Respiratory hypersensitivity reactions to NSAIDs in Europe: the global allergy and asthma network (GA2 LEN) survey.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prevalent drugs inducing hypersensitivity reactions. The aim of this analysis was to estimate the prevalence of NSAID-induced respiratory symptoms in population across Europe and to assess its association with upper and lower respiratory tract disorders. METHODS: The GA2 LEN survey was conducted in 22 centers in 15 European countries. Each of 19 centers selected random samples of 5000 adults aged 15-74 from their general population, and in three centers (Athens, Munich, Oslo), a younger population was sampled. Questionnaires including questions about age, gender, presence of symptoms of asthma, allergic rhinitis, chronic rhinosinusitis, smoking status, and history of NSAID-induced hypersensitivity reactions were sent to participants by mail. Totally, 62 737 participants completed the questionnaires. RESULTS: The mean prevalence of NSAID-induced dyspnea was 1.9% and was highest in the three Polish centers [Katowice (4.9%), Krakow (4.8%), and Lodz (4.4%)] and lowest in Skopje, (0.9%), Amsterdam (1.1%), and Umea (1.2%). In multivariate analysis, the prevalence of respiratory reactions to NSAIDs was higher in participants with chronic rhinosinusitis symptoms (Odds Ratio 2.12; 95%CI 1.78-2.74), asthma symptoms in last 12 months (2.7; 2.18-3.35), hospitalization due to asthma (1.53; 1.22-1.99), and adults vs children (1.53; 1.24-1.89), but was not associated with allergic rhinitis. CONCLUSION: Our study documented significant variation between European countries in the prevalence of NSAID-induced respiratory hypersensitivity reactions, and association with chronic airway diseases, but also with environmental factors.

The relation of airway obstruction to asthma, chronic rhinosinusitis and age: results from a population survey of adults.

RATIONALE: There is conflicting evidence on whether patients with asthma experience an accelerated decline in lung function with age. We examined the association between postbronchodilator lung function, asthma, chronic rhinosinusitis (CRS), and atopy with age using a large European sample. METHODS: In 17 centers in 11 European countries, case-control studies were nested within representative cross-sectional surveys of adults aged less than 75 years. Representative samples of participants with asthma, CRS or both and controls were assessed for postbronchodilator ventilatory function, smoking history, atopy, and treatment. Multiple regression was used to assess the interactive effects of age and diagnostic group on decline in postbronchodilator ventilatory function. RESULTS: A total of 3337 participants provided adequate data (778 with asthma, 399 with CRS, 244 with both asthma and CRS and 1916 controls who had neither asthma nor CRS). Participants with asthma had lower FEV1 /FVC (-4.09% (95% CI: -5.02, -3.15, P < 0.001) and a steeper slope of FEV1 /FVC against age (-0.14%/annum [95%CI: -0.19, -0.08]) equivalent to smoking 1-2 packs of cigarettes per day. Those with atopy had a slope equivalent to controls. CONCLUSIONS: People with asthma have a steeper decline in postbronchodilator lung function with age, but neither CRS nor atopy alone were associated with such decline.

Geographical variation in the prevalence of sensitization to common aeroallergens in adults: the GA(2) LEN survey.

BACKGROUND: Geographical variation in the prevalence of sensitization to aeroallergens may reflect differences in exposure to risk factors such as having older siblings, being raised on a farm or other unidentified exposures. OBJECTIVE: We wanted to measure geographical variation in skin prick test positivity and assess whether it was explained by differences in family size and/or farm exposure. We also compared prevalence in younger and older subjects. METHODS: Within the Global Allergy and Asthma European Network (GA(2) LEN) survey, we measured the prevalence of skin prick positivity to a panel of allergens, and geometric mean serum total immunoglobulin E (IgE), in 3451 participants aged 18-75 years in 13 areas of Europe. Estimated prevalence was standardized to account for study design. We compared prevalence estimates in younger and older subjects and further adjusted for age, gender, smoking history, farm exposure, number of older siblings and body mass index (BMI). RESULTS: Skin prick test positivity to any one of the measured allergens varied within Europe from 31.4% to 52.9%. Prevalence of sensitization to single allergens also varied. Variation in serum total IgE was less marked. Younger participants had higher skin prick sensitivity prevalence, but not total IgE, than older participants. Geographical variation remained even after adjustment for confounders. CONCLUSION: Geographical variation in the prevalence of skin prick test positivity in Europe is unlikely to be explained by geographical variation in gender, age, smoking history, farm exposure, family size and BMI. Higher prevalence in younger, compared to older, adults may reflect cohort-associated increases in sensitization or the influence of ageing on immune or tissue responses.

