Saccadic oscillations as a biomarker of clinical symptoms in amyotrophic lateral sclerosis.

BACKGROUND: Among eye movements in amyotrophic lateral sclerosis (ALS), we identified the characteristics of square-wave jerks (SWJs) seen during times without visual fixation (VF) and analyzed their relationships with clinical parameters. MATERIALS AND METHODS: Clinical symptoms were evaluated and eye movements were tested using electronystagmography in 15 patients with ALS (10 men, 5 women; mean age, 66.9 ± 10.5 years). SWJs with and without VF were recorded, and their characteristics were identified. Relationships between each SWJ parameter and clinical symptoms were evaluated. Results were compared with eye movement data from 18 healthy individuals. RESULTS: The frequency of SWJs without VF was significantly higher in the ALS group than in the healthy group (P < 0.001). When the condition was changed from VF to no-VF in the ALS group, the frequency of SWJs was significantly higher in healthy subjects (P = 0.004). A positive correlation was seen between frequency of SWJs and percentage predicted forced vital capacity (%FVC) (R = 0.546, P = 0.035). CONCLUSION: The frequency of SWJs was higher with VF in healthy people, and was suppressed without VF. In contrast, the frequency of SWJs was not suppressed without VF in ALS patients. This suggests that SWJs without VF have some clinical significance in ALS patients. Moreover, a relationship was noted between the parameters of SWJs without VF in ALS patients and results of pulmonary function tests, suggesting that SWJs during times without VF may offer a clinical parameter of ALS.

Intrinsic chemosensitivity of rostral ventrolateral medullary sympathetic premotor neurons in the in situ arterially perfused preparation of rats.

Brainstem hypoperfusion is a major excitant of sympathetic activity triggering hypertension, but the exact mechanisms involved remain incompletely understood. A major source of excitatory drive to preganglionic sympathetic neurons originates from the ongoing activity of premotor neurons in the rostral ventrolateral medulla (RVLM sympathetic premotor neurons). The chemosensitivity profile of physiologically characterized RVLM sympathetic premotor neurons during hypoxia and hypercapnia remains unclear. We examined whether physiologically characterized RVLM sympathetic premotor neurons can sense brainstem ischaemia intrinsically. We addressed this issue in a unique in situ arterially perfused preparation before and after a complete blockade of fast excitatory and inhibitory synaptic transmission. During hypercapnic hypoxia, respiratory modulation of RVLM sympathetic premotor neurons was lost, but tonic firing of most RVLM sympathetic premotor neurons was elevated. After blockade of fast excitatory and inhibitory synaptic transmission, RVLM sympathetic premotor neurons continued to fire and exhibited an excitatory firing response to hypoxia but not hypercapnia. This study suggests that RVLM sympathetic premotor neurons can sustain high levels of neuronal discharge when oxygen is scarce. The intrinsic ability of RVLM sympathetic premotor neurons to maintain responsivity to brainstem hypoxia is an important mechanism ensuring adequate arterial pressure, essential for maintaining cerebral perfusion in the face of depressed ventilation and/or high cerebral vascular resistance.

Hydrogen sulfide production in the medullary respiratory center modulates the neural circuit for respiratory pattern and rhythm generations.

