Levodopa-Induced Dyskinesias are Frequent and Impact Quality of Life in Parkinson's Disease: A 5-Year Follow-Up Study.

BACKGROUND: Levodopa-induced dyskinesias (LID) are frequent in Parkinson's disease (PD). OBJECTIVE: To analyze the change in the frequency of LID over time, identify LID related factors, and characterize how LID impact on patients' quality of life (QoL). PATIENTS AND METHODS: PD patients from the 5-year follow-up COPPADIS cohort were included. LID were defined as a non-zero score in the item "Time spent with dyskinesia" of the Unified Parkinson's Disease Rating Scale-part IV (UPDRS-IV). The UPDRS-IV was applied at baseline (V0) and annually for 5 years. The 39-item Parkinson's disease Questionnaire Summary Index (PQ-39SI) was used to asses QoL. RESULTS: The frequency of LID at V0 in 672 PD patients (62.4 ± 8.9 years old; 60.1% males) with a mean disease duration of 5.5 ± 4.3 years was 18.9% (127/672) and increased progressively to 42.6% (185/434) at 5-year follow-up (V5). The frequency of disabling LID, painful LID, and morning dystonia increased from 6.9%, 3.3%, and 10.6% at V0 to 17.3%, 5.5%, and 24% at V5, respectively. Significant independent factors associated with LID (P < 0.05) were a longer disease duration and time under levodopa treatment, a higher dose of levodopa, a lower weight and dose of dopamine agonist, pain severity and the presence of motor fluctuations. LID at V0 (ß = 0.073; P = 0.027; R2 = 0.62) and to develop disabling LID at V5 (ß = 0.088; P = 0.009; R2 = 0.73) were independently associated with a higher score on the PDQ-39SI. CONCLUSION: LID are frequent in PD patients. A higher dose of levodopa and lower weight were factors associated to LID. LID significantly impact QoL.

Long-term alterations in brain and behavior after postnatal Zika virus infection in infant macaques.

Zika virus (ZIKV) infection has a profound impact on the fetal nervous system. The postnatal period is also a time of rapid brain growth, and it is important to understand the potential neurobehavioral consequences of ZIKV infection during infancy. Here we show that postnatal ZIKV infection in a rhesus macaque model resulted in long-term behavioral, motor, and cognitive changes, including increased emotional reactivity, decreased social contact, loss of balance, and deficits in visual recognition memory at one year of age. Structural and functional MRI showed that ZIKV-infected infant rhesus macaques had persistent enlargement of lateral ventricles, smaller volumes and altered functional connectivity between brain areas important for socioemotional behavior, cognitive, and motor function (e.g. amygdala, hippocampus, cerebellum). Neuropathological changes corresponded with neuroimaging results and were consistent with the behavioral and memory deficits. Overall, this study demonstrates that postnatal ZIKV infection in this model may have long-lasting neurodevelopmental consequences.

Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques.

The Zika virus (ZIKV) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital ZIKV syndrome. Postnatal ZIKV infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. We show that postnatal ZIKV infection of infant rhesus macaques (RMs) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls. We demonstrate ZIKV lymphoid tropism and neurotropism in infant RMs and histopathologic abnormalities in the peripheral and central nervous systems including inflammatory infiltrates, astrogliosis, and Wallerian degeneration. Structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) show persistent enlargement of lateral ventricles, maturational changes in specific brain regions, and altered functional connectivity (FC) between brain areas involved in emotional behavior and arousal functions, including weakened amygdala-hippocampal connectivity in two of two ZIKV-infected infant RMs several months after clearance of ZIKV RNA from peripheral blood. ZIKV infection also results in distinct alterations in the species-typical emotional reactivity to acute stress, which were predicted by the weak amygdala-hippocampal FC. We demonstrate that postnatal ZIKV infection of infants in this model affects neurodevelopment, suggesting that long-term clinical monitoring of pediatric cases is warranted.

Development of relational memory processes in monkeys.

The present study tested whether relational memory processes, as measured by the transverse patterning problem, are late-developing in nonhuman primates as they are in humans. Eighteen macaques ranging from 3 to 36 months of age, were trained to solve a set of visual discriminations that formed the transverse patterning problem. Subjects were trained at 3, 4-6, 12, 15-24 or 36 months of age to solve three discriminations as follows: 1) A+ vs. B-; 2) B+ vs. C-; 3) C+ vs. A. When trained concurrently, subjects must adopt a relational strategy to perform accurately on all three problems. All 36 month old monkeys reached the criterion of 90% correct, but only one 24-month-old and one 15-month-old did, initially. Three-month-old infants performed at chance on all problems. Six and 12-month-olds performed at 75-80% correct but used a 'linear' or elemental solution (e.g. A>B>C), which only yields correct performance on two problems. Retraining the younger subjects at 12, 24 or 36 months yielded a quantitative improvement on speed of learning, and a qualitative improvement in 24-36 month old monkeys for learning strategy. The results suggest that nonspatial relational memory develops late in macaques (as in humans), maturing between 15 and 24 months of age.

