Video mirror feedback induces more extensive brain activation compared to the mirror box: an fNIRS study in healthy adults.

BACKGROUND: Mirror therapy (MT) has been shown to be effective for motor recovery of the upper limb after a stroke. The cerebral mechanisms of mirror therapy involve the precuneus, premotor cortex and primary motor cortex. Activation of the precuneus could be a marker of this effectiveness. MT has some limitations and video therapy (VT) tools are being developed to optimise MT. While the clinical superiority of these new tools remains to be demonstrated, comparing the cerebral mechanisms of these different modalities will provide a better understanding of the related neuroplasticity mechanisms. METHODS: Thirty-three right-handed healthy individuals were included in this study. Participants were equipped with a near-infrared spectroscopy headset covering the precuneus, the premotor cortex and the primary motor cortex of each hemisphere. Each participant performed 3 tasks: a MT task (right hand movement and left visual feedback), a VT task (left visual feedback only) and a control task (right hand movement only). Perception of illusion was rated for MT and VT by asking participants to rate the intensity using a visual analogue scale. The aim of this study was to compare brain activation during MT and VT. We also evaluated the correlation between the precuneus activation and the illusion quality of the visual mirrored feedback. RESULTS: We found a greater activation of the precuneus contralateral to the visual feedback during VT than during MT. We also showed that activation of primary motor cortex and premotor cortex contralateral to visual feedback was more extensive in VT than in MT. Illusion perception was not correlated with precuneus activation. CONCLUSION: VT led to greater activation of a parieto-frontal network than MT. This could result from a greater focus on visual feedback and a reduction in interhemispheric inhibition in VT because of the absence of an associated motor task. These results suggest that VT could promote neuroplasticity mechanisms in people with brain lesions more efficiently than MT. CLINICAL TRIAL REGISTRATION: NCT04738851.

Neural Substrates for Hand and Shoulder Movement in Healthy Adults: A Functional near Infrared Spectroscopy Study.

Characterization of cortical activation patterns during movements in healthy adults may help our understanding of how the injured brain works. Upper limb motor tasks are commonly used to assess impaired motor function and to predict recovery in individuals with neurological disorders such as stroke. This study aimed to explore cortical activation patterns associated with movements of the hand and shoulder using functional near-infrared spectroscopy (fNIRS) and to demonstrate the potential of this technology to distinguish cerebral activation between distal and proximal movements. Twenty healthy, right-handed participants were recruited. Two 10-s motor tasks (right-hand opening-closing and right shoulder abduction-adduction) were performed in a sitting position at a rate of 0.5 Hz in a block paradigm. We measured the variations in oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR) concentrations. fNIRS was performed with a 24-channel system (Brite 24®; Artinis) that covered most motor control brain regions bilaterally. Activation was mostly contralateral for both hand and shoulder movements. Activation was more lateral for hand movements and more medial for shoulder movements, as predicted by the classical homunculus representation. Both HbO2 and HbR concentrations varied with the activity. Our results showed that fNIRS can distinguish patterns of cortical activity in upper limb movements under ecological conditions. These results suggest that fNIRS can be used to measure spontaneous motor recovery and rehabilitation-induced recovery after brain injury. The trial was restropectively registered on January 20, 2023: NCT05691777 (clinicaltrial.gov).

Effect of the Level of Physical Activity on Prefrontal Cortex Hemodynamics in Older Adults During Single- and Dual-Task Walking.

The present study aimed to examine the impact of the level of physical activity on prefrontal cortex activation in older adults during single- and dual-task walking. Thirty physically inactive and 36 active older adults (60-85 years old) performed six 2-min tasks on a treadmill: two static cognitive tasks, two single-task walking tests, and two dual-task walking tests. Hemodynamics at the level of the prefrontal cortex were measured continuously using functional near-infrared spectroscopy to evaluate cortical activation. The perceived difficulty of the task, cognitive performance, and gait parameters were also measured. During the walking tasks, the level of prefrontal cortex activation, the perceived difficulty of the task, cognitive performance, and motor parameters were not significantly different between active and inactive older adults. This unchanged activation with physical activity was likely the consequence of a similar motor and cognitive load and cardiorespiratory fitness in both active and inactive older adults.

