Combined EEG and immersive virtual reality unveil dopaminergic modulation of error monitoring in Parkinson's Disease.

Detecting errors in your own and others' actions is associated with discrepancies between intended and expected outcomes. The processing of salient events is associated with dopamine release, the balance of which is altered in Parkinson's disease (PD). Errors in observed actions trigger various electrocortical indices (e.g. mid-frontal theta, error-related delta, and error positivity [oPe]). However, the impact of dopamine depletion to observed errors in the same individual remains unclear. Healthy controls (HCs) and PD patients observed ecological reach-to-grasp-a-glass actions performed by a virtual arm from a first-person perspective. PD patients were tested under their dopaminergic medication (on-condition) and after dopaminergic withdrawal (off-condition). Analyses of oPe, delta, and theta-power increases indicate that while the formers were elicited after incorrect vs. correct actions in all groups, the latter were observed in on-condition but altered in off-condition PD. Therefore, different EEG error signatures may index the activity of distinct mechanisms, and error-related theta power is selectively modulated by dopamine depletion. Our findings may facilitate discovering dopamine-related biomarkers for error-monitoring dysfunctions that may have crucial theoretical and clinical implications.

Modification of the Patient Competency Rating Scale to Measure Anosodiaphoria after Severe Acquired Brain Injury: Preliminary Findings.

OBJECTIVE: Impaired self-awareness (ISA) of altered functional capacities is a common sequelae of severe acquired brain injury that can severely hamper neuro-rehabilitation in this clinical population. ISA is frequently associated with anosodiaphoria and/or apathy. Although several scales are available to measure apathy, no tools have been published to specifically assess anosodiaphoria after acquired brain injury. In this paper, we reported an initial effort to develop an anosodiaphoria subscale in a commonly used measure of ISA, that is, the Patient Competency Rating scale-neurorehabilitation form (PCRS-NR). METHOD: A sample of 46 participants with severe acquired brain injury completed a functional, ISA, apathy, and anosodiaphoria assessment. One informal caregiver of each patient participated in the study. Thus, we were able to obtain external data on his/her level of functional competencies, and self-awareness, which allowed separating patients with low self-awareness (LSA) from those with high self-awareness (HSA). Finally, the patients were compared with 44 healthy age-gender-years of formal education matched control participants (HCs). RESULTS: Compared to both patients with HSA and HCs, patients with LSA demonstrated greater anosodiapvhoria and lower levels of functioning than both HSA patients and HCs. A stronger relationship emerged between ISA and anosodiaphoria rather than with apathy. CONCLUSIONS: These initial findings provide support that PCRS scale can be adapted to measure anosodiaphoria as well as ISA. The findings reveal a stronger correlation between this measure of anosodiaphoria and ISA compared with the correlation of apathy to ISA. The present method for measuring anosodiaphoria takes into account the actual levels of patients' functioning.

Effectiveness of a sensor-based technology in upper limb motor recovery in post-acute stroke neurorehabilitation: a randomized controlled trial.

Sensor-based technological therapy devices could be a possible neurorehabilitation strategy for motor rehabilitation in patients with stroke during the post-acute hospitalization, especially for treating upper extremities function limitations. The audio-visual feedback devices are characterized by interactive therapy games that allow training the movement of shoulders, elbows, and wrist, measuring the strength and the active range of motion of upper limb, registering data in an electronic database to quantitatively monitoring measures and therapy progress. This study aimed to investigate the effects of sensor-based motor rehabilitation in add-on to the conventional neurorehabilitation for improving the upper limb functions in patients with subacute stroke. Thirty-seven patients were enrolled in the study and randomly assigned to the experimental group and the control group. The training consisting of twelve sessions of upper limb training compared with twelve sessions of upper limb sensory-motor training, without robotic support. Both rehabilitation programs were performed for 40 minutes three times a week, for 4 weeks, in addition to conventional therapy. All patients were evaluated at the baseline (T0) and after 4 weeks of training (T1). The within-subject analysis showed a statistically significant improvement in both groups in all clinical scales. The analysis of effectiveness revealed that, compared with baseline (T0), the improvement percentage in the Modified Barthel Index was greater in the experimental group than the control group. The use of a sensor-based training with audio-video-feedback could be a useful complementary strategy for improving upper limb motor functions in patients with stroke during post-acute neurorehabilitation.

