Effectiveness of Three-Dimensional Multiple-Object Tracking in Patients with Multiple Sclerosis: A Pilot Trial.

BACKGROUND: Computerized cognitive training remains an attractive supplemental modality to enhance rehabilitation in multiple sclerosis (MS). The objective of the present study was to assess the usability of three-dimensional multiple-object tracking (3D-MOT) in patients with MS. METHODS: In this pilot study, 16 patients with relapsing-remitting MS and nine age-matched controls participated in four 30-minute training sessions of 3D-MOT. Computerized neuropsychological tests, including driving readiness (ie, Useful Field of View) and cognitive function (ie, Stroop Color and Word Test, Paced Visual Serial Addition Test, Symbol Digit Modalities Test) were conducted at baseline and at the conclusion of training. RESULTS: Although scoring lower in 3D-MOT, the MS group improved their 3D-MOT scores in similar magnitude as the control group. The 3D-MOT training led to significant improvements in driving readiness in the MS group. Taken together, 3D-MOT training showed similar effectiveness in patients with MS as in age-matched controls. CONCLUSIONS: Training with 3D-MOT may be an accessible and remotely administrable supplement to cognitive rehabilitation protocols for patients with MS.

The Impact on Central Blood Pressure and Arterial Stiffness Post Renal Denervation in Patients With Stage 3 and 4 Chronic Kidney Disease: The Prairie Renal Denervation Study.

BACKGROUND: Central aortic blood pressures and arterial stiffness are better indicators of cardiovascular outcomes than brachial blood pressures. However, their response to renal denervation (RDN) in patients with stage 3 and stage 4 chronic kidney disease (CKD) has not yet been examined. OBJECTIVE: To evaluate the impact of RDN on central blood pressures, brachial (office and ambulatory) blood pressures, arterial stiffness, glomerular filtration rate (GFR), 24-hour urine protein, and selective cardiac parameters observed on echocardiograms. DESIGN: Single-center, single-arm with pre-RDN/post-RDN follow-up. SETTING: Patients are being recruited from the multidisciplinary CKD clinic. PATIENTS: Fifty consecutive patients with stage 3 or stage 4 CKD and resistant hypertension, with no radiological or laboratory evidence of secondary causes of hypertension. MEASUREMENTS: The key measurements are central blood pressures, pulse wave velocity, ambulatory 24-hour blood pressure, office blood pressures on BP Tru, GFR, 24-hour urine protein and sodium, blood pressure medication, and doses. METHODS: For our primary outcome, we will compare changes in central blood pressures from baseline to 6 months post RDN using a paired t test or Mann-Whitney U test. Secondary outcomes will examine changes in central blood pressures from baseline to 3, 12, 18, and 24 months post RDN as well as changes in office pressures, GFR, 24-hour urine protein and sodium, and medications at all time points using mixed-model analyses of variance or Friedman test. Multiple regression may be used to control for potential covariates. LIMITATIONS: Single-center study, with no sham arm. CONCLUSIONS: Aortic blood pressure, rather than brachial blood pressure, optimally reflects the load placed on the left ventricle. Aortic blood pressure is also better associated with cardiovascular outcomes. If our study shows a preferential decrease in central blood pressures and improvements in cardiac parameters on echocardiograms post RDN, this may influence the way in which blood pressures are managed in clinics and offices. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01832233).