Hydrogen sulfide (H2S), which is synthesized in the brain, modulates the neural network. Recently, the importance of H2S in respiratory central pattern generation has been recognized, yet the function of H2S in the medullary respiratory network remains poorly understood. Here, to evaluate the functional roles of H2S in the medullary respiratory network, the Bötzinger complex (BötC), the pre-Bötzinger complex (preBötC), and the rostral ventral respiratory group (rVRG), we observed the effects of inhibition of H2S synthesis at each region on the respiratory pattern by using an in situ arterially perfused preparation of decerebrated male rats. After microinjection of an H2S synthase inhibitor, cystathionine ß-synthase, into the BötC or preBötC, the amplitude of the inspiratory burst decreased and the respiratory frequency increased according to shorter expiration and inspiration, respectively. These alterations were abolished or attenuated in the presence of a blocker of excitatory synaptic transmission. On the other hand, after microinjection of the H2S synthase inhibitor into the rVRG, the amplitude of the inspiratory burst was attenuated, and the respiratory frequency decreased, which was the opposite effect to those obtained by blockade of inhibitory synaptic transmission at the rVRG. These results suggest that H2S synthesized in the BötC and preBötC functions to limit respiratory frequency by sustaining the respiratory phase and to maintain the power of inspiration. In contrast, H2S synthesized in the rVRG functions to promote respiratory frequency by modulating the interval of inspiration and to maintain the power of inspiration. The underlying mechanism might facilitate excitatory synaptic transmission and/or attenuate inhibitory synaptic transmission.

Lateral Habenula Regulates Cardiovascular Autonomic Responses via the Serotonergic System in Rats.

The lateral habenula (LHb) plays essential roles in behavioral responses to stressful events. Stress is tightly linked to autonomic responses such as cardiovascular responses, yet how the LHb regulates these responses is not well understood. To address this issue, we electrically stimulated the LHb in rats, measured its effects on heart rate (HR) and mean arterial pressure (MAP), and investigated the neural circuits that mediate these LHb-induced cardiovascular responses via the autonomic nervous system. We observed that stimulation of the LHb induced bradycardia and pressor responses, whereas stimulation of the adjacent areas changed neither the HR nor the MAP. Bilateral vagotomy and administration of a muscarinic receptor antagonist suppressed the LHb stimulation effect on the HR but not on the MAP, whereas administration of a ß-adrenoceptor antagonist partly attenuated the effect on the MAP but not on the HR. Thus, the LHb-induced cardiovascular responses of the HR and the MAP were likely caused by activations of the cardiac parasympathetic nerves and the cardiovascular sympathetic nerves, respectively. Furthermore, administration of a non-selective 5-HT receptor antagonist significantly attenuated the LHb stimulation effects on both the MAP and the HR. A 5-HT2 receptor antagonist also attenuated the LHb stimulation effects. A low dose of a 5-HT1A receptor antagonist enhanced the LHb stimulation effects, but a high dose of the drug attenuated them. 5-HT1B and 5-HT1D receptor antagonists as well as a 5-HT7 receptor antagonist did not affect the LHb stimulation effects. Taken together, our findings suggest that the LHb regulates autonomic cardiovascular responses at least partly through the serotonergic system, particularly via the 5-HT1A and 5-HT2 receptors.

Clinical Application of the Vestibular Stimulation Effect on Balance Disorders with Dementia.

BACKGROUND: In a previous study on Alzheimer's disease (AD), we showed that vestibular dysfunction derived from cerebral disorders contributes to balance disorders. No previous clinical study has attempted to prevent the progression of balance disorders in dementia patients through vestibular stimulation using an air caloric device. OBJECTIVE: The purpose of this pilot study was to delay the progression of balance disorders by inducing vestibular compensation, specifically by utilizing the effect of vestibular stimulation to activate the cerebrum. METHODS: Fifteen individuals were randomized and classified into a stimulation group or a nonstimulation group. Eight AD patients underwent vestibular stimulation every 2 weeks for 6 months in the stimulation group. Seven AD patients participated in the nonstimulation group (the control group). Both groups were subsequently evaluated using a Mini-Mental State Examination (MMSE), stepping test, caloric test, and smooth pursuit eye movement test just before starting the study and 6 months later. RESULTS: For balance parameters, the various tests did not show any significant differences between the two groups. However, in the stepping test, the decline rate tended to be higher in the nonstimulation group than in the stimulation group. The stimulation group's rate of decline in MMSE scores was lower than that of the nonstimulation group (p=0.015). No adverse events were tracked during the present study. CONCLUSION: Repeated vestibular stimulation might help patients retain greater balance and higher function. To prove these effects, the future clinical application will require an increased number of cases and longer periods of vestibular stimulation. This study showed that vestibular stimulation by air caloric device is safe and tolerable in patients with AD.

