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Thiopurines are in widespread clinical use for the treatment of immunological disorders and certain cancers. However, treatment failure due to resistance or adverse drug reactions are common, asking for new therapeutic strategies. We investigated the potential of 6-thioguanosine monophosphate (6sGMP) prodrugs to overcome resistance to 6-thioguanine. We successfully developed synthetic routes toward diverse 6sGMP prodrugs, tested their proliferation inhibitory potential in different cell lines, and examined their mode of action. Our results show that 4-acetyloxybenzyl- and

Both, decline of sensorimotor functions and cortical thickness are known processes in healthy aging. Physical activity has been suggested to enhance the execution of daily routine activities and to extend the time of functional independence in advanced age. We hypothesized that cortical thickness of motor areas in retired individuals could be related to physical demands of the profession carried out during working life. Depending on their former occupations, 69 cognitively healthy individuals (range 70–85 years) were divided into higher and lower physically complex occupations (HPCO n = 27 and LPCO n = 42) according to the international standard classification of occupations (ISCO-08). Participants underwent a high-resolution 3T T1-weighted MRI scan. Surface-based analysis revealed higher cortical thickness in the left precentral (P = 0.001) and postcentral gyrus (P P = 0.001) for the HPCO relative to the LPCO group (corrected for multiple comparisons, sex, age and leisure activities in the past 20 years). Physical leisure activities associated with exertion were positively correlated with cortical thickness in the left pre- and postcentral gyrus (P = 0.037) of the LPCO group. Time since retirement was negatively associated with cortical thickness in the left postcentral gyrus (P = 0.004) of the HPCO group. Executing a higher physically complex occupation before retirement was related to relative higher cortical thickness in the primary motor and somatosensory cortex in later life, supporting the hypothesis that physical activity contributes to neural reserve in these regions. However, these benefits appear to vanish when physical activity is reduced due to retirement.

Objective Cognitive impairment in multiple system atrophy (MSA) is common, but remain poorly characterized. We evaluated cognitive and behavioral features in MSA patients and assessed between‐group differences for MSA subtypes and the effect of orthostatic hypotension (OH) on cognition. Methods This retrospective study included 54 patients with clinical diagnosis of possible and probable MSA referred to the Department of Neurology at Medical University of Innsbruck between 2000 and 2018. Neurological work‐up included comprehensive neuropsychological testing including Consortium to Establish a Registry for Alzheimer's Disease (CERAD‐plus) test battery, Frontal Assessment Battery (FAB), digit span test (DST), clock drawing task (CLOX1), and Hospital Anxiety and Depression Scale (HADS‐D). Results The mean MMSE score was 27.6 points. Overall, slight to moderate cognitive impairment was noted in up to 40% of patients, with predominant impairment of executive function and verbal memory. Patients with the cerebellar variant performed significantly worse than patients with the parkinsonian type (P

Recent evidence has suggested that the hippocampus supports learning and retrieval of arithmetic facts during childhood and adolescence. Whether the hippocampus is also involved in retrieving overlearned arithmetic facts (such as 3 × 5 = 15) during adult age is open for investigation. In this study, we assessed whether patients with hippocampal atrophy due to Alzheimer’s disease (AD) are still able to retrieve overlearned arithmetic facts from memory. Sixteen patients (n = 13 with AD, n = 3 with Mild Cognitive Impairment – MCI) were evaluated using standard radiological, neurological, and neuropsychological test procedures. We adopted a multiple single-case analysis in order to acknowledge possible dissociations between hippocampal degeneration and intact arithmetic fact retrieval. All patients performed a neuropsychological screening battery assessing episodic memory as well as arithmetic processing, and underwent a 3-Tesla MRI procedure. A morphometric analysis comprising estimation of both cortical thickness and hippocampal volume, which also included a subfield analysis, was conducted. All patients had marked hippocampal atrophy (bilateral n = 15, unilateral n = 1) in comparison to healthy matched controls and showed deficits in episodic memory (delayed recall). However, 13 out of 16 patients performed in the average range of standardised norms during retrieval of overlearned arithmetic facts (i.e. multiplication tables). Our results suggest that intact retrieval of consolidated arithmetic facts from memory does not depend on the integrity of the hippocampus. This is in line with the view that the hippocampus plays a dynamic and time-limited role in arithmetic processing. While the hippocampus seems to be necessary for learning and consolidating new arithmetic facts in memory, it might not be critically involved in retrieving arithmetic facts when these are well consolidated in memory.

Patients with restless legs syndrome (RLS) use various terms when describing their symptoms. Whether gender might influence this has not been investigated so far. The aim of this study was to evaluate possible gender differences in spontaneous descriptions of RLS symptoms. This prospective study, conducted in 100 consecutive German-speaking RLS patients, used a single standardized question. Answers were digitally recorded and transcribed. A content-related linguistic analysis of the transcripts was performed by two independent blinded raters. The lengths of the answers and content-related linguistic features were compared between women and men. Ninety-eight patients were included in the final analysis, 59 women (60.2%) and 39 men (39.8%), with a median age of 62 (23-94) and 63 (31-82) years, respectively (p = 0.602). Demographic and clinical features, including educational level and RLS treatment class, did not differ between genders (p > 0.05). Total word or sentence count showed no gender differences (p = 0.159 and 0.259, respectively), although men used more words per sentence than women (p = 0.018). More men than women described quiescegenic (i.e., triggered by rest or inactivity) symptoms (p = 0.006) and successful attempts at relief (p = 0.039). There was a non-significant trend toward a more frequent use of the first-person perspective in men (median times used = 5 [0-10.5] vs. 3.8 [0-17.5], p = 0.068). The more frequent mention of quiescegenic symptoms and successful attempts at relief in men could indicate differences in phenotypic presentation of RLS between genders, a more precise description of RLS symptoms or a higher experience of self-efficacy in men compared to women.

Background: Agraphia is a typical feature in the clinical course of Alzheimer’s disease (AD). Objective: Assess the differences between AD and normal aging as regards kinematographic features of handwriting and elucidate writing deficits in AD. Methods: The study included 23 patients with AD (78.09 years/SD = 7.12; MMSE 21.39/SD = 3.61) and 34 healthy controls (75.56 years/SD = 5.85; MMSE 29.06/SD = 0.78). Both groups performed alphabetical and non-alphabetical writing tasks. The kinematographic assessment included the average number of inversions per stroke (NIV; number of peaks in the velocity profile in a single up or down stroke), percentage of automated segments, frequency (average number of strokes per second), writing pressure, and writing velocity on paper. Results: A total of 14 patients showed overt writing difficulties reflected by omissions or substitutions of letters. AD patients showed less automated movements (as measured by NIV), lower writing velocity, and lower frequency of up-and-down strokes in non-alphabetical as well as in alphabetical writing. In the patient group, Spearman correlation analysis between overt writing performance and NIV was significant. That means patients who had less errors in writing a sentence showed a higher automaticity in handwriting. The correctness of alphabetical writing and some kinematographic measures in writing non-alphabetical material reached excellent diagnostic values in ROC analyses. There was no difference in the application of pressure on the pen between patients and controls. Conclusion: Writing disorders are multi-componential in AD and not strictly limited to one processing level. The slow and poorly automated execution of motor programs is not bound to alphabetical material.

