because they process information in parallel. The axon of the corticopontine neuron descends towards the pons and forms synapses with the basal nuclei of the ventral part of the pons. These basal nuclei are neurons scattered throughout the ventral or basal part of the pons, that receive corticopontine projections. There are two distinct corticopontine bundles: a front pontine bundle and a parietotemporooccipital bundle. Both systems bring information from the cortex to the pons. At the pons, the basal nuclei project this information contralaterally towards the cerebellar cortex, giving rise to the transverse fibers that from the pons go towards the cerebellum and enter at the middle cerebellar peduncle. In this case the information is crossed, going from the right side to the left half of the cerebellum and v.v. This is to account for the crossing of the fibers that occurs at the level of the pyramidal pathway. This way, the right hemisphere, i.e., a right corticospinal neuron, controls the left half of the body, i.e., a left lower motor neuron in the spinal cord. Since cerebellar sensory information is homolateral, in order to control the left half of the body that receives motor information from the right hemisphere, a decussation at the level of the pons is necessary. In this case, the corticopontine neurons project on the pontine nuclei, that decussate the midline and form the transverse fibers directly towards the cerebellar cortex. At this level, all the sensory information concerning proprioceptive information (e.g. the status of contraction and relaxation of the muscles, balance information concerning the position of our body in the three dimensional space and the information concerning ongoing motor commands) is received and integrated in the cerebellar cortex to generate a response/output from the cerebellum. An example would be taking an object on a shelf: the corticospinal pathway gives a command to the lower motor neurons to move the upper limb to reach the object on the shelf. In parallel, at the level of the cerebellum, the motor command is sent through the corticopontocerebellar pathway, while information on balance, the position of the head in the three-dimensional space and the status of contraction of other muscles is sent to the cerebellum via the spinocerebellar pathways and the vestibulocerebellar pathways. All this information joins at the level of the cerebellar cortex and is integrated. The cerebellum generates an output that leads to a contraction of the muscles of the back and the leg, that allows the body to stabilize its position, maintain its balance and reach the object without falling down or missing the target. So, while the corticospinal reflects the simple action of the arm moving towards the object, the cerebellum reflects all the prerequisite conditions for this to occur in safety without losing balance and allowing to reach the target, by integrating the motor command, spinocerebellar information, proprioceptive information, and vestibular information. Efferent pathway of the esopyramidal system The second component of the esopyramidal system, the efferent component, arises from the cerebellar cortex and projects to the deep cerebellar nuclei (particularly the dentate nucleus) and from the nuclei arise axons that enter the superior cerebellar peduncle, cross the midline, and reach the red nucleus at the level of the midbrain. This is how the output of the cerebellum is transmitted from the cerebellar cortex to the brainstem. In this case, there is a crossing of the pathway. The red nucleus represents an intermediate station in which the cerebellar output is split into two parts: an ascending component (rubrothalamocortical) and a descending component (rubrospinal). At the red nucleus, the output of the cerebellum informs the cerebral cortex of the adjustments that are being performed, from the red nucleus towards the thalamus and from the thalamus towards the cortex (rubrothalamocortical). The rubrothalamocortical projection ends on the same region of the cerebral cortex from which the motor command arose. This way, the corticopontine and the corticospinal neurons are informed of the adjustments 12 that the cerebellum is performing, taking into consideration the proprioceptive and vestibular information that it receives from the other parts of the brainstem. At the same time, the cerebellum acts autonomously, through the rubrospinal pathway by modulating the activity of the lower motor neurons through this pathway going from the red nucleus towards the spinal cord. Thus, on