Dopamine, Salience, and Response Set Shifting in Prefrontal Cortex.

Dopamine is implicated in multiple functions, including motor execution, action learning for hedonically salient outcomes, maintenance, and switching of behavioral response set. Here, we used a novel within-subject psychopharmacological and combined functional neuroimaging paradigm, investigating the interaction between hedonic salience, dopamine, and response set shifting, distinct from effects on action learning or motor execution. We asked whether behavioral performance in response set shifting depends on the hedonic salience of reversal cues, by presenting these as null (neutral) or salient (monetary loss) outcomes. We observed marked effects of reversal cue salience on set-switching, with more efficient reversals following salient loss outcomes. L-Dopa degraded this discrimination, leading to inappropriate perseveration. Generic activation in thalamus, insula, and striatum preceded response set switches, with an opposite pattern in ventromedial prefrontal cortex (vmPFC). However, the behavioral effect of hedonic salience was reflected in differential vmPFC deactivation following salient relative to null reversal cues. l-Dopa reversed this pattern in vmPFC, suggesting that its behavioral effects are due to disruption of the stability and switching of firing patterns in prefrontal cortex. Our findings provide a potential neurobiological explanation for paradoxical phenomena, including maintenance of behavioral set despite negative outcomes, seen in impulse control disorders in Parkinson's disease.

Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways.

Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6-hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons.

Inferring subjective states through the observation of actions.

Estimating another person's subjective confidence is crucial for social interaction, but how this inference is achieved is unknown. Previous research has demonstrated that the speed at which people make decisions is correlated with their confidence in their decision. Here, we show that (i) subjects are able to infer the subjective confidence of another person simply through the observation of their actions and (ii) this inference is dependent upon the performance of each subject when executing the action. Crucially, the latter result supports a model in which motor simulation of an observed action mediates the successful understanding of other minds. We conclude that kinematic understanding allows access to the higher-order cognitive processes of others, and that this access plays a central role in social interactions.

Sex differences in cognitive performance and alcohol consumption in High Alcohol-Drinking (HAD-1) rats.

Excessive alcohol (ethanol) consumption negatively impacts social, emotional, as well as cognitive function and well-being. Thus, identifying behavioral and/or biological predictors of excessive ethanol consumption is important for developing prevention and treatment strategies against alcohol use disorders (AUDs). Sex differences in alcohol consumption patterns are observed in humans, primates, and rodents. Selectively bred high alcohol-drinking rat lines, such as the "HAD-1" lines are recognized animal models of alcoholism. The present work examined sex differences in alcohol consumption, object recognition, and exploratory behavior in male and female HAD-1 rats. Naïve male and female HAD-1 rats were tested in an object recognition test (ORT) prior to a chronic 24 h intermittent ethanol access procedure for five weeks. Object recognition parameters measured included exploratory behavior, object investigation, and time spent near objects. During the initial training trial, rearing, active object investigation and amount of time spent in the object-containing section was significantly greater in female HAD-1 rats compared to their male counterparts. During the subsequent testing trial, time spent in the object-containing section was greater in female, compared to male, rats; but active object investigation and rearing did not statistically differ between females and males. In addition, female HAD-1 rats consumed significantly more ethanol than their male counterparts, replicating previous findings. Moreover, across all animals there was a significant positive correlation between exploratory behavior in ORT and ethanol consumption level. These results indicate there are significant sex differences in cognitive performance and alcohol consumption in HAD-1 rats, which suggests neurobiological differences as well.

Low dose rotenone treatment causes selective transcriptional activation of cell death related pathways in dopaminergic neurons in vivo.

Mitochondrial complex I inhibition has been implicated in the degeneration of midbrain dopaminergic (DA) neurons in Parkinson's disease. However, the mechanisms and pathways that determine the cellular fate of DA neurons downstream of the mitochondrial dysfunction have not been fully identified. We conducted cell-type specific gene array experiments with nigral DA neurons from rats treated with the complex I inhibitor, rotenone, at a dose that does not induce cell death. The genome wide screen identified transcriptional changes in multiple cell death related pathways that are indicative of a simultaneous activation of both degenerative and protective mechanisms. Quantitative PCR analyses of a subset of these genes in different neuronal populations of the basal ganglia revealed that some of the changes are specific for DA neurons, suggesting that these neurons are highly sensitive to rotenone. Our data provide insight into potentially defensive strategies of DA neurons against disease relevant insults.

Behavioral effects of dopaminergic agonists in transgenic mice overexpressing human wildtype alpha-synuclein.