T Lymphocyte Serotonin 5-HT7 Receptor Is Dysregulated in Natalizumab-Treated Multiple Sclerosis Patients.

Serotonin (5-HT) is known as a potent immune cell modulator in autoimmune diseases and should be protective in the pathogenesis of multiple sclerosis (MS). Nevertheless, there is limited knowledge about receptors involved in 5-HT effects as well as induced mechanisms. Among 5-HT receptors, the 5-HT7 receptor is able to activate naïve T cells and influence the inflammatory response; however, its involvement in the disease has never been studied so far. In this study, we collected blood sample from three groups: acute relapsing MS patients (ARMS), natalizumab-treated MS patients (NTZ), and control subjects. We investigated the 5-HT7 expression on circulating lymphocytes and evaluated the effects of its activation on cytokine production with peripheral blood mononuclear cell (PBMC) cultures. We found a significant increase in the 5-HT7 surface expression on T lymphocytes and on the different CD4+ T cell subsets exclusively in NTZ-treated patients. We also showed that the selective agonist 5-carboxamidotryptamine (5-CT)-induced 5-HT7R activation significantly promotes the production of IL-10, a potent immunosuppressive cytokine in PBMCs. This study provides for the first time a dysregulation of 5-HT7 expression in NTZ-MS patients and its ability to promote IL-10 release, suggesting its protective role. These findings strengthen the evidence that 5-HT7 may play a role in the immuno-protective mechanisms of NTZ in MS disease and could be considered as an interesting therapeutic target in MS.

Relation between Cortical Activation and Effort during Robot-Mediated Walking in Healthy People: A Functional Near-Infrared Spectroscopy Neuroimaging Study (fNIRS).

Force and effort are important components of a motor task that can impact rehabilitation effectiveness. However, few studies have evaluated the impact of these factors on cortical activation during gait. The purpose of the study was to investigate the relation between cortical activation and effort required during exoskeleton-mediated gait at different levels of physical assistance in healthy individuals. Twenty-four healthy participants walked 10 m with an exoskeleton that provided four levels of assistance: 100%, 50%, 0%, and 25% resistance. Functional near-infrared spectroscopy (fNIRS) was used to measure cerebral flow dynamics with a 20-channel (plus two reference channels) device that covered most cortical motor regions bilaterally. We measured changes in oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR). According to HbO2 levels, cortical activation only differed slightly between the assisted conditions and rest. In contrast, bilateral and widespread cortical activation occurred during the two unassisted conditions (somatosensory, somatosensory association, primary motor, premotor, and supplementary motor cortices). A similar pattern was seen for HbR levels, with a smaller number of significant channels than for HbO2. These results confirmed the hypothesis that there is a relation between cortical activation and level of effort during gait. This finding should help to optimize neurological rehabilitation strategies to drive neuroplasticity.

Disturbed expression of autophagy genes in blood of Parkinson's disease patients.

Parkinson's disease (PD) is a common neurodegenerative disorder which affects dopaminergic neurons leading to alteration of numerous cellular pathways. Several reports highlight that PD disturbs also other cells than CNS neurons including PBMCs, which could lead, among other things, to dysfunctions of immune functions. Because autophagy could be altered in PD, a monocentric pilot study was performed to quantify the transcripts levels of several autophagy genes in blood cells. MAP1LC3B, GABARAP, GABARAPL1, GABARAPL2 and P62/SQSTM1 were found to be overexpressed in patients. On the contrary, transcripts for HSPA8 and GAPDH were both decreased. Expression of MAP1LC3B and GABARAP was able to successfully segregate PD patients from healthy controls. The accuracy of this segregation was substantially increased when combined expressions of MAP1LC3B and GAPDH or GABARAP and GAPDH were used as categorical variables. This pilot study suggests that autophagy genes expression is dysregulated in PD patients and may open new perspectives for the characterisation of prediction markers.

