Reliability and validity of DTI-based indirect disconnection measures.

White matter connections enable the interaction within and between brain networks. Brain lesions can cause structural disconnections that disrupt networks and thereby cognitive functions supported by them. In recent years, novel methods have been developed to quantify the extent of structural disconnection after focal lesions, using tractography data from healthy controls. These methods, however, are indirect and their reliability and validity have yet to be fully established. In this study, we present our implementation of this approach, in a tool supplemented by uncertainty metrics for the predictions overall and at voxel-level. These metrics give an indication of the reliability and are used to compare predictions with direct measures from patients' diffusion tensor imaging (DTI) data in a sample of 95 first-ever stroke patients. Results show that, except for small lesions, the tool can predict fiber loss with high reliability and compares well to direct patient DTI estimates. Clinical utility of the method was demonstrated using lesion data from a subset of patients suffering from hemianopia. Both tract-based measures outperformed lesion localization in mapping visual field defects and showed a network consistent with the known anatomy of the visual system. This study offers an important contribution to the validation of structural disconnection mapping. We show that indirect measures of structural disconnection can be a reliable and valid substitute for direct estimations of fiber loss after focal lesions. Moreover, based on these results, we argue that indirect structural disconnection measures may even be preferable to lower-quality single subject diffusion MRI when based on high-quality healthy control datasets.

The course of post-stroke apathy in relation to cognitive functioning: a prospective longitudinal cohort study.

Apathy is common after stroke and has been associated with cognitive impairment. However, causality between post-stroke apathy and cognitive impairment remains unclear. We assessed the course of apathy in relation to changes in cognitive functioning in stroke survivors. Using the Apathy Scale (AS) and cognitive tests on memory, processing speed and executive functioning at six- and 15 months post-stroke we tested for associations between (1) AS-scores and (change in) cognitive scores; (2) apathy course (persistent/incident/resolved) and cognitive change scores. Of 117 included participants, 29% had persistent apathy, 13% apathy resolving over time and 10% apathy emerging between 6-15 months post-stroke. Higher AS-scores were cross-sectionally and longitudinally associated with lower cognitive scores. Relations between apathy and cognitive change scores were ambiguous. These inconsistent relations between apathy and changes in cognition over time suggest that post-stroke apathy does not directly impact cognitive performance. Both these sequelae of stroke require separate attention.

The impact of etiology in lesion-symptom mapping - A direct comparison between tumor and stroke.

INTRODUCTION: Lesion-symptom mapping is a key tool in understanding the relationship between brain structures and behavior. However, the behavioral consequences of lesions from different etiologies may vary because of how they affect brain tissue and how they are distributed. The inclusion of different etiologies would increase the statistical power but has been critically debated. Meanwhile, findings from lesion studies are a valuable resource for clinicians and used across different etiologies. Therefore, the main objective of the present study was to directly compare lesion-symptom maps for memory and language functions from two populations, a tumor versus a stroke population. METHODS: Data from two different studies were combined. Both the brain tumor (N = 196) and stroke (N = 147) patient populations underwent neuropsychological testing and an MRI, pre-operatively for the tumor population and within three months after stroke. For this study, we selected two internationally widely used standardized cognitive tasks, the Rey Auditory Verbal Learning Test and the Verbal Fluency Test. We used a state-of-the-art machine learning-based, multivariate voxel-wise approach to produce lesion-symptom maps for these cognitive tasks for both populations separately and combined. RESULTS: Our lesion-symptom mapping results for the separate patient populations largely followed the expected neuroanatomical pattern based on previous literature. Substantial differences in lesion distribution hindered direct comparison. Still, in brain areas with adequate coverage in both groups, considerable LSM differences between the two populations were present for both memory and fluency tasks. Post-hoc analyses of these locations confirmed that the cognitive consequences of focal brain damage varied between etiologies. CONCLUSION: The differences in the lesion-symptom maps between the stroke and tumor population could partly be explained by differences in lesion volume and topography. Despite these methodological limitations, both the lesion-symptom mapping results and the post-hoc analyses confirmed that etiology matters when investigating the cognitive consequences of lesions with lesion-symptom mapping. Therefore, caution is advised with generalizing lesion-symptom results across etiologies.

Action blindsight and antipointing in a hemianopic patient.

Blindsight refers to the observation of residual visual abilities in the hemianopic field of patients without a functional V1. Given the within- and between-subject variability in the preserved abilities and the phenomenal experience of blindsight patients, the fine-grained description of the phenomenon is still debated. Here we tested a patient with established "perceptual" and "attentional" blindsight (c.f. Danckert and Rossetti, 2005). Using a pointing paradigm patient MS, who suffers from a complete left homonymous hemianopia, showed clear above chance manual localisation of 'unseen' targets. In addition, target presentations in his blind field led MS, on occasion, to spontaneous responses towards his sighted field. Structural and functional magnetic resonance imaging was conducted to evaluate the magnitude of V1 damage. Results revealed the presence of a calcarine sulcus in both hemispheres, yet his right V1 is reduced, structurally disconnected and shows no fMRI response to visual stimuli. Thus, visual stimulation of his blind field can lead to "action blindsight" and spontaneous antipointing, in absence of a functional right V1. With respect to the antipointing, we suggest that MS may have registered the stimulation and subsequently presumes it must have been in his intact half field.

Acute neglect rehabilitation using repetitive prism adaptation: a randomized placebo-controlled trial.

PURPOSE: At present, prism adaptation is probably the most promising rehabilitation procedure for hemi-neglect. However, randomised controlled trials are lacking and no data are available on the effectiveness of prism adaptation in the treatment of acute neglect. METHODS: We followed sixteen neglect patients using a randomised controlled design in which six patients received four-day-in-a-row placebo treatment (CG) and ten patients received four-day-in-a row experimental treatment with 10 degrees rightward deviating prisms (EG) during their stay on the stroke unit. We examined whether patients in the EG improved faster than the CG by administering three neglect tasks (Schenkenberg Line Bisection, Letter Cancellation, Gainotti Scene Copying) immediately before and after each treatment. Second, we examined whether patients in the EG demonstrated a better long-term outcome at one month post-treatment (Behavioural Inattention Test). RESULTS: Patients in the EG improved faster on spatial tasks (line bisection, cancellation) than the CG but not on visuo-construction. Patients in the EG showed no differences with the CG in neglect outcome at one month post-treatment. CONCLUSIONS: Four consecutive prism sessions produced beneficial effects in patients with acute neglect. However, prism effects were either short-term, or placebo treatment with repeated pointing and/or repeated neglect testing was more helpful than we anticipated. Our results emphasize the importance of a placebo condition and a follow-up in rehabilitation studies.

Perception of facial expressions in obsessive-compulsive disorder: a dimensional approach.

The study examined the perception of facial expressions of different emotional intensities in obsessive-compulsive disorder (OCD) subtypes. Results showed that the High Risk Assessment and Checking subtype was more sensitive in perceiving the emotions fear and happiness. This suggests that altered affective processing may underlie the clinical manifestation of OCD.

Neuropsychological and neuroanatomical correlates of perseverative responses in subacute stroke.

Patients with left-sided neglect frequently show repetitive behaviour on the ipsilesional side, such as re-markings on cancellation tasks or extensive elaboration on drawings. It is unclear whether these perseverative responses occur as a symptom of hemi-neglect or inattention in general, and/or whether they are related to anatomical brain correlates such as lesion location, lesion side or volume. In a first study, we examined the prevalence and neuropsychological correlates of perseverative responses in 206 subacute stroke patients and 63 healthy controls. Perseverative responses were considered present when there was at least one re-marking on the Star Cancellation, and both the degree and spatial distribution of re-markings were examined. A distinction was made between hemi-neglect and non-lateralized inattention. Spatial and verbal working memory were assessed with the Corsi Block Span and the Digit Span. Verbal and non-verbal executive function was assessed with the Visual Elevator and Letter Fluency. Stroke patients without inattention demonstrated re-markings that were related to executive performance, and the degree of perseveration was equally distributed across the sheet. Hemi-neglect patients but not patients with generalized inattention demonstrated more re-markings than controls, suggesting that a lateralized spatial attention bias triggers the perseverative responses. Patients with left and right hemi-neglect showed the same prevalence of perseveration, but the distribution of re-markings was more lateralized towards the ipsilesional side in patients with right-hemispheric stroke. The degree of perseveration in patients with hemi-neglect was related to the severity of the neglect. The goal of the second study on a subset of patients (n = 127) was to determine the neuroanatomical correlates of perseverative responses in the early phase of stroke. Lesion anatomy was administered by indicating involvement of frontal, parietal, temporal, occipital lobe, caudate nucleus, lenticular nucleus and/or thalamus. Lesion volume was calculated using a manual tracing technique. Lesion analyses indicated that perseverative behaviour is strongly associated with lesions involving the caudate nucleus or the lenticular nucleus, independent of lesion volume. The caudate nucleus was an important correlate of perseveration independent of the presence of hemi-neglect. No association was found between lesion side and perseverative responses, in contrast to previous studies. In conclusion, a stroke involving the basal ganglia and the presence of (left- or right-sided) hemi-neglect are two important associates of perseverative responses in the subacute phase of stroke.

Reaching errors in optic ataxia are linked to eye position rather than head or body position.

When reaching towards a visual stimulus, spatial information about the target must be transformed into an appropriate motor command. Visual information is coded initially in retinotopic coordinates, while the reaching movement ultimately requires the specification of the target position in limb-centred coordinates. It is well established that the posterior parietal cortex (PPC) plays an important role in transforming visual target information into motor commands. Lesions in the PPC can result in optic ataxia, a condition in which the visual guidance of goal-directed movements is impaired. Here, we present evidence from two patients with unilateral optic ataxia following right PPC lesions, that the pattern of reaching errors is linked to an eye-centred frame of reference. Both patients made large errors when reaching to visual targets on the left side of space, while facing and fixating straight ahead. By varying the location of fixation and the orientation of the head and body, we were able to establish that these large errors were made specifically to targets to the left of eye-fixation, rather than to the left of head-, body-, or limb-relative space. These data support the idea that visual targets for reaching movements are coded in eye-centred coordinates within the posterior parietal cortex.

Cognitive and functional outcome after intravenous recombinant tissue plasminogen activator treatment in patients with a first symptomatic brain infarct.

OBJECTIVE: To examine whether intravenous recombinant tissue plasminogen activator (rt-PA) treatment given in the acute phase of ischaemic stroke has a favourable effect on cognitive and functional outcome at six months post-stroke. METHODS: The present study included 92 patients with a first-ever symptomatic infarct, of whom 25 (27%) were subjected to rt-PA treatment in the first three hours post-stroke. Multivariate logistic regression analyses adjusted for stroke severity, education, age, and sex were performed to examine whether rt-PA treatment influenced cognitive outcome (assessed with a neuropsychological examination covering 7 cognitive domains), basic ADL independence (modified Barthel Index > or = 19), and instrumental ADL independence (Frenchay Activities Index > or = 15) after six months. RESULTS: The adjusted odds ratio for intact cognition was 1.0 (95% CI 0.2 to 4.3), that for basic ADL outcome 13.5 (95 % CI 1.4 to 129.4) and for instrumental ADL 7.1 (95 % CI 1.2 to 42.2). CONCLUSION: Our findings suggest that rt-PA treatment is associated with a favourable basic and instrumental ADL outcome, but not with a beneficial cognitive outcome after 6 months.

Early cognitive impairment predicts long-term depressive symptoms and quality of life after stroke.

OBJECTIVE: The aim of the present study was to examine the predictive value of cognitive impairment in the acute phase after stroke as a risk factor for long-term (six to ten months after stroke) depressive symptoms (DS) and a reduced quality of life (QOL), independent of demographic and neurological predictors. METHODS: We evaluated 143 patients within the first 3 weeks post-stroke. Predictor variables included domain-specific cognitive function, demographic data, vascular risk factors, lesion characteristics, and clinical factors. Predictor variables associated with long-term DS (Montgomery Asberg Depression Rating Scale >or=7) and QOL (Stroke-Specific Quality of Life Scale) were identified with multiple logistic and linear regression. RESULTS: Long-term DS were independently predicted by cognitive impairment at baseline, DS at baseline, female sex, diabetes mellitus, and previous TIA(s). Cognitive impairment, increasing age, and functional dependence predicted a reduced QOL, whereas hypercholesterolaemia predicted a better QOL. Among all cognitive disorders, unilateral neglect was the greatest risk factor for DS after 6 months, whereas a disorder in visual perception and construction affected QOL the most. CONCLUSIONS: Cognitive impairment and vascular risk factors are important predictors of long-term DS and QOL after stroke. The prognostic value of cognition suggests a reactive component in the development or continuation of long-term DS.

Cognitive deficits and changes in neurometabolites after a lacunar infarct.

In contrast to earlier observations, recent studies have demonstrated that supratentorial lacunar infarcts in the white matter may cause mild neuropsychological impairments. The origin of these cognitive disturbances is yet unknown. In the current study proton magnetic resonance spectroscopy (1H MRS) was used to elucidate the hypothesized relation between a lacunar infarct, metabolic alterations, and neuropsychological function. Patients with a single supratentorial lacunar infarct (n = 26) were compared with patients with a mild myocardial infarct (n = 12) and healthy controls (n = 12) on a comprehensive neuropsychological examination, and on the N-acetyl-aspartate/creatine, choline/creatine and lactate/creatine ratios. The volume of interest of the MRI/MRS examination was located in normal-appearing white matter of the centrum semiovale at a distance from the infarct, in both the ipsilateral and contralateral hemisphere. On neuropsychological examination patients with a lacunar infarct performed worse than both patients with a myocardial infarct and healthy controls. The N-acetyl-aspartate/creatine ratio was decreased in patients with a lacunar infarct compared with the other two groups. More important, this decrease in neurometabolites was significantly correlated to the level of cognitive functioning for the ipsilateral hemisphere and, although to a lesser extent, for the contralateral hemisphere. We conclude that a single symptomatic lacunar infarct in the white matter is associated with (distant) disturbances in neurometabolites and that this decrease is related to a reduced cognitive capacity.

Early depressive symptoms after stroke: neuropsychological correlates and lesion characteristics.

OBJECTIVE: To examine the relation between depressive symptoms and specific cognitive functions in patients with a recent stroke and to examine associations with lesion characteristics. METHODS: We studied 126 of 183 consecutive patients within 3 weeks after a first-ever symptomatic stroke (mean interval, 8.3+/-4.3 days). Presence and severity of depressive symptoms was assessed with the Montgomery Asberg Depression Rating Scale. Neuropsychological functioning was examined by means of a detailed neuropsychological examination covering six cognitive domains. We included a healthy control group (N=75) to obtain normative data for the neuropsychological examination. Functional impairment was measured with the modified Barthel Index and the modified Rankin Scale. Symptomatic and preexistent lesion characteristics were determined on CT or MRI. RESULTS: Of the included patients, 40% demonstrated mild and 12% moderate to severe depressive symptoms. Severity of depressive symptoms was related to lesion volume (p=0.008), functional impairment (all p<0.004), and degree of overall cognitive impairment (p=0.005). After adjustment for lesion size, a specific neuropsychological profile emerged in patients with moderate to severe depressive symptoms, affecting primarily memory, visual perception, and language (all p<0.05). No association was found between severity of depressive symptoms and lesion location, presence of preexistent lesions (white matter lesions and silent infarcts), and demographic factors (age, education, and gender). CONCLUSIONS: Moderate or severe symptoms of depression in the early stage poststroke are associated with a specific pattern of cognitive impairment, lesion size, and functional status. We suggest that depressive symptoms early after stroke are, at least in part, a reactive phenomenon secondary to severe cognitive and functional deficits.

Early neuropsychological evaluation in patients with ischaemic stroke provides valid information.

OBJECTIVES: This study describes the feasibility and validity of neuropsychological evaluation in the early stage post-stroke. Early information on cognitive functioning in stroke patients could improve discharge decision, programming of rehabilitation strategies, and better prepare proxies for the problems they can be presented with in daily life. In this explorative study, our primary focus was on the feasibility of early neuropsychological evaluation. Furthermore, we looked at the possible prognostic relevance of early examination. PATIENTS AND METHODS: Fifty-seven consecutive patients (age 19-80) were enrolled within 4-20 days after their first ischaemic stroke (Modified-Rankin Scale (M-RS): 2-4). Patients were re-tested after 12-24 months, and functional outcome was assessed. RESULTS: In the early stage 44 (77%), patients could complete 82% of the administered tasks. At second evaluation, test performances improved, but a stable test profile was found with respect to abnormalities on the different tasks (P<0.0001). Moreover, initial sum scores of all composite cognitive domains including intellectual functioning (R2=0.80), language (R2=0.76), memory (R2=0.32), perception and visuospatial construction (R2=0.60), attention and psychomotor-functioning (R2=0.80) had significant predictive validity with respect to functional outcome (P<0.001). CONCLUSION: This study supports the feasibility of early neuropsychological evaluation after ischaemic stroke onset and the prognostic validity for cognitive outcome in the long term.

Restrictions of the Mini-Mental State Examination in acute stroke.

While the Mini-Mental State Examination (MMSE) was originally developed to screen for dementia and delirium, many neurologists use this measure as a screening instrument for 'cognitive impairment' in hospitalized stroke patients. However, the validity of the MMSE as such has never been evaluated in acute stroke. We administered the MMSE in addition to a neuropsychological examination covering six cognitive domains to 34 stroke patients (mean interval between stroke and examination, 6.5+/-2.9 days) and 34 healthy controls. The area under the receiver operating characteristic curve (AUC) was calculated in addition to the sensitivity and specificity for various cut-off points on the MMSE. Seventy percent of the patients were impaired in at least one cognitive domain. The accuracy of the MMSE in detecting cognitive impairment was no better than chance (AUC = 0.67; p = 0.13). No optimum MMSE cut-off value could be identified. The MMSE is particularly insensitive to impairments in abstract reasoning, executive functioning, and visual perception/construction.

[Diabetic encephalopathy: an underexposed complication of diabetes mellitus]. / Diabetische encefalopathie: een onderbelichte complicatie van diabetes mellitus.

Diabetes mellitus seems to be associated with gradually developing end-organ damage to the central nervous system. This relatively unknown complication of both diabetes type 1 and type 2 can be referred to as 'diabetic encephalopathy'. Measurable manifestations are electrophysiological and structural changes and limitations in the cognitive functioning. The mechanisms responsible for this diabetic encephalopathy are only partially known. Chronic metabolic and vascular changes seem to play an important role. The effects of diabetes on the brain are most distinct in the elderly. This may be the consequence of interactions between the mechanisms that underlie the ageing of the brain, dementia and the origin of diabetic complications. At present there are few leads for the targeted diagnostics and treatment of individual patients.

The posterior parietal paradox: Why do functional magnetic resonance imaging and lesion studies on episodic memory produce conflicting results?

Recent functional magnetic resonance imaging (fMRI) studies addressing healthy subjects point towards posterior parietal cortex (PPC) involvement in episodic memory tasks. This is noteworthy, since neuropsychological studies usually do not connect parietal lesions to episodic memory impairments. Therefore an inventory of the possible factors behind this apparent paradox is warranted. This review compared fMRI studies which demonstrated PPC activity in episodic memory tasks, with findings with studies of patients with PPC lesions. A systematic evaluation of possible explanations for the posterior parietal paradox indicates that PPC activation in fMRI studies does not appear to be attributable to confounding cognitive/psychomotor processes, such as button pressing or stimulus processing. What may be of more importance is the extent to which an episodic memory task loads on three closely related cognitive processes: effort and attention, self-related activity, and scene and image construction. We discuss to what extent these cognitive processes can account for the paradox between lesion and fMRI results. They are strongly intertwined with the episodic memory and may critically determine in how far the PPC plays a role in a given memory task. Future patient studies might profit from specifically taking these cognitive factors into consideration in the task design.

Hearing a voice in the noise: auditory hallucinations and speech perception.

BACKGROUND: It has recently been suggested that auditory hallucinations are the result of a criterion shift when deciding whether or not a meaningful signal has emerged. The approach proposes that a liberal criterion may result in increased false-positive identifications, without additional perceptual deficit. To test this hypothesis, we devised a speech discrimination task and used signal detection theory (SDT) to investigate the underlying cognitive mechanisms. METHOD: Schizophrenia patients with and without auditory hallucinations and a healthy control group completed a speech discrimination task. They had to decide whether a particular spoken word was identical to a previously presented speech stimulus, embedded in noise. SDT was used on the accuracy data to calculate a measure of perceptual sensitivity (Az) and a measure of response bias (beta). Thresholds for the perception of simple tones were determined. RESULTS: Compared to healthy controls, perceptual thresholds were higher and perceptual sensitivity in the speech task was lower in both patient groups. However, hallucinating patients showed increased sensitivity to speech stimuli compared to non-hallucinating patients. In addition, we found some evidence of a positive response bias in hallucinating patients, indicating a tendency to readily accept that a certain stimulus had been presented. CONCLUSIONS: Within the context of schizophrenia, patients with auditory hallucinations show enhanced sensitivity to speech stimuli, combined with a liberal criterion for deciding that a perceived event is an actual stimulus.