CONTEXTE: La mesure de la pression centrale et de la rigidité artérielle sont de meilleurs indicateurs de troubles cardiovasculaires que la mesure de la pression sanguine par l'artère brachiale. Cependant, leur réponse à une dénervation rénale chez les patients atteints d'insuffisance rénale chronique (IRC) de stade 3 et 4 n'a pas encore été étudiée. OBJECTIF DE L'ÉTUDE: Évaluer l'effet d'une dénervation rénale sur les mesures de la pression artérielle centrale et brachiale (par le médecin ou ambulatoire), sur la rigidité artérielle, le débit de filtration glomérulaire (DFG), le taux de protéines dans les urines sur une période de 24 heures, de même que sur les paramètres cardiaques sélectifs observés sur les échocardiogrammes. TYPE D'ÉTUDE: Une étude à une seule branche avec un suivi des patients avant et après la dénervation rénale. CADRE DE L'ÉTUDE: Les patients sont recrutés au sein d'une clinique multidisciplinaire spécialisée dans les soins offerts aux personnes atteintes d'IRC. PATIENTS: Cinquante patients atteints à la fois d'IRC de stade 3 ou de stade 4 et d'hypertension résistante, et pour qui il n'existe aucun signe radiologique ou biochimique de causes secondaires de l'hypertension. MESURES: Les principaux paramètres qui seront analysés sont la pression centrale, la vélocité de l'onde de pouls, la pression artérielle mesurée par le patient lui-même (ambulatoire) sur une période de 24 heures, la pression sanguine mesurée par BP Tru dans le bureau du médecin, le DFG, le taux de protéines et de sodium dans les urines sur 24 heures, de même que la liste des médicaments prescrits pour traiter l'hypertension et les doses correspondantes. MÉTHODOLOGIE: Pour atteindre notre objectif principal, nous allons comparer les variations de la valeur de la pression centrale mesurée six mois après la dénervation rénale par rapport à la valeur initiale. Cette comparaison sera effectuée à l'aide d'un test T jumelé ou d'un test U de Mann-Whitney. Les résultats secondaires examineront les variations observées dans la mesure de la pression centrale initiale par rapport aux mesures faites à 3, 12, 18 et 24 mois après la dénervation rénale. On analysera également les variations dans les valeurs de la pression artérielle mesurées au bureau du médecin, dans les valeurs de DFG et dans les taux de protéines et de sodium mesurés dans les urines sur 24 heures. Tout au long de l'étude, les changements dans la médication seront analysés en utilisant le modèle mixte d'ANOVA ou le Test de Friedman. Un modèle de régression multiple pourrait aussi être utilisé pour tenir compte des possibles covariables. LIMITE DE L'ÉTUDE: Les résultats seront limités par le fait qu'il s'agit d'une étude à une seule branche et qu'elle se tiendra dans un seul établissement. CONCLUSIONS: La mesure de la pression centrale reflète, mieux que la mesure de la pression de l'artère brachiale, la charge imposée au ventricule gauche. La pression sanguine à la sortie de l'aorte est également associée de façon plus spécifique aux troubles cardiovasculaires. Si notre étude montre une diminution préférentielle de la pression centrale et une amélioration des paramètres cardiaques observés sur les échocardiogrammes pratiqués, ces résultats seraient susceptibles d'influencer la façon dont la pression artérielle est prise en charge dans les cliniques et les bureaux de médecins.

Renal Denervation in Patients With Loin Pain Hematuria Syndrome.

Loin pain hematuria syndrome (LPHS) is a painful and incapacitating condition that typically affects young women. Treatment options, including opiates and/or surgical denervation of the renal nerves by autotransplantation, have variable success. In this report, we describe the successful use of endovascular renal nerve ablation in this population. Four women with LPHS and intractable pain unresponsive to conservative measures underwent endovascular ablation of the renal nerves between July and November 2015 using the Vessix renal denervation system. The number and frequency of pain medications and responses to the EQ-5D, McGill Pain Questionnaire, Geriatric Depression Score, 36-Item Short-Form Health Survey, and Oswestry Disability Index were measured at baseline and 3 and 6 months postprocedure to evaluate changes in pain, disability, quality of life, and mood. There were improvements in pain, disability, and quality of life from baseline to 6 months postprocedure. By 6 months, 2 of 4 patients had discontinued all pain medications, whereas the other 2 had reduced their doses of these medications by 75%. These results suggest that percutaneous catheter-based renal nerve ablation with radiofrequency energy may be a treatment option for some patients with LPHS.

Parvovirus leading to thrombotic microangiopathy in a healthy adult.

