Stroke damages attentional maintenance in working memory.

Stroke is the main cause of acquired disability in adults, and specific deficits in working memory (WM) are among the most common cognitive consequences. In neuropsychological routine, WM is most of the time investigated in the framework of the multicomponent model (Baddeley & Hitch, 1974, The psychology of learning and motivation, 47). Using a more recent theoretical WM model, the time-based resource-sharing (TBRS) model (Barrouillet et al., 2011, Psychol. Rev., 118, 175), the aim of the present study was to investigate in young post-stroke patients to which extent attentional maintenance is impaired in WM. To address this question, we discarded other factors known to directly influence WM performance, that is processing speed and short-term memory span. We proposed to 53 post-stroke patients and to 63 healthy controls a complex span paradigm in which participants were asked to alternate between the memorization of a series of images and a concurrent parity judgement task of a series of digits. To investigate the attentional maintenance processes, we manipulated the cognitive load (CL) of the concurrent task. CL effect is typically interpreted as the involvement of attentional maintenance processes. The task was adapted to each participant according to their processing speed and memory span. As expected, the results showed higher recall performance in healthy controls compared with post-stroke patients. Consistent with the literature, we also observed higher performance when the CL was low compared with high. However, the improvement in recall at low CL was smaller for post-stroke patients compared with controls, suggesting that post-stroke WM deficit could be in part due to a deficit of the attentional maintenance processes.

Ipsilateral hand impairment predicts long-term outcome in patients with subacute stroke.

BACKGROUND: Ipsilateral hand (ILH) impairment is documented following motor stroke, but its impact on long-term outcome remains unknown. We assessed ILH impairment in subacute stroke and tested whether ILH impairment predicted long-term outcome. METHODS: We performed a longitudinal study in 209 consecutive patients with unilateral stroke and sensorimotor deficit at admission. ILH impairment was evaluated using the Purdue Pegboard Test (PPT) and handgrip strength and defined as mild (z-score < -1) or moderate (z-score < -1.65). We used logistic regression (LR) to predict outcome assessed 9 (range, 7-12) months post-stroke with the modified Rankin scale (mRS) categorized into good (mRS ≤ 1) and poor outcome (mRS ≥ 2). For internal validation, LR-bootstrapping and cross-validation with LASSO and Random Forest were performed. RESULTS: ILH impairment assessed at 89.04 ± 45.82 days post-stroke was moderate in 10.53% (95% CI 6.7, 14.83) for PPT and 17.22% (95% CI 11.96, 22.49) for grip, and mild in 21.05% (95% CI 15.78, 26.79) for PPT and 35.89 (95% CI 29.67, 42.58) for grip. Good outcome was predicted by ILH-PPT (B = 1.03 [95% CI 0.39, 3.31]), ILH-grip (B = 1.16 [95% CI 0.54, 3.53]), low NIHSS-discharge (B = -1.57 [95% CI -4.0, -1.19]), and no depression (B = -0.62 [95% CI -1.63, -0.43]), accounting for stroke delay (B = -0.011 [95% CI -0.06, 0.01]). Model efficiency was 91.6% (AUC = 0.977; 95% CI 0.959, 0.996). LASSO and Random Forest methods provided similar results, confirming the LR model robustness. CONCLUSIONS: ILH impairment is frequent after motor stroke and predicts long-term outcome. We propose to integrate ILH impairment into rehabilitation programs to improve recovery and serve research interventions such as neuromodulation.

White matter tract disruption is associated with ipsilateral hand impairment in subacute stroke: a diffusion MRI study.