Staphylococcus aureus enterotoxin-specific IgE is associated with asthma in the general population: a GA(2)LEN study.

BACKGROUND: Specific IgE to Staphylococcus aureus enterotoxins (SE-IgE) has been associated with asthma. In the general population, we aimed to determine the prevalence of and risk factors for serum SE-IgE and to examine the association with asthma. METHODS: A postal questionnaire was sent to a random sample of adults in 19 centers across Europe. A random sample of respondents was invited for clinical examination upon which they answered a questionnaire, underwent skin prick tests (SPTs) for common aeroallergens, and provided blood for measurement of total IgE and SE-IgE. Risks were analyzed within centers using weighted logistic regression, and overall estimates calculated using fixed-effects meta-analysis. RESULTS: 2908 subjects were included in this analysis. Prevalence of positive SE-IgE was 29.3%; no significant geographic variation was observed. In contrast to positive skin prick tests, SE-IgE was more common in smokers (<15 pack-year: OR 1.11, P = 0.079, ≥15 pack-year: OR 1.70, P < 0.001), and prevalence did not decrease in older age-groups or in those with many siblings. Total IgE concentrations were higher in those with positive SE-IgE than in those with positive SPT. SE-IgE was associated with asthma (OR 2.10, 95% confidence interval [1.60-2.76], P = 0.001) in a concentration-dependent manner. This effect was independent of SPT result and homogeneous across all centers. CONCLUSIONS: We report for the first time that SE-IgE is common in the general population throughout Europe and that its risk factors differ from those of IgE against aeroallergens. This is the first study to show that SE-IgE is significantly and independently associated with asthma in the general population.

Asthma in adults and its association with chronic rhinosinusitis: the GA2LEN survey in Europe.

BACKGROUND: The prevalence of asthma and its association with chronic rhinosinusitis (CRS) have not been widely studied in population-based epidemiological surveys. METHODS: The Global Allergy and Asthma Network of Excellence (GA(2) LEN) conducted a postal questionnaire in representative samples of adults living in Europe to assess the presence of asthma and CRS defined by the European Position Paper on Rhinosinusitis and Nasal Polyps. The prevalence of self-reported current asthma by age group was determined. The association of asthma with CRS in each participating centre was assessed using logistic regression analyses, controlling for age, sex and smoking, and the effect estimates were combined using standard methods of meta-analysis. RESULTS: Over 52,000 adults aged 18-75 years and living in 19 centres in 12 countries took part. In most centres, and overall, the reported prevalence of asthma was lower in older adults (adjusted OR for 65-74 years compared with 15-24 years: 0.72; 95% CI: 0.63-0.81). In all centres, there was a strong association of asthma with CRS (adjusted OR: 3.47; 95% CI: 3.20-3.76) at all ages. The association with asthma was stronger in those reporting both CRS and allergic rhinitis (adjusted OR: 11.85; 95% CI: 10.57-13.17). CRS in the absence of nasal allergies was positively associated with late-onset asthma. CONCLUSION: Geographical variation in the prevalence of self-reported asthma was observed across Europe, but overall, self-reported asthma was more common in young adults, women and smokers. In all age groups, men and women, and irrespective of smoking behaviour, asthma was also associated with CRS.

Reliability of EP3OS symptom criteria and nasal endoscopy in the assessment of chronic rhinosinusitis--a GA² LEN study.