one side we have a direct effect on the lower motor neurons (contraction of the leg, contraction of the muscles of the trunk in order to maintain balance) while simultaneously sending feedback to the cortex about this adjustment. To conclude, the esopyramidal pathway represents the system through which the cerebellum integrates all this information at the level of the cerebellar cortex and generates an output that allows us to safely perform movements without losing balance and to coordinate consecutive movements. Question: In which funiculus is the rubrospinal tract found? Answer: The rubrospinal tract is found deep within the lateral funiculus, close to the corticospinal tract. In the terminal part, they are both found at the level of the lateral funiculus but the pyramidal/corticospinal tract is more medial, while the rubrospinal tract is more lateral. 1/2 part of lecture is over, 20 mins break Until now, the lecture has covered the afferences of the cerebellum (how the information comes to the cerebellar cortex) and the pathways that lead to the cerebellar output. Next will be covered: The integration of different information (proprioceptive information, vestibular information, motor information) in the cerebellum, particularly at the level of the cerebellar cortex The generation of responses from the cerebellum Basic Histological slide of Cerebellar Cortex The cerebellar cortex represents the outermost gray matter layer of the cerebellum that covers the deep white matter and processes all cerebellar afferences. From a histological point of view (fig14, stained by Hematoxylin & Eosin staining), the cerebellar cortex can be divided into three distinct layers. fig14 13 On fig14, the deep white matter of the cerebellum contains both the afferent and efferent axons that carry all the sensory information coming from the periphery towards the cerebellum. These axons contact the cerebellar cortex for further elaboration. Efferent axons generate the output from the cerebellar cortex, which is directed towards the deep cerebellar nuclei and the rest of the nervous system through the: Cerebello-dentato-rubro-thalamo-cortical pathway (NoS = There are many ways to call this pathway. The professor called this pathway “CerebelloDento-Rubro-Pathway, but the correct term should be “Dentato-thalamic tract”, or “Dentatorubro-thalamic tract”) Rubrospinal tract 3 Layers of Cerebellar Cortex with Histological Sample fig15 Fig15. The cerebellar cortex is composed of 3 distinct layers. Molecular layer, Purkinje layer, and Granular layer. The picture above shows the overall composition and location of each layer. 14 Molecular layer fig16 It is the most superficial layer, found close to the external meningeal surface of the cerebellum. It is made of dendrites, axons, and small cells, which all derive from the other two layers (NoS = The professor did not explain in detail what it is composed of. The molecular layer is composed of the flattened dendritic trees of Purkinje cells penetrated by an array of granular layer parallel fibers. It also contains two types of inhibitory interneurons: stellate cells and basket cells). It regulates the fine tuning of movement and the electrical signals processing, related to the astrocyte. “Molecular” refers to the sparse cells within these layers that look like small molecules dispersed in the white matter, as visible from the staining of this layer. Purkinje layer fig17 The Purkinje layer is composed of a single layer of very large neurons called Purkinje cells. Purkinje cells are the largest neurons of the human brain and the main receiving neurons of the cerebellar cortex. This layer receives all incoming signals, integrates them, and generates the output (Purkinje neurons are the only output source of cerebellum). The axons of the Purkinje neurons go deeply within the white matter and contact the deep cerebellar nuclei, that in turn project to the brainstem: this is the Cerebello-dentato-rubro-thalamic pathway (Remember, this output originates solely and exclusively from the Purkinje neurons). Purkinje neurons have a wide dendritic arborization (tree-like branching) that spans across the molecular layer. Axons passing and contacting the dendrites of the Purkinje neurons are represented in black, as perpendicular fibers travelling across the molecular layer and they represent the point of junction of the signals. Dendrites of the Purkinje neurons convey the signals, travelling deeply to reach the deep cerebellar nuclei and give rise to the cerebellar output. 