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1.  VENTILATORY PATTERN AND ENERGY EXPENDITURE ARE ALTERED IN CYSTIC FIBROSIS MICE 
Background
Altered ventilatory pattern and increased energy expenditure are facets of the complex cystic fibrosis (CF) phenotype. Whether these are inherent attributes of CF, secondary consequences of lung infection or other disease complications is not known.
Methods
Studies were performed in congenic C57BL/6J, F508del (Cftrtm1kth) and CF gut-corrected (F508del) mice. Ventilatory patterns were measured using whole-body plethysmography. Indirect calorimetry was used to determine oxygen consumption, carbon dioxide production and resting energy expenditure.
Results
CF mice (F508del and F508del gut-corrected) have a significantly faster respiratory rate and increased ventilatory pattern variability as compared to non-CF mice. F508del but not CF gut-corrected mice had significantly increased energy expenditure per gram body weight.
Conclusions
CF mice exhibit a faster, more variable ventilatory pattern. These changes were present in the absence of detectable infection or illness due to gastrointestinal obstruction. Increased resting energy expenditure does not completely account for these differences.
doi:10.1016/j.jcf.2012.11.008
PMCID: PMC3620718  PMID: 23290341
Cystic Fibrosis; Ventilatory Pattern; Energy Expenditure; Respiratory Rate
2.  Characterization of Tissue-Specific and Developmentally Regulated Alternative Splicing of Exon 64 in the COL5A1 Gene 
Connective tissue research  2011;53(3):267-276.
The COL5A1 gene, a member of the clade B fibrillar collagen gene family, was recently shown to contain two alternatively spliced exons (64A and 64B) that encode 23 amino acids in the carboxyl-terminal propeptide. The two are identical in length, very similar in sequence, and used in a mutually exclusive fashion because of the small intron that separates them. Each COL5A1 allele uses both exons, but a given transcript will contain only one of the two exons. The sequences in other species are highly conserved at the amino acid level. The expression profile of the two isoforms was determined from analysis of RNA levels in a panel of murine tissues. While both isoforms were found in all tissues studied, actively proliferating tissues (liver, lung) used isoform B more often, while a less mitotically-active tissue, brain, had a higher proportion of exon 64A. The high degree of conservation between the two exons is consistent with a regional genomic duplication. The presence of the two isoforms as far back as pufferfish (tetraodon) implies an important functional significance. The exact role determined by the two sequences is not known, but involvement in the determination of chain composition of mature type V collagen or regulation of cell activity are possible, given the differences in tissue distribution.
doi:10.3109/03008207.2011.636160
PMCID: PMC3999617  PMID: 22149965
Type V collagen; alternative splicing; tissue distribution; developmental profile
3.  Association of Autoimmune Addison's Disease with Alleles of STAT4 and GATA3 in European Cohorts 
PLoS ONE  2014;9(3):e88991.
Background
Gene variants known to contribute to Autoimmune Addison's disease (AAD) susceptibility include those at the MHC, MICA, CIITA, CTLA4, PTPN22, CYP27B1, NLRP-1 and CD274 loci. The majority of the genetic component to disease susceptibility has yet to be accounted for.
Aim
To investigate the role of 19 candidate genes in AAD susceptibility in six European case-control cohorts.
Methods
A sequential association study design was employed with genotyping using Sequenom iPlex technology. In phase one, 85 SNPs in 19 genes were genotyped in UK and Norwegian AAD cohorts (691 AAD, 715 controls). In phase two, 21 SNPs in 11 genes were genotyped in German, Swedish, Italian and Polish cohorts (1264 AAD, 1221 controls). In phase three, to explore association of GATA3 polymorphisms with AAD and to determine if this association extended to other autoimmune conditions, 15 SNPs in GATA3 were studied in UK and Norwegian AAD cohorts, 1195 type 1 diabetes patients from Norway, 650 rheumatoid arthritis patients from New Zealand and in 283 UK Graves' disease patients. Meta-analysis was used to compare genotype frequencies between the participating centres, allowing for heterogeneity.
