Longitudinal positron emission tomography and postmortem analysis reveals widespread neuroinflammation in SARS-CoV-2 infected rhesus macaques.

BACKGROUND: Coronavirus disease 2019 (COVID-19) patients initially develop respiratory symptoms, but they may also suffer from neurological symptoms. People with long-lasting effects after acute infections with severe respiratory syndrome coronavirus 2 (SARS-CoV-2), i.e., post-COVID syndrome or long COVID, may experience a variety of neurological manifestations. Although we do not fully understand how SARS-CoV-2 affects the brain, neuroinflammation likely plays a role. METHODS: To investigate neuroinflammatory processes longitudinally after SARS-CoV-2 infection, four experimentally SARS-CoV-2 infected rhesus macaques were monitored for 7 weeks with 18-kDa translocator protein (TSPO) positron emission tomography (PET) using [18F]DPA714, together with computed tomography (CT). The baseline scan was compared to weekly PET-CTs obtained post-infection (pi). Brain tissue was collected following euthanasia (50 days pi) to correlate the PET signal with TSPO expression, and glial and endothelial cell markers. Expression of these markers was compared to brain tissue from uninfected animals of comparable age, allowing the examination of the contribution of these cells to the neuroinflammatory response following SARS-CoV-2 infection. RESULTS: TSPO PET revealed an increased tracer uptake throughout the brain of all infected animals already from the first scan obtained post-infection (day 2), which increased to approximately twofold until day 30 pi. Postmortem immunohistochemical analysis of the hippocampus and pons showed TSPO expression in cells expressing ionized calcium-binding adaptor molecule 1 (IBA1), glial fibrillary acidic protein (GFAP), and collagen IV. In the hippocampus of SARS-CoV-2 infected animals the TSPO+ area and number of TSPO+ cells were significantly increased compared to control animals. This increase was not cell type specific, since both the number of IBA1+TSPO+ and GFAP+TSPO+ cells was increased, as well as the TSPO+ area within collagen IV+ blood vessels. CONCLUSIONS: This study manifests [18F]DPA714 as a powerful radiotracer to visualize SARS-CoV-2 induced neuroinflammation. The increased uptake of [18F]DPA714 over time implies an active neuroinflammatory response following SARS-CoV-2 infection. This inflammatory signal coincides with an increased number of TSPO expressing cells, including glial and endothelial cells, suggesting neuroinflammation and vascular dysregulation. These results demonstrate the long-term neuroinflammatory response following a mild SARS-CoV-2 infection, which potentially precedes long-lasting neurological symptoms.

Brain Inflammation and Intracellular α-Synuclein Aggregates in Macaques after SARS-CoV-2 Infection.

SARS-CoV-2 causes acute respiratory disease, but many patients also experience neurological complications. Neuropathological changes with pronounced neuroinflammation have been described in individuals after lethal COVID-19, as well as in the CSF of hospitalized patients with neurological complications. To assess whether neuropathological changes can occur after a SARS-CoV-2 infection, leading to mild-to-moderate disease, we investigated the brains of four rhesus and four cynomolgus macaques after pulmonary disease and without overt clinical symptoms. Postmortem analysis demonstrated the infiltration of T-cells and activated microglia in the parenchyma of all infected animals, even in the absence of viral antigen or RNA. Moreover, intracellular α-synuclein aggregates were found in the brains of both macaque species. The heterogeneity of these manifestations in the brains indicates the virus' neuropathological potential and should be considered a warning for long-term health risks, following SARS-CoV-2 infection.

Electrical stimulation of the nucleus basalis of meynert: a systematic review of preclinical and clinical data.

Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been clinically investigated in Alzheimer's disease (AD) and Lewy body dementia (LBD). However, the clinical effects are highly variable, which questions the suggested basic principles underlying these clinical trials. Therefore, preclinical and clinical data on the design of NBM stimulation experiments and its effects on behavioral and neurophysiological aspects are systematically reviewed here. Animal studies have shown that electrical stimulation of the NBM enhanced cognition, increased the release of acetylcholine, enhanced cerebral blood flow, released several neuroprotective factors, and facilitates plasticity of cortical and subcortical receptive fields. However, the translation of these outcomes to current clinical practice is hampered by the fact that mainly animals with an intact NBM were used, whereas most animals were stimulated unilaterally, with different stimulation paradigms for only restricted timeframes. Future animal research has to refine the NBM stimulation methods, using partially lesioned NBM nuclei, to better resemble the clinical situation in AD, and LBD. More preclinical data on the effect of stimulation of lesioned NBM should be present, before DBS of the NBM in human is explored further.

Preclinical Marmoset Model for Targeting Chronic Inflammation as a Strategy to Prevent Alzheimer's Disease.

Due to the aging population, modern society is facing an increasing prevalence of neurological diseases such as Alzheimer's disease (AD). AD is an age-related chronic neurodegenerative disorder for which no satisfying therapy exists. Understanding the mechanisms underlying the onset of AD is necessary to find targets for protective treatment. There is growing awareness of the essential role of the immune system in the early AD pathology. Amyloidopathy, the main feature of early-stage AD, has a deregulating effect on the immune function. This is reciprocal as the immune system also affects amyloidopathy. It seems that the inflammatory reaction shows a heterogeneous pattern depending on the stage of the disease and the variation between individuals, making not only the target but also the timing of treatment important. The lack of relevant translational animal models that faithfully reproduce clinical and pathogenic features of AD is a major cause of the delay in developing new disease-modifying therapies and their optimal timing of administration. This review describes the communication between amyloidopathy and inflammation and the possibility of using nonhuman primates as a relevant animal model for preclinical AD research.

Ketamine treatment upon memory retrieval reduces fear memory in marmoset monkeys.

Emotionally arousing experiences are retained very well as seen in posttraumatic stress disorder (PTSD). Various lines of evidence indicate that reactivation of these memories renders them labile which offers a potential time-window for intervention. We tested in non-human primates whether ketamine, administered during fear memory reactivation, affected passive (inhibitory) avoidance learning. For the consolidation of contextual emotional memory, the unescapable foot-shock paradigm in a passive avoidance task with two compartments (dark vs illuminated) was used. After entering the dark compartment, marmoset monkeys received four random foot-shocks (1 mA, 4 s) within 15-min. This stressful exposure increased the saliva cortisol and heart rate and impaired REM-sleep (p<0.05). One week later the monkeys were re-exposed to the stressful situation for the reconsolidation of the fearful experience. During the re-exposure the monkeys were treated with ketamine (0.5 mg/kg) or saline. In week 3, the monkeys were placed in the experimental setting to test their memory for the fearful experience. In contrast to the vehicle-treated monkeys, who avoided the dark compartment, the ketamine-treated monkeys entered the dark compartment that was previously associated with the fearful experience (p<0.05). Post-mortem analysis of the hippocampus showed that ketamine-treated animals exhibited less doublecortin positive neurons and BrdU-labeled cells in the dentate gyrus. This study reveals that a single low dose of ketamine, administered upon fear retrieval in monkeys, reduce contextual fear memory and attenuate neurogenesis in the hippocampus. These are important findings for considering ketamine as a potential candidate to target traumatic memories in PTSD.

Involvement of the Red Nucleus in the Compensation of Parkinsonism may Explain why Primates can develop Stable Parkinson's Disease.