A healthy 47-year-old man initially presented with symptoms of body rash, myalgias, dark urine, nausea and vomiting. Acute kidney injury, and positive urine analysis for blood and protein warranted a kidney biopsy, which revealed micro thrombi in kidney vasculature, suggestive of thrombotic microangiopathy. Serology revealed positive parvovirus B19 IgM antibodies and biopsy tests revealed a viral genome on PCR. Despite plasma exchanges and treatment with rituximab, renal function continued to deteriorate to end-stage renal disease.

Bone mineral density screening and its accordance with Canadian clinical practice guidelines from 2000-2013: an unchanging landscape in Saskatchewan, Canada.

UNLABELLED: We examined the clinical characteristics of patients who underwent initial dual energy X-ray absorptiometry (DXA) testing at a primary care facility from 2000 to 2013, and whether these factors changed over time in accordance with Canadian clinical practice guidelines. The burden of osteoporosis remains high and largely unchanged and clinical practice guidelines are not being followed, overall. PURPOSE: This study examined the clinical risk factors, therapeutic health behaviors, and bone mineral density (BMD) status of patients who underwent initial DXA testing at a primary care facility in Saskatchewan, Canada, and whether these factors changed over time from 2000 to 2013 in accordance with Canadian clinical practice guidelines. METHODS: We conducted a retrospective cross-sectional medical chart audit of 800 patients 50 years of age and older who underwent their first DXA test to assess BMD status. Data was extracted from 2000 to 2013 and further stratified into four periods (2000-2001, 2002-2006, 2007-2009, and 2010-2013; n = 200 each period) based on the years when practice guidelines were implemented. Extracted data included BMD outcomes, clinical risk factor indicators for DXA testing, and recommendations for therapeutic health behaviors outlined in the clinical practice guidelines. RESULTS: There were no differences in BMD status across the four time stratas (p = 0.430). Overall, most clinical risk factors had little change over time. The number of males screened significantly increased over time (p < 0.05), and osteoporosis drug therapy use decreased from 2000-2001 to 2010-2013 (p < 0.001). Increasing age, body mass <60 kg, and history of adult fracture were significant independent predictors of osteoporosis diagnosis. CONCLUSIONS: The burden of osteoporosis remains high and largely unchanged in Saskatchewan, Canada. These results serve to inform strategies to enhance health-care provider awareness and compliance with practice guidelines, as well as improve screening rates and patient health behaviors.

Validating a scoring tool to predict acute kidney injury (AKI) following cardiac surgery.

BACKGROUND: Acute kidney injury (AKI) after cardiac surgery is associated with an increased risk of mortality. Preoperative risk scores can identify patients at risk for AKI and facilitate preventive strategies. Currently, validated risk scores are used to predict AKI requiring dialysis (AKI-D); less is known about whether these tools predict less severe forms of AKI. OBJECTIVE: To evaluate the Cleveland Clinic scoring tool in predicting both AKI-D and less severe stages of AKI in patients after cardiac surgery in a Canadian tertiary care center. DESIGN: Retrospective case-control study. SETTING: Regina Qu'Appelle Health Region (RQHR) from 2007 to 2011. PATIENTS: Patients who underwent cardiac surgery and developed postoperative kidney injury (n = 2316). MEASUREMENTS: Data on risk factors for AKI and outcomes of cardiac surgery were collected from a retrospective chart review. METHODS: The primary outcome was AKI, defined as Stage 1 (increase in serum creatinine 1.5-1.9 X baseline within 5 days), Stage 2 (increase 2.0-2.9 X baseline), or Stage 3 (increase 3.0 X baseline or more OR initiation of dialysis during hospital stay). We assessed the performance of a modified version of the Cleveland Clinic tool using receiver operating curve analyses. RESULTS: The incidence of AKI was 6.1% (Stage 1), 2.6% (Stage 2), and 5.8% (Stage 3). The area under the curve (AUC) for the Cleveland score was 0.61 (95% CI: 0.56 to 0.65; p < 0.001) for Stage 1, 0.61 (95% CI: 0.54 to 0.68; p < 0.01) for Stage 2, and 0.78 (95% CI: 0.74 to 0.82; p < 0.001) for Stage 3. Greater level of risk on the Cleveland tool was associated with a higher risk of Stage 3 AKI. LIMITATIONS: Lack of prospective validation. CONCLUSIONS: The modified Cleveland Clinic tool was valid in identifying patients with severe stages of AKI but did not have strong discrimination for early AKI stages.

