The relationship between executive functions and fluid intelligence in multiple sclerosis.

BACKGROUND & OBJECTIVE: Deficits in cognitive functions dependent upon the integrity of the prefrontal cortex have been described in Multiple Sclerosis (MS). In a series of studies we have shown that fluid intelligence (g) is a substantial contributor to frontal deficits and that, for some classical "executive" tasks, frontal deficits were entirely explained by g. However, for another group of frontal tasks deficits remained once g was introduced as a covariate. This second set of tests included multitasking and theory of mind tasks. In the present study, we aimed at determining the role of fluid intelligence in frontal deficits seen in patients with MS. METHODS: A group of patients with Relapsing Remitting MS (n = 36) and a group of control subjects (n = 42) were assessed with a battery of classical executive tests (which included the Wisconsin Card Sorting Test, Verbal Fluency, and Trail Making Test B), a multitasking test, a theory of mind test and a fluid intelligence test. RESULTS: MS patients showed significant deficits in the fluid intelligence task. We found differences between patients and control subjects in all tests except for the multitasking test. The differences in the classical executive tests became non-significant once fluid intelligence was introduced as a covariate, but differences in theory of mind remained. CONCLUSIONS: The present results suggest that fluid intelligence can be affected in MS and that this impairment can play a role in the executive deficits described in MS

Elevated moral condemnation of third-party violations in multiple sclerosis patients

Recent research has demonstrated impairments in social cognition associated with multiple sclerosis (MS). The present work asks whether these impairments are associated with atypical moral judgment. Specifically, we assessed whether MS patients are able to integrate information about intentions and outcomes for moral judgment (i.e., appropriateness and punishment judg- ments) in the case of third-party acts. We found a complex pattern of moral judgments in MS patients: although their moral judgments were comparable to controls’ for specific types of acts (e.g., accidental or intentional harms), they nevertheless judged behaviors to be less appropriate and endorsed more severe punishment across the board, and they were also more likely to report that others’ responses would be congruent with theirs. Further analyses suggested that elevated levels of externally oriented cognition in MS (due to co-occurring alexithymia) explain these effects. Additionally, we found that the distinction between appropriateness and punishment judgments, whereby harmful outcomes influence punishment judgments to a greater extent than appropriateness judgments, was preserved in MS despite the observed disruptions in the affective and motivational components of empathy. The current results inform the two-process model for intent-based moral judgments as well as possible strategies for improving the quality of life in MS patients

Turning behavior induced by injections of glutamate receptor antagonists into the substantia nigra of the rat

We have found recently that muscimol microinjections into the subthalamic nucleus produce contralateral turning activity [Murer and Pazo (1993) NeuroReport, 4:1219-1222]. To test the hypothesis that a reduced glutamate action on substantia nigra pars reticulata neurons mediates this turning response, we examined the effect of unilateral intranigral microinjections of the AMPA/kainate receptor antagonist 6,7-dinitro- quinoxaline-2,3-dione (DNQX) and the competitive N-methyl-D-aspartate (NMDA) receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP-5). DNQX and AP-5 both produced a dose-dependent contralateral turning response, while vehicle administration did not induce turning activity. Application of glutamate receptor antagonists at adjacent regions of the mesencephalic tegmentum were also ineffective. Coadministration of NMDA or AMPA significantly reduced the turning response induced by AP-5 or DNQX, respectively. Lesions of the nigrostriatal pathway by 6-hydroxydopamine did not modify the response to DNQX or AP-5 administration into the nigra. However, their behavioral effects were significantly reduced by a lesion of the ipsilateral subthalamic nucleus. Our results show that the blockade of a tonic input acting on AMPA/kainate and NMDA receptors located at the substantia nigra produces contralateral turning behavior. The effect seems to involve pars reticulata cells since this area remains unchanged after destruction of dopaminergic neurons. The subthalamic nucleus seems to be the endogenous source of the agonist acting on the nigral glutamate receptors related to turning behavior

Perspective taking deficits and their relationship with theory of mind abilities in patients with relapsing-remitting multiple sclerosis (RRMS)