Relationships between brain perfusion and early recanalization after intravenous thrombolysis for acute stroke with large vessel occlusion.

In large vessel occlusion (LVO) stroke, it is unclear whether severity of ischemia is involved in early post-thrombolysis recanalization over and above thrombus site and length. Here we assessed the relationships between perfusion parameters and early recanalization following intravenous thrombolysis administration in LVO patients. From a multicenter registry, we identified 218 thrombolysed LVO patients referred for thrombectomy with both (i) pre-thrombolysis MRI, including diffusion-weighted imaging (DWI), T2*-imaging, MR-angiography and dynamic susceptibility-contrast perfusion-weighted imaging (PWI); and (ii) evaluation of recanalization on first angiographic run or non-invasive imaging ≤ 3 h from thrombolysis start. Infarct core volume on DWI, PWI-DWI mismatch volume and hypoperfusion intensity ratio (HIR; defined as Tmax ≥ 10 s volume/ Tmax ≥ 6 s volume, low HIR indicating milder hypoperfusion) were determined using a commercially available software. Early recanalization occurred in 34 (16%) patients, and multivariable analysis was associated with lower HIR (P = 0.006), shorter thrombus on T2*-imaging (P < 0.001) and more distal occlusion (P = 0.006). However, the relationship between HIR and early recanalization was robust only for thrombus length <14 mm. In summary, the present study disclosed an association between lower HIR and early post-thrombolysis recanalization. Early post-thrombolysis recanalization is therefore determined not only by thrombus site and length but also by severity of ischemia.

Better Collaterals Are Independently Associated With Post-Thrombolysis Recanalization Before Thrombectomy.

Background and Purpose- In acute stroke patients with large vessel occlusion, the goal of intravenous thrombolysis (IVT) is to achieve early recanalization (ER). Apart from occlusion site and thrombus length, predictors of early post-IVT recanalization are poorly known. Better collaterals might also facilitate ER, for instance, by improving delivery of the thrombolytic agent to both ends of the thrombus. In this proof-of-concept study, we tested the hypothesis that good collaterals independently predict post-IVT recanalization before thrombectomy. Methods- Patients from the registries of 6 French stroke centers with the following criteria were included: (1) acute stroke with large vessel occlusion treated with IVT and referred for thrombectomy between May 2015 and March 2017; (2) pre-IVT brain magnetic resonance imaging, including diffusion-weighted imaging, T2*, MR angiography, and dynamic susceptibility contrast perfusion-weighted imaging; and (3) ER evaluated ≤3 hours from IVT start on either first angiographic run or noninvasive imaging. A collateral flow map derived from perfusion-weighted imaging source data was automatically generated, replicating a previously validated method. Thrombus length was measured on T2*-based susceptibility vessel sign. Results- Of 224 eligible patients, 37 (16%) experienced ER. ER occurred in 10 of 83 (12%), 17 of 116 (15%), and 10 of 25 (40%) patients with poor/moderate, good, and excellent collaterals, respectively. In multivariable analysis, better collaterals were independently associated with ER ( P=0.029), together with shorter thrombus ( P<0.001) and more distal occlusion site ( P=0.010). Conclusions- In our sample of patients with stroke imaged with perfusion-weighted imaging before IVT and intended for thrombectomy, better collaterals were independently associated with post-IVT recanalization, supporting our hypothesis. These findings strengthen the idea that advanced imaging may play a key role for personalized medicine in identifying patients with large vessel occlusion most likely to benefit from IVT in the thrombectomy era.

APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.

BACKGROUND: Amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series. METHODS AND FINDINGS: We report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid ß (Aß)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification. CONCLUSIONS: Our findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.

Molecular and clinical analyses with neuropsychological assessment of a case of del(10)(q26.2qter) without intellectual disability: Genomic and transcriptomic combined approach and review of the literature.