CONTEXTE: L'insuffisance rénale aiguë (IRA) survenant après une chirurgie cardiaque est liée à un risque accru de mortalité. Divers outils d'évaluation du risque préopératoire permettent de dépister les patients à risque d'IRA, facilitant ainsi les stratégies de prévention. Présentement, les scores de risque validés sont utilisés pour prédire une IRA nécessitant une dialyse (IRA-D); nous avons toutefois peu d'information sur l'utilité de ces outils d'évaluation pour prédire des formes moins sévères d'IRA. OBJECTIF DE L'ÉTUDE: Déterminer la valeur prédictive de l'outil d'évaluation de la Cleveland Clinic, en ce qui concerne l'IRA-D et des formes moins sévères d'IRA, chez des patients en phase postopératoire cardiaque, dans un établissement de soins tertiaires canadien. TYPE D'ÉTUDE: Étude cas-témoins. CONTEXTE: Regina Qu'Appelle Health Region (RQHR) pour la période de 2007 à 2011. PATIENTS: Échantillon de patients ayant subi une chirurgie cardiaque, et ayant développé une IRA postopératoire (n = 2316). MESURES: Les données concernant les facteurs de risque d'IRA, et les résultats de la chirurgie cardiaque ont été colligés à partir d'un examen rétrospectif des dossiers. MÉTHODE: La première complication rapportée était l'IRA : de stade 1 (avec élévation du taux de créatininémie de 1,5 -1,9 X par rapport à la valeur de référence, à l'intérieur de 5 jours); de stade 2 (élévation de 2,0-2,9 X la valeur de référence), ou de stade 3 (élévation minimale de 3 X la valeur de référence ou dialyse initiée pendant le séjour à l'hôpital). Nous avons évalué la performance d'une version modifiée de l'outil d'évaluation de la Cleveland Clinic en analysant la courbe ROC (receiver operating curve). RÉSULTATS: La fréquence d'IRA était de 6,1% (stade 1), 2,6% (stade 2), et de 5,8% (stade 3). L'aire sous la courbe, pour le score de Cleveland était de 0,61 (IC 95%: de 0,56 à 0,65; p < 0.001) pour l'IRA de stade 1, de 0,61 (IC 95%; de 0,54 à 0,68; p < 0.01) pour le stade 2, et de 0,78 (IC 95%: de 0,74 à 0,82; p < 0.001) pour le stade 3. Un risque accru avec l'outil d'évaluation de la Cleveland Clinic était lié à un risque accru d'IRA de stade 3. LIMITES DE L'ÉTUDE: Absence de validation prospective. CONCLUSIONS: La version modifiée de l'outil d'évaluation de la Cleveland Clinic dépistait adéquatement les patients atteints de l'IRA dans ses formes sévères, mais ne permet aucune distinction claire pour ce qui est des stades moins sévères de l'IRA.

PSA density improves prediction of prostate cancer.

INTRODUCTION: Prostate-specific antigen (PSA) and the digital rectal exam (DRE) have moderate sensitivity but low specificity for cancer diagnosis, potentially causing unnecessary treatment complications with prostate biopsy. Transrectal ultrasound (TRUS) to evaluate prostate size and calculate PSA density can improve the specificity of PSA in predicting cancer. We evaluated the sensitivity and specificity of different pre-biopsy tests to detect prostate cancer. MATERIALS AND METHODS: Pre-biopsy data were collected from 521 men referred for biopsy from January-December 2011 and cancer aggressiveness data from 96 men who had radical prostatectomy. Model predictors included total PSA, DRE, the ratio of free to total PSA (PSAf/t), and PSA density. We used logistic regression and ROC curve analyses to compare the accuracy of different models to predict positive biopsy. RESULTS: The area under the curve (AUC) for model A (PSA total, DRE, PSAf/t) was moderate, but significant (AUC = .59, p < .05); only PSAf/t was a significant independent predictor of positive biopsy (OR = .002, p < .05). In model B (PSAf/t and PSA density; AUC= .66, p < .05), PSA density was the only strong predictor (OR = 1067.93, p < .05). Both models had comparable sensitivity (74% versus 72%) but model B had greater specificity (44% versus 61%). PSA density was also a significant predictor of different indices of aggressive cancer. CONCLUSIONS: PSA density has discriminative predictive power for prostate cancer. It had similar sensitivity, but greater specificity compared to using PSA total, DRE and PSAf/t. These results support the value of using PSA density to improve prediction of prostate cancer and reduce unnecessary biopsies.

Dynamic fluctuations in dopamine efflux in the prefrontal cortex and nucleus accumbens during risk-based decision making.

Mesocorticolimbic dopamine (DA) has been implicated in cost/benefit decision making about risks and rewards. The prefrontal cortex (PFC) and nucleus accumbens (NAc) are two DA terminal regions that contribute to decision making in distinct manners. However, how fluctuations of tonic DA levels may relate to different aspects of decision making remains to be determined. The present study measured DA efflux in the PFC and NAc with microdialysis in well trained rats performing a probabilistic discounting task. Selection of a small/certain option always delivered one pellet, whereas another, large/risky option yielded four pellets, with probabilities that decreased (100-12.5%) or increased (12.5-100%) across four blocks of trials. Yoked-reward groups were also included to control for reward delivery. PFC DA efflux during decision making decreased or increased over a session, corresponding to changes in large/risky reward probabilities. Similar profiles were observed from yoked-rewarded rats, suggesting that fluctuations in PFC DA reflect changes in the relative rate of reward received. NAc DA efflux also showed decreasing/increasing trends over the session during both tasks. However, DA efflux was higher during decision making on free- versus forced-choice trials and during periods of greater reward uncertainty. Moreover, changes in NAc DA closely tracked shifts in choice biases. These data reveal dynamic and dissociable fluctuations in PFC and NAc DA transmission associated with different aspects of risk-based decision making. PFC DA may signal changes in reward availability that facilitates modification of choice biases, whereas NAc DA encodes integrated signals about reward rates, uncertainty, and choice, reflecting implementation of decision policies.

Separate prefrontal-subcortical circuits mediate different components of risk-based decision making.

Choosing between smaller, assured rewards or larger, uncertain ones requires reconciliation of competing biases toward more certain or riskier options. We used disconnection and neuroanatomical techniques to reveal that separate, yet interconnected, neural pathways linking the medial prefrontal cortex (PFC), the basolateral amygdala (BLA), and nucleus accumbens (NAc) contribute to these different decision biases in rats. Disrupting communication between the BLA and NAc revealed that this subcortical circuit biases choice toward larger, uncertain rewards on a probabilistic discounting task. In contrast, disconnections between the BLA and PFC increased choice of the Large/Risky option. PFC-NAc disconnections did not affect choice but did increase choice latencies and trial omissions. Neuroanatomical studies confirmed that projection pathways carrying axons from BLA-to-PFC transverse a distinctly different route relative to PFC-to-BLA pathways (via the ventrolateral amydalofugal pathway and ventromedial internal capsule, respectively). We exploited these dissociable axonal pathways to selectively disrupt bottom-up and top-down communication between the BLA and PFC. Subsequent disconnection studies revealed that disruption of top-down (but not bottom-up) information transfer between the medial PFC and BLA increased choice of the larger, riskier option, suggesting that this circuit facilitates tracking of actions and outcomes to temper urges for riskier rewards as they become less profitable. These findings provide novel insight into the dynamic competition between these cortical/subcortical circuits that shape our decision biases and underlie conflicting urges when evaluating options that vary in terms of potential risks and rewards.

Dissociable contributions by prefrontal D1 and D2 receptors to risk-based decision making.

Choices between certain and uncertain rewards of different magnitudes have been proposed to be mediated by both the frontal lobes and the mesocorticolimbic dopamine (DA) system. In rats, systemic manipulations of DA activity or inactivation of the medial prefrontal cortex (PFC) disrupt decision making about risks and rewards. However, it is unclear how PFC DA transmission contributes to these processes. We addressed this issue by examining the effects of pharmacological manipulations of D(1) and D(2) receptors in the medial (prelimbic) PFC on choice between small, certain and large, yet probabilistic rewards. Rats were trained on a probabilistic discounting task where one lever delivered one pellet with 100% probability, and the other delivered four pellets, but the probability of receiving reward decreased across blocks of trials (100, 50, 25, 12.5%). D(1) blockade (SCH23390) in the medial PFC decreased preference for the large/risky option. In contrast, D(2) blockade (eticlopride) reduced probabilistic discounting and increased risky choice. The D(1) agonist SKF81297 caused a slight, nonsignificant increase in preference for the large/risky lever. However, D(2) receptor stimulation (quinpirole) induced a true impairment in decision making, flattening the discounting curve and biasing choice away from or toward the risky option when it was more or less advantageous, respectively. These findings suggest that PFC D(1) and D(2) receptors make dissociable, yet complementary, contributions to risk/reward judgments. By striking a fine balance between D(1)/D(2) receptor activity, DA may help refine these judgments, promoting either exploitation of current favorable circumstances or exploration of more profitable ones when conditions change.

Differential effects of dopaminergic manipulations on risky choice.

RATIONALE: Evaluation of risks and rewards associated with different options is facilitated by components of the mesocorticolimbic dopamine (DA) system. Augmenting or reducing DA activity increases or decreases preference for larger, uncertain rewards when reward probabilities decrease within a session. However, manipulations of DA activity may differentially alter risky choice when shifts in the relative value of probabilistic rewards are greater or lesser than those experienced previously. OBJECTIVES: We investigated the effects of amphetamine and the DA antagonist flupenthixol on risk discounting, whereby we altered the manner in which reward probabilities changed. METHODS: Rats chose between a "Small/Certain" (one pellet) and a "Large/Risky" lever that delivered four pellets in a probabilistic manner that changed during a session. Separate groups of rats were trained with a descending (100%, 50%, 25%, 12.5%), ascending (12.5-100%) or mixed (100%, 12.5%, 25%, 50%) order of probabilities associated with the large/risky option. RESULTS: Flupenthixol consistently decreased preference for the large/risky option. In contrast, amphetamine increased preference for the large/risky lever when the probabilities decreased over a session, but reduced preference in the ascending condition. CONCLUSIONS: Reductions in normal DA tone consistently biases choice away larger, probabilistic rewards. In contrast, increases in DA release may disrupt adjustments in behavior in response to changes in the relative value of certain versus uncertain rewards. These findings further clarify the role of DA in mediating risk/reward judgments and how perturbations in DA signaling may interfere with the ability to adjust decision making in response to changes in reward contingencies.

Prefrontal cortical contribution to risk-based decision making.

Damage to various regions of the prefrontal cortex (PFC) impairs decision making involving evaluations about risks and rewards. However, the specific contributions that different PFC subregions make to risk-based decision making are unclear. We investigated the effects of reversible inactivation of 4 subregions of the rat PFC (prelimbic medial PFC, orbitofrontal cortex [OFC], anterior cingulate, and insular cortex) on probabilistic (or risk) discounting. Rats were well trained to choose between either a "Small/Certain" lever that always delivered 1 food pellet, or another, "Large/Risky" lever, which delivered 4 pellets, but the probability of receiving reward decreased across 4 trial blocks (100%, 50%, 25%, and 12.5%). Infusions of gama-aminobutyric acid agonists muscimol/baclofen into the medial PFC increased risky choice. However, similar medial PFC inactivations decreased risky choice when the Large/Risky reward probability increased over a session. OFC inactivation increased response latencies in the latter trial blocks without affecting choice. Anterior cingulate or insular inactivations were without effect. The effects of prelimbic inactivations were not attributable to disruptions in response flexibility or judgments about the relative value of probabilistic rewards. Thus, the prelimbic, but not other PFC regions, plays a critical role in risk discounting, integrating information about changing reward probabilities to update value representations that facilitate efficient decision making.

Fundamental contribution by the basolateral amygdala to different forms of decision making.