Inhibitory synaptic modulation of renshaw cell activity in the lumbar spinal cord of neonatal mice.

In the mammalian spinal cord, Renshaw cells (RCs) are excited by axon collaterals of motoneurons (MNs), and in turn, provide recurrent inhibition of MNs. They are considered an important element in controlling the motor output. However, how RCs are modulated by spinal circuits during motor behaviors remains unclear. In this study, the physiological nature of inhibitory synaptic inputs to RCs in the lumbar segment during spontaneous motoneuronal activity was examined in the isolated spinal cord taken from glutamate decarboxylase 67-green fluorescent protein (GAD67-GFP) knock-in mouse neonates. Whole cell recordings of RCs in current-clamp mode showed that they receive phasic inhibition that could modulate the RC firing evoked by excitation of MNs. In voltage-clamp recording, we observed a barrage of spontaneous inhibitory postsynaptic currents (sIPSCs) mediated by glycine and/or GABA. These sIPSCs persisted in the presence of mecamylamine, a nicotinic receptor antagonist, indicating that excitation of other RCs by MN axon collaterals may not be essential for these inhibitory actions. Simultaneous recording of RC and the ventral root in the same segment showed that the RCs received inhibitory inputs when spontaneous MN firing occurred. Paired recordings of a RC and a MN showed that during the bursting activity in the ventral root, the magnitude of the RC sIPSCs and the magnitude of the excitatory inputs that MNs receive are highly correlated. These results indicate that RCs are modulated by inhibition that matches the MN excitation in timing and amplitude during motor behaviors.

The viscerosympathetic response in rabbits is mediated by GABAergic and glutamatergic inputs into the sympathetic premotor neurons of the rostral ventrolateral medulla.

Neurons in the rostral ventrolateral medulla (RVLM) receive inputs from various sources, including baroreceptors, and then regulate the activity of sympathetic preganglionic neurons in the spinal cord. Whether RVLM neurons mediate the viscerosympathetic reflex has yet to be clarified. In the present study, we investigated the role of RVLM neurons in the viscerosympathetic reflex in anaesthetized and vagotomized rabbits. Electrical stimulation of the greater splanchnic nerve (SplN) evoked reflex responses in renal sympathetic activity that were composed of inhibitory and/or excitatory components. Bilateral microinjection of muscimol, a GABA(A) receptor agonist, into the RVLM blocked the reflex responses. Bilateral microinjection of bicuculline, a GABA(A) receptor antagonist, largely attenuated the inhibitory component, whereas kynurenic acid, a glutamate receptor antagonist, eliminated the excitatory component. The activities of 21 RVLM barosensitive bulbospinal neurons were recorded. Twenty of the neurons responded to the SplN stimulation. The responses also consisted of inhibitory and/or excitatory components. The excitatory component of these neurons preceded that of the renal sympathetic nerve activity by about 100 ms. This latency difference was almost the same as that of the inhibitory responses evoked by aortic nerve stimulation. Therefore, the renal sympathetic reflex responses evoked by SplN stimulation are mediated by RVLM neurons, and GABAergic and glutamatergic transmission in the RVLM are related to this reflex.

Endogenous hydrogen sulfide maintains eupnea in an in situ arterially perfused preparation of rats.