Introduction and objectives: In recent years, research has reported that between 45% and 70% of patients with Multiple Sclerosis (MS) have cognitive deficits, the most prominent being those associated with the frontal lobe. Among these deficits, we can find Theory of Mind (ToM), which is the ability to infer feelings and thoughts of others. Although it has been suggested that ToM relies on more basic skills, such as perspective taking (PT), no studies have investigated this association in patients with MS. The aim of this study was to investigate PT abilities in patients with MS and to establish their relationship with ToM deficits. Material and methods: 36 patients with relapsing-remitting multiple sclerosis (RRMS) and 42 healthy controls matched by age, sex and educational level were evaluated. Both groups were tested to estimate premorbid and current intellectual capacity, PT, ToM (Reading the Mind in the Eyes Test -RMET- and Faux Pas) and complementary scales (fatigue, depression and disability). Results: Patients with RRMS presented significant differences from controls in both PT and ToM tests. The PT test showed positive correlation with RMET, one of our ToM tests. Conclusion: The results show that there is a relationship between ToM and PT abilities. Our findings are of clinical and academic relevance to both the assessment and interpretation as well as the rehabilitation of social deficits in MS.Fil: Bruno, Diana. Universidad Catolica de Cuyo - Sede San Luis; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Galiani, Agostina. Universidad Favaloro; ArgentinaFil: Golfeder, María. Universidad Favaloro; ArgentinaFil: Pagani Cassará, Fatima. Universidad Favaloro; ArgentinaFil: Duncan, John. University of Cambridge; Estados UnidosFil: Sinay, Vladimiro. Universidad Favaloro; ArgentinaFil: Roca, María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentin

Impact of fatigue and mood symptoms on cognitive functioning in patients with Relapsing-Remitting Multiple Sclerosis

Introduction and objectives Fatigue is a common symptom in multiple sclerosis (MS) and is accompanied by mood symptoms subjectively associated with the impact of the disease in daily life. At least 65% of patients with MS present executive deficits. Previous studies have suggested that there is a relationship between fatigue and information processing speed, and between mood symptoms and attention. Little has been researched into how these symptoms impact on other executive functions, such as cognitive flexibility, inhibitory control, multitasking ability and working memory. The aim of this study was to examine the relationship between fatigue and mood symptoms with various executive performance tests in patients with RRMS. Material and methods 36 patients and 42 controls were assessed with the BDI-II, a fatigue questionnaire and a neuropsychological battery that included executive functions. Results Patients showed significant differences as compared with controls in all study variables (fatigue, mood symptoms and executive functioning). Both fatigue and mood symptoms correlate with processing speed, attention alternation, working memory and multitasking ability, while only fatigue correlates positively with inhibitory control. Conclusion The symptoms of fatigue experienced by patients with RRMS impacted not only on patients? processing speed but also on other executive measures. Mood symptoms are associated with attention deficits and multitasking ability impairments.Introducción y objetivos La fatiga es un síntoma frecuente en esclerosis múltiple (EM) y se acompaña de síntomas anímicos asociados subjetivamente al impacto de la enfermedad en la vida cotidiana. Al menos el 65% de los pacientes con EM presenta déficits ejecutivos. Estudios previos han sugerido que existe relación entre la fatiga y la velocidad de procesamiento de la información, y entre los síntomas anímicos y la atención. Poco se ha indagado sobre cómo estos síntomas impactan en otras funciones ejecutivas como flexibilidad cognitiva, control inhibitorio, capacidad de multitasking y memoria de trabajo. El objetivo del presente estudio fue examinar la relación entre la fatiga y los síntomas anímicos con el rendimiento en diversas pruebas ejecutivas en pacientes con esclerosis múltiple en brote remisión (EMBR). Material y métodos Se evaluó a 36 pacientes y 42 controles con el BDI-II, un cuestionario de fatiga y una batería neuropsicológica que incluyó pruebas ejecutivas. Resultados Los pacientes presentaron diferencias significativas con los controles en todas las variables de estudio (fatiga, síntomas anímicos y funcionamiento ejecutivo). Se observó que tanto la fatiga como los síntomas anímicos se correlacionan positivamente con la velocidad de procesamiento, la alternancia atencional, la memoria de trabajo y tareas de multitasking, mientras que solo la fatiga se correlaciona positivamente con el control inhibitorio. Conclusión Los síntomas de fatiga que presentan los pacientes con EMBR impactan no solo en la velocidad de procesamiento de los pacientes, sino también en otras medidas ejecutivas. Los síntomas anímicos se relacionan con déficits atencionales y con fallas en tareas de multitasking.Fil: Bruno, Diana. Instituto de Neurología Cognitiva; ArgentinaFil: Pagani Cassará, Fatima. Instituto de Neurología Cognitiva; ArgentinaFil: Sinay, Vladimiro. Instituto de Neurología Cognitiva; ArgentinaFil: Torralva, Teresa. Instituto de Neurología Cognitiva; ArgentinaFil: Manes, Facundo Francisco. Instituto de Neurología Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencias Cognitivas y Traslacional; ArgentinaFil: Roca, María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencias Cognitivas y Traslacional; Argentina. Instituto de Neurología Cognitiva; Argentin

