Low-frequency stimulation

The slow (deep sleep) -waves probably originate in the eortex beeause they survive separation from, or lesions of, the thalamus. However, the rhythm and appearanee of spindles in earlier phases of the sleep eyele do depend on links with the thalamus (see Steriade 1999). Unlike stimulation of the specific sensory relay nuclei in the thalamus, which only affects neurons in the appropriate sensory areas of the cortex, the nonspecific nuclei can produce responses throughout the cortex and may not only control, but also generate, cortical activity. Certainly, in vitro studies show that neurons of the non-specific reticular thalamic nucleus (NspRTN) can fire spontaneously at about 8-12 Hz (equivalent to EEG a-rhythm) or lower, and that low-frequency stimulation of this area can induce sleep. 

Administration of HA and its effect on sleep-wakefulness Local application of HA (5, 30 and 60 pg) in the TMN region of cats increased the latency to sleep, increased arousal, and reduced NREM sleep in a site-specific, dose-dependent manner. The highest dose produced the maximal effect, which lasted for 6 h. The HA-induced arousal was completely blocked when the cats were pretreated intraperitoneally with the Hi receptor antagonist mepyramine (Lin et at, 1986, 1988). In rats, intraventricular administration of HA blocked the increase in delta and theta activity (0-6 Hz) in the EEG induced by repeated low-frequency stimulation of the midbrain reticular formation. This effect was blocked if specific thalamic nuclei were lesioned (Tasaka et at, 1993) or by simultaneous administration of an Hi receptor antagonist, but not by an H2 receptor antagonist (Tasaka et at, 1989). Application of HA... 

In contrast to LTP, LTD is induced by low-frequency stimulation. This causes the selective activation of PP2B (calcineurin), which maintains inhibitor-1 in its dephos-phorylated state. Several studies, including those using inhibitor-1 knockout mice and transgenic mice expressing a constitutively active form of inhibitor-1, demonstrate that the control of PP1 activity by inhibitor-1 in the hippocampus affects neuronal plasticity and learning and memory. 

Thus, the mechanistic properties of the NMDA receptor can help account for the properties of temporal specificity, cooperativity, and associativity of LTP. They can also explain why both high-frequency stimulation (100 Hz) and pairing low-frequency stimulation with postsynaptic depolarization can induce LTP. The occurrence of presynaptic activity followed by postsynaptic activity determines a temporal sequence and specificity. To generate sufficient depolarization in the postsynaptic cell to expel Mg2+ from NMDAR channels usually requires cooperative depolarization at many synapses. Moreover, the requirement of postsynaptic depolarization also underlies associativity since the depolarization caused by the strongly activated synapses can relieve the Mg2+ blockade of the NMDA receptors on weakly activated synapses. 

B. Long-term potentiation in the dentate gyrus recorded in vivo. The graph plots the early rising slope of the field excitatory postsynaptic potential (EPSP) in response to low frequency stimulation (700 pA, 100 ms, 0.05 Hz). Four trains of high frequency stimulation (700 pA, 82.5 ms, 400 Hz) were dehvered at time 0. This produced an immediate increase in the EPSP slope (post-tetanic potentiation) and a sustained relatively constant enhancement that lasted for at least 60 minutes. Representative traces are included below the graph. Note the obvious increase in size of the superimposed population spike (downward deflection). 

Pre-clinical work and neuroimaging suggest potential frequency-dependent effects of rTMS. Thus, higher frequencies may increase while lower frequencies may decrease brain metabolism (205). Clinically, repetitive, high frequency stimulation (i.e., >1 Hz or HF-rTMS) and repetitive, low frequency stimulation (i.e., 1 Hz or SF-rTMS), have been used. 

Cunha RA, Johansson B, Constantino MD, Sebastiao AM, Fredholm BB (1996a) Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H] CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors. Naunyn Schmiedebergs Arch Pharmacol 353(3) 261-271 Cunha RA, Vizi ES, Ribeiro JA, Sebastiao AM (1996b) Preferential release of ATP and its extracellular catabolism as a source of adenosine upon high- but not low-frequency stimulation of rat hippocampal slices. J Neurochem 67(5) 2180—2187 de Mendonca A, Sebastiao AM, Ribeiro JA (1995) Inhibition of NMDA receptor-mediated currents in isolated rat hippocampal neurones by adenosine A1 receptor activation. Neuroreport 6(8) 1097-1100... 

