Reversing Pathological Neural Activity Using Targeted Plasticity

Mikell, Charles; Sisti, Michael B; McKhann, Guy M II

doi: 10.1227/
Science Times

The doctrine that the anatomic and functional structures of the nervous system are characterized by gradual change between quasi-stable states is so well accepted as to be common knowledge. At the end of the 19th century, William James described it thus in his Principles of Psychology:

“Plasticity, then, in the wide sense of the word, means the possession of a structure weak enough to yield to an influence, but strong enough not to yield all at once. Each relatively stable phase of equilibrium in such a structure is marked by what we may call a new set of habits. Organic matter, especially nervous tissue, seems endowed with a very extraordinary degree of plasticity of this sort.”1

James describes plasticity in the setting of a chapter on behavioral habits, but he may as well have been describing any number of chronic diseases characterized by misdirection of synaptic plasticity, including epilepsy, chronic pain, and tinnitus. Each of these conditions is characterized by what James would call “a stable phase of equilibrium” in nervous tissue; and because these equilibria are indeed stable, they are difficult to treat and often require lifelong therapy. However, recent advances in neuromodulation have made induction of neural plasticity a treatment for these diseases.

Tinnitus in particular is known to be characterized by altered connectivity within primary auditory cortex.2 For reasons related to decreased inhibitory function and deafferentation, large parts of the typically tonotopic auditory cortex begin to respond to the same frequencies. This is perceived by the patient as high-frequency ringing or humming, which can be quite disabling. While masking and behavioral therapies for tinnitus are available, no highly effective treatment exists.3 This is likely due to the high stability of the circuits in the auditory circuits that cause the ringing, and no current therapy has been successful in inducing plasticity in these structures.

A recent fascinating study by Engineer and colleagues published in Nature represents a major advance in this regard (Nature. Jan 12, 2011, epub ahead of print).4 While prior studies have elegantly demonstrated reinduction of plasticity, especially in ocular dominance columns,5 this work from the Kilgard Laboratory at University of Texas at Dallas is the first to use direct induction of plasticity to treat tinnitus in an animal model. Intriguingly, they used stimulation of the vagus nerve, widely used by neurosurgeons to treat epilepsy, as their method of inducing cortical plasticity. Initially, using control rats, the authors show that pairing of short trains of VNS with tones increased the areas of cortex that respond to those tones, suggesting that VNS pulses induce some sort of plastic changes in the cortex. They then showed that pairing of VNS with tones was able to reverse the process. They used a common model of tinnitus, auditory noise trauma, to cause rats to lose the ability to discriminate between high frequency tones of either 8 kHz or 10 kHz in a discrimination test. The presumption is that the intervening frequencies are filled with high-pitched noise. Pairing of VNS trains were able to reverse this failure in gap discrimination, and this improvement persisted for several weeks (Figure, A). Further, stimulation reversed noise-induced changes in the tonotopic map (eg, reversed the response of neurons to frequencies outside their conventional tuning curves) (Figure, B).

While these findings are highly intriguing, caution is merited because several rats in the control group apparently regained normal gap discrimination without treatment. In addition, longer term follow up of this type of therapy is warranted to make sure that stimulation does not induce a treatment “honeymoon” similar to that seen with many antiepileptic compounds, that the brain is subsequently able to pathologically circumvent.

A key strength of this paper, and its obvious source of interest to neurosurgeons, is its rapid potential for translation to humans. VNS Therapy (Cyberonics, Inc., Houston, Texas) is FDA-approved for the treatment of epilepsy and depression, and hundreds of devices are implanted each year. While VNS is capable of adjustment, current devices are not designed for the kind of paired-stimulus pulse trains described by Engineer and colleagues, although this does not appear to present a major technical challenge. This study also suggests that a mechanism of VNS efficacy in epilepsy and depression might relate to plasticity, rather than modulation of brainstem neurotransmitter systems. Moreover, this approach may hold promise for other diseases such as chronic pain that are characterized by a “stable phase of equilibrium”, and could potentially respond to treatment through induction of plasticity.

Charles Mikell

Michael B. Sisti

Guy M. McKhann II

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1. James W. The principles of psychology. New York: H. Holt and Company; 1890.
2. Roberts LE, Eggermont JJ, Caspary DM, Shore SE, Melcher JR, Kaltenbach JA. Ringing ears: the neuroscience of tinnitus. J Neurosci. 2010;30(45):14972-14979.
3. Seidman MD, Standring RT, Dornhoffer JL. Tinnitus: current understanding and contemporary management. Curr Opin Otolaryngol Head Neck Surg. 2010;18(5):363-368.
4. Engineer ND, Riley JR, Seale JD, et al. Reversing pathological neural activity using targeted plasticity. Nature. Jan 12 2011. Publish Ahead of Print.
5. Southwell DG, Froemke RC, Alvarez-Buylla A, Stryker MP, Gandhi SP. Cortical plasticity induced by inhibitory neuron transplantation. Science. 2010;327(5969):1145-1148.
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