This is a response I wrote today:
CA,
Interesting write-up, and let me appreciate the clear, succinct manner in which you presented it.
Now let us look at the findings of the studies quoted:
1. The number of new neurons formed increases with an increase in the number of ECS, and the new neurons differentiate and survive for at least 3 months (Scott et al, 2000; Madsen et al, 2000; Hellsten et al, 2002).
What does this study imply? Does it mean increased number of ECS should continue? Till when? Till how far is increase in ECS number connected with the new neuron formation? What happens after three months? How specific is new neuron formation to ECS, as different from psychopharmacology, psychotherapy, etc? Were these double blind placebo controlled trials? Any comparative studies?
2. The vascular infrastructure of the hippocampus similarly proliferates, possibly to support the neuronal proliferation (Hellsten et al, 2004).
This is obviously a supplementary reaction. Is it in any way specifically related to new neurons, or would occur even in injury/insult to the brain, or as a reaction to the electrical stimulation itself?
3. Repeated ECS also induces glial cell proliferation in the amygdala. This proliferation remains evident 3 weeks after ECS, when some of the cells show differentiation into mature oligodendrocytes (Wennstrom et al, 2004).
Glial cell proliferation, even oligodendrocyte formation, is a supportive phenomenon. What about neurogenesis? How useful is the former in the absence of the latter?
4. Finally, repeated ECS stimulates vascular and glial (but not neuronal) proliferation in the rat frontal cortex, as well (Madsen et al, 2005).
Rat studies confirm vascular and glial proliferation in frontal cortex. In the absence of neural proliferation, how significant are these findings?
5. Important findings of Hellsten et al (2005) were:
i. Oxygenation did not abolish the ECS-induced proliferation of endothelial cells in the dentate gyrus of the hippocampus.
ii. ECS induced a 30% increase in the total number of endothelial cells, and a 16% increase in vessel length.
Proliferation of endothelial cells is, I take it, is cells of the vasculature, which can be understandable even due to electrical stimulation, even if the hypoxia element is accounted for. How do we connect it with clinical improvement and new neuron formation, if any?
6. In rat models, oxygenation does not abolish ECS-induced proliferation of vasculature in the hippocampus. These findings suggest that similar vascular growth is induced by ECT in clinical situations.
Agreed. Even then, the issue of how is it connected to clinical improvement, and how it is not a non-specific effect of electrical stimulation, remain.
7. Kodama et al (2004) showed that chronic (21-day) but not brief (7-day) administration of olanzapine and fluoxetine increased neurogenesis in the hippocampus, and non-neuronal cell proliferation in the prefrontal cortex. The combined effect of the two drugs was not greater than their separate effects. New cell formation did not occur in other areas, such as the subventricular zone or the primary motor cortex.
Both neurogenesis and non-neuronal proliferation occurred with drugs. Was it temporally correlated with improvement? Did both remain even after drug stoppage? Did both proliferations regress with drug stoppage? Did they reduce with drug reduction? There are obvious long-term implications for therapy in this.
9. It is unlikely that histological effects suffice to explain the mechanism of action of ECT or drugs. This is because the formation, maturation, and integration of new cells take weeks, whereas in most patients who receive drugs or ECT the benefits develop within the first fortnight, itself. It is conceivable that neurotransmitter effects explain early actions, and cellular effects explain sustained benefits.
A neat conclusion.
It is also possible we have not still developed sophisticated enough methods to study early histological changes. Neurotransmitter effects are a good explanation, but they must be correlated with histological changes of some type. Otherwise they may become a convenient explanation, but insufficient on further probing. And they should not, in any case, stymie histological studies.
I think a robust correlation of histological findings with evidential neurotransmitter connection (evidential, as different from speculative) will ensure significant progress in understanding the biological processes underlying both mental illnesses and their recovery process.
We know biological psychiatry has a long way to go. But if its fundamentals are clear, and its adherents unrelenting, something significant should result in a couple of decades. Earlier would be a bonus. Later, well, that's possible, because the two riders mentioned must be fulfilled.
Ajai
30 May 2006
....................................................
andrade
With reference to:
(Can we have some landmark studies which make you come to these
conclusions, CA? Ajai)
Ajai, this is a SynergyTimes article which I had written earlier this year.