Results
We report significant association with alleles of two STAT4 markers in AAD cohorts (rs4274624: P = 0.00016; rs10931481: P = 0.0007). In addition, nominal association of AAD with alleles at GATA3 was found in 3 patient cohorts and supported by meta-analysis. Association of AAD with CYP27B1 alleles was also confirmed, which replicates previous published data. Finally, nominal association was found at SNPs in both the NF-κB1 and IL23A genes in the UK and Italian cohorts respectively.
Conclusions
Variants in the STAT4 gene, previously associated with other autoimmune conditions, confer susceptibility to AAD. Additionally, we report association of GATA3 variants with AAD: this adds to the recent report of association of GATA3 variants with rheumatoid arthritis.
doi:10.1371/journal.pone.0088991
PMCID: PMC3948621  PMID: 24614117
4.  Molecular Mechanisms of Classical Ehlers-Danlos Syndrome 
Human mutation  2009;30(6):10.1002/humu.21000.
Classical Ehlers-Danlos syndrome (EDS) is a heritable disorder characterized by joint hypermobility, skin hyperextensibility, and abnormal wound healing. The majority of affected individuals have alterations in one of the two type V collagen genes, COL5A1 and COL5A2. The most common mechanism is COL5A1 haploinsufficiency due to instability of the transcript of one allele. In dermal fibroblasts from our population of 76 individuals with clinical features of classical EDS, there were 21 (29.5%) with decreased expression of one COL5A1 allele, consistent with published estimates of the frequency of null alleles. We identified the causative mutation in 9 of these cell strains (mutations for 7 others had been previously described), and found two nonsense mutations, five splice mutations, and two insertion/deletions. The same type of genomic change at splice sites can have different effects at the RNA level and the outcome could not be predicted from the primary genomic DNA alteration.
doi:10.1002/humu.21000
PMCID: PMC3827857  PMID: 19370768
classical Ehlers-Danlos syndrome; EDS; type V collagen; COL5A1; COL5A2; haploinsufficiency; G530S
5.  User Profiles of a Smartphone Application to Support Drug Adherence — Experiences from the iNephro Project 
PLoS ONE  2013;8(10):e78547.
Purpose
One of the key problems in the drug therapy of patients with chronic conditions is drug adherence. In 2010 the initiative iNephro was launched (www.inephro.de). A software to support regular and correct drug intake was developed for a smartphone platform (iOS). The study investigated whether and how smartphone users deployed such an application.
Methods
Together with cooperating partners the mobile application “Medikamentenplan” (“Medication Plan”) was developed. Users are able to keep and alter a list of their regular medication. A memory function supports regular intake. The application can be downloaded free of charge from the App Store™ by Apple™. After individual consent of users from December 2010 to April 2012 2042338 actions were recorded and analysed from the downloaded applications. Demographic data were collected from 2279 users with a questionnaire.
Results
Overall the application was used by 11688 smartphone users. 29% (3406/11688) used it at least once a week for at least four weeks. 27% (3209/11688) used the application for at least 84 days. 68% (1554/2279) of users surveyed were male, the stated age of all users was between 6–87 years (mean 44). 74% of individuals (1697) declared to be suffering from cardiovascular disease, 13% (292) had a previous history of transplantation, 9% (205) were suffering from cancer, 7% (168) reported an impaired renal function and 7% (161) suffered from diabetes mellitus. 69% (1568) of users were on <6 different medications, 9% (201) on 6 – 10 and 1% (26) on more than 10.
Conclusion
A new smartphone application, which supports drug adherence, was used regularly by chronically ill users with a wide range of diseases over a longer period of time. The majority of users so far were middle-aged and male.