In wild-type atrial preparations, increasing concentrations of the nonselective a2-AR agonist UK-14,304 dose dependently inhibited electrically-stimulated [3H]norepinephrine release (21). Consistent with previous studies, a2A-AR ablation did not completely attenuate the effects of UK-14,304 in suppressing [3H]norepinephrine release. In contrast, atrial preparations derived from o ac-AR 7 mice were completely unresponsive to UK-14,304 in this functional assay. Additional studies revealed that the o a-AR and o c-AR subtypes serve distinct roles in the regulation of neurotransmitter release (Table 1). Frequency inhibition studies showed that the a2C-AR is fine-tuned to respond to low-frequency stimulation (i.e., low norepinephrine concentrations), whereas the o a-AR is geared to respond to high-frequency stimulation (i.e., high norepinephrine concentrations as would be elicited by sympathetic activation). 

The activation of vesicle recycling in the above experiments was associated with a massive accumulation of clathrin-coated pits in the plasma membrane around active zones (Fig. 7B). At early times (10-20 s) after addition of Ca +, early stages of coated pits (i.e. shallow coated pits) were relatively more abundant, whereas at later times (2 min), late stages (i.e. invaginated coated pits with narrow necks) predominated. Synaptic vesicle recycling under conditions of low-frequency stimulation also appears to be predominantly or exclusively mediated by clathrin-mediated endocytosis. In axons maintained at rest, clathrin-coated pits... 

In the nucleus accumbens immunocytochemical labelling shows that, in contrast to the hippocampus, CBi receptors are located on glutamatergic nerve terminals (Robbe et al. 2001). In a mouse brain slice preparation, low-frequency stimulation (13 Hz for 10 min) evoked LTD of field EPSPs or EPSCs recorded in the nucleus accumbens (Robbe et al. 2002,2003). This LTD apparently depended on the activity of endocannabinoids, since it was occluded by 0.3 pM WIN55,212-2, blocked by 0.1-1 pM rimonabant or 2 pM AM251, and critically, it was absent in CBr " mice. While the use of CBr " mice shows that CBi receptors are essential for this form of synaptic plasticity in the nucleus accumbens, the cannabinoid ligands were not tested in CBr " animals, and so although it is likely, it is not certain that they produced their effects via the CBi receptor. In a similar study, low-frequency stimulation (10 Hz for 5 min) induced LTD of the population spike recorded in... 

In slices of rat cerebellum, LTD of parallel fibre inputs to Purkinje cells can be induced by pairing low-frequency stimulation (1 Hz for 5 min) with post-synaptic depolarisation. Both WIN55, 212-2 (1 pM) and CP55,940 (400 nM) reduced the EPSC by about 50%, and impaired the induction of LTD, an effect which was blocked by rimonabant (1 pM) (Levenes et al. 1998). In this pathway, therefore, it appears that cannabinoid effects on synaptic plasticity may be secondary to changes in baseline responses. 

At the neuromuscular junction, nicotinic function is enhanced by inhibition of AChE. However, unlike muscle nAChRs, some neuronal nAChRs, particularly those bearing the a7 subunit, recognize both acetylcholine and its metabolite choline as full agonists (Pereira et al., 2002). Therefore, cholinesterase inhibition may not necessarily enhance functions mediated by these nAChRs. In fact, cholinesterase inhibitors do not affect a7 nAChR-mediated synaptic transmission evoked by low-frequency stimulation of cholinergic fibers in chick cUiary ganglia (Zhang et al., 1996). 

Weiss, S.B.R., Li, X.L., Rosen, J.B., Li, H., and Heynen, T. Post RM. Quenching inhibition of development and expression of amygdale kindled seizures with low frequency stimulation. Neuroreport 1995,4 2171. 

Long-term potentiation is considered to be an experimental model of memory at the cellular level. In the CA] region of the hippocampus, a low frequency stimulation frees glutamate which, by activating the AMPA receptors leads to sodium influx and production of a post-synaptic potential of a certain amplitude. Under these conditions, the NMDA receptor is inactivated, blocked by Mg" " ions. 

Wildsmith JAW, Brown DT, Paul D, Johnson S. Structure-activity relationships in differential nerve block at high and low frequency stimulation. Br J Anaesth 1989 63 444-452. 

Figure 8.9 Pressure sensation vs driving voltage of low-frequency stimulation for SA I.

Nuhr MJ, Pette D, Berger R, et al. Beneficial effects of chronic low-frequency stimulation of thigh muscles in patients with advanced chronic heart failure. Eur Heart J 2004 25 136-143. 

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