Task and resting-state fMRI studies in first-episode schizophrenia: A systematic review
Introduction
Schizophrenia is a debilitating psychotic disorder that presents with major losses in global functioning and is thought to result from neurobiological deficits (Cannon, 2008, Kraepelin, 1913). The first episode of schizophrenia typically occurs in the late teens or the early twenties (Häfner and Nowotny, 1995) and once individuals developed psychotic symptoms, they tend to remain prone to relapsing or developing into chronic episodes (Fenton, 2000, McGlashan and Fenton, 1993), suggesting that studies on first episode-schizophrenia (Fleischhacker et al.) have the potential to provide fundamental understanding of pathological changes in schizophrenia. Moreover, FES patients are less likely to be confounded by chronicity and antipsychotic medication effects (Fenton, 2000, Linszen, 2004). In the two decades since the first functional Magnetic Resonance Imaging (fMRI) studies reported in 1991–1992 (Bandettini et al., 1992, Belliveau et al., 1991), there is an increase on task and resting-state studies exploring the level of brain functional changes by using Blood Oxygen Level Dependent (BOLD) signal. This method has been suggested in order to provide a better understanding of the underlying neurobiology and its associated endophenotypes in schizophrenia (Northoff and Qin, 2011, Palaniyappan et al., 2013). However, it remains unclear as to whether brain functional changes during the resting state are sensitive to the same brain regions during task fMRI. Thus, we reviewed task and resting-state BOLD fMRI studies that investigated brain pathological changes in FES.
BOLD is a widely used technique in fMRI studies; it relies on the magnetic susceptibility effects of deoxyhaemoglobin on echoplanar or routine gradient echo sequences. When the brain is activated by tasks, a net increase in the signal intensity is observed in regions activated by the tasks. This can attributed to a greater increase in regional oxygenated blood flow that exceeds regional oxygen consumption. To measure the relationship between task demands and brain neurophysiological responses, scholars have used different cognitive tasks, including executive functioning, emotional processing, memory, language, and implicit learning tasks. In schizophrenia, the brain deficit in most of these tasks—in particular, executive functions, learning and memory—has consistently been found in the fronto-temporal pathway (Barch, 2002, Becker et al., 2008, Minzenberg et al., 2009, Young et al., 2004). In particular, abnormal activations in relation to memory and executive tasks have been reported in the ventromedial and superior temporal lobes, prefrontal cortices, and limbic structures in schizophrenia (Orellana et al., 2012). Since schizophrenia symptoms are thought to be associated with cognitive deficits (Gopal and Variend, 2005, Kurtz et al., 2001, Ralevski et al., 2012, Snitz et al., 2006, Valdois et al., 2004), studies using cognitive tasks to elicit brain activities may be helpful in our understanding of schizophrenia psychopathology.
Resting-state BOLD fMRI technique is a relatively novel approach; participants are typically asked to rest quietly with their eyes open or closed for several minutes and without performing any tasks. Resting-state fMRI studies have been suggested to have advantages over task studies, especially in studying schizophrenia, as it is practically easy to perform and does not involve any complicated tasks (Fox and Raichle, 2007). Therefore, it allows for comparison of subjects suffering from severe episodes of schizophrenia, who otherwise may not be able to perform cognitive tasks at a satisfactory level (Fox and Raichle, 2007, Greicius, 2008). Moreover, studies suggest that resting-state activity facilitates the engagement of the brain networks necessary for performing tasks and/or responding to external stimuli (Raichle and Mintun, 2006), and the mental activity occurring during rest-state is thought to be relevant to the phenomenology of schizophrenia (Malaspina et al., 2004). Thus, resting-state studies have potential to overcome several limitations of task-induces fMRI studies.
The resting-state fMRI studies focused on analyzing either the functional connectivity (FC) or the amplitude of low frequency fluctuations (Fritz et al., 2003). FC refers to the temporal correlation of a neurophysiological parameter measured in distinct brain areas, either during rest or when processing external stimuli (Friston, 2009). The FC indexes of temporal correlations among spontaneous low frequency fluctuations in the fMRI BOLD signal are attributed by intrinsic brain activity (Fox and Raichle, 2007). Meanwhile, the ALFF for a voxel's time course refers to the calculated power in the very low frequencies, usually 0.01–0.08 Hz (Fritz et al., 2003). The patterns of synchronous intrinsic brain activity demarcate numerous neuroanatomical functional circuits or networks (Damoiseaux et al., 2006). For instance, The default mode network which comprises medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), and medial temporal lobe (MTL) regions including the hippocampus, and the lateral temporoparietal area (Buckner et al., 2008) has been found to have greater activation during rest than during engagement in goal-directed tasks (Gusnard et al., 2001, Mazoyer et al., 2001, Raichle et al., 2001) and its impairment in connectivity has been correlated with clinical symptoms in schizophrenia (Whitfield-Gabrieli and Ford, 2012). Moreover, resting-state fMRI studies that focused on FES patients identified decreased ALFF in the ventromedial pre-frontal cortex that was increased in the left and right putamen (Huang et al., 2010, Lui et al., 2009). Taken together these findings suggest that the impairment in FC or ALFF during resting-state in some specific brain regions may be playing a key role in schizophrenia pathophysiology.
