Cortical and Subcortical Substrates of Cranial Nerve Function Mohit Agarwal, MD, John L

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Cortical and Subcortical Substrates of Cranial Nerve Function Mohit Agarwal, MD, John L. Ulmer, MD, Andrew P. Klein, MD, and Leighton P. Mark, MD

The pivotal role of cranial nerves in a wholesome life experience cannot be overemphasized. Research has opened new avenues to understand cranial nerve function. Classical concept of strict bilateral cortical control of cranial nerves has given way to concepts of hemispheric dominance and hemispheric lateralization. An astute Neuroradiologist should keep abreast of these concepts and help patients and referring physicians by applying this knowledge in reading images. This chapter provides an overview of cranial nerve function and latest concepts pertaining to their cortical and subcortical control. Semin Ultrasound CT MRI 36:275-290 Published by Elsevier Inc.

lthough the human brain endlessly mystifies in its infarct involving the corticobulbar fibers on the opposite side in Acomplexity and perfect integration, it is the cranial nerves the brainstem above the CN nucleus would have the same (CNs) that serve as the broker between mind and perception. clinical syndrome as those of bilateral opercular infarcts. These From admiring artwork to engaging in an enchanting musical lesions may or may not be separated in time. The nature of experience, from savoring a culinary delight to emotionally lesions can also differ. A person with an old multiple sclerosis connecting to another with a smile, CNs enable us to make the lesion on one side can develop an infarct or may have a most out of life. It is no wonder then that onset of CN traumatic injury, infection, or neoplasm on the opposite side. dysfunction is so troubling to individuals and that physicians Despite knowledge of extensive networks, the supranuclear are often tasked with uncovering the source of pathology. cortical and subcortical components of CN function often do In radiology, deficits of CN function elicit a knee jerk reaction not command much attention from the radiologist. Part of this to look for abnormalities involving the nuclear and infranuclear inattention is probably because of the poor anatomical components. The relative lack of emphasis on the supranuclear definition of these areas. This article attempts to delineate component stems from the classical thought of CNs being anatomical supranuclear cortical and subcortical regions that represented equally in both cerebral cortices, in which case contribute to CN function to improve our intuitive under- functional deficits of CNs by one-sided lesions are not expected. standing of CN deficits and empower clinical neuroradiology. Recent clinical and experimental data however challenge this Additionally, concepts of hemispheric laterality, dominance, traditional notion and suggest concepts of unequal representa- and plasticity would be discussed. tion and hemispheric dominance. These concepts are impor- A single CN can perform many functions and a single tant to understand clinical symptomatology and functional function can be performed by many CNs. For instance, the recoverability. Seeing bilateral lesions in homotopic areas of the facial nerve controls facial movements but also carries taste cortex is not impossible, in which case, even with the classical sensation. On the contrary, the sensation of taste is carried by concept, clinical CN deficits can occur with cortical disease. facial, glossopharyngeal, and vagus nerves. The current Bilateral lesions can also cause the same clinical syndrome with discussion uses an approach focusing on functional units involvement of supranuclear subcortical regions if the contrala- rather than individual CNs. teral lesion affects the pathway of the same CN. As an example, an infarct in one opercular region and a strategically located Smell Department of Radiology, Medical College of Wisconsin, Milwaukee, WI. Address reprint requests to Mohit Agarwal, MD, Section of Neuroradiology, Smell is an evolutionary primitive sensation that serves as a Department of Radiology, Medical College of Wisconsin, 9200 W major drive among the lesser privileged animals for instinctive Wisconsin Ave, Milwaukee, WI 53226. E-mail: [email protected] behavior related to feeding, procreation, and sensation of http://dx.doi.org/10.1053/j.sult.2015.05.008 275 0887-2171/Published by Elsevier Inc.