doi:10.1371/journal.pone.0078547
PMCID: PMC3806829  PMID: 24194946
6.  What does the mediodorsal thalamus do? 
Dense amnesia can result from damage to the medial diencephalon in humans and in animals. In humans this damage is diffuse and can include the mediodorsal nuclei of the thalamus. In animal models, lesion studies have confirmed the mediodorsal thalamus (MD) has a role in memory and other cognitive tasks, although the extent of deficits is mixed. Anatomical tracing studies confirm at least three different subgroupings of the MD: medial, central, and lateral, each differentially interconnected to the prefrontal cortex (PFC). Moreover, these subgroupings of the MD also receive differing inputs from other brain structures, including the basal ganglia thus the MD subgroupings form key nodes in interconnected frontal-striatal-thalamic neural circuits, integrating critical information within the PFC. We will provide a review of data collected from non-human primates and rodents after selective brain injury to the whole of the MD as well as these subgroupings to highlight the extent of deficits in various cognitive tasks. This research highlights the neural basis of memory and cognitive deficits associated with the subgroupings of the MD and their interconnected neural networks. The evidence shows that the MD plays a critical role in many varied cognitive processes. In addition, the MD is actively processing information and integrating it across these neural circuits for successful cognition. Having established that the MD is critical for memory and cognition, further research is required to understand how the MD specifically influences these cognitive processing carried out by the brain.
doi:10.3389/fnsys.2013.00037
PMCID: PMC3738868  PMID: 23950738
prefrontal cortex; memory; executive function; macaque; rodent; animal models; learning
7.  The role of functionally defective rare germline variants of sialic acid acetylesterase in autoimmune Addison's disease 
European Journal of Endocrinology  2012;167(6):825-828.
Background
Autoimmune Addison's disease (AAD) is a rare condition with a complex genetic basis. A panel of rare and functionally defective genetic variants in the sialic acid acetylesterase (SIAE) gene has recently been implicated in several common autoimmune conditions. We performed a case–control study to determine whether these rare variants are associated with a rarer condition, AAD.
Method
We analysed nine SIAE gene variants (W48X, M89V, C196F, C226G, R230W, T312M, Y349C, F404S and R479C) in a United Kingdom cohort of 378 AAD subjects and 387 healthy controls. All samples were genotyped using Sequenom iPlex chemistry to characterise primer extension products.
Results
A heterozygous rare allele at codon 312 (312*M) was found in one AAD patient (0.13%) but was not detected in the healthy controls. The commoner, functionally recessive variant at codon 89 (89*V) was found to be homozygous in two AAD patients but was only found in the heterozygous state in controls. Taking into account all nine alleles examined, 4/378 (1.06%) AAD patients and 1/387 (0.25%) healthy controls carried the defective SIAE alleles, with a calculated odds ratio of 4.13 (95% CI 0.44–97.45, two-tailed P value 0.212, NS).
Conclusion
We demonstrated the presence of 89*V homozygotes and the 312*M rare allele in the AAD cohort, but overall, our analysis does not support a role for rare variants in SIAE in the pathogenesis of AAD. However, the relatively small collection of AAD patients limits the power to exclude a small effect.
doi:10.1530/EJE-12-0579
PMCID: PMC3494867  PMID: 23011869
8.  Respiratory chain complex I deficiency caused by mitochondrial DNA mutations 
Defects of the mitochondrial respiratory chain are associated with a diverse spectrum of clinical phenotypes, and may be caused by mutations in either the nuclear or the mitochondrial genome (mitochondrial DNA (mtDNA)). Isolated complex I deficiency is the most common enzyme defect in mitochondrial disorders, particularly in children in whom family history is often consistent with sporadic or autosomal recessive inheritance, implicating a nuclear genetic cause. In contrast, although a number of recurrent, pathogenic mtDNA mutations have been described, historically, these have been perceived as rare causes of paediatric complex I deficiency. We reviewed the clinical and genetic findings in a large cohort of 109 paediatric patients with isolated complex I deficiency from 101 families. Pathogenic mtDNA mutations were found in 29 of 101 probands (29%), 21 in MTND subunit genes and 8 in mtDNA tRNA genes. Nuclear gene defects were inferred in 38 of 101 (38%) probands based on cell hybrid studies, mtDNA sequencing or mutation analysis (nuclear gene mutations were identified in 22 probands). Leigh or Leigh-like disease was the most common clinical presentation in both mtDNA and nuclear genetic defects. The median age at onset was higher in mtDNA patients (12 months) than in patients with a nuclear gene defect (3 months). However, considerable overlap existed, with onset varying from 0 to >60 months in both groups. Our findings confirm that pathogenic mtDNA mutations are a significant cause of complex I deficiency in children. In the absence of parental consanguinity, we recommend whole mitochondrial genome sequencing as a key approach to elucidate the underlying molecular genetic abnormality.