Terminal deletion of the long arm of the chromosome 10 is a rare but well known abnormality, with a large phenotypic variability. Very few data are available about subtelomeric deletion 10q26 patients without intellectual disability. Herein, we report the case of a young adult with a classical 10q26.2qter deletion. She exhibited mainly short stature at birth and in childhood/adulthood without intellectual disability or behavioral problems. After clinical and neuropsychological assessments, we performed genomic array and transcriptomic analysis and compared our results to the data available in the literature. The patient presents a 6.525 Mb heterozygous 10q26.2qter deletion, encompassed 48 genes. Among those genes, DOCK1, C10orf90, and CALY previously described as potential candidate genes for intellectual disability, were partially or completed deleted. Interestingly, they were not deregulated as demonstrated by transcriptomic analysis. This allowed us to suggest that the mechanism involved in the deletion 10qter phenotype is much more complex that only the haploinsufficiency of DOCK1 or other genes encompassed in the deletion. Genomic and transcriptomic combined approach has to be considered to understand this pathogenesis. © 2016 Wiley Periodicals, Inc.

Oral festination in Parkinson's disease: biomechanical analysis and correlation with festination and freezing of gait.

In Parkinson's disease (PD), festination corresponds to a tendency to speed up when performing repetitive movements. First described in gait (and then in handwriting and speech), festination is one of the most disabling axial symptoms. To establish the phenomenology of oral festination (OF) and the condition's potential links with other axial disorders, we submitted a simple, rhythmic, repetitive, vocal motor task to 40 PD patients and 20 controls. Forty-five percent of the 40 patients presented OF, which was strongly associated with gait festination but not with the severity of freezing of gait (FOG) or dysarthria. With respect to the two pathophysiological hypotheses that have been put forward, a possible link with tremor (as previously suggested in tapping) was not confirmed in this study and so, in view of the significant increase in variability observed, we conclude that OF shares the same pathophysiology as gait disorders.

The place of perceptual analysis of dysarthria in the differential diagnosis of corticobasal degeneration and Parkinson's disease.

OBJECTIVE: To characterize the dysarthria in patients with corticobasal degeneration (CBD) and determine if analysis of speech in isolation helps to distinguish CBD patients from patients with Parkinson's disease (PD). METHODS: 60 subjects were assessed by means of perceptual analysis of speech: 15 patients with CBD, 15 patients with PD and 30 control subjects. A detailed profile was furnished with the help of 33 perceptual items. A global perceptual approach was used to classify patients by judges blind to the medical diagnosis. Rating scales were adapted to quantify the degree of spasticity and hypokinesia in the speech of each patient. RESULTS: Dysarthria was frequent in CBD even though it remained mild for a long period of time. Group analysis revealed the importance of temporal errors of speech control in CBD patients while voice disturbances were most frequent in PD patients. However, attempts to classify patients according to global perceptual analysis remained below a reasonable level of clinical acceptability. Finally, even though the widespread neuropathological changes suggest that deviant speech dimensions of several types of dysarthria might be found in CBD, evidence for a mixed dysarthria with presence of spastic elements could not be established. CONCLUSION: The findings support the view that even though perceptual analysis is mandatory in the management of dysarthric patients, it does not help in the clinical differential diagnosis of CBD.

Orofacial apraxia in corticobasal degeneration, progressive supranuclear palsy, multiple system atrophy and Parkinson's disease.

OBJECTIVES: To determine whether the assessment of orofacial praxis is useful for the differential diagnosis of parkinsonian syndromes and to understand the neural mechanisms underlying OFA, searching for the respective roles of cortical and subcortical structures. METHODS: Forty-four patients were assessed: 12 with idiopathic Parkinson's disease (IPD), 8 with multiple system atrophy (MSA), 12 with progressive supranuclear palsy (PSP) and 12 with corticobasal degeneration (CBD). An easy bedside scale was used, exploring single gestures, gestures with noise production and multiple sequential gestures. We searched for group and task effects. RESULTS: Patients with CBD were significantly more impaired than those with IPD, MSA or PSP (p<0.001). Our assessment was unable to distinguish between the IPD, MSA and PSP groups. There was a clear task effect in CBD with a major impairment in multiple sequential gestures (p<0.0001). CONCLUSION: Assessment of orofacial praxis helps in the clinical diagnosis of CBD. Patients with IPD, MSA and PSP did not present with OFA. We suggest that the deficit in multiple sequential gestures in CBD is related to simultaneous lesions of the parietal lobule and the supplementary motor area.