Downloaded for Anonymous User (n/a) at Massachusetts General Hospital from ClinicalKey.com by Elsevier on December 21, 2017. For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. 276 M. Agarwal et al. surroundings. The effects of this sensation on human behavior ipsilateral olfactory bulb, cortical neurons have access to are not entirely dissimilar. The heavily hedonic themes of bilateral input.4,5 Furthermore, it has been found that the right perfume advertisements vouch for that! As scientific proof of hemisphere is more important to the sense of smell than the left the importance of this sensation, studies have found that almost hemisphere, opening the door for hemispheric dominance.6,7 one-third of patients with olfactory dysfunction report depres- A rather clear inference from the aforementioned discussion sion, poor mood, and poor ability to enjoy food and social would be that complete anosmia (total loss of smell sensation) is interactions.1 Yet, this important sense is often ignored at the possible only after bilateral primary olfactory cortex lesions. time of a “complete” neurologic examination and its symptoms Although cortical causes of anosmia are far less frequent, lesions are often brushed aside as unimportant. This clinical apathy in these areas of the cortex are fairly common (we see often translates to radiological apathy, thus causing many of us bitemporal contusions in our reading room on a daily basis). to ignore looking at important brain regions related to smell. Of interest here is the occurrence of anosmia after unilateral lesions.8 Although this may happen owing to the presence of a prior lesion on the opposite side, there is accumulating evidence Olfactory Pathway of hemispheric dominance and functional lateralization.9 First-order olfactory receptor neurons in the nasal mucosa From the aforementioned observations one can deduce carry the sensation to the mitral and tufted cells in the that unilateral lesions of the primary olfactory cortex would olfactory bulb, whose axons coalesce to form the olfactory cause ipsilateral hyposmia. However, clinically testing tract. Caudal to the olfactory bulb is the anterior olfactory unilateral smell sensation is difficult. Up to 15% of nucleus (AON). Cells in AON synapse with the fibers in the individuals with no complaints of decreased smell sensation olfactory tact. The olfactory tract divides into a medial demonstrate lateralized smell loss and most of them do not olfactory stria, which contains fibers from the AON, passing notice this as long as olfactory function of the better nostril via the anterior commissure to the opposite AON. A lateral remains within the normal range.10 olfactory stria terminates in the piriform cortex and amygdala. An injury to the secondary olfactory cortex such as the OFC The piriform cortex and the medial and cortical nuclei of the results in a deficit of discrimination and recognition of odors.11 amygdaloid complex form the major component of the OFC is found to have a critical role also in conscious olfactory primary olfactory cortex. Entorhinal cortex, tenia tecta, perception.12 Once again, studies have indicated a right AON, and the olfactory tubercle are also variably considered hemispheric dominance.12,13 parts of the primary olfactory cortex. The primary olfactory cortex has reciprocal connections with both the orbitofrontal and insular cortices, the major components of the secondary Thalamus olfactory cortex or the olfactory association cortex. These The belief that the mediodorsal nucleus of the thalamus connections may be direct or via the medial dorsal nucleus of (MDNT) is part of the olfactory circuitry in humans is based the thalamus. Visceral, autonomic, hormonal, and sexual on its functional magnetic resonance imaging and magneto- 14,15 responses to olfactory stimuli may be processed in the encephalographic activation during a smell task. Interest- orbitofrontal cortex (OFC), insula, cingulate cortex, and ingly, the MDNT is also involved in the processing of memory, hypothalamus, arriving via direct projections from the olfac- as are other parts of the olfactory circuit, and maintains that tory cortex, by thalamic connections, or by corticocortical functional-anatomical connection. The nostalgic experiences connections. with certain types of odors are probably the result of this connection. The MDNT may be involved in top-down modulation of attention to olfactory stimuli or corticocortical The Primary and Secondary Olfactory Cortices communication between the olfactory cortex and OFC. It has and Concepts of Laterality been suggested that the MDNT may become recruited when 16 The primary olfactory cortex is mainly formed by the piriform task complexity increases. There are case reports in which cortex and the medial and cortical nuclei of the amygdaloid bilateral thalamic infarctions cause parosmia—a change in the 17,18 complex. The OFC and insula constitute the secondary perception of pleasantness or unpleasantness of an odor. olfactory or olfactory association cortex. Functionally, although Unilateral lesions of the MDNT have been reported to cause 19 odor perception and odor intensity detection are associated impairment of unilateral odor discrimination. Despite the with piriform cortex and amygdala activity, the OFC is frequency of thalamic infarcts, odor abnormalities are rarely involved in odor identification and olfactory memory.2 reported in clinical notes. This could be owing to deempha- The classical concept of cortical representation of olfactory sized clinical testing. Possible association of memory deficits sensation is of a pure ipsilateral projection of olfactory with MDNT lesions may also mask olfactory dysfunction. sensation to the primary olfactory cortex with no definite Nevertheless, it is important to be mindful of olfactory hemispheric dominance. Data however suggest that AON abnormalities after medial thalamic lesions. association fibers project directly to the ipsilateral olfactory cortex and to contralateral olfactory cortex via the anterior Taste commissure.3,4 Bilateral olfactory cortices also have strong reciprocal connections via the anterior commissure. Thus, It is apt to discuss taste and smell together because of their although the olfactory sensory neurons project largely to the related functional connection. When battling an upper

Downloaded for Anonymous User (n/a) at Massachusetts General Hospital from ClinicalKey.com by Elsevier on December 21, 2017. For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. Cortical and subcortical substrates of cranial nerve function 277 respiratory illness and struggling with dulling of both taste and cause taste recognition deficits. It has been found that there smell, one can truly appreciate this relationship. In addition, is enhanced activation of OFC and insular cortex in both senses respond to similar chemical stimuli. These senses patients with taste disorders compared with normogeusic are synergistic to the perception of pleasant or unpleasant controls, suggesting a compensatory boosting of the nature of food and serve as a protective mechanism against gustatory or chemosensory network in response to an consuming inedible or rotten food. These senses also play a impaired sense of taste. This may be useful to prognosticate role in feeding behavior and long-term control of body gustatory dysfunction in individual patients25 and may weight.17 indicate a potential area that may be recruited at the time of recovery. Gustatory Pathway Branches of the facial nerve, the chorda tympani, innervate Laterality of Taste Sensation and Concept of taste buds in the anterior two-thirds of the tongue and part Hemispheric Dominance of the soft palate. The glossopharyngeal nerve innervates Studies have suggested that the central gustatory pathway the posterior one-third of the tongue. Both the vagus and ascends ipsilaterally from the medulla to the pons, branches at glossopharyngeal nerves innervate the pharynx and epi- the upper pons, and then ascends bilaterally from the midbrain glottis. Axons of these 3 CNs terminate on second-order to the cerebral cortex.26 However, clinical data from other sensory neurons in the rostral part of nucleus of the studies have shown ipsilateral, contralateral, and bilateral solitary tract. From this site in the rostral medulla, second- ageusia after lesions of the primary gustatory cortex, suggesting order neurons travel through the ipsilateral central that branching at the level of pons is probably variable and may tegmental tract to the third-order sensory neurons in the not be equal. The variability in clinical manifestations has also ventroposteromedial (VPM) nucleus of the thalamus. The spurred research on hemispheric lateralization. More studies VPM nucleus projects to the ipsilateral gustatory cortex have been in favor of left hemispheric lateralization for taste27-29 located near the postcentral gyrus or to the insular with some studies suggesting that there is a gustatory 20 cortex. Brodmann area 43 in the insulo-opercular cortex representation of both hemitongues in the left cerebral hemi- constitutes the primary gustatory cortex. The OFC and the sphere, whereas only the right hemitongue is represented in anterior insular cortex form the secondary gustatory the right hemisphere.30,31 At the very least, findings force us to cortex. question the classical model of strict ipsilateral cortical representation for taste. Primary Gustatory Cortex The insulo-opercular cortex forms a key part of primary Thalamus 21,22 taste cortex. The primary taste cortex is at the base of That the VPM nucleus of thalamus is part of the gustatory the primary somatosensory cortex and is in the vicinity of circuit is not by chance. The VPM nucleus also forms part of the area of somatosensory cortex that represents general the ascending somatosensory pathway, which includes general intraoral sensation. The overall experience of taste is sensation from intraoral structures. Relay or processing of taste chemoreception combined with general sensation of tex- with sensations of touch, pain, and temperature from intraoral ture and temperature of food. Pain also plays a role in the structures at a common location in the VPM nucleus is part of hotness of food. The close anatomical location of primary the functional-structural connection. The overall taste experi- gustatory cortex to the somatosensory cortex responsible ence is an integration of chemoreception, thermoception, for intraoral sensation is therefore strategic. Lesions of the nociception, and touch. As the branching of taste fibers occurs gustatory cortex usually cause ipsilateral loss of taste at the level of pons, each VPM nucleus carries taste sensation sensation (ageusia). from both hemitongues. Ageusia after thalamic lesions can be unilateral (ipsilateral or contralateral) or bilateral,32 probably Secondary Gustatory Cortex depending on individual variability of crossing at the pons. Some reports of bilateral ageusia with left VPM nucleus lesions Rolls et al23 discovered a taste area in the lateral part of the however support left hemispheric dominance.33 OFC and showed that this was the secondary taste cortex, receiving a major projection from the primary taste 24 cortex. Studies suggest that although taste sensation Ocular Movements could be computed in the primary taste cortex, recognition requires further processing by structures located in the The extreme importance of vision in our lives, not to mention anteromedial temporal lobe and caudolateral OFC.8 The the lives of radiologists, cannot be overemphasized. The OFC is known to be an area of multisensory integration. It complex neural mechanism of vision and its control has been receives inputs from primary olfactory, somatosensory, expertly dealt with elsewhere in this book. The following auditory, visual, and gustatory areas, thus modulating discussion focuses on the control of ocular movements, an awareness of flavor, taste recognition, and discrimination. important aspect of vision that exists in its most basic form to Components of gustatory memory are probably processed maintain clear images on the retina by controlling the position here as well.24 Lesions of the OFC have been reported to of the fovea.

