applied Neural PLasticity & dynamics

The brain has the amazing ability to change and rewire itself.

Lets use that as a tool and basis for treatment.

The 3 ‘L’s of plasticity

(Plus one)

For the most part, neurons communicate with each other across small gaps called synapses. The sending neuron expels small molecules, neurotransmitters, into this small gap. These neurotransmitters are then picked up by special receptors on the receiving neuron.  In most cases, it takes numerous synapses onto a receiving neuron to make that neuron reach a threshold of inputs and send out its own message to the next neuron in the chain of neurons. This is the one of the key principles of plasticity — these connections change!  While growing new neurons is fairly restricted, the changes in connectivity between neurons is almost limitless. These synapses can become stronger (LTP) or weaker (LTD), and new synapses can be created or existing connections eliminated. These changes are what make lasting changes in how we react and act.

First the 3 Ls, then more about making and losing synapses:

 

1) Long Term Potentiation (LTP)

LTP is a well described process in neurons, and the basis of our understanding of learning. The principle is fairly simple—with certain types of activity happening together, the ability of the sender neurons to push the receiving neuron to fire off its message is increased. This either happens through increasing how sensitive the receiving side of the synapse is through the creation of more receptors for the signal, and can also include making the area between the neurons (the synapse) larger to make room for more receptors. (Also see about synaptogenesis below!)

In this case, the changes are also relatively permanent. There are cases of the strength across a synapse temporally increasing, called short term potentiation, a process that may be involved in short term memory and  what is called working memory—things that you need to temporarily hold in memory, but don’t need to store for more than a few moments.

Many are looking at this process for the answer to addiction and perseverative behaviors. That is both good and bad. Increasing the power of neurons in the flexible system is a key to gaining back cognitive flexibility. However, also making the habitual system stronger doesn’t alter the balance between the systems and may just work to more highly ingrain perseverative behavior! Recently ‘super learner’ mice have been created by over expressing a certain protein in one of the receptors that aids in making the LTP permanent. However, others are showing that drugs of abuse can also increase how much of this protein gets made. There are also pharmaceutical that are ’cognitive enhancing’ in that they accelerate how quickly and permanently animals learn. As in both cases these changes are universal,  cognitive acquisition is helped, but at a cost of cognitive flexibility, as the animal’s ability to alter the learned behavior is lessened. Sounds much the same as addiction to me.  We need to use this knowledge, but in a way that helps restore cognitive flexibility!

 

2) Long Term Depression

This process is similar to LTP above, except that the direction of change is the opposite. Depending on how signals get sent to a neuron, a synapse can be made LESS sensitive, so the volume the receiver hears is much less. It is a way of turning down a  signal that is not productive or that is disruptive.

This process may be part of the reason that the flexible system loses its ability to over-ride the habitual system that allows perseverative behaviors to dominate: The connections from the flexible system to the behavioral gate have undergone LTD. (also see dendritic pruning below!)

This area has seen very little interest, but could be very important, particularly give depotentiation below.

 

3) Depotentiation

Once a neurons synapses have undergone LTP or LTD, that isn’t necessarily the end of the story. Remember the brain is AMAZINGLY plastic! If signal are transmitted in a specific way between neurons that have undergone LTP or LTD, that signal can reset that neuron back towards a more neutral strength.  It is the brain’s way of saying “hey—wait a minute, I think we missed something! Lets reset and see if the connections are still correct.”

Remember that ‘super learner’ protein above? Turns out that when that protein gets stuck into receptors in a synapse, that synapse is HIGHLY resistant to depotentiation. Super learning, but loss of cognitive flexibility as if a synapse undergoes LTP with too much of that protein around, that synapse doesn’t want to change again. And so you start to get behaviors that can’t be altered, as the wiring is too resistant to adapting to new input.

While this has been researched from cognitive enhancement and promoting of LTP discussed above, little has been done regarding how to facilitate depotentiation of these stuck synapses.

 

Remodeling

One more aspect of plasticity, on a larger scale. The brain doesn’t just change strength of existing connections between neurons, but is also very capable of making new connections (synaptogenesis) and of pruning away existing connections (deafferentation). This is the type of plasticity relied on in treating stroke and brain injury, and is also seen with loss of extremities.

For stroke and brain injuries, it is applied in therapy designed to make the brain alter its structure and start using still healthy areas to  take over for the missing or injured areas. With loss of extremities,  the opposite happens, the healthy areas that used to interact with that extremity no longer get or give signals, and so the adjoining areas start taking over those areas and get used for other extremities.

Both stress and drugs of abuse have been shown to cause this deafferentation in flexible memory systems, decreasing how powerful and how effective this system is. This is also particularly critical in the hippocampus, where these losses occur primarily in the parts that are needed for detecting changes in the outside world, while it leaves the output of the hippocampus mostly intact. How can you change your behavior if it doesn’t detect the need to change at this very low level of processing?

We know from work with stroke and brain injury patients that we can drive reafferentation and synaptogenesis.

We are also currently using this plasticity to help prevent and reverse aging related cognitive decline , so why aren’t we looking for ways to do the same with addiction and perseverative behavior patients?

Get these structure back to where they can detect the errors and send signals that the behavior needs to be changed and restore cognitive flexibility. 

Neural plasticity is much like recycling. Neurons in a healthy brain are in a constant state of recycling, reusing, and reorganizing themselves.

The problem is when the neurons get stuck and can’t change themselves, or get weak and fall out of the cycle completely.

Cognitive flexibility relies on 3 ‘l’s:

 

1) Long Term Potentiation (LTP)

2) Long Term depression (LTD)

3) Depotentiation of LTP and LTD

 

Plus remodeling…