15 Granular cell layer fig18 The deepest layer of the cerebral cortex grey matter, forming a boundary with the deep white matter. The name “Granular cell layer” refers to the appearance of the neurons found in this layer that look like small grains of sand. These neurons have very strong basophilic cytoplasm that gives them a typical violet appearance in H&E staining. These neurons receive a series of sensory information and forward it to the Purkinje neurons and other cells of the molecular layer. fig19 Fig19 (left) shows the silver staining of the cerebellar cortex. The three layers of cells are clearly definable. In addition to that, on the image above (right), cerebellar folia are visible (In white, unstained). Cerebellar folia are a fine convolution (Very fine gyri) of cerebellar cortex located at the outermost section of molecular layer. Signal Processing at the level of the Cerebellar Cortex Information incoming to the cerebellar cortex can be divided into 2 different types, which are the mossy fibers and the climbing fibers: Mossy fiber (Divergence of signaling) 16 fig20 A wide category of fibers that shows very evident projection to the cerebellar cortex. The term “Mossy” derives from the peculiar axonal ending of these fibers that resembles a piece of moss. The axon terminals of mossy fibers separate into few branches, forming a claw-like shape. Mossy fibers comprise most of the afference neurons that are directed to the cerebellum. Mossy fibers comprise 3 of the main afferent pathways of Cerebellum: Cortico-ponto-cerebellar pathway spino-cerebellar pathway vestibulo-cerebellar pathway These pathways have different origins and signaling types but all of them have morphologically identical synapses and belong to the family of mossy fibers. Synapse of Mossy Fibers (Cerebellar Glomerulus) fig21 The mossy fibers enter the cerebellar cortex and form synapses at the level of the granule cell layer. This type of synapse is called cerebellar glomerulus and occurs at the level of the granular cell layer. The cerebellar glomerulus is a small, intertwined mass of nerve fiber terminals, consisting of post-synaptic granular cell dendrites and pre-synaptic Golgi cell axon terminals. These 2 structures surround the presynaptic terminals of mossy fibers. The mossy fibers contact many granule cells (the ratio of granule cell dendrite to mossy fiber is around 20:1). Mossy fiber = Carries signal from periphery (Afferent) to granule cell Granular cell dendrites = Receive signaling from mossy fibers, carries signal to molecular layer Golgi cell = Inhibition of signaling (Regulation and feedback of signaling) 17 The cerebellar glomerulus is the first “processing station” for afferent nerve fibers entering the cerebellum. Input comes from the mossy fibers, which terminate there and synapse with the Golgi and granule cell fibers. How the signaling is carried from mossy fiber to granular cell dendrites fig22 Fig22 describes the signaling pathway that passes through mossy fibers and granular cell dendrites. 1. The information is carried by mossy fibers to the soma of granular cells 2. The granule cell in turn projects this information through a particular type of axon. 3. The axon of the granular cell starts from the granular layer and ascends all the way towards the molecular layer 4. At the level of molecular layer, the axon splits into two, giving rise to a T-shape and starts travelling through the molecular layer in a direction parallel to the surface of the cerebellum (thus they are called parallel fibers) 5. The parallel fibers form multiple synapses with the dendritic arborizations (i.e., the dendrites) of the Purkinje neurons. 6. The Purkinje neuron has its dendrites directed towards the surface of the cerebellum at the molecular layer and its axon directed towards the deeper part of cerebellum to contact the deep cerebellar nuclei. The parallel fibers are perpendicular to the dendritic arborizations of the Purkinje cells. This mechanism allows: 1. A massive contact of the dendrites. There are numerous synapses occurring between the parallel fibers and the dendrites of a Purkinje neuron. 