Depression, apathy and impaired self-awareness following severe traumatic brain injury: a preliminary investigation.

Primary Objective: The primary aim of this study was to determine the frequency of severe impaired self-awareness (ISA) in patients with severe traumatic brain injury (TBI) and the correlates of selected clinical, neuropsychiatric and cognitive variables. The secondary aim of the study was to assess depression and apathy on the basis of their level of self-awareness. Methods: Thirty patients with severe TBI and 30 demographically matched healthy control subjects (HCs) were compared on measures of ISA, depression, anxiety, alexithymia, neuropsychiatric symptoms and cognitive flexibility. Results: Twenty percent of the patients demonstrated severe ISA. Severe post-acute ISA was associated with more severe cognitive inflexibility, despite the absence of differences in TBI severity, as evidenced by a Glasgow Coma Scale (GCS) score lower than 9 in all cases in the acute phase. Patients with severe ISA showed lower levels of depression and anxiety but tended to show more apathy and to have greater difficulty describing their emotional state than patients with severe TBI who showed minimal or no disturbance in self-awareness. Conclusion: These findings support the general hypothesis that severe ISA following severe TBI is typically not associated with depression and anxiety, but rather with apathy and cognitive inflexibility.

The SonicHand Protocol for Rehabilitation of Hand Motor Function: A Validation and Feasibility Study.

Musical sonification therapy is a new technique that can reinforce conventional rehabilitation treatments by increasing therapy intensity and engagement through challenging and motivating exercises. The aim of this paper is to evaluate the feasibility and validity of the SonicHand protocol, a new training and assessment method for the rehabilitation of hand function. The study was conducted in 15 healthy individuals and 15 stroke patients. The feasibility of implementation of the training protocol was tested in stroke patients only, who practiced a series of exercises concurrently to music sequences produced by specific movements. The assessment protocol evaluated hand motor performance during pronation/supination, wrist horizontal flexion/extension, and hand grasp without sonification. From hand position data, 15 quantitative parameters were computed evaluating mean velocity, movement smoothness, and angular excursions of hand/fingers. We validated this assessment in terms of its ability to discriminate between patients and healthy subjects, test-retest reliability and concurrent validity with the upper limb section of the Fugl-Meyer scale (FM), the functional independence measure (FIM), and the Box and Block Test (BBT). All patients showed a good understanding of the assigned tasks and were able to correctly execute the proposed training protocol, confirming its feasibility. A moderate-to-excellent intraclass correlation coefficient was found in 8/15 computed parameters. The moderate-to-strong correlation was found between the measured parameters and the clinical scales. The SonicHand training protocol is feasible and the assessment protocol showed good to excellent between-group discrimination ability, reliability, and concurrent validity, thus enabling the implementation of new personalized and motivating training programs employing sonification for the rehabilitation of hand function.

Theory of Mind after Severe Acquired Brain Injury: Clues for Interpretation.

Background. Recently, increased interest has been shown in Theory of Mind (ToM) abilities of individuals with severe acquired brain injury (sABI). ToM impairment following sABI can be associated with altered executive functioning and/or with difficulty in decoding and elaborating emotions. Two main theoretical models have been proposed to explain the mechanisms underlying ToM in the general population: Theory Theory and Simulation Theory. This review presents and discusses the literature on ToM abilities in individuals with sABI by examining whether they sustain the applicability of the Theory Theory and/or Simulation Theory to account for ToM deficits in this clinical population. We found 32 papers that are directly aimed at investigating ToM in sABI. Results did not show the univocal predominance of one model with respect to the other in explaining ToM deficits in sABI. We hypothesised that ToM processes could be explained by coinvolvement of the two models, i.e., according to personal experience, cognitive features, or the emotional resources of the persons with sABI.