doi:10.1038/ejhg.2011.18
PMCID: PMC3137493  PMID: 21364701
respiratory chain; complex I; mitochondrial DNA; mutation; genetic counselling
9.  DIFFUSION-WEIGHTED IMAGING TRACTOGRAPHY-BASED PARCELLATION OF THE HUMAN PARIETAL CORTEX AND COMPARISON WITH HUMAN AND MACAQUE RESTING STATE FUNCTIONAL CONNECTIVITY 
Despite the prominence of parietal activity in human neuromaging investigations of sensorimotor and cognitive processes there remains uncertainty about basic aspects of parietal cortical anatomical organization. Descriptions of human parietal cortex draw heavily on anatomical schemes developed in other primate species but the validity of such comparisons has been questioned by claims that there are fundamental differences between the parietal cortex in humans and other primates. A scheme is presented for parcellation of human lateral parietal cortex into component regions on the basis of anatomical connectivity and the functional interactions of the resulting clusters with other brain regions. Anatomical connectivity was estimated using diffusion-weighted magnetic resonance image (MRI) based tractography and functional interactions were assessed by correlations in activity measured with functional MRI (fMRI) at rest. Resting state functional connectivity was also assessed directly in the rhesus macaque lateral parietal cortex in an additional experiment and the patterns found reflected known neuroanatomical connections. Cross-correlation in the tractography-based connectivity patterns of parietal voxels reliably parcellated human lateral parietal cortex into ten component clusters. The resting state functional connectivity of human superior parietal and intraparietal clusters with frontal and extrastriate cortex suggested correspondences with areas in macaque superior and intraparietal sulcus. Functional connectivity patterns with parahippocampal cortex and premotor cortex again suggested fundamental correspondences between inferior parietal cortex in humans and macaques. In contrast, the human parietal cortex differs in the strength of its interactions between the central inferior parietal lobule region and the anterior prefrontal cortex.
doi:10.1523/JNEUROSCI.5102-10.2011
PMCID: PMC3091022  PMID: 21411650
AIP; MIP; LIP; VIP; IPL; SPL
10.  Ventrolateral prefrontal cortex is required for performance of a strategy implementation task but not reinforcer devaluation effects in rhesus monkeys 
The European journal of neuroscience  2009;29(10):2049-2059.
The ability to apply behavioral strategies to obtain rewards efficiently and make choices based on changes in the value of rewards is fundamental to the adaptive control of behavior. The extent to which different regions of prefrontal cortex are required for specific kinds of decisions is not well-understood. We tested rhesus monkeys with bilateral ablations of ventrolateral prefrontal cortex on tasks that required the use of behavioral strategies to optimize the rate with which rewards were accumulated, or to modify choice behavior in response to changes in the value of particular rewards. Monkeys with ventrolateral prefrontal lesions were impaired in performing the strategy-based task, but not on value-based decision making. In contrast, orbital prefrontal ablations produced the opposite impairments in the same tasks. These findings support the conclusion that independent neural systems within the prefrontal cortex are necessary for control of choice behavior based on strategies or on stimulus value.
doi:10.1111/j.1460-9568.2009.06740.x
PMCID: PMC2688497  PMID: 19453635
macaque; monkey; prefrontal cortex; reward; reinforcement; rules
11.  Trends in thyroid hormone prescribing and consumption in the UK 
BMC Public Health  2009;9:132.
Background
Thyroid hormone replacement is one of the most commonly prescribed and cost effective treatments for a chronic disease. There have been recent changes in community prescribing policies in many areas of the UK that have changed patient access to necessary medications. This study aimed to provide a picture of thyroid hormone usage in the UK and to survey patient opinion about current community prescribing policies for levothyroxine.
Methods
Data on community prescriptions for thyroid hormones in England between 1998 and 2007, provided by the Department of Health, were collated and analysed. A survey of UK members of a patient support organisation (the British Thyroid Foundation) who were taking levothyroxine was carried out.
