In 1890 William James defined the term ‘Plasticity’ as, “The possession of a structure weak enough to yield to an influence, but strong enough not to yield all at once.” As with all things in life, plasticity is something we need our brains to have, but in moderation. Plasticity enables us to learn new skills and adapt to new environments. On a neurological level it is what enables a healthy/typically developing brain to strengthen and weaken connections between regions and develop networks to enable us to synthesize complex pieces of information into coordinated thoughts and behaviors. This strengthening and weakening of connections is a highly regulated process that involves mechanisms that promote change and mechanisms that keep these changes in check such that it is not an “all or nothing.” These feedback systems avoid a situation whereby neural networks are pushed too far too fast such that certain brain regions or networks are always active and others are always suppressed.
So what happens when these plasticity mechanisms go awry? Are there ways to bring the brain back into balance? As you may expect since the mechanisms of plasticity are highly regulated and critically involved in the functioning of the brain, imbalance in either direction leads to brain network dysfunction, which in turn often manifests as mental or behavioral disorders. The specific behavioral domain that is affected depends on when, where, and which form of plasticity is aberrant.
One example of a disorder that has been conceived of as a resulting from aberrant plasticity is Autism Spectrum Disorder (ASD). Despite the clear variability at the behavioral level and the multiple potential causal mechanisms, one very consistent finding is that of disordered network connectivity. I have often used the analogy of the autistic brain as similar to a city built with a whole lot of side roads, but few highways. If you want to get from point A to point B, there are likely multiple different paths you could take but you’ll probably have to go through H, R, and S or perhaps M, F, and Y before you can get to B in the brain of an individual with ASD. In that way, the process may take longer and be more complex, and perhaps you may get lost, but that is how the brain of someone with ASD is set up. At a neural level, we believe this is due to reduced capacity for homeostatic plasticity (the regulatory breaks in the system) during early postnatal neurodevelopment. Each time the child experiences something new a new connection is forged rather than stabilizing the existing one. Due to the timing of this dysfunction in homeostatic plasticity (during the first years of life) and the natural course of neural development, the networks responsible for higher-level cognitive processing including language production and social skills are the most affected.
A disorder that represents both the other end of the age-span as well as the other side of this double edged sword of brain plasticity is Alzheimer’s Disease (AD). In AD the brain loses its capacity to learn new skills and adapt to new environments. On a neural level, this impaired excitatory plasticity is thought to be a result of a build up of toxic forms of the amyloid ß (Aβ) protein initially in the medial temporal lobe of the brain, a critical region for memory encoding then spreading to the entire brain in the late stages. Though we all have age-related changes in plasticity, those with AD are on a steeper curve due to the Aβ “clogging up” the synapse (connection between neurons). An interesting “silver lining” so to speak exists in terms of the relationship between ASD and AD. As ASD and AD are characterized by opposite pathologies in terms of plasticity, we have suggested and have preliminary data to support the idea that those with ASD are relatively protected against developing AD since their natural trajectory starts out at a higher baseline level.
A third example of a condition that may have its origin in aberrant plasticity is chronic pain following traumatic injury. When someone experiences an injury, pain receptors at the site of injury become overly activated due to local inflammation. This local short-lasting overactivation leads to a corresponding “wind-up” in synaptic plasticity in the spinal cord and release of excitatory neurotransmitters in the brain. When this process does not resolve right away, such as in the case of chronic pain conditions, ongoing excitatory neurotransmitter release leads to a state of maladaptive plasticity that facilitates neuronal pain transmission which underlies and perpetuates the experience of chronic pain.
So, what do these three conditions have in common, besides being based in maladaptive neural plasticity? All of the above conditions are potentially amenable to transcranial magnetic stimulation (TMS) therapeutic interventions. TMS works via modulation of neural plasticity. Different TMS protocols have been shown to affect specific neurotransmitter systems, namely excitatory NMDA receptor activity and inhibitory GABA receptor activity. By modulating these key neurotransmitters, TMS can lead to network-wide changes in how the brain responds to stimuli (social, environmental, pain, new information, etc.). Animal work also suggests that TMS may also reduce neuroinflammation (present in both chronic pain as well as AD) by modulating cells called astrocytes and microglia. These cells become hyperactive in chronic pain and AD leading to neuroinflammation and further exacerbation of the symptoms. Thus, TMS may be able to reestablish brain plasticity equilibrium in the context of developmental, age-related, or injury-related pathological processes. Clinical trials are currently underway to evaluate the true potential of TMS for the treatment of each of these disorders.