PURPOSE: The ipsilateral hand (ILH) is impaired after unilateral stroke, but the underlying mechanisms remain unresolved. Based on the degeneracy theory of network connectivity that many connectivity patterns are functionally equivalent, we hypothesized that ILH impairment would result from the summation of microstructural white matter (WM) disruption in the motor network, with a task-related profile. We aimed to determine the WM disruption patterns associated with ILH impairment. METHODS: This was a cross-sectional analysis of patients in the ISIS-HERMES Study with ILH and diffusion-MRI data collected 1 month post-stroke. Patients performed three tasks, the Purdue Pegboard Test (PPT), handgrip strength, and movement time. Fractional anisotropy (FA) derived from diffusion MRI was measured in 33 WM regions. We used linear regression models controlling for age, sex, and education to determine WM regions associated with ILH impairment. RESULTS: PPT was impaired in 42%, grip in 59%, and movement time in 24% of 29 included patients (mean age, 51.9 ± 10.5 years; 21 men). PPT was predicted by ipsilesional corticospinal tract (i-CST) (B = 17.95; p = 0.002) and superior longitudinal Fasciculus (i-SLF) (B = 20.52; p = 0.008); handgrip by i-CST (B = 109.58; p = 0.016) and contralesional anterior corona radiata (B = 42.69; p = 0.039); and movement time by the corpus callosum (B = - 1810.03; p = 0.003) i-SLF (B = - 917.45; p = 0.015), contralesional pons-CST (B = 1744.31; p = 0.016), and i-corticoreticulospinal pathway (B = - 380.54; p = 0.037). CONCLUSION: ILH impairment was associated with WM disruption to a combination of ipsilateral and contralesional tracts with a pattern influenced by task-related processes, supporting the degeneracy theory. We propose to integrate ILH assessment in rehabilitation programs and treatment interventions such as neuromodulation.

Using tools effectively despite defective hand posture: A single-case study.

Apraxia, a cognitive disorder of motor control, can severely impair transitive actions (object-related) and may lead to action errors (e.g., rubbing a hammer on a nail instead of pounding it) and hand posture errors (e.g., grasping a tool in a wrong way). Here, we report a rare observation of a left-handed patient, left-lateralized for language, who developed a severe apraxia following a right brain lesion. Interestingly the patient showed a significant number of hand posture errors, while she perfectly demonstrated the actual use of tools. This case stressed the predictions made by the current theories of tool use. According to the manipulation-based approach, the hand posture errors should be associated with an impaired manipulation knowledge. According to the reasoning-based approach, the absence of action errors should be associated with spared mechanical knowledge. Moreover, to better understand the neurocognitive origins of the deficit observed in VF, we examined several potential brain lateralization of praxis functions. We initiated a systematic examination of VF's performance in several contexts of tool use allowing us to investigate which kinds of tool-use representations were potentially impaired in VF. Our investigation did not reveal any major deficit of manipulation knowledge. This can hardly account for the high frequency of hand posture errors, contrary to the predictions of the manipulation-based approach. In contrast, in line with the reasoning-based approach, mechanical knowledge was spared and can explain the absence of action errors. We also found that VF probably had a bilateral organization of praxis functions, but irrespective of the possible brain lateralization considered, none of which established a satisfactory association between manipulation knowledge and hand posture errors. Taken together, the manipulation-based approach fails to explain fully the deficit presented by this patient and should lead us to consider alternative explanations.

Spatiotemporal patterns of sensorimotor fMRI activity influence hand motor recovery in subacute stroke: A longitudinal task-related fMRI study.

Motor hand deficits impact autonomy in everyday life, and neuroplasticity processes of motor recovery can be explored using functional MRI (fMRI). However, few studies have used fMRI to explore the mechanisms underlying hand recovery following stroke. Based on the dual visuomotor model positing that two segregated dorsomedial and dorsolateral cerebral networks control reach and grasp movements, we explored the relationship between motor task-related activity in the sensorimotor network and hand recovery following stroke. Behavioral recovery was explored with a handgrip force task assessing simple grasp, and a visuomotor reaching and precise grasping task, the Purdue Pegboard Test (PPT). We used a passive wrist flexion-extension task to measure fMRI activity in 36 sensorimotor brain areas. Behavioral and fMRI measurements were performed in 27 patients (53.2 ± 9.5 years) 1-month following stroke, and then 6-month and 24-month later. The effects of sensorimotor activity on hand recovery were analyzed using correlations and linear mixed models (LMMs). PPT and handgrip force correlated with fMRI activity measures in the sensorimotor and parietal areas. PPT recovery was modeled by fMRI measures in the ipsilesional primary motor cortex (MI-4p), superior parietal lobule (SPL-7M) and parietal operculum OP1, and lesion side. Handgrip force was modeled by ipsilesional MI-4a, OP1, and contralesional inferior parietal lobule (IPL-PFt). Moreover, the relationship between fMRI activity and hand recovery was time-dependent, occurring in the early recovery period in SPL-BA-7M, and later in MI. These results suggest that areas of both dorsolateral and dorsomedial networks participate to visuomotor reach and grasp tasks (PPT), while dorsolateral network areas may control recovery of simple grasp (handgrip force), suggesting that the type of movement modulates network recruitment. We also found functional dissociations between MI-4p related to PPT that required independent finger movements and MI-4a related to simple grasp without independent finger movements. These findings need to be replicated in further studies.

Continuous positive airway pressure treatment impact on memory processes in obstructive sleep apnea patients: a randomized sham-controlled trial.

OBJECTIVE: The aim of this study was to investigate the changes in a large panel of memory processes after six weeks of continuous positive airway pressure (CPAP) in obstructive sleep apnea (OSA) patients. This randomized controlled trial compared the influence of effective CPAP to sham CPAP over six weeks on different memory processes in OSA patients. METHODS: The study took place in a sleep laboratory and outpatient sleep clinic in a French tertiary-care university hospital. A total of 36 patients with OSA were randomized to receive either CPAP (n = 18) or sham CPAP (n = 18) for six weeks. Interventions were either effective CPAP or non-effective sham CPAP, for six weeks. All patients underwent an extensive battery of tasks evaluating three separate memory systems, before and after treatment. Verbal episodic memory was tested after forced encoding, procedural memory was tested using simplified versions of mirror drawing and reading tests, and working memory was examined with validated paradigms based on a theoretical model. RESULTS: The study subjects were 55 ± 11 years of age and 72.2% were male. The mean body mass index was 29.5 ± 4.1 kg/m2 and the apnea-hypopnea index was 37.1 ± 16.3/h. Prior to treatment, memory performances of OSA patients were altered. In an intention-to-treat analysis, memory deficits were not significantly improved after six weeks of effective CPAP compared to sham CPAP treatment. Verbal episodic, procedural, and working memory scores were comparable between both groups. CONCLUSION: Using cautious methodology in comparing effective CPAP to sham CPAP and a well-defined set of memory assessments, we did not find improvement in memory performance after six weeks of treatment.

Intravenous Injection of Clinical Grade Human MSCs After Experimental Stroke: Functional Benefit and Microvascular Effect.

Stroke is the leading cause of disability in adults. Many current clinical trials use intravenous (IV) administration of human bone marrow-derived mesenchymal stem cells (BM-MSCs). This autologous graft requires a delay for ex vivo expansion of cells. We followed microvascular effects and mechanisms of action involved after an IV injection of human BM-MSCs (hBM-MSCs) at a subacute phase of stroke. Rats underwent a transient middle cerebral artery occlusion (MCAo) or a surgery without occlusion (sham) at day 0 (D0). At D8, rats received an IV injection of 3 million hBM-MSCs or PBS-glutamine. In a longitudinal behavioral follow-up, we showed delayed somatosensory and cognitive benefits 4 to 7 weeks after hBM-MSC injection. In a separate longitudinal in vivo magnetic resonance imaging (MRI) study, we observed an enhanced vascular density in the ischemic area 2 and 3 weeks after hBM-MSC injection. Histology and quantitative polymerase chain reaction (qPCR) revealed an overexpression of angiogenic factors such as Ang1 and transforming growth factor-1 (TGF-1) at D16 in hBM-MSC-treated MCAo rats compared to PBS-treated MCAo rats. Altogether, delayed IV injection of hBM-MSCs provides functional benefits and increases cerebral angiogenesis in the stroke lesion via a release of endogenous angiogenic factors enhancing the stabilization of newborn vessels. Enhanced angiogenesis could therefore be a means of improving functional recovery after stroke.

Microvascular plasticity after experimental stroke: a molecular and MRI study.

BACKGROUND: Microvasculature plays a key role in stroke pathophysiology both during initial damage and extended neural repair. Moreover, angiogenesis processes seem to be a promising target for future neurorestorative therapies. However, dynamic changes of microvessels after stroke still remain unclear, and MRI follow-up could be interesting as an in vivo biomarker of these. METHODS: The aim of this study is to characterize the microvascular plasticity 25 days after ischemic stroke using both in vivo microvascular 7T-MRI (vascular permeability, cerebral blood volume (CBV), vessel size index (VSI), vascular density) and quantification of angiogenic factor expressions by RT-qPCR in a transient middle cerebral artery occlusion rat model. CBV and VSI (perfused vessel caliber) imaging was performed using a steady-state approach with a multi gradient-echo spin-echo sequence before and 2 min after intravenous (IV) injection of ultrasmall superparamagnetic iron particles. Vascular density (per mm2) was derived from the ratio [ΔR2/(ΔR2*)²/³]. Blood brain barrier leakage was assessed using T1W images before and after IV injection of Gd-DOTA. Additionally, microvessel immunohistology was done. RESULTS: 3 successive stages were observed: 1) 'Acute stage' from day 1 to day 3 post-stroke (D1-D3) characterized by high levels of angiopoietin-2 (Ang2), vascular endothelial growth factor receptor-2 (VEGFR-2) and endothelial NO synthase (eNOS) that may be associated with deleterious vascular permeability and vasodilation; 2) 'Transition stage' (D3-D7) that involves transforming the growth factors ß1 (TGFß1), Ang1, and tyrosine kinase with immunoglobulin-like and endothelial growth factor-like domains 1 (Tie1), stromal-derived factor-1 (SDF-1), chemokine receptor type 4 (CXCR-4); and 3) 'Subacute stage' (D7-D25) with high levels of Ang1, Ang2, VEGF, VEGFR-1 and TGFß1 leading to favorable stabilization and maturation of microvessels. In vivo MRI appeared in line with the angiogenic factors changes with a delay of at least 1 day. All MRI parameters varied over time, revealing the different aspects of the post-stroke microvascular plasticity. At D25, despite a normal CBV, MRI revealed a limited microvessel density, which is insufficient to support a good neural repair. CONCLUSIONS: Microvasculature MRI can provide imaging of different states of functional (perfused) microvessels after stroke. These results highlight that multiparametric MRI is useful to assess post-stroke angiogenesis, and could be used as a biomarker notably for neurorestorative therapy studies. Additionally, we identified that endogenous vessel maturation and stabilization occur during the 'subacute stage'. Thus, pro-angiogenic treatments, such as cell-based therapy, would be relevant during this subacute phase of stroke.

Hidden dysfunctioning in subacute stroke.

