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Background: Postmarketing surveillance studies (PMS) are an important tool for evaluating a drug’s effectiveness and safety in clinical practice. To our knowledge, no PMS on memantine monotherapy for moderately-severe-to-severe Alzheimer’s disease (AD) according to National Institute of Neurological and Communicative Disorders and Stroke — Alzheimer’s Disease and Related Disorders Association criteria has been conducted to date. Objective: The Lombardy Health Office, Italy, promoted this PMS to evaluate the effectiveness and safety of memantine in the treatment of moderately-severe-to-severe AD in clinical practice. Methods: A total of 451 patients with moderately-severe-to-severe AD (mean age 77 ± 7 years; 72% female), free of cholinergic medication, received memantine (standard titration to 10 mg twice daily). After 6 months of therapy, treatment effectiveness was evaluated according to two definitions of response (‘no deterioration’ and ‘improvement’), as measured by changes in baseline scores on the Clinical Global Impression of Change, Mini-Mental State Examination, Neuropsychiatric Inventory and Activities of Daily Living scales. The safety measure was the frequency of adverse events (AEs). Results: At 6-month assessment, 26.8% of subjects showed no deterioration and 3.8% showed improvement. In those showing no deterioration, response to treatment at the 3-month assessment was associated with a greater probability of a response at 6 months (adjusted odds ratio = 8.54; 95% CI 4.54, 16.05). Seventy patients (15.5%) experienced at least one AE and 39 (8.6%) discontinued treatment prematurely because of an AE. Of those who experienced an AE, 27 (38.6%) manifested behavioural and psychological symptoms of dementia. Conclusion: The proportion of responders to memantine treatment in this PMS was similar to that reported in a previous randomized clinical trial (26.8% vs 29%, respectively). The proportion of patients who discontinued treatment prematurely because of an AE (8.6%) was similar to that reported in two previous randomized clinical trials (10% and 12.4%). This PMS provides additional evidence that both the effectiveness and the tolerability of memantine may be transferred into real world medicine, where AD patients receiving treatment are not selected according to strict criteria.

Humans are able to flexibly devise and implement rules to reach their desired goals. For simple situations, we can use single rules, such as “if traffic light is green then cross the street.” In most cases, however, more complex rule sets are required, involving the integration of multiple layers of control. Although it has been shown that prefrontal cortex is important for rule representation, it has remained unclear how the brain encodes more complex rule sets. Here, we investigate how the brain represents the order in which different parts of a rule set are evaluated. Participants had to follow compound rule sets that involved the concurrent application of two single rules in a specific order, where one of the rules always had to be evaluated first. The rules and their assigned order were independently manipulated. By applying multivariate decoding to fMRI data, we found that the identity of the current rule was encoded in a frontostriatal network involving right ventrolateral prefrontal cortex, right superior frontal gyrus, and dorsal striatum. In contrast, rule order could be decoded in the dorsal striatum and in the right premotor cortex. The nonhomogeneous distribution of information across brain areas was confirmed by follow-up analyses focused on relevant regions of interest. We argue that the brain encodes complex rule sets by “decomposing” them in their constituent features, which are represented in different brain areas, according to the aspect of information to be maintained.

Rules are widely used in everyday life to organize actions and thoughts in accordance with our internal goals. At the simplest level, single rules can be used to link individual sensory stimuli to their appropriate responses. However, most tasks are more complex and require the concurrent application of multiple rules. Experiments on humans and monkeys have shown the involvement of a frontoparietal network in rule representation. Yet, a fundamental issue still needs to be clarified: Is the neural representation of multiple rules compositional, that is, built on the neural representation of their simple constituent rules? Subjects were asked to remember and apply either simple or compound rules. Multivariate decoding analyses were applied to functional magnetic resonance imaging data. Both ventrolateral frontal and lateral parietal cortex were involved in compound representation. Most importantly, we were able to decode the compound rules by training classifiers only on the simple rules they were composed of. This shows that the code used to store rule information in prefrontal cortex is compositional. Compositional coding in rule representation suggests that it might be possible to decode other complex action plans by learning the neural patterns of the known composing elements.