Neurological compensatory mechanisms help our brain to adjust to neurodegeneration as in Parkinson's disease. It is suggested that the compensation of the damaged striato-thalamo-cortical circuit is focused on the intact thalamo-rubro-cerebellar pathway as seen during presymptomatic Parkinson, paradoxical movement and sensorimotor rhythm (SMR). Indeed, the size of the red nucleus, connecting the cerebellum with the cerebral cortex, is larger in Parkinson's disease patients suggesting an increased activation of this brain area. Therefore, the red nucleus was examined in MPTP-induced parkinsonian marmoset monkeys during the presymptomatic stage and after SMR activation by neurofeedback training. We found a reverse significant correlation between the early expression of parkinsonian signs and the size of the parvocellular part of the red nucleus, which is predominantly present in human and non-human primates. In quadrupedal animals it consists mainly of the magnocellular part. Furthermore, SMR activation, that mitigated parkinsonian signs, further increased the size of the red nucleus in the marmoset monkey. This plasticity of the brain helps to compensate for dysfunctional movement control and can be a promising target for compensatory treatment with neurofeedback technology, vibrotactile stimulation or DBS in order to improve the quality of life for Parkinson's disease patients.

Sensorimotor rhythm neurofeedback as adjunct therapy for Parkinson's disease.

Neurofeedback may enhance compensatory brain mechanisms. EEG-based sensorimotor rhythm neurofeedback training was suggested to be beneficial in Parkinson's disease. In a placebo-controlled study in parkinsonian nonhuman primates we here show that sensorimotor rhythm neurofeedback training reduces MPTP-induced parkinsonian symptoms and both ON and OFF scores during classical L-DOPA treatment. Our findings encourage further development of sensorimotor rhythm neurofeedback training as adjunct therapy for Parkinson's disease which might help reduce L-DOPA-induced side effects.

Acceleration of Amyloidosis by Inflammation in the Amyloid-Beta Marmoset Monkey Model of Alzheimer's Disease.

BACKGROUND: The immune system is increasingly mentioned as a potential target for Alzheimer's disease (AD) treatment. OBJECTIVE: In the present pilot study, the effect of (neuro)inflammation on amyloidopathy was investigated in the marmoset monkey, which has potential as an AD animal model due to its natural cerebral amyloidosis similar to humans. METHODS: Six adult/aged marmosets (Callithrix jacchus) were intracranial injected with amyloid-beta (Aß) fibrils at three cortical locations in the right hemisphere. Additionally, in half of the monkeys, lipopolysaccharide (LPS) was co-injected with the Aß fibrils and injected in the other hemisphere without Aß fibrils. The other three monkeys received phosphate buffered saline instead of LPS, as a control for the inflammatory state. The effect of inflammation on amyloidopathy was also investigated in an additional monkey that suffered from chronic inflammatory wasting syndrome. Mirror histology sections were analyzed to assess amyloidopathy and immune reaction, and peripheral blood for AD biomarker expression. RESULTS: All LPS-injected monkeys showed an early AD immune blood cell expression profile on CD95 and CD45RA. Two out of three monkeys injected with Aß and LPS and the additional monkey, suffering from chronic inflammation, developed plaques. None of the controls, injected with Aß only, developed any plaques. CONCLUSION: This study shows the importance of immune modulation on the susceptibility for amyloidosis, a hallmark of AD, which offers new perspectives for disease modifying approaches in AD.

Individual and Familial Susceptibility to MPTP in a Common Marmoset Model for Parkinson's Disease.

INTRODUCTION: Insight into susceptibility mechanisms underlying Parkinson's disease (PD) would aid the understanding of disease etiology, enable target finding and benefit the development of more refined disease-modifying strategies. METHODS: We used intermittent low-dose MPTP (0.5 mg/kg/week) injections in marmosets and measured multiple behavioral and neurochemical parameters. Genetically diverse monkeys from different breeding families were selected to investigate inter- and intrafamily differences in susceptibility to MPTP treatment. RESULTS: We show that such differences exist in clinical signs, in particular nonmotor PD-related behaviors, and that they are accompanied by differences in neurotransmitter levels. In line with the contribution of a genetic component, different susceptibility phenotypes could be traced back through genealogy to individuals of the different families. CONCLUSION: Our findings show that low-dose MPTP treatment in marmosets represents a clinically relevant PD model, with a window of opportunity to examine the onset of the disease, allowing the detection of individual variability in disease susceptibility, which may be of relevance for the diagnosis and treatment of PD in humans.