Results
The amount of prescribed thyroid hormones used in England has more than doubled, from 7 to almost 19 million prescriptions, over the last 10 years. The duration of prescriptions has reduced from 60 to 45 days, on average over the same time. Two thousand five hundred and fifty one responses to the patient survey were received. Thirty eight percent of levothyroxine users reported receiving prescriptions of 28 days' duration. 59% of respondents reported being dissatisfied with 28-day prescribing.
Conclusion
Amongst users of levothyroxine, there is widespread patient dissatisfaction with 28-day prescription duration. Analysis of the full costs of 28-day dispensing balanced against the potential savings of reduced wastage of thyroid medications, suggests that this is unlikely to be an economically effective public health policy.
doi:10.1186/1471-2458-9-132
PMCID: PMC2683823  PMID: 19432950
12.  Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal–temporal interaction 
Theories of dorsolateral prefrontal cortex (DLPFC) involvement in cognitive function variously emphasize its involvement in rule implementation, cognitive control, or working and/or spatial memory. These theories predict broad effects of DLPFC lesions on tests of visual learning and memory. We evaluated the effects of DLPFC lesions (including both banks of the principal sulcus) in rhesus monkeys on tests of scene learning and strategy implementation that are severely impaired following crossed unilateral lesions of frontal cortex and inferotemporal cortex. Dorsolateral lesions had no effect on learning of new scene problems postoperatively, or on the implementation of preoperatively acquired strategies. They were also without effect on the ability to adjust choice behaviour in response to a change in reinforcer value, a capacity that requires interaction between the amygdala and frontal lobe. These intact abilities following DLPFC damage support specialization of function within the prefrontal cortex, and suggest that many aspects of memory and strategic and goal-directed behaviour can survive ablation of this structure.
doi:10.1111/j.1460-9568.2008.06353.x
PMCID: PMC2522287  PMID: 18702721
episodic; frontal cortex; macaque; memory; strategy
13.  Dorsolateral prefrontal lesions do not impair tests of scene learning and decision-making that require frontal-temporal interaction 
Theories of dorsolateral prefrontal cortex (DLPFC) involvement in cognitive function variously emphasize its involvement in rule implementation, cognitive control, or working and/or spatial memory. These theories predict broad effects of DLPFC lesions on tests of visual learning and memory. We evaluated the effects of DLPFC lesions (including both banks of the principal sulcus) in rhesus monkeys on tests of scene learning and strategy implementation that are severely impaired following crossed unilateral lesions of frontal cortex and inferotemporal cortex. Dorsolateral lesions had no effect on learning of new scene problems postoperatively, or on the implementation of preoperatively acquired strategies. They were also without effect on the ability to adjust choice behavior in response to a change in reinforcer value, a capacity that requires interaction between the amygdala and frontal lobe. These intact abilities following DLPFC damage support specialization of function within the prefrontal cortex, and suggest that many aspects of memory and strategic and goal-directed behavior can survive ablation of this structure.
doi:10.1111/j.1460-9568.2008.06353.x
PMCID: PMC2522287  PMID: 18702721
episodic; frontal cortex; macaque; memory; strategy
14.  Dissociable performance on scene learning and strategy implementation after lesions to magnocellular mediodorsal thalamic nucleus 
Monkeys with aspiration lesions of the magnocellular division of the mediodorsal thalamus (MDmc) are impaired in object-in-place scene learning, object recognition and stimulus-reward association. These data have been interpreted to mean that projections from MDmc to prefrontal cortex are required to sustain normal prefrontal function in a variety of task settings. In the present study, we investigated the extent to which bilateral neurotoxic lesions of the MDmc impair a pre-operatively learnt strategy implementation task that is impaired by a crossed lesion technique that disconnects the frontal cortex in one hemisphere from the contralateral inferotemporal cortex. Postoperative memory impairments were also examined using the object-in-place scene memory task. Monkeys learnt both strategy implementation and scene memory tasks separately to a stable level pre-operatively. Bilateral neurotoxic lesions of the MDmc, produced by 10 × 1 μl injections of a mixture of ibotenate and N-methyl-D-aspartate did not affect performance in the strategy implementation task. However, new learning of object-in-place scene memory was substantially impaired. These results provide new evidence about the role of the magnocellular mediodorsal thalamic nucleus in memory processing, indicating that interconnections with the prefrontal cortex are essential during new learning but are not required when implementing a preoperatively acquired strategy task. Thus not all functions of the prefrontal cortex require MDmc input. Instead the involvement of MDmc in prefrontal function may be limited to situations in which new learning must occur.