Multiple sevoflurane exposures in infant monkeys do not impact the mother-infant bond.

Exposure to general anesthesia during the postnatal period is associated with death of brain cells as well as long-term impairments in cognitive and emotional behavior in animal models. These models are critical for investigating mechanisms of pediatric anesthetic neurotoxicity as well as for testing potential strategies for preventing or mitigating this toxicity. Control conditions for anesthesia exposure involve separation of conscious infants from their mothers for variable periods of time, which could have its own effect on subsequent behavior because of stress to the mother and/or infant as a consequence of separation.We are conducting a long-term study of infant rhesus monkeys exposed three times for 4h each to sevoflurane anesthesia during the first six postnatal weeks, with a comparison condition of control infant monkeys that undergo brief maternal separations on the same schedule, to equate the period of time each infant is conscious and separated from its mother. Because mothers are separated from their infants longer for infants in the anesthesia condition, this could modify maternal behavior toward the infant, which may influence subsequent socioemotional behavior in the infants. In this study, we analyzed maternal behavior immediately after the first post-anesthesia (or control) reunion, as well as during reintroduction of the mother-infant pair to the larger social group 24 hpost-anesthesia or control separation, and found no differences between the conditions with mothers spending most of their time in contact with infants in all conditions analyzed. This indicates that the different durations of maternal separation in this study design do not impact the mother-infant bond, strengthening conclusions that subsequent differences in behavior between monkeys exposed to anesthesia compared to controls are a consequence of anesthesia exposure and not differential maternal behavior in the two conditions.

Effects of Separate or Combined Neonatal Damage to the Orbital Frontal Cortex and the Inferior Convexity on Object Recognition in Monkeys.

Unlike adult damage, neonatal damage to the inferior prefrontal convexity (IC) in monkeys spares learning and performance on the delayed nonmatching-to-sample (DNMS) task ( Málková et al. 2000). We investigated whether this sparing was due to compensation by undamaged orbital frontal cortex (O), an area also critical for DNMS, by comparing combined IC and O damage (Neo-ICO) with damage to O alone (Neo-O). Group Neo-ICO was impaired on DNMS learning at 3 months and 2 years of age. In contrast, Group Neo-O was impaired at 3 months, but recovered this function by 2 years, compared with Neo-IC and controls (N). We propose that the intact IC assumed the function of learning the DNMS rule for Group Neo-O. The persistent impairment after Neo-ICO lesions suggests that whereas O may likely support the rule acquisition in the absence of IC, no compensatory mechanisms are available after the combined damage. For the memory of lists of items, all groups were impaired at 3 months. At 2 years, the performance of Groups N and Neo-IC dramatically improved, whereas that of groups with O damage (Neo-O and Neo-ICO) remained impaired, indicating a critical role for O in recognition memory that cannot be substituted by another area.

Multiple Anesthetic Exposure in Infant Monkeys Alters Emotional Reactivity to an Acute Stressor.

BACKGROUND: Retrospective studies in humans have shown a higher prevalence of learning disabilities in children that received multiple exposures to general anesthesia before the age of 4 yr. Animal studies, primarily in rodents, have found that postnatal anesthetic exposure causes neurotoxicity and neurocognitive deficits in adulthood. The authors addressed the question of whether repeated postnatal anesthetic exposure was sufficient to cause long-term behavioral changes in a highly translationally relevant rhesus monkey model, allowing study of these variables against a background of protracted nervous system and behavioral development. METHODS: Rhesus monkeys of both sexes underwent either three 4-h exposures to sevoflurane anesthesia (anesthesia group n = 10) or brief maternal separations (control group n = 10) on postnatal day 6 to 10 that were repeated 14 and 28 days later. Monkeys remained with their mothers in large social groups at all times except for overnight observation after each anesthetic/control procedure. At 6 months of age, each monkey was tested on the human intruder paradigm, a common test for emotional reactivity in nonhuman primates. RESULTS: The frequency of anxiety-related behaviors was significantly higher in monkeys that were exposed to anesthesia as neonates as compared with controls: anesthesia 11.04 ± 1.68, controls 4.79 ± 0.77, mean ± SEM across all stimulus conditions. CONCLUSION: Increased emotional behavior in monkeys after anesthesia exposure in infancy may reflect long-term adverse effects of anesthesia.

The influence of context on recognition memory in monkeys: effects of hippocampal, parahippocampal and perirhinal lesions.

