High frequency stimulation (HFS) applied in the brain has been shown to be efficient for treating several brain disorders, such as Parkinson's disease and epilepsy. But the mechanisms underlying HFS are not clear. In particular, the effect of HFS on axons has been intriguing since axonal propagation plays an important role in the functional outcome of HFS. In order to study the potential effect of axonal block by HFS in-vivo, both orthodromic- and antidromic-HFS (O-HFS, A-HFS) with biphasic pulses were applied to the hippocampal CA1 region in anaesthetized rats. Changes in the amplitude and latency of orthodromic- and antidromic-population spikes within 1-min long period of stimulation at 50, 100 and 200 Hz HFS were analyzed. The results show that except for a short onset period, activity evoked by O-HFS with a frequency over 100 Hz could not be sustained. For A-HFS at frequencies over 100 Hz, the amplitudes and the latencies of antidromic population spike (APS) greatly decreased and increased respectively. Significantly larger changes in APS latency were observed in HFS than those generated at low frequency, suggesting a suppression of axon conduction by HFS. Furthermore, the CA1 somata remained excitable while failing to respond to excitation from orthodromic or antidromic HFS. Taken together, these results show that HFS produces an axonal block of both afferent and efferent fibres localized to the area of stimulation since it does not affect the excitability of CA1 somata. This effect of HFS on axons causes a functional disconnection of axonal pathways that is reversible and temporary. The reversible disconnection or temporary deafferentation between putative therapeutic targets could have extensive implication for various clinical applications of HFS to treat brain diseases.

Background The therapeutic mechanisms of deep brain stimulations (DBS) are not fully understood. Axonal block induced by high frequency stimulation (HFS) has been suggested as one possible underlying mechanism of DBS. Objective To investigate the mechanism of the generation of HFS-induced axonal block. Methods High frequency pulse trains were applied to the fiber tracts of alveus and Schaffer collaterals in the hippocampal CA1 neurons in anaesthetized rats at 50, 100 and 200 Hz. The amplitude changes of antidromic-evoked population spikes (APS) were measured to determine the degree of axonal block. The amplitude ratio of paired-pulse evoked APS was used to assess the changes of refractory period. Results There were two distinct recovery stages of axonal block following the termination of HFS. One frequency-dependent faster phase followed by another frequency-independent slower phase. Experiments with specially designed temporal patterns of stimulation showed that HFS produced an extension of the duration of axonal refractory period thereby causing a fast recovery phase of the axonal block. Thus, prolonged gaps inserted within HFS trains could eliminate the axonal block and induced large population spikes and even epileptiform activity in the upstream or downstream regions. Conclusions Extension of refractory period plays an important role on HFS induced axonal block. Stimulation pattern with properly designed pauses could be beneficial for different requirements of excitation or inhibition in DBS therapies.

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Summary:Purpose: It has been shown that a low-calcium high-potassium solution can generate ictal-like epileptiform activity in vitro and in vivo. Moreover, during status epileptiform activity, the concentration of [K + ] o increases, and the concentration of [Ca 2+ ] o decreases in brain tissue. Therefore we tested the hypothesis that long-lasting persistent spike activity, similar to one of the patterns of status epilepticus, could be generated by a high-potassium, low-calcium solution in the hippocampus in vivo.Methods: Artificial cerebrospinal fluid was perfused over the surface of the exposed left dorsal hippocampus of anesthetized rats. A stimulating electrode and a recording probe were placed in the CA1 region.Results: By elevating K + concentration from 6 to 12 mM in the perfusate solution, the typical firing pattern of low-calcium ictal bursts was transformed into persistent spike activity in the CA1 region with synaptic transmission being suppressed by calcium chelator EGTA. The activity was characterized by double spikes repeated at a frequency ∼4 Hz that could last for >1 h. The analysis of multiple unit activity showed that both elevating [K + ] o and lowering [Ca 2+ ] o decreased the inhibition period after the response of paired-pulse stimulation, indicating a suppression of the after-hyperpolarization (AHP) activity.Conclusions: These results suggest that persistent status epilepticus-like spike activity can be induced by nonsynaptic mechanisms when synaptic transmission is blocked. The unique double-spike pattern of this activity is presumably caused by higher K + concentration augmenting the frequency of typical low-calcium nonsynaptic burst activity.

It has been clearly established that nonsynaptic interactions are sufficient for generating epileptiform activity in brain slices. However, it is not known whether this type of epilepsy model can be generated in vivo. In this paper we investigate low-calcium nonsynaptic epileptiform activity in an intact hippocampus. The calcium chelator EGTA was used to lower [Ca2+]o in the hippocampus of urethane anesthetized rats. Spontaneous and evoked field potentials in CA1 pyramidal stratum and in CA1 stratum radiatum were recorded using four-channel silicon recording probes. Three different types of epileptic activity were observed while synaptic transmission was gradually blocked by a decline in hippocampal [Ca2+]o. A short latency burst, named early-burst, occurred during the early period of EGTA application. Periodic slow-waves and a long latency high-frequency burst, named late-burst, were seen after synaptic transmission was mostly blocked. Therefore these activities appear to be associated with nonsynaptic mechanisms. Moreover, the slow-waves were similar in appearance to the depolarization potential shifts in vitro with low calcium. In addition, excitatory postsynaptic amino acid antagonists could not eliminate the development of slow-waves and late-bursts. The slow-waves and late-bursts were morphologically similar to electrographic seizure activity seen in patients with temporal lobe epilepsy. These results clearly show that epileptic activity can be generated in vivo in the absence of synaptic transmission. This type of low-calcium nonsynaptic epilepsy model in an intact hippocampus could play an important role in revealing additional mechanisms of epilepsy disorders and in developing novel anti-convulsant drugs.