Though resting and task fMRI studies have provided useful information on neuropathological abnormalities in schizophrenia, it remains unknown as to whether cognitive task and resting state fMRI techniques provide consistent brain dysfunction abnormalities in FES. Moreover, both of these techniques have some advantages and limitations. Though cognitive tasks can help to measure the relationship between task demands and brain neurophysiological responses, different tasks activate different brain regions, and different subjects produce different results on the same task due to variation of the task ratings with each individual (Zhou et al., 2014). Resting-state, which is a relatively novel approach, has been reported to be advantageous over cognitive task fMRI studies because it allows a more direct comparison between groups including comparison of patient groups of different conditions as well as subjects at varying stages of disease severity and development (Fox and Raichle, 2007). However, it is not possible to standardize the resting state of the brain, for we cannot control the participant's mental state during either visual fixation or when their eyes are closed. Since the primary goal of any fMRI techniques is to provide a clear brain region or regions with neuronal activation or deactivation in association with a given mental operation Kindermann et al. (1997)), a systematic review that focuses on identifying consistent brain regions across cognitive task and resting fMRI within the same schizophrenia sub-group, using a similar study design, is likely to provide useful information on the convergent findings in FES between these two physiological states.
Therefore, to address the issues presented in the review, we conducted a systematic search of fMRI studies that explored the brain changes in FES. In order to reduce the methodological heterogeneity, we limited the scope of this study on cross-sectional case–control resting-state and task-activation fMRI studies that used BOLD fMRI in FES. The aim was to address the convergent functional neuroanatomical impairments between resting-state and task-activation. Our assumption was that if a region does not function as normal during resting-state, then performance of a particular cognitive task may indicate a persistent and consistent brain dysfunction that might be the fundamental underlying feature for schizophrenia psychopathology. Specifically, we sought to determine whether there is any correspondence in dysfunction of certain specific brain regions across resting and task states in BOLD fMRI studies; and if so, which tasks are involved. The reason for identifying a task was to determine the relationship between a particular brain disruption and the associated cognitive impairment.
Section snippets
Search strategies
A systematic search was conducted by two independent researchers (TEM and YL) from two electronic databases: PubMed and Embase. The search was performed to identify studies reporting task or resting fMRI or both of these states in subjects with FES. FES was defined as those patients who were diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder within the past 18 months with no previous episodes of psychosis as per the Diagnostic and Statistical Manual for Mental
Number of studies found
Nineteen studies (7 resting-state fMRI studies and 12 task fMRI studies) met the inclusion criteria (Fig. 1). The resting-state studies included 371 patients, with 65% of patients having history of a short duration of antipsychotic medication use, defined as the allowed exposure to antipsychotic treatment of less than 2 weeks in the year preceding study entry or 6 weeks life time exposure (Fleischhacker et al., 2005). The rest were drug naïve patients, and the patient group was age- and
Discussion
The aim of this systematic review was to combine the information from resting-state and task-activation studies, in order to locate the corresponding brain regions with dysfunction between resting state and task-activation in FES as compared to healthy controls. The convergent brain dysfunction during task and resting states were found within the fronto-temporal pathway with convergence in the DLPFC, Orbital frontal cortex and the left STG. These abnormalities were associated with emotional
Conclusion
Although the reviewed cognitive tasks and resting state fMRI studies in FES patients reported both commonalities as well as differences of the brain regional changes, the convergent functional abnormalities among these studies were within the prefronto-temporal pathway, especially in the DLPFC, orbital frontal cortex and the left STG. These regions have extensive reciprocal connections with the each other (Alvarez and Emory, 2006), indicating its structural and functional relationship. The
Contributors
TEM and ZL designed the study and wrote the protocol; TEM, GW, XH, AH, DL, and CL collected the information; TEM, YL, HA, XC, LZ, ZX, HT and WZ managed the reference search; TEM and undertook the sorting of the references and analysis; TEM, JF, and ZL wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.
Role of the funding source
The sponsor has no any influence on designing the study; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgement
This work was supported by the National Natural Science Foundation of China (ZL grant number 81271485, 81471362) (ZX grant number 81171287).
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