Review articleConverging effects of diverse treatment modalities on frontal cortex in schizophrenia: A review of longitudinal functional magnetic resonance imaging studies
Introduction
Schizophrenia is a disabling mental disorder, the etiology of which remains elusive (Haller et al., 2014). Antipsychotic medications (APM), the mainstay of treatment, are relatively effective at improving the positive symptoms of this condition, but they are less effective in treating negative (Chue and Lalonde, 2014) and cognitive symptoms (Carter, 2005), the best predictors of functional outcome, often do not produce sustained recovery (Lehman et al., 2004), and are associated with a number of serious side effects. There is an urgent need for more effective treatments.
Non-pharmacological approaches are also commonly used to treat schizophrenia and include talk therapies like cognitive behavioral therapy for psychosis (CBTp). CBTp teaches patients to self-monitor thoughts and question the evidence supporting abnormal beliefs. It also teaches ways to cope with the distress caused by persistent psychotic symptoms (Addington and Lecomte, 2012). CBTp has been shown to improve positive and negative symptoms (Tarrier et al., 1998, Sensky et al., 2000), adherence to treatment (Kemp et al., 1996), depression (Turkington et al., 2002) and insight in patients with schizophrenia (Rathod et al., 2005).
In addition, more novel treatment strategies such as cognitive remediation therapy (CRT) and avatar therapy, and non-invasive brain stimulation techniques, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have been applied in an attempt to ameliorate cognitive deficits and other psychosis symptoms resistant to APM. CRT, a behavioral intervention that aims to improve cognitive deficits via repeated behavioral training (Kern et al., 2009), has been shown to enhance cognitive performance and psychosocial functioning in patients with schizophrenia (McGurk et al., 2007, Medalia and Saperstein, 2013, Wykes et al., 2011). rTMS, which involves non-invasive electromagnetic stimulation of specific brain areas (Quan et al., 2015), has been applied to the treatment of auditory hallucinations (Chibbaro et al., 2005, Hoffman et al., 2005, Jandl, 2010, Vercammen et al., 2009, Hoffman et al., 2013), working memory (WM) (Brunoni and Vanderhasselt, 2014) and negative symptoms (Quan et al., 2015). tDCS is another non-invasive neurostimulation technique that modulates brain activity via a low-intensity electric current applied directly to the head through scalp electrodes (Nitsche et al., 2008). Studies using tDCS have demonstrated improvement in cognitive performance (Hoy et al., 2014) and reduction in auditory hallucinations in schizophrenia (Brunelin et al., 2012).
Despite the increase in the number of therapeutic options available and/or emerging, it remains unclear what effect these treatments have on the brain. Yet, in order to develop more targeted and effective therapies for schizophrenia, it is crucial to recognize the effects of current treatments on brain function (Sharma, 2003). Indeed, the NIMH has recently shifted focus of clinical trials for both pharmacological and non-pharmacological interventions to an experimental therapeutics approach (Insel and Gogtay, 2014), which emphasizes evaluation of the potential for a treatment to engage a hypothesized target (e.g. neural circuits) rather than studying efficacy of a treatment whose mechanisms have not yet been clearly established.
Functional neuroimaging is one approach that enables observation of the functional alterations that can occur with a treatment in clinically-relevant timescales (Sharma, 2003). Among the techniques in this category, single photon emitted computed tomography (SPECT) and positron emission tomography (PET) have been used to identify changes in brain function, blood flow, metabolism and neuroreceptor and neurotransmitter activity due to drug treatments (Davis et al., 2005). Another approach, functional magnetic resonance imaging (fMRI) can be used to measure changes in the blood oxygen level dependent signal, an indicator of neuronal activity and brain function (Abbott et al., 2013). Task-dependent fMRI investigations measure changes in brain activity by detecting BOLD signal alterations during the performance of specific tasks. Functional connectivity (FC) during task-independent fMRI can identify intrinsic networks, which demonstrate synchronous low-frequency (<0.1 Hz) BOLD oscillations during resting-state. FC reflects the level of integration across brain regions, and can provide insight into the “dysconnectivity” or disintegration of brain networks in schizophrenia (Smucny et al., 2014, Tregellas, 2009, Stephan et al., 2009). As a non-invasive and relatively safe tool for investigating in vivo brain function with high spatial resolution, fMRI can be used to measure the biological effects of candidate treatment strategies, and may provide a useful biomarker in clinical trials (Smucny et al., 2014, Tregellas, 2014). The promise of these approaches have been demonstrated in recent work indicating that functional connectivity of the striatum can predict response to APMs in first episode psychosis (Sarpal et al., 2015) and that striatal activity during reward anticipation predicts weight gain in response to subsequent APM therapy (Nielsen et al., 2016).
In the current paper, we aimed to review functional brain changes associated with currently available treatments for schizophrenia, and, more specifically, to identify whether there are any treatment-related functional brain changes that the diverse approaches have in common. We did not find any clinical trials evaluating the impact of CRT, rTMS, tDCS and avatar therapy with PET or SPECT, so we review only longitudinal fMRI studies which address the impact of various treatment modalities in patients with schizophrenia. We present our analysis for each modality in order (and in associated Tables). For each modality, we consider resting state FC, FC during task activation, and regional brain activation during tasks in order because these represent related but distinct aspects of brain activity. We then provide a summary of our observations at the end of each modality section. In the Discussion section, we summarize our findings and synthesize the information to provide a perspective for the reader. We conclude that functional changes are observed in frontal cortex across treatment modalities, which we hypothesize are related to known brain abnormalities in schizophrenia. In this process, we also highlight the sources of heterogenetity in this literature as well as the limitations inherent in fMRI approaches.
Section snippets
Methods
We performed a systematic search of longitudinal schizophrenia studies utilizing fMRI methods in the PubMed database, using logical combinations of the following terms: “schizophrenia,” “psychosis,” “functional magnetic resonance imaging,” “fMRI,” “antipsychotic treatment,” “transcranial magnetic stimulation,” “transcranial direct current stimulation,” “avatar therapy, ” “cognitive remediation therapy” and “cognitive behavioral therapy”. The bibliographies of the published papers were also
Results
A total of 36investigations were included in this review. Seventeen studies assessed changes in functional brain activity related to APM (Sarpal et al., 2015, Hadley et al., 2014, Lui et al., 2010, Stephan et al., 2001, Bertolino et al., 2004, Blasi et al., 2009, van Veelen et al., 2011, Keedy et al., 2009, Meisenzahl et al., 2006, Schlagenhauf et al., 2008, Honey et al., 1999, Snitz et al., 2005, Ikuta et al., 2014, Sambataro et al., 2010, Kraguljac et al., 2016a, Kraguljac et al., 2016b, Li
Discussion
In the present review, we examined fMRI-based outcome measures in treatment studies of schizophrenia. The treatment modalities included APM, rTMS, CRT, CBTp and tDCS. Taking the findings of our systematic review together, we have found that the most consistent finding across studies is the normalization of functional activity in frontal cortical regions. For example, eight out of nine brain activation studies and six out of eight FC studies identified this pattern in APM studies. Likewise, four
Conflict of interest
The authors declare no conflicts of interest.
Role of the funding source
The funding source played no role in the conception, execution, or reporting of this project.
Acknowledgments
This work was supported by K24MH104449 to DO.
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