Kuhn et al. (2016) showed in healthy humans that one night of total sleep deprivation increases non-invasive indices of net synaptic strength in the cortex (a lower transcranial magnetic stimulation intensity needed to evoke a 1-mV motor potential, and elevated wake EEG theta activity) while converting paired-associative-stimulation-induced long-term potentiation (LTP)-like plasticity into long-term depression (LTD)-like plasticity, with plasma BDNF changes tracking the excitability change. The subsequent literature confirms that the phenomenology replicates and has been quantitatively refined, but the mechanistic core remains open: no study has identified the cellular and circuit mechanisms in humans that produce the wake-related upscaling, none has discriminated the three competing explanations for the LTP-to-LTD reversal (a Bienenstock-Cooper-Munro-type homeostatic shift of the induction threshold, facilitated LTD induction, or coincidence of stimulation with local cortical down-states), and the causal role of BDNF remains untested. The open problem is to supply that mechanistic account.

Background

The synaptic homeostasis hypothesis (SHY) of sleep-wake regulation (Tononi and Cirelli, Neuron 81:12-34, 2014, DOI 10.1016/j.neuron.2013.12.025) proposes that net synaptic strength increases during wakefulness towards saturation and is renormalized during sleep, renewing the brain's capacity to encode new information. Because synapses cannot be observed directly in living humans, SHY has been tested in humans with non-invasive electrophysiology. Transcranial magnetic stimulation (TMS) over the primary motor cortex elicits motor-evoked potentials (MEPs) in peripheral muscles; the TMS intensity required to evoke an MEP of about 1 mV peak-to-peak (called SI1mVSI_{1\mathrm{mV}} here) is a standard global index of corticospinal excitability that SHY predicts should fall (implying higher excitability) as wakefulness accumulates. Wake EEG theta activity (roughly 4-8 Hz spectral power during quiet waking) is a second standard index of sleep pressure. Paired associative stimulation (PAS) is a protocol in which peripheral nerve stimulation is repeatedly paired with TMS pulses over the motor cortex at a fixed interval; depending on the interval it produces an LTP-like or LTD-like change in MEP amplitude, where 'LTP-like'/'LTD-like' mean bidirectional, input- and timing-dependent modulation of cortical responsiveness that resembles the synaptic long-term potentiation and long-term depression studied in vitro. Kuhn, Wolf, Maier, et al. (Nature Communications 7:12455, 2016, DOI 10.1038/ncomms12455) compared one night of sleep with one night of total sleep deprivation in a within-subject design and found, after sleep deprivation, indices of increased net synaptic strength (reduced SI1mVSI_{1\mathrm{mV}}, elevated wake theta) alongside reduced LTP-like plasticity: the same PAS protocol that increased MEP amplitudes in 70% of participants after sleep decreased them in 75% after sleep deprivation. Declarative memory formation was also impaired, and plasma brain-derived neurotrophic factor (BDNF, a neurotrophin that supports LTP and synaptic strengthening) decreased after sleep deprivation, with the size of that decrease predicting the size of the excitability change. The authors noted that a marker of axon membrane excitability (resting motor threshold) was unaffected, and raised three competing mechanistic explanations for the plasticity reversal: (1) a homeostatic shift of the LTP/LTD induction threshold in the sense of the Bienenstock-Cooper-Munro (BCM) theory, the classical model in which the threshold between potentiation and depression adjusts to the level of prior postsynaptic activity (Bienenstock, Cooper and Munro, Journal of Neuroscience 2:32-48, 1982, DOI 10.1523/JNEUROSCI.02-01-00032.1982); (2) a facilitation of LTD induction, for which rodent hippocampal evidence existed; and (3) coincidence of the stimulation with local cortical down-states ('local sleep', off-like states intruding into awake cortex as described by Vyazovskiy et al., Nature 472:443-447, 2011, DOI 10.1038/nature10009). Their own data argued against but did not exclude the last two. In humans the underlying cellular variables (excitatory/inhibitory synaptic balance, receptor trafficking, membrane bistability) must be inferred from indirect measures such as paired-pulse TMS protocols, in which short-interval intracortical inhibition (SICI) indexes GABA-A-mediated intracortical inhibition and intracortical facilitation (ICF) indexes glutamatergic facilitation.

Problem Statement

Identify the cellular and circuit mechanisms by which sustained wakefulness and sleep recalibrate synaptic plasticity in the human cortex, as probed non-invasively in the paradigm of Kuhn et al. (2016). The mechanisms to be identified are those that explain two linked phenomena and the role of one candidate mediator: (1) the mechanism producing the wake-related increase in neurophysiological indices of net synaptic strength in humans - the reduction of the TMS intensity SI1mVSI_{1\mathrm{mV}} needed to evoke a 1-mV motor-evoked potential and the elevation of wake EEG theta activity - including the relative roles of intracortical excitation/inhibition balance, membrane bistability and local 'off'-states, and synaptic receptor properties; and (2) the mechanism by which the same paired associative stimulation protocol induces LTP-like plasticity after sleep but LTD-like plasticity after sleep deprivation - in particular, discriminating among the three competing hypotheses left open by the source study: a homeostatic shift of the LTP/LTD induction threshold in the sense of the Bienenstock-Cooper-Munro theory, a facilitation of LTD induction, and coincidence of stimulation with local cortical down-states ('local sleep'); together with (3) establishing or excluding a causal role of BDNF in these effects - whether BDNF mediates homeostatic upscaling or protects against over-saturation, and how peripheral (plasma/serum) BDNF relates to central BDNF activity. The source study's separate questions on assay standardization and on generalization to chronic partial sleep loss, ageing and clinical populations are outside this problem's completion boundary.

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