Reversing pathological neural activity using targeted plasticity

Cortical Plasticity Laboratory, Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, Texas 75080, USA.
Nature (Impact Factor: 41.46). 02/2011; 470(7332):101-4. DOI: 10.1038/nature09656
Source: PubMed


Brain changes in response to nerve damage or cochlear trauma can generate pathological neural activity that is believed to be responsible for many types of chronic pain and tinnitus. Several studies have reported that the severity of chronic pain and tinnitus is correlated with the degree of map reorganization in somatosensory and auditory cortex, respectively. Direct electrical or transcranial magnetic stimulation of sensory cortex can temporarily disrupt these phantom sensations. However, there is as yet no direct evidence for a causal role of plasticity in the generation of pain or tinnitus. Here we report evidence that reversing the brain changes responsible can eliminate the perceptual impairment in an animal model of noise-induced tinnitus. Exposure to intense noise degrades the frequency tuning of auditory cortex neurons and increases cortical synchronization. Repeatedly pairing tones with brief pulses of vagus nerve stimulation completely eliminated the physiological and behavioural correlates of tinnitus in noise-exposed rats. These improvements persisted for weeks after the end of therapy. This method for restoring neural activity to normal may be applicable to a variety of neurological disorders.

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    • "Previous studies [21] [22] used a reduction in cortical EEG power during slow wave sleep to assess effective delivery of VNS in rats. In a first experiment, we examined whether hippocampal EEG during the awake state can also be used to assess effective VNS delivery. "
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    ABSTRACT: Background: Vagus Nerve Stimulation (VNS) has seizure-suppressing effects but the underlying mechanism is not fully understood. To further elucidate the mechanisms underlying VNS-induced seizure suppression at a neurophysiological level, the present study examined effects of VNS on hippocampal excitability using dentate gyrus evoked potentials (EPs) and hippocampal electroencephalography (EEG). Methods: Male Sprague-Dawley rats were implanted with a VNS electrode around the left vagus nerve. A bipolar stimulation electrode was implanted in the left perforant path and a bipolar recording electrode was implanted in the left dentate gyrus for EEG and dentate field EP recording. Following recovery, VNS was applied in freely moving animals, using a duty cycle of 7 s on/18 s off, 30 Hz frequency, 250 µs pulse width, and an intensity of either 0 (SHAM), 25 µA or 1000 µA, while continuously monitoring EEG and dentate field EPs. Results: VNS at 1000 µA modulated dentate field EPs by decreasing the field excitatory post-synaptic potential (fEPSP) slope and increasing the latency and amplitude of the population spike. It additionally influenced hippocampal EEG by slowing theta rhythm from 7 Hz to 5 Hz and reducing theta peak and gamma band power. No effects were observed in the SHAM or 25 µA VNS conditions. Conclusion: VNS modulated hippocampal excitability of freely moving rats in a complex way. It decreased synaptic efficacy, reflected by decreased fEPSP slope and EEG power, but it simultaneously facilitated dentate granule cell discharge indicating depolarization of dentate granule cells.
    Brain Stimulation 09/2015; DOI:10.1016/j.brs.2015.09.009 · 4.40 Impact Factor
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    • "In several cases, these findings have led to ongoing clinical trials. For example, a recent study on the role of vagus nerve stimulation paired with tones for treating tinnitus was based on the gap detection paradigm in rats (Engineer et al., 2011) and is currently under clinical trial. Our studies, which also utilized the gap detection paradigm, revealed a novel KCNQ2/3 channel activator as a clinical candidate for preventing tinnitus (Kalappa et al., 2015). "
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    ABSTRACT: Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in DCN fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus.
    eLife Sciences 08/2015; 4. DOI:10.7554/eLife.07242 · 9.32 Impact Factor
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    • "This included reversal of increased neural synchrony in the primary auditory cortex. Acoustic stimuli were necessary to target neural populations within the auditory cortex, but VNS was concluded essential to promoting plastic change through a "synergistic action of multiple neuromodulators" (Engineer 2011), with a likely significant role for acetylcholine (Engineer 2013). Acoustic stimulation or VNS alone were insufficient for these changes to occur. "

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