You have posed a very broad series of questions---the regulation of both DA and 5-HT is governed by a number of complex mechanisms, including synthesis, reuptake, autoreceptors, etc. How stimulation effects any or all of these mechanisms long-term is certainly an interesting question, although I don't know to what extent it's been addressed. Certainly, there is a wealth of published literature (in animal models) looking at both DA and 5-HT release, as well as regulatory mechanisms for storage/synthesis, etc. The following articles might at least point you in the right direction:

http://www.ncbi.nlm.nih.gov/pubmed/20723248

http://www.ncbi.nlm.nih.gov/pubmed/22778401

Dr. Hoffman.

Thanks for your comments and articles.

At least in the case of Deep Brain Stimulation (DBS), the axonal pre-synaptic terminal has the lowest threshold to activation and consequently can drive synaptic release of neurotransmitters. However, it is important to realize that the same action potential in the presynaptic terminal that causes the release of neurotransmitters simultaneously is antidrormically conducted to the cell body from which the axon arose. Further, the antidromic potential also can branch to an axon collateral in an orthodromic manner. Hence, the effects of electrical stimulation are propagated widely. Thus, it would be a mistake to interpret the effects of brain stimulation as in the case of DBS, to the structure in which the electrical contacts are located. Indeed, there is evidence the therapeutic effects of DBS in the subthalamic nucleus (STN) has little to do with stimulation of neurons in the STN but rather stimulation of the axons passing to or through the STN. It also is important to recognize that information in the brain is processed and transmitted electrically. Thus, it is the pattern of electrical activity that determines function. To focus on neurotransmitters is like focusing on electrons in a computer. Certainly a computer cannot function without electrons but there is nothing inherent in an electron that determines the functions of the computer.

Hello Erwin, Thanks so much for your wonderful comments on how deep brain stimulation works. As you said its not necessary that we see the direct effect of electrical stimulation at the same site rather it can have a significant effects on axonal projections from the stimulation site (as in case of subthalamic nucleus). So do we need to know and control the flow of information that which way it have to travel after stimulation, or we do not care about that as long as the simulation has the therapeutic effect? Also I partially agree with you that information in the brain processed and transmitted electrically from soma to end of the axonal sites. But after reaching the axons from the cell body, how this electrically transmitted information crosses the synapse between two neurons. Is this electrical information convert into the chemical information and than again change back in electrical form to travel further? We know that Arvid Carlsson,s work on chemical neurotransmission in brain gives us an break through and insight to understand the involvement of different neurotransmitters in pathological state of brain and how we can modulate the brain function by just alteration of these chemicals. It may be possible that electrical stimulation for the movement disorders and psychological disorders (Prof. Meyberg has shown that stimulating the brodmann area 25 serves therapeutic site for depression patients) as works on the same principle, but is there a different mechanism involved when we stimulate the brain for these two different reasons? It would be very helpful to understand the neural network involved in different pathological conditions of the brain if we know how to control the flow for information by any means of stimulation.

Thanks so much!!

First, it is important to understand what is the nature of "information" and the time scales over which information operates. There have been remarkable conceptual advances in understanding of information ranging from Shannon's Information theory to the Second Law of Thermodynamics. Information at its basic is a non-random transition between states and the rate of change in states determines the dynamics, bandwidth or time-scale of the information.

Consider the example of Morse Code whose information is conveyed as a sequence of dots and dashes (plus the intervening null state that separates the dots and dashes). If the key is held down constantly, then no information is conveyed. There is no non-random state transitions.\

Next consider Morse Code where a dot is realized by a key depression lasting 2 hour, the dash, a key depression lasting 3 hours, and the intervening null state lasting 1 hour. As can be appreciated, this would be an very ineffectual way to convey information because of the very slow time scale and dynamics.