Best wishes,
CA
Jan 27, 2006; Vol 6 No 12
HISTOLOGICAL MECHANISMS OF ECT
Histological mechanisms of ECT have been described. In animal models, electroconvulsive shocks (ECS) have been shown to result in nerve cell proliferation in the hippocampus. The number of new
neurons formed increases with an increase in the number of ECS, and the new neurons differentiate and survive for at least 3 months (Scott et al, 2000; Madsen et al, 2000; Hellsten et al,
2002). The vascular infrastructure of the hippocampus similarly proliferates, possibly to support the neuronal proliferation (Hellsten et al, 2004). Repeated ECS also induces glial cell
proliferation in the amygdala. This proliferation remains evident 3 weeks after ECS, when some of the cells show differentiation into mature oligodendrocytes (Wennstrom et al, 2004). Finally,
repeated ECS stimulates vascular and glial (but not neuronal) proliferation in the rat frontal cortex, as well (Madsen et al, 2005).
Hypoxia is known to induce angiogenesis. Therefore, is the endothelial response to ECT in the hippocampus a result of hypoxia during ECT or the ECT, itself? The issue was studied by Hellsten et al (2005) in an experiment in which repeated ECS with and without oxygenation were administered to adult rats.
Important findings were:
1. Oxygenation did not abolish the ECS-induced proliferation of endothelial cells in the dentate gyrus of the hippocampus.
2. ECS induced a 30% increase in the total number of endothelial cells, and a 16% increase in vessel length.
Conclusions
In rat models, oxygenation does not abolish ECS-induced proliferation of vasculature in the hippocampus. These findings suggest that similar vascular growth is induced by ECT in
clinical situations.
Comments
1. The ECT-induced proliferation of nerve cells, glial cells, and endothelial cells occurs in structures such as the hippocampus, amygdala, and frontal cortex, all of which have been implicated
in psychiatric disorders. If the new cells are well-integrated into the existing brain tissues, their contributions may underlie the mechanism of action of ECT. This is an appealing idea because it could help explain why ECT is effective in disorders with
contrasting neurotransmitter mechanisms.
2. It may be noted that antidepressant and antipsychotic drugs also induce new cell formation in the CNS. For example, Kodama et al (2004) showed that chronic (21-day) but not brief (7-day) administration of olanzapine and fluoxetine increased neurogenesis in the hippocampus, and non-neuronal cell proliferation in the prefrontal cortex. The combined effect of the two drugs was not greater than their separate effects. New
cell formation did not occur in other areas, such as the subventricular zone or the primary motor cortex.
3. It is unlikely that histological effects suffice to explain the mechanism of action of ECT or drugs. This is because the formation, maturation, and integration of new cells take weeks,
whereas in most patients who receive drugs or ECT the benefits develop within the first fortnight, itself. It is conceivable that neurotransmitter effects explain early actions, and cellular
effects explain sustained benefits.
References
Hellsten J, Wennstrom M, Mohapel P, Ekdahl CT,
Bengzon J, Tingstrom A. Electroconvulsive seizures increase hippocampal neurogenesis after chronic corticosterone treatment. Eur J Neurosci 2002; 16: 283-290.
Hellsten J, Wennstrom M, Bengzon J, Mohapel P, Tingstrom A. Electroconvulsive seizures induce endothelial cell proliferation in adult rat hippocampus. Biol Psychiatry 2004; 55: 420-427.
Hellsten J, West MJ, Arvidsson A, Ekstrand J, Jansson L, Wennstrom M et al. Electroconvulsive seizures induce angiogenesis in adult rat hippocampus. Biol Psychiatry 2005; 58: 871-878.
Kodama M, Fujioka T, Duman RS. Chronic olanzapine or fluoxetine administration increases cell proliferation in hippocampus and prefrontal cortex of adult rat. Biol Psychiatry 2004; 56: 570-580.
Madsen TM, Treschow A, Bengzon J, Bolwig TG, Lindvall O, Tingstrom A. Increased neurogenesis in a model of electroconvulsive therapy. Biol Psychiatry 2000; 47: 1043-1049.
Madsen TM, Yeh DD, Valentine GW, Duman RS. Electroconvulsive seizure treatment increases cell proliferation in rat frontal cortex. Neuropsychopharmacology 2005; 30: 27-34.
Scott BW, Wojtowicz JM, Burnham WM. Neurogenesis in the dentate gyrus of the rat following electroconvulsive shock seizures. Exp Neurol 2000; 165: 231-236.
Wennstrom M, Hellsten J, Tingstrom A. Electroconvulsive seizures induce proliferation of NG-2 expressing glial cells in adult rat amygdala. Biol Psychiatry 2004; 55: 464-471.
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