BACKGROUND AND PURPOSE: Determining cognitive dysfunctioning (CDF) after stroke is an important issue because it influences choices for management in terms of return to previous activities. Because previous research in subacute stroke has shown important variations in CDF rates, we aimed to describe the frequency and neuropsychological profile of CDF in subacute stroke outside dementia. We used a large battery of tests to screen any potentially hidden CDF. METHODS: Patients with Mini-Mental State Examination scores >or=23 were prospectively and consecutively included 2 weeks after a first-ever ischemic brain infarct. Stroke features were based on MRI. Four domains were evaluated: instrumental and executive functions, episodic memory, and working memory (WM). Patients were scored using means and compared with education- and age-matched control subjects. Then we attributed Z-scores for each test and each domain. The most relevant cognitive tests characterizing CDF were determined using logistic regression. RESULTS: Among 177 patients (mean age, 50.6 years), 91.5% failed in at least one cognitive domain. WM was the most impaired domain (87.6%) with executive functions (64.4%), episodic memory (64.4%), and instrumental functions (24.9%) being relatively preserved. CDF was associated with age, education, depression, neurological deficit, and leukoaraiosis in bivariate analysis. Using logistic regression, WM tests and age predicted CDF (Modified Paced Auditorial Serial Addition Test: OR=0.96 CI=0.93 to 0.98; Owen-spatial-WM: OR=1.07 CI=1.02 to 1.12; age: OR=0.96 CI=0.93 to 0.98). CONCLUSIONS: CDF appears to be almost constant, although underestimated, in subacute stroke. WM could reflect some hidden dysfunctioning, which may interfere with rehabilitation and return to work. Clinical routine may include WM tests in young patients with mild stroke.

Which memory processes are affected in patients with obstructive sleep apnea? An evaluation of 3 types of memory.

STUDY OBJECTIVE: To investigate which memory processes are affected by obstructive sleep apnea (OSA). DESIGN: Three separate memory systems were investigated in patients with OSA and normal subjects. Verbal episodic memory was tested after forced encoding, in order to control the level of attention during item presentation; procedural memory was tested using a simplified version of a standard test with an interfering task; lastly, working memory was examined with validated paradigms based on a theoretical model. SETTING: Sleep laboratory and outpatient sleep clinic in a French tertiary-care university hospital. PARTICIPANTS: Ninety-five patients with OSA and 95 control subjects matched for age and level of education. Group 1 (54 patients, 54 controls) underwent an extensive battery of tasks evaluating verbal episodic, procedural, and working memory. Group 2 (16 patients, 16 controls) underwent procedural memory tests only, and group 3 (25 patients, 25 controls) working memory tests only. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Compared with matched controls, patients with OSA exhibited a retrieval deficit of episodic memory but intact maintenance, recognition, and forgetfulness; decreased overall performance in procedural memory, although pattern learning did occur; and impairment of specific working memory capabilities despite normal short-term memory. No consistent correlation was found between OSA severity and memory deficit. The long duration of the test session did not negatively impact the patients' performance. CONCLUSIONS: Memory impairment in OSA is mild and does not affect all memory processes but, rather, specific aspects, underscoring the need for extensive and specific memory testing in clinical and research settings.

Analysis of error profiles occurring during the OSLER test: a sensitive mean of detecting fluctuations in vigilance in patients with obstructive sleep apnea syndrome.

The OSLER test represents a simple alternative to the maintenance of wakefulness test. Standard analysis of OSLER test results yields a mean sleep latency (MSL). The aim of this study was to use both MSL and errors (nonresponses to stimulations) to characterize daytime sleepiness in apneic patients. OSLER test results at 9:00 A.M., 11:00 A.M. and 1:30 P.M. were compared in 27 obstructive sleep apnea syndrome patients (50.4 +/- 10.4 years; apnea-hypopnea index: 43.05 +/- 25.08) and 20 control subjects (C). Not only did obstructive sleep apnea syndrome patients demonstrate earlier sleep onset than control subjects (MSL: 1,788 seconds +/- 511 versus 2,335 seconds +/- 139, p < 0.001), but they also spent a greater percentage of time making errors than control subjects (5.4% +/- 4.7 of total test time versus 0.4% +/- 0.4, p < 0.001) with specific error profiles (high prevalence of three to six consecutive errors). When error profile analysis was added to standard sleep latency assessment, up to 40% of patients with normal sleep latency were exhibiting abnormal fluctuation in vigilance. A single 9:00 A.M. OSLER session appeared as sensitive as three consecutive sessions in its use as a means of identifying patients with significant daytime sleepiness. On the other hand, the 1:30 P.M. OSLER test session was least specific to distinguish apneic subjects from normal subjects, suggesting that the OSLER test can identify the afternoon peak in physiologic somnolence.