The dynamics or time scales of the information has to be appropriate to the time-scales or dynamics of the purpose to which the information is to be applied. Consider a simple reaction time task. One sees a cup about to spill and quickly reaches for the cup. The reaction time is on the order of 80 ms or 8 100th of a second. Next consider the wide range of neural structures and the enormous number of neurons that participate during the 80 ms. Even in Parkinson's disease, similar reaction times are on the order of 100 to 150 ms. Can pharmacologically administered levodopa which has a plasma half-life of 90 minutes replicate the temporarily dynamics required of information processing within the 150 ms reaction time? Clearly not.

The only situation in which pharmacologically administered levodopa could be considered approximating the normal physiological role of dopamine is if one believes that the temporal dynamics of dopamine function in the brain corresponds to the nearly static or steady state associated with pharmacologically administered levodopa.

In fact, what was described above is exactly the case. The dynamics of the basal ganglia are thought be static, that is allow or not allow a movement. This clearly underestimates the contribution of the basal ganglia to the dynamics of movement (if interested, you can read my chapter on neurophysiology from the latest (5th edition?) of the Handbook of Parkinson's disease edited by Pahwa and Lyons)..

The dynamics of the current concepts of basal ganglia physiology and pathophysiology can be described as one-dimensional push-pull systems and I would argue, clearly inappropriate. However, the question arises how did such one-dimensional push-pull dynamics become so commonplace. Note theories of psychiatric disorders similarly couched in terms of relative excess of deficiencies of various neurotransmitters share this same one-dimensional push-pull dynamics.

The answer is routed in our history dating back to Aristotle's notion of contraries that were extrapolated to Galen's notion of the humors (to see the inheritance of Galen on modern psychiatry see Passions and Tempers: A History of the Humours by Noga Arikha). Then there is the notion of neurological symptoms as relative excess or loss of functions by Hughlings Jacksno. All of these can be seen as one-dimensional push-pull systems.

Next consider the number of possible behaviors which effectively are nearly infinite. Are there enough neurotransmitters to encode al the possible behaviors? Consider the situation of 20 neurotransmitters of which any 5 are operating in a specific region of the brain. The number of possible combinations (without repetition which is appropriate to one-dimensional system) would b 1860480 or far less than the number of behaviors possible. Consequently, it is impossible for such a system to encode all the behaviors an organism is capable off. Hence there cannot be any one-to-one correspondence between a set of neurotransmitters and a specific behavior. In other words, there must be some other source of information that allows for the specific encoding of the necessary information.

Consider what happens when repetition is allowed. The number of possible combinations becomes 3200000. Consider next if the number of transmitters can be repeatedly selected for a total of 20 selections, the number of combinations becomes 9.53674316e+13 or 95 followed by 16 zeros. Thus, the ability to repeatedly apply neurotransmitters in specific orders greatly increases the number of states and hence information. The conclusion is that the information is encoded not in a specific neurotransmitter by the number of times a neurotransmitter is applied and the order in which the various neurotransmitters available are applied.

The critical question is what controls the timing and order of neurotransmitter application? Clearly, it is not the nature of the neurotransmitter itself. The only answer is the precise electronic processing of information in the pre-synaptic and post-synaptic electrical potentials. The temporal dynamics of such electronic processing comports with the necessary time scale of the dynamics of behavior.

An alternative conceptualization of the basal ganglia-thalamic-cortical system (and perhaps other regions of the nervous system) is one of a large complex network of loosely coupled reentrant non-linear oscillators that self-organize. The various size oscillators provide the bandwidth necessary for processing information at the appropriate time scales. Further, the system can self-organize into meta-stable states that persist on longer time scales, perhaps providing a bias for a particular type of processing. There is considerable empiric evidence to support this notion.

For example, is has been demonstrated that an immediate past visual experience establishes ongoing activity that reflects the past experience and thus, facilitates re-experiencing. Also, mentally rehearsing a motor act facilitates actual performance.