Neural control of saccades:

FEF CN PEF

SN Visual smuli

SC Cerebellum

Other sensory smuli Gaze Oculomotor Centers neurons

Figure 1 Neural control of saccades. The cerebral cortex chooses significant objects in the environment as targets for eye movements via visual and behavioral stimuli. Visual stimuli activate neurons in the FEF, PEF, and SC. Activation of the FEF is more closely related to the motor command, whereas that of the PEF is more related to the visual attention. FEF and PEF activate movement-related neurons in the SC. FEF activates the CN which inhibits the SN and releases the SC from its inhibitory effect. SC forms a map of potential eye movements by multisensory integration. The signals converge on the horizontal and vertical gaze centers which provide the final velocity and position instructions to the oculomotor neurons. The cerebellum gives precision to the overall eye movement. Refer to the Table for deficits produced by lesions.34-37,50,51,62,64 CN, caudate nucleus; FEF, frontal eye fields;PEF,parietaleyefields; SC, superior colliculus; SN, substantia nigra. Solid line: activation signal, dashed line: inhibitory signal. (Color version of figure is available online.)

Neural control of smooth pursuit movements:

Moving target Eye and head posion signals

MT VN

FEF PEF

DPN

Cerebellum

Gaze Oculomotor Centers neurons

Figure 2 Neural control of smooth pursuit movements. Neurons in the MT calculate the velocity of the target. The MT activates the FEF and the integrated signal from these cortical areas is relayed by the DPN, which project to the cerebellar vermis and flocculus. The VN carry signals of eye velocity and head position. They project to the oculomotor nuclei in the midbrain and receive projections from the flocculus of the cerebellum. Smooth pursuit is thus carried out through an intricate network with real-time computation and matching of target and eye movement velocities. When the eye speeds up to match target speed, the relative speed of the target's motion on the retina decreases. Neurons in the MT stop firing and terminate the movement. Refer to the Table for lesions.34-37,50,51,62,64 DPN, dorsolateral pontine nuclei; FEF, frontal eye fields; MT, motion- sensitive area of the temporal lobe; PEF, parietal eye fields; VN, vestibular nuclei. (Color version of figure is available online.)

Table Functions of Cortical and Subcortical Regions Involved in the Control of Eye Movements and the Effects of Lesions34–37,45,47–64 Cortical/Subcortical Location Function Effects of Lesions Region Frontal eye ﬁelds Precentral gyrus and sulcus Main area providing motor Unilateral lesions cause anterior to the hand motor command for eye movements paresis of contralateral gaze area by projecting to horizontal (Fig. 3) and vertical gaze centers Main motor projection to the Bilateral lesions cause superior colliculus profound inability to make saccades, especially if associated with lesions of the superior colliculus Projection to caudate nucleus inhibits substantia nigra and releases the superior colliculus from its inhibitory effects

Parietal eye fields Posterior intraparietal sulcus Provide visual attention signals Increased latency of saccades to the superior colliculus Inaccurate saccade targeting during eye movement Hemispatial neglect and generation and control attention deficits, especially visually guided reflexive after right-sided lesions saccades Affect triggering of reflexive visually guided saccades

Supplementary eye Anterior to supplementary Control of motor programming ﬁelds motor area