Muscle contractile properties as an explanation of the higher mean power output in marmosets than humans during jumping.

The muscle mass-specific mean power output (PMMS,mean) during push-off in jumping in marmosets (Callithrix jacchus) is more than twice that in humans. In the present study it was tested whether this is attributable to differences in muscle contractile properties. In biopsies of marmoset m. vastus lateralis (VL) and m. gastrocnemius medialis (GM) (N=4), fibre-type distribution was assessed using fluorescent immunohistochemistry. In single fibres from four marmoset and nine human VL biopsies, the force-velocity characteristics were determined. Marmoset VL contained almost exclusively fast muscle fibres (>99.0%), of which 63% were type IIB and 37% were hybrid fibres, fibres containing multiple myosin heavy chains. GM contained 9% type I fibres, 44% type IIB and 47% hybrid muscle fibres. The proportions of fast muscle fibres in marmoset VL and GM were substantially larger than those reported in the corresponding human muscles. The curvature of the force-velocity relationships of marmoset type IIB and hybrid fibres was substantially flatter than that of human type I, IIA, IIX and hybrid fibres, resulting in substantially higher muscle fibre mass-specific peak power (PFMS,peak). Muscle mass-specific peak power output (PMMS,peak) values of marmoset whole VL and GM, estimated from their fibre-type distributions and force-velocity characteristics, were more than twice the estimates for the corresponding human muscles. As the relative difference in estimated PMMS,peak between marmosets and humans is similar to that of PMMS,mean during push-off in jumping, it is likely that the difference in in vivo mechanical output between humans and marmosets is attributable to differences in muscle contractile properties.

Improvement of preclinical animal models for autoimmune-mediated disorders via reverse translation of failed therapies.

The poor translational validity of autoimmune-mediated inflammatory disease (AIMID) models in inbred and specific pathogen-free (SPF) rodents underlies the high attrition of new treatments for the corresponding human disease. Experimental autoimmune encephalomyelitis (EAE) is a frequently used preclinical AIMID model. We discuss here how crucial information needed for the innovation of current preclinical models can be obtained from postclinical analysis of the nonhuman primate EAE model, highlighting the mechanistic reasons why some therapies fail and others succeed. These new insights can also help identify new targets for treatment.

Anti-Parkinson effects of a selective alpha2C-adrenoceptor antagonist in the MPTP marmoset model.

Current dopamine replacement therapies, in Parkinson's disease (PD), result in aversive side effects and rapid drug dose escalation over time. Therefore, a non-dopaminergic treatment would be an advantageous supplement to lower the dose of dopamine replacement treatment postponing the occurrence of side effects. The noradrenergic system plays an important role in the facilitation or maintenance of the activity of the nigrostriatal dopamine pathways. Here the putative anti-Parkinson effects of the oral selective alpha2C-adrenoceptor antagonist (JNJ27063699 0.1-10mg/kg p.o.) and of vehicle (fruit syrup) were evaluated in the MPTP-marmoset model. Dose-related anti-Parkinson effects were assessed by means of a behavioural rating scale covering parkinsonian symptoms, body weight and body temperature, and two test systems assessing locomotor activity and complex motor skills of hand-eye coordination for controlled movements in MPTP- or saline-pretreated marmosets. JNJ27063699, at the middle and higher doses, consistently improved locomotor activity and hand-eye coordination capabilities, which indicates an improvement in the coordination of motor control -or movements- in MPTP-pretreated monkeys. No additional effects on the parkinsonian symptoms or side effects were observed on other test systems. Overall, the findings link deficit in motor coordination with dysfunctional adrenergic signalling and it suggest that selective alpha2C adrenergic antagonism may contribute to behavioural improvement in the MPTP-monkey model of PD. In multi-drug medication JNJ27063699 might have potential in the treatment of motor deficit in PD.

