Hyperperfusion in the cerebellum lobule VIIb in patients with epileptic seizures.

BACKGROUND: The cerebellum plays an important role in motor control, however, its involvement in epilepsy has not been fully understood. Arterial spin labelling perfusion magnetic resonance image (ASL) is a noninvasive method to evaluate cerebral and cerebellar blood flow. We investigated cerebellar perfusion in patients with epileptic seizures using ASL. METHODS: Adult patients with epileptic seizures who underwent ASL in three post labeling delay (PLD) conditions (1525, 1800, and 2500 msec) and conventional electroencephalography (EEG) on the same day were investigated. Clinical and EEG characteristics of them were retrospectively analyzed. RESULTS: Six patients (6 women, age; 36.2 ± 17.9 years (mean ± SD)) showed hyperperfusion in selective areas in the cerebellar paravermis of lobule VIIb. One patient with generalized epilepsy (tentative diagnosis of juvenile myoclonic epilepsy or epilepsy with myoclonic absences) showed unilateral hypoperfusion in PLD 1525 msec and hyperperfusion in PLD 1800 and 2500 msec at the area while EEG showed generalized spike-wave complexes. After successful treatment, these perfusion abnormalities disappeared. In two patients with focal epilepsy manifesting with asymmetrical motor symptoms, cerebellar hyperperfusion was found on the opposite side to the seizure focus estimated by seizure semiology. Besides hyperperfusion of the VIIb lobule, hypoperfusion at the same area was detected in shorter PLD condition in four patients and in longer PLD condition in one patient. CONCLUSION: The cerebellar paravermis of lobule VIIb can be a component of motor circuit and participate in epileptic network in humans. Cerebellar perfusion abnormalities can be associated with neurovascular coupling via capillary bed.

Hemicrania Continua Subsequent to Vertebral Artery Dissection: A Case Report.

We herein report the case of a 45-year-old woman who developed a continuous hemicranial headache subsequent to vertebral artery dissection (VAD). After remission of VAD, the patient repeatedly experienced right forehead and temporal region throbbing headache, accompanied by nausea, ocular hyperemia and lacrimation of the right eye, nasal congestion, and rhinorrhea. Magnetic resonance angiography did not reveal the recurrence of dissection. Daily use of indomethacin (190.8 mg/day) showed an excellent effect on the headache, suggesting that the patient had developed hemicrania continua subsequent to VAD.

Suvorexant for the treatment of primary insomnia: A systematic review and meta-analysis.

Suvorexant is a dual orexin receptor agonist and is currently approved for the treatment of insomnia in the United States and Japan. We conducted a systematic review and meta-analysis to assess the efficacy and safety of suvorexant for the treatment of primary insomnia. We searched PubMed, EMBASE, and the Cochrane central register of controlled trials, contacted a relevant pharmaceutical company, and accessed websites of the U.S. Food and Drug Administration (FDA) and Pharmaceuticals and Medical Devices Agency (PMDA) for published and unpublished data. A total of four randomized trials involving 3076 patients with primary insomnia were included in our analysis. Our analysis suggested that suvorexant was associated with significant improvements in subjective time to sleep onset, subjective total sleep time, and subjective quality of sleep at 1 mo and 3 mo. Somnolence, fatigue, and abnormal dreams were the most common adverse effects. We concluded that suvorexant was associated with improvement in some sleep parameters and some adverse effects. To determine the place of suvorexant in the treatment of insomnia, comparative effectiveness trials are needed.

Suvorexant-Induced Dream Enactment Behavior in Parkinson Disease: A Case Report.

ABSTRACT: Suvorexant is a new insomnia drug, and it is generally safe and well tolerated. Here, we report a rare but potentially important adverse effect of suvorexant in a patient with Parkinson disease.

Mogrol Derived from Siraitia grosvenorii Mogrosides Suppresses 3T3-L1 Adipocyte Differentiation by Reducing cAMP-Response Element-Binding Protein Phosphorylation and Increasing AMP-Activated Protein Kinase Phosphorylation.

This study investigated the effects of mogrol, an aglycone of mogrosides from Siraitia grosvenorii, on adipogenesis in 3T3-L1 preadipocytes. Mogrol, but not mogrosides, suppressed triglyceride accumulation by affecting early (days 0-2) and late (days 4-8), but not middle (days 2-4), differentiation stages. At the late stage, mogrol increased AMP-activated protein kinase (AMPK) phosphorylation and reduced glycerol-3-phosphate dehydrogenase activity. At the early stage, mogrol promoted AMPK phosphorylation, inhibited the induction of CCAAT/enhancer-binding protein ß (C/EBPß; a master regulator of adipogenesis), and reduced 3T3-L1 cell contents (e.g., clonal expansion). In addition, mogrol, but not the AMPK activator AICAR, suppressed the phosphorylation and activity of the cAMP response element-binding protein (CREB), which regulates C/EBPß expression. These results indicated that mogrol suppressed adipogenesis by reducing CREB activation in the initial stage of cell differentiation and by activating AMPK signaling in both the early and late stages of this process.

