Alteration of brain structural organization after sepsis with Fatigue-a structural brain network analysis

In our recent cross-sectional investigation, we found in sepsis survivors with persistent cognitive impairment a high number of patients who still suffer from Fatigue. This fi nding is of importance because Fatigue is highlighted as an associated long-term sequela after sepsis and therefore these patients require an appropriate rehabilitation therapy. The aim of this study was to verify whether sepsis survivors with both cognitive impairment and Fatigue show any alteration in brain structure. 19 survivors of severe sepsis (longer than 2 years post sepsis) with persistent cognitive defi cits ascertained with a battery of neuropsychological tests with cognitive and motor Fatigue symptoms (according to two German Fatigue scales) were investigated with a high-resolution. T1 weighted image of the brain at a 3.0 Tesla MRI scanner. The Voxel-based morphometry (VBM) was performed using VBM8 toolbox. 19 ageand sex-matched healthy control subjects were also scanned with MRI. VBM analysis revealed signifi cant gray matter volume reduction in sepsis survivors particularly in the lateral frontal operculum and anterior cingulate cortex. These regions are part of the cingulo-opercular network which maintains alertness. Gray matter volume loss of the orbitofrontal cortex is functionally associated with Fatigue. These fi ndings emphasize that networks of structural brain organization can be altered with corresponding clinical symptoms and neuropsychological defi cits after sepsis. Research Article Alteration of brain structural organization after sepsis with Fatigue a structural brain network analysis Gundula Seidel1,2*, Alexander Ritter1, Florian Bähr1,3 and Farsin Hamzei1,2 1Section of Neurological Rehabilitation, Hans Berger Department of Neurology, Jena University Hospital, Germany 2Department of Neurology, Moritz Klinik Bad Klosterlausnitz, Germany 3Department of Sports Medicine and Health Promotion, Friedrich Schiller University Jena, Germany Received: 24 April, 2021 Accepted: 04 June, 2021 Published: 07 June, 2021 *Corresponding author: Gundula Seidel, Section of Neurological Rehabilitation, Hans Berger Department of Neurology, Jena University Hospital, Germany, E-mail: https://www.peertechzpublications.com

In a recent study of sepsis survivors with cognitive impairments we also found a high number of patients with motor and cognitive Fatigue [14]. The underlying neurophysiological processes of persistent cognitive deterioration and Fatigue symptoms in sepsis survivors are still not fully understood.
Therefore, in the current study we search for alteration of Citation: Seidel  structural (gray matter and white matter) organization of the brain in sepsis survivors with persistent cognitive decline and Fatigue that can explain any relationship between cognitive impairment and Fatigue. The Voxel-based morphometry analysis [15] is used as an objective method that does not require an a priori hypothesis about localization of possible structural changes.

Patients and Methods
Subjects 19 sepsis survivors (mean age 53.7 years, range 38 to 69 years, n = 8 female) were recruited from a former study [14].
They were included because they had a severe sepsis or a septic shock (with an ICU stay of at least 48h) longer than one year before inclusion. They presented in one domain out of a battery of neuropsychological tests a T-value less than 40 to represent a "below average" value of a cognitive test and in two German

Neuropsychological assessment
The following battery of tests were evaluated with the

Fatigue
Two German Fatigue questionnaires are used ("Würzburger Erschöpfungsinventar" WEIMuS [17,18] and "Fatigue Skala für Motorik und Kognition" FSMK [19]. Both contain items for cognitive and motor Fatigue symptoms and corresponding cutoff values. For both scales the obtained scores were transformed into z-values and separately averaged for a Fatigue total, a Fatigue cognitive and a Fatigue motor score.

Voxel-based morphometry and statistical analysis
Data were processed and analyzed using the SPM8 software (Wellcome Department of Imaging Neuroscience Group, London, UK; http://www.fi l.ion.ucl.ac.uk/spm), where we applied VBM implemented in the VBM8 toolbox (http://dbm. neuro.uni-jena.de/vbm.html) with default parameters (for details see e. g [20]. After VBM was performed the modulated volumes were smoothed with a Gaussian kernel of 10 mm full width at half maximum (FWHM). Voxel-wise gray matter (GM) and white matter (WM) differences between sepsis survivors and controls were examined using independentsample t-tests. In order to avoid possible edge effects between different tissue types, we excluded all voxels with GM or WM values of less than 0.1 (absolute threshold masking). A threshold of p<0.001 (corrected for multiple comparisons) with an extent of 200 voxels across the whole brain was applied. Age was used as nuisance effect, which means that all effect that can be explained by age was removed from the data. Additionally, these regions must be selected from networks that are anatomically related to tonic alertness and Fatigue.
These networks were the Cingulo-Opercular (CO) network that is related to alertness [21,22] and the orbito-frontal cortex that is associated to Fatigue [23].

Neuropsychological assessment
All sepsis survivors showed in one and more tests defi cits (10 patients with defi cits in two or more domains). Tonic alertness was most frequently affected (in 12 patients, 63%), followed by working memory (in 10 patients).

VBM
In sepsis survivors, the VBM analysis revealed reduced gray matter volume in the right temporal gyrus (in particular, middle temporal gyrus, medial temporal pole and inferior temporal gyrus) compared to healthy control subjects. Also reduced gray matter volume in sepsis survivors was evident in the right lateral operculum, in the right anterior cingulate cortex and in the left anterior and middle cingulate cortex as well as in the left orbitofrontal gyrus with extension to the left inferior frontal gyrus (Table 1, Figure 1).
In VBM analysis of white matter no difference between groups was found. The anterior cingulate cortex and the lateral frontal operculum are part of the cinguloopercular (CO) network. The CO network is suggested to underlie intrinsically maintained tonic alertness [20,21] and is clearly distinguishable from other attention networks (i.e. dorsal attention network, frontoparietal control network) at functional level [21,22,25]. Tonic alertness denotes mentally effortful, endogenously increased responsiveness [16,26] which is considered as precondition for higher attention functions as well as higher cognitive demands [26][27][28]. Affected basic attention function is therefore associated with higher cognitive defi cits. This might explain the decline of higher cognitive functions like memory or executive functions in sepsis survivors.
Recent studies also represented structural damage in sepsis survivors with cognitive defi cits in different regions, e.g. hippocampus, insula, cingulate cortex, precuneus, thalamus, cerebellum and frontal lobe [5,13,14], also in white matter regions [29]. The use of different methods explains diversity of fi ndings. Studies used electroencephalography, or calculated volume of specifi c regions, applied diffusion tensor imaging or analyzed VBM but immediately after the onset of initial neurological defi cit. These structural changes even with different methodological approaches emphasizes the idea, that sepsis as a systemic disease induces individually different fi nger prints of cognitive impairment in relation to affected brain structure and function. The affected COnetwork in the current study could be the "tip of the iceberg", Citation: Seidel  Gray matter volume loss of left OFC with a maximum at the medial part is functionally associated with (task-related) Fatigue sensation [23]. The orbitofrontal cortex is generally affected by chronic stress [30][31][32]; for animals see [33][34][35] which is closely associated with Fatigue [36][37][38]. Moreover, alterations of the OFC are also associated with depression [39][40][41] which is often in co-occurrence with Fatigue [42][43][44]. Consequently, patients with clinical symptoms of Fatigue and alertness defi cits after sepsis have altered networks of structural brain organization.
In the current descriptive study, we did not investigate the exact way how gray matter is declined in sepsis survivors and which variables are closely associated with these changes.
Clinical variables during acute stage of ICU stay e. g. occurrence of delirium, duration of delirium [4,5,8,9,12,10,45,46] and further specifi c risk factors like age, premorbid status of cognitive functioning or comorbidity of the sepsis patients [7] are risk factors for long-lasting cognitive impairment.
Longitudinal serial data collection beginning from acute stage are necessary to understand the association between different clinical symptoms, laboratory-chemical tests, and other variables with brain structure changes.

Conclusion
In the current study we compared sepsis survivors with cognitive defi cits and Fatigue with a healthy sex-and agematched control group. We found reduced gray matter volume in sepsis survivors in specifi c networks (CO-network, OFC) that are related to specifi c cognitive impairment and Fatigue.
The use of another control group, for example sepsis survivors without cognitive defi cits would probably present less alteration  The lateral frontal operculum and anterior cingulate cortex are part of the cingulo-opercular (CO) network that is related to alertness. Sepsis survivors with cognitive defi cits (mostly with alertness defi cits) and Fatigue demonstrate gray matter alteration in specifi c network of CO and orbitofrontal cortex that is associated to Fatigue. Individual T-values of tonic alertness are close correlated with gray matter intensity of the anterior cingulate cortex (peak voxel with the maximum intensity difference with MNI coordinates x, y, z: 15,41,18). Individual Fatigue score are closely negative associated with the gray matter intensity of the orbitofrontal cortex. Higher Fatigue score is associated with less gray matter density (peak voxel with the maximum intensity difference with MNI coordinates x, y, z: -30, 41, 3).
Citation: Seidel  in gray matter than a comparison with a healthy control group. Therefore, this circumstance warrants further investigation. However, affection of the alertness network in Fatigue sufferers after sepsis renders the fact that physicians should be aware of Fatigue in sepsis survivors to provide patients with an appropriate therapy regime and to consider neuropsychological defi cits for an adequate therapy [14].