اثر تمرین استقامتی بر ساختارهای مغزی در بیماران مبتلا به اسکیزوفرنی مزمن و افراد سالم

The objective of this longitudinal magnetic resonance (MR) imaging study was to examine the effects of endurance training on hippocampal and grey matter volumes in schizophrenia patients and healthy controls. 20 chronic schizophrenia patients and 21 age- and gender-matched healthy controls underwent 3 months of endurance training (30 min, 3 times per week). 19 additionally recruited schizophrenia patients played table soccer (“foosball” in the USA) over the same period. MR imaging with 3D-volumetric T1-weighted sequences was performed on a 3 T MR scanner at baseline, after 6 weeks and after the 3-month intervention and 3 additional training-free months. In addition to voxel-based morphometry (VBM), we performed manual and automatic delineation of the hippocampus and its substructures. Endurance capacity and psychopathological symptoms were measured as secondary endpoints. No significant increases in the volumes of the hippocampus or hippocampal substructures were observed in schizophrenia patients or healthy controls. However, VBM analyses displayed an increased volume of the left superior, middle and inferior anterior temporal gyri compared to baseline in schizophrenia patients after the endurance training, whereas patients playing table soccer showed increased volumes in the motor and anterior cingulate cortices. After the additional training-free period, the differences were no longer present. While endurance capacity improved in exercising patients and healthy controls, psychopathological symptoms did not significantly change. The subtle changes in the left temporal cortex indicate an impact of exercise on brain volumes in schizophrenia. Subsequent studies in larger cohorts are warranted to address the question of response variability of endurance training.

Structural brain alterations with local and overall volume reductions are well-documented findings in multi- and first-episode schizophrenia patients (Honea et al., 2005, Ellison-Wright and Bullmore, 2010, Leung et al., 2011 and Cooper et al., 2014). In addition to global atrophy and larger ventricles, the most pronounced reduction of grey matter volume has been observed in the heteromodal association cortices of the left hemisphere, especially in the superior temporal gyrus (STG). More specifically, hippocampal volumes have been found to be smaller in schizophrenia (DeLisi et al., 2004, Honea et al., 2005, Steen et al., 2006, Velakoulis et al., 2006, Vita et al., 2006 and Vita and de Peri, 2007). Reductions of hippocampal volumes have been linked to impaired declarative memory function, which is considered a core clinical feature of schizophrenia (Tamminga et al., 2010 and Hasan et al., 2013). Changes in STG volume are discussed to be related to general symptom severity (Mitelman et al., 2007) and auditory verbal hallucinations (Palaniyappan et al., 2012, Modinos et al., 2013 and van Tol et al., 2014). Furthermore, a growing body of evidence documents that these structural brain changes and especially the cortical grey matter deficits are progressive over the course of the illness and are regionally distinct (Hulshoff Pol et al., 2002, Mane et al., 2009, Kempton et al., 2010, Ho et al., 2011b, Olabi et al., 2011 and Vita et al., 2012). However, the underlying pathophysiology of these changes is still unclear and may be related to antipsychotic medications (Lieberman et al., 2005), alcohol and drug use (Van Haren et al., 2012) and differences in activity levels (Vancampfort et al., 2012). Endurance training is known to induce both structural and functional brain changes, but these changes do not necessarily reflect reversibility of changes that are directly related to the disease process underlying schizophrenia. In animal models, exercise-induced neurogenesis and angiogenesis in the hippocampus in adult and ageing mice led to long-term potentiation and production of neurotrophic factors like BDNF and improved cognitive functioning (Voss et al., 2013). In healthy humans, cross-sectional and longitudinal studies underpin these observations and point to preserved grey matter and hippocampal volumes and cognitive functioning in higher age due to endurance training (Erickson and Kramer, 2009, Honea et al., 2009, Erickson et al., 2010 and Erickson et al., 2011). Pereira et al. (2007) showed that endurance training increased cerebral blood volume (CBV) in the dentate gyrus of the hippocampus in healthy humans and mice. The elevated CBV was also correlated with increased aerobic fitness and cognitive function. The first proof-of-concept study investigating the efficacy of 3 months of endurance training in addition to standard antipsychotic treatment in eight chronic schizophrenia patients reported increased hippocampal volumes and elevated hippocampal N-acetylaspartate to creatine ratios (Pajonk et al., 2010). These changes correlated with improved aerobic fitness, indicating that the hippocampus of schizophrenia patients is responsive to a plasticity-inducing stimulus. Subsequent analysis of cortical surface expansion of the same cohort did not reveal any significant changes in the schizophrenia exercise group (Falkai et al., 2013). A randomised controlled trial (RCT) with 63 probands comparing 6 months of endurance training to occupational therapy in schizophrenia could not replicate these initial findings (Scheewe et al., 2013b), but showed improved cardiovascular fitness following the intervention. Until now, only these two neuroimaging studies with contradictory results have reported the impact of endurance training on brain structure and function in schizophrenia (Malchow et al., 2013). Furthermore, it is unknown whether the pattern of brain structure changes outlasts the intervention period in terms of a consolidation process of whether endurance-induced brain volume changes represent only short-term effects. In addition, a combination of aerobic exercise with targeted cognitive remediation in terms of an enriched environment intervention may increase the beneficial effect of the exercise interventions. The primary objective of this study was to investigate the effects of 3 months' endurance training combined with cognitive stimulation with add-on computer assisted cognitive remediation (CACR) training from week six to three months on cortical and subcortical brain structures in schizophrenia patients. We also intended to assess whether the effects remained after a subsequent 3 months' resting period with no endurance training or cognitive remediation. Further objectives were to investigate the impact of exercise on hippocampal subfields, psychopathology and endurance capacity.