BACKGROUND: The European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS) incorporates symptomatic, endoscopic, and radiologic criteria in the clinical diagnosis of chronic rhinosinusitis (CRS), while in epidemiological studies, the definition is based on symptoms only. We aimed to assess the reliability and validity of a symptom-based definition of CRS using data from the GA(2) LEN European survey. METHODS: On two separate occasions, 1700 subjects from 11 centers provided information on symptoms of CRS, allergic rhinitis, and asthma. CRS was defined by the epidemiological EP3OS symptom criteria. The difference in prevalence of CRS between two study points, the standardized absolute repeatability, and the chance-corrected repeatability (kappa) were determined. In two centers, 342 participants underwent nasal endoscopy. The association of symptom-based CRS with endoscopy and self-reported doctor-diagnosed CRS was assessed. RESULTS: There was a decrease in prevalence of CRS between the two study phases, and this was consistent across all centers (-3.0%, 95% CI: -5.0 to -1.0%, I(2) = 0). There was fair to moderate agreement between the two occasions (kappa = 39.6). Symptom-based CRS was significantly associated with positive endoscopy in nonallergic subjects, and with self-reported doctor-diagnosed CRS in all subjects, irrespective of the presence of allergic rhinitis. CONCLUSION: Our findings suggest that a symptom-based definition of CRS, according to the epidemiological part of the EP3OS criteria, has a moderate reliability over time, is stable between study centers, is not influenced by the presence of allergic rhinitis, and is suitable for the assessment of geographic variation in prevalence of CRS.

Chronic rhinosinusitis in Europe--an underestimated disease. A GA²LEN study.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common health problem, with significant medical costs and impact on general health. Even so, prevalence figures for Europe are unavailable. In this study, conducted by the GA²LEN network of excellence, the European Position Paper on Rhinosinusitis and nasal Polyps (EP³OS) diagnostic criteria are applied to estimate variation in the prevalence of Chronic rhinosinusitis (CRS) for Europe. METHOD: A postal questionnaire was sent to a random sample of adults aged 15-75 years in 19 centres in Europe. Participants reported symptoms of CRS, and doctor diagnosed CRS, allergic rhinitis, age, gender and smoking history. Definition of CRS was based on the EP³OS diagnostic criteria: the presence of more than two of the symptoms: (i) nasal blockage, (ii) nasal discharge, (iii) facial pain/pressure or (iv) reduction in sense of smell, for >12 weeks in the past year--with at least one symptom being nasal blockage or discharge. RESULTS: Information was obtained from 57,128 responders living in 19 centres in 12 countries. The overall prevalence of CRS by EP³OS criteria was 10.9% (range 6.9-27.1). CRS was more common in smokers than in nonsmokers (OR 1.7: 95% CI 1.6-1.9). The prevalence of self-reported physician-diagnosed CRS within centres was highly correlated with the prevalence of EP³OS-diagnosed CRS. CONCLUSION: This is the first European international multicentre prevalence study of CRS. In this multicentre survey of adults in Europe, about one in ten participants had CRS with marked geographical variation. Smoking was associated with having CRS in all parts of Europe.

Differential contribution of motor cortex and caudate nucleus to instrumental tongue-forelimb synchronization in rats: a functional ablation study.

The functional ablation technique was used to assess the role of motor cortex and caudate nucleus in a complex skilled movement. Rats were trained to synchronize tongue and forepaw movements in a drinking box equipped with a retractable spout which was automatically withdrawn after every lick but could be returned by pressing and releasing a lever placed 4 cm below the spout. The animals learned to perform short presses synchronized with the lick cycle in such a way as to allow continuous drinking. Neural circuits implementing these lick-associated instrumental movements were blocked by intracranial injection of 10 ng of tetrodotoxin. Bilateral blockade of the motor cortex interfered with lick-synchronized bar pressing, but did not significantly influence licking from a stationary spout. Both licking and bar-pressing were impaired by bilateral injection of tetrodotoxin into the lateral part of the caudate nucleus for the duration of the tetrodotoxin-induced inactivation of the target region. The instrumental tongue-forelimb synchronization recovered considerably later, i.e. after two to three days. Functional blockade of the medial part of the caudate nucleus caused only a partial impairment of lick-synchronized bar pressing lasting less than 7 h and did not significantly influence consummatory licking. It is concluded that the tongue-forepaw synchronization is disrupted by blockade of motor cortex or lateral caudate considerably longer than the performance of the isolated component movements.

The effect of direct administration of drugs into the licking generator in rats.