Overexpression of alpha-synuclein causes familial Parkinson's disease and abnormal aggregates of the protein are present in sporadic cases of the disease. We have examined the behavioral effects of direct and indirect dopaminergic agonists in transgenic mice expressing human alpha-synuclein under the Thy-1 promoter (Thy1-aSyn, alpha-synuclein overexpressor), which exhibit progressive impairments in behavioral tests sensitive to nigrostriatal dopamine dysfunction. Male Thy1-aSyn and wild-type mice received vehicle, benserazide/L-DOPA (25 mg/kg, i.p.), high (2 mg/kg, s.c.) and low doses (0.125, 0.25, 0.5 mg/kg, s.c.) of apomorphine, and amphetamine (5 mg/kg, i.p.), beginning at 3 months of age, and were tested on the challenging beam, spontaneous activity, pole test, and gait. l-DOPA had a paradoxical effect and worsened the deficits in Thy1-aSyn mice compared with controls, whereas the high dose of apomorphine only produced few deficits above those already present in Thy1-aSyn. In contrast to wild-type mice, Thy1-aSyn mice did not show amphetamine-induced stereotypies. The results indicate that chronic overexpression of alpha-synuclein led to abnormal pharmacological responses in mice.

DAMGO and DPDPE facilitation of brain stimulation reward thresholds is blocked by the dopamine antagonist cis-flupenthixol.

The role of dopamine neurotransmission in opioid reward was investigated using a rate-independent measure for determining brain stimulation reward (BSR) thresholds. Intra-accumbens infusions of the mu- and delta-specific peptides, D-Ala2, N-Me-Phe4, Gly-ol5-Enkephalin and D-Pen2, D-Pen5-Enkephalin caused significant lowering of BSR thresholds. The dopamine D1/D2 antagonist, cis-flupenthixol, blocked these effects at a dose that did not significantly alter thresholds when given alone. These data suggest both mu- and delta-opioid potentiation of BSR is dopamine dependent.

CNS plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury.

We have reviewed a battery of useful tests for evaluating sensorimotor function and plasticity acutely and chronically in unilateral rat models of central nervous system injury. These tests include forelimb use for weight shifting during vertical exploration in a cylindrical enclosure, an adhesive removal test of sensory function, and forelimb placing. These tests monitor recovery of sensorimotor function independent of the extent of test experience. Data are presented for four models, including permanent focal ischemia, focal injury to the forelimb area of sensorimotor cortex, dopaminergic neurodegeneration of the nigrostriatal system, and cervical spinal cord injury. The effect of the dendrite growth promoting factor, Osteogenic Protein-1 (OP-1) on outcome following permanent middle cerebral artery (MCA) occlusion was used as an example to illustrate how the tests can be applied preclinically. OP-1 showed a beneficial effect on limb use asymmetry in the cylinder test.

Triple endoscopy: a neglected essential in head and neck cancer.

Surgeons are sometimes embarrassed to discover a second unanticipated cancer while focusing attention on an already evident cancer in the head and neck area, the bronchus, or the esophagus. we began in October, 1976, to do direct laryngoscopy, esophagoscopy, and bronchoscopy on each of the 134 cases admitted to our unit with suspected head and neck cancer. In 10 of the 134 patients in whom triple endoscopy was done, no malignancy was found. Of 24 of 124 (20%) patients with head and neck cancer, 16 patients (13%) had synchronous carcinoma and eight patients (7%) had metachronous carcinoma in this 2-year period. The incidence can be expected to rise steadily with time and mandates "triple endoscopy" on all patients with a suspected cancer in the head and neck area, the bronchus, or the esophagus, as these structures form a closely related unstable field. The discovery of several patients with dysplastic mucosal changes, carcinoma in situ, or very early invasive cancer, not only of the head and neck but also of the esophagus and bronchus, presents new problems of management.

Prefrontal cortex infusions of SCH 23390 cause immediate and delayed effects on ventral tegmental area stimulation reward.