doi:10.1523/JNEUROSCI.1835-07.2007
PMCID: PMC2241732  PMID: 17978029
Mediodorsal thalamus; strategy; episodic memory; amnesia; monkey; prefrontal cortex
15.  Neurotoxic lesions of the medial mediodorsal nucleus of the thalamus disrupt reinforcer devaluation effects in rhesus monkeys 
The mediodorsal thalamus is a major input to the prefrontal cortex and is thought to modulate cognitive functions of the prefrontal cortex. Damage to the medial, magnocellular part of the mediodorsal thalamus (MDmc) impairs cognitive functions dependent on prefrontal cortex, including memory. The contribution of MDmc to other aspects of cognition dependent on prefrontal cortex has not been determined. The ability of monkeys to adjust their choice behavior in response to changes in reinforcer value, a capacity impaired by lesions of orbital prefrontal cortex, can be tested in a reinforcer devaluation paradigm. In the present study, rhesus monkeys with bilateral neurotoxic MDmc lesions were tested in the devaluation procedure. Monkeys learned visual discrimination problems in which each rewarded object is reliably paired with one of two different food rewards, and then were given choices between pairs of rewarded objects, one associated with each food. Selective satiation of one of the food rewards reduces choices of objects associated with that food in normal monkeys. Monkeys with bilateral neurotoxic lesions of MDmc learned concurrently-presented visual discrimination problems as quickly as unoperated control monkeys, but showed impaired reinforcer devaluation effects. This finding suggests that the neural circuitry for control of behavioral choice by changes in reinforcer value includes MDmc.
doi:10.1523/JNEUROSCI.1914-07.2007
PMCID: PMC2242856  PMID: 17942723
amygdala; choice behavior; decision-making; devaluation; medial thalamus; orbitofrontal cortex; prefrontal cortex; reward
16.  Orbital prefrontal cortex is required for object-in-place scene memory but not performance of a strategy implementation task 
The orbital prefrontal cortex is thought to be involved in behavioral flexibility in primates, and human neuroimaging studies have identified orbital prefrontal activation during episodic memory encoding. The goal of the present study was to ascertain whether deficits in strategy implementation and episodic memory that occur after ablation of the entire prefrontal cortex can be ascribed to damage to the orbital prefrontal cortex. Rhesus monkeys were preoperatively trained on two behavioral tasks, performance of both of which is severely impaired by the disconnection of frontal cortex from inferotemporal cortex. In the strategy implementation task, monkeys were required to learn about two categories of objects, each associated with a different strategy that had to be performed to obtain food reward. The different strategies had to be applied flexibly in order to optimize the rate of reward delivery. In the scene memory task, monkeys learned 20 new object-in-place discrimination problems in each session. Monkeys were tested on both tasks before and after bilateral ablation of orbital prefrontal cortex. These lesions impaired new scene learning but had no effect on strategy implementation. This finding supports a role for the orbital prefrontal cortex in memory, but places limits on the involvement of orbital prefrontal cortex in the representation and implementation of behavioral goals and strategies.
doi:10.1523/JNEUROSCI.3369-07.2007
PMCID: PMC2092501  PMID: 17942727
macaque; frontal; rule; learning; category; episodic
17.  Neurotoxic lesions of ventrolateral prefrontal cortex impair object-in-place scene memory 
The European journal of neuroscience  2007;25(8):2514-2522.