Mechanical output in jumps of marmosets (Callithrix jacchus).

In this study we determined the mechanical output of common marmosets (Callithrix jacchus) during jumping. Vertical ground reaction forces were measured in 18 animals while they jumped from an instrumented crossbar to a crossbar located 70 cm higher. From the vertical force time histories, we calculated the rate of change of mechanical energy of the centre of mass (dE/dt). The mean value of dE/dt during the push-off amounted to 51.8±6.2 W kg(-1) body mass, and the peak value to 116.4±17.6 W kg(-1) body mass. We used these values in combination with masses of leg muscles, determined in two specimens, to estimate mean and peak values of dE/dt of 430 and 970 W kg(-1) muscle, respectively. These values are higher than values reported in the literature for jumps of humans and bonobos, but smaller than those of jumps of bushbabies. Surprisingly, the mean value of dE/dt of 430 W kg(-1) muscle was close to the maximal power output of 516 W kg(-1) muscle reported in the literature for isokinetic contractions of rat medial gastrocnemius, one of the fastest mammalian muscles. Further study of the force-velocity relationship of muscle tissue of small primates is indicated.

Oral treatment with the NADPH oxidase antagonist apocynin mitigates clinical and pathological features of parkinsonism in the MPTP marmoset model.

This study evaluates the therapeutic efficacy of the NADPH oxidase inhibitor apocynin, isolated as principal bioactive component from the medicinal plant Picrorhiza kurroa, in a marmoset MPTP model of Parkinson's disease (PD). The methoxy-substituted catechol apocynin has a similar structure as homovanillic acid (HVA), a metabolite of dopamine (DA). Apocynin acquires its selective inhibitory capacity of the reactive oxygen species generating NADPH oxidase via metabolic activation by myeloperoxidase (MPO). As MPO is upregulated in activated brain microglia cells of PD patients and in MPTP animal models, the conditions for metabolic activation of apocynin and inhibition of microglia NADPH oxidase are in place. Marmoset monkeys received oral apocynin (100 mg/kg; p.o.) (n = 5) or Gum Arabica (controls; n = 5) three times daily until the end of the study, starting 1 week before PD induction with MPTP (1 mg/kg s.c. for 8 days). Parkinsonian symptoms, motor function, home-cage activity and body weight were monitored to assess the disease development and severity. Post-mortem numbers of the tyrosine hydroxylase expressing DA neurons in the substantia nigra were counted. During the MPTP injections, apocynin limited the body weight loss and relieved parkinsonian symptoms compared to controls (Linear regression, P < 0.05) indicating a reduction of disease progression. During the last test week, apocynin also improved the hand-eye coordination performance compared with vehicle treatment (resp. 39.3 ± 4.5 % and 17.7 ± 6.7 %; P = 0.048) and improved the home cage activity with 32 % (P = 0.029), indicating anti-Parkinson efficacy. Apocynin also increased the number of surviving DA neurons in MPTP-treated marmosets with 8.5 % (P = 0.059), indicating a tendency towards a neuroprotective efficacy. In conclusion, compensation for the loss of DA and its metabolite HVA by apocynin mitigates the PD progression and limits the parkinsonian signs and motor-function deterioration.

Neuroprotective effects of riluzole in early phase Parkinson's disease on clinically relevant parameters in the marmoset MPTP model.

