Katrin Hanken

The representation of inflammatory signals in the brain - a model for subjective fatigue in multiple sclerosis

In multiple sclerosis (MS) patients, fatigue is rated as one of the most common and disabling symptoms. However, the pathophysiology underlying this fatigue is not yet clear. Several lines of evidence suggest that immunological factors, such as elevated levels of pro-inflammatory cytokines, may contribute to subjective fatigue in MS patients. Pro-inflammatory cytokines represent primary mediators of immune-to-brain-communication, modulating changes in the neurophysiology of the central nervous system. Recently, we proposed a model arguing that fatigue in MS patients is a subjective feeling, which is related to inflammation. Moreover, it implies that fatigue can be measured behaviorally only by applying specific cognitive tasks related to alertness and vigilance. In the present review, we focus on the subjective feeling of MS-related fatigue. We examine the hypothesis that the subjective feeling of MS-related fatigue may be a variant of inflammation-induced sickness behavior, resulting from cytokine-mediated activity changes within brain areas involved in interoception and homeostasis including the insula, the anterior cingulate, and the hypothalamus. We first present studies demonstrating a relationship between pro-inflammatory cytokines and subjective fatigue in healthy individuals, in people with inflammatory disorders, and particularly in MS patients. Subsequently, we discuss studies analyzing the impact of anti-inflammatory treatment on fatigue. In the next part of this review, we present studies on the transmission and neural representation of inflammatory signals, with a special focus on possible neural concomitants of inflammation-induced fatigue. We also present two of our studies on the relationship between local gray and white matter atrophy and fatigue in MS patients. Finally, we discuss some implications of our findings and future perspectives.

Is there a cognitive signature for MS-related fatigue?

The compensatory approach of fatigue argues that it is a state caused by task load. The neuropsychiatric approach argues that fatigue is a trait (like depression), unrelated to environmental challenges. We propose that fatigue is an internal state that can be measured behaviorally only by applying specific cognitive tasks. PubMed was searched for articles concerning the relation between fatigue and cognitive performance or brain atrophy or functional MRI, distinguishing between the following cognitive domains: learning/memory, cognitive speed/selective attention, language, visuospatial processing, working memory, alerting/vigilance. Only tasks assessing alerting/vigilance are strongly related to fatigue. Areas with brain atrophy in fatigue patients overlap with brain regions activated in healthy controls performing alerting/vigilance tasks. Fatigue is not a compensatory state, nor a psychogenic trait. It is a feeling with behavioral effects that seems to be caused by brain atrophy or a neurochemical dysfunction of the alerting/vigilance system.

Impact of collateral circulation on early outcome and risk of hemorrhagic complications after systemic thrombolysis.

Background In stroke patients, collateral flow can rapidly be assessed on computed tomography angiography (CTA). Aims In this study, the impact of baseline collaterals on early outcome and risk of symptomatic intracerebral hemorrhages after systemic thrombolysis in patients with proximal arterial occlusions within the anterior circulation were analyzed. Methods Collateralization scores were determined on the CT angiography source images (0 = absent; 1 ≤ 50%, 2 > 50% but <100%, and 3 = 100% collateral filling) of patients with distal intracranial carotid artery and/or M1 segment occlusions treated from 2008 to December 2011. A collateral score of 0 to 1 was designated as poor and 2 to 3 as good collateral vessel status. Outcome variables included in hospital mortality, favorable outcome at discharge (modified Rankin score ≤ 2), and rates of symptomatic intracerebral hemorrhage based on the European–Australasian Acute Stroke Study II definition. Results Among 246 subjects (mean age of 74 years; median National Institutes of Health Stroke Scale N at admission 14), 205 patients (83%) had good collaterals, whereas 41 patients (17%) had poor collaterals, respectively. Patients with poor collaterals had significantly higher rates of in-hospital mortality (41% vs. 12%, P < 0·001), of symptomatic intracerebral hemorrhage (15% vs. 4·9%, P < 0·05) and had significantly lower rates of favorable early clinical outcome (0% vs. 28%, P < 0·001) compared with those with good collaterals. The grade of collateralization was independently associated with in-hospital mortality (P < 0·001), early clinical outcome (P < 0·01), and rates of symptomatic intracerebral hemorrhage (P < 0·01). Conclusion Patients with proximal arterial occlusions within the anterior circulation and poor baseline collaterals have a poor early functional outcome and high rates of symptomatic intracerebral hemorrhage after systemic thrombolysis. Since similar findings have also been reported after endovascular therapy, strategies to improve collateral blood flow should be assessed in this patient population.

Integrity of hypothalamic fibers and cognitive fatigue in multiple sclerosis

Cognitive fatigue is a common and disabling symptom of multiple sclerosis (MS), but little is known about its pathophysiology. The present study investigated whether the posterior hypothalamus, which is considered as the waking center, is associated with MS-related cognitive fatigue. We analyzed the integrity of posterior hypothalamic fibers in 49 patients with relapsing-remitting MS and 14 healthy controls. Diffusion tensor imaging (DTI) parameters were calculated for fibers between the posterior hypothalamus and, respectively, the mesencephalon, pons and prefrontal cortex. In addition, DTI parameters were computed for fibers between the anterior hypothalamus and these regions and for the corpus callosum. Cognitive fatigue was assessed using the Fatigue Scale for Motor and Cognitive Functions. Analyses of variance with repeated measures were performed to investigate the impact of cognitive fatigue on diffusion parameters. Cognitively fatigued patients (75.5%) showed a significantly lower mean axial and radial diffusivity for fibers between the posterior hypothalamus and the mesencephalon than cognitively non-fatigued patients (Group(⁎)Target area(⁎)Diffusion orientation: F=4.047; p=0.023). For fibers of the corpus callosum, MS patients presented significantly higher axial and radial diffusivity than healthy controls (Group(⁎)Diffusion orientation: F=9.904; p<0.001). Depressive mood, used as covariate, revealed significant interaction effects for anterior hypothalamic fibers (Target area(⁎)Diffusion orientation(⁎)Depression: F=5.882; p=0.021; Hemisphere(⁎)Diffusion orientation(⁎) Depression: F=8.744; p=0.008). Changes in integrity of fibers between the posterior hypothalamus and the mesencephalon appear to be associated with MS-related cognitive fatigue. These changes might cause an altered modulation of hypothalamic centers responsible for wakefulness. Furthermore, integrity of anterior hypothalamic fibers might be related to depression in MS.

Counteracting Fatigue in Multiple Sclerosis with Right Parietal Anodal Transcranial Direct Current Stimulation

Background Fatigue in multiple sclerosis (MS) patients appears to correlate with vigilance decrement as reflected in an increase in reaction time (RT) and errors with prolonged time-on-task. Objectives The aim of this study was to investigate whether anodal transcranial direct current stimulation (tDCS) over the right parietal or frontal cortex counteracts fatigue-associated vigilance decrement and subjective fatigue. Methods In study I, a randomized double-blind placebo-controlled study, anodal tDCS (1.5 mA) was delivered to the right parietal cortex or the right frontal cortex of 52 healthy participants during the first 20 min of a 40-min lasting visual vigilance task. Study II, also a randomized double-blind placebo-controlled study, investigated the effect of anodal tDCS (1.5 mA) over the right parietal cortex in 46 MS patients experiencing cognitive fatigue. tDCS was delivered for 20 min before patients performed a 20-min lasting visual vigilance task. Results Study I showed that right parietal stimulation, but not right frontal stimulation, counteracts the increase in RT associated with vigilance decrement. Hence, only right parietal stimulation was applied to the MS patients in study II. Stimulation had a significant effect on vigilance decrement in mildly to moderately cognitively fatigued MS patients. Vigilance testing significantly increased the feeling of fatigue independent of stimulation. Conclusion Anodal tDCS over the right parietal cortex can counteract the increase in RTs during vigilance performance, but not the increase in subjective fatigue. This finding is compatible with our model of fatigue in MS, suggesting a dissociation between the feeling and the behavioral characteristics of fatigue.

Cross-Sectional and Longitudinal Relationships between Depressive Symptoms and Brain Atrophy in MS Patients.

Introduction: Depressive symptoms are a frequent and distressing phenomenon in Multiple Sclerosis (MS) patients. Cross-sectional research links these symptoms to reduced brain gray matter volumes in parts of the prefrontal and temporal lobe as well as subcortical structures like the hippocampus, nucleus caudatus and globus pallidus. Nevertheless, prospective relationships between regional gray matter volume and the course of depressive symptoms are poorly understood. Methods: Forty-four patients with relapsing–remitting or secondary progressive MS participated in a prospective study with two assessments of depressive symptoms and high-resolution MRI with an inter-test-interval of 17 months. Relationships between baseline gray matter volume and baseline depressive symptoms, as well as prospective associations between the development of atrophy and depression were assessed using voxel-based morphometry (VBM). Results: Cross-sectional analyses revealed an association between depressive symptoms and gray matter loss in the left temporal lobe. Prospective analysis showed that gray matter losses in the right middle cingulate and middle frontal gyrus at baseline predicted increasing depressive symptoms during follow-up. Increase in depressive symptoms was related to a concomitant increase in atrophy in the left thalamus and right globus pallidus. Discussion: Our results fit well into the concept of a disturbed cortico–striatal–pallido–thalamic loop in depression. In this framework, progressive gray matter loss in limbic basal ganglia structures including globus pallidus and thalamus may lead to depression-typical deficits in hedonic motivation, whereas atrophy of the prefrontal cortex may contribute to maladaptive coping strategies, promoting an unfavorable development of depressive symptoms.

The impact of MS-related cognitive fatigue on future brain parenchymal loss and relapse: A 17-month follow-up study

Background Fatigue is a disabling syndrome in multiple sclerosis (MS), which may be associated with inflammation and faster disease progression. Objective To analyze the significance of cognitive fatigue for subsequent disease progression. Method We followed 46 MS patients and 14 healthy controls in a study over 17 months. At the beginning (t1) and at the end (t2) of the study participants scored their fatigue, performed the Multiple Sclerosis Functional Composite and received MRI scanning, encompassing MPR T1, FLAIR, and DTI sequences. At t1, MS patients were divided into those with and those without cognitive fatigue (cut-off score for moderate cognitive fatigue of the Fatigue Scale for Motor and Cognition). We calculated ANCOVAs for repeated measurement to analyze the relevance of cognitive fatigue status for the number of relapses and for MRI parameters. Results At t1, but not at t2, patients with cognitive fatigue showed increased axial and radial diffusivity of corpus callosum fibers. At t2, these patients showed significantly more loss of brain parenchyma and greater enlargement of lateral ventricles. Moreover, they developed more relapses, but there was no difference in lesion load or in performance deterioration. Additional analyses showed that only cognitive fatigue but not a more general score for fatigue (Fatigue Severity Scale) had an impact on the worsening of the disease status. Conclusion Patients with cognitive fatigue may develop more brain atrophy and relapses during the next 17 months than patients without cognitive fatigue. Hence, experiencing cognitive fatigue might indicate more aggressive inflammatory processes and subsequent neurodegeneration.

Different cortical underpinnings for fatigue and depression in MS

BACKGROUND Fatigue is a common complaint in MS patients but its origins are still not fully understood. A major difficulty is that fatigue seems strongly correlated with depression. METHODS 95 MS patients and 15 healthy control subjects were included. The Fatigue Severity Scale and Becks Depression Inventory were used to assess symptom-severity and to determine group membership for five groups: MS patients with and without fatigue, and with or without depressive mood, healthy controls. Participants were scanned using high-resolution structural 3D T1-weighted imaging. Cortical thickness for 84 areas was calculated using the NeuroQLab software in combination with the atlas for the Automated Anatomical Labeling software. A stepwise forward regression analysis was performed to predict group membership of the MS patients by thickness of cortical areas. We also performed a series of post-hoc ANOVAs to explore differences between the four patients groups and the healthy controls. RESULTS About 20% of the patients suffered only from fatigue or only from depressive mood. Regression analysis explained 17.3% of the variance and thickness of the right inferior parietal cortex, middle temporal pole and parahippocampus contributed significantly to the model. Patients with pure fatigue showed a specific decrease in cortical thickness in the inferior parietal lobe, patients with both depressive mood and fatigue in the right middle temporal pole. Additional ANOVAs revealed cortical thinning in the right middle cingulate cortex in the group with pure fatigue as well as the groups with depression. CONCLUSION Fatigue and depression can be dissociated in larger MS-patient groups using questionnaires and cortical thickness measures, but the cortical thickness measures only explain a small portion of variance of these neuropsychiatric symptoms.

On the relation between self-reported cognitive fatigue and the posterior hypothalamic-brainstem network

Various causes have been suggested for multiple sclerosis (MS) related fatigue. Hypothalamus‐brainstem fibres play a role in sleep−wake regulation and in hypothalamic deactivation during inflammatory states. Hence, they may play a role for experiencing fatigue by changing bottom‐up hypothalamic activation.

Subjective Cognitive Fatigue and Autonomic Abnormalities in Multiple Sclerosis Patients

Background Cognitive fatigue and autonomic abnormalities are frequent symptoms in MS. Our model of MS-related fatigue assumes a shared neural network for cognitive fatigue and autonomic failures, i.e., aberrant vagus nerve activity induced by inflammatory processes. Therefore, they should occur in common. Objective To explore the relationship between cognitive fatigue and autonomic symptoms in MS patients, using self-reported questionnaires. Methods In 95 MS patients, cognitive fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions and autonomic abnormalities with the Composite Autonomic Symptom Scale-31 (COMPASS-31). We used exploratory correlational analyses and hierarchical regression analysis, controlling for age, depressive mood, disease status, and disease duration, to analyze the relation between autonomic abnormalities and cognitive fatigue. Results The cognitive fatigue score strongly correlated with the COMPASS-31 score (r = 0.47, p < 0.001). Regression analysis revealed that a model, including the COMPASS-31 domains: pupillomotor, orthostatic intolerance, and bladder, best predict the level of cognitive fatigue (R2 = 0.47, p < 0.001) after forcing the covariates into the model. Conclusion In MS patients, cognitive fatigue and autonomic dysfunction share a proportion of variance. This supports our model assuming that fatigue might be explained at least partially by inflammation-induced vagus nerve activity.