Does Dopamine Depletion Trigger a Spreader Lexical-Semantic Activation in Parkinson's Disease? Evidence from a Study Based on Word Fluency Tasks.

It has been hypothesised that, in Parkinson's disease (PD), dopamine might modulate spreading activation of lexical-semantic representations. We aimed to investigate this hypothesis in individuals with PD without dementia by assessing word frequency and typicality in verbal fluency tasks. We predicted that the average values of both of these parameters would be lower in PD patients with respect to healthy controls (HC). We administered letter-cued and category-cued fluency tasks to early PD patients in two experimental conditions: the tasks were administered both after 12-18 hours of dopaminergic stimulation withdrawal ("OFF" condition) and after the first daily dose of dopaminergic therapy ("ON" condition). HC were also given the two tasks in two conditions with the same intersession delay as PD patients but without taking drugs. Results showed that in both OFF and ON treatment conditions PD patients did not differ from HC in word frequency or typicality. Moreover, in the PD group, no significant difference was found between the experimental conditions. Our results show that semantic spreading was not altered in the PD sample examined; this suggests that in early PD the functioning of the semantic system is relatively independent from the activity of dopamine brain networks.

Blindfolded Balance Training in Patients with Parkinson's Disease: A Sensory-Motor Strategy to Improve the Gait.

Aim. Recent evidence suggested that the use of treadmill training may improve gait parameters. Visual deprivation could engage alternative sensory strategies to control dynamic equilibrium and stabilize gait based on vestibulospinal reflexes (VSR). We aimed to investigate the efficacy of a blindfolded balance training (BBT) in the improvement of stride phase percentage reliable gait parameters in patients with Parkinson's Disease (PD) compared to patients treated with standard physical therapy (PT). Methods. Thirty PD patients were randomized in two groups of 15 patients, one group treated with BBT during two weeks and another group treated with standard PT during eight weeks. We evaluated gait parameters before and after BBT and PT interventions, in terms of double stance, swing, and stance phase percentage. Results. BBT induced an improvement of double stance phase as revealed (decreased percentage of double stance phase during the gait cycle) in comparison to PT. The other gait parameters swing and stance phase did not differ between the two groups. Discussion. These results support the introduction of complementary rehabilitative strategies based on sensory-motor stimulation in the traditional PD patient's rehabilitation. Further studies are needed to investigate the neurophysiological circuits and mechanism underlying clinical and motor modifications.

Brain structure, cognition and negative symptoms in schizophrenia are associated with serum levels of polysialic acid-modified NCAM.

The neural cell adhesion molecule (NCAM) is a glycoprotein implicated in cell-cell adhesion, neurite outgrowth and synaptic plasticity. Polysialic acid (polySia) is mainly attached to NCAM (polySia-NCAM) and has an essential role in regulating NCAM-dependent developmental processes that require plasticity, that is, cell migration, axon guidance and synapse formation. Post-mortem and genetic evidence suggests that dysregulation of polySia-NCAM is involved in schizophrenia (SZ). We enrolled 45 patients diagnosed with SZ and 45 healthy individuals who were submitted to polySia-NCAM peripheral quantification, cognitive and psychopathological assessment and structural neuroimaging (brain volumes and diffusion tensor imaging). PolySia-NCAM serum levels were increased in SZ patients, independently of antipsychotic treatment, and were associated with negative symptoms, blunted affect and declarative memory impairment. The increased polySia-NCAM levels were associated with decreased volume in the left prefrontal cortex, namely Brodmann area 46, in patients and increased volume in the same brain area of healthy individuals. As this brain region is involved in the pathophysiology of SZ and its associated phenomenology, the data indicate that polySia-NCAM deserves further scrutiny because of its possible role in early neurodevelopmental mechanisms of the disorder.

Italian Frontotemporal Dementia Network (FTD Group-SINDEM): sharing clinical and diagnostic procedures in Frontotemporal Dementia in Italy.