2. Due to the long course of the parallel fibers, a simple parallel fiber will be able to contact up to 400 different Purkinje neurons along the molecular layer. Pre-condition for action potential formation In the end, a single mossy fiber contacts over 20 granule neurons, and each granular cell gives rise to a parallel fiber that can contact up to 400 Purkinje neurons. Thus, from a single fiber there is a wide spreading 18 of the signal, contacting numerous cells of the cerebellar cortex. However, the intensity of the signal delivered by a single mossy fiber to the Purkinje neurons is very weak, therefore numerous mossy fibers must be activated together to give rise to an action potential in the Purkinje neurons. An action potential travels through the parallel fibers, giving rise to a depolarization in the dendrites of the Purkinje neurons, the response of the Purkinje neuron travels down its axon all the way to the deep cerebellar nuclei. This gives rise to the output of the cerebellum (Cerebello-dentato-rubro-thalamic pathway). Golgi Cell in Cerebellar Glomerulus and its inhibitory mechanism for signaling Activation of the parallel fiber also leads to an activation of the Golgi cell, an inhibitory cell, that leads to the inhibition of the synaptic formation of the cerebellar glomerulus (i.e., a feedback mechanism). A signal activates the granule cell, which forwards the signal but to stop the signal from producing ongoing effects there is feedback of the Golgi cell that will inhibit the synapse occurring between the mossy fiber and the granule cells. This allows for specific and temporary activation of signaling. Olivary Nuclei and Climbing Fibers (1:1 signaling) The second type of fiber at the level of the cerebellar cortex are the climbing fibers. While most of the afferent pathways (Cortico-ponto-cerebellar, spino-cerebellar, vestibulo-cerebellar pathways etc.) form mossy fibers, the olivo-cerebellar projection gives rise to climbing fibers. This is a different type of afference that reflects a more elaborated signal coming from the olivary nuclei. The olivary nuclei are located at the level of medulla oblongata and perform many different roles Preintegration center for motor information Receive proprioceptive information Receive motor information coming from cerebral cortex Since all of the processing is done directly in the olivary nuclei, the climbing fiber does not require such a complex structure as the cerebellar glomerulus to interact with the Purkinje cells. 19 fig24 The climbing fibers (fig24, orange) have a 1:1 ratio with Purkinje neurons, i.e. a single climbing fiber contacts a single Purkinje neuron, forming “en passant” synapses (as opposed to the mossy fibers, that can contact up to 400 Purkinje neurons). Each climbing fiber wraps around a single Purkinje neuron, following the course of its dendrites at the level of molecular layer, allowing for the selective activation of a single Purkinje neuron by a single climbing fiber. This 1:1 signaling is also known as convergent signaling, whereas mossy fibers are an example of divergent signaling. Whichever type of signaling is used, mossy fibers and climbing fibers give rise to an activation of the Purkinje neuron, which in turn projects down to the deep cerebellar nuclei and leads to the activation of the dentato-rubro-thalamic pathway. The dentato-rubro-thalamic pathway (dentatothalamic/dentatorubrothalamic tract) Activates once signal delivery by Purkinje neuron is made (either from mossy fiber and climbing fiber) Involved in motor coordination and planning of movement Once the deep cerebellar nuclei are activated by the purkinje neurons, the deep cerebellar nuclei project to various targets in the brainstem and beyond through different pathways, including the superior cerebellar peduncle originates in the dentate nucleus and follows the ipsilateral superior cerebellar peduncle, decussating later and reaching the contralateral red nucleus and the contralateral thalamus. 20 Steps of dentato-rubro-thalamic pathway (NOS = Professor kept saying Cerebello Dento Rubro thalamic pathway instead) 3 1. The dentate nucleus is one of the deep cerebellar nuclei that receives input from Purkinje cells in the cerebellar cortex 2. From the dentate nucleus, information is relayed to the red nucleus and then to the thalamus 3. From the thalamus, information is sent to the cerebral cortex to provide feedback on the activity occurring in the cerebellum 2 4. In addition, information from the red nucleus can also be sent directly to the spinal cord to modulate lower motor neurons and perform motor adjustments 1 Clinical Aspect of Cerebellum (cerebellar lesions) Cerebellar lesions have a series of clinical manifestations. The most common consequence of a cerebellar lesions is ataxia, which refers to the lack of coordination between muscle groups. Remember, the cerebellum receives proprioceptive information concerning the status of contraction and relaxation of muscle groups which it integrates in order to coordinate muscle