This study further investigated the specific contributions of the medial temporal lobe structures to contextual recognition memory. Monkeys (Macaca mulatta) with either neurotoxic lesions of the hippocampus, aspiration lesions of the perirhinal cortex and parahippocampal areas TH/TF, or sham operations were tested on five conditions of a visual-paired comparison (VPC) task in which 3-dimensional objects were presented over multicolored backgrounds. In two conditions (Conditions 1 and 2: Context-changes), the sample object was presented on a new background during the retention tests, whereas in the three others (Conditions 3-5: No-context-changes) the sample object was presented over its familiar background. Novelty preference scores of control animals were weaker, but still significantly different from chance, in the Context-changes conditions than on the No-context-changes conditions. Animals in the three experimental groups showed strong preference for novelty on the No-context-change conditions, but weaker novelty preference on the Context-change conditions than controls. Thus, animals in all three lesion types had greater difficulty recognizing an object when its background was different from that used during encoding. The data are consistent with the view that the hippocampal formation, areas TH/TF, and perirhinal cortex contribute interactively to contextual memory processes.

Neonatal hippocampal damage impairs specific food/place associations in adult macaques.

This study describes a novel spatial memory paradigm for monkeys and reports the effects of neonatal damage to the hippocampus on performance in adulthood. Monkeys were trained to forage in eight boxes hung on the walls of a large enclosure. Each box contained a different food item that varied in its intrinsic reward value, as determined from food preference testing. Monkeys were trained on a spatial and a cued version of the task. In the spatial task, the boxes looked identical and remained fixed in location whereas in the cued task, the boxes were individuated with colored plaques and changed location on each trial. Ten adult Rhesus macaques (5 neonatal sham-operated and 5 with neonatal neurotoxic hippocampal lesions) were allowed to forage once daily until they preferentially visited boxes containing preferred foods. The data suggest that all monkeys learned to discriminate preferred from nonpreferred food locations, but that monkeys with neonatal hippocampal damage committed significantly more working memory errors than controls in both tasks. Furthermore, following selective satiation, controls altered their foraging pattern to avoid the satiated food, whereas lesioned animals did not, suggesting that neonatal hippocampal lesions prohibit learning of specific food-place associations. We conclude that whereas an intact hippocampus is necessary to form specific item-in-place associations, in its absence, cortical areas may support more broad distinctions between food types that allow monkeys to discriminate places containing highly preferred foods.

The effects of selective hippocampal damage on tests of oddity in rhesus macaques.

The oddity task (e.g., A-, A-, B+) is classified as a conjunctive or relational task in which accurate performance depends upon learning to attend to stimulus relationships, not stimulus identity, and has no retention component as stimuli are presented simultaneously. It has been suggested that the hippocampus may play a particular role in learning this type of task in humans and animals. To test this, we trained adult rhesus macaques with selective neurotoxic damage to the hippocampal formation on their ability to learn and apply an oddity rule. The results suggest that the monkeys were able to adapt simple strategies to solve variations of the oddity task, however as the opportunity for such strategies was reduced, monkeys with hippocampal damage were increasingly impaired.

Comparison of the effects of damage to the perirhinal and parahippocampal cortex on transverse patterning and location memory in rhesus macaques.

Monkeys with damage to the parahippocampal (TH/TF) or perirhinal (PRh) cortex were tested on two sets of the transverse patterning (TP) problem (A+/B-, B+/C-, C+/A- and D+/E-, E+/F-, F+/D-) and delayed nonmatching-to-location paradigm (DNML), with delays ranging from 10 to 600 s. Damage to either area impaired acquisition and performance of TP but not of linear discriminations (e.g., A>B>C>X). Damage to areas TH/TF impaired performance of the DNML at all delays but only affected memory for objects at the longest delay, as measured by a delayed nonmatching-to-sample task (DNMS) (Nemanic et al., 2004). Damage to the PRh impaired performance of the DNMS but not of the DNML. The results present a dissociation in object and place memory for these two cortical regions and suggest a role for each in the cortical circuitry supporting configural/relational memory.

Selective neurotoxic damage to the hippocampal formation impairs performance of the transverse patterning and location memory tasks in rhesus macaques.

Monkeys with neurotoxic (ibotenic acid) damage to the hippocampal formation and unoperated controls were trained on two sets of transverse patterning problems (A+/B-, B+/C-, C+/A-, and D+/E-, E+/F-, F+/D-) and a delayed nonmatching-to-location paradigm (DNML) with delays of 10s, 30s, 120s, and 600s. Hippocampal lesions produced a size- and area-dependent impairment on transverse patterning. Damage largely limited to the right hippocampus in one subject had no effect on performance on the task. Of the remaining four subjects, two with hippocampal damage greater than 40% bilaterally were unable to solve the two transverse patterning sets, but could solve the linear set of discriminations (A+/B-, B+/C-, C+/X-). The two remaining operated animals were impaired in acquisition of both sets, but were eventually able to solve one of the two transverse patterning discrimination sets. All five operated monkeys were impaired relative to normal controls on DNML, but not on the standard delayed nonmatching-to-sample (DNMS) version with trial-unique objects. The results confirm our previous findings (Alvarado et al., Hippocampus 12:421-433, 2002) using aspiration lesions of the hippocampal formation and strengthen the view that the hippocampal formation is critical for object and spatial relational memory.