In the prospect of improved disease management and future clinical trials in Frontotemporal Dementia, it is desirable to share common diagnostic procedures. To this aim, the Italian FTD Network, under the aegis of the Italian Neurological Society for Dementia, has been established. Currently, 85 Italian Centers involved in dementia care are part of the network. Each Center completed a questionnaire on the local clinical procedures, focused on (1) clinical assessment, (2) use of neuroimaging and genetics; (3) support for patients and caregivers; (4) an opinion about the prevalence of FTD. The analyses of the results documented a comprehensive clinical and instrumental approach to FTD patients and their caregivers in Italy, with about 1,000 newly diagnosed cases per year and 2,500 patients currently followed by the participating Centers. In analogy to other European FTD consortia, future aims will be devoted to collect data on epidemiology of FTD and its subtypes and to provide harmonization of procedures among Centers.

The Corticospinal Tract in Huntington's Disease.

Huntington's disease (HD) is characterized by progressive motor impairment. Therefore, the connectivity of the corticospinal tract (CST), which is the main white matter (WM) pathway that conducts motor impulses from the primary motor cortex to the spinal cord, merits particular attention. WM abnormalities have already been shown in presymptomatic (Pre-HD) and symptomatic HD subjects using magnetic resonance imaging (MRI). In the present study, we examined CST microstructure using diffusion tensor imaging (DTI)-based tractography in 30-direction DTI data collected from 100 subjects: Pre-HD subjects (n = 25), HD patients (n = 25) and control subjects (n = 50), and T2*-weighted (iron sensitive) imaging. Results show decreased fractional anisotropy (FA) and increased axial (AD), and radial diffusivity (RD) in the bilateral CST of HD patients. Pre-HD subjects had elevated iron in the left CST, regionally localized between the brainstem and thalamus. CAG repeat length in conjunction with age, as well as motor (UHDRS) assessment were correlated with CST FA, AD, and RD both in Pre-HD and HD. In the presymptomatic phase, increased iron in the inferior portion supports the "dying back" hypothesis that axonal damage advances in a retrograde fashion. Furthermore, early iron alteration may cause a high level of toxicity, which may contribute to further damage.

Recommendations of the Sleep Study Group of the Italian Dementia Research Association (SINDem) on clinical assessment and management of sleep disorders in individuals with mild cognitive impairment and dementia: a clinical review.

Clinical assessment and management of sleep disturbances in patients with mild cognitive impairment and dementia has important clinical and social implications. Poor sleep results in an increased risk of morbidities and mortality in demented patients and is a source of stress for caregivers. Sleep disturbances show high prevalence in mild cognitive impairment and dementia patients and they are often associated one to another in the same patient. A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of individuals with cognitive decline. The Sleep Study Group of the Italian Dementia Research Association (SINDem) reviewed evidence from original research articles, meta-analyses and systematic reviews published up to December 2013. The evidence was classified in quality levels (I, II, III) and strength of recommendations (A, B, C, D, E). Where there was a lack of evidence, but clear consensus, good practice points were provided. These recommendations may not be appropriate for all circumstances and should therefore be adopted only after a patient's individual characteristics have been carefully evaluated.

MRI measures of corpus callosum iron and myelin in early Huntington's disease.

Increased iron in subcortical gray matter (GM) structures of patients with Huntington's disease (HD) has been suggested as a causal factor in neuronal degeneration. But how iron content is related to white matter (WM) changes in HD is still unknown. For example, it is not clear whether WM changes share the same physiopathology (i.e. iron accumulation) with GM or whether there is a different mechanism. The present study used MRI to examine iron content in premanifest gene carriers (PreHD, n = 25) and in early HD patients (n = 25) compared with healthy controls (n = 50). 3T MRI acquisitions included high resolution 3D T1, EPI sequences for diffusion tensor imaging (DTI) as an indirect measure of tissue integrity, and T2*-weighted gradient echo-planar imaging for MR-based relaxometry (R2*), which provides an indirect measure of ferritin/iron deposition in the brain. Myelin breakdown starts in the PreHD stage, but there is no difference in iron content values. Iron content reduction manifests later, in the early HD stage, in which we found a lower R2* parameter value in the isthmus. The WM iron reduction in HD is temporally well-defined (no iron differences in PreHD subjects and iron differences only in early HD patients). Iron level in callosal WM may be regarded as a marker of disease state, as iron does not differentiate PreHD subjects from controls but distinguishes between PreHD and HD.