Dorsolateral prefrontal Saccade inhibition Inhibited prolonged ﬁxation cortex

MT area of temporal lobe Occipito-temporo-parietal Activated during smooth Diminished smooth pursuit junction pursuit to calculate the velocity of the target and send signals to FEF for coordination of smooth pursuit Also activated during Deﬁcit of the OKN with a optokinetic movements and reduction in ipsiversive slow vestibulo-ocular reﬂex phase velocity

Superior colliculus Midbrain Forms a map of potential eye Increased saccade latency movement by integrating Transient inability to generate multisensory signals and saccades motor commands

Thalamus Thalamic region for eye Function not well understood Can cause vertical gaze palsy movement control is the but reciprocal pathways for internal medullary lamina eye movement control exist within cortex, superior colliculus, and brainstem

Rostral interstitial Upper midbrain, close to Vertical gaze center Unilateral lesions cause nucleus of MLF CNIII nucleus ipsilateral loss of vertical saccades (Fig. 5) Bilateral lesions cause loss of all vertical saccades

Interstitial nucleus of Upper midbrain Major center for vertical and Unilateral lesions cause Cajal torsional gaze holding torsional nystagmus with fast phase to the side of lesion Bilateral lesions impair eccentric gaze holding and vertical VOR

Table (continued )

Cortical/Subcortical Location Function Effects of Lesions Region

Paramedian pontine Rostral and midpons Horizontal gaze center Ipsilateral gaze palsy reticular formation

Cerebellum Flocculus or paraﬂocculus Saccade and pursuit precision Impaired smooth tracking Gaze-evoked nystagmus on eccentric eye movements

Cerebellum Fastigial nucleus Saccade precision Ipsiversive saccade overshoot and contraversive undershoot (Fig. 4)

Cerebellum Dorsal vermis Precision Impairment of ipsilateral pursuit

Cerebellum Uvula Smooth pursuit modulation, Deﬁcient smooth pursuit VOR and OKN modulation Impaired VOR suppression

Medial longitudinal Paramidline brainstem Important pathway for control Lesions cause ipsilateral loss fasciculus of conjugate eye movements of adduction on attempted lateral gaze to opposite side; with left MLF lesions, left eye fails to adduct when patient looks to the right— internuclear ophthalmoplegia Bilateral lesions cause bilateral internuclear ophthalmoplegia MLF, medial longitudinal fasciculus; MT, motion-sensitive area of the temporal lobe.

Totally 6 different systems control the eye: fixation keeps the the eyes drift back toward the midposition because the cells fovea still on a target, saccades move the fovea from one object of responsible for the integrated step signal that keeps the eyes at interest to another, smooth pursuit keeps the fovea on a moving the new position are dysfunctional.34 target, vestibular and optokinetic movements keep the eye still in space when the head moves, and vergence adjusts the individual angles of each eye to keep objects at a certain depth focused on Optokinetic Nystagmus equivalent retinal positions. In addition, movements of the head Large moving visual fields lead to slow compensatory eye help position the fovea on a target in the visual field. Combined movements in the direction of the moving field. The eyes move eye and head movements are called gaze movements.34 The neural control of saccadic and smooth pursuit eye movements is described in Figs. 1 and 2.TheTable describes the role of different areas and the deficits caused by lesions to these areas. The other eye movements are described later.

Gaze Holding or Fixation Gaze holding permits a stable eye position between eye movements. Gaze holding is accomplished by a neural integrator mechanism that is constituted by the medial vestibular nucleus and nucleus prepositus hypoglossi for horizontal positions and by the superior vestibular nucleus and interstitial nucleus of Cajal for vertical and torsional eye positions. The neural integrator sustains the discharge of ocular motor neurons to generateatoniceyepositioncommandintheabsenceofany fl ongoing external input (eg, a saccade command). The occulus Figure 3 A 78-year-old woman presents with left double vision and left or paraflocculus modulates activity in a positive feedback loop facial droop. Examination reveals forced gaze deviation to the right around the brainstem neural integrator and improves its with loss of eye movements to the left (loss of contralateral saccades). performance by bringing precision.37 A monkey with a lesion Note the infarct involving the frontal eye fields (arrow). (Color version of these areas (Table) makes normal saccades, but after a saccade of figure is available online.)

The pathways controlling OKN are also under visual cortex control. Bilateral occipital lobectomy in monkeys impairs OKN41 and patients with cortical blindness due to occipital lesions lack optokinetic responses.42

Vestibulo-Ocular Reflex The vestibulo-ocular reflex (VOR) stabilizes the retinal image during head movement when fixating on an earthbound target. A small gaze movement consists of a saccade followed by head movement and then a compensatory VOR that moves the eyes back to the center of the orbit in the new position. For larger gaze movements, the eyes and the head move simultaneously in the same direction. As the VOR ordinarily moves the eyes in the direction opposite that of the head, the reflex must be temporarily suppressed for the eyes and the head to move simultaneously. Fixating gaze on a target that moves Figure 4 A 56-year-old man with horizontal gaze-evoked nystagmus, with the head also requires suppression of VOR.43 fast component to left. Note the left cerebellar infarct involving the The visual cortex, the superior temporal sulcus, occipito- vermis and part of the fastigial nucleus (arrow). The cerebellum acts to temporal region, and the posterior parietal cortex play impor- facilitate contraversive saccades and contributes to the termination of ipsiversive saccades. Consequently, lesions cause ipsiversive saccadic tant roles in visual-vestibular interaction. These areas send hypermetria (overshoot) and contraversive hypometria, resulting in efferent signals to the dorsolateral pontine nuclei and the 43 gaze-evoked nystagmus. (Color version of figure is available online.) cerebellum, which then regulate eye movements. Cortical processing of vestibular signals may contribute to establishing back quickly when the moving field is out of view. The the internal representation of space, in which different sensory combination of the slow compensatory and fast resetting eye inputs are integrated and organized in ego-centered and object- movements is called optokinetic nystagmus (OKN). Two centered coordinates. At the same time, cortical outputs to the fi vestibular nuclei regulate vestibular function for appropriate cortical areas mainly control OKN. The rst involves the 43 extrastriate temporal area including motion-sensitive area of movement and posture in space. Once again stimulation and the temporal lobe, which receives well-defined visual and suppression of VOR is brought about by close coordination of vestibular velocity signals likely involved in heading percep- visual, vestibular, cerebellar, and motor systems. tion. The second involves the parietal cortex, which gives perception of peripersonal space and self-referential process- Accommodation 38,39 ing. Lesions of the motion-sensitive area of the temporal Accommodation and vergence are linked. Blurring of images lobe (Table) and parietal areas can cause deficits of OKN with a on the retina is the stimulus that induces accommodation. 40 reduction in ipsiversive slow phase velocity (Fig. 6). Retinal blur and binocular disparity activate image-blur-sensitive