Disconnection of the frontal lobe from the inferotemporal cortex produces deficits in a number of cognitive tasks that require the application of memory-dependent rules to visual stimuli. The specific regions of frontal cortex that interact with the temporal lobe in performance of these tasks remain undefined. One capacity that is impaired by frontal-temporal disconnection is rapid learning of new object-in-place scene problems, in which visual discriminations between two small typographic characters are learned in the context of different visually complex scenes. In the present study, we examined whether neurotoxic lesions of ventrolateral prefrontal cortex in one hemisphere, combined with ablation of inferior temporal cortex in the contralateral hemisphere, would impair learning of new object-in-place scene problems. Male macaque monkeys learned 10 or 20 new object-in-place problems in each daily test session. Unilateral neurotoxic lesions of ventrolateral prefrontal cortex produced by multiple injections of a mixture of ibotenate and N-methyl-D-aspartate did not affect performance. However, when disconnection from inferotemporal cortex was completed by ablating this region contralateral to the neurotoxic prefrontal lesion, new learning was substantially impaired. Sham disconnection (injecting saline instead of neurotoxin contralateral to the inferotemporal lesion) did not affect performance. These findings support two conclusions: first, that the ventrolateral prefrontal cortex is a critical area within the frontal lobe for scene memory; and second, the effects of ablations of prefrontal cortex can be confidently attributed to the loss of cell bodies within the prefrontal cortex, rather than to interruption of fibers of passage through the lesioned area.
doi:10.1111/j.1460-9568.2007.05468.x
PMCID: PMC1855623  PMID: 17445247
Macaque; Monkey; Episodic; Memory; Prefrontal
18.  Neurotoxic lesions of ventrolateral prefrontal cortex impair object-in-place scene memory 
The European Journal of Neuroscience  2007;25(8):2514-2522.
Disconnection of the frontal lobe from the inferotemporal cortex produces deficits in a number of cognitive tasks that require the application of memory-dependent rules to visual stimuli. The specific regions of frontal cortex that interact with the temporal lobe in performance of these tasks remain undefined. One capacity that is impaired by frontal–temporal disconnection is rapid learning of new object-in-place scene problems, in which visual discriminations between two small typographic characters are learned in the context of different visually complex scenes. In the present study, we examined whether neurotoxic lesions of ventrolateral prefrontal cortex in one hemisphere, combined with ablation of inferior temporal cortex in the contralateral hemisphere, would impair learning of new object-in-place scene problems. Male macaque monkeys learned 10 or 20 new object-in-place problems in each daily test session. Unilateral neurotoxic lesions of ventrolateral prefrontal cortex produced by multiple injections of a mixture of ibotenate and N-methyl-d-aspartate did not affect performance. However, when disconnection from inferotemporal cortex was completed by ablating this region contralateral to the neurotoxic prefrontal lesion, new learning was substantially impaired. Sham disconnection (injecting saline instead of neurotoxin contralateral to the inferotemporal lesion) did not affect performance. These findings support two conclusions: first, that the ventrolateral prefrontal cortex is a critical area within the frontal lobe for scene memory; and second, the effects of ablations of prefrontal cortex can be confidently attributed to the loss of cell bodies within the prefrontal cortex rather than to interruption of fibres of passage through the lesioned area.
doi:10.1111/j.1460-9568.2007.05468.x
PMCID: PMC1855623  PMID: 17445247
episodic; macaque; memory; monkey; prefrontal
19.  Ventrolateral prefrontal cortex is required for performance of a strategy implementation task but not reinforcer devaluation effects in rhesus monkeys 
The European Journal of Neuroscience  2009;29(10):2049-2059.
The ability to apply behavioral strategies to obtain rewards efficiently and make choices based on changes in the value of rewards is fundamental to the adaptive control of behavior. The extent to which different regions of the prefrontal cortex are required for specific kinds of decisions is not well understood. We tested rhesus monkeys with bilateral ablations of the ventrolateral prefrontal cortex on tasks that required the use of behavioral strategies to optimize the rate with which rewards were accumulated, or to modify choice behavior in response to changes in the value of particular rewards. Monkeys with ventrolateral prefrontal lesions were impaired in performing the strategy-based task, but not on value-based decision-making. In contrast, orbital prefrontal ablations produced the opposite impairments in the same tasks. These findings support the conclusion that independent neural systems within the prefrontal cortex are necessary for control of choice behavior based on strategies or on stimulus value.
doi:10.1111/j.1460-9568.2009.06740.x
PMCID: PMC2688497  PMID: 19453635
macaque; monkey; prefrontal cortex; reinforcement; reward; rules

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