Impairments in decision making about risks and rewards have been observed in patients with amygdala damage. Similarly, lesions of the basolateral amygdala (BLA) in rodents disrupts cost/benefit decision making, reducing preference for larger rewards obtainable after a delay or considerable physical effort. We assessed the effects of inactivation of the BLA on risk- and effort-based decision making, using discounting tasks conducted in an operant chamber. Separate groups of rats were trained on either a risk- or effort-discounting task, consisting of four blocks of 10 free-choice trials. Selection of one lever always delivered a smaller reward (one or two pellets), whereas responding on the other delivered a larger, four pellet reward. For risk discounting, the probability of receiving the larger reward decreased across trial blocks (100-12.5%), whereas on the effort task, the larger reward was delivered after a ratio of presses that increased across blocks (2-20). Infusions of GABA agonists baclofen/muscimol into the BLA disrupted risk discounting, inducing a risk-averse pattern of choice, and increased response latencies and trial omissions, most prominently during trial blocks that provided the greatest uncertainty about the most beneficial course of action. Similar inactivations also increased effort discounting, reducing the preference for larger yet more costly rewards, even when the relative delays to reward delivery were equalized across response options. These findings point to a fundamental role for the BLA in different forms of cost/benefit decision making, facilitating an organism's ability to overcome a variety of costs (work, uncertainty, delays) to promote actions that may yield larger rewards.

Dopaminergic modulation of risk-based decision making.

Psychopharmacological studies have implicated the mesolimbic dopamine (DA) system in the mediation of cost/benefit evaluations about delay or effort-related costs associated with larger rewards. However, the role of DA in risk-based decision making remains relatively unexplored. The present study investigated the effects of systemic manipulations of DA transmission on risky choice using a probabilistic discounting task. Over discrete trials, rats chose between two levers; a press on the 'small/certain' lever always delivered one reward pellet, whereas a press on the other, 'large/risky' lever delivered four pellets, but the probability of receiving reward decreased across the four trial blocks (100, 50, 25, 12.5%). In separate groups of well-trained rats we assessed the effects of the DA releaser amphetamine, as well as receptor selective agonists and antagonists. Amphetamine consistently increased preference for the large/risky lever; an effect that was blocked or attenuated by co-administration of either D(1) (SCH23390) or D(2) (eticlopride) receptor antagonists. Blockade of either of these receptors alone induced risk aversion. Conversely, stimulation of D(1) (SKF81297) or D(2) (bromocriptine) receptors also increased risky choice. In contrast, activation of D(3) receptors with PD128,907 reduced choice of the large/risky lever. Likewise, D(3) antagonism with nafadotride potentiated the amphetamine-induced increase in risky choice. Blockade or stimulation of D(4) receptors did not reliably alter behavior. These findings indicate that DA has a critical role in mediating risk-based decision making, with increased activation of D(1) and D(2) receptors biasing choice toward larger, probabilistic rewards, whereas D(3) receptors appear to exert opposing effects on this form of decision making.

Cortico-limbic-striatal circuits subserving different forms of cost-benefit decision making.

Research on the neural basis that underlies decision making in humans has revealed that these processes are mediated by distributed neural networks that incorporate different regions of the frontal lobes, the amygdala, the ventral striatum, and the dopamine system. In the present article, we review recent studies in rodents investigating the contribution of these systems to different forms of cost-benefit decision making and focus on evaluations related to delays, effort, or risks associated with certain rewards. Anatomically distinct regions of the medial and orbital prefrontal cortex make dissociable contributions to different forms of decision making, although lesions of these regions can induce variable effects, depending on the type of tasks used to assess these functions. The basolateral amygdala and the nucleus accumbens play a more fundamental role in these evaluations, helping an organism overcome different costs to obtain better rewards. Dopamine activity biases behavior toward more costly yet larger rewards, although abnormal increases in dopamine transmission can exert opposing actions on different types of decision making. The fact that similar neural circuits are recruited to solve these types of problems in both humans and animals suggests that animal models of decision making will prove useful in elucidating the mechanisms mediating these processes.