The theory is that the basal ganglia-thalamic-cortical system of oscillators are able to process information and establish meta-stable states through processes such as negative and positive resonance, beat interactions, and simultaneous transmission and processing of multiple streams of information based on non-commensurate oscillator carrier functions. These same processes can create differing meta-stable states that may confer some bias towards specific manners of information processing.

It may be the meta-stable bias that may account for the longer timescale behaviors such as depression etc. It may well be that psychotropic agents exert their longer timescale properties via this bias on information processing. However, it would be a mistake to equate the biasing towards information processing with the information itself.

One might argue that DBS is "dumb" in that it provides only a single frequency of stimulation, analogous to only a series of dots in Morse code which would not convey information. That is true, however, the sequence of pulses (or dots) has a specific frequency that can affect the oscillations within the basal ganglia-thalamic-cortical system by resonance. The resonance would amplify the signal (information)-to-noise ratio just as the oscillator in a AM radio selects a specific radio station (amplifies that signal above all others that would be considered noise).

Finally, while it is important that DBS works, most are not satisfied with that fact. If everyone was, then most would have to accept Freudian psychology at least for neuroses as it appears to work. Further, it advance medical care it is important to understand how DBS works so it can be made to work better for more disorders.

This is a simple and very good answer, and my personal answer is: We don´t know. It is intringuing how deep brain stimulation (DBS) is so effective in Parkinson´s disease….dystonia and other conditions. First it was suggested that DBS might be acting by releasing dopamine….but this is not clear at all. DBS can be excitatory and inhibitory…at the same time depending on what structure is involved (soma or axon) (see Satomi Chiken and Atsushi Nambu  Disrupting neuronal transmission: mechanism of DBS? Frontiers in systems Neuroscience 2014). Probably  DBS dissociates inputs and outputs, resulting in disruption of abnormal signal transmission. Another interesting approach is suggested by Vinata et al, according to these authors, DBS might act increasing neurogenesis  (Vinata Vedam-Mai1 Increased Precursor Cell Proliferation after Deep Brain Stimulation for Parkinson’s Disease: A Human Study. PLOS 2014) or by induction of different gene expression (T. SCHULTE et al Neuroscience  2006; 138: 1377–1385). In any case we often use very effective treatments years (or decades) before we understand the exact mechanism, this is the case of DBS…but also L-Dopa etc

This is a simple and very good  question, and my personal answer is: We don´t know. It is intringuing how deep brain stimulation (DBS) is so effective in Parkinson´s disease….dystonia and other conditions. First it was suggested that DBS might be acting by releasing dopamine….but this is not clear at all. DBS can be excitatory and inhibitory…at the same time depending on what structure is involved (soma or axon) (see Satomi Chiken and Atsushi Nambu  Disrupting neuronal transmission: mechanism of DBS? Frontiers in systems Neuroscience 2014). Probably  DBS dissociates inputs and outputs, resulting in disruption of abnormal signal transmission. Another interesting approach is suggested by Vinata et al, according to these authors, DBS might act increasing neurogenesis  (Vinata Vedam-Mai1 Increased Precursor Cell Proliferation after Deep Brain Stimulation for Parkinson’s Disease: A Human Study. PLOS 2014) or by induction of different gene expression (T. SCHULTE et al Neuroscience  2006; 138: 1377–1385). In any case we often use very effective treatments years (or decades) before we understand the exact mechanism, this is the case of DBS…but also L-Dopa etc

Hi, I was just looking at random stuff that come to my mind and this topic showed up. Someone has found or know some study relating this topic/questions to electrochemical measurements? Because I would say if you are applying electrical stimulation, you can drive an electrochemical reaction that could be responsible for dopamine/serotonin release (both have very similar electrochemical behaviour I think). Of course, when you apply a potential you can modify the fluidity of cell membranes, and depending on the applied potential it can drive several coupled reactions at the same time and ionic diffusion across the membrane. I do not know, these are just things that may be helpful or not but I hope they can be useful for discussion. Cheers!