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1.  Inverted-U shaped dopamine actions on human working memory and cognitive control 
Biological psychiatry  2011;69(12):e113-e125.
Brain dopamine has long been implicated in cognitive control processes, including working memory. However, the precise role of dopamine in cognition is not well understood, partly because there is large variability in the response to dopaminergic drugs both across different behaviors and across different individuals. We review evidence from a series of studies with experimental animals, healthy humans and patients with Parkinson’s disease, which highlight two important factors that contribute to this large variability. First, the existence of an optimum dopamine level for cognitive function implicates the need to take into account baseline levels of dopamine when isolating dopamine’s effects. Second, cognitive control is a multi-factorial phenomenon, requiring a dynamic balance between cognitive stability and cognitive flexibility. These distinct components might implicate the prefrontal cortex and the striatum respectively. Manipulating dopamine will thus have paradoxical consequences for distinct cognitive control processes depending on distinct basal or optimal levels of dopamine in different brain regions.
doi:10.1016/j.biopsych.2011.03.028
PMCID: PMC3111448  PMID: 21531388
Working memory; cognitive control; prefrontal cortex; striatum; dopamine; fMRI
2.  Enhanced frontal function in Parkinson’s disease 
Brain  2009;133(1):225-233.
We investigated the role of dopamine in working memory by examining effects of withdrawing dopaminergic medication in patients with Parkinson’s disease. Resistance to distraction during a delayed response task was abnormally enhanced in Parkinson’s disease patients OFF medication relative to controls. Conversely, performance on a backward digit span test was impaired in these same Parkinson’s disease patients OFF medication. Dopaminergic medication reinstated susceptibility to distraction and backward digit span performance, so that performance of Parkinson’s disease patients ON medication did not differ from that of controls. We hypothesize that the enhanced distractor resistance and impaired backward digit span in Parkinson’s disease reflects low dopamine levels in the striatum, and perhaps upregulated frontal dopamine levels. Dopaminergic medication may reinstate distractibility by normalizing the balance between striatal and prefrontal dopamine transmission.
doi:10.1093/brain/awp301
PMCID: PMC2801327  PMID: 19995871
working memory; cognitive deficits; dopamine; Parkinson’s disease; basal ganglia
3.  Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration 
Individual variability in reward-based learning has been ascribed to quantitative variation in baseline levels of striatal dopamine. However, direct evidence for this pervasive hypothesis has hitherto been unavailable. We demonstrate that individual differences in reward-based reversal learning reflect variation in baseline striatal dopamine synthesis capacity, as measured with neurochemical positron emission tomography. Subjects with high baseline dopamine synthesis in the striatum showed relatively better reversal learning from unexpected rewards than from unexpected punishments, whereas subjects with low baseline dopamine synthesis in the striatum showed the reverse pattern. In addition, baseline dopamine synthesis predicted the direction of dopaminergic drug effects. The D2 receptor agonist bromocriptine improved reward- relative to punishment-based reversal learning in subjects with low baseline dopamine synthesis capacity, while impairing it in subjects with high baseline dopamine synthesis capacity in the striatum. Finally, this pattern of drug effects was outcome-specific, and driven primarily by drug effects on punishment-, but not reward-based reversal learning. These data demonstrate that the effects of D2 receptor stimulation on reversal learning in humans depend on task demands and baseline striatal dopamine synthesis capacity.
doi:10.1523/JNEUROSCI.4467-08.2009
PMCID: PMC2940719  PMID: 19193900
dopamine; reward; punishment; striatum; PET; Learning
4.  Biological changes associated with healthy versus pathological aging: A symposium review 
Ageing research reviews  2009;8(2):140-146.
The Douglas Mental Health University Institute, in collaboration with the McGill Centre for Studies in Aging, organized a two day symposium entitled “Biological Changes Associated with Healthy Versus Pathological Aging” that was held in December 13 and 14, 2007 on the Douglas campus. The symposium involved presentations on current trends in aging and dementia research across several sub-disciplines: genetics, neurochemistry, structural and functional neuroimaging and clinical treatment and rehabilitation. The goal of this symposium was to provide a forum for knowledge-transfer between scientists and clinicians with different specializations in order to promote cross-fertilization of research ideas that would lead to future collaborative neuroscience research in aging and dementia. In this review article we summarize the presentations made by the thirteen international scientists at the symposium and highlight: (i) past research, and future research trends in neuroscience of aging and dementia and (ii) links across levels of analysis that can lead to fruitful transdisciplinary research programs that will advance knowledge about the neurobiological changes associated with healthy aging and dementia.
doi:10.1016/j.arr.2009.01.003
PMCID: PMC2671241  PMID: 19274854
healthy aging; dementia; hippocampus; prefrontal cortex; amyloid deposition; MRI; volumetry; dopamine
5.  Prefrontal contributions to domain-general executive control processes during temporal context retrieval 
Neuropsychologia  2007;46(4):1088-1103.