Cerebral Air Embolism with Pneumomediastinum Resulting from Emesis: A Case Report.

Cerebral air embolism (CAE) is a rare cause of stroke. Most cerebral air emboli are caused by iatrogenic factors, such as invasive cardiac and pulmonary procedures. Here, we report an unusual case of CAE not related to any medical intervention. An 87-year-old woman became unresponsive after vomiting. A computed tomography (CT) scan of the head 6 hours after the onset of the vomiting revealed multiple air emboli, mainly in the watershed area between the right anterior and middle cerebral arteries. Magnetic resonance imaging with T2* gradient echo showed the air emboli as granular hypointensities. Diffusion-weighted imaging revealed an area of hyperintensity along the cortical region of the right frontal lobe. Head CT scans showed that the size and number of the air emboli rapidly decreased on day 2 and disappeared on day 9. We also performed a chest CT and found pneumomediastinum, which gradually improved over the clinical course. We also found pulmonary fibrosis and bronchiectasis, suggesting an underlying pulmonary vulnerability. In this case, the emesis may have been a trigger for the CAE, which was followed by pneumomediastinum. This case suggests that CAE can occur in a noniatrogenic situation, especially in a patient with pulmonary vulnerability.

Initiation of the optokinetic response (OKR) in mice.

To study the initial part of the mouse optokinetic response, OKR (approximately 500 ms from the onset of visual stimulus motion), we recorded the ocular response to a vertical sinusoidal grating moving at a constant velocity. We found that the magnitude of the response monotonically increased as the stimulus contrast increased. The response showed a narrow band-pass property for the spatiotemporal frequency, with the largest sustained response observed at 0.125 cycle/deg and 1.5 Hz. We also found that temporal frequencies higher than 1.5 Hz elicited transient increase in the eye velocity, but weak or no sustained eye movements. Thus the initial OKR in mice is characterized by the spatiotemporal frequency of the visual stimuli. Our results suggest that the initial OKR contains two components: a transient that diminishes within approximately 200 ms, and a tonic that is maintained for more than 400 ms, and that the initial part of the OKR in mice is an appropriate measurement parameter for studies of the visual and motor systems, like ocular following response (OFR) in primates.

The effects of prolonged viewing of motion on short-latency ocular following responses.

The adaptive effects of prolonged viewing of conditioning motion on ocular following responses (OFRs) elicited by brief test motion of a random-dot pattern were studied in humans. We found that the OFRs were significantly reduced when the directions of the conditioning and test motions were the same. The effect of conditioning motion was still observed when the speeds of the conditioning and test motions did not match. The effect was larger when the conditioning duration was longer, and decayed over time with increased temporal separation between the conditioning and test periods. These results are consistent with the characteristics of motion adaptation on the initial smooth pursuit responses. We also obtained data suggesting that the persistence of the effect depends on visual stimulation in the time between the conditioning and test periods, and that the presence of a stationary visual stimulus facilitates recovery from the motion adaptation.

Eye movements in response to dichoptic motion: evidence for a parallel-hierarchical structure of visual motion processing in primates.

Brief movements of a large-field visual stimulus elicit short-latency tracking eye movements termed "ocular following responses" (OFRs). To address the question of whether OFRs can be elicited by purely binocular motion signals in the absence of monocular motion cues, we measured OFRs from monkeys using dichoptic motion stimuli, the monocular inputs of which were flickering gratings in spatiotemporal quadrature, and compared them with OFRs to standard motion stimuli including monocular motion cues. Dichoptic motion did elicit OFRs, although with longer latencies and smaller amplitudes. In contrast to these findings, we observed that other types of motion stimuli categorized as non-first-order motion, which is undetectable by detectors for standard luminance-defined (first-order) motion, did not elicit OFRs, although they did evoke the sensation of motion. These results indicate that OFRs can be driven solely by cortical visual motion processing after binocular integration, which is distinct from the process incorporating non-first-order motion for elaborated motion perception. To explore the nature of dichoptic motion processing in terms of interaction with monocular motion processing, we further recorded OFRs from both humans and monkeys using our novel motion stimuli, the monocular and dichoptic motion signals of which move in opposite directions with a variable motion intensity ratio. We found that monocular and dichoptic motion signals are processed in parallel to elicit OFRs, rather than suppressing each other in a winner-take-all fashion, and the results were consistent across the species.

Trial-by-trial updating of the gain in preparation for smooth pursuit eye movement based on past experience in humans.