Hydrogen sulfide (H2S) is constitutively generated in the human body and works as a gasotransmitter in synaptic transmission. In this study, we aimed to evaluate the roles of endogenous H2S in generating eupnea at the respiratory center. We employed an in situ arterially perfused preparation of decerebrated rats and recorded the central respiratory outputs. When the H2S-producing enzyme cystathionine ß-synthase (CBS) was inhibited, respiration switched from the 3-phase eupneic pattern, which consists of inspiration, postinspiration, and expiration, to gasping-like respiration, which consists of inspiration only. On the other hand, when H2S synthesis was inhibited via cystathionine γ-lyase (CSE) or when H2S synthesis was activated via CBS, eupnea remained unchanged. These results suggest that H2S produced by CBS has crucial roles in maintaining the neuronal network to generate eupnea. The mechanism of respiratory pattern generation might be switched from a network-based system to a pacemaker cell-based system in low H2S conditions.

Abnormal Saccadic Intrusions with Alzheimer's Disease in Darkness.

BACKGROUND: Classified as saccadic intrusions, Square-Wave Jerks (SWJs) have been observed during Visual Fixation (VF) in Alzheimer's Disease (AD). However, the pathological significance of this phenomenon remains unclear. OBJECTIVE: The present study analyzed the characteristics of SWJs in patients with AD with their eyes open in the dark without VF. METHODS: Fifteen patients with AD and 15 healthy age- and sex-matched controls were investigated and compared. Saccadic intrusions with and without VF were detected as SWJs and measured using an electronystagmogram. RESULTS: No significant difference in the frequency of SWJs was observed between control and AD groups with VF, but significantly more SWJs were observed in the AD group than in the control group in the absence of VF (p<0.01). In the control group, the frequency of SWJs was significantly higher with VF as compared to without VF. Conversely, the frequency in the AD group was significantly higher without VF. Furthermore, a directly proportional relationship was observed between the frequency of SWJs and higher-order function (R>0.55) in the AD group. CONCLUSION: SWJs without VF may have pathological significance in AD. In healthy individuals, SWJs are generated by VF and suppressed without VF. Conversely, in AD, SWJs are generated rather than suppressed in the absence of VF. These pathognomonic SWJs without VF also appear to be correlated with higher-order dysfunction, reflecting AD-related cortical damage. These findings suggest that pathological SWJs without VF observed in AD derive from cortical damage and may constitute an important marker of a higher-order function.

Vestibular dysfunction as cortical damage with amyotrophic lateral sclerosis.

BACKGROUND: Cortical damage in areas such as the frontal lobe is reported in amyotrophic lateral sclerosis (ALS). However, aside from executive dysfunction, the pathological significance of this cortical damage has yet to be clarified. The present study investigated the effects of cortical damage on vestibular function in ALS. METHODS: Subjects comprised 18 ALS patients and 18 age- and sex-matched healthy controls. Cold air caloric stimulation was performed in all subjects to induce vestibular nystagmus, which was analysed to evaluate vestibular function. Visual suppression testing to investigate the suppressive effects of visual stimuli on vestibular nystagmus was expressed as suppression rate (SR, %). Executive function was tested using the frontal assessment battery (FAB). RESULTS: Suppression rate and FAB score were significantly lower in the ALS group than in the control group (p < 0.01 each). A positive correlation was also observed between SR and FAB score (R = 0.65, p = 0.023). CONCLUSION: Visual suppression testing showed significant damage to the central nervous system vestibular control mechanisms, which utilize visual information in the ALS group and a positive correlation between SR and FAB score suggest a relationship between frontal lobe damage and impaired vestibular control. A simple vestibular function test may be useful as a tool to objectively monitor the progression of cerebral lesions in ALS.

Abnormal Pyramidal Decussation and Bilateral Projection of the Corticospinal Tract Axons in Mice Lacking the Heparan Sulfate Endosulfatases, Sulf1 and Sulf2.