The hippocampal/parahippocampal regions and recognition memory: insights from visual paired comparison versus object-delayed nonmatching in monkeys.

Recognition memory was assessed by submitting the same adult monkeys to visual paired comparison (VPC) with mixed delays (10-120 sec), followed by three consecutive versions of object-delayed nonmatching-to-sample (DNMS): increasing delays (10-600 sec), lengthened lists (3-10 objects), and intervening distractors in the delays (light at 10 sec, motor task at 30-600 sec, or context change at 600 sec). Four groups were tested: normal controls, monkeys with ibotenic acid lesions of the hippocampal formation (H), and monkeys with aspiration lesions of either the perirhinal (PRh) or parahippocampal (areas TH/TF) cortex. Group H was impaired on VPC at delays > or =60 sec but had difficulty on DNMS only at 600 sec delays with distraction. In group TH/TF, the VPC impairment emerged earlier (30 sec); yet, once the nonmatching rule was mastered, no significant change occurred on any DNMS condition. Only group PRh behaved congruently on VPC and DNMS, exhibiting a deficit at the easiest condition that worsened with increasing delays as well as in DNMS lengthened list and distraction conditions. These results led us to postulate that VPC and DNMS, as previously administered to monkeys, were not equivalent visual recognition memory probes. Specifically, we propose that, for VPC, because of passive (incidental) encoding, the animal's performance rests on both item familiarity and event recollection, whereas, for DNMS, because of active (purposeful) encoding, performance relies more on item familiarity. This proposal converges with current models postulating distinct, but interactive, mnemonic roles for the hippocampal and adjacent TH/TF regions.

Assessment of locus and extent of neurotoxic lesions in monkeys using neuroimaging techniques: a replication.

In a recent study, [Hippocampus 11 (2001) 361] demonstrated that in vivo neuroimaging techniques could be used to accurately quantify the extent of neuronal damage after ibotenic acid injections in non-human primates. The present study was undertaken to replicate these findings and to further estimate whether the concentration of ibotenic acid used (10-15 mg/ml) to produce the neuronal loss did not affect the fibers coursing within or around the targeted brain area. Magnetic resonance (MR) images (T1-weighted and FLAIR) were acquired in three monkeys before and after they received neurotoxic lesions of the hippocampal formation. The postsurgical FLAIR images were taken 7-10 days after surgery to visualize the hyperintense signals produced by increased edema at the injection sites. One year post-surgically, T1-weighted images were acquired and compared with T1-weighted images obtained pre-surgery to estimate reduction in hippocampal volume resulting from neuronal loss. Estimated neuronal loss was then compared with actual cell loss found during histological evaluation of brain tissue. Both neuroimaging techniques accurately estimated the extent of hippocampal damage and damage to surrounding structures. In addition, the concentration of ibotenic acid (10 mg/ml) used in the present study did not appear to have significantly damaged or de-myelinated fibers coursing through or around the hippocampal formation. Together with the previous results of [Hippocampus 11 (2001) 361], the present data strongly demonstrate that in vivo neuroimaging techniques provide powerful tools to estimate reliably and rapidly the extent and localization of brain lesions in non-human primates.

Object and spatial relational memory in adult rhesus monkeys is impaired by neonatal lesions of the hippocampal formation but not the amygdaloid complex.

Adult rhesus monkeys with neonatal aspiration lesions of the hippocampal formation or the amygdaloid complex (including their respective subjacent cortices) and their age-matched controls were tested on the transverse patterning problem (A+ vs. B-, B+ vs. C- and C+ vs. A-) and a spatial version of the delayed nonmatching-to-sample (DNMS) task with delays of 10 s to 30 s, 60 s, 120 s, and 600 s. Monkeys with neonatal damage to the amygdaloid complex learned both tasks and did not differ from controls at any delay of the spatial DNMS task. Monkeys with neonatal hippocampal damage, however, were unable to learn transverse patterning, though they easily transferred to a linear series (A+ vs. B-, B+ vs. C-, and C+ vs. X-). Three of the four were also unable to reach criterion on the spatial DNMS task within the limits of testing, and the performance of all four monkeys deteriorated with increasing choice delays. The data suggest a role of the primate hippocampal region in both object and spatial relational learning.