Treatments for dysarthria in Parkinson's disease.

Dysarthria in Parkinson's disease can be characterised by monotony of pitch and loudness, reduced stress, variable rate, imprecise consonants, and a breathy and harsh voice. Use of levodopa to replenish dopamine concentrations in the striatum seems to improve articulation, voice quality, and pitch variation, although some studies show no change in phonatory parameters. Traditional speech therapy can lead to improvement of dysarthria, and intensive programmes have had substantial beneficial effects on vocal loudness. Unilateral surgical lesions of subcortical structures are variably effective for the alleviation of dysarthria, whereas bilateral procedures typically lead to worsening of speech production. Among deep-brain stimulation procedures, only stimulation of the subthalamic nucleus improves some motor components of speech although intelligibility seems to decrease after surgery. Due to the variable treatment effects on parkinsonian speech, management of dysarthria is still challenging for the clinician and should be discussed with the patient.

Effects of subthalamic nucleus stimulation on parkinsonian dysarthria and speech intelligibility.

Subthalamic stimulation is known to improve tremor, akinesia and rigidity in Parkinson's disease. However, other signs such as hypophonia and swallowing disorders can be relatively resistant to this technique. The effect on dysarthria remains unclear. The aim of this study was to investigate the effects of implantation of electrode and stimulation of the subthalamic nucleus (STN) on parkinsonian dysarthria. Seven patients were prospectively included. Electrodes (Medtronic) were implanted in both STN. The electrode contacts and stimulation parameters were adjusted to provide best relief of symptoms with fewest side effects. Assessment used global scales (Unified Parkinson Disease Rating Scale, UPDRS II and III), dyskinesia scale, exhaustive dysarthria assessment (bucco-facial movements, voice, articulation, intelligibility) and the 'dysarthria' item from the UPDRS III. Evaluations were performed in six conditions: before and three months after surgery (pre-op, post-op) stimulation turned off or on (off-stim, onstim), and without or with a suprathreshold levodopa dose (offdrug, on-drug). Performance level on the UPDRS III significantly improved following electrode implantation and stimulation. For dysarthria, modest beneficial effects were observed on several motor parameters, especially lip movements. Voice mildly improved, especially for the modulation in loudness and pitch. Articulation was not affected. Furthermore, intelligibility was slightly reduced in the on-stimulation condition, especially when patients received levodopa. At an individual level, negative effects on intelligibility were observed in two patients, and this was associated with a discrete increase in facial and trunk dyskinesias, but not with the electrode position or stimulation parameters. In conclusion, surgery had weak effects on dysarthria. Intelligibility can be worsened, especially in the on-drug condition. Thus, adaptation of the stimulation parameters can be difficult.

[Speech therapy of dysarthria in Parkinson's disease]. / La rééducation orthophonique de la dysarthrie dans la maladie de Parkinson.

The treatment of speech impairment, a factor of loneliness, speech therapy to treat dysarthria in Parkinson's disease is a fundamental aspect of patient management. The impact of medicinal treatment of dysarthria is controversial and surgery appears to worsen the problem. Various speech therapy approaches are relaxation, postural rehabilitation, respiration, phonation, articulation and prosodic re-education. AN INTERESTING METHOD: This overview underlines the fundamental principles of speech therapy in Parkinson's disease and compares the main methods and their results. We particularly insist on the Lee Silverman Voice Treatment (LSVT), phonation re-education method that has been widely developed in the United-States. Our aim is to provide better knowledge on this re-education method in France.