Background Previous studies reported reduced decision‐making abilities for patients with multiple sclerosis (MS) relative to healthy controls (HC). This study aimed to evaluate whether these problems arise when sampling information or when pondering about the evidence collected. Methods In a cross‐sectional, controlled study, 43 relapsing‐remitting MS patients (RRMS; Expanded Disability Status Scale 1.5, range 0–4) and 53 HC performed an information sampling task (‘beads task’), a health‐related framing task, and neuropsychological background tests. Results In the beads task, patients collected as much information as HC prior to a decision. However, there were twice as many patients as HC making irrational decisions, that is, decisions against the evidence collected (RRMS: 26/43, 60%; HC: 16/53, 30%; p = 0.003). Compared to HC, patients also showed a stronger framing effect, that is, they were more strongly biased by the way health‐related information was presented (p, This study shows that patients with multiple sclerosis (MS) collect as much information as healthy controls (HC) do prior to making a decision. However, twice as many patients as HC make irrational decisions, that is, decisions against the evidence collected. Compared to HC, patients also show stronger framing effects, that is, they are more strongly biased by the way health‐related information is presented. These results warrant caution in communication, especially in the medical context, with patients.

OBJECTIVE To assess the role of cognitive reserve, age, gender and brain structure in proper name retrieval in advanced age. METHOD Performance in 2 naming tasks (asking for proper names or common names) and 2 memory tasks was assessed. In separate hierarchical regressions, we evaluated whether retrieval was predicted by gray matter thickness or volume in selected structures (Model 1) and whether the addition of age and gender (Model 2) or of education (Model 3) explained significantly more variance. Participants were healthy persons (ages 70-90 years). Out of 91 individuals, 18 were excluded after inspection of magnetic resonance imaging scans showing relevant white matter changes. The remaining 73 individuals (47 women) showed good cognitive abilities. RESULTS Age was a significant predictor for the retrieval of well-known proper names, whereas selected gray matter measures and education had no significant effect. In contrast, education was predictive of common names retrieval and performance in the memory tasks. Gray matter measures predicted performance in the 2 memory tasks. CONCLUSIONS Cognitive reserve has a differential effect on cognitive abilities in advances age. Education did not support the retrieval of well-known proper names but positively affected the retrieval of common names and performance in memory tasks. Cognitive reserve has to be considered in neuropsychological diagnostic procedures. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Introduction: Previous studies have shown an association between a high health numeracy and good cognitive functioning. Objective: To investigate the moderation effect of education on this relationship and which brain structures support health numeracy. Methods: We examined 70 healthy older persons (66% females; mean ± SD: age, 75.73 ± 4.52 years; education, 12.21 ± 2.94 years). The participants underwent a T1-weighted 3-T MRI and a neuropsychological assessment including a health numeracy task. Statistical parametric mapping was applied to identify focal changes in cortical thickness throughout the entire brain and to correlate image parameters with behavioral measures. Results: Executive functions and mental calculation emerged as predictors of health numeracy (B = 0.22, p < 0.05, and B = 0.38, p < 0.01). An interaction was found between education and executive functions (B = –0.16, p = 0.01) and between education and mental calculation (B = –0.11, p < 0.05). Executive functions and mental calculation had an impact on health numeracy in participants with a low to intermediate edu­cation (≤12 years) but not in those with a higher education (>12 years). Health numeracy scores were associated with cortical thickness in the right dorsomedial prefrontal cortex and the right superior temporal gyrus (p = 0.01). Conclusions: Older people with a higher education perform better in health numeracy tasks than those with a lower education. They have access to previously acquired knowledge about ratio concepts and do not need to rely on executive functions and computational skills. This is highly relevant when decisions about health care have to be made.

Background and purpose People with multiple sclerosis (MS) have to face important decisions with regard to their medical treatment. The aim of this study was to evaluate whether a targeted cognitive training reduces framing effects and thus improves medical judgments. Methods This was a randomized, double‐blind, cross‐over study enrolling patients with relapsing‐remitting MS and healthy controls (HCs). Participants were randomly assigned to training order A (first week, numerical training; second week, control training) or B (reverse order). The primary endpoint was changed in a framing task score (framing effect). In the framing task, participants evaluated the success of fictive medications on a 7‐point scale. Medications were described in either positive or negative terms. Results A total of 37 patients and 73 HCs performed either training order A (n = 56) or B (n = 54). The framing effect decreased after the numerical training regardless of training order. No such decrease was found after the control training. Mean change in framing effect was −0.3 ± 0.8 after the numerical training and 0.03 ± 0.6 after the control training. This specific effect of training type was comparable between groups. Conclusion Judgments of medical information improve in both patients with relapsing‐remitting MS and HCs after a targeted numerical training. Thus, a specific cognitive intervention may help patients making informed decisions.

Background Patients with mild cognitive impairment (MCI) show lower decision making and ratio processing abilities as compared to healthy peers. Objective To evaluate whether cognitive training on number processing and/or executive functions improves performance on ratio processing and decision making under risk. Methods In a controlled cross-over study, patients with MCI (n = 23; mean MMSE 26.48, SD 2.43) underwent a week of numerical training followed by a week of executive-functions training (subgroup A), or vice versa (subgroup B). Before training (T1), patients performed experimental tasks of decision making (Game of Dice Task, GDT; Probability-Associated Gambling task, PAG-60 task) and of ratio processing as well as a neuropsychological background assessment. Experimental tasks were also administered after the first (T2) and the second (T3) training week. Results The numerical training and the training of executive functions had a differential effect on experimental tasks of ratio processing. Only the numerical training proved to be effective. The effects of the two training types on decision making under risk were less clear-cut. While no changes over time were observed in the GDT, performance on the PAG-60 task improved in both training subgroups. These improvements were apparent in one subgroup after a period of executive-functions training, in the other subgroup after both training weeks. That means, improvements are not attributable to one specific training type. Conclusion Patients with MCI can profit from a cognitive training on number processing and executive functions. Improvements are reflected in higher ratio processing abilities and more advantageous decisions after training. These results are consistent with assumptions of current cognitive models.

Background A number of neuropsychological alterations have been found in patients who have attempted suicide. Most studies investigating decision making (DM) abilities in suicide attempters so far have used one single DM task and included patients with a lifetime history of suicide attempts. These studies have yielded conflicting results. Method In this study, currently depressed in-patients who had a recent suicide attempt (within the last six months) (n = 21), depressed in-patients without a lifetime history of suicide attempts (n = 31) and a healthy control group (n = 26) were assessed with two tasks for the assessment of DM. The Game of Dice Task (GDT) measures DM under risk and the Iowa Gambling Task (IGT) DM under ambiguity. Further, depression severity, impulsiveness and suicidal intent of the current suicide attempt were assessed. Results Both depressed groups differed from controls with respect to marital and partnership status, smoking, impulsiveness and psychiatric family history. In terms of DM, IGT scores did not differ significantly between groups. However, suicide attempters made significantly more risky decisions as assessed with the GDT than both control groups (p Limitations The available tasks assess DM under laboratory conditions which may not reflect the emotional status of suicidal individuals. No general cognitive assessment was included. Conclusions Depressed suicide attempters differed with regard to DM under risk but not DM under ambiguity. When studying DM it appears crucial to take varying aspects of DM into account.

