View brief animation explaining
how targeted plasticity can treat patients
Listen to a podcast
describing our work from Nature
Support
Basic Research to Find a Cure for Tinnitus
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
child’s eye for only a week or two will cause the brain to ignore inputs from
that eye for the rest of the child’s life.
More than five percent of the world’s 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, Alzheimer’s disease, and
Parkinson’s 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 brain’s 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. Kilgard’s 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,
www.clinicaltrials.gov
[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.
Support Basic Research to
Find a Cure for Tinnitus