To understand how the CNS uses past experiences to generate movements that accommodate minute-by-minute environmental changes, we studied the trial-by-trial updating of the gain for initiating smooth pursuit eye movements and how this relates to the history of previous trials. Ocular responses in humans elicited by a small perturbing motion presented 300 ms after appearance of a target were used as a measure of the gain of visuomotor transmission. After the perturbation, the target was either moved horizontally (pursuit trial) or remained in a stationary position (fixation trial). The trial sequence randomly included pursuit and fixation. The amplitude of the response to the perturbation was modulated in a trial-by-trial manner based on the immediately preceding trial, with preceding fixation and pursuit trials decreasing and increasing the gain, respectively. The effect of the previous trial was larger with shorter intertrial intervals, but did not diminish for at least 2,000 ms. A time-series analysis showed that the response amplitude was significantly correlated with the past few trials, with dynamics that could be approximated by a first-order linear system. The results suggest that the CNS integrates recent experiences to set the gain in preparation for upcoming tracking movements in a changing environment.

Preparatory gain modulation of visuomotor transmission for smooth pursuit eye movements in monkeys.

It has been reported that the visuomotor processing underlying the initiation of smooth pursuit eye movement is modulated in relation to the recent experience of eye movements: the initial pursuit eye velocity is larger after experiencing repeated pursuits than saccades. To assess which parameters of the previously executed pursuits play an essential role in modulating the gain of visuomotor transmission, we recorded the ocular responses of monkeys to a brief perturbing motion of the tracking target injected before the start of the eye movements. First, we compared the perturbation responses among the blocks in which the duration of executing pursuit was varied. We found that the response amplitude increased with the increase of the pursuit duration and it reached a plateau level at 100-200 ms of the duration. Second, a comparison of the perturbation responses in the blocks in which target velocity was different showed a gradual increase of the response as a function of the required pursuit velocity. Third, when the animals repeatedly performed pursuits, the response amplitude gradually increased with increasing interval between the appearance of the target and the onset of perturbation. On the other hand, such an increase was not observed when the animals repeatedly performed saccades. These results suggest that before initiating eye movements, the pursuit system modulates the gain of visuomotor transmission so as to be closely related to the properties of the repeatedly experienced eye movements and this gain modulation is triggered by the target's appearance.

The effects of preceding moving stimuli on the initial part of smooth pursuit eye movement.

We examined whether there are any adaptive effects on the pursuit initiation after a prolonged exposure to moving visual stimuli. The eye movements of six human subjects were recorded with the scleral search-coil technique or a Dual Purkinje Image Eye-tracker system. A random-dot image appeared on a CRT monitor and moved coherently in one direction (rightward or leftward) at 10 deg/s for 4 s, while the subject fixated on a stationary target (conditioning stimulus). The screen was blanked for 0.2 s, and then the target stepped to the right or left of the center and moved 10 deg/s leftward or rightward. We measured change in the eye position over the open-loop period of the pursuit initiation. When the pursuit target moved in the same direction as the preceding visual stimulus, a significant reduction in the initial tracking responses (55.9% decrease on average) was found. We then studied in detail the properties of the motion adaptation in pursuit initiation by varying the visual conditions systematically and obtained the following findings. When the subjects tracked the target that moved at 10 deg/s, the pursuit initiation was affected not only by the conditioning stimulus of the same speed as the target, but also by those of different speeds. Further, the conditioning stimulus moving at 10 deg/s affected the pursuit initiation not only when the target moved with the same speed but also when it moved at different speeds (more remarkable for slower speeds). The effect of conditioning stimuli on the pursuit initiation was larger when the duration of the conditioning period was longer. The effect of conditioning stimuli decayed as the duration of the blank period became longer. The findings from the present study are consistent with the properties of neurons in the middle temporal area of monkeys.

The visual motion detectors underlying ocular following responses in monkeys.

Psychophysical evidence indicates that visual motion can be sensed by low-level (energy-based) and high-level (feature-based) mechanisms. The present experiments were undertaken to determine which of these mechanisms mediates the initial ocular following response (OFR) that can be elicited at ultra-short latencies by sudden motion of large-field images. We used the methodology of Sheliga, Chen, Fitzgibbon, and Miles (Initial ocular following in humans: A response to first-order motion energy. Vision Research, 2005a), who studied the initial OFRs of humans, to study the initial OFRs of monkeys. Accordingly, we applied horizontal motion to: (1) vertical square-wave gratings lacking the fundamental ("missing fundamental stimulus") and (2) vertical grating patterns consisting of the sum of two sinusoids of frequency 3f and 4f, which created a repeating pattern with beat frequency, f. Both visual stimuli share a critical property: when subject to 1/4-wavelength steps, their overall pattern (feature) shifts in the direction of the steps, whereas their major Fourier component shifts in the reverse direction (because of spatial aliasing). We found that the initial OFRs of monkeys to these stimuli, like those of humans, were always in the opposite direction to the 1/4-wavelength shifts, i.e., in the direction of the major Fourier component, consistent with detection by (low-level) oriented spatio-temporal filters as in the well-known energy model of motion analysis. Our data indicate that the motion detectors mediating the initial OFR have quantitatively similar properties in monkeys and humans, suggesting that monkeys provide a good animal model for the human OFR.