In this study, we investigated the effects of age and of mild cognitive impairment (MCI) on decision making under risk by adopting a task representing real-life health-related situations and involving complex numerical information. Moreover, we assessed the relationship of real-life decision making to other cognitive functions such as number processing, executive functions, language, memory, and attention. For this reason, we compared the performance of 19 healthy, relatively younger adults with that of 18 healthy older adults and the performance of the 18 healthy older adults with that of 17 patients with MCI. Results indicated difficulties in real-life decision making for the healthy older adults compared with the healthy, relatively younger adults. Difficulties of patients with MCI relative to the healthy older adults arose in particular in difficult items requiring processing of frequencies and fractions. Significant effects of age and of MCI in processing frequencies were also evident in a ratio number comparison task. Decision-making performance of healthy participants and of the patient group correlated significantly with number processing. There was a further significant correlation with executive functions for the healthy participants and with reading comprehension for the patients. Our results suggest that healthy older individuals and patients with MCI make less advantageous decisions when the information is complex and high demands are put on executive functions and numerical abilities. Moreover, we show that executive functions and numerical abilities are not only essential in laboratory gambling tasks but also in more realistic and ecological decision situations within the health context.

The study of RNA dynamics, specifically RNA transcription and decay rates, has gained increasing attention in recent years because various mechanisms have been discovered that affect mRNA half-life, thereby ultimately controlling protein output. Therefore, there is a need for methods enabling minimally invasive, simple and high-throughput determination of RNA stability that can be applied to determine RNA transcription and decay rates in cells and organisms. We have recently developed a protocol which we named TUC-seq to directly distinguish newly synthesized transcripts from the preexisting pool of transcripts by metabolic labeling of nascent RNAs with 4-thiouridine (4sU) followed by osmium tetroxide-mediated conversion of 4sU to cytidine (C) and direct sequencing. In contrast to other related methods (SLAM-seq, TimeLapse-seq), TUC-seq converts 4sU to a native C instead of an alkylated or otherwise modified nucleoside derivative. TUC-seq can be applied to any cell type that is amenable to 4sU labeling. By employing different labeling strategies (pulse or pulse-chase labeling), it is suitable for a broad field of applications and provides a fast and highly efficient means to determine mRNA transcription and decay rates.

Trust is one of the foundations of human society and pervades all aspects of human live. Research on humans focused primarily on identifying the biological basis of trust behavior in healthy subjects, and this evidence hints to certain brain areas, hormones, and genetic factors to be fundamentally involved. The contribution of cortisol in trust has not yet elicited much attention in research, especially when specifically examined at basal cortisol levels. Trust has been previously studied in some neurological diseases but not in patients with epilepsy, and the influence of hormones on trust in these diseases remains yet unknown. Against this background, we designed an experimental study with a group of patients with juvenile myoclonic epilepsy and a group of healthy controls to compare trust behavior and plasma cortisol levels between the two groups. This economic game is frequently used in research to operationalize trust behavior. All participants further underwent neuropsychological assessment. Our results showed that there was no significant difference in trust behavior during the trust game, but a trend toward lower trust in patients. Furthermore, there was a significant difference in cortisol levels between groups with lower levels in patients. Interestingly, cortisol levels correlated with trust only in the patient group, but not in the control group. Future studies should specifically differentiate the effect of induced cortisol increases (e.g., acute stress) versus the effect of basal cortisol levels reflecting homeostasis or chronic stress on trust behavior and leverage the potential of comparison between patients and healthy controls.

Studies indicate that a brief period of wakeful rest after learning supports memory retention, whereas distraction weakens it. It is open for investigation whether advanced age has a significant effect on the impact of post-learning wakeful rest on memory retention for verbal information when compared to a cognitively demanding distraction task. In this study, we examined (1) whether post-learning rest promotes verbal memory retention in younger and older adults and (2) whether the magnitude of the rest benefit changes with increasing age. Younger adults and older adults learned and immediately recalled two consecutive word lists. After one word list, participants rested wakefully for 8 min; after the other list, they solved matrices. Memory performance was again tested in a surprise free recall test at the end of the experimental session. We found that, overall, younger adults outperformed older adults. Also, memory retention was higher following a wakeful rest phase compared to distraction. A detailed analysis revealed that this wakeful rest benefit was significant for the older adults group, whereas the younger adults group retained a similar amount of information in both post-encoding conditions. We assume that older adults can profit more from a wakeful rest phase after learning and are more prone to distraction than younger adults. With increasing age, a short break immediately after information uptake may help better retain the previously learned information, while distraction after learning tends to weaken memory retention.

Background and purpose CACNA1A encodes the α1 subunit of the neuronal calcium channel P/Q. CACNA1A mutations underlie three allelic disorders: familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6). A clear-cut genotype-phenotype correlation is often lacking since clinical manifestations may overlap. Several case reports have described cognitive and behavioral features in CACNA1A disorders, but studies in larger case series are lacking. Methods Genetically confirmed CACNA1A cases were retrieved from the database of the ataxia outpatient clinic of the Department of Neurology at Innsbruck Medical University. Clinical charts and neuropsychological test results were retrospectively analyzed. In addition, a review of the literature including only genetically confirmed cases was performed. Results Forty-four CACNA1A cases were identified in our database. Delayed psychomotor milestones and poor school performance were described in seven (four FHM1, three EA2) and eight (three FHM1, five EA2) patients, respectively. Psychiatric comorbidities were diagnosed in eight patients (two FHM1, six EA2). Neuropsychological testing was available for 23 patients (11 FHM1, 10 EA2, two SCA6). Various cognitive deficits were documented in 21 cases (all patients except one SCA6). Impairments were predominantly seen in figural memory, visuoconstructive abilities and verbal fluency. In the literature, an early psychomotor delay is described in several children with EA2 and FHM1, whilst reports of cognitive and psychiatric findings from adult cases are scarce. Conclusions Neuropsychiatric manifestations are common in episodic CACNA1A disorders. In the case of otherwise unexplained developmental delay and a positive family history, CACNA1A mutations should be considered in the differential diagnosis.

OBJECTIVE Previous studies have reported deficits in decision making under ambiguity for patients with mesial temporal lobe epilepsy (mTLE). It is unknown whether mTLE is also associated with alterations at a predecisional stage. This study aimed to gain insight into predecisional processing of patients with mTLE. METHOD We compared performance of patients with mTLE (n = 25) with that of healthy controls (n = 75) on the information sampling task (IST), a task assessing reflection-impulsivity and predecisional information sampling. RESULTS Patients and healthy controls showed a similar performance pattern in both conditions of the IST as indicated by the amount of information gathered, the degree of uncertainty tolerated, and the number of decision errors made. They both also demonstrated a significant sensitivity to the different reward characteristics of the task. For the patient group, we found no significant effects on performance on the IST of epilepsy lateralization, abnormality side, structural abnormality (hippocampus vs. amygdala), and medication (monotherapy vs. polytherapy). CONCLUSIONS Reflection processes and predecisional information sampling as tested by the IST are intact in mTLE. Patients collect as much information as healthy individuals and adapt their behavior according to the changing reward conditions. Our findings indicate that in well-defined risk situations, where memory demands are sufficiently minimized, patients with mTLE should be able to gather sufficient information, weight risks and benefits, and make advantageous decisions.