The corticospinal tract (CST) plays an important role in controlling voluntary movement. Because the CST has a long trajectory throughout the brain toward the spinal cord, many axon guidance molecules are required to navigate the axons correctly during development. Previously, we found that double-knockout (DKO) mouse embryos lacking the heparan sulfate endosulfatases, Sulf1 and Sulf2, showed axon guidance defects of the CST owing to the abnormal accumulation of Slit2 protein on the brain surface. However, postnatal development of the CST, especially the pyramidal decussation and spinal cord projection, could not be assessed because DKO mice on a C57BL/6 background died soon after birth. We recently found that Sulf1/2 DKO mice on a mixed C57BL/6 and CD-1/ICR background can survive into adulthood and therefore investigated the anatomy and function of the CST in the adult DKO mice. In Sulf1/2 DKO mice, abnormal dorsal deviation of the CST fibers on the midbrain surface persisted after maturation of the CST. At the pyramidal decussation, some CST fibers located near the midline crossed the midline, whereas others located more laterally extended ipsilaterally. In the spinal cord, the crossed CST fibers descended in the dorsal funiculus on the contralateral side and entered the contralateral gray matter normally, whereas the uncrossed fibers descended in the lateral funiculus on the ipsilateral side and entered the ipsilateral gray matter. As a result, the CST fibers that originated from 1 side of the brain projected bilaterally in the DKO spinal cord. Consistently, microstimulation of 1 side of the motor cortex evoked electromyogram responses only in the contralateral forelimb muscles of the wild-type mice, whereas the same stimulation evoked bilateral responses in the DKO mice. The functional consequences of the CST defects in the Sulf1/2 DKO mice were examined using the grid-walking, staircase, and single pellet-reaching tests, which have been used to evaluate motor function in mice. Compared with the wild-type mice, the Sulf1/2 DKO mice showed impaired performance in these tests, indicating deficits in motor function. These findings suggest that disruption of Sulf1/2 genes leads to both anatomical and functional defects of the CST.

Upbeat nystagmus is a useful sign in the regional diagnosis of trigeminal nerve disorder with multiple sclerosis.

Trigeminal nerve disorder is an important neurological sign that is often seen with multiple sclerosis (MS). We investigated eye movements in three MS patients with trigeminal disorder due to pontine lesions near the trigeminal root entry zone (REZ). Upbeat nystagmus was observed in all MS patients with trigeminal REZ lesions. We conjecture that trigeminal nerve disorder and upbeat nystagmus appeared due to simultaneous damage to both the trigeminal nerve and the vestibulo-ocular reflex pathway. If upbeat nystagmus appears in MS patients exhibiting a trigeminal nerve disorder, such as trigeminal neuralgia, and paralysis, pontine lesions near the trigeminal REZ should be considered. Upbeat nystagmus can be understood as a useful sign for the clinical regional diagnosis of trigeminal nerve disorder.

The Successful Application of Plasmapheresis in the Treatment of a Patient with Opsoclonus and Autoantibodies to Glutamate Receptor δ2.

Glutamate receptor δ2 (GluRδ2) is expressed in the neuronal postsynaptic densities at the junctions between the Purkinje cells and the parallel fibers. Recent reports have described patients with opsoclonus who possess anti-GluRδ2 antibodies. We report the case of a 53-year-old man with opsoclonus whose cerebrospinal fluid was positive for anti-GluRδ2 antibodies. Electronystagmography revealed abnormal sinusoidal eye movements, which were definitively identified as opsoclonus. The frequency and amplitude of saccadic oscillations diminished after plasmapheresis (PE). The patient's opsoclonus was altered after PE, suggesting that anti-GluRδ2 antibodies may act on the saccade generator in the brainstem via the cerebellum and that they may be involved in the onset of opsoclonus.

Local regulation of skin blood flow during cooling involving presynaptic P2 purinoceptors in rats.