Neuroimaging studies have reported increased prefrontal cortex (PFC) activity during temporal context retrieval versus recognition memory. However, it remains unclear if these activations reflect PFC contributions to domain-general executive control processes or domain-specific retrieval processes. To gain a better understanding of the functional roles of these various PFC regions during temporal context retrieval we propose it is necessary to examine PFC activity across tasks from different domains, in which parallel manipulations are included targeting specific cognitive processes. In the current fMRI study, we examined domain-general and domain-specific PFC contributions to temporal context retrieval by increasing stimulus (but maintaining response number) and increasing response number (but maintaining stimulus number) across temporal context memory and ordering control tasks, for faces. The control task required subjects to order faces from youngest to oldest. Our behavioral results indicate that the combination of increased stimulus and response numbers significantly increased task difficulty for temporal context retrieval and ordering tasks. Across domains, increasing stimulus number, while maintaining response numbers, caused greater right lateral premotor cortex (BA 6/8) activity; whereas increasing response number, while maintaining stimulus number, caused greater domain-general left DLPFC (BA 9) and VLPFC (BA 44/45) activity. In addition, we found domain-specific right DLPFC (BA 9) activity only during retrieval events. These results highlight the functional heterogeneity of frontal cortex, and suggest its involvement in temporal context retrieval is related to its role in various cognitive control processes.
doi:10.1016/j.neuropsychologia.2007.10.023
PMCID: PMC2703612  PMID: 18155254
episodic memory; working memory; selection; monitoring; face stimuli; fMRI
6.  Eosinophilia-myalgia syndrome: selective cognitive impairment, longitudinal effects, and neuroimaging findings 
OBJECTIVE—To identify the specific nature of the neurocognitive impairments of eosinophilia-myalgia syndrome (EMS) in an unselected population, and to present longitudinal patterns.
METHODS—A consecutive sample of 23 patients with EMS and 18 age and education matched control subjects were assessed on a comprehensive neuropsycho- logical battery. Longitudinal results were gathered from six patients.
RESULTS—Neurocognitive impairments were found which represent a subset of deficits reported in previous group and case study reports. Deficits were limited to complex visual memory, conceptual set shifting, and attention, which suggest a selective dysexecutive syndrome. The motor slowing and verbal memory deficits previously reported were not found. Although depression, fatigue, sleep deprivation, and pain were significant symptoms, they were unassociated with deficits with the exception of an association of depression with one deficit. There was no pattern of overall decline over time in a subset of the group, although considerable heterogeneity in the longitudinal patterns of neurocognitive tests was found. Abnormalities of white matter appeared in the MRI of eight of 12patients.
CONCLUSIONS—The neurocognitive and neuroimaging findings contribute to the evidence which indicates that the neural substrate of EMS is white matter damage.


PMCID: PMC2169832  PMID: 9408106
7.  Constraints on the cerebral basis for semantic processing from neuroimaging studies of Alzheimer's disease 
OBJECTIVE—Functional activation studies of semantic processing in healthy adults have yielded conflicting results. The purpose was to evaluate the relative role of the brain regions implicated in semantic processing with converging evidence from imaging studies of patients with impaired semantic processing.
METHODS—Semantic memory was assessed in patients with Alzheimer's disease using two measures, and these performance patterns were related to profiles of reduced cerebral functioning obtained with high resolution single photon emission computed tomography (SPECT). Patients with frontotemporal degeneration were similarly evaluated as a control group.
RESULTS—Reduced relative cerebral perfusion was seen in parietal and posterior temporal brain regions of patients with Alzheimer's disease but not patients with frontotemporal degeneration. Impairments on semantically guided category membership decision tasks were also seen in patients with Alzheimer's disease but not those with frontotemporal degeneration. Performance on the semantic measures correlated with relative cerebral perfusion in inferior parietal and superior temporal regions of the left hemisphere only in Alzheimer's disease. Relative perfusion was significantly lower in these regions in patients with Alzheimer's disease with semantic difficulty compared with patients with Alzheimer's disease with relatively preserved semantic processing.
