Trait or state? A longitudinal neuropsychological evaluation and fMRI study in schizoaffective disorder

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Abstract

Schizoaffective patients can have neurocognitive deficits and default mode network dysfunction while being acutely ill. It remains unclear to what extent these abnormalities persist when they go into clinical remission. Memory and executive function were tested in 22 acutely ill schizoaffective patients; they also underwent fMRI scanning during performance of the n-back working memory test. The same measures were obtained after they had been in remission for ≥ 2 months. Twenty-two matched healthy individuals were also examined. In clinical remission, schizomanic patients showed an improvement of memory but not of executive function, while schizodepressive patients did not change in either domain. All schizoaffective patients in clinical remission showed memory and executive impairment compared to the controls. On fMRI, acutely ill schizomanic patients had reversible frontal hypo-activation when compared to clinical remission, while activation patterns in ill and remitted schizodepressive patients were similar. The whole group of schizoaffective patients in clinical remission showed a failure of de-activation in the medial frontal gyrus compared to the healthy controls. There was evidence for memory improvement and state dependent changes in activation in schizomanic patients across relapse and remission. Medial frontal failure of de-activation in remitted schizoaffective patients, which probably reflects default mode network dysfunction, appears to be a state independent feature of the illness.

Introduction

Since the first description of schizoaffective disorder in 1933 (Kasanin, 1933), its nosological status has been debated repeatedly (Pope et al., 1980, Marneros, 2003, Heckers, 2009, Jager et al., 2011). This uncertainty remains until today, with DSM-V considering removing it as a separate category and instead adding mood symptoms as a dimension to schizophrenia and schizophreniform disorder. However, the category was ultimately maintained; it was felt that there was not enough neurobiological data to support this motion (Allin et al., 2010, Cosgrove and Suppes, 2013).

From a neuropsychological point of view, cognitive impairment, mainly attention and memory deficits and executive dysfunction, is well documented in patients with schizoaffective disorder (e.g. Torrent et al., 2007, Bora et al., 2009, Studentkowski et al., 2010, Amann et al., 2012). Conversely, there exists less functional neuroimaging data: Our group recently published results of 32 acutely ill schizoaffective patients who, using a working memory task, activated prefrontal, parietal and temporal regions significantly less than healthy subjects (Madre et al., 2013). They also showed failure of de-activation in the medial frontal cortex which was more pronounced in the schizodepressed than in the schizomanic group. The finding of failure of deactivation was interpreted as evidence of dysfunction in the so-called default mode network, a series of interconnected brain regions which are metabolically active at rest but whose activity diminishes while the brain performs a wide range of cognitive tasks (Gusnard and Raichle, 2001, Raichle et al., 2001). Similar failure of de-activation during cognitive task performance has also been found in schizophrenia (Pomarol-Clotet et al., 2008, Whitfield-Gabrieli et al., 2009, Milanovic et al., 2011, Salgado-Pineda et al., 2011, Schneider et al., 2011) and bipolar disorder (Allin et al., 2010, Fernandez-Corcuera et al., 2013, Pomarol-Clotet et al., 2012).

A question that has not yet been addressed in the literature is whether and to what extent neuropsychological and functional imaging changes seen in schizoaffective disorder persist into remission or in other words: Are detected abnormalities a state or trait phenomenon of the disease? This is pertinent to the relationship of the disorder to schizophrenia and bipolar disorder, since neuropsychological deficits in the former disorder are widely considered to be static and unchanging, whereas those in bipolar disorder are presumed to resolve with clinical remission (e.g. Murray et al., 2004), even if the phenomenon of euthymic cognitive impairment indicates that this is not complete in all cases (e.g. Martinez-Aran et al., 2004, Robinson et al., 2006). Similarly, while functional imaging changes in schizophrenia are usually considered to be persistent, studies comparing patients in different phases of bipolar disorder, together with a small number of longitudinal studies, clearly point to changes between phases of illness and euthymia (Chen et al., 2010, Lim et al., 2013).

The present study was undertaken to examine the neuropsychological and functional neuroimaging features of schizoaffective disorder from a longitudinal perspective. We used a sample that contained roughly equal numbers of schizomanic and schizodepressive patients. Participants were studied when they were ill, and again when they were in clinical remission. We hypothesized that brain function, measured with cognitive tests and fMRI, differed in the two states.

Section snippets

Participants

The patient sample consisted of 22 patients with schizoaffective disorder, bipolar type and were part of the sample of a previously published study of our group (Madre et al., 2013). They all met Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for schizoaffective disorder, based on a psychiatrist interview and the review of case-notes. We used these criteria because they are the most detailed of all available criteria for schizoaffective disorder. They posit that patients show

Demographic and clinical data

Demographic and clinical data for the schizoaffective patients and controls are shown in Table 1.