The present study evaluates neuroprotection in a marmoset MPTP (1-methyl-1,2,3,6-tetrahydropyridine) model representing early Parkinson's disease (PD). The anti-glutamatergic compound riluzole is used as a model compound for neuroprotection. The compound is one of the few protective compounds used in the clinic for a neurodegenerative disorder. Marmoset monkeys were randomized into three groups of six: 1) an MPTP group receiving a total MPTP dose of 7 mg/kg (4 injections over two weeks, s.c.) 2) a riluzole group receiving besides MPTP, a twice daily dose of riluzole (10 mg/kg, p.o.), starting one week before MPTP and continuing for one week after the final MPTP injection and 3) a control group receiving saline instead of MPTP and riluzole. The marmosets' Parkinsonian symptoms were scored daily and their activity level, hand-eye coordination, jumping behavior, axial turning and night sleep parameters were tested and recorded weekly. At three weeks following the last MPTP challenge, brains were dissected and dopamine levels in the striatum and the tyrosine hydroxylase (TH) expressing dopamine (DA) neurons in the substantia nigra (SN) were compared. MPTP affected all behavioral parameters and sleep architecture and induced a relatively mild (50%) decline of DA neurons in the substantia nigra (SN). Riluzole relieved the Parkinsonian signs, and improved the hand-eye coordination as well as turning ability. Moreover, riluzole prevented the impact of MPTP on sleep architecture and rapid eye movement behavioral disorder (RBD). Riluzole also increased the number of surviving DA neurons in MPTP-treated marmosets to 75%. However, riluzole did not prevent the MPTP-induced impairments on locomotor activity and jumping activity. In conclusion, reduction of excitotoxicity by riluzole appeared to be effective in reducing progressive neurodegeneration and relieved several clinically relevant PD symptoms in an animal model representing the early phase of PD.

REM sleep behavior disorder in the marmoset MPTP model of early Parkinson disease.

STUDY OBJECTIVES: Sleep problems are a common phenomenon in most neurological and psychiatric diseases. In Parkinson disease (PD), for instance, sleep problems may be the most common and burdensome non-motor symptoms in addition to the well-described classical motor symptoms. Since sleep disturbances generally become apparent in the disease before motor symptoms emerge, they may represent early diagnostic tools and a means to investigate early mechanisms in PD onset. The sleep disturbance, REM sleep behavior disorder (RBD), precedes PD in one-third of patients. We therefore investigated sleep changes in marmoset monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), the non-human primate model for idiopathic PD. DESIGN: Mild parkinsonism was induced in 5 marmoset monkeys (3M/2F) over a 2-week period of subchronic MPTP treatment. Electroencephalograms (EEGs) and electromyograms (EMGs) were recorded weekly. Motor activity and hand-eye coordination were also measured weekly, and any signs of parkinsonism were noted each day. Sleep parameters, motor activity, and performance data before and after MPTP treatment were compared between MPTP-treated marmosets and 4 control marmosets (1M/3F). RESULTS: MPTP increased the number of sleep epochs with high-amplitude EMG bouts during REM sleep relative to control animals (mean ± SEM percentage of REM 58.2 ± 9.3 vs. 29.6 ± 7.7; P < 0.05). Of all sleep parameters measured, RBD-like measures discriminated best between MPTP-treated and control animals. On the other hand, functional motor behavior, as measured by hand-eye coordination, was not affected by MPTP treatment (correct trials MPTP: 23.40 ± 3.56 vs. control: 36.13 ± 5.88 correct trials; P = 0.32). CONCLUSIONS: This REM sleep-specific change, in the absence of profound changes in wake motor behaviors, suggests that the MPTP marmoset model of PD could be used for further studies into the mechanisms and treatment of RBD and other sleep disorders in premotor symptom PD.

Non-enzymatic pretreatment of nerve agent (soman) poisoning: a brief state-of-the-art review.