Figure 5 A 4-year-old boy with vasculitis presented with diplopia. Note the infarct in the region of the right thalamo- mesencephalic junction (arrow). Based on the clinical picture, we can deduce that it involves the rostral interstitial nucleus ofthemediallongitudinalfasciculus(riMLF).(Colorversionofﬁgure is available online.)

Figure 6 A 57-year-old man with diplopia. No lesions were found in the frontal or parietal lobes, cerebellum, or brainstem. Note the infarct involving the motion-sensitive area of the temporal lobe (MT) (arrow), important in the control of smooth pursuit, vestibulo-ocular reflex, and optokinetic reflex. (Color version of figure is available online.) neurons in the visual cortex, which in turn activate the frontal midbrain, through the reticular substance of the pons and eye fields. Via the paramedian pontine reticular formation, medulla, and finally in the anterolateral columns of the cervical premotor neurons for convergence in the midbrain reticular and probably first 2 thoracic cord segments.46 formation (dorsal and lateral to the oculomotor nucleus) are activated. These premotor neurons activate the oculomotor nucleus, which causes contraction of bilateral medial rectus muscles. They also activate the Edinger-Westphal nucleus Facial Sensation (EWN), which causes constriction of the ciliary and iris The importance of general sensation of touch, pain, pressure, sphincter muscles. The linked systems of accommodation, temperature, and vibration to the face can be easily understood vergence, and pupillary constriction comprise the near by the lion's share of surface area given to the face on the response.34 primary sensory cortical strip on the postcentral gyrus. Besides In addition to the posterior parietal and the frontal cortex carrying out sensory function to a much greater precision than (Brodmann area 8), the preoccipital cortex (Brodmann areas most other body parts (with the exception of only fingers), 18, 19, and 22) is considered to be the cortical convergence facial sensation also serves to provide spatial orientation and center.44,45 provides vestibular inputs of head position.

Light and Dark Reaction Facial Sensory Pathway The afferent limb of the light and dark reaction is carried in the The sensory division of CN V carries general sensation from optic nerve through the retina. The known site for the efferent most areas of the head and face. CNs VII, IX, and X contribute limb of pupillary constriction is the EWN in the midbrain. to a lesser extent. Skin sensation from the posterior part of the Fibers from this nucleus travel in CN III and synapse in the external ear is carried by CN VII, whereas the remaining skin of ciliary ganglion, ending in the constrictor muscles of the iris. the external ear, parts of the tympanic membrane, wall of the Similarly, the efferent limb for pupillary dilatation ascends upper pharynx, and the posterior third of the tongue are through the sympathetic chain to the superior cervical ganglion represented by CN IX. Areas of the external auditory meatus and ends in the iris dilators via the sympathetic plexus draped and some parts of the tympanic membrane are represented by around the arteries. The pathways by which the pupillary CN X. Sensory afferents carrying discriminative touch and dilatation and constriction signals reach the EWN and the proprioception have pseudounipolar cell bodies in the cranial sympathetic chain are poorly understood. Some studies ganglia of the trigeminal, facial, glossopharyngeal, and vagus suggest that contralateral frontal and occipital lobe pupillary nerves. Their central axons enter the brainstem and synapse constrictor fibers travel in the lateral ventricular wall to the with the main sensory nucleus of CN V. The second-order lateral geniculate nucleus and the thalamus, finally synapsing neurons decussate immediately after leaving the sensory in the EWN.46 Pupillary dilatation fibers from the cortex reach nucleus and ascend in the contralateral trigeminal lemniscus the hypothalamus by a poorly understood pathway. From the to synapse in the VPM nucleus of thalamus. Third-order hypothalamus, fibers pass through the tegmentum of the neurons travel in the posterior limb of the internal capsule