Anticipatory gain modulation in preparation for smooth pursuit eye movements.

We studied the effect of the probability of required tracking on the gain of visuomotor transmission for pursuit initiation in monkeys. We recorded the ocular responses to a brief movement (perturbation) of a target located at an eccentric position from the central fixation spot. As soon as the central fixation spot went off, the animal was required to make a saccade to the target if it remained stationary or to track if it moved. The probability of an upcoming ramp motion of the target (horizontal, 20 degrees /sec), requiring pursuit, was varied (target motion probability [TMP] = 0, 0.25, 0.5, 0.75, and 1, which was fixed in a block). We found that the magnitude of the response to the perturbation increased gradually as the TMP increased. The initial pursuit response and the perturbation response showed very similar dependence on the TMP, suggesting that the response to the perturbation could be used as an index of the gain of visuomotor transmission for pursuit initiation. We also found that the changes in the ocular responses after the TMP was changed from one probability to another occurred rapidly (decay constant of only a few trials). These results suggest that the gain of visuomotor transmission in preparing for pursuit is rapidly modulated in accordance with the anticipated future need for pursuit.

A model of smooth pursuit in primates based on learning the target dynamics.

While the predictive nature of the primate smooth pursuit system has been evident through several behavioural and neurophysiological experiments, few models have attempted to explain these results comprehensively. The model we propose in this paper in line with previous models employing optimal control theory; however, we hypothesize two new issues: (1) the medical superior temporal (MST) area in the cerebral cortex implements a recurrent neural network (RNN) in order to predict the current or future target velocity, and (2) a forward model of the target motion is acquired by on-line learning. We use stimulation studies to demonstrate how our new model supports these hypotheses.

Computational study on monkey VOR adaptation and smooth pursuit based on the parallel control-pathway theory.

Much controversy remains about the site of learning and memory for vestibuloocular reflex (VOR) adaptation in spite of numerous previous studies. One possible explanation for VOR adaptation is the flocculus hypothesis, which assumes that this adaptation is caused by synaptic plasticity in the cerebellar cortex. Another hypothesis is the model proposed by Lisberger that assumes that the learning that occurs in both the cerebellar cortex and the vestibular nucleus is necessary for VOR adaptation. Lisberger's model is characterized by a strong positive feedback loop carrying eye velocity information from the vestibular nucleus to the cerebellar cortex. This structure contributes to the maintenance of a smooth pursuit driving command with zero retinal slip during the steady-state phase of smooth pursuit with gain 1 or during the target blink condition. Here, we propose an alternative hypothesis that suggests that the pursuit driving command is maintained in the medial superior temporal (MST) area based on MST firing data during target blink and during ocular following blank, and as a consequence, we assume a much smaller gain for the positive feedback from the vestibular nucleus to the cerebellar cortex. This hypothesis is equivalent to assuming that there are two parallel neural pathways for controlling VOR and smooth pursuit: a main pathway of the semicircular canals to the vestibular nucleus for VOR, and a main pathway of the MST-dorsolateral pontine nuclei (DLPN)-flocculus/ventral paraflocculus to the vestibular nucleus for smooth pursuit. First, we theoretically demonstrate that this parallel control-pathway theory can reproduce the various firing patterns of horizontal gaze velocity Purkinje cells in the flocculus/ventral paraflocculus dependent on VOR in the dark, smooth pursuit, and VOR cancellation as reported in Miles et al. at least equally as well as the gaze velocity theory, which is the basic framework of Lisberger's model. Second, computer simulations based on our hypothesis can stably reproduce neural firing data as well as behavioral data obtained in smooth pursuit, VOR cancellation, and VOR adaptation, even if only plasticity in the cerebellar cortex is assumed. Furthermore, our computer simulation model can reproduce VOR adaptation automatically based on a heterosynaptic interaction model between parallel fiber inputs and climbing fiber inputs. Our results indicate that different assumptions about the site of pursuit driving command maintenance computationally lead to different conclusions about where the learning for VOR adaptation occurs. Finally, we propose behavioral and physiological experiments capable of discriminating between these two possibilities for the site of pursuit driving command maintenance and hence for the sites of learning and memory for VOR adaptation.