1. This study investigated a local effect of cooling on the plantar skin blood flow (PSBF) of tetrodotoxin-treated rats by laser-Doppler flowmetry. 2. When the air temperature around the left foot was locally cooled from 25 to 10 degrees C, the PSBF of the left foot decreased. 3. The response was inhibited by the alpha-adrenoceptor antagonist phentolamine, the alpha1-adrenoceptor antagonist bunazosin, the alpha2-adrenoceptor antagonist RS79948, and bretylium and guanethidine that inhibit noradrenaline release from sympathetic nerves. Adrenalectomy of the rats did not affect the cooling-induced response. 4. The P2 purinoceptor antagonists suramin and PPADS also significantly suppressed the cooling-induced reduction of PSBF. However, the inhibitory effect of PPADS on the cooling-induced response was abolished after the treatment with phentolamine. Intra-arterial injections of ATPgammaS, a stable P2 purinoceptor agonist, at 25 degrees C caused a transient decrease in PSBF in a dose-dependent manner, which was significantly inhibited by phentolamine and guanethidine. 5. These results suggest a novel mechanism for local cooling-induced reduction of skin blood flow in vivo; moderate cooling of the skin induces the release of ATP, which stimulates presynaptic P2 purinoceptors on sympathetic nerve terminals and facilitates the release of noradrenaline, thereby causing contractions of skin blood vessels via the activation of alpha1-and alpha2-adrenoceptors.

Vestibular Impairment in Frontotemporal Dementia Syndrome.

BACKGROUND: No studies to date have attempted to evaluate frontotemporal lobar degeneration from the perspective of the vestibular system. OBJECTIVE: The present study examined vestibular function in patients with frontotemporal dementia (FTD) clinical syndrome and evaluated whether vestibular disorders are involved in the clinical symptoms due to FTD. METHODS: Fourteen patients with FTD syndrome, as well as healthy elderly controls without dementia, were included in the present study. All subjects underwent vestibular function tests using electronystagmography, such as caloric tests and visual suppression (VS) tests, in which the induced caloric nystagmus was suppressed by visual stimuli. The association between clinical symptoms and vestibular function in the FTD syndrome group was further examined. RESULTS: In the FTD syndrome group, caloric nystagmus was not necessarily suppressed during VS tests. Furthermore, VS was observed to be significantly impaired in FTD syndrome patients with gait disturbance as compared to those without such disturbance. CONCLUSION: The present study revealed that impairment of VS in patients with FTD results in an inability to regulate vestibular function by means of visual perception, regardless of multiple presumed neuropathological backgrounds. This could also be associated with gait disturbance in patients with FTD syndrome.

Reticulospinal neurons inactivated by warming of the preoptic area and anterior hypothalamus of rabbits.

To identify the premotor neurons for vasoconstrictors of the skin, activities of reticulospinal neurons in the rostroventral medulla, the ear sympathetic nerve (ESNA) and the renal sympathetic nerve (RSNA) were recorded in anesthetized and immobilized Japanese White or New Zealand White rabbits. Two groups of neurons were identified according to their responses to thermal stimulation of the preoptic area and the anterior hypothalamus (POAH) and to electrical stimulation of baroreceptor afferents, the aortic nerve (AN). Neurons (Type I neurons, n = 21) whose activity was inhibited by warm stimulation of the POAH but not inhibited by the AN stimulation were located in sites medial to the rostral ventrolateral medulla (RVLM). The other neurons (Type II neurons, n = 20) whose activity was not inhibited by warm stimulation of the POAH but inhibited by the AN stimulation were located in the RVLM. Because the time course of the inhibitory response of Type I neurons to warm stimulation of the POAH was very similar to that of the inhibitory response of the ESNA and activities of these neurons and the ESNA were not inhibited by the stimulation of the AN, it was suggested the Type I neurons might participate in regulation of activity of the vasoconstrictors of the ear skin. The Type II neurons are considered to be the barosensitive RVLM neurons that regulate systemic arterial pressure by controlling the activity of visceral or muscular sympathetic vasoconstrictors or cardiac sympathetic fibers.

Vestibular Function Impairment in Alzheimer's Disease.

BACKGROUND: Falls and fractures due to impaired balance in patients with Alzheimer's disease (AD) have an adverse effect on the clinical course of the disease. OBJECTIVE: To evaluate balance impairment in AD from the viewpoint of vestibular functional impairment. METHODS: The subjects were 12 patients with AD, 12 dementia-free elderly adults, and 12 younger adults. Vestibular function was assessed using a stepping test, caloric nystagmus, and a visual suppression (VS) test. RESULTS: The stepping test was abnormal in 9 of the 12 patients in the AD group. An abnormal stepping test was not associated with self-reported dizziness or tendency to fall. Significant VS abnormalities were present in the AD group. The suppression rate of VS was lower in AD patients with either a tendency to fall or constructional apraxia than in AD patients without either. The velocity of the rapid phase of caloric nystagmus before the VS test was similar in the AD group and the elderly control group. Significant abnormalities of both caloric nystagmus and VS were not present in either the elderly or the younger control groups. CONCLUSION: AD could involve impairments in the vestibular control of balance. The VS test is useful for assessing the tendency to fall in AD. Impairment of VS in AD might arise from cerebral vestibular cortex impairment rather than comorbid peripheral vestibular disorders.

Rhythmic activities of the sympatho-excitatory neurons in the medulla of rabbits: neurons controlling cutaneous vasomotion.

Spontaneous activities of the reticulospinal neurons in the reticular formation of the rostroventral medulla, of the ear sympathetic nerve (ESNA) and of the renal sympathetic nerve (RSNA) were analyzed with regard to cardiac cycle- and respiration-related rhythm in the anesthetized, vagotomized and immobilized rabbits. A reticulospinal neuron that was concurrently excited with increase in the ESNA and/or reduction of the blood flow of the ear skin by electrical stimulation of the dorsomedial hypothalamus was tentatively named as a cutaneous sympatho-excitatory neuron (Cu neuron). More than half of the Cu neurons (13/22) had a respiration-related rhythmic activity as well as the ESNA. Activity of most of the Cu neurons (19/22) was not modulated with the frequency of the heartbeat and the ESNA had little or no cardiac cycle-related activity. Simultaneous recording shows that the degree of modulation (relative power of the power spectrum of the post event time histogram at the frequency of the respiration) of activity of the Cu neurons correlated with that of the ESNA. On the other hand, most (13/18) of the barosensitive sympatho-excitatory reticulospinal neurons in the rostral ventrolateral medulla (RVLM neurons) had both cardiac cycle- and respiration-related activity as well as the RSNA had. The Cu neurons were located at the medial sites to the location of the RVLM neurons. These results further showed that the Cu neurons controlled the cutaneous vasoconstrictor fibers and that the sympatho-excitatory neurons were located at the different sites in the ventral medulla according to their function.

Downbeat nystagmus associated with damage to the medial longitudinal fasciculus of the pons: a vestibular balance control mechanism via the lower brainstem paramedian tract neurons.

The paramedian tract (PMT) neurons, a group of neurons associated with eye movement that project into the cerebellar flocculus, are present in or near the medial longitudinal fasciculus (MLF) in the paramedian region of the lower brainstem. A 66-year-old man with multiple sclerosis in whom downbeat nystagmus appeared along with right MLF syndrome due to a unilateral pontomedullary lesion is described. In light of these findings, a possible schema for the vestibular balance control mechanism circuit of the PMT neurons via the flocculus is presented. Damage to the PMT neurons impaired the elective inhibitory control mechanism of the anterior semicircular canal neural pathway by the flocculus. This resulted in the appearance of anterior semicircular canal-dominant vestibular imbalance and the formation of downbeat nystagmus. From the pathogenesis of this vertical vestibular nystagmus, the action of the PMT neurons in the vestibular eye movement neuronal pathway to maintain vestibular balance was conjectured to be as follows. PMT neurons transmit vestibular information from the anterior semicircular canals to the cerebellum, forming a cerebellum/brainstem feedback loop. Vestibular information from that loop is integrated in the cerebellum, inhibiting only the anterior semicircular canal neuronal pathway via the flocculus and controlling vestibular balance.