Acquisition of numerical knowledge and understanding of numerical information are crucial for coping with the changing demands of our digital society. In this study, we assessed arithmetic learning in older and younger individuals in a training experiment including brain imaging. In particular, we assessed age-related effects of training intensity, prior arithmetic competence, and neuropsychological variables on the acquisition of new arithmetic knowledge and on the transfer to new, unknown problems. Effects were assessed immediately after training and after 3 months. Behavioural results showed higher training effects for younger individuals than for older individuals and significantly better performance after 90 problem repetitions than after 30 repetitions in both age groups. A correlation analysis indicated that older adults with lower memory and executive functions at baseline could profit more from intensive training. Similarly, training effects in the younger group were higher for those individuals who had lower arithmetic competence and executive functions prior to intervention. In younger adults, successful transfer was associated with higher executive functions. Memory and set-shifting emerged as significant predictors of training effects in the older group. For the younger group, prior arithmetic competence was a significant predictor of training effects, while cognitive flexibility was a predictor of transfer effects. After training, a subgroup of participants underwent an MRI assessment. A voxel-based morphometry analysis showed a significant interaction between training effects and grey matter volume of the right middle temporal gyrus extending to the angular gyrus for the younger group relative to the older group. The reverse contrast (older group vs. younger group) did not yield any significant results. These results suggest that improvements in arithmetic competence are supported by temporo-parietal areas in the right hemisphere in younger participants, while learning in older people might be more widespread. Overall, our study indicates that arithmetic learning depends on the training intensity as well as on person-related factors including individual age, arithmetic competence before training, memory, and executive functions. In conclusion, we suggest that major progress can be also achieved by older participants, but that interventions have to take into account individual variables in order to provide maximal benefit.

Many decision situations in everyday life involve mathematical considerations. In decisions under objective risk, i.e., when explicit numeric information is available, executive functions and abilities to handle exact numbers and ratios are predictors of objectively advantageous choices. Although still debated, exact numeric abilities, e.g., normative calculation skills, are assumed to be related to approximate number processing skills. The current study investigates the effects of approximative numeric abilities on decision making under objective risk. Participants (N = 153) performed a paradigm measuring number-comparison, quantity-estimation, risk-estimation, and decision-making skills on the basis of rapid dot comparisons. Additionally, a risky decision-making task with exact numeric information was administered, as well as tasks measuring executive functions and exact numeric abilities, e.g., mental calculation and ratio processing skills, were conducted. Approximative numeric abilities significantly predicted advantageous decision making, even beyond the effects of executive functions and exact numeric skills. Especially being able to make accurate risk estimations seemed to contribute to superior choices. We recommend approximation skills and approximate number processing to be subject of future investigations on decision making under risk.

Recent models on decision making under risk conditions have suggested that numerical abilities are important ingredients of advantageous decision-making performance, but empirical evidence is still limited. The results of our first study show that logical reasoning and basic mental calculation capacities predict ratio processing and that ratio processing predicts decision making under risk. In the second study, logical reasoning together with executive functions predicted probability processing (numeracy and probability knowledge), and probability processing predicted decision making under risk. These findings suggest that increasing an individual's understanding of ratios and probabilities should lead to more advantageous decisions under risk conditions.

Recent evidence suggests axonal injury after aneurysmal subarachnoid haemorrhage (aSAH). The microtubule-associated protein, tau, has been shown to be elevated in the cerebrospinal fluid after aSAH, however, brain extracellular tau levels and their relation to long-term neurological and cognitive outcomes have not been investigated.Serial cerebral microdialysis (CMD) samples were collected from 22 consecutive aSAH patients with multimodal neuromonitoring to determine CMD-total-tau by ELISA. CMD-total-tau was analysed considering other brain metabolic parameters, brain tissue oxygen tension (PbtO2), and functional and neuropsychological outcome at 12 months. All outcome models were analysed using generalised estimating equations with an autoregressive working correlation matrix to account for multiple measurements of brain extracellular proteins per subject.CMD-total-tau levels positively correlated with brain extracellular fluid levels of lactate (r=0.40, p0.001), glutamate (r=0.45, p0.001), pyruvate (r=0.26, p0.001), and the lactate-pyruvate ratio (r=0.26, p0.001), and were higher in episodes of hypoxic (PbtO220 mm Hg) brain extracellular lactate elevation (4 mmol/L) (p0.01). More importantly, high CMD-total-tau levels were associated with poor functional outcome (modified Rankin Scale ≥4) 12 months after aSAH even after adjusting for disease severity and age (p=0.001). A similar association was found with 3/5 neuropsychological tests indicative of impairments in cognition, psychomotor speed, visual conceptualisation and frontal executive functions at 1 year after aSAH (p0.01).These results suggest that CMD-total tau may be an important biomarker for predicting long-term outcome in patients with severe aSAH. The value of axonal injury needs further confirmation in a larger patient cohort, preferably combined with advanced imaging techniques.

The study aimed at investigating health numeracy in cognitively well performing healthy participants aged from 50 to 95 years as well as in participants with cognitive impairment, but no dementia (CIND). In cognitively well performing participants (n = 401), demographic variables and cognitive abilities (executive functions, reading comprehension, mental calculation, vocabulary) were associated with health numeracy. Older age, lower education, female gender as well as lower cognitive functions predicted low health numeracy. The effect of older age was partly mediated by executive functions and calculation abilities. Participants with CIND (n = 51) performed significantly lower than healthy controls in health numeracy. The findings suggest that cognitively well performing old individuals have difficulties in understanding health-related numerical information. The risk of misunderstanding health-related numerical information is increased in persons with CIND. As these population groups are frequently involved in health care decisions, particular attention has to be paid to providing numerical information in comprehensible form.

Highlights • We assessed midbrain–hindbrain in a large series of cortical malformation patients. • Midbrain–hindbrain malformations are commonly linked to cortical malformations. • Midbrain–hindbrain malformations are associated with severe clinical phenotype., Summary Midbrain–hindbrain malformations (MHM) may coexist with malformations of cortical development (MCD). This study represents a first attempt to investigate the spectrum of MHM in a large series of patients with MCD and epilepsy. We aimed to explore specific associations between MCD and MHM and to compare two groups of patients: MCD with MHM (wMHM) and MCD without MHM (w/oMHM) with regard to clinical and imaging features. Two hundred and twenty patients (116 women/104 men, median age 28 years, interquartile range 20–44 years at the time of assessment) with MCD and epilepsy were identified at the Departments of Neurology and Pediatrics, Innsbruck Medical University, Austria. All underwent high-resolution MRIs (1.5-T) between 01.01.2002 and 31.12.2011. Midbrain–hindbrain structures were visually assessed by three independent raters. MHM were seen in 17% (38/220) of patients. The rate of patients wMHM and w/oMHM differed significantly (p = 0.004) in three categories of MCD (category I – to abnormal neuronal proliferation; category II – to abnormal neuronal migration; and category III – due to abnormal neuronal late migration/organization): MCD due to abnormal neuronal migration (31%) and organization (23%) were more commonly associated with MHM compared to those with MCD due to abnormal neuronal proliferation (9%). Extensive bilateral MCD were seen more often in patients wMHM compared to those w/oMHM (63% vs. 36%; p = 0.004). In wMHM group compared to w/oMHM group there were higher rates of callosal dysgenesis (26% vs. 4%; p

Executive dysfunction (ED) is a frequent consequence of neurological disorders, such as stroke, trauma or dementia, but also appears in normal aging. We developed a German version of the Frontal Assessment Battery (FAB-D), a short test which has previously been developed (Dubois et al., Neurology 55:1621-1626, 2000) to detect ED during bedside screening. A sample of 401 cognitively intact subjects aged 50-95 was tested with the FAB-D and several neuropsychological tests tapping executive functions, memory and calculation abilities. Aim of the study was to receive normative data for different age and educational groups, and to learn which tests predict performance on the FAB-D. We found clear effects of age and education; furthermore, FAB-D performance was predicted by other tests of executive functioning, but also by calculation and memory abilities. The present study reports data of healthy individuals and may be useful for comparing patients' performance with a normative sample.

Background Few studies have investigated in detail which factors influence activities of daily (ADL) in Alzheimer's disease (AD). Objective To assess the influence of cognitive, gender, and other factors on ADL in patients with mild to moderate AD. Methods This study is part of the Prospective Registry on Dementia in Austria (PRODEM) project, a multicenter dementia research project. A cohort of 221 AD patients (130 females; means: age 76 years, disease duration 34.4 months, MMSE 22.3) was included in a cross-sectional analysis. Everyday abilities were assessed with the Disability Assessment for Dementia scale, and cognitive functions with the CERAD plus neuropsychological test battery. Two models of multiple linear regressions were performed to find factors predicting functional decline, one entering demographical and disease related factors, and a joint model combining demographical and disease variables with neuropsychological scores. Results Non-cognitive factors explained 18%, whereas the adding of neuropsychological variables explained 39% of variance. Poor figural and verbal memory, constructional abilities, old age, longer disease duration, depression, and male gender were independent risk factors for reduced ADL. Instrumental and basic ADL were predicted by similar factors, except gender (predicting only instrumental ADL) and phonological fluency (predictor of basic ADL). Conclusion In addition to demographical factors, disease duration, and depression, neuropsychological variables are valuable predictors of the functional status in AD in an early disease stage.

In this study, we assessed to what extent reasoning improves performance in decision making under risk in a laboratory gambling task (Game of Dice Task-Double, GDT-D). We also investigated to what degree individuals with above average mathematical competence decide better than those with average mathematical competence. Eighty-five participants performed the GDT-D and several numerical tasks. Forty-two individuals were asked to calculate the probabilities and the outcomes associated with the different options of the GDT-D before performing it. The other 43 individuals performed the GDT-D at the beginning of the test session. Both reasoning and mathematical competence had a positive effect on decision making. Different measures of mathematical competence correlated with advantageous performance in decision making. Results suggest that decision making under explicit risk conditions improves when individuals are encouraged to reflect about the contingencies of a decision situation. Interventions based on numerical reasoning may also be useful for patients with difficulties in decision making.

Recent neuroimaging studies have reported structural and functional brain abnormalities in patients with juvenile myoclonic epilepsy (JME), which may also involve cortical and subcortical networks that are important for decision making. This study is the first attempt to examine decision making in JME. Twenty-two patients with JME (median age 26.00, range 18-50) and 33 healthy controls (median age 26.00, range 18-57) participated in the study. For the JME group, the median age at seizure onset was 14.00 years (range 1-20); the median epilepsy duration was 11.50 years (range 3-45). Eleven patients (50 %) had pharmacoresistant seizures. All participants completed the Iowa Gambling Task (IGT), a widely used standard task of decision making. In this task, contingencies are not explained and feedback on previous decisions has to be used in order to learn to choose the advantageous alternatives. In the IGT, patients with JME showed difficulty in learning to choose advantageously compared to healthy controls. Difficulty was enhanced for the patients with pharmacoresistant seizures. A correlation analysis revealed an association between decision-making performance of patients with JME and executive functions. Results indicate that patients with JME have difficulty in making advantageous decisions and that persistence of seizures might be a critical factor for cognitive functioning. Findings of this study add a new aspect to the neuropsychological profile of JME. Difficulty in decision making may impair functioning of patients with JME in everyday life and affect their adherence to treatment plans.

OBJECTIVE To investigate long-term cognitive outcome, mood, and quality of life in a family with genetically proven familial hemiplegic migraine (FHM). BACKGROUND FHM is a rare autosomal-dominant subtype of migraine with aura, characterized by some degree of hemiparesis during the aura. In a previous study, we showed preserved and impaired cognitive functions in patients with FHM. Until now, the progression of cognitive dysfunctions has not been known. However, the ability to predict progression is important for counseling patients about education, career, and family life. METHODS Seven years after extensive baseline neuropsychological testing, we retested 6 members of a family with FHM, including questionnaires about mood and quality of life. RESULTS The follow-up assessment revealed no global cognitive decline. All the patients' linguistic abilities and verbal memory remained intact; however, their figural memory, attention, and some aspects of executive function were impaired. Half the patients had a slight deterioration in their visuoconstructional functions. Half had higher scores on the trait and state anxiety measures. CONCLUSIONS Cognitive deficits in a family with FHM persisted, but without marked progression. Worsening of visuoconstructional abilities may be related to executive dysfunction, confirming a disturbance of cerebrocerebellar circuits.

In this study we describe a patient (FR) with left frontal lesions due to a cerebrovascular disorder of embolic origin. Beyond a general slowness, FR showed deficits in simple multiplication only when problems were presented in a mixed operations list (multiplication, addition, and subtraction), while no such deficits were observed for the same multiplication problems in blocked presentation. Deficits were restricted to trials directly affected by a switch (increased switch costs), but not to subsequent trials (no increased mixing costs). Thus, we provide the first detailed description of a condition which could be termed 'task-switching acalculia' in a stroke patient. This case highlights the need for mixed operation lists in the diagnosis of acalculia.

It is not known whether and in which way patients with mild cognitive impairment (MCI) and patients with mild Alzheimer's disease (AD) are affected by the information frame when judging the outcome of a medication. This study aimed to compare framing effects between healthy older adults, MCI patients, and mild AD patients.Participants performed a framing task where they had to judge the outcome of unknown medications on a 7-point scale. Medications were described either by using positive terms (positive frame) or by using negative terms (negative frame).All three groups showed framing effects and judged more favourably the positively-framed medications than the negatively-framed medications. However, framing effects were more pronounced in MCI patients and mild AD patients than in healthy older adults.This study suggests that the way information is conveyed is critical and that health-related decisions of patients with slight cognitive impairment may be relevantly biased by positive and negative formulations. The development of standardised, easily understandable means of patient information is recommended.