Polygenic determinants of white matter volume derived from GWAS lack reproducibility in a replicate sample.

A recent publication reported an exciting polygenic effect of schizophrenia (SCZ) risk variants, identified by a large genome-wide association study (GWAS), on total brain and white matter volumes in schizophrenic patients and, even more prominently, in healthy subjects. The aim of the present work was to replicate and then potentially extend these findings. According to the original publication, polygenic risk scores-using single nucleotide polymorphism (SNP) information of SCZ GWAS-(polygenic SCZ risk scores; PSS) were calculated in 122 healthy subjects, enrolled in a structural magnetic resonance imaging (MRI) study. These scores were computed based on P-values and odds ratios available through the Psychiatric GWAS Consortium. In addition, polygenic white matter scores (PWM) were calculated, using the respective SNP subset in the original publication. None of the polygenic scores, either PSS or PWM, were found to be associated with total brain, white matter or gray matter volume in our replicate sample. Minor differences between the original and the present study that might have contributed to lack of reproducibility (but unlikely explain it fully), are number of subjects, ethnicity, age distribution, array technology, SNP imputation quality and MRI scanner type. In contrast to the original publication, our results do not reveal the slightest signal of association of the described sets of GWAS-identified SCZ risk variants with brain volumes in adults. Caution is indicated in interpreting studies building on polygenic risk scores without replication sample.

"If two witches would watch two watches, which witch would watch which watch?" tDCS over the left frontal region modulates tongue twister repetition in healthy subjects.

Recent studies have demonstrated that transcranial direct current stimulation (tDCS) modulates cortical activity in the human brain. In the language domain, it has already been shown that during a naming task tDCS reduces vocal reaction times in healthy individuals and speeds up the recovery process in left brain-damaged aphasic subjects. In this study, we wondered whether tDCS would influence the ability to articulate tongue twisters during a repetition task. Three groups of 10 healthy individuals were asked to repeat a list of tongue twisters in three different stimulation conditions: one group performed the task during anodal tDCS (atDCS) (20 min, 2 mA) over the left frontal region; a second group during cathodal tDCS delivered over the same region; and, in a third group, sham stimulation was applied. Accuracy and vocal reaction times in repeating each tongue twister before, during and 1h after the stimulation were recorded. Participants were more accurate and faster at repeating the stimuli during atDCS than at baseline, while cathodal tDCS significantly reduced their performance in terms of accuracy and reaction times. No significant differences were observed among the three time points during the sham condition. We believe that these data clearly confirm that the left frontal region is critically involved in the process of speech repetition. They are also in line with recent evidence suggesting that frontal tDCS might be used as a therapeutic tool in patients suffering from articulatory deficits.

Functional connectivity changes within specific networks parallel the clinical evolution of multiple sclerosis.

BACKGROUND: In multiple sclerosis (MS), the location of focal lesions does not always correlate with clinical symptoms, suggesting disconnection as a major pathophysiological mechanism. Resting-state (RS) functional magnetic resonance imaging (fMRI) is believed to reflect brain functional connectivity (FC) within specific neuronal networks. OBJECTIVE: RS-fMRI was used to investigate changes in FC within two critical networks for the understanding of MS disabilities, namely, the sensory-motor network (SMN) and the default-mode network (DMN), respectively, implicated in sensory-motor and cognitive functions. METHODS: Thirty-four relapsing-remitting (RR), 14 secondary progressive (SP) MS patients and 25 healthy controls underwent MRI at 3T, including conventional images, T1-weighted volumes, and RS-fMRI sequences. Independent component analysis (ICA) was employed to extract maps of the relevant RS networks for every participant. Group analyses were performed to assess changes in FC within the SMN and DMN in the two MS phenotypes. RESULTS: Increased FC was found in both networks of MS patients. Interestingly, specific changes in either direction were observed also between RR and SP MS groups. CONCLUSIONS: FC changes seem to parallel patients' clinical state and capability of compensating for the severity of clinical/cognitive disabilities.

