Orbitofrontal dopamine depletion upregulates caudate dopamine and alters behavior via changes in reinforcement sensitivity.

Schizophrenia is associated with upregulation of dopamine (DA) release in the caudate nucleus. The caudate has dense connections with the orbitofrontal cortex (OFC) via the frontostriatal loops, and both areas exhibit pathophysiological change in schizophrenia. Despite evidence that abnormalities in dopaminergic neurotransmission and prefrontal cortex function co-occur in schizophrenia, the influence of OFC DA on caudate DA and reinforcement processing is poorly understood. To test the hypothesis that OFC dopaminergic dysfunction disrupts caudate dopamine function, we selectively depleted dopamine from the OFC of marmoset monkeys and measured striatal extracellular dopamine levels (using microdialysis) and dopamine D2/D3 receptor binding (using positron emission tomography), while modeling reinforcement-related behavior in a discrimination learning paradigm. OFC dopamine depletion caused an increase in tonic dopamine levels in the caudate nucleus and a corresponding reduction in D2/D3 receptor binding. Computational modeling of behavior showed that the lesion increased response exploration, reducing the tendency to persist with a recently chosen response side. This effect is akin to increased response switching previously seen in schizophrenia and was correlated with striatal but not OFC D2/D3 receptor binding. These results demonstrate that OFC dopamine depletion is sufficient to induce striatal hyperdopaminergia and changes in reinforcement learning relevant to schizophrenia.

The role of the orbitofrontal cortex and medial striatum in the regulation of prepotent responses to food rewards.

An impairment in learning to inhibit prepotent responses to positive stimuli is associated with damage to the orbitofrontal cortex (OFC) in rats, monkeys, and humans performing discrimination reversal, extinction, and detour reaching tasks. In contrast, a recent study showed that OFC-lesioned rhesus monkeys could learn to select the smaller of 2 quantities of food reward in order to receive the larger reward, at an equivalent rate to controls, despite the requirement to inhibit a prepotent response. Given this result, the aim of the present study was to further specify the contexts under which the OFC regulates responding and to identify additional components of limbic circuitry that contribute to such regulation. Marmosets with lesions of the OFC and medial striatum (MS), but not the amygdala, made more prepotent responses to a clear Perspex box containing high incentive food before learning to choose the box containing low incentive food, to obtain reward. However, having learned the incongruent incentive discrimination OFC- and MS-lesioned monkeys were impaired upon reversal of the reward contingencies, repeatedly selecting the previously rewarded low incentive object. These findings identify the critical contribution of the OFC and MS in the regulation of responding by affective cues.

Cognitive inflexibility after prefrontal serotonin depletion is behaviorally and neurochemically specific.

We have previously demonstrated that prefrontal serotonin depletion impairs orbitofrontal cortex (OFC)-mediated serial discrimination reversal (SDR) learning but not lateral prefrontal cortex (PFC)-mediated attentional set shifting. To address the neurochemical specificity of this reversal deficit, Experiment 1 compared the effects of selective serotonin and selective dopamine depletions of the OFC on performance of the SDR task. Whereas serotonin depletions markedly impaired performance, OFC dopamine depletions were without effect. The behavioral specificity of this reversal impairment was investigated in Experiment 2 by examining the effect of OFC serotonin depletion on performance of a modified SDR task designed to distinguish between 3 possible causes of the impairment. The results showed that the reversal deficit induced by prefrontal serotonin depletion was not due to a failure to approach a previously unrewarded stimulus (enhanced learned avoidance) or reduced proactive interference. Instead, it was due specifically to a failure to inhibit responding to the previously rewarded stimulus. The neurochemical and behavioral specificity of this particular form of cognitive inflexibility is of particular relevance to our understanding of the aetiology and treatment of inflexible behavior apparent in many neuropsychiatric and neurodegenerative disorders involving the PFC.

Prefrontal serotonin depletion affects reversal learning but not attentional set shifting.

Recently, we have shown that serotonin (5-HT) depletion from the prefrontal cortex (PFC) of the marmoset monkey impairs performance on a serial discrimination reversal (SDR) task, resulting in perseverative responding to the previously correct stimulus (Clarke et al., 2004). This pattern of impairment is just one example of inflexible responding seen after damage to the PFC, with performance on the SDR task being dependent on the integrity of the orbitofrontal cortex. However, the contribution of 5-HT to other forms of flexible responding, such as attentional set shifting, an ability dependent on lateral PFC (Dias et al., 1996a), is unknown. The present study addresses this issue by examining the effects of 5,7-dihydroxytryptamine-induced PFC 5-HT depletions on the ability to shift attention between two perceptual dimensions of a compound visual stimulus (extradimensional shift). Monkeys with selective PFC 5-HT lesions, despite being impaired in their ability to reverse a stimulus-reward association, were unimpaired in their ability to make an extradimensional shift when compared with sham-operated controls. These findings suggest that 5-HT is critical for flexible responding at the level of changing stimulus-reward contingencies but is not essential for the higher-order shifting of attentional set. Thus, psychological functions dependent on different loci within the PFC are differentially sensitive to serotonergic modulation, a finding of relevance to our understanding of cognitive inflexibility apparent in disorders such as obsessive-compulsive disorder and schizophrenia.

Cognitive inflexibility after prefrontal serotonin depletion.

Serotonergic dysregulation within the prefrontal cortex (PFC) is implicated in many neuropsychiatric disorders, but the precise role of serotonin within the PFC is poorly understood. Using a serial discrimination reversal paradigm, we showed that upon reversal, selective serotonin depletion of the marmoset PFC produced perseverative responding to the previously rewarded stimulus without any significant effects on either retention of a discrimination learned preoperatively or acquisition of a novel discrimination postoperatively. These results highlight the importance of prefrontal serotonin in behavioral flexibility and are highly relevant to obsessive-compulsive disorder, schizophrenia, and the cognitive sequelae of drug abuse in which perseveration is prominent.

Factors associated with intended use of a Web site among family practice patients.

BACKGROUND: The World Wide Web has become a widely utilized source of health information. Although the frequency of health related queries is impressive, the demographics associated with patients making queries has not been clearly delineated. OBJECTIVE: This study s objective was to determine health related Internet usage patterns of family medicine patients. METHODS: Internet use among 824 eligible patients 18 years or older attending seven university based family practice clinics during a two week period in November of 1999 was studied. The survey instrument included 10 items and was designed to collect data in less than five minutes using a paper and pencil format. Statistical significance associated with intended Web site use was computed using a multiple logistic regression model. RESULTS: A response rate of 72.2% was observed with 63.1% being females and 36.9% being males. The mean and median age were 44.0 and 45.7 years, respectively. A steady decline in intended Web site use was observed with advancing age with significant differences observed above 65 years (OR = 0.30; 95% CI = 0.14 - 0.64; p<.002). Other significant findings associated with intended use of a Web site by clinic based patients included having a home computer (OR = 1.99; 95%, CI = 1.05 3.76; p<0.03) and having Internet access at home (OR=5.6, 95%, CI = 2.83-11.18; p<.001). A lack of association between intended Web site use and health insurance status was observed. CONCLUSIONS: Results from this study suggest that Web sites are not likely to be alternative sources of health information for the uninsured or elderly in the near future.

Reducing cervical cancer among First Nations women.

First Nations women in British Columbia have a four to six times higher mortality rate from cancer of the cervix than do women in the general population. Their participation in the provincial Cervical Cytology Screening Program (CCSP) is less regular and less frequent than other women in B.C. Likewise, they have more difficulty in obtaining culturally suitable health care services from respectful and consistent professionals. These issues should be of critical concern to nurses, as nurses provide the majority of health services to First Nations people.

Comox Valley Nursing Centre: from collaboration to empowerment.

The Comox Valley Nursing Centre was initiated as a two year demonstration project by the Registered Nurses Association of British Columbia (RNABC) and funded by the Ministry of Health. The purpose of the project was to demonstrate innovative nursing practice in a primary health care context. Findings from the project were expected to inform provincial health care planning, nursing scope of practice, and health and nursing policy development. A free standing nursing center was planned and implemented through a collaborative effort by RNABC, nurses and community residents. An external team of researchers evaluated the project using a variety of methods, including participatory action research. During the project an innovative nursing practice, based on principles of collaboration, developed and has continued during the extended provincial and regional funding of the Centre. Drawing from the evaluation findings, case studies and using Henneman, Lee and Cohen's (1995) concept analysis of collaboration, this paper describes how the principles of collaboration were actualized or suppressed. The paper examines how collaboration impacted empowerment for nurses, clients and the community. Lessons learned about the reciprocal relationships between collaboration and empowerment, implications for nursing practice, and how the approach can contribute to a better understanding of the impact of collaborative practice approaches on health care delivery are discussed.

Research in nursing and cultural diversity: working with first nations peoples.

The current Canadian demographic profile indicates a society that is ethnically, culturally, and racially plural (Masi, 1993). Such diversity in our population is likely to increase with broad-based immigration, the implications of which have not been well addressed in nursing and health care. While nurses and other health-care professionals must attend to understanding the cultural aspects of health and healing, there is little published valid and reliable research to assist with this, especially with respect to specific populations. Research approaches and designs must be culturally suitable to the specific populations, to generate valid knowledge about their culture and to develop theory, and to translate that into culturally suitable nursing and health care. In the past, many culturally diverse groups have been the subject of research that has been culturally inappropriate, patronizing, culturally threatening, and disempowering. This paper discusses critical ethnography as a culturally suitable research method and describes its application to studies involving First Nations (FN) peoples. Important issues in doing culturally suitable research, such as partnerships, ethical concerns, and ownership, are also discussed.

Cervical cytology screening. How can we improve rates among First Nations women in urban British Columbia?

OBJECTIVE: To determine Pap smear screening rates among urban First Nations women in British Columbia; to identify facilitators and barriers; and to develop, implement, and evaluate specific interventions to improve Pap smear screening in Vancouver. DESIGN: Computer records of band membership lists and the Cervical Cytology Screening Program registry were compared to determine screening rates; personal interviews and community meetings identified facilitators and barriers to urban screening programs. A community advisory committee and the project team collaborated on developing specific interventions. SETTING AND PARTICIPANTS: Purposive sample of British Columbia First Nations women, focusing on women living in Vancouver. INTERVENTIONS: Poster, art card, and follow-up pamphlet campaign; articles in First Nations community papers; community meetings; and Pap smear screening clinics for First Nations women. MAIN OUTCOME MEASURES: Pap smear screening rates among BC First Nations women according to residence and reasons for not receiving Pap smears. RESULTS: Pap smear screening rates were substantially lower among First Nations women than among other British Columbia women; older women had even lower rates. No clear differences were found among First Nations women residing on reserves, residing in Vancouver, or residing off reserves elsewhere in British Columbia. Facilitators and barriers to screening were similar among women residing on reserves and in Vancouver. Many First Nations women are greatly affected by health care providers' attitudes, abilities to provide clear information, and abilities to establish trusting relationships. CONCLUSIONS: Family physicians are an important source of information and motivation for Pap smear screening among First Nations women.