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Externally Directed Neural Plasticity for the Treatment of Neurological Disease

All levels of the nervous system can change in response to new experiences or injury.This capacity for change is called neural plasticity[1].Neural plasticity in response to new experiences provides the biological basis for all of our skills and memories.

Learning and memory are critical for survival and evolution has fine-tuned the chemistry, architecture, and dynamics of our brains to precisely regulate neural plasticity.Even millisecond differences in the relative timing of a few nerve impulses can mean the difference between a 50% increase and a 50% decrease in the strength of individual synapses[2].To function properly, different brain regions (and even different synapses on the same neuron) must exhibit slightly different forms of these highly precise learning rules.Unfortunately by optimizing our brains for learning, evolution has left us vulnerable to pathological forms of plasticity in the event of nervous system damage or genetic defect[3].

The Nobel Prize winning work of Hubel and Wiesel refuted the notion that the brain is hard-wired and provided the first evidence that relatively minor insults can trigger devastating plasticity that causes lifelong disability[4].An insult that interferes with vision in a childís eye for only a week or two will cause the brain to ignore inputs from that eye for the rest of the childís life.More than five percent of the worldís population is amblyopic due to this pathological plasticity.Back strains and hearing damage can trigger plasticity that patients perceive as chronic pain or disturbing sound (tinnitus).Like amblyopia, these disabling conditions can persist for decades after the initial injury.Neuroscientists are just beginning to understand the nature of the brain changes that contribute to the progression of other neurological and psychiatric conditions, such as stroke, traumatic brain injury, autism, schizophrenia, Alzheimerís disease, and Parkinsonís disease.

A great deal of research has gone into identifying drugs to treat brain disorders.†† Although we now have drugs that reduce some of the symptoms of brain disease, drugs are not effective at restoring normal function.Surgical approaches have also met with limited success in treating the brain.With hundreds of millions of synapses in every cubic millimeter of brain tissue[5], it should not be surprising that both drugs and surgery lack the precision needed to repair damaged circuits.We need a new better targeted approach to treating brain disease.

The optimal method would allow physicians to precisely target changes in specific neural circuits with millisecond and micrometer precision.In 1998, Dr. Michael Kilgard demonstrated that it is possible to rewire neurons in the auditory cortex in a precise and long-lasting manner[6].The method involves repeatedly pairing tones with precisely timed electrical activation of neurons in the basal forebrain that release the neurotransmitter acetylcholine.Dr. Kilgard subsequently showed that this method could be used to generate every known form of plasticity by pairing different sounds with the same precisely timed electrical stimulation.The brief period of acetylcholine release opens up a brief period during which circuits in the adult brain can be changed as needed.The nature of the changes depends on the pattern of activity triggered by different sounds.Pairing rapid trains of sounds with stimulation was sufficient to increase the rate at which the brain processes information and pairing slow trains decreased the brainís processing speed[7].Pairing other sounds can be used to increase or decrease the sensitivity and selectivity of auditory cortex neurons[8].It is even possible to create neurons that are selective to specific sequences of sounds[9].Although in principle stimulation of the basal forebrain could be used to reverse pathological plasticity associated with human disease, it is impractical to implant stimulating electrodes deep in the brain of patients with neurological or psychiatric disease[10].

Dr. Kilgardís laboratory has recently developed a new method to direct plasticity using brief periods of vagus nerve stimulation instead of deep brain stimulation.Pairing vagus nerve stimulation with different sounds is sufficient to generate highly reliable changes in the way auditory cortex neurons process spectral information and temporal information.This new method may prove useful in directing therapeutic neural plasticity in patients without the need for invasive brain surgery[11].No significant side effects are expected because this method uses precisely timed stimulation requiring fifty times less vagus nerve stimulation than currently used to treat intractable epilepsy.

Pairing brief periods of vagus nerve stimulation with tones has been shown to be effective in reversing tinnitus (and the pathological plasticity that causes it) in rats with noise induced hearing loss[12].Ongoing studies are testing the efficacy of brief episodes of VNS in improving sensory discrimination and motor performance in animal models of neurological disease.It may soon be possible to direct highly specific of neural plasticity to restore normal function to abnormal brain circuits[13].


[1] Cortical plasticity: from synapses to maps Buonomano and Merzenich, Annual Review of Neuroscience, 1998; Homeostatic plasticity in neuronal networks: the more things change, the more they stay the same Turrigiano, Trends in Neurosciences, 1999.

[2] Spike timing-dependent plasticity: from synapse to perception Dan and Poo, Physiological reviews, 2006

[3] Neural plasticity and disorders of the nervous system, Moller, 2006

[4] Plasticity of ocular dominance columns in monkey striate cortex, Hubel, Wiesel, LeVay, 1977

[5] Principles of neural science Kandel, Schwartz, Jessell, 2000

[6] Nucleus Basalis Activity Enables Cortical Map Reorganization, Kilgard and Merzenich, Science, 1998.

[7] Plasticity of Temporal Information Processing in the Primary Auditory Cortex, Kilgard and Merzenich, Nature Neuroscience, 1998.

[8] Cortical Network Reorganization Guided by Sensory Input Features, Kilgard, Pandya, Engineer, Moucha, Biological Cybernetics, 2002.

[9] Order Sensitive Plasticity in Adult Primary Auditory Cortex, Kilgard and Merzenich, Proceeding of the National Academy of Sciences, 2002.

[10] Cortical Plasticity and Rehabilitation. Moucha and Kilgard, Progress in Brain Research, 2006.

[11] A Proof-of-Concept Pilot Study Assessing Vagus Nerve Stimulation (VNS) Paired With Tones for Tinnitus,

[12] Reversing pathological neural activity using targeted plasticity. Engineer ND, Riley JR, Seale JD, Vrana WA, Shetake JA, Sudanagunta SP, Borland MS, Kilgard MP. Nature. 2011 Feb 3;470(7332):101-4.

[13] Harnessing plasticity to reset dysfunctional neurons. Lozano AM. New England Journal of Medicine. 2011 Apr 7;364(14):1367-8.


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