Anatomical brain connectivity can assess cognitive dysfunction in multiple sclerosis.

BACKGROUND: Brain disconnection plays a major role in determining cognitive disabilities in multiple sclerosis (MS). We recently developed a novel diffusion-weighted magnetic resonance imaging (DW-MRI) tractography approach, namely anatomical connectivitity mapping (ACM), that quantifies structural brain connectivity. OBJECTIVE: Use of ACM to assess structural connectivity modifications in MS brains and ascertain their relationship with the patients' Paced-Auditory-Serial-Addition-Test (PASAT) scores. METHODS: Relapsing-remitting MS (RRMS) patients (n = 25) and controls (n = 25) underwent MRI at 3T, including conventional images, T1-weighted volumes and DW-MRI. Volumetric scans were coregistered to fractional anisotropy (FA) images, to obtain parenchymal FA maps for both white and grey matter. We initiated probabilistic tractography from all parenchymal voxels, obtaining ACM maps by counting the number of streamlines passing through each voxel, then normalizing by the total number of streamlines initiated. The ACM maps were transformed into standard space, for statistical use. RESULTS: RRMS patients had reduced grey matter volume and FA, consistent with previous literature. Also, we showed reduced ACM in the thalamus and in the head of the caudate nucleus, bilaterally. In our RRMS patients, ACM was associated with PASAT scores in the corpus callosum, right hippocampus and cerebellum. CONCLUSIONS: ACM opens a new perspective, clarifying the contribution of anatomical brain disconnection to clinical disabilities in MS.

The potential prognostic role of cardiovascular autonomic failure in α-synucleinopathies.

Cardiovascular autonomic failure is the second most common dysautonomic feature of α-synucleinopathies and has significant impact on daily activities and quality of life. Here we provide a systematic review of cardiovascular autonomic failure in α-synucleinopathies, emphasizing its impact on cognitive functions and disease outcomes. Articles spanning the period between January 1985 and April 2012 were identified from the PubMed database using a keyword-based search. Epidemiological studies highlight the negative prognostic effect of cardiovascular autonomic failure on cardiovascular and cerebrovascular outcomes and overall mortality in all α-synucleinopathies. Altered cerebral perfusion, vascular pressure stress, and related disruption of the blood-brain barrier may also contribute to the white matter hyperintensities and cognitive dysfunction frequently found in patients affected by neurocardiovascular instability. These findings support the hypothesis that cardiovascular autonomic failure may play a negative prognostic role in α-synucleinopathies and suggest that precocious screening and therapeutic management of cardiovascular autonomic failure may positively impact disease course.

Effect of levodopa on both verbal and motor representations of action in Parkinson's disease: a fMRI study.

Previous studies have demonstrated that non-demented Parkinson's disease (PD) patients have a specific impairment of verb production compared with noun generation. One interpretation of this deficit suggested the influence of striato-frontal dysfunction on action-related verb processing. The aim of our study was to investigate cerebral changes after motor improvement due to dopaminergic medication on the neural circuitry supporting action representation in the brain as mediated by verb generation and motor imagery in PD patients. Functional magnetic resonance imaging on 8 PD patients in "ON" dopaminergic treatment state (DTS) and in "OFF" DTS was used to explore the brain activity during three different tasks: Object Naming (ObjN), Generation of Action Verbs (GenA) in which patients were asked to overtly say an action associated with a picture and mental simulation of action (MSoA) was investigated by asking subjects to mentally simulate an action related to a depicted object. The distribution of brain activities associated with these tasks whatever DTS was very similar to results of previous studies. The results showed that brain activity related to semantics of action is modified by dopaminergic treatment in PD patients. This cerebral reorganisation concerns mainly motor and premotor cortex suggesting an involvement of the putaminal motor loop according to the "motor" theory of verb processing.