The place of Free Will: the freedom of the prisoner.

Debates about the concept of Free Will date back to ancient times. About 40 years ago, Benjamin Libet designed an experiment showing that the conscious intention to move is preceded by a specific pattern of brain activation. His finding suggested that unconscious processes determine our decisions. Libet-style experiments have continued to dominate the debate about Free Will, pushing some authors to argue that the existence of Free Will is a mere illusion. We believe that this dispute is because we often measure Free Will using arbitrary human decisions rather than deliberate actions. After reviewing the definition of Free Will and the related literature, we conclude that the scientific evidence does not disprove the existence of Free Will. However, our will encounters several constraints and limitations that should be considered when evaluating our deeds' personal responsibility.

The Effect of Dopaminergic Replacement Therapy on Creative Thinking and Insight Problem-Solving in Parkinson's Disease Patients.

Parkinson's disease (PD) patients receiving dopaminergic treatment may experience bursts of creativity. Although this phenomenon is sometimes recognized among patients and their clinicians, the association between dopamine replacement therapy (DRT) in PD patients and creativity remains underexplored. It is unclear, for instance, whether DRT affects creativity through convergent or divergent thinking, idea generation, or a general lack of inhibition. It is also unclear whether DRT only augments pre-existing creative attributes or generates creativity de novo. Here, we tested a group of PD patients when "on" and "off" dopaminergic treatment on a series of tests of creative problem-solving (Alternative Uses Task, Compound Remote Associates, Rebus Puzzles), and related their performance to a group of matched healthy controls as well as to their pre-PD creative skills and measures of inhibition/impulsivity. Results did not provide strong evidence that DRT improved creative thinking in PD patients. Rather, PD patients "on" medication showed less flexibility in divergent thinking, generated fewer ideas via insight, and showed worse performance in convergent thinking overall (by making more errors) than healthy controls. Pre-PD creative skills predicted enhanced flexibility and fluency in divergent thinking when PD patients were "on" medication. However, results on convergent thinking were mixed. Finally, PD patients who exhibited deficits in a measure of inhibitory control showed weaker convergent thinking while "on" medication, supporting previous evidence on the importance of inhibitory control in creative problem-solving. Altogether, results do not support the hypothesis that DRT promotes creative thinking in PD. We speculate that bursts of artistic production in PD are perhaps conflated with creativity due to lay conceptions of creativity (i.e., an art-bias).

Mechanical knowledge does matter to tool use even when assessed with a non-production task: Evidence from left brain-damaged patients.

In the literature on apraxia of tool use, it is now accepted that using familiar tools requires semantic and mechanical knowledge. However, mechanical knowledge is nearly always assessed with production tasks, so one may assume that mechanical knowledge and familiar tool use are associated only because of their common motor mechanisms. This notion may be challenged by demonstrating that familiar tool use depends on an alternative tool selection task assessing mechanical knowledge, where alternative uses of tools are assumed according to their physical properties but where actual use of tools is not needed. We tested 21 left brain-damaged patients and 21 matched controls with familiar tool use tasks (pantomime and single tool use), semantic tasks and an alternative tool selection task. The alternative tool selection task accounted for a large amount of variance in the single tool use task and was the best predictor among all the semantic tasks. Concerning the pantomime of tool use task, group and individual results suggested that the integrity of the semantic system and preserved mechanical knowledge are neither necessary nor sufficient to produce pantomimes. These results corroborate the idea that mechanical knowledge is essential when we use tools, even when tasks assessing mechanical knowledge do not require the production of any motor action. Our results also confirm the value of pantomime of tool use, which can be considered as a complex activity involving several cognitive abilities (e.g., communicative skills) rather than the activation of gesture engrams.

Neural Correlates of Anosognosia in Alzheimer's Disease and Mild Cognitive Impairment: A Multi-Method Assessment.

Patients with Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) may present anosognosia for their cognitive deficits. Three different methods have been usually used to measure anosognosia in patients with AD and MCI, but no studies have established if they share similar neuroanatomical correlates. The purpose of this study was to investigate if anosognosia scores obtained with the three most commonly used methods to assess anosognosia relate to focal atrophy in AD and MCI patients, in order to improve understanding of the neural basis of anosognosia in dementia. Anosognosia was evaluated in 27 patients (15 MCI and 12 AD) through clinical rating (Clinical Insight Rating Scale, CIRS), patient-informant discrepancy (Anosognosia Questionnaire Dementia, AQ-D), and performance discrepancy on different cognitive domains (self-appraisal discrepancies, SADs). Voxel-based morphometry correlational analyses were performed on magnetic resonance imaging (MRI) data with each anosognosia score. Increasing anosognosia on any anosognosia measurement (CIRS, AQ-D, SADs) was associated with increasing gray matter atrophy in the medial temporal lobe including the right hippocampus. Our results support a unitary mechanism of anosognosia in AD and MCI, in which medial temporal lobes play a key role, irrespectively of the assessment method used. This is in accordance with models suggesting that anosognosia in AD is primarily caused by a decline in mnemonic processes.

Antibody profile may predict outcome in ocular myasthenia gravis.

An unsolved issue remains whether there are clinical and immunological features to predict in a single patient the risk of conversion from ocular Myasthenia Gravis (OMG) to generalized disease (GMG) as 50-60% of patients may progress within 1-2 years since onset. Anti-acetylcholine receptor antibodies (AChR Abs) are found in up to 50% of OMG patients; muscle-specific tyrosine kinase antibodies (MuSK-Abs) are present in about 70% of the whole seronegative (SN), who usually develop a severe disease with bulbar involvement. We surveyed a cohort of 175 OMG patients with purely ocular symptoms and we compare the outcome of patients with antibodies to AChR or to MuSK with those seronegative for both Abs (DSN). All patients had purely ocular signs for at least 24 months. Gender, age at onset, time to generalization or to worsening in quantitative ocular QMG scores, electrophysiological results were analyzed. Males were 58.9%, females 41.1%. Patients with late onset of symptoms after 50 years (LOMG) were 78.3%. We assayed anti-MuSK-Abs in 4.7%, anti-AChR Abs in 38.5%; 57.3% were defined DSN. Thirty-seven patients (21.1%) progressed to GMG during the observational time: 23 were females, 62% of the whole group of the generalized subjects, 75% of MuSK-positive OMG converted to GMG versus the 26.2% of AChR positive and 13.7% of DSN. Statistical analysis showed that gender and presence of antibodies either to AChR or to MuSK were independent predictors of worse outcome; the DSN subjects had lower risk of conversion to GMG.

Factors affecting outcome in ocular myasthenia gravis.

AIM OF THE STUDY: 50%-60% of patients with ocular myasthenia gravis (OMG) progress to generalized myasthenia gravis (GMG) within two years. The aim of our study was to explore factors affecting prognosis of OMG and to test the predictive role of several independent clinical variables. MATERIALS AND METHODS: We reviewed a cohort of 168 Caucasian patients followed from September 2000 to January 2016. Several independent variables were considered as prognostic factors: gender, age of onset, results on electrophysiological tests, presence and level of antibodies against acetylcholine receptors (AChR Abs), treatments, thymic abnormalities. The primary outcome was the progression to GMG and/or the presence of bulbar symptoms. Secondary outcomes were either achievement of sustained minimal manifestation status or worsening in ocular quantitative MG subscore (O-QMGS) or worsening in total QMG score (T-QMGS), assessed by Myasthenia Gravis Foundation of America (MGFA) quantitative scores. Changes in mental and physical subscores of health-related quality of life (HRQoL) were assessed with SF-36 questionnaire. Variance analysis was used to interpret the differences between AChR Ab titers at different times of follow up among the generalized and non-generalized patients. RESULTS: Conversion to GMG occurred in 18.4% of patients; it was significantly associated with sex, later onset of disease and anti-AChR Ab positivity. Antibody titer above the mean value of 25.8 pmol/mL showed no significant effect on generalization. Sex and late onset of disease significantly affected T-QMGS worsening. None of the other independent variables significantly affected O-QMGS and HRQoL. CONCLUSIONS: Sex, later onset and anti-AChR Ab positivity were significantly associated with clinical worsening.

A selenium species in cerebrospinal fluid predicts conversion to Alzheimer's dementia in persons with mild cognitive impairment.

BACKGROUND: Little is known about factors influencing progression from mild cognitive impairment to Alzheimer's dementia. A potential role of environmental chemicals and specifically of selenium, a trace element of nutritional and toxicological relevance, has been suggested. Epidemiologic studies of selenium are lacking, however, with the exception of a recent randomized trial based on an organic selenium form. METHODS: We determined concentrations of selenium species in cerebrospinal fluid sampled at diagnosis in 56 participants with mild cognitive impairment of nonvascular origin. We then investigated the relation of these concentrations to subsequent conversion from mild cognitive impairment to Alzheimer's dementia. RESULTS: Twenty-one out of the 56 subjects developed Alzheimer's dementia during a median follow-up of 42 months; four subjects developed frontotemporal dementia and two patients Lewy body dementia. In a Cox proportional hazards model adjusting for age, sex, duration of sample storage, and education, an inorganic selenium form, selenate, showed a strong association with Alzheimer's dementia risk, with an adjusted hazard ratio of 3.1 (95% confidence interval 1.0-9.5) in subjects having a cerebrospinal fluid content above the median level, compared with those with lower concentration. The hazard ratio of Alzheimer's dementia showed little departure from unity for all other inorganic and organic selenium species. These associations were similar in analyses that measured exposure on a continuous scale, and also after excluding individuals who converted to Alzheimer's dementia at the beginning of the follow-up. CONCLUSIONS: These results indicate that higher amounts of a potentially toxic inorganic selenium form in cerebrospinal fluid may predict conversion from mild cognitive impairment to Alzheimer's dementia.

A topographical organization for action representation in the human brain.

How the human brain represents distinct motor features into a unique finalized action still remains undefined. Previous models proposed the distinct features of a motor act to be hierarchically organized in separated, but functionally interconnected, cortical areas. Here, we hypothesized that distinct patterns across a wide expanse of cortex may actually subserve a topographically organized coding of different categories of actions that represents, at a higher cognitive level and independently from the distinct motor features, the action and its final aim as a whole. Using functional magnetic resonance imaging and pattern classification approaches on the neural responses of 14 right-handed individuals passively watching short movies of hand-performed tool-mediated, transitive, and meaningful intransitive actions, we were able to discriminate with a high accuracy and characterize the category-specific response patterns. Actions are distinctively coded in distributed and overlapping neural responses within an action-selective network, comprising frontal, parietal, lateral occipital and ventrotemporal regions. This functional organization, that we named action topography, subserves a higher-level and more abstract representation of finalized actions and has the capacity to provide unique representations for multiple categories of actions.

A one-year prospective study of refractory status epilepticus in Modena, Italy.

Refractory status epilepticus (RSE) is a particular critical condition characterized by seizures that continue despite the use of first- and second-line therapies and by high mortality. To date, only one prospective study investigated clinical features and prognostic factors in RSE. In this study, we performed a one-year prospective survey to identify clinical features, outcomes, and variables associated with the development of RSE in the adolescent and adult population of Modena, northern Italy. We observed 83 episodes of SE in 83 patients. In 31% of the cases, third-line therapy (anesthetic drug) was needed. Among this group, 14% resolved and were classified as RSE, while, in 17%, seizures recurred at withdrawal of anesthetics and were classified as super-RSE. The development of RSE/super-RSE was associated with a stuporous/comatose state at presentation and with the absence of a previous history of epilepsy. Refractory status epilepticus/super-refractory status epilepticus showed a worse outcome compared with responsive SE: 54% versus 21% for 30-day mortality; 19% versus 56% for a return to baseline condition. This prospective study confirms stupor/coma at onset as a relevant clinical factor associated with SE refractoriness. We observed a rate of RSE comparable with previous reports, with high mortality and morbidity. Mortality in the observed RSE was higher than in previous studies; this result is probably related to the low rate of a previous epilepsy history in our population that reflects a high incidence of acute symptomatic etiologies, especially the inclusion of patients with postanoxic SE who have a bad prognosis per se. This article is part of a Special Issue entitled "Status Epilepticus".

Methylprednisolone-induced Toxic Hepatitis After Intravenous Pulsed Therapy for Multiple Sclerosis Relapses.

High-dose, intravenous methylprednisolone (MP) is the only recommended first-line treatment for multiple sclerosis relapses. However, there are increasing reports on liver toxicity induced by this treatment regimen. We report of 4 multiple sclerosis patients with no history of viral/metabolic liver disorders or alcohol/hepatotoxic drug intake, who developed hypertransaminasaemia following intravenous MP. In 2 of the patients, liver biopsy showed periportal fibrosis, piecemeal necrosis, and inflammatory cell infiltrates. A rechallenge test confirmed a causal association in 1 case. MP-induced liver toxicity may be more frequent than commonly thought and it is important to report this adverse reaction, which is potentially lethal, and to raise awareness on the potential hepatotoxicity of corticosteroid pulses.

Cerebrospinal fluid tau proteins in status epilepticus.