The rapid onset of toxic signs following nerve agent intoxication and the apprehension that current therapy (atropine, oxime, diazepam) may not prevent brain damage, requires supportive pretreatment. Since the current pretreatment drug pyridostigmine fails in protecting brain-AChE, more effective pretreatment is necessary. A main focus of present-day pretreatment research is on bioscavengers, another is on centrally active reversible AChE-inhibitors combined with drugs showing anti-cholinergic, anti-glutamatergic, neuroprotective and non-sedating GABA-ergic activity. Strategies aimed at improving efficacy of pharmacological pretreatment will briefly be discussed. Galantamine, given as a pretreatment or stand-alone therapy, emerged as one of the best medical countermeasures against nerve agent poisoning in guinea pigs. Other preclinical studies demonstrated effective pretreatment consisting of physostigmine combined with procyclidine, scopolamine or bupropion (all single injections), against nerve agent poisoning in guinea pigs. A long sign-free pretreatment with physostigmine (Alzet pump), combined with single injection of procyclidine just before soman poisoning, enhanced the efficacy of a post-poisoning therapy consisting of 3 autoinjector equivalents of HI-6, atropine and diazepam, considerably.

The MPTP marmoset model of parkinsonism: a multi-purpose non-human primate model for neurodegenerative diseases.

Aging societies face an increasing prevalence of neurodegenerative disorders for which no cure exists. The paucity of relevant animal models that faithfully reproduce clinical and pathogenic features of neurodegenerative diseases is a major cause for the lack of effective therapies. Clinically distinct disorders, such as Alzheimer's and Parkinson's disease, are driven by overlapping pathogenic mechanisms that converge onto vulnerable neurons to ultimately cause abnormal clinical outcomes. These similarities, particularly in the early phases of neurodegeneration, might help identify appropriate animal model systems for studying of cell pathology. While reviewing some of the cellular mechanisms of disease progression, we discuss the MPTP-induced model of Parkinsonism in marmoset monkeys as a model system for construct, face and predictive validity in neurodegenerative studies.

Neurofeedback training on sensorimotor rhythm in marmoset monkeys.

Neurofeedback research in a model closely related to humans is recommended to rule out placebo effects and unspecific factors bridging the gap between nonvalidated empirical and standardized controlled research. In this article, telemetric sensorimotor rhythm (SMR; 11-14 Hz) feedback training in the marmoset monkey is applied to examine the monkey's capability to voluntary control their brain activity. Four monkeys, provided with two epidural bioelectric electrodes above the sensorimotor cortex, were trained with positive reinforcement on SMR measured by online analyses of 1.28 s electroencephalogram epochs in 30-min sessions. These monkeys learned within five sessions to increase their alpha activity. The first evidence of nonhuman primates having an operant control over the SMR is provided, an initial step for a much-needed scientific basis to neurofeedback.

A less stressful animal model: a conditioned avoidance behaviour task for guineapigs.

In the conventional shuttle box, animals are trained to avoid electric foot-shocks. As a consequence of these stress-inducing foot-shocks the animals become anxious and are difficult to train. The aim of the present study was to avoid the stress-inducing foot-shocks and to develop a fast and reliable conditioned avoidance behaviour task for guineapigs. We examined whether narrowband noises at four different sound levels above hearing threshold could be used as conditioned stimulus (CS). The unconditioned stimulus (UCS) was a stream of air, which was used instead of the conventionally used electric foot-shocks. The animals were initially trained with a CS of 78 dB sound pressure level (SPL). In this initial training, guineapigs learned to detect a narrowband noise of 78 dB SPL. Interestingly, during the first additional training session in which three other sound levels were applied, guineapigs did not immediately generalize the learned response at 78 dB SPL to lower sound levels of 58 and 68 dB SPL. However, in this session a noise level of 88 dB SPL led immediately to a high level of responses. The response latency decreased with increasing sound level, from approximately 7 s at 58 dB SPL to approximately 3 s at 88 dB SPL. The escape latency during the UCS was approximately 0.6 s. The present results demonstrate that after reducing the level of stress guineapigs can acquire a response in only a few sessions and furthermore, although the guineapigs were less anxious, training at sound levels of 78 and 88 dB SPL was influenced by an aversive reaction by the guineapig. The results indicate that this aversive reaction of the guineapig is crucial for the training.