movement. If the cerebellum does not receive this information, it results in a lack of coordination, i.e., ataxia. Symptoms of Ataxia Ataxia leads to the disjointed activity of muscle groups. A patient suffering from ataxia commonly shows dysrhythmia, dysmetria and an unsteady gait as symptoms. Dysrhythmia: Inability to perform rhythmic movements Dysmetria: Inability to correctly reach a target due to a miscalculation of the distance (e.g., people with dysmetria have difficulty picking up items from a shelf) Anesthetic gait: The inability to coordinate the movements of the lower limbs to walk properly and the inability to maintain balance (also commonly encountered in people with alcohol intoxication, as alcohol toxically affects neurons, especially cerebellar neurons) In addition to the symptoms mentioned above, there can be other symptoms such as vertigo, nausea, and headaches. These symptoms are more general and less specific but often encountered in case of cerebral lesions. 21 Types of Ataxias Ataxia is generally distinguished into 2 different types of manifestation: truncal ataxia and appendicular ataxia. Truncal ataxia Uncoordinated movements of the trunk Caused by lesions at the level of the cerebellar vermis, close to the midline, which mediates main axis of the body Characterized by strongly unsteady gait and a drunk-like walking pattern Appendicular ataxia Uncoordinated movements of the limbs Caused by lesions of the cerebellar hemispheres and the more lateral parts of the cerebellum, which mediate the movement of upper & lower limbs Examination for Truncal Ataxia Romberg Test: Commonly used to examine truncal ataxia. This measures the level of balances that patient manages to maintain while standing up Steps are as follows 1. The patient is asked to remove their shoes and stand with their two feet together 2. The arms are held next to the body or crossed in front of the body. 3. The clinician asks the patient to first stand quietly with eyes open, and subsequently with eyes closed. 4. The patient tries to maintain their balance while the clinician observes for a full minute. 5. For safety, it is essential that the observer stand close to the patient to prevent potential injury if the patient were to fall. The Romberg test is scored by counting the seconds the patient can stand with their eyes closed. If the patient has a lesion of the cerebellum, they are unable to maintain their balance and collapse toward the homolateral side of the lesion (i.e., falling to the same side as where the lateral lesion is located. If it is on the left, they will fall to their left side. If it is on the right, they will fall to their right side) Gait Test = Examination of gait. Patients with a cerebellar lesion are unable to perform this test. Steps are as follows. 1. Patient is asked to stand straight 2. Patient is asked to walk in a straight line (tandem gait testing) as if on a rope 3. While the patient performs the action, the examiner checks the stance posture and stability of the patient 22 Examination for Appendicular Ataxia There are 2 commonly performed examinations for appendicular ataxia: Finger-to-nose test 1. 2. 3. 4. This examination seeks to measure smooth, coordinated upper-extremity movement The patient is asked to touch the tip of his nose with index finger The patient is instructed to touch the examiner’s finger, which is about an arm’s length away Step 2-3 is repeated but the point the patient’s finger has to reach changes (right, left, up, down, to exactly find out which lateral side of cerebellum is damaged) 5. The examiner needs to pay close attention, especially for overshooting, which is typical sign of cerebellar lesions (patient is unable to reach the target, often missing and going beyond the target) Other ways to perform finger to nose test is using pen with cap. Patient is asked to hold the pen cap and put it back to the pen which is held by the examiner. A patient with appendicular ataxia is unable to insert the cap into the pen directly and it takes them more time or they circle around the pen Heel-to-shin test This test is performed if the patient is unable to stand. 