To describe the cognitive functions, mood, and quality of life in a family with genetically proved familial hemiplegic migraine (FHM), carrying a missense mutation on chromosome 19 (T666M), corresponding to the most frequent FHM subtype.FHM is an autosomal dominant subtype of migraine with an aura, characterized by hemiparesis during the aura. Whereas the genetic background of FHM has been studied intensely, less attention has been paid to cognitive functions and mood between attacks.Six patients performed neuropsychologic assessment between attacks. Depression, anxiety, and quality of life were evaluated by questionnaires. Cerebral magnetic resonance imaging was performed.Neuropsychologic assessment revealed a distinct pattern of preserved and impaired functions. Whereas linguistic abilities and verbal memory were intact, all patients showed deficits in figural memory, executive functions, in some aspects of attention, and in dexterity. Intelligence of 1 patient was below average. All but 1 patient reported normal quality of life; there were no symptoms of depression or state anxiety. All patients showed cerebellar atrophy and cerebellar ataxia.Cognitive abnormalities and cerebellar atrophy were found in all patients. FHM-related cognitive deficits may be associated to a disturbance of cerebrocerebellar circuits.

Objectives: Hippocampal abnormalities may coexist with malformations of cortical development (MCD). This cross-sectional MRI study aimed at categorizing hippocampal abnormalities in a large group of MCD and comparing MCD patients with (group W) and without (group W/O) hippocampal abnormalities. Methods: Hippocampal anatomy, rotation, size, internal structure, and MRI signal alterations were assessed visually by 3 independent raters in patients with MCD and epilepsy. Four types of hippocampal abnormalities were examined in 220 patients (116 women, mean age 31 ± 16.6, range 2-76 years): partially infolded/hypoplastic hippocampus (HH), hippocampal sclerosis (HS), malrotated hippocampus (MH), and enlarged hippocampus (EH). The commonest MCD in the cohort were focal cortical dysplasia (27%), polymicrogyria (PMG) (21%), developmental tumors (15%), and periventricular nodular heterotopia (PNH) (14%). Results: Hippocampal abnormalities were seen in 69/220 (31%) patients: HH in 34/69 (49%); HS in 18/69 (26%); MH in 15/69 (22%); and EH in 2/69 (3%). PNH (21/30 [70%]) and PMG (22/47 [47%]) were most commonly associated with hippocampal abnormalities. Compared to the W/O group, patients in the W group had a higher rate of learning disability (W 41/69 [59%] vs W/O 56/151 [37%]; p = 0.003) and delayed developmental milestones (W 36/69 [52%] vs W/O 53/151 [35%]; p = 0.025); groups did not differ otherwise with regard to clinical presentation. HH was associated with symptomatic generalized epilepsies (11/34 [32%]) and high rate of learning disability (27/34 [79%]), neurologic deficits (25/34 [73%]), and delayed developmental milestones (23/34 [68%]). Conclusions: About a third of patients with malformations of cortical development had hippocampal abnormalities. Patients with hypoplastic hippocampus had the most severe clinical phenotype.

Objectives This study aimed to investigate whether patients with mild cognitive impairment (MCI) present difficulties in making decisions under ambiguity and under risk. Methods Performance of MCI patients in the Iowa Gambling Task (IGT) and in the Probability-Associated Gambling Task-Revised (PAG-R) was compared with performance of healthy aging peers. Results In the IGT, controls made increasingly frequent advantageous selections over time; MCI patients selected randomly from advantageous and disadvantageous decks, with no significant change in performance over time. In the PAG-R, controls decided advantageously in conditions of both (low, high) winning probabilities; patients made less advantageous decisions than controls in conditions of low winning probability. Discussion In the decision under ambiguity task (IGT), MCI patients experienced difficulties in learning from feedback and in maintaining an advantageous strategy over time. In the decision under risk task (PAG-R), patients had problems in integrating information from different sources and in adapting their strategy to changes in the decision situation. In summary, MCI patients present difficulties in advantageous decision making that resemble those reported for patients with mild dementia.

It is widely accepted that the human brain is remarkably adaptive not only in child development, but also during adulthood. Aim of this work is to offer an overview and a systematic analysis of neuroimaging studies on the acquisition of arithmetic expertise. In normally developing children and adults, the gain of arithmetic competence is reflected by a shift of activation from frontal brain areas to parietal areas relevant for arithmetic processing. A shift of activation is also observed within the parietal lobe from the intraparietal sulci to the left angular gyrus. Increases in angular gyrus activation with gaining of expertise have also been documented in other cognitive domains. It appears that the left angular gyrus activation is modulated by inter-individual differences in arithmetic performance. The comparison of normal individuals with exceptionally performing individuals (e.g., calculating prodigies) suggests that the experts' arithmetic proficiency relies on a more extended activation network than the network found in non-experts. In expert individuals with long-lasting, extensive mathematical training, specific structural brain modifications are also evident.

Recent imaging studies could show that fact acquisition in arithmetic is associated with decreasing activation in several frontal and parietal areas, and relatively increasing activation within the angular gyrus, indicating a switch from direct calculation to retrieval of a learned fact from memory. So far, however, little is known about the transfer of learned facts between arithmetic operations. The aim of the present fMRI study was to investigate whether and how newly acquired arithmetic knowledge might transfer from trained multiplication problems to related division problems. On the day before scanning, ten complex multiplication problems were trained. Within the scanner, trained multiplication problems were compared with untrained multiplication problems, and division problems related to multiplication (transfer condition) were compared with unrelated division problems (no-transfer condition). Replicating earlier results, untrained multiplication problems activated several frontal and parietal brain areas more strongly than trained multiplication problems, while trained multiplication problems showed relatively stronger activation in the left angular gyrus than untrained multiplication problems. Concerning division, an ROI analysis indicated that activation in the left angular gyrus was relatively stronger for the transfer condition than for the no-transfer condition. We also observed distinct inter-individual differences with regard to transfer that modulated activation within the left angular gyrus. Activation within the left angular gyrus was generally higher for participants who showed a transfer effect for division problems. In conclusion, the present study yielded some evidence that successful transfer of knowledge between arithmetic operations is accompanied by modifications of brain activation patterns. The left angular gyrus seems not only to be involved in the retrieval of stored arithmetic facts, but also in the transfer between arithmetic operations.

Objective and Background: Decision under ambiguity and decision under risk are fundamental in every-day life. Methods: We investigated these 2 types of decision in traumatic brain injury (TBI) patients through the Iowa Gambling Task (IGT), the Probability-associated Gambling (PAG) task, and a counsel version of the PAG task. Although in the IGT rules for gain and losses are implicit and probability information is missing, in the PAG task and the counsel task rules are explicit and probabilities are well-defined. Results: In the IGT, TBI patients selected more disadvantageously than healthy controls and failed to develop an advantageous strategy over time. Patients also made less advantageous choices than controls in the PAG task and the counsel task. Compared with controls, TBI patients gambled more frequently with low probabilities and less frequently with high probabilities. Overall, participants decided more advantageously in the counsel task, which does not provide feedback, than in the PAG task. Importantly, our results indicate that TBI patients’ performance on all decision tasks correlated with executive functions. Conclusions: Our study shows that TBI patients have difficulties in decision under risk and decision under ambiguity. Difficulties may be attributed to deficient learning from feedback and to reduced risk estimation, but not to impulsive risk taking behavior.