Spontaneous licking of thirsty rats was investigated under the effect of GYKI (an AMPA/kainate receptor antagonist) and of 2-amino-5-phosphonopentanoic acid (AP5, an NMDA receptor antagonist) applied intracranially into the central rhythm generator of licking. Adult Long Evans male rats were stereotaxically implanted with guiding cannulae aimed at the oral part of nucleus reticularis gigantocellularis (NRG). After a recovery (1 week at least), animals after 24 h water deprivation were trained to drink in an experimental box. Then 1 microl of GYKI (1 mM solution) or 1 microl of AP5 (20 mM solution) was administrated by microinjection through the guiding cannula directly into the target structure. Lick-lick interval (LLI) was recorded by an electrical lick sensor and analysed with a laboratory computer Pentium. Localisation of the administration was checked by a routine histological method. GYKI administration significantly prolonged the LLI i.e. slowed down licking frequency. The effect was immediate and began to dwindle in the period between 10 min to 2 h. Licking frequency under the influence of AP5 was faster (shorter LLI). This effect culminated after 30 min and almost disappeared after 2 h. Both our findings are in a good accordance with those of Grillner's group that NMDA receptors are important for slow swimming movements while non-NMDA receptors are responsible for fast ones.

Synchronisation of tongue and forepaw movements in the rat: a model of instrumental muscle synergy.

Acquisition of new skills is often implemented by the formation of coordinated movements of functionally unrelated muscles. This situation was modelled in rats trained to lick at a retractable spout which was automatically withdrawn after termination of every lick but could be returned by pressing and releasing a lever placed 4 cm below the spout. Rats (n = 12) learned to perform short presses (50 ms) synchronized with the lick cycle in a way allowing continuous drinking. When the distance of the lever from the box was increased from 5 mm to 12.5 mm or when the force required for lever operation was raised from 20 g to 90 g, the lick-press interval increased in multiples of the interlick interval. Licking ceased during the lever pressing but regular timing of subsequent licks indicated uninterrupted activity of the licking generator. It is concluded that the coordination of orofacial and forelimb muscles engaged in licking and lever pressing, respectively, is accomplished by propagation of the activity of the lick generator to cortical and subcortical motor centers.

Functional ablation of deep cerebellar nuclei temporarily impairs learned coordination of forepaw and tongue movements.

The role of the cerebellum in complex skilled movements was assessed by the use of functional ablation technique. Rats were trained to synchronize tongue and forepaw movements in a drinking box equipped with a retractable spout which was automatically withdrawn after every lick but could be returned by pressing and releasing a lever placed 4 cm below the spout. The animals learned to perform short presses synchronized with the lick cycle in such a way as to allow continuous drinking. The contribution of the neocerebellum to these lick-associated instrumental movements was estimated by intracranial injection of 2 ng of tetrodotoxin into the dentate and lateral part of interposed nuclei. Bilateral blockade of the mainly neocerebellar output interfered with learned synchronization of licking and bar pressing, but did not suppress licking from a stationary spout and only decreased the licking frequency by 10%. It is concluded that the tongue-forepaw synchronization is disrupted by elimination of the neocerebellar output but for a much shorter time (< 9 h) than the tetrodotoxin-induced inactivation of the lateral part of the caudate nucleus (72 h) reported earlier. The results confirm participation of cerebellar hemispheres in learned tongue-forepaw synchronization, but indicate at the same time that elimination of this link can be easily compensated.

Unit activity of motor cortex during acoustically signalled reaching in rats.

Changes of unit activity, accompanying a discriminated instrumental reaction were studied in the motor cortex of rats (n = 15) trained to reach into a narrow tubular feeder for food pellets. A shutter opened the feeder for 1280 ms while the presence of food was signalled by 600 Hz (CS+) tone and its absence by a 3000 Hz (CS-) tone. The electrophysiological experiments were performed after the rats had developed a preference for reaching with the left or right forepaw and when their discriminations were 75% correct. Unit activity was recorded in the motor cortex contralateral to the preferred forepaw using capillary microelectrodes and a head-mounted microdrive. Post-stimulus histograms (PSHs) to CS+ (n = 71) showed an increase of firing rate in the first 120 ms after CS onset (40% units) and a tonic excitation (55% units) starting some 200 ms later. The second component was related to movement as revealed by simultaneously plotted peri-reach histograms. The first component was related to preparatory activity and was also present in the PSHs obtained during correct reactions to CS- (n = 29). Then, absence of reaching was manifested by inhibition replacing the second excitatory component. The first but not the second excitatory components were seen in the PSHs plotted during negative reactions to CS+ (n = 18). It is concluded that the conditioned stimuli elicit in the motor cortex preparatory activity preceding actual movement by 200-250 ms. The neuronal populations engaged in the preparatory activity and movement execution overlap.