A reward-relevant relationship between dopamine projection regions of the ventral tegmental area (VTA) was investigated through the use of brain stimulation reward (BSR) thresholds. Using a rate-free method, changes in VTA BSR thresholds were determined after intracranial injections of the dopamine D1 antagonist, SCH 23390 into the prefrontal cortex (PFC), or the nucleus accumbens (NAcc). Reward thresholds assessed immediately after the infusion of SCH 23390 into the NAcc (0.5 microgram/0.5 microliter/side) were significantly higher than those assessed just after saline infusions, indicating a drug-induced attenuation of the rewarding effects of the brain stimulation. The effects of this dose subsided when tested 24 h later. Conversely, intra-PFC infusions of SCH 23390 at the same dose (0.5 microgram/0.5 microliter/side) resulted in lowered BSR thresholds when rats were tested immediately after infusion. In addition, animals tested 24 h after receiving the lowest dose (0.125 microgram/0.5 microliter/side) demonstrated a robust delayed threshold-lowering effect. These immediate and delayed effects of the intra-PFC dopamine antagonist demonstrate a facilitation of VTA BSR and are consistent with the view that PFC dopamine serves a modulatory role over important reward elements within the NAcc. The deferred effects of intra-prefrontal cortex DA receptor blockade on brain stimulation reward thresholds may reflect adaptive responses of subcortical structures to changes in PFC dopamine neurotransmission. It has been suggested that neural adjustments of this type may underlie long term changes in central nervous system functioning brought about by disease, drug use or behavioral conditioning.

The effect of hypothalamic peptide YY on hippocampal acetylcholine release in vivo: implications for limbic function in binge-eating behavior.

Central injection of peptide YY (PYY) in sated rats produces the most powerful stimulating effect of food intake known to date. The neural mechanisms by which PYY regulates appetite are not clear but may be important because abnormal levels of PYY have been implicated in the neurobiology of bulimia nervosa. Interactions between brain acetylcholine (ACh) and PYY had not been studied. Therefore, the present experiments were designed to explore the in vivo release of ACh from the hippocampus (HPC) of rats in response to hypothalamic infusion of PYY. Hippocampal ACh release was found to increase 400% in response to 10 microg PYY. In a separate experiment, blockade of the same area of the HPC with bilateral intracerebral injections of 3.5 microg scopolamine did not affect intake stimulated by intrahypothalamic injection of 4 microg PYY. Furthermore, a third experiment showed, for the first time, that PYY (2.5-10.0 microg) can elicit robust feeding when infused directly into the HPC. The significance of these findings to the activation of limbic functions such as memory, reinforcement, and obsessional processes that accompany human binge-eating syndromes is discussed.

Involvement of delta- and mu-opioid receptors in the potentiation of brain-stimulation reward.

A rate-free method of determining brain-stimulation reward thresholds was used to identify the rewarding effects of the delta-opioid receptor and mu-opioid receptor agonist peptides, [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Ala2-MePhe4-Gly(o1)5]enkephalin (DAMGO). The nucleus accumbens-delivered opioid receptor agonists produced marked lowering of the threshold for ventral tegmental area brain-stimulation reward. No change in baseline thresholds was seen after peripheral administration of the nonpeptide delta-opioid receptor antagonist, naltrindole. However, an unexpected finding was that naltrindole blocked the threshold-lowering effects of both DPDPE and DAMGO. These data demonstrate nucleus accumbens activation of delta- and mu-opioid receptors and ventral tegmental area brain-stimulation reward share common brain substrates. In addition, the interference of both delta- and mu-opioid receptor mediated reward by naltrindole may have implications for therapeutic use.

Partial laryngectomy: analysis of associated swallowing disorders.

Evaluation of postoperative swallowing ability in thirty-eight patients having had partial laryngectomy indicates that there are marked differences in the degree of dysphagia among individuals with similar surgical defects. This variation in swallowing disability, however, appears to have definable limits. Rehabilitation is possible for many patients disabled by postoperative dysphagia. A transoral surgical technic for reconstruction of the obliterated pyriform sinus is described.

Amino-terminal pro-brain natriuretic peptide in normal and hypertensive pregnancy.

OBJECTIVES: To investigate serum levels of amino-terminal pro-brain natriuretic peptide (Nt pro-BNP) as an index of left-ventricular function in normal pregnancy and pregnancies complicated by hypertension and also to investigate levels in both primigravid and multigravid women. METHODS: Women with hypertension in pregnancy (at least two readings of systolic blood pressure > 140 mm Hg and diastolic blood pressure > 90 mm Hg) (n = 24) and normotensive women (n = 42) were included in the study. Serum Nt pro-BNP was measured using an enzyme-linked immunosorbent assay technique. RESULTS: The median serum Nt pro-BNP level in pregnancies complicated by hypertension was 420 fmol/L, which was significantly greater than that measured in samples obtained from normotensive women in pregnancy (340 fmol/L) (p = 0.03). There was a nonsignificant trend toward increased levels in proteinuric as compared to nonproteinuric hypertension in pregnancy. Multigravida had higher Nt pro-BNP levels (n = 26; median Nt pro-BNP = 358 fmol/L) than primigravida (n = 16; median Nt pro-BNP = 278 fmol/L) (p = 0.01) in association with normal pregnancy. Multigravida also demonstrated a dramatic rise in serum Nt pro-BNP levels in association with hypertension in pregnancy (n = 13; median Nt pro-BNP = 572 fmol/L) as compared to normal pregnancy (n = 26; median Nt pro-BNP = 358 fmol/L) (p = 0.009). CONCLUSION: Serum Nt pro-BNP is elevated in women with hypertensive disorders of pregnancy, indicating elevated left-ventricular filling pressures. Measured serum levels in both normal and hypertensive pregnancy are higher in multigravida than in primigravida.