The present study investigated arithmetic processing in patients with mild dementia of Alzheimer's type (DAT) and patients with mild cognitive impairment (MCI) without dementia. Arithmetic processing (e.g., 2 + 3 = ?, 3 × 4 = ?) was evaluated in (1) ‘blocked’ condition (without extra load on attentional and executive functions), in (2) ‘mixed’ condition (shifting between different operations was required), and in (3) ‘Stroop-like’ condition (executive control and inhibition of automatic retrieval processes were needed). Both DAT and MCI patients showed intact arithmetic knowledge retrieval from long-term memory in the blocked condition. However, DAT patients were compromised whenever load was put on executive functions, whereas MCI patients succeeded to shift between operations (mixed condition) but had difficulties to inhibit overlearned associations (Stroop-like condition). In line with previous studies, these findings point to the contribution of attentional and executive functions in arithmetic. The present investigation is also of clinical relevance: it suggests that it may be important to assess arithmetic processing not only in blocked presentation but also in mixed presentation. The mixed condition has a high ecological value because it mimics daily-life arithmetic activities (e.g., checking the grocery bill). As indicated by the present results, DAT and MCI patients who are in the normal range at routine neuropsychological (blocked) arithmetic assessments may experience difficulties by extra requirement of non-numerical resources. That means, they possibly process arithmetic not efficiently in daily-life situations.

Months, days of the week, and numbers differ from other verbal concepts because they are ordered in a sequence, whereas no order is imposed on members of other categories, such as animals or tools. Recent studies suggest that numbers activate a representation of their quantity within the intraparietal sulcus (IPS) automatically, that is, in tasks that do not require the processing of quantity. It is unclear, however, whether ordered verbal materials in general and not only numbers activate the IPS in such tasks. In the present functional magnetic resonance imaging study word generation of months, numbers, and animals were compared. Word generation of numbers and nonnumerical materials from an ordered category (months) activated the IPS more strongly than generating items from a not‐ordered category such as animals or the verbal control conditions. An ROI analysis of three subregions within the anterior IPS revealed that the most anterior and lateral of these regions, human intraparietal area hIP2, shows a greater sensitivity to ordered materials than the other two areas, hIP1 and hIP3. Interestingly, no difference in activation was observed within the IPS between numbers and months suggesting that the activation of the IPS might not be modulated by the additional quantity information carried by numbers. Hum Brain Mapp, 2008. © 2007 Wiley‐Liss, Inc.

BackgroundThe aim of the present study was to investigate possible sex differences in the recognition of facial expressions of emotion and to investigate the pattern of classification errors in schizophrenic males and females. Such an approach provides an opportunity to inspect the degree to which males and females differ in perceiving and interpreting the different emotions displayed to them and to analyze which emotions are most susceptible to recognition errors.MethodsFifty six chronically hospitalized schizophrenic patients (38 men and 18 women) completed the Penn Emotion Recognition Test (ER40), a computerized emotion discrimination test presenting 40 color photographs of evoked happy, sad, anger, fear expressions and neutral expressions balanced for poser gender and ethnicity.ResultsWe found a significant sex difference in the patterns of error rates in the Penn Emotion Recognition Test. Neutral faces were more commonly mistaken as angry in schizophrenic men, whereas schizophrenic women misinterpreted neutral faces more frequently as sad. Moreover, female faces were better recognized overall, but fear was better recognized in same gender photographs, whereas anger was better recognized in different gender photographs.ConclusionsThe findings of the present study lend support to the notion that sex differences in aggressive behavior could be related to a cognitive style characterized by hostile attributions to neutral faces in schizophrenic men.

Making advantageous decisions is important in everyday life. This study aimed at assessing how patients with mild cognitive impairment (MCI) make decisions under risk. Additionally, it investigated the relationship between decision making, ratio processing, basic numerical abilities, and executive functions. Patients with MCI (n = 22) were compared with healthy controls (n = 29) on a complex task of decision making under risk (Game of Dice Task-Double, GDT-D), on two tasks evaluating basic decision making under risk, on a task of ratio processing, and on several neuropsychological background tests. Patients performed significantly lower than controls on the GDT-D and on ratio processing, whereas groups performed comparably on basic decision tasks. Specifically, in the GDT-D, patients obtained lower net scores and lower mean expected values, which indicate a less advantageous performance relative to that of controls. Performance on the GDT-D correlated significantly with performance in basic decision tasks, ratio processing, and executive-function measures when the analysis was performed on the whole sample. Patients with MCI make sub-optimal decisions in complex risk situations, whereas they perform at the same level as healthy adults in simple decision situations. Ratio processing and executive functions have an impact on the decision-making performance of both patients and healthy older adults. In order to facilitate advantageous decisions in complex everyday situations, information should be presented in an easily comprehensible form and cognitive training programs for patients with MCI should focus--among other abilities--on executive functions and ratio processing.

Summary This study assessed decision-making and its associations with executive functions and sleep-related factors in patients with obstructive sleep apnea. Thirty patients with untreated obstructive sleep apnea and 20 healthy age- and education-matched controls performed the Iowa Gambling Task, a decision-making task under initial ambiguity, as well as an extensive neuropsychological test battery. Patients, but not controls, also underwent a detailed polysomnographic assessment. Results of group analyses showed that patients performed at the same level of controls on the Iowa Gambling Task. However, the proportion of risky performers was significantly higher in the patient group than in the control group. Decision-making did not correlate with executive functions and subjective ratings of sleepiness, whereas there was a significant positive correlation between advantageous performance on the Iowa Gambling Task and percentage of N2 sleep, minimal oxygen saturation, average oxygen saturation and time spent below 90% oxygen saturation level. Also, the minimal oxygen saturation accounted for 27% of variance in decision-making. In conclusion, this study shows that a subgroup of patients with obstructive sleep apnea may be at risk of disadvantageous decision-making under ambiguity. Among the sleep-related factors, oxygen saturation is a significant predictor of advantageous decision-making.

Background Pallidal deep brain stimulation (DBS) is effective in alleviating motor symptoms of medication refractory cervical dystonia, but little is known about effects on cognitive functions. Methods As part of the first randomized, sham-controlled multicenter trial on DBS in medication-refractory primary cervical dystonia ( ClinicalTrials.gov , number NCT00148889 ), a subgroup of 13 patients aged 39 to 69 underwent prospective neuropsychological long-term follow-up assessments. Various cognitive domains (memory, executive functions, attention, visual perception, mental arithmetic and verbal intelligence) were examined before and after 12 months of continuous DBS. Results Only the number of produced words in a verbal fluency task which included alternating categories decreased after stimulation (p = 0.020). All other cognitive domains remained unchanged. Conclusions These findings indicate that long-term pallidal DBS for the treatment of primary cervical dystonia seems to be safe regarding global cognitive functioning.

The main purpose of the present study was to learn how mathematical abilities are located and develop in the brain with respect to language. Mathematical abilities were assessed in six right-handed patients affected by aphasia following a lesion to their non-dominant hemisphere (crossed aphasia) and in two left-handed aphasics with a right-sided lesion. Acalculia, although in different degrees, was found in all cases. The type of acalculia depended on the type of aphasia, following patterns that have been previously observed in the most common aphasias resulting from left hemisphere lesions. No sign of right hemisphere or spatial acalculia (acalculia in left lateralised right-handed subjects) was detected. These results suggest that, as a rule, language and calculation share the same hemisphere. A primitive computational mechanism capable of recursion may be the precursor of both functions.

