Serum brain‐derived neurotrophic factor (BDNF) in sleep‐disordered patients: relation to sleep stage N3 and rapid eye movement (REM) sleep across diagnostic entities

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There is evidence from rodent research that neuroplasticity and sleep are intertwined phenomena. Especially, sleep stage N3, or slow‐wave sleep, is assumed to be a sensitive marker of cortical synaptic strength and network synchronization (Esser et al., 2007). Moreover, it has been shown that cortical brain‐derived neurotrophic factor (BDNF), a modulator of neuroplasticity, induces sleep stage N3 in the subsequent sleep period (Faraguna et al., 2008). From findings in adolescent mice it could be concluded that sleep is associated with neuronal spine loss (Maret et al., 2012). Tononi's synaptic homeostasis hypothesis proposes that “sleep is the price the brain pays for plasticity”: synaptic potentiation may occur primarily in the awake stage, when the individual interacts with the environment, while renormalization of synaptic strength and neuronal spine loss may happen mainly during sleep (Tononi and Cirelli, 2014). This hypothesis is based on rodent research, but may provide a framework for understanding the relationship between sleep, neuroplasticity and learning in healthy subjects and patients with neuropsychiatric disorders.
In humans, there are several sources of evidence associating neurotrophic factors with sleep. First, the BDNF Val66Met genotype is related to polysomnographic features, with Met carriers showing decreased spectral power in the alpha band in N1 stage and decreased theta power in N2 and sleep stage N3 (Guindalini et al., 2014). In contrast, homozygous Val carriers had higher sleep stage N3 intensity compared with Val/Met carriers (Bachmann et al., 2012). Second, in healthy controls and patients with a lifetime diagnosis of restless legs syndrome (RLS) or periodic limb movement (Giese et al., 2013), as well as in female patients with disturbed sleep (Nishich et al., 2013), sleep disturbances are related to low BDNF. In contrast, in patients with narcolepsy being characterized by daytime sleepiness and increased rapid eye movement (REM) sleep, serum BDNF was found to be increased (Klein et al., 2013).
Next to these epidemiological and clinical observations, the association of sleep with BDNF has mainly been examined in pharmacological studies in depressed patients, as it is widely accepted that the expression of BDNF is reduced in the brain and blood of patients with affective disorders (Lee et al., 2007). First, it was shown that in depressed patients, sleep disturbance is related to low plasma levels of BDNF (Dell'Osso et al., 2010). In addition, ketamine has been identified to regulate sleep stage N3 and brain BDNF levels in depressed patients in a coordinated manner (Duncan et al., 2014). Lastly, it has repeatedly been shown that antidepressants acting on monoamines may increase BDNF concentrations in animals and depressed patients (Brunoni et al., 2008; Nibuya et al., 1995). Within this context, however, a considerable heterogeneity was observed with some antidepressants having strong effects, while others may hardly change BDNF concentrations (Molendijk et al., 2011). Our research showed the effect of various antidepressants on serum BDNF to differ (amitriptyline > paroxetine; mirtazapine > venlafaxine; Deuschle et al., 2013; Hellweg et al., 2008). Based on these data, it may be hypothesized that antidepressants with sleep‐promoting properties (amitriptyline, mirtazapine) have stronger effects on serum BDNF than antidepressants without major effects on sleep (paroxetine, venlafaxine). These findings contributed to the neurotrophin hypothesis of depression (Duman and Monteggia, 2006), with stress and neuroplasticity being considered key elements in the pathophysiology of affective disorders (MacQueen and Frodl, 2011). In contrast to depression, BDNF levels in sleep disorders received less attention.
Taken together, substantial experimental and clinical evidence suggests an association between daytime neuroplasticity and BDNF on the one hand and nighttime sleep on the other.
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