Memory and executive test performance

When compared to clinical remission, the schizomanic group showed a significant improvement in memory (WMS: 29 ± 5 vs. 36 ± 9, p = 0.036) but not in executive function (BADS: 76 ± 21 vs. 80 ± 20, p = 0.67). In contrast, there were no changes on either measure in the schizodepressive patients in comparison to clinical remission (WMS: 30 ± 6 vs. 31 ± 9, p = 1; BADS: 67 ± 27 vs. 78 ± 28, p = 0.55). The whole group of

Discussion

To the best of our knowledge, this study is the first to examine changes in neuropsychological performance and brain activation patterns in schizoaffective disorder longitudinally, comparing illness and remission. We found some evidence of improvement in memory in the schizomanic sample once in clinical remission but no changes in executive function in this group and no changes in either cognitive domain in the schizodepressive group. Furthermore, changes in brain activation were observed,

Role of Funding Source

The study received support by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and grant support from the Instituto de Salud Carlos III (Spanish Ministry of Health) by a Miguel Servet Research Contract to B. L. Amann (CP06/0359) and two specific research projects to B.L. Amann (PI07/1278 and PI10/02622).

Contributors

MM, EPC, and BLA designed the study and wrote the protocol. MM and BLA managed the literature searches. BLA, FP and MM recruited patients and followed them up. JR, MM, SA and RL undertook the statistical and neuroimaging analysis. MM and BLA wrote the first draft of the manuscript which was revised by EPC. All authors contributed to and have approved the final manuscript.

Conflict of interest

All authors exclude any actual or potential conflict of interest including any financial, personal or other relationships with other people or organizations within three (3) years of beginning the work submitted that could have inappropriately influenced, or be perceived to influence, their work.

Acknowledgements

We acknowledge the generous support by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and grant support from the Instituto de Salud Carlos III (Spanish Ministry of Health): Miguel Servet Research Contract to B. L. Amann (CP06/0359), R. Salvador (CP07/00048), and E. Pomarol-Clotet (CP10/00596); Río Hortega research contract to J. Radua (CM11/00024); Research Projects to B.L. Amann (PI07/1278 and PI10/02622), E. Pomarol-Clotet (PI10/01058) and R. Salvador (PI05/1874). We

References (51)

  • L.J. Robinson et al.

    A meta-analysis of cognitive deficits in euthymic patients with bipolar disorder

    J. Affect. Disord.

    (2006)
  • P. Salgado-Pineda et al.

    Correlated structural and functional brain abnormalities in the default mode network in schizophrenia patients

    Schizophr. Res.

    (2011)
  • F.C. Schneider et al.

    Modulation of the default mode network is task-dependant in chronic schizophrenia patients

    Schizophr. Res.

    (2011)
  • S.M. Smith et al.

    Advances in functional and structural MR image analysis and implementation as FSL

    Neuroimage

    (2004)
  • J. Townsend et al.

    fMRI abnormalities in dorsolateral prefrontal cortex during a working memory task in manic, euthymic and depressed bipolar subjects

    Psychiatry Res.

    (2010)
  • G. Xu et al.

    Neuropsychological performance in bipolar I, bipolar II and unipolar depression patients: a longitudinal, naturalistic study

    J. Affect. Disord.

    (2012)
  • M.P. Allin et al.

    A functional MRI study of verbal fluency in adults with bipolar disorder and their unaffected relatives

    Psychol. Med.

    (2010)
  • B. Amann et al.

    Executive dysfunction and memory impairment in schizoaffective disorder: a comparison with bipolar disorder, schizophrenia and healthy controls

    Psychol. Med.

    (2012)
  • C.F. Beckmann et al.

    Applying FSL to the FIAC data: model-based and model-free analysis of voice and sentence repetition priming

    Hum. Brain Mapp.

    (2006)
  • E. Bora et al.

    Cognitive functioning in schizophrenia, schizoaffective disorder and affective psychoses: meta-analytic study

    Br. J. Psychiatry

    (2009)
  • V.D. Calhoun et al.

    Temporal lobe and "default" hemodynamic brain modes discriminate between schizophrenia and bipolar disorder

    Hum. Brain Mapp.

    (2008)
  • C.H. Chen et al.

    A longitudinal fMRI study of the manic and euthymic states of bipolar disorder

    Bipolar Disord.

    (2010)
  • V.E. Cosgrove et al.

    Informing DSM-5: biological boundaries between bipolar I disorder, schizoaffective disorder, and schizophrenia

    BMC Med.

    (2013)
  • D.C. Glahn et al.

    Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia

    Hum. Brain Mapp.

    (2005)
  • D.A. Gusnard et al.

    Searching for a baseline: functional imaging and the resting human brain

    Nat. Rev. Neurosci.

    (2001)
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