Type 2 diabetes, cognitive function and dementia: vascular and metabolic determinants.

Type 2 diabetes is a common metabolic disease with a rising global prevalence. It is associated with slowly progressive end-organ damage in the eyes and kidneys, but also in the brain. The latter complication is often referred to as "diabetic encephalopathy" and is characterized by mild to moderate impairments in cognitive functioning. It is also associated with an increased risk of dementia. To date, its pathogenetic mechanisms are largely unclear. Cognitive impairments in patients with type 2 diabetes have been associated both with vascular risk factors, such as hypertension and dyslipidemia, and with diabetes-related factors, such as glycemic control, duration of the disease and treatment modality. Studies that address these associations generally focus on statistical (in)dependence of certain risk factors in the association between type 2 diabetes and cognitive decline rather than the causality of the association, which, from a mechanistic point of view, is more relevant. In this review we describe the association between type 2 diabetes and cognitive dysfunction and dementia. Furthermore, potential determinants of impaired cognition in type 2 diabetes are addressed both from the perspective of statistical associations and from a mechanistic point of view.

Cognitive disorders in acute stroke: prevalence and clinical determinants.

BACKGROUND: Although cognitive impairment early after stroke is a powerful predictor of long-term functional dependence and dementia, little is known about the characteristics and determinants of cognitive dysfunction in acute stroke. METHODS: We administered a neuropsychological examination covering 7 cognitive domains to 190 patients within 3 weeks after a first stroke. We also assembled lesion characteristics, clinical factors at admission, demographic characteristics and vascular risk factors. Multivariate logistic regression adjusted for age, gender and education was performed to examine determinants of acute cognitive impairment. RESULTS: Overall, 74% of patients with a cortical stroke, 46% with a subcortical stroke and 43% with an infratentorial stroke demonstrated acute cognitive impairment. Disorders in executive functioning (39%) and visual perception/construction (38%) were the most common. The prevalence and severity of deficits in executive functioning, language, verbal memory and abstract reasoning was more pronounced following left compared to right cortical stroke (all p < 0.05). Intracerebral haemorrhage (OR = 5.6; 95% CI = 1.2-25.4) and cortical involvement of the stroke (OR = 3.6; 95%, CI = 1.3-9.9) were independent determinants of acute cognitive impairment, whereas premorbid moderate alcohol consumption exerted a protective effect (OR = 0.4; 95% CI = 0.1-1.1). CONCLUSIONS: Cognitive impairment is common in the first weeks after stroke, with executive and perceptual disorders being the most frequent. Intracerebral haemorrhage, cortical involvement of the lesion and premorbid moderate alcohol consumption are independently associated with acute cognitive impairment.

Type 2 diabetes, cognitive function and dementia: vascular and metabolic determinants.

Type 2 diabetes is a common metabolic disease with a rising global prevalence. It is associated with slowly progressive end-organ damage in the eyes and kidneys, but also in the brain. The latter complication is often referred to as "diabetic encephalopathy" and is characterized by mild to moderate impairments in cognitive functioning. It is also associated with an increased risk of dementia. To date, its pathogenetic mechanisms are largely unclear. Cognitive impairments in patients with type 2 diabetes have been associated both with vascular risk factors, such as hypertension and dyslipidemia, and with diabetes-related factors, such as glycemic control, duration of the disease and treatment modality. Studies that address these associations generally focus on statistical (in)dependence of certain risk factors in the association between type 2 diabetes and cognitive decline rather than the causality of the association, which, from a mechanistic point of view, is more relevant. In this review we describe the association between type 2 diabetes and cognitive dysfunction and dementia. Furthermore, potential determinants of impaired cognition in type 2 diabetes are addressed both from the perspective of statistical associations and from a mechanistic point of view.