Brain imaging studies as well as neuropsychological case studies suggest an important role for basal ganglia in arithmetic processing. Aim of this study was to assess possible numerical deficits in PD and functional relations between numerical and other cognitive deficits. Fifteen non-demented patients with early PD (stable responders treated by l-dopa) were compared to 28 healthy age and education matched controls. Both groups underwent a neuropsychological assessment focussing on numerical abilities (quantity processing, arithmetic fact retrieval, complex mental and written calculation, transcoding, arithmetic set-shifting, calculation span), working memory and executive functions. Patients with PD showed deficits in complex mental calculation and calculation span tasks. Results of this study suggest that impairments in working memory as well as in executive functions, such as inhibition of interference, lead to secondary deficits in numerical processing. The study contributes to better understanding the specific cognitive deficits in early PD and the neurocognitive architecture of arithmetic processing.

Patients affected by Alzheimer's disease (DAT) showed considerable difficulties assessing the numerosity of complex dot patterns (up to 30 dots). Patients' and controls' performance was found to be modulated by the spatial array of dot patters. Dots presented in curved lines were easier to count than dots in circle arrays or in random arrays. Highly significant between group differences were found in counting dots in circle arrays, but not in counting curved lines. Patients and controls differed in the choice of counting strategies. While controls efficiently adapted their counting strategies to the respective dot patterns, DAT patients were not able to adapt counting strategies to the requirements of the spatial arrays. Analysis of error types further evidenced the particular difficulties of patients. Several recounts in counting circle arrays reflected difficulties to stop counting, while omissions in random patterns suggested deficits in monitoring already counted items. Results of this study suggest that deficits in executive functions prevented patients from selecting and adapting counting strategies in order to keep track of already counted items, to enhance accuracy and to reduce demands on cognitive resources.

The present functional magnetic resonance imaging (fMRI) study investigates modifications of brain activation patterns related to the training of two different arithmetic operations, multiplication and subtraction. Healthy young adults were trained in five sessions to answer multiplication and subtraction problems. In the following fMRI session, trained and new untrained problems closely matched for difficulty were presented in blocked order. Contrasts between untrained and trained operations showed stronger activation of inferior frontal and parietal regions, especially along the banks of the intraparietal sulcus. The reverse contrasts, trained minus untrained operations, yielded significantly higher activation in the left angular gyrus for multiplication but no significantly activated area for subtraction. This suggests that training leads to a reduction of general purpose processes, such as working memory and executive control in both operations, indicated by the decrease of activation in inferior frontal areas. For multiplication, however, the increase of activation in the left angular gyrus indicates a switching of cognitive processes. Trained subtraction therefore seems to lead to faster and more efficient strategies, while trained multiplication showed a shift from quantity-based processing (supported by the areas along the intraparietal sulci) to more automatic retrieval (supported by the left angular gyrus). The same training method caused changes in brain activation patterns that depended on the given operation. The effects of learning on the brain therefore seem not only to depend on the method of learning but also on its content.

This study aimed at investigating the neural correlates of a number-size congruity task. Using an event-related fMRI design, we presented one-digit number pairs to 17 participants in a number-size interference task that required subjects to focus on one stimulus property (e.g., numerical size) and to ignore the other (physical size). In different blocks, participants were asked to decide which digit of a digit pair was numerically larger (numerical comparison task) or physically larger (physical comparison task). Stimuli were classified into three categories: (a) congruent: physical and numerical comparison leads to the same response; (b) incongruent: physical and numerical comparison leads to different responses; (c) neutral: the stimuli differ only with regard to the task-relevant stimulus property. Behavioral results reflect robust distance effects (quicker reaction times for long distances relative to short ones) and size congruity effects (longer reaction times for incongruent relative to congruent stimuli) in both tasks. Imaging results reveal that–compared to congruent trials–incongruent trials led to a stronger activation in the dorsolateral prefrontal cortex and the anterior cingulate cortex, areas associated with attentional control. The distance effect (neutral condition only) led to a stronger activation in bilateral parietal areas including the intraparietal sulcus (IPS).

Aim of the present functional magnet resonance imaging (fMRI) study was to detect modifications of cerebral activation patterns related to learning arithmetic. Thirteen right-handed subjects were extensively trained on a set of 18 complex multiplication problems. In the following fMRI session, trained and untrained problems (closely matched for difficulty) were presented in blocked order alternating with a number matching task and a fact retrieval task. Importantly, left hemispheric activations were dominant in the two contrasts between untrained and trained condition, suggesting that learning processes in arithmetic are predominantly supported by the left hemisphere. Contrasting untrained versus trained condition, the left intraparietal sulcus showed significant activations, as well as the inferior parietal lobule. A further significant activation was found in the left inferior frontal gyrus. This activation may be accounted for by higher working memory demands in the untrained as compared to the trained condition. Contrasting trained versus untrained condition a significant focus of activation was found in the left angular gyrus. Following the triple-code model [Science 284 (1999) 970], the shift of activation within the parietal lobe from the intraparietal sulcus to the left angular gyrus suggests a modification from quantity-based processing to more automatic retrieval. The present study shows that the left angular gyrus is not only involved in arithmetic tasks requiring simple fact retrieval, but may show significant activations as a result of relatively short training of complex calculation.

Basal ganglia lesions have a high prevalence for associated behavioural impairments. However, the exact pattern of cognitive impairments and its relationship to individual basal ganglia lesion have rarely been investigated by means of a detailed neuropsychological and lesion study. Furthermore, different mechanisms have been proposed as relevant for the observed cognitive deficits; among these, the hypothesis of fronto-subcortical loops (Alexander et al., 1986) has made predictions regarding the relationship between the damage of particular striato-frontal circuits and the resulting behavioural impairment which await clinical confirmation. We present a study of two subjects who suffered a MRI-documented focal left basal ganglia hematoma. The two patients differed in their lesions; in one patient (PJ) large parts of the caudate nucleus were destroyed whereas in the other (AS) mainly the pallidum and putamen were lesioned and the caudate suffered only minor damage. In the acute phase, the behavioural and neuropsychological abnormalities were similar in both cases and included mainly abulia, an impairment of executive and attentional functions, and a severe amnestic syndrome. After several months many functions were restored in AS, whereas PJ's abilities remained largely defective. Based on these data and on previous case studies several conclusions are drawn. Left caudate lesions induce marked and long-lasting behavioural and neuropsychological impairments comprising predominantly drive, executive control, attention, and memory. The extent of lesion in the head of the caudate nucleus is the critical factor regarding the severity and the outcome of the syndrome, whereas damage to the putamen and pallidum is less crucial for cognitive functions. A subset of behavioural alterations, among them abulia, attentional and frontal-executive dysfunctions, can well be attributed to lesions of the anterior cingulate circuit and the dorsolateral-frontal circuit at the basal ganglia level. Other impairments, most importantly the prominent amnestic syndrome, are more difficult to interpret on the grounds of this hypothesis and may be related to other pathomechanisms.