The role of cardiac troponin I in determining the necessity for exercise electrocardiography in low risk patients with chest pain.

BACKGROUND: Assessment of non-cardiac chest pain places a considerable burden on healthcare resources. The current practice of serial electrocardiographs (ECGs), serum creatinine phosphokinase and by pre-discharge exercise electrocardiography gives an average in-hospital stay of 3.7 days. AIMS: This study assess the use of a sensitive assay for cardiac troponin I (cTnI) to identify a low risk group for whom exercise ECG may not be indicated. METHOD: Ninety-five patients with acute chest pain and with peak cTnI < 0.1 ng/ml and a non-diagnostic resting ECG were studied. Patients were divided into two groups. Group one had normal range cTnI (< 0.03 ng/ml). Group two had minimal elevation of cTnI (0.03-0.099 ng/ml). Average follow-up was 172 days. RESULTS: Nineteen patients had minimal elevation in cTnI of whom five developed significant ST shift on exercise and five had adverse events. No patient with a normal range cTnI had a positive stress test and none suffered an adverse event (p < 0.001). CONCLUSION: CTnI in the normal range can identify patients with acute chest pain who have a negligible event rate and for whom exercise electrocardiography is not required.

Behavioral and histopathological consequences of paraquat intoxication in mice: effects of alpha-synuclein over-expression.

Genetic variability in the alpha-synuclein gene and long-term exposure to the pesticide paraquat constitute possible risk factors for sporadic Parkinson's disease. The goal of the present study was to further characterize the effects of paraquat in mice as a model of Parkinson's disease and to determine whether it acted synergistically with alpha-synuclein over-expression to cause nigrostriatal cell death or dysfunction. Paraquat (10 mg/kg i.p.) was administered once a week for 3 weeks to mice over-expressing human alpha-synuclein under the Thy1 promoter and their wild-type littermates. The effect of paraquat on catecholaminergic neurons was reminiscent of that of Parkinson's disease, with preferential loss of dopaminergic neurons in the ventral tier of the substantia nigra pars compacta and loss of tyrosine hydroxylase staining in the locus coeruleus. alpha-Synuclein over-expression did not increase paraquat-induced cell loss, and paraquat did not worsen the behavioral deficits observed in the transgenic mice. However, paraquat markedly increased proteinase-K-resistant alpha-synuclein aggregates in substantia nigra of the transgenic mice. The data further validate the use of paraquat to model Parkinson's disease in mice and show that although paraquat and alpha-synuclein over-expression act synergistically to increase protein aggregation in vivo, this interaction does not result in short-term neuroprotection or increased vulnerability of nigrostriatal neurons.

Feeding device for glossectomy patients.

Instructions are provided for making a feeding spoon from a plastic syringe for use by patients who have had a glossectomy. This adaptation may be accomplished using only a hacksaw blade and sandpaper. Such a device may be indicated for patients who have had at least 60% of their tongue resected, but who are not at significant risk of aspiration.

Cardiac troponins in suspected acute coronary syndrome: a meta-analysis of published trials.

We performed a meta-analysis of published trials to determine the predictive value of cardiac troponin I (cTnI) and T (cTnT) levels for adverse events (death and myocardial infarction) in acute coronary syndrome without ST elevation (ACS). The accumulated odds ratio (OR) for adverse events (30 days) in ACS with elevated cTnI (n = 5,759) and cTnT (n = 5,483) was 4.9 (95% confidence interval, CI, 3.9-6.2) and 4.6 (95% CI 3.8-5.5), respectively. Trials that mandated timed serum sampling (6 or more hours after symptom onset) had an improved predictive value for elevated cTnI (n = 2,807, OR 8.8; 95% CI 5.9-13.2) and cTnT (n = 1,990, OR 8.5; 95% CI 5.9-12.5). In conclusion, cTnI and cTnT provide similar information in ACS. The risk of adverse events is 4-fold higher in patients with suspected ACS and elevated serum cTn. For patients with an elevated timed (6-hour) sample the risk is over 8-fold higher.