Abstract
Repetitive transcranial magnetic stimulation (rTMS) is considered a promising therapeutic tool for treating neuropsychiatric diseases. Previously, we found intermittent theta-burst stimulation (iTBS) rTMS to be most effective in modulating cortical excitation-inhibition balance in rats, accompanied by improved cortical sensory processing and sensory learning performance. Using an animal schizophrenia model based on maternal immune activation (MIA) we tested if iTBS applied to either adult or juvenile rats can affect the behavioral phenotype in a therapeutic or preventive manner, respectively. In a sham-controlled fashion, iTBS effects in MIA rats were compared with rats receiving vehicle NaCl injection instead of the synthetic viral strand. Prior to iTBS, adult MIA rats showed deficits in sensory gating, as tested with prepulse inhibition (PPI) of the acoustic startle reflex, and deficits in novel object recognition (NOR). No differences between MIA and control rats were evident with regard to signs of anxiety, anhedonia and depression but MIA rats were somewhat superior to controls during the training phase of Morris Water Maze (MWM) test. MIA but not control rats significantly improved in PPI following iTBS at adulthood but without significant differences between verum and sham application. If applied during adolescence, verum but not sham-iTBS improved NOR at adulthood but no difference in PPI was evident in rats treated either with sham or verum-iTBS. MIA and control rat responses to sham-iTBS applied at adulthood differed remarkably, indicating a different physiological reaction to the experimental experiences. Although verum-iTBS was not superior to sham-iTBS, MIA rats seemed to benefit from the treatment procedure in general, since differences—in relation to control rats declined or disappeared. Even if classical placebo effects can be excluded, motor or cognitive challenges or the entire handling procedure during the experiments appear to alleviate the behavioral impairments of MIA rats.
Highlights
Schizophrenia is considered a neurodevelopmental disorder originating from disturbed neuronal maturation at prenatal stage and/or during adolescence (Insel, 2010; Selemon and Zecevic, 2015)
We recently described that maternal immune activation (MIA) rats show disturbed long-range synchrony of neuronal thetaoscillations, in particular between medial prefrontal cortex and ventral hippocampus, aberrant prefrontal gammatheta phase coupling and an overall increase in the ratio of low to high frequency oscillations of brain activity (Lippmann et al, 2021). repetitive transcranial magnetic stimulation (rTMS) with intermittent theta-burst stimulation (iTBS) protocol and deep brain stimulation (DBS) within mPFC were able to normalize these activity patterns at least acutely
The decrease in time spent on the open arms of the elevated plus maze (EPM) after iTBS could be interpreted as increased anxiety
Summary
Schizophrenia is considered a neurodevelopmental disorder originating from disturbed neuronal maturation at prenatal stage and/or during adolescence (Insel, 2010; Selemon and Zecevic, 2015). Epidemiological studies demonstrate a relationship between infections during pregnancy and increased risk of the offspring to develop a schizophrenic phenotype during early adulthood (Mednick et al, 1988; Brown et al, 2004; Brown, 2012; Estes and McAllister, 2016). Based on these findings rodent maternal immune activation (MIA) models have been launched which use injections of either viral or bacterial pathogens to pregnant dams at a particular state of gestation (Zuckerman et al, 2003; Zuckerman and Weiner, 2005; Meyer, 2014; for review see Bergdolt and Dunaevsky, 2019). As non-invasive brain stimulation (NIBS) techniques, like transcranial direct current stimulation (tDCS) and repetitive transcranial magnetic stimulation (rTMS), have been shown to modulate cortical excitability and plasticity (Huang et al, 2005; Ziemann and Siebner, 2008; Ridding and Ziemann, 2010; Dayan et al, 2013), they may be considered as alternative therapeutic or possible preventive tools (Post and Keck, 2001; Padberg and George, 2009; Rajji et al, 2013; Kuo et al, 2017; Iimori et al, 2019; Hadar et al, 2020) in the context of schizophrenia (Hadar et al, 2018, 2020)
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