Tau protein is a phosphorylated microtubule-associated protein, principally localized at neuronal level in the central nervous system (CNS). Tau levels in the cerebrospinal fluid (CSF) are considered to index both axonal and neuronal damage. To date, however, no study has specifically evaluated the CSF levels of tau proteins in patients with status epilepticus (SE). We evaluated these established biomarkers of neuronal damage in patients with SE who received a lumbar puncture during SE between 2007 and 2014. Status epilepticus cases due to acute structural brain damage, including CNS infection, were excluded. Clinical, biological, therapeutic, and follow-up data were collected. Group comparison between patients stratified according to SE response to antiepileptic drugs (AEDs), disability, and epilepsy outcomes were performed. Twenty-eight patients were considered for the analyses (mean age 56 years): 14 patients had abnormally high CSF t-tau level, six patients had abnormally high CSF p-tau level, and only three patients had abnormally low Aß1-42 level. Cerebrospinal fluid t-tau value was higher in patients who developed a refractory SE compared to patients with seizures controlled by AED. Cerebrospinal fluid t-tau values were positively correlated with SE duration and were higher in patients treated with propofol anesthesia compared to patients that had not received this treatment. Patients with higher CSF t-tau had higher risk of developing disability (OR = 32.5, p = 0.004) and chronic epilepsy (OR = 12; p = 0.016) in comparison with patients with lower CSF t-tau level. Our results suggest that CSF t-tau level might be proposed as a biomarker of SE severity and prognosis. Prospective studies are needed to evaluate the effects of propofol on tau pathology in this setting. This article is part of a Special Issue entitled "Status Epilepticus".

Hypoxia markers are expressed in interneurons exposed to recurrent seizures.

An early but transient decrease in oxygen availability occurs during experimentally induced seizures. Using pimonidazole, which probes hypoxic insults, we found that by increasing the duration of pilocarpine-induced status epilepticus (SE) from 30 to 120 min, counts of pimonidazole-immunoreactive neurons also increased (P < 0.01, 120 vs 60 and 30 min). All the animals exposed to SE were immunopositive to pimonidazole, but a different scenario emerged during epileptogenesis when a decrease in pimonidazole-immunostained cells occurred from 7 to 14 days, so that only 1 out of 4 rats presented with pimonidazole-immunopositive cells. Pimonidazole-immunoreactive cells robustly reappeared at 21 days post-SE induction when all animals (7 out of 7) had developed spontaneous recurrent seizures. Specific neuronal markers revealed that immunopositivity to pimonidazole was present in cells identified by neuropeptide Y (NPY) or somatostatin antibodies. At variance, neurons immunopositive to parvalbumin or cholecystokinin were not immunopositive to pimonidazole. Pimonidazole-immunopositive neurons expressed remarkable immunoreactivity to hypoxia-inducible factor 1α (HIF-1α). Interestingly, surgical samples obtained from pharmacoresistant patients showed neurons co-labeled by HIF-1α and NPY antibodies. These interneurons, along with parvalbumin-positive interneurons that were negative to HIF-1α, showed immunopositivity to markers of cell damage, such as high-mobility group box 1 in the cytoplasm and cleaved caspase-3 in the nucleus. These findings suggest that interneurons are continuously endangered in rodent and human epileptogenic tissue. The presence of hypoxia and cell damage markers in NPY interneurons of rats and patients presenting with recurrent seizures indicates a mechanism of selective vulnerability in a specific neuronal subpopulation.

Primary progressive versus relapsing-onset multiple sclerosis: presence and prognostic value of cerebrospinal fluid oligoclonal IgM.

BACKGROUND: There is increasing evidence on cerebrospinal fluid (CSF) oligoclonal IgM (OCIgM) predicting a more aggressive disease course in relapsing-remitting Multiple Sclerosis (MS), while there is a scarcity of data for primary progressive MS (PPMS). OBJECTIVE: Our aim was to investigate the presence and possible prognostic value of CSF OCIgM in a group of PPMS and in a group of relapsing-onset MS patients. The possible prognostic role of other clinical and biological factors was also evaluated. METHODS: We calculated the impact of single clinical and biological factors, including CSF OCIgM at onset, on the probability of reaching an Expanded Disability Status Scale of 3 and 4 in 45 PPMS and 104 relapsing-onset MS patients. RESULTS: CSF OCIgM were found in only 13% of PPMS patients and did not influence the time taken to reach an Expanded Disability Status Scale of 3 and 4. Conversely, they were present in 46% of relapsing-onset MS patients and increased the risk of reaching an Expanded Disability Status Scale of 4. Clinical factors with a negative prognostic value in PPMS were age at onset <30 years and onset with pyramidal symptoms, while onset with sensory symptoms in relapsing-onset MS predicted a more favourable course. CONCLUSION: This study confirms that, in relapsing-onset MS patients, the presence of CSF OCIgM at onset predicts a worse disease course. In the cohort of PPMS patients, however, CSF OCIgM were rare, suggesting that heterogeneous pathogenetic mechanisms may be involved in the different MS forms.

