Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

Thalamocortical control of propofol phase-amplitude coupling.

The anesthetic propofol elicits many different spectral properties on the EEG, including alpha oscillations (8-12 Hz), Slow Wave Oscillations (SWO, 0.1-1.5 Hz), and dose-dependent phase-amplitude coupling (PAC) between alpha and SWO. Propofol is known to increase GABAA inhibition and decrease H-current strength, but how it generates these rhythms and their interactions is still unknown. To investigate both generation of the alpha rhythm and its PAC to SWO, we simulate a Hodgkin-Huxley network model of a hyperpolarized thalamus and corticothalamic inputs. We find, for the first time, that the model thalamic network is capable of independently generating the sustained alpha seen in propofol, which may then be relayed to cortex and expressed on the EEG. This dose-dependent sustained alpha critically relies on propofol GABAA potentiation to alter the intrinsic spindling mechanisms of the thalamus. Furthermore, the H-current conductance and background excitation of these thalamic cells must be within specific ranges to exhibit any intrinsic oscillations, including sustained alpha. We also find that, under corticothalamic SWO UP and DOWN states, thalamocortical output can exhibit maximum alpha power at either the peak or trough of this SWO; this implies the thalamus may be the source of propofol-induced PAC. Hyperpolarization level is the main determinant of whether the thalamus exhibits trough-max PAC, which is associated with lower propofol dose, or peak-max PAC, associated with higher dose. These findings suggest: the thalamus generates a novel rhythm under GABAA potentiation such as under propofol, its hyperpolarization may determine whether a patient experiences trough-max or peak-max PAC, and the thalamus is a critical component of propofol-induced cortical spectral phenomena. Changes to the thalamus may be a critical part of how propofol accomplishes its effects, including unconsciousness.

Thalamic mechanisms underlying alpha-delta sleep with implications for fibromyalgia.

Alpha-delta sleep is the abnormal intrusion of alpha activity (8- to 13-Hz oscillations) into the delta activity (1- to 4-Hz oscillations) that defines slow-wave sleep. Alpha-delta sleep is especially prevalent in fibromyalgia patients, and there is evidence suggesting that the irregularities in the sleep of these patients may cause the muscle and tissue pain that characterizes the disorder. We constructed a biophysically realistic mathematical model of alpha-delta sleep. Imaging studies in fibromyalgia patients suggesting altered levels of activity in the thalamus motivated a thalamic model as the source of alpha activity. Since sodium oxybate helps to alleviate the symptoms of fibromyalgia and reduces the amount of alpha-delta sleep in fibromyalgia patients, we examined how changes in the molecular targets of sodium oxybate affected alpha-delta activity in our circuit. Our model shows how alterations in GABAB currents and two thalamic currents, Ih (a hyperpolarization-activated current) and a potassium leak current, transform a circuit that normally produces delta oscillations into one that produces alpha-delta activity. Our findings suggest that drugs that reduce Ih conductances and/or increase potassium conductances, without necessarily increasing GABAB conductances, might be sufficient to restore delta sleep. Furthermore, they suggest that delta sleep might be restored by drugs that preferentially target these currents in the thalamus; such drugs might have fewer side effects than drugs that act systemically.

Potential network mechanisms mediating electroencephalographic beta rhythm changes during propofol-induced paradoxical excitation.

Propofol, like most general anesthetic drugs, can induce both behavioral and electroencephalographic (EEG) manifestations of excitation, rather than sedation, at low doses. Neuronal excitation is unexpected in the presence of this GABA(A)-potentiating drug. We construct a series of network models to understand this paradox. Individual neurons have ion channel conductances with Hodgkin-Huxley-type formulations. Propofol increases the maximal conductance and time constant of decay of the synaptic GABA(A) current. Networks range in size from 2 to 230 neurons. Population output is measured as a function of pyramidal cell activity, with the electroencephalogram approximated by the sum of population AMPA activity between pyramidal cells. These model networks suggest propofol-induced paradoxical excitation may result from a membrane level interaction between the GABA(A) current and an intrinsic membrane slow potassium current (M-current). This membrane level interaction has consequences at the level of multicellular networks enabling a switch from baseline interneuron synchrony to propofol-induced interneuron antisynchrony. Large network models reproduce the clinical EEG changes characteristic of propofol-induced paradoxical excitation. The EEG changes coincide with the emergence of antisynchronous interneuron clusters in the model networks. Our findings suggest interneuron antisynchrony as a potential network mechanism underlying the generation of propofol-induced paradoxical excitation. As correlates of behavioral phenomenology, these networks may refine our understanding of the specific behavioral states associated with general anesthesia.