1. Test of cerebellar function that assesses coordination of lowerextremity movement 2. The patient is lying down in a supine position. Ask the patient to place the heel of one foot just below their opposite kneecap 3. Then slide the heel in a straight line down the shin bone to the ankle 4. The examiner looks for evidence of dysmetria, which is evidenced by difficulty in controlling the range of movement and can result in undershooting or overshooting the target (i.e., the shin bone). Clinical Cases of Ataxia Case 1 Age = 70-year-old Gender = male Occupation = janitor Pre-existing medical condition = Hypertension Report: The patient went to work at 7 am and had a sudden onset of nausea, vomiting and unsteadiness, then he was unable to stand on his legs. In the ER, a neurological examination was performed and revealed mild, slurred speech. He was unable to speak properly and had slow tongue movements. He showed dysmetria as he was unable to reach the target on the finger-to-nose test on left side (right side works fine). On the heel-to-shin test, the patient was unable perform on the left 23 Case 2 Case 3 side. He displays dysdiadochokinesia (Inability to perform rhythmically alternating movement) on left side (Right side could perform rhythmic movement). Romberg test showed the patient falling onto his left side with eyes opened (Unable to stand properly). No other signs were detected Diagnosis ✔ Lesion is on the left side as he shows normal functioning of right side ✔ Patient failed to perform finger-to-nose and heel-to-shin on left side = appendicular ataxia ✔ Patient failed to perform Romberg test on left side = Signs of truncal ataxia ✔ Patient suffers both from truncal & appendicular ataxia due to damage to both vermis and left cerebellar hemisphere ✔ The symptoms started the same morning = Acute symptom ✔ The patient has suffered hypertension = Very important aspect to consider. ✔ Patient had ischemic lesions on the left half of the vermis and left cerebellar hemisphere Age = 76-year-old Gender = male Occupation = none Pre-existing medical condition = none, but history of cigarette smoking habit Report: Developed progressive walking difficulty over the course of 1 month. Feeling boozy, shows drunk-like gait (although patient has not consumed alcohol). Often loses balance while standing. Mild headache that progressively worsens. Diagnosis ✔ Tendency to fall on left side during Romberg test and tandem walking = Left vermis lesion ✔ No signs of ataxia in the finger to nose or heel to shin test = No cerebellar hemisphere lesion ✔ Rapidly alternating movements were normal = No dysdiadochokinesia ✔ The development was chronic, which indicate less possibility of vessel rupture ✔ Patient had lung carcinoma that formed a metastasis in the cerebellar vermis, selectively affecting the left cerebellar vermis Age = 13-year-old Gender = male Occupation = student Pre-existing medical condition = none Report: 2 months progressive left occipital headaches, nausea, slurred speech, and unsteadiness (slurred speech is another manifestation of cerebellar involvement, since speech is also a motor act that requires coordination). Symptoms began with headaches in the left occipital region sometimes accompanied with nausea and vomiting. Shows difficulties concentrating and learning, gait instability and mildly slurred speech. Neurological examination reveals mild bilateral papilledema, horizontal and vertical nystagmus, worse upwards. Marked dysmetria on finger to nose testing. Displays dysdiadochokinesia (worse on the left). Heel-to-shin movements are ataxic on the left. Wide-based unsteady gait, staggering to the left and unable to perform tandem walking. Romberg test does not worsen the already present instability. Diagnosis ✔ Lesion is on the left side of the cerebellum involving both vermis & hemisphere ✔ Manifestation is like case 2, which had chronic development of symptoms ✔ However, there is nausea and headache, which indicates rising intracranial pressure due to a 24 space-occupying lesion (like case 1) ✔ Diagnosis is pediatric tumor of the posterior cranial fossa, compressing the left hemisphere and left vermis causing truncal and appendicular ataxia = Explains why the headaches get progressively worse (because tumor is growing). The pain is mediated within the cranial cavity by the meninges (brain itself is not innervated by pain terminals). Other diagnosis by students ✔ Friedreich’s ataxia (or any neurodegenerative disorder): In Friedreich’s ataxia there is a genetic lesion of the spinocerebellar pathways and other sensory pathways. However, the patient shows nausea and headaches which are not typical of neurodegenerative diseases but rather related to space-occupying lesions. ✔ Hemorrhage after head trauma: Patient has no history of head trauma ✔ Hydrocephalus: Would have more widespread neurological manifestations as it doesn’t only affect cerebellum. Would develop bilaterally, but patient suffers only on left vermis & hemisphere 25