Brain networks responsive to aversive visual stimuli in humans.

The neural mechanisms subserving recognition of noxious stimuli and empathy for pain appear to involve at least in part the cortical regions associated with the processing of pain affect. An important issue concerns the specificity of brain networks associated with observing and representing painful conditions, in comparison with other unpleasant stimuli. Recently, we found both similarities and differences between the brain patterns of activity related to the observation of noxious or disgusting stimuli delivered to one hand or foot. Overlap regions included the perigenual anterior cingulate (pACC), whose activity was related to the perceived unpleasantness. We aimed here at revealing how pACC functional connectivity changes in relationship to the different experimental conditions, using a psychophysiological interaction model. Activity in pACC during the observation of painful stimuli was specifically and positively related to regions in the right hemisphere, including portions of the prefrontal, midcingulate and insular cortex. On the other hand, positive changes in pACC connectivity during the vision of disgusting stimuli were present in the right basal ganglia. These data suggest that pACC activity is part of different networks involved in the recognition of painful or disgusting stimuli.

Age-related decline in mentalizing skills across adult life span.

In the literature, there are few and conflicting reports regarding age-related changes in adult mentalizing abilities: whereas Happe et al. (1998, Developmental Psychology, 34, 358-362) showed better performances of elderly compared with young subjects in an advanced theory of mind (ToM) task, Mayor et al. (2002, British Journal of Psychology, 93, 465-485) and Sullivan and Ruffmann (2004, British Journal of Psychology, 95(Pt 1), 1-18) found an age-related decline. Former studies addressing the issue compared young to elderly subjects and did not investigate earlier changes in middle-aged adults. To shed light on changes in ToM skills along adulthood, the authors used the revised version of the "Reading the Mind in the Eyes Test" (Baron-Cohen et al., 2001, Journal of Child Psychology and Psychiatry, 42, 241-251) to compare four groups of people of different ages covering the whole span of adult life. The authors found aged-related decline in ToM skills as early as the fifth decade of life. Awareness of the age-related changes in adult mentalizing is important to differentiate normal aging effects from ToM impairments due to neuropsychiatric diseases.

Does it look painful or disgusting? Ask your parietal and cingulate cortex.

Looking at still images of body parts in situations that are likely to cause pain has been shown to be associated with activation in some brain areas involved in pain processing. Because pain involves both sensory components and negative affect, it is of interest to explore whether the visually evoked representations of pain and of other negative emotions overlap. By means of event-related functional magnetic resonance imaging, here we compare the brain areas recruited, in female volunteers, by the observation of painful, disgusting, or neutral stimuli delivered to one hand or foot. Several cortical foci were activated by the observation of both painful and disgusting video clips, including portions of the medial prefrontal cortex, anterior, mid-, and posterior cingulate cortex, left posterior insula, and right parietal operculum. Signal changes in perigenual cingulate and left anterior insula were linearly related to the perceived unpleasantness, when the individual differences in susceptibility to aversive stimuli were taken into account. Painful scenes selectively induced activation of left parietal foci, including the parietal operculum, the postcentral gyrus, and adjacent portions of the posterior parietal cortex. In contrast, brain foci specific for disgusting scenes were found in the posterior cingulate cortex. These data show both similarities and differences between the brain patterns of activity related to the observation of noxious or disgusting stimuli. Namely, the parietal cortex appears to be particularly involved in the recognition of noxious environmental stimuli, suggesting that areas involved in sensory aspects of pain are specifically triggered by observing noxious events.

Progressive supranuclear gaze palsy without parkinsonism: a case of neuro-Whipple.

We report the case of a 69-year-old man with a 7-month history of severe progressive supranuclear gaze palsy associated with mild cognitive decline and sleep disturbances, but not parkinsonism. After a period spent consulting a range of different specialists, the appearance of brachial myoclonus prompted his referral to a movement disorders specialist. Duodenum biopsy confirmed the suspicion of neuro-Whipple disease. Antibiotic therapy was started but the delay in the diagnosis proved fatal to this patient. This noteworthy case shows unusual neurological features of a rare but treatable disease, often misdiagnosed as progressive supranuclear palsy.