CONCLUSION—These findings provide converging evidence to support the contribution of superior temporal and inferior parietal regions of the left hemisphere to semantic processing.


PMCID: PMC2169652  PMID: 9285450
8.  At least three human homeoboxes on chromosome 12 belong to the same transcription unit. 
Nucleic Acids Research  1988;16(12):5379-5390.
Mammalian homeoboxes show a clustered chromosomal organization. In the mouse, at least seven homeoboxes on chromosome 6 and at least six on chromosome 11 identify the murine Hox-1 and Hox-2 loci, respectively. A number of homeoboxes on chromosome 7 define the human HOX-1 locus and homeoboxes on chromosome 17 define the human HOX-2 locus. We studied the genomic organization of three homeobox sequences of the HOX-3 locus on chromosome 12 and analyzed transcripts from this region. Structural characterization and sequencing of several cDNA clones reveal that the three homeobox sequences present in this chromosomal region identify a single transcription unit. Primary transcripts are alternatively processed to give mature messengers with a common 5' noncoding exon encoding different proteins containing one of the three homeodomains.
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PMCID: PMC336773  PMID: 2898768
9.  The human HOX gene family. 
Nucleic Acids Research  1989;17(24):10385-10402.
We report the identification of 10 new human homeobox sequences. Altogether, we have isolated and sequenced 30 human homeoboxes clustered in 4 chromosomal regions called HOX loci. HOX1 includes 8 homeoboxes in 90 kb of DNA on chromosome 7. HOX2 includes 9 homeoboxes in 180 kb on chromosome 17. HOX3 contains at least 7 homeoboxes in 160 kb on chromosome 12. Finally, HOX4 includes 6 homeoboxes in 70 kb on chromosome 2. Homeodomains obtained from the conceptual translation of the isolated homeoboxes can be attributed to 13 homology groups on the basis of their primary peptide sequence. Moreover, it is possible to align the 4 HOX loci so that corresponding homeodomains in all loci share the maximal sequence identity. The complex of these observations supports and extends an evolutionary hypothesis concerning the origin of mammalian and fly homeobox gene complexes. We also determined the coding region present in 3 HOX2 cDNA clones corresponding to HOX2G, HOX2H and HOX2I.
PMCID: PMC335308  PMID: 2574852
10.  Isolation and mapping of EVX1, a human homeobox gene homologous to even-skipped, localized at the 5' end of HOX1 locus on chromosome 7. 
Nucleic Acids Research  1991;19(23):6541-6545.
We isolated and mapped the human homeobox gene EVX1. This gene encodes a protein of 407 amino acid residues containing a homeodomain closely related to the Drosophila even-skipped (eve) segmentation gene of the pair-rule class. EVX1 belongs to a small family of vertebrate eve-related homeobox genes including human EVX1 and EVX2 genes, their murine homologs, Evx 1 and Evx 2, and the frog Xhox-3 gene. We previously reported that EVX2 is localized at the 5' end of the HOX4 locus on chromosome 2. We show here that EVX1 is localized at the 5' end of the HOX1 locus on chromosome 7, 48 kb upstream from the most 5' of the eleven HOX1 genes, namely HOX1J. Both EVX genes are transcribed in an opposite orientation as compared to that of adjacent HOX genes. Human HOX1 and HOX4 complex loci appear to be both closely linked to a homeobox gene of the EVX family.
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PMCID: PMC329215  PMID: 1684419
11.  PCR-based immortalization and screening of hierarchical pools of cDNAs. 
Nucleic Acids Research  1994;22(22):4806-4809.
Starting from sequences of at least 60 bp, PCR-based screening has been developed to recover cDNAs from libraries without the necessity for hybridization or extensive DNA extraction steps. The method maintains the indefinite availability of even scarce cDNA libraries and provides an estimate of the relative abundance of the mRNA species. Isolation of a cDNA clone can be done in less than a week. cDNAs were isolated that were cognate for fragments of expressed sequences and for an exon predicted from genomic sequence.
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PMCID: PMC308534  PMID: 7984433

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