Interstrain differences in cognitive functions in rats in relation to status epilepticus.

Cognitive functions of Long Evans (N=30) and Wistar rats (N=32) were compared using a Morris water maze. Under control conditions the Long Evans rats were more efficient in this test, their average escape latency after 5 days of training (6.4+/-0.1 s, mean+/-S.E.M.) was significantly shorter than that of the Wistar rats (11.0+/-0.1 s). When the training was completed seizures were induced by an intraperitoneal injection of pilocarpine (330 mg/kg in the Long Evans strain and 350 mg/kg in the Wistar rats) 30 min after pretreatment with N-methylscopolamine (1 mg/kg i.p.). Clonazepam (1 mg/kg i.p.) was used to interrupt clonic seizures after 2 hours of continuous activity. Approximately one quarter of rats in both strains did not develop seizures. Severe convulsive status epilepticus was common in Long Evans rats (23 out of 30). In contrast, only 12 Wistar rats generated convulsive status epilepticus and the same number of animals exhibited only bursts of motor seizures separated by periods without convulsions (temporary seizures). Mortality after pilocarpine-induced status epilepticus was considerably higher in the Long Evans rats than in the Wistar rats. After a latency of 2-3 weeks spontaneous recurrent seizures appeared in all animals surviving status. Cognitive memory was tested during the 'silent period' between status and recurrent seizures. The Long Evans rats were unable to find the platform at the 3rd and 6th day after status but then their performance rapidly improved. The performance of the Wistar rats undergoing status epilepticus was seriously deteriorated and it never normalized, whereas the animals with temporary seizures exhibited only a transitory marginal prolongation of latencies. The hippocampal formation was damaged by status epilepticus in rats of both strains - the Long Evans rats exhibited more extensive damage of subfields CA1 and CA3, whereas in the Wistar rats a complete destruction of hilar neurons was observed in addition to partial CA1 and CA3 damage.

Systemic ketamine blocks cortical spreading depression but does not delay the onset of terminal anoxic depolarization in rats.

Ketamine (KET)-induced blockade of cortical spreading depression (CSD) was examined in rats (n = 51) anesthetized with pentobarbital (50 mg/kg). CSD was elicited by intracortical injection of 1 microliter of 0.15 mol/l potassium acetate 10-40 min after i.p. injection of 6-50 mg/kg KET. KET was almost ineffective at 6 mg/kg but prevented CSD propagation at 12 mg/kg and at higher dosages. The blockade was maximal 20 min after injection. Terminal anoxic depolarization elicited by N2 breathing developed in control rats after a latency which was not significantly different from that in rats pretreated with 50 and 100 mg/kg KET. The failure of CSD blocking dosages of KET to delay the onset of terminal anoxic depolarization indicates that excitotoxic amino acids play different roles in the mechanism of the anoxia-elicited and CSD-related autoregenerative ionic shifts.

Auditory frequency and intensity discrimination in pigmented rats.

Auditory function was investigated in seven pigmented hooded rats (strain Long-Evans) with the aid of an operant conditioning procedure. Frequency difference limen was measured at frequencies from 0.5 to 64 kHz at 50 dB sensation level (SL). Weber ratios (frequency difference limen/frequency) in this range varied between 3.7 and 7.3%. The decline in the intensity of the stimulus from 50 to 10 dB SL was accompanied by a slight increase in the frequency difference limen. The frequency difference limen values were similar for frequency shifts upwards or downwards. Intensity discrimination was measured at 50 dB SL at frequencies of 2, 8 and 32 kHz. Intensity difference limen was frequency independent and amounted to 2.9 +/- 0.5 dB in conditions of upward intensity shift. The values of intensity difference limen measured in conditions of downward intensity shift were significantly larger and amounted to 6.5 +/- 1.6 dB. The characteristics of hearing function found in these experiments correspond with those described by other authors in albino rats and indicate that albinism in the rat has no significant influence on auditory frequency and intensity discrimination.

Level of vigilance influences licking frequency in rats.

