Cortical spreading depression synaptically induced by brief high-frequency electrical stimulation of the rat brain

Electrical stimulation (ES) at the surface of the rat brain (10–200 Hz; brief trains of 10 pulses) was found to be most effective for evoking waves of spreading depression (SD) in the cortex. Repeated stimuli spaced at 10–15 min intervals did not produce convulsive activity and nor did mechanisms of SD inhibition set in under these conditions. A 5–6-fold reduction in SD threshold occurred when the intra-burst rate was increased from 10 to 200 Hz. Temporal summation of residual processes occurring with suprathreshold ES applied at the rate of 50 and 200 Hz resulted in significant broadening of the SD focus in the ES area and regular occurrence of additional SD foci on the side ipsilateral to stimulation and in the contralateral cortex. The protracted changes in cortical excitation lingering after ES by high-frequency currents brought about a decline in SD threshold and pointed to the active part played by synaptic processes in triggering this reaction.Institute of Higher Nervous Activity and Neurophysiology, Academy of Sciences of the USSR, Moscow. Translated from Neirofiziologiya, Vol. 21, No. 6, pp. 789–796, November–December, 1989.     

Bicarbonate and ammonia changes in brain during spreading depression

An alkaline, followed by an acid-going transient, characterizes acid-base changes in the interstitial space during spreading depression in a variety of brain structures. In rat, such changes are associated with a significant rise in brain lactate content. How brain proton buffers behave during spreading depression is unknown. Techniques to significantly improve the response time of gas permeable membrane semimicroelectrodes for carbon dioxide and ammonia are reported. Measurements with such electrodes, when coupled to measurements of hydrogen ion concentration (from microelectrodes), permit rapid changes to be determined in bicarbonate concentration or ammonia and ammonium ion concentration, respectively. Bicarbonate concentration fell from 30 +/- 1 (n = 16) to 14 +/- 1 mM (n = 16) during spreading depression. On the other hand, ammonia concentration rose from 2.3 +/- 0.1 to 4.4 +/- 0.3 microM (n = 17) while ammonium ion concentration rose from 116 +/- 11 (n = 17) to 382 +/- 30 microM (n = 17) during spreading depression. Bicarbonate changes probably reflect titration of brain bicarbonate stores by accumulated lactic acid. Similar physicochemical changes do not explain the rise in ammonia and ammonium ion concentrations. Instead, elevation of the latter can only result from an increase in ammonia content of the interstitial space.     

Light distribution and thermal effects in the rat brain under optogenetic stimulation

Optical brain stimulation gained a lot of attention in neuroscience due to its superior cell‐type specificity. In the design of illumination strategies, predicting the light propagation in a specific tissue is essential and requires knowledge of the optical properties of that tissue. We present the estimated absorption and reduced scattering in rodent brain tissue using non‐destructive contact spatially resolved spectroscopy (cSRS). The obtained absorption and scattering in the cortex, hippocampus and striatum are similar, but lower than in the thalamus, leading to a less deep but broader light penetration profile in the thalamus. Next, the light distribution was investigated for different stimulation protocols relevant for fiber‐optic based optogenetic experiments, using Monte Carlo simulation. A protocol specific analysis is proposed to evaluate the potential of thermally induced side effects.

     

Properties of spreading depression during different phases of cyclic excitation of the rat neocortex

Properties of cortical spreading depression were studied during different phases of cyclic excitation developing in the neocortex of rats under the influence of low-frequency electrical stimulation. Waves of spreading depression appeared in the cortex spontaneously or after microinjection of potassium chloride. During each excitation cycle a state preventing the passage and appearance of these waves developed in the region of electrical stimulation. The degree of blocking in other areas of the cortex outside the region of stimulation depended on the distance from the site of electrical stimulation and on generalization of excitatation over the cortex. After the end of the excitation phase, while the current continued to act, the ability of the cortex to conduct the depression wave was restored. In intervals of cyclic excitation the duration of the waves of spreading depression remained on average only half its duration in the absence of stimulation. The time course of development and the character of recovery of depression during the intervals confirm the hypothesis that activation of the potassium-sodium pump may have a role in the blocking mechanism and enable the temporal parameters of this process to be estimated.     

Deep brain stimulation for treatment-resistant depression

Treatment-resistant depression is a severely disabling disorder with no proven treatment options once multiple medications, psychotherapy, and electroconvulsive therapy have failed. Based on our preliminary observation that the subgenual cingulate region (Brodmann area 25) is metabolically overactive in treatment-resistant depression, we studied whether the application of chronic deep brain stimulation to modulate BA25 could reduce this elevated activity and produce clinical benefit in six patients with refractory depression. Chronic stimulation of white matter tracts adjacent to the subgenual cingulate gyrus was associated with a striking and sustained remission of depression in four of six patients. Antidepressant effects were associated with a marked reduction in local cerebral blood flow as well as changes in downstream limbic and cortical sites, measured using positron emission tomography. These results suggest that disrupting focal pathological activity in limbic-cortical circuits using electrical stimulation of the subgenual cingulate white matter can effectively reverse symptoms in otherwise treatment-resistant depression.     

Cortical afterdischarges during Leao's cortical spreading depression.

Cortical spreading depression (CSD) has been employed in unanesthetized curarized rats, in order to analyse the role of the cerebral cortex in the generation of epileptic self-sustained parozysms produced by direct cortical electrical stimulation. CSD was preferred because it is reversible and may be repeated several times in the same animal. CSD evoked in the hemisphere contralateral to the stimulated cortex decreased the duration of the afterdischarge by 40% and modified its form and amplitude both at the cortical and reticular levels. The possible role of cortical and subcortical structures in the development of after-discharges is discussed.     

Phosphorylation of cerebral cortex proteins during spreading cortical depression

Spreading cortical depression induced by the topical application of 25 % KC1 onto on hemisphere of the rat brain produced an increase in 32P radioactivity in the proteins of the microsomal [+39 %] and membrane [+21 %] fraction of the affected hemicortex compared with the intact contralateral hemicortex; conversely, radioactivity in the cytosol fraction fell by 19 %, while in the mitochondrial fraction it remained the same. The results are evaluated from the aspects of a possible difference in the response of cAMP-dependent and cAMP-independent protein phosphorylation to the depolarization of cortical cells in vivo.     

Targeted tissue oxidation in the cerebral cortex induces local prolonged depolarization and cortical spreading depression in the rat brain

Spreading depression (SD) has been linked to several neurological disorders as epilepsy, migraine aura, trauma, and cerebral ischemia, which were also influenced by disorderliness of the brain redox homeostasis. To investigate whether local tissue oxidation directly induces SD, we oxidized a restricted local area of the rat cerebral cortex using photo-dynamic tissue oxidation (PDTO) technique and examined the cerebral blood flow (CBF) and direct current (DC) potential in and around the oxidized area. Intensive PDTO induced prolonged depolarization only in the photo-oxidized area, which led to global changes of CBF and DC potential: synchronous negative shifts of DC potential (with an amplitude of approximately 20 mV) and hyperperfusion of CBF occurred. The changes in DC potential and CBF spread at a rate of around 3mm/min beyond the oxidized area to the whole hemisphere of the cerebral cortex, indicating that intensive local oxidation induces SD in the rat brain.     

Dynamic changes of brain serotonergