Neural indicators of fatigue in chronic diseases : A systematic review of MRI studies

The authors would like to thank the Sir Jules Thorn Charitable Trust for their financial support.Peer reviewedPublisher PD

Neuropsychological assessment and functional magnetic resonance imaging of verbal declarative memory performance in relatives of schizophrenia patients and controls

BACKGROUND: While the aetiology of schizophrenia has yet to be established, genetic liability is currently the most robust determinant of propensity for the development of schizophrenia, with a risk rate of between 15 and 20% in first-degree relatives of schizophrenia patients. Unaffected relatives of schizophrenics have shown similar, but less severe neuropsychological impairments, to those seen in schizophrenia patients, which are stable over time in individuals beyond the age of risk for the disorder. Such deficits may be reflective of a genetic vulnerability to the disorder (Byrne et al 2003; (Faraone et al 1999). Declarative memory has emerged as a core cognitive impairment in schizophrenia (Cirillo and Seidman 2002) and evidence shows functional brain response differences between patients and controls in frontal, temporal, and parietal areas during tests of memory (Ragland et al 2004). Nonetheless, it is unclear how far behavioural and functional deficits reflect increased risk, at what stage, if at all, these deteriorate in those who develop the disorder, or whether pre-morbid impairments in those who go on to develop schizophrenia could be predictive of psychosis. The Edinburgh High Risk Study recruited 162 individuals (16-25 years) with at least one first or second degree relative with schizophrenia and 43 closely matched controls. A broad neuropsychological and clinical assessment battery was administered every 18-24 months over 10 years, while participants underwent between 1 and 3 functional magnetic resonance imaging (fMRI) scans during a verbal memory and executive function task over 5 years. | | METHODS: Baseline predictors of schizophrenia, performance changes over 2 neuropsychological assessments, and the influence of genetic liability were examined in high risk participants with (HR+) and without psychotic symptoms (HR-), those who are now ill (Scz) and controls (C), using one-way ANOVAs and repeated measures ANCOVAs. Aspects of verbal and non-verbal learning and memory were also compared between the HR and C in the first 100 participants to undergo a functional MRI scan using one-way ANOVAs. In the same participants, differences between groups in blood oxygen level dependent (BOLD) fMRI brain responses during an event related verbal encoding (word classification) and retrieval task were investigated using fixed and random effects general linear models. | | RESULTS: On a test of verbal learning at baseline, Scz performed significantly less well than HR However, there were no significant interactions of time by group, and HR showed stable impairments relative to controls on immediate and delayed prose recall, delayed list recall and response suppression across both assessments before and after controlling for IQ. A measure of quantitative genetic liability was inversely correlated with delayed prose recall over time. HR showed poorer cued delayed recall, and less word retention between short and long delay recall trials on a verbal learning test. A visual recognition test also significantly discriminated between HR and C. Behavioural analysis of the fMRI verbal encoding and retrieval task revealed no differences between groups in reaction time or accuracy. However, during a word classification task (encoding) there was a greater BOLD response in the right inferior frontal lobe (BA45/44) in HR relative to C and in the right inferior parietal lobule (BA7/40) in HR+ relative to C and HR-. A greater bilateral cerebellar and left inferior frontal response was also apparent in HR relative to C, and an increased ventral anterior thalamus response in HR- relative to HR+, during correct recognition compared to correct rejection responses. | | CONCLUSIONS: Stable differences in NP performance over time suggest a trait deficit, which is relatively unaffected by the presence of psychotic symptoms and schizophrenia onset, although small numbers might have precluded detection of significant time by group interactions. Poorer verbal memory performance overall in Scz suggests that this deficit is more pronounced in those who go on to develop schizophrenia. Non-verbal learning impairments reflect encoding deficits, while verbal learning impairments reflect encoding and retention difficulties in the HR group. Increased BOLD response in frontal and cerebellar areas in the HR group could be due to a requirement for greater effort to perform the task equivalently to C, and may reflect a biological trait deficit in the brains of relatives of schizophrenia patients. Subtle differences in the inferior parietal lobe between HR+ and HR- and C may be indicative of state related functional abnormalities, which possibly herald the onset of schizophrenia

Neuronale Synchronisation während perzeptueller Organisation in Schizophrenie-Patienten

Current theories of schizophrenia suggest that the pathophysiology of the disorder may be the result of a deficit in the coordination of neural activity within and between areas of the brain, which may lead to impairments in basic cognitive functions such as contextual disambiguation and dynamic grouping (Phillips and Silverstein, 2003). This notion has been supported by recent studies showing that patients with schizophrenia are characterized by reduced synchronous, oscillatory activity in the gamma-frequency band during sensory processing (Spencer et al. 2003, Green et al. 2003, Wynn et al. 2005). However, it is currently unclear to what extent high-frequency gamma-band oscillations (> 60 Hz) contribute to impaired neural synchronization as research has so far focussed on gamma-band oscillations between 30 and 60 Hz. In addition, it is not known whether deficits in high-frequency oscillations are already present at the onset of the disorder and to what extent reductions may be related to the confounding influence of antipsychotic medication. Finally, the neural generators underlying impairments in synchronous oscillatory activity in schizophrenia have not been investigated yet. To address these questions, we recorded MEG activity during a visual closure task (Mooney faces task) in medicated chronic schizophrenia patients, drug-naive first-episode schizophrenia patients and healthy controls. MEG data were analysed for spectral power between 25 and 150 Hz, and beamforming techniques were used to localize the sources of oscillatory gamma-band activity. In healthy controls, we observed that the processing of Mooney faces was associated with sustained high-frequency gamma-band activity (> 60 Hz). A time-resolved analysis of the neural generators underlying perceptual closure revealed a network of distributed sources in occipito-temporal, parietal and frontal regions, which were differentially activated during specific time intervals. In chronic schizophrenia patients, we found a pronounced reduction of high-frequency gamma-band oscillatory activity that was accompanied by an impairment in perceptual organization and involved reduced source power in various brain regions associated with perceptual closure. First-episode patients were also characterized by a deficit in high-frequency gamma-band activity and reductions of source power in multiple areas; these impairments, however, were less pronounced than in chronic patients. Regarding behavioral performance, first-episode patients were not impaired in their ability to detect Mooney faces, but exhibited a loss in specificity of face detection. In conclusion, our results suggest that schizophrenia is associated with a widespread reduction in high-frequency oscillations that indicate local network abnormalities. These dysfunctions are independent of medication status and already present at illness onset, suggesting a possible progressive deficit during the course of the disorder.Aktuelle Theorien gehen davon aus, dass die Pathophysiologie der Schizophrenie auf eine Störung in der Koordination neuronaler Prozesse zurückzuführen ist, welche zu einer Beeinträchtigung in der Integration von Informationen führt und sich in Defiziten bei frühen Wahrnehmungsprozessen und höheren kognitiven Funktionen widerspiegelt. Diese Hypothese wird durch eine Reihe von Studien gestützt, die eine Reduktion oszillatorischer Aktivität im Beta- und Gamma-Frequenzband im Elektroenzephalogramm während visueller Wahrnehmungsprozesse bei Patienten mit Schizophrenie nachweisen konnten. Die Bedeutung von hochfrequenten Gamma-Band Oszillationen (> 60 Hz) für das Verständnis von perzeptuellen Dysfunktionen bei Patienten mit Schizophrenie ist jedoch bislang wenig erforscht. Zudem ist unklar, ob und in welchem Umfang eine Veränderung oszillatorischer Aktivität bereits zu Beginn der Erkrankung und ohne den Einfluss von antipsychotischen Medikamenten vorhanden ist. Des Weiteren gibt es bislang keine Befunde zu den neuronalen Quellen, die den Defiziten oszillatorischer Aktivität bei Schizophrenie-Patienten zugrunde liegen. Um diese Fragen zu untersuchen, wurden im Rahmen der vorliegenden Dissertation drei Studien durchgeführt, in denen die Hirnaktivität während einer visuellen Gestaltaufgabe (Mooney faces-Aufgabe) bei chronischen medizierten Schizophrenie-Patienten, ersterkrankten nicht-medizierten Schizophrenie-Patienten sowie bei gesunden Kontrollprobanden mittels Magnetoenzephalographie (MEG) gemessen wurde. Die Auswertung der MEG-Daten beinhaltete auf der Sensoren-Ebene eine Auswertung der spektralen Power zwischen 25 und 150 Hz und auf der Quellen-Ebene eine Rekonstruktion der Generatoren oszillatorischer Aktivität mit Hilfe von Beamforming-Techniken. Die Hauptbefunde lassen sich wie folgt zusammenfassen: Das neuronale Netzwerk perzeptueller Organisation bei Mooney faces zeigte eine ausgeprägte oszillatorische Aktivität im hochfrequenten Gamma-Band (> 60 Hz) in gesunden Kontrollprobanden und umfasste okzipito-temporale, parietale und frontale Areale, die zu verschiedenen Zeitpunkten der Informationsverarbeitung aktiviert wurden. Unsere Ergebnisse lassen vermuten, dass perzeptuelle Organisationsprozesse bei Mooney faces auf einer frühen Interaktion zwischen Arealen beruhen, die mit der Verarbeitung von Schattierungsreizen zusammenhängen, gesichtsspezifischen Arealen, und Arealen, die mit dem Abruf von Informationen aus dem Langzeitgedächtnis in Verbindung stehen. Im Vergleich zu den Kontrollprobanden zeigten chronische Schizophrenie-Patienten ein deutliches Defizit in der hochfrequenten (60 – 120 Hz) Gamma-Band Power, welches mit reduzierten Detektionsraten bei der Mooney faces-Aufgabe und mit verringerten Aktivierungen in den für perzeptuelle Organisationsprozesse relevanten Arealen einherging. Ersterkrankte nicht-medizierte Schizophrenie-Patienten zeigten ebenfalls eine Reduktion hochfrequenter Gamma-Band Power in verschiedenen Hirnarealen. Dieses Defizit war jedoch weniger stark ausgeprägt als in den chronischen Schizophrenie-Patienten. Im Gegensatz zu den chronischen Patienten zeigten die ersterkrankten Patienten keine Beeinträchtigung bei der Detektion von Gesichtern in aufrecht präsentierten Mooney face Stimuli; jedoch wiesen sie ein Defizit in der Diskrimination zwischen Gesichtern und Nicht-Gesichtern auf. Unsere Befunde deuten darauf hin, dass bei Patienten mit Schizophrenie ausgeprägte Defizite in lokalen Synchronisationsprozessen vorliegen, welche mit perzeptuellen Dysfunktionen einhergehen. Die beeinträchtigte Koordination neuronaler Aktivität könnte auf Veränderungen in GABAergen und glutamatergen Neurotransmittersystemen bei Schizophrenie-Patienten zurückzuführen sein. Unsere Ergebnisse zeigen weiterhin, dass Beeinträchtigungen neuronaler Synchronisation bereits zu Beginn der Erkrankung und ohne den Einfluss von antipsychotischer Medikation vorhanden sind. Die stärkere Beeinträchtigung in den chronischen im Vergleich zu den ersterkrankten Patienten deutet auf einen progressiven Verlauf der Beeinträchtigung oszillatorischer Aktivität bei Schizophrenie-Patienten hin

Identifying characteristics of thalamo-cortical changes and their relationship with symptoms in schizophrenia [Utvrđivanje obilježja talamo-kortikalnih promjena i njihovog odnosa sa simptomima u shizofreniji]

Hypothesis of the doctoral thesis was that, using resting-state functional magnetic resonance imaging (fMRI), patients diagnosed with schizophrenia would exhibit stable and specific patterns of thalamic connectivity changes that will show different relationship with specific symptoms of psychotic disorders. The aims of the study were to characterize in a more detailed way changes in thalamo-cortical connectivity (over- and under-connectivity) in a clinical sample compared to healthy controls, by using state-of-the-art resting-state functional resonance and Human Connectome Project protocols, as well as to more specifically determine within-thalamus differences and their relative contribution to described connectivity changes. Finally, the aim was to determine relationship between identified connectivity changes and specific symptoms of the disorder. Subjects for the study were pooled from multiple centers, as part of an existing initiative, Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium, created with a goal of investigating intermediate phenotypes across psychotic disorders. Study procedures and data analyses were done under the approved Yale University project Characterizing Clinical and Pharmacological Neuroimaging Biomarkers. Following identification of subjects that passed stringent quality controls for fMRI data, and matching with the clinical and healthy control populations, study included 436 psychosis probands (167 schizophrenia patients, 119 schizoaffective disorder patients, and 150 patients diagnosed with bipolar disorder with history of psychosis) and 219 matched healthy controls. Whole-thalamus seed-based analyses were used to determine thalamic connectivity changes, followed by parcellation of thalamus using a priori defined functional subnuclei, and data-driven clustering, to define details of the thalamo-cortical dysconnectivity in schizophrenia and psychotic disorders. Both in schizophrenia, and in the wider psychosis spectrum, there was a robust pattern of thalamic over-connectivity with sensory and motor regions, as well as with associative areas tasked with integration of lower-level inputs, and under-connectivity with cerebellar regions. Interestingly, previously reported under-connectivity with prefrontal regions was evident only in dorsal attention functional thalamic subnucleus connectivity map. Nine functional thalamic subnuclei showed relatively different thalamic connectivity changes, ranging from altogether missing effects to wide-spread over- /under-connectivity, but overall followed same general dysconnectivity pattern described for the whole thalamus. Clustering analyses revealed that the data-driven clustering, released from constraints of a priori defined thalamic subnuclei, resulted in solutions that significantly differed from existing functional subnuclei or anatomical divisions, with areas centered on mediodorsal nucleus and ventral lateral areas driving the dysconnectivity effect. In schizophrenia, thalamo-cortical connectivity changes showed relationship with negative symptoms, as well as with excitation and disorganization subscale scores, suggesting that a more pronounced over- or under-connectivity effect predicted more pronounced specific symptoms. Under-connectivity effect of the dorsal attention functional subnucleus (including reduced connectivity with prefrontal cortical regions) also correlated with disorientation. In conclusion, thalamo-cortical dysconnectivity patterns of seemingly correlated over- and under-connectivity effects seems to be robustly present in schizophrenia, but also across the psychosis spectrum. Although the same general pattern exists across different thalamic regions, its extent differs among different thalamic functional subnuclei suggesting that the effect is driven by specific associative functional subnuclei. Finally, although thalamo-cortical connectivity changes might be linked to a more non-specific disease severity or trait indicators, negative symptoms, disorganization, and excitation seem to be connected more directly to those changes than positive symptoms or emotional dysregulation

Functional neural correlates of first-episode psychoses during sensory, cognitive, language, and emotional processing

Background. Numerosi studi hanno evidenziato che i pazienti affetti da esordi sindromici dello spettro schizofrenico presentano alterazioni neurofunzionali durante l’esecuzione di compiti che coinvolgono le funzioni sensoriali, cognitive, linguistiche ed emotive. Obiettivo. Paragonare pazienti con esordio psicotico a individui sani al fine di studiare il network neurale coinvolto nelle risposte a compiti sensoriali, cognitive, linguistiche ed emotive, identificando le similarità e le differenze nelle attivazioni cerebrali correlate all’esecuzione degli stessi compiti. Metodo. Abbiamo eseguito una meta-analisi ALE utilizzando il database costruito su ventisei studi di risonanza magnetica funzionale condotti su 516 pazienti con esordio e 546 soggetti sani durante l’esecuzione di task sensoriali, cognitivi, linguistici ed emotivi. Risultati. Le analisi within-group hanno dimostrato che i controlli sani manifestavano in risposta a tutti i task attivazioni significative in un circuito bilaterale fronto-parietale, mentre i pazienti in un circuito bilaterale parietale-precentrale. Le analisi between-groups hanno evidenziato iperattivazioni del lobulo parietale inferiore di destra, del giro medio frontale sinistro e della corteccia temporale destra nei sani e del cingolo di destra nei pazienti. L’analisi condotta separatamente per gruppi di compiti ha evidenziato che la performance di task attentivo-mnestici si correlava ad attivazione di aree prefrontali nei sani e parietali bilaterali negli esordi; l’esecuzione di task emotivi si correlava ad attivazione della corteccia dorsolaterale prefrontale (DLPFC) bilaterale, della corteccia parietale destra, del cingolo di sinistra e dell’amigdala di destra nei sani e del giro fusiforme di destra nei pazienti; solo i sani hanno evidenziato attivazioni in aree corticali di sinistra incentrate sull’insula, la DLPFC e la corteccia temporale in correlazione a compiti linguistici. Conclusioni. Il risultato principale di questa meta-analisi è l’evidenza di deficit funzionale della DLPFC di sinistra in pazienti con esordio psicotico durante l’esecuzione di task sensoriali, cognitivi, linguistici ed emotivi. Il giro del cingolo di destra, le cortecce parietali e la temporale di destra hanno anch’esse un ruolo importante nella neurofisiopatologia degli esordi. Questo studio ha anche evidenziato che i pazienti attivano circuiti cerebrali diversi rispetto ai sani in risposta a compiti attentivo-mnestici (attivazione predominante in aree parietali bilaterali), emotivi (attivazione predominante nel giro fusiforme destro) e linguistici (mancata attivazione di aree corticali di sinistra).Background: Several studies reported neural functional alterations in patients with schizophrenia spectrum first-episode psychosis (FEP) during performance of tasks that involve sensory, attentional memory, language, and emotional (SAMLE) processing. Aim: To compare meta-analytically FEP and healthy control (CTR) samples regarding the circuitries engaged in responding to a set of SAMLE tasks and identifying commonalities and differences in task-related brain activations. Method: We performed an activation likelihood estimation (ALE) meta-analysis using a database built on 26 fMRI studies, conducted on 516 FEP patients and 546 CTRs during SAMLE task performance. Results: Within-Group analyses showed that the CTR group has significant SAMLE task-related cortical activations in the context of a bilateral fronto-parietal network; FEP patients showed taskrelated activations of a bilateral parietal-precentral network. Between-Groups analyses showed hyperactivation of the right inferior parietal lobule, left middle frontal gyrus, and right temporal cortex in CTRs, and hyperactivation of the right cingulate gyrus in FEP. Segregated analyses of tasks showed that brain activations to attentional and memory-related tasks mainly occurred in prefrontal areas in CTRs, and in bilateral parietal areas in FEP; emotional task-related activations concerned the bilateral dorsolateral prefrontal cortex (DLPFC), right parietal cortex, left cingulate cortex and right amygdala in CTRs, whereas in FEP the activation concerned the right fusiform gyrus; we found significant left-sided language task-related activations only in the CTR group, centred on the insula, DLPFC, and temporal cortex. Conclusions: The major finding of this study is the evidence of a functional deficit of the left DLPFC in FEP during the SAMLE task performance. A prominent role in the neuropathophysiology of FEP appears also to be played by the right dorsal anterior cingulate, bilateral parietal, and right temporal cortices. This study also underlined that FEP patients activate different circuits than CTRs in response to attentional- and memory-tasks (predominant activation of bilateral parietal areas), emotional (predominant activation of the right fusiform gyrus), and language (lack of activation of left-sided cortical areas) tasks

Cortisol, cognition and the ageing prefrontal cortex

The structural and functional decline of the ageing human brain varies by brain region, cognitive function and individual. The underlying biological mechanisms are poorly understood. One potentially important mechanism is exposure to glucocorticoids (GCs; cortisol in humans); GC production is increasingly varied with age in humans, and chronic exposure to high levels is hypothesised to result in cognitive decline via cerebral remodelling. However, studies of GC exposure in humans are scarce and methodological differences confound cross-study comparison. Furthermore, there has been little focus on the effects of GCs on the frontal lobes and key white matter tracts in the ageing brain. This thesis therefore examines relationships among cortisol levels, structural brain measures and cognitive performance in 90 healthy, elderly community-dwelling males from the Lothian Birth Cohort 1936. Salivary cortisol samples characterised diurnal (morning and evening) and reactive profiles (before and after a cognitive test battery). Structural variables comprised Diffusion Tensor Imaging measures of major brain tracts and a novel manual parcellation method for the frontal lobes. The latter was based on a systematic review of current manual methods in the context of putative function and cytoarchitecture. Manual frontal lobe brain parcellation conferred greater spatial and volumetric accuracy when compared to both single- and multi-atlas parcellation at the lobar level. Cognitive ability was assessed via tests of general cognitive ability, and neuropsychological tests thought to show differential sensitivity to the integrity of frontal lobe sub-regions. The majority of, but not all frontal lobe test scores shared considerable overlap with general cognitive ability, and cognitive scores correlated most consistently with the volumes of the anterior cingulate. This is discussed in light of the diverse connective profile of the cingulate and a need to integrate information over more diffuse cognitive networks according to proposed de-differentiation or compensation in ageing. Individuals with higher morning, evening or pre-test cortisol levels showed consistently negative relationships with specific regional volumes and tract integrity. Participants whose cortisol levels increased between the start and end of cognitive testing showed selectively larger regional volumes and lower tract diffusivity (correlation magnitudes <.44). The significant relationships between cortisol levels and cognition indicated that flatter diurnal slopes or higher pre-test levels related to poorer test performance. In contrast, higher levels in the morning generally correlated with better scores (correlation magnitudes <.25). Interpretation of all findings was moderated by sensitivity to type I error, given the large number of comparisons conducted. Though there were limited candidates for mediation analysis, cortisol-function relationships were partially mediated by tract integrity (but not sub-regional frontal volumes) for memory and post-error slowing. This thesis offers a novel perspective on the complex interplay among glucocorticoids, cognition and the structure of the ageing brain. The findings suggest some role for cortisol exposure in determining age-related decline in complex cognition, mediated via brain structure