The impact of neuromyelitis optica on the recognition of emotional facial expressions: A preliminary report

Although neuromyelitis optica (NMO) is classically recognized as an affectation of optic nerves and spinal cord, recent reports have shown brain atrophy and cognitive dysfunction in this condition. Importantly, emotion-related brain regions appear to be impaired in NMO. However, no studies of NMO’ emotional processing have been published. The goal of the current study was to investigate facial emotion recognition in 10 patients with NMO and 10 healthy controls by controlling for relevant cognitive factors. Consistent with previous reports, NMO patients performed poorly across cognitive domains (divided attention, working memory, and information-processing speed). Our findings further evidence the relative inability of NMO patients to recognize negative emotions (disgust, anger, and fear), in comparison to controls, with these deficits not explained by other cognitive impairments. Results provide the first evidence that NMO may impair the ability to recognize negative emotions. These impairments appear to be related to possible damage in brain regions underling emotional networks, including the anterior cingulate cortex, amygdala, and medial prefrontal cortex. Findings increased both our understanding of NMO’s cognitive impairment, and the neural networks underlying negative emotions.Fil: Cardona Londoño, Juan Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Neurología Cognitiva; Argentina. Fundación Favaloro; ArgentinaFil: Sinay, Vladimiro. Fundación Favaloro; Argentina. Instituto de Neurología Cognitiva; ArgentinaFil: Amoruso, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Neurología Cognitiva; Argentina. Fundación Favaloro; ArgentinaFil: Hesse Rizzi, Eugenia Fátima. Fundación Favaloro; Argentina. Instituto de Neurología Cognitiva; ArgentinaFil: Manes, Facundo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Neurología Cognitiva; Argentina. Fundación Favaloro; Argentina. Universidad Diego Portales; ChileFil: Ibáñez Barassi, Agustín Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto de Neurología Cognitiva; Argentina. Fundación Favaloro; Argentina. Universidad Diego Portales; Chil

Cognitive but Not Affective Theory of Mind Deficits in Mild Relapsing-Remitting Multiple Sclerosis

OBJECTIVE: We studied theory of mind (ToM) in patients with mild relapsing-remitting multiple sclerosis (MS), seeking possible dissociations between its 2 components: cognitive ToM (the ability to infer others' intentions) and affective ToM (the ability to infer others' emotional states). We analyzed the relationship of ToM to executive function, depression, and fatigue. BACKGROUND: Dissociations between cognitive and affective ToM have been found in several neurologic and neuropsychiatric diseases. Most ToM studies in patients with MS have shown general ToM deficits but have not analyzed the cognitive and affective aspects individually. METHODS: We used the Faux Pas test of ToM and tests of executive function to assess 18 patients with mild relapsing-remitting MS and 16 control participants. RESULTS: Our patients showed deficits in cognitive ToM, but their affective ToM seemed to be spared. Their cognitive ToM deficits were not related to executive dysfunction, depression, or fatigue. CONCLUSIONS: Our study is the first differential analysis showing cognitive but not affective ToM deficits in mild relapsing-remitting MS. Further research is needed to determine the exact nature and the real impact of these deficits, and to establish their relationship with the neuropathology and progression of MS.Fil: Roca, María. Instituto de Neurología Cognitiva; Argentina. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentina. Universidad Diego Portales; Chile. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Manes, Facundo Francisco. Instituto de Neurología Cognitiva; Argentina. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gleichgerrcht, Ezequiel. Instituto de Neurología Cognitiva; Argentina. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; ArgentinaFil: Ibáñez Barassi, Agustín Mariano. Universidad Diego Portales; Chile. Instituto de Neurología Cognitiva; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Toledo, María E. González de. Instituto de Neurología Cognitiva; Argentina. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; ArgentinaFil: Marenco, Victoria. Instituto de Neurología Cognitiva; ArgentinaFil: Bruno, Diana. Instituto de Neurología Cognitiva; ArgentinaFil: Torralva, Teresa. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentina. Instituto de Neurología Cognitiva; ArgentinaFil: Sinay, Vladimiro. Instituto de Neurología Cognitiva; Argentina. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentin

Safety, Patient-Reported Well-Being, and Physician-Reported Assessment of Walking Ability in Patients with Multiple Sclerosis for Prolonged-Release Fampridine Treatment in Routine Clinical Practice: Results of the LIBERATE Study

Background: Prolonged-release fampridine (PR-FAM) 10-mg tablet twice daily is the only approved pharmacological treatment for improvement of walking ability in adults with multiple sclerosis (MS). LIBERATE assessed the safety/effectiveness of PR-FAM in the real-world. Objectives: The aim of this study was to collect additional safety data, including the incidence rate of seizures and other adverse events (AEs) of interest, from patients with MS taking PR-FAM in routine clinical practice (including patients aged ≥ 65 years and those with pre-existing cardiovascular risk factors). Other objectives included change over time in patient-reported evaluation of physical and psychological impact of MS while taking PR-FAM, and change over time in physician-reported assessment of walking ability in MS patients taking PR-FAM. Methods: Patients with MS newly prescribed PR-FAM were recruited (201 sites, 13 countries). Demographic/safety data were collected at enrolment through 12 months. Physician-rated Clinical Global Impression of Improvement (CGI-I) scores for walking ability, and Multiple Sclerosis Impact Scale-29 (MSIS-29) were assessed. Results: Safety analysis included 4646 patients with 3534.8 patient-years of exposure; median (range) age, 52.6 (21–85) years, 87.3% < 65 years, and 65.7% women. Treatment-emergent AEs (TEAEs) were reported in 2448 (52.7%) patients, and serious TEAEs were reported in 279 (6.0%) patients, of whom 37 (< 1%) experienced treatment-emergent serious AEs (TESAEs) considered related to PR-FAM. AEs of special interest (AESI) occurred in 1799 (38.7%) patients, and serious AESI in 128 (2.8%) patients. Seventeen (< 1%) patients experienced actual events of seizure. Overall, 1158 (24.9%) patients discontinued treatment due to lack of efficacy. At 12 months, a greater proportion of patients on-treatment had improvement from baseline in CGI-I for walking ability versus those who discontinued (61% vs. 11%; p < 0.001). MSIS-29 physical impact score improved significantly for patients on-treatment for 12 months versus those who discontinued (mean change, baseline to 12 months: − 9.99 vs. − 0.34 points; p < 0.001). Results were similar for MSIS-29 psychological impact. Conclusion: No new safety concerns were identified in this real-world study, suggesting that routine risk-minimization measures are effective. CGI-I and MSIS-29 scores after 12 months treatment with PR-FAM treatment show clinical benefits consistent with those previously reported. Trial Registration: ClinicalTrials.gov: NCT01480063

Fatigue in multiple sclerosis is associated to multimodal interoceptive abnormalities

Background: Fatigue ranks among the most common and disabling symptoms in multiple sclerosis (MS). Recent theoretical works have surmised that this trait might be related to alterations across interoceptive mechanisms. However, this hypothesis has not been empirically evaluated. Objectives: To determine whether fatigue in MS patients is associated with specific behavioral, structural, and functional disruptions of the interoceptive domain. Methods: Fatigue levels were established via the Modified Fatigue Impact Scale. Interoception was evaluated through a robust measure indexed by the heartbeat detection task. Structural and functional connectivity properties of key interoceptive hubs were tested by magnetic resonance imaging (MRI) and resting-state functional MRI. Machine learning analyses were employed to perform pairwise classifications. Results: Only patients with fatigue presented with decreased interoceptive accuracy alongside decreased gray matter volume and increased functional connectivity in core interoceptive regions, the insula, and the anterior cingulate cortex. Each of these alterations was positively associated with fatigue. Finally, machine-learning analysis with a combination of the above interoceptive indices (behavioral, structural, and functional) successfully discriminated (area under the curve > 90%) fatigued patients from both non-fatigued and healthy controls. Conclusion: This study offers unprecedented evidence suggesting that disruptions of neurocognitive markers subserving interoception may constitute a signature of fatigue in MS.Fil: Gonzalez Campo, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Salamone, Paula Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Rodríguez Arriagada, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Richter, Fabian. Universidad de Colonia; AlemaniaFil: Herrera, Eduar. Universidad Icesi; ColombiaFil: Bruno, Diana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Pagani Cassara, Fátima. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Sinay, Vladimiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: García, Adolfo Martín. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentina. Universidad Nacional de Cuyo. Facultad de Educación Elemental y Especial; ArgentinaFil: Ibañez, Agustin Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Sedeño, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentin