Dissociable contributions of dorsal and ventral striatal regions on a rodent cost/benefit decision-making task requiring cognitive effort.

Cognitive effort is a ubiquitous process, yet surprisingly little is known about the brain mechanisms responsible for evaluating it. Here, we utilize the rat Cognitive Effort Task (rCET) to probe the striatum's role in deciding between options that vary in the amount of cognitive effort required for success. In the rCET, animals choose to perform either an easy trial, in which the attentional demand is low but the potential reward is small, or a difficult trial which is more attentionally demanding but can yield twice the sugar pellets. Twenty-six male Long Evans rats were trained on the rCET and the effects of pharmacologically inactivating the dorsomedial striatum (DMS) and core region of the nucleus accumbens were determined. Temporary inactivation of the DMS decreased all animals' choice of the high-effort, high-reward option, impaired attentional accuracy, and robustly increased premature responding without impairing general indices of motor ability. The DMS therefore appears necessary for the integration of cognitive signals required for optimal performance. In stark contrast, following temporary inactivation of the ventral striatum, subjects were fundamentally unable to perform the task, as reflected by a drastic decrease in the number of trials initiated and an increase in omitted responses. Together, these data suggest the striatum is likely part of a larger cortico-limbic-striatal network whose function is to optimize decisions requiring cognitive effort costs, at least in the attentional domain, and that striatal subregions have dissociable roles in the adjudication and application of this form of cognitive effort.

[A system of prescriptions without drug approval: example of baclofen]. / Un dispositif de prescriptions hors-AMM : exemple du baclofène.

Baclofen is an anti-spastic drug that acts as an agonist of GABA-B receptors. It also seems to decrease the appetence for alcohol (anti-craving effect), although this effect has not been certified by Authorities for drug approval in France (AMM). However, baclofen receives a great deal of demand by patients hoping to reduce their alcohol consumption. Nonetheless, the lack of AMM and the high doses of baclofen supposed to exert an anti-craving effect often discourage practitioners from prescribing this drug in current medical practice. Therefore, it is preferable for a drug like baclofen to be prescribed under specific regulations. As such, certain criteria similar to those required in clinical trials are necessary to protect patients as well as the prescribing doctors. The criteria that are proposed here are: the use of drugs without AMM approval as a last resort (all other treatments must have failed), the collegiate decision for the drug prescription, good knowledge of the potency of the drug as well as good record keeping of patients and proper supervision. The departments of addiction, pharmacology and pharmacovigilance of the University Hospital of Lille, France present here a medical process named "multidisciplinary consultations for resort treatments of addictions" (CAMTEA). This process is designed to meet all the above mentioned criteria and to allow the use of baclofen as an anti-craving drug in safest conditions. If this proves to be successful with baclofen, it is possible to extend the use of CAMTEA to other drugs without AMM approval in addictologic pathologies.

The incidence and management of tolerance in intrathecal baclofen therapy.

STUDY DESIGN: Retrospective study. OBJECTIVES: To study the incidence and management of tolerance in patients treated with intrathecal baclofen (ITB) therapy. SETTING: Department of neurology and neurosurgery, University Medical Center Groningen, The Netherlands. METHODS: Medical records of all patients who had received an implantable ITB pump at our clinic during 1991-2005 were reviewed. RESULTS: A total of 37 patients (representing 116 pump years) were included. Mean follow-up time was 38 months (range 3-120 months). Baclofen dose increased in the first 18 months after implantation (P<0.05), and then stabilized around a mean dose of 350 microg per day. Eight patients (22%) developed tolerance, defined as a dose increase of >100 microg per year. No predictive factors for development of tolerance could be determined. Three different treatment regimens for tolerant patients were analyzed. Altering the infusion mode from simple to complex continuous (n=6) had no effect on the development of tolerance. Pulsatile bolus infusion (n=1) and a drug holiday (n=2) were both effective in reducing the daily baclofen dose. Patients who needed surgical revision of the pump system because of mechanical failures (n=11) showed a significant dose decrease during the first month after revision, indicating that the preoperative dose increase most likely had been caused by the pump failure. Pump-related complications occurred once per 10.5 years of ITB treatment. Drug-related side effects had an annual risk of 13.8%. The reported events were mostly mild. CONCLUSIONS: ITB therapy is effective and safe, also in the long term and causes tolerance in only 22% of the treated patients.

[Assessment of spasticity therapy with baclofen pump in children]. / Ocena wyników leczenia spastycznosci u dzieci za pomoca pompy baklofenowej.

THE AIM OF THE STUDY: The aim of this study was to assess of treatment of spasticity in children with baclofen pump, before and after pump implantation. MATERIAL AND METHOD: In a group of 17 patients with spastic hemiparesis, with a different etiology, 2 groups were separated. In the group of 12 the most injured children, spasticity was measured by The Modified Ashworth Scale, before and after baclofen pump implantation. In the group of 5 patients spasticity was assessed by The Modified Ashworth Scale, functional benefits were evaluated with the Barthel index score, and the digree of disability with the Rankin Scale. RESULTS: In the group of 12 patients, after pump implantation, was observed reduction in spasticity to 2 points in the Modified Ashworth Scale and this effect improves general ease of care and passive excersises. In the second group 3 of 5 patients, have started to walk alone or with orthopedic help. CONCLUSION: Intrathecal baclofen therapy resulted in the good effects in treatment of spasticity in the both groups.

[Management of increase in spasticity in patients with intrathecal baclofen pumps]. / Conduite à tenir devant une recrudescence de spasticité chez un patient porteur d'une pompe à baclofène.

INTRODUCTION: The incidence of complications after baclofen pump implantation is relatively high. Diagnosis of these complications can be difficult. A diagnostic tree would be a useful tool in cases of suspected malfunctioning of the intrathecal bacolfen infusion system and would standardise the diagnostic procedure. METHOD: From results in the literature and the experience of our department, we designed a diagnostic tree to aid in finding the cause of a recrudescence of spasticity in patients with implanted baclofen pumps. RESULTS: The potential causes of recrudescence of spasticity are described and a diagnostic pathway is proposed. DISCUSSION: The aim of a standardised hierarchical method of diagnosis of the cause of increased spasticity in patients with intrathecal baclofen pumps is to gain time in the diagnosis and treatment. Such diagnosis should improve patient care by permitting rapid restoration of an adequate level of baclofen infusion as well as decreasing the length of hospital stay and, as a consequence, the cost relating to malfunctioning pumps.

Electrophysiological assessment of the effect of intrathecal baclofen in spastic children.

OBJECTIVES: To evaluate the effect of intrathecal baclofen in a group of spastic children using electrophysiological procedures described in adults. METHODS: Six children (aged 1-14 years) with severe spasticity of various aetiologies underwent transcranial magnetic stimulation, H reflex and flexor reflex studies before and after intrathecal injection of baclofen. Ashworth scale was used for clinical evaluation of spasticity. RESULTS: Motor evoked potentials, present in two patients before baclofen, were preserved after injection. Before baclofen, H reflex was present in 5 patients (H(max)/M(max) from 0.23 to 0.84) and absent in one who had infantile neuroaxonal dystrophy. After baclofen, it was absent in 4 patients and markedly reduced in one. Surface of flexor reflex significantly decreased after baclofen (P=0.01), while threshold significantly increased (P=0.003). CONCLUSIONS: In spastic children, the action of baclofen on spinal pathways may be quantified by the same electrophysiological procedures as in adults. This approach may contribute to select optimal dosage.

Cost analysis of the treatment of severe spinal spasticity with a continuous intrathecal baclofen infusion system.

OBJECTIVE: The purpose of our study was to analyse and evaluate the costs of continuous intrathecal baclofen administration as a modality in the treatment of severe spasticity in the Netherlands. DESIGN: A cost analysis was conducted as part of a prospective, multicentre, multidisciplinary, randomised and placebo-controlled clinical trial. The study covered the period from December 1991 to September 1995. The data on medical consumption and costs were collected over a 3-year period from different sources: administrative databases of health insurance companies, hospital registries and a patient survey. These data were structured by means of a flowchart analysis of the medical decision-making by specialists and general practitioners (GPs). They included data on in- and outpatient care, home care and care in nursing homes. The cost analysis was conducted using data from 18 patients included in the trial and from 15 so-called 'match' patients. The latter group are patients with comparable diseases leading to spasticity and living in comparable circumstances. Next to absolute costs (direct and indirect) of care and treatment for the 2 groups of patients, cost differences between the 2 groups were considered (differential cost analysis). SETTING: Per patient cost data, collected prospectively for 2 years during the phase of clinical evaluation, and retrospectively 1 year before implantation. The data were collected on patients from in- and outpatient care, home care and care in nursing home settings. PATIENTS AND PARTICIPANTS: The trial patients (8 men) had a mean age of 46 years; 11 patients had multiple sclerosis and 7 patients had spinal cord injuries. The match patients (7 men) had a mean age of 48 years; 9 patients had multiple sclerosis and 6 patients had spinal cord injuries. INTERVENTIONS: Trial patients were treated with a subcutaneously implanted programmable continuous infusion pump (SynchroMed, Medtronic), filled with baclofen (a muscle relaxant) to treat patients with chronic disabling spasticity who did not respond to a maximum dose of oral baclofen, dantrolene and tizanidine. MAIN OUTCOME MEASURES AND RESULTS: An analysis of hospital stay between both groups showed a significant difference during the implantation year. The average number of hospital days per patient in the year in the treated group was 31.5 days and in the match group was 18.7 days. Significant cost differences between both groups in the year that started with pump implantation and the following year can be attributed mostly to the costs of implantation of the pump and related hospitalisation days. The total costs of patient selection, testing, implanting the pump and follow-up amounted to $US28,473 for the first year. Savings must be taken into consideration as well. The savings of direct costs were due to withdrawal of oral medication (estimated annual total of between $US1950 and $US2800 per patient). Indirect savings on employment and nursing home costs, amounted annually to $US1047 and $US5814, respectively. Scenarios make it possible to consider policy consequences. The case of 'extending' the indications for this treatment to a larger population has been calculated and visualised. CONCLUSIONS: The costs of the therapy (continuous intrathecal infusion of baclofen) can be attributed mostly to implantation of the pump and related hospitalisation days. Savings originated from withdrawal of oral medication, job preservation and avoidance or delay of admission to a nursing home.