Two experiments investigated whether dealing with a homogeneous subset of syllogisms with time-constrained responses encouraged participants to develop and use heuristics for abstract (Experiment 1) and thematic (Experiment 2) syllogisms. An atmosphere-based heuristic accounted for most responses with both abstract and thematic syllogisms. With thematic syllogisms, a weaker effect of a belief heuristic was also observed, mainly where the correct response was inconsistent with the atmosphere of the premises. Analytic processes appear to have played little role in the time-constrained condition, whereas their involvement increased in a self-paced, unconstrained condition. From a dual-process perspective, the results further specify how task demands affect the recruitment of heuristic and analytic systems of reasoning. Because the syllogisms and experimental procedure were the same as those used in a previous neuroimaging study by Goel, Buchel, Frith, and Dolan (2000), the result also deepen our understanding of the cognitive processes investigated by that study.

Elementary deduction is the ability of unreflectively drawing conclusions from explicit or implicit premises, on the basis of their logical forms. This ability is involved in many aspects of human cognition and interactions. To date, limited evidence exists on its cortical bases. We propose a model of elementary deduction in which logical inferences, memory, and meta-logical control are separable subcomponents. We explore deficits in patients with left, medial and right frontal lesions, by both studying patients' deductive abilities and providing measures of their meta-logical sensitivity for proof difficulty. We show that lesions to left lateral and medial frontal cortex impair abilities at solving elementary deductive problems, but not so lesions to right frontal cortex. Furthermore, we show that memory deficits differentially affect patients according to the locus of the lesion. Left lateral patients with working memory deficits had defective deductive abilities, but not so left lateral patients with spared working memory. In contrast, in medial patients both deductive and meta-deductive abilities were affected regardless of the presence of memory deficits. Overall, the results are compatible with a componential view of elementary deduction, and call for the elaboration of more fine-grained models of deductive abilities.

The neural correlates of inductive reasoning are still poorly understood. In order to explore them, we administered a revised version of the Brixton test [Cortex 32 (2) (1996a) 241], a rule attainment task, to a group of 40 patients with a focal frontal brain lesion of mixed aetiology and to 43 control subjects. To interpret an impairment on the test as suggesting an inductive reasoning deficit a number of alternative hypotheses need first to be considered, namely whether the Brixton impairment could be explained by: (i) a working memory deficit; (ii) a monitoring deficit; (iii) a difficulty in applying an already induced rule; (iv) greater impulsivity. The patients with left lateral (LL) frontal lesions were significantly impaired on the Brixton test; more importantly they were the only group in which none of the alternative hypotheses we explored proved able to explain the flawed performance. In sharp contrast, right lateral lesion patients did not make significantly more errors on the Brixton test than controls, but they produced three times more capture errors (a sign of impaired monitoring processes). The results were interpreted as suggesting functional dissociations between inductive reasoning, monitoring and working memory and a localisation of key processes for induction in left lateral frontal cortex and in right lateral cortex for monitoring and checking.

This study tested the impact of prefrontal-cortex lesion on learning hierarchically structured action sequences. Using a visual-manual serial reaction time task, we had subjects first perform five blocks of trials with a hierarchically structured 14-element action sequence and then tested for sequence-specific learning by introducing a pseudo-random transfer sequence. Relative to control subjects (N = 39), we found that both lateral frontal (N = 16) and medial frontal (N = 18) patients showed reduced overall performance benefits across the training phase. In contrast, the negative transfer test showed significantly increased reaction times in all patient groups, indicating robust sequence-specific learning. This learning was not significantly different from that of the control group. Taken together, the data suggest that learning hierarchically structured action sequences is unimpaired in patients with prefrontal-cortex lesion.