In rats, the basic licking rhythm is generated by the central pattern generator located in the brainstem. Nevertheless, the licking frequency can be regulated between about 7.5 and 4 Hz by changing the drinking conditions. If these conditions are kept constant, the licking frequency can be influenced only to a minor degree by factors such as deprivation level, type of solution, and phase of the session. The aim of our study was to compare the licking frequency of rats at different levels of vigilance. We investigated spontaneous licking of rats by an electrical lick sensor; parallel behavior monitoring was also performed. Animals kept in a stable environment and showing a lower level of vigilance licked at a rate of 5.96 Hz, fully vigilant rats licked significantly more rapidly at a frequency 6.57 Hz. The fastest rate of licking (6.49 Hz and 6.82 Hz, respectively) was encountered in alert rats under a mild stress caused by the presence of a second animal in the experimental box. The vigilance level is thus another factor affecting the licking rate of rats that should be taken into account in behavioral licking experiments.

Acquisition and retrieval of conditioned taste aversion is impaired by brain damage caused by two hours of pilocarpine-induced status epilepticus.

The effect of Cavalheiro's pilocarpine model of epileptogenesis upon conditioned taste aversion (CTA), an important example of nondeclarative memory, was studied in adult Long Evans rats. Deterioration of CTA was studied during the silent period between pilocarpine-induced status epilepticus (SE) and delayed spontaneous recurrent seizures. SE was elicited by i.p. injection of pilocarpine (320 mg/kg ) and interrupted after 2 hours by clonazepame (1 mg/kg i.p.). Peripheral cholinergic symptoms were suppressed by methylscopolamine (1 mg/kg i.p.), administered together with pilocarpine. CTA was formed against the salty taste of isotonic LiCl. In the experiment of CTA acquisition, the CTA was formed and tested during the silent period after SE. In the experiment of CTA retrieval, the CTA was acquired before SE and the retrieval itself was tested during the silent period. Retrieval of CTA acquired before SE was impaired more than the retrieval of CTA formed during the silent period. Our findings indicate that epileptic seizures can disrupt even non-declarative memory but that CTA formed by the damaged brain can use its better preserved parts for memory trace formation. Ketamine (50 mg/kg i.p.) applied 2 min after the onset of pilocarpine-induced status epilepticus protected memory deterioration.

Electrophysiological analysis of conditioned taste aversion in rats.

The memory mechanisms of conditioned taste aversion (CTA) were examined using electrophysiological methods. Presentation of the aversive taste to CTA trained animals inhibited unit activity in gustatory cortex, amygdala and ventromedial hypothalamus and caused delayed excitation of neurons in lateral hypothalamus. Lick-triggered rewarding stimulation of medial forebrain bundle substituted the taste CS in CTA experiments. The same stimulation triggered by nose-poking failed to be associated with subsequent poisoning. Importance of specific brain areas for CTA retrieval was assessed by the effect of lick-triggered stimulation of the examined site on gustatory discrimination. The disruption threshold was lowest in amygdala and lateral hypothalamus. Stimulation of other brain structures did not interfere with gustatory discrimination at current intensities subthreshold for disruption of licking. Unilateral electrical stimulation of vestibular nuclei following ingestion of saccharin elicited marked aversion to this taste.

The effect of otolith and semicircular canal convergence on the VOR during eccentric rotation.

VOR gain modulation was systematically investigated in the Rhesus monkey (M. mulatta) during centric and variable eccentric (up to 50 cm) sinusoidal rotation (4 Hz, 0.75 degree) with the nose facing in- or outward to test convergence of otolith and semicircular canal afferences. Earth-stationary lit LED-targets were placed at different distances (12-180 cm) from the monkey. Results were compared to biological demands. During centric rotation at 4 Hz when smooth pursuit mechanisms do not play a role, VOR gain--as expected--was approximately 1 without dependence on target distance. Phase of VOR and centrifuge were shifted by about 180 degrees as was predicted. If the monkey was rotated eccentrically with the nose facing outward the expected gain enhancement for close targets was obtained. Maximal experimental VOR gain during 4 Hz rotation was 4.4 which was close to demand at 50 cm eccentricity and 15 cm target distance (predicted gain: 4.6). If the nose points inward three situations have to be distinguished from simulation: (1) target behind the axis of rotation--VOR gain decrement should occur; (2) target on the axis of rotation--"inverse VOR suppression"; (3) target between monkey and axis of rotation--phase reversal. Experimentally, VOR gain decrement was obtained (situation 1). VOR gain was minimal (but not zero) for targets around the axis of rotation (situation 2). Situation 3 has not been investigated in detail so far.