Primary Somatosensory Cortex Primary somatosensory cortex (S1) for face is located within the postcentral gyrus, inferior and lateral to the hand area. The areas representing tongue and pharynx extend further inferior toward the insula and operculum. S1 lesions cause contrala- Figure 7 A 47-year-old man presented with right facial numbness. teral loss of facial sensation. Note the small acute infarct in the left thalamus (arrow). (Color version of ﬁgure is available online.) Secondary Somatosensory Cortex the face with or without a stimulus. Any stimulus may have an Secondary somatosensory cortex (S2) resides in Brodmann unpleasant feeling and pain may be aggravated by nonsomatic area 40 of the inferior parietal lobe. S2 is believed to perform stimuli like loud sounds or even emotional disturbance. This higher-order functions, including sensorimotor integration, pain syndrome can also be caused by cortical lesions in the integration of information from the 2 body halves, attention, insulo-opercular region, in which case it is called “pseudotha- learning, and memory.65-68 S2 is the target of independent lamic syndrome.” Another interesting thalamic sensory syn- pathways for the processing and integration of nonpainful and drome associated with this thalamic region is the Cheiro-oral painful somatosensory stimuli salient for further high-order syndrome, which entails contralateral sensory impairment elaborate sensation.69 restricted to the perioral area and homolateral distal ﬁnger(s). This is likely related to close somatotopy of the face and hand Other Cortical Sensory Areas areas in the thalamus. The posterior insular cortex, medial parietal operculum, and Reports of bilateral representation have also been found in 75 the midcingulate areas have been described in functional the thalamus, especially for painful stimuli. Although most imaging studies (positron emission tomography imaging and data favor contralateral representation, there are a few reports 76-78 functional magnetic resonance imaging) as being the areas most of bilateral thalamic representation to facial stimuli. frequently and strongly activated by noxious, thermal, and mechanical stimuli.70,71 Within these regions, the opercular- insular area is thought to sustain sensory spinothalamic Laterality and Hemispheric Dominance processing, whereas the cingulate area is considered to support As is true with other CN function modalities, the classical orienting and withdrawal reactions driven by noxious stimuli.72 concept of strict and complete contralateral representation of Lesions of the operculo-insular region may cause develop- facial sensory stimuli has been challenged. It has been ment of a pain syndrome referred to as “pseudothalamic suggested that sensory afferents innervating various parts of pain.”72 Operculo-insular pain is a distinct central pain the face and the intraoral region project to both contralateral syndrome that can be clinically suspected and objectively and ipsilateral S1 cortices via the trigeminothalamic tract with diagnosed with combined radiological and electrophysiolog- the contralateral ascending pathway of projection being 79,80 ical methods.73 Other distinct symptoms associated with dominant. A few studies also suggest hemispheric lateral- 81,82 lesions of these areas are unknown and inconsistent. ization and right hemispheric dominance. Data for bilateral activation of cortical sensory areas are stronger for nociceptive stimuli. In addition, the magnitude Thalamus and timing of the signal increases are similar on both sides of The ventromedial and intralaminar nuclei of the thalamus relay the brain including signals in the thalamus.75-78,83 sensory information from the face. Lesions of the thalamus cause contralateral sensory symptoms (Fig. 7). An interesting syndrome with thalamic lesions is the Recoverability “thalamic pain syndrome.” First described by Dejerine and Whereas it has long been known that S2 is reciprocally Roussy,74 it is a syndrome of spontaneous pain or discomfort of connected with ipsilateral S1 via corticocortical

Downloaded for Anonymous User (n/a) at Massachusetts General Hospital from ClinicalKey.com by Elsevier on December 21, 2017. For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. 284 M. Agarwal et al. connections,84-86 evidences from several mammalian species, explain the contralateral lower facial paralysis in middle including nonhuman primates, suggest the presence of direct cerebral artery stroke is quite surprising. In fact, neuronal thalamocortical projections to S2.87-91 In addition to cortico- tracing studies dating as far back as the late 1950s conducted in cortical connections, there is a body of anatomical and human and nonhuman primates do not fully support this electrophysiological evidence for interhemispheric connec- idea.96,97 tions between the somatosensory cortices via the corpus Studies show that 2 types of facial paralyses occur. In callosum.84,85,92 In particular, S2 cortices are known to have “volitional facial paralysis,” patients have impaired voluntary reciprocal connections and most S2 neurons display bilateral movements of their lower facial muscles after contralateral receptive fields.84,85,93 Further, S2 is reciprocally and somato- cortical lesions. However, patients can overcome the paralysis topically connected to contralateral S1.85 In summary, much of when responding to emotionally provocative or humorous the existing animal literature suggests that in the initial steps of remarks. In contrast to this is the “emotional facial paralysis” somatosensory information processing a unilateral sensory characterized by the inability to smile on one side of the face, or stimulus is first transmitted to contralateral S1 and S2 cortices flattening of affect, but preserved voluntary control over the via thalamocortical connections. After some intrahemispheric same set of muscles.98-102 integration, the information is then relayed to S1 and S2 In a landmark study on rhesus monkeys, it was found that cortices ipsilateral to the sensory stimulus via corticocallosal corticofacial afferents from primary motor cortex, caudal connections from S1 to opposite S1 and S2, and from S2 to cingulate, and ventrolateral premotor cortex (LPMCv) inner- opposite S2 for early interhemispheric integration.94 These vate primarily the contralateral lower facial muscles. Bilateral connections may be useful at the time of recovery from S1 or innervation of the upper face is supplied by the supplementary S2 lesions. motor area and rostral cingulate cortex. A component of the corticofacial projection is also found to arise from the limbic cortices, which suggests a potential anatomical substrate that Motor Control of Face may contribute to the clinical dissociation of emotional and volitional facial paralysis.103 It has been postulated that the In the words of the great Roman philosopher Marcus Cicero, influence of M1 on the upper facial muscles may not be as “The face is a picture of the mind.” It is curious how synergistic significant as classically interpreted, and the frequent clinical movements of the facial muscles in different combinations can phenomenon of upper face sparing following middle cerebral display the state of mind, crossing barriers of language. Besides artery infarction may be related to other potential projection muscles of facial expression, facial movements are controlled systems.104 A direct corticobulbar projection from the supple- also by movements of the jaw, tongue, and palate. Facial mentary motor area to the facial nucleus has been demon- movements also play a role in other complex activities like strated in the nonhuman primate.103 The corticofacial speech, chewing, and swallowing. Most orofacial motor func- projection from the rostral cingulate has been found to tions involve activation of multiple subsystems of muscles. This terminate bilaterally, with a large number of terminals occur- coordinated activity is dependent on higher brain center ring within the dorsal and intermediate subnuclei (known to projections (eg, from face motor area) to the CN motor nuclei innervate the upper facial musculature).103 The characteristic in the brainstem and on complex brainstem neural circuitries. blunted facial appearance seen in patients following anterior The CN motor nuclei include the trigeminal (V) motor nucleus, cerebral artery infarction may also be related to the destruction the motoneurons that supply most jaw muscles; the facial (VII) of a facial nucleus projection from the anterior cingulate cortex nucleus that provides the motor innervation to the muscles of as well as the general finding that the cingulate motor cortex facial expression; the nucleus ambiguus that gives rise to the represents a critical anatomical entry point for limbic input to motor supply to the palatal, laryngeal, and pharyngeal muscles the cortical motor system. Thus, it seems plausible to suggest via the vagus (X) and glossopharyngeal (IX) nerves; and the that the corticofacial projection from the cingulate cortex might hypoglossal (XII) nucleus, which supplies the extrinsic and be associated structurally with cortical association areas that intrinsic muscles of the tongue.104 Although it is well estab- have known roles in complex behaviors such as emotion, lished that voluntary orofacial motor functions are initiated by attention, and decision making. This corticobulbar projection and are under the control of the primary motor area (M1) in the may interact as a neural bridge between the cortex and cerebral cortex, studies in the last 2 decades suggest the brainstem in ways that are essential for the mediation of involvement of face M1 also in the generation and control of higher-order facial responses.101,105,106 the semiautomatic orofacial movements such as chewing and Further evidence for alternate pathways for facial motor swallowing that for many years were considered to be under the control comes from patients with biopercular syndrome, control of brainstem central pattern generators.95 otherwise known as Foix-Chavany-Marie syndrome. These patients have lesions in bilateral opercular regions and manifest pseudobulbar symptoms with voluntary paralysis of mastica- The Dichotomy of Voluntary and Emotional tory, facial, pharyngeal, and lingual muscles. Patients with Facial Movements biopercular syndrome have spared function for upper facial The continued teaching of the tenet that upper facial muscu- musculature.107 lature receives bilateral innervation from the primary motor Besides damage to the midline frontal cortex, emotional cortex and the lower face only contralateral innervation to facial paralysis has also been reported to occur in patients with

more severe, and possibly longer lasting, deficits in the lower facial musculature due to the combinedlossofbothprojection systems to the lower face opposite a unilateral hemispheric lesion.108 Of additional significance, and particularly from a clinical perspective, is the localization of a moderate ipsilateral projection from LPMCv to motor neurons supplying the lower face.103 It has been suggested that this projection, which potentially resides in the undamaged hemisphere, may play an influential role in the recovery process of lower facial weakness, particularly if both M1 and LPMCv were compromised in the injured hemisphere.103 Another mechanism for recovery after facial paralysis is thought to be midline crossing of facial motor axons by means of collateral reinnervation of orphan myofibers from contralateral motor axons.117 This is probably independent of the central mechanisms of recovery. Concepts of multiple motor representations also prevail with independent representations of body movements in each motor area.118

Figure 8 A 53-year-old man with left facial droop. The only lesion found was a left caudate head infarct (arrow). The striatal pathway of Hearing fi emotional facial motor control is a possible mechanism of this de cit. The Vedas are the most ancient Hindu scriptures, written in Incidental sebaceous cyst is located in the right parietal scalp. (Color early Sanskrit. Unlike other nonmusical text, there is prime version of figure is available online.) importance of sound throughout the Vedic literature, where every single letter is called a “beej”—seed (of existence). Every damage to the insula, thalamus, striatocapsular region (Fig. 8), syllable has a meaning, is connected to, and affects the human and pons. Collectively, these observations also support the body in a certain way. “Om”, the presumed resounding hypothesis of separate neural systems controlling voluntary vibration of the universe, is the sum of all syllables and is and emotional movements of the face.108 Also, the much more believed by Vedas to be the sound of creation, life, and end. frequent condition of voluntary facial palsy with sparing of Sound is critical to our way of life, in music, words, language, emotional movements can occur after brainstem lesions. The and communication. finding of dissociation between emotional and voluntary facial movements at the level of the brainstem is extremely interesting. This indicates that the 2 systems are completely inde- The Auditory Pathway pendent up to the facial nucleus.107 A striking feature of Sound information proceeds from the Organ of Corti to spiral emotional facial palsy related to focal lesions is that it is ganglion cells and the CN VIII afferents in the ear, to the unilateral, indicating that emotional movements of each half of cochlear nuclei. Many fibers cross in the trapezoid body and the face are represented separately.109-111 ascend to the superior olive in the brainstem. From here, all In animals such as cats and rats a specialized emotional ascending fibers reach the inferior colliculus (IC) in the motor pathway descends from the amygdala, the lateral midbrain, ascend to the medial geniculate body in the hypothalamus, and the bed nucleus of the stria terminalis to thalamus, and then reach the cortex in the superior temporal the periaqueductal gray matter. This in turn projects to facial gyrus (STG). All auditory afferents synapse in the cochlear premotor neurons in the lateral reticular formation and, to a nuclei and in the thalamus. Afferents are generally distributed lesser extent, directly to facial motoneurons.112-114 This system bilaterally so unilateral damage at any level does not usually may serve as an outline to a similar pathway controlling result in deafness in either ear. Sound ascends into the brain in muscles of facial expression in humans.115 2 ways. In the fast acting system, fibers synapse in the dorsal cochlear nucleus, and may function as a general warning (as when you might jump from a loud sound). These fibers Hemispheric Dominance and Recoverability decussate and ascend in the lateral lemniscus to the IC. The It has been shown that the face or head region of the LPMCv, slow acting system involves much more processing and may which resides anterior to the facial area of M1, innervates the provide more detailed information about the sound, such as its facial nucleus.103,116 From a clinical perspective, in the event location and character. These fibers synapse in the ventral that damage is isolated to M1, it is possible that the projection cochlear nucleus. Fibers from the ventral cochlear nucleus from LPMCv may contribute to recovery of contralateral lower synapse in the ipsilateral and contralateral superior olivary facial paresis.108 The finding of a strong contralateral projection nuclei. Some fibers from the ventral cochlear nucleus cross the from LPMCv to the lower facial musculature further suggests midline in the trapezoid body. Thus, cells in the superior olive that concomitant damage to LPMCv and M1 would give rise to receive inputs from both ears and are the first place in the

Downloaded for Anonymous User (n/a) at Massachusetts General Hospital from ClinicalKey.com by Elsevier on December 21, 2017. For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. 286 M. Agarwal et al. central auditory system, where binaural processing (stereo deficits, consistent with the notion that the right hemisphere hearing) is possible. The output of the superior olive travels in is involved in spatial analysis.132 Speech-related stimuli are the lateral lemniscus. Some nuclei within the lateral lemniscus shown to activate selectively the supratemporal plane lateral to further process the sound. Most of these afferents synapse in Heschl's gyrus bilaterally. Processing of auditory motion is the IC. All afferents then synapse in the medial geniculate body thought to occur in the anterior insula. of the thalamus. Thalamic afferents reach the STG through the sublenticular portion of the internal capsule.20 Medial Geniculate Nucleus of Thalamus The medial geniculate nucleus (MGN) is the nuclear mass The Primary Auditory Cortex of the thalamic auditory relay nucleus, an integration center for Brodmann areas 41 and 42 in the temporal lobes, also known the central auditory pathways that receives fibers from the IC as Heschel's gyrus, constitute the primary auditory cortex. and chiefly projects to the ipsilateral STG via the geniculato- There is strong bilateral representation of both ears in bilateral temporal or auditory radiation. The thalamus actively regulates primary auditory cortices from which stems the belief that the flow of sensory information and modulates sensory signals cortical deafness is only theoretical. This belief withstands a that serve as the inputs to the cortex. This modulation in the typical office testing of auditory function. However, deficits can MGN is enabled by dynamic interactions between ascending be detected in these patients with sophisticated psychoacoustic inputs from the inferior IC in the midbrain and corticofugal and electrophysiological testing. Patients with cortical lesions projections. MGN neurons receive both excitatory and inhib- can have impaired sound localization for the sound field itory inputs from the IC and excitatory inputs from the contralateral to the lesion.119,120 Listening tasks with distorted cortex.133,134 The MGN may have roles in the spectral analysis stimuli such as accelerated, retarded (decelerated), and filtered of sound, sound pattern recognition, auditory memory, and speech are often poorly performed. Also, speech discrimina- the localization of sound in space.135,136 Lesions can cause tion in a noisy environment is typically impaired.119 Deficits auditory illusions and auditory spatial deficits.136,137 The right created by left and right lesions may also be different. In thalamus is known to play a much more important role in the patients with left-sided lesions, there are difficulties in under- differential allocation of attention to input from the 2 ears than standing verbal stimuli, whereas in patients with right-sided does the left.137 lesions, there is greater difficulty discriminating environmental sounds.120 When specifically testing language tasks, patients with left hemisphere lesions tend to make semantic errors on Inferior Colliculus auditory tasks and patients with right hemisphere lesions tend The unilateral IC receives afferent projections from most to make perceptual errors on auditory tasks.121-126 brainstem auditory nuclei, but chiefly from the contralateral A unilateral dominant temporal lobe lesion may result in cochlear nuclear complex. The crossed pathway is dominant in pure word deafness. Such a lesion, which may be cortical or the brainstem auditory pathway to the level of the IC. The subcortical, is thought to isolate Wernicke'sareafromthe monaural auditory inputs ascend mainly to the contralateral ipsilateral and contralateral auditory cortex. An auditory IC. The IC gives rise to crossed projections to the ipsilateral (to agnosia for speech results so that the patient is unable to the ear) temporal lobe through the commissural fibers of the IC identify spoken words despite recognizing that the sounds as well as uncrossed projections to the contralateral (to the ear) represent speech.127 Pure word deafness is more commonly temporal lobe. Descending collicular input is capable of the result of bilateral lesions of the superior temporal modulating levels of excitability within the olivary nucleus cortex.128,129 and the cochlea.138 IC plays an important role in sound perception not just by relaying signals from the cochlear nuclei to the auditory cortex, Other Cortical Areas of Auditory Processing but also contributing to auditory processing.139 In humans, Distinct areas outside the primary auditory cortex have been bilateral lesions of the IC have resulted in central deafness140 or identified. The primary auditory cortex appears to be sur- auditory agnosia—an impaired capacity to recognize sound rounded by rostrolateral and caudomedial areas that may despite adequate hearing.139,141 Bilateral lesions are also constitute a hierarchically intermediate level. It is proposed that known to cause pure word deafness.142 Unilateral lesions of auditory information is processed in the human auditory the IC cause decreased speech recognition in the presence of cortex along 2 distinct pathways.120,130 The caudomedial parts background noise, impaired binaural processing, and the oftheSTGareconsideredtheoriginofa“where” stream for inability in locating a sound source in the hemifield contrala- auditory processing. The rostrolateral parts of the STG, on the teral to the lesioned side.141,143 contrary, seem to integrate information relevant for auditory object identification and form an auditory “what” stream. Posterior infarcts involving the posterior STG and parietal Trapezoid Body, Superior Olivary Complex, cortex lead to profound disturbances in the localization of and Lateral Lemniscus sounds. By contrast, lesions of the anterior STG region lead to The brainstem structures involved in hearing serve the dual problems with sound recognition.131 Right hemispheric purpose of transmitting signals to higher centers and sound lesions cause more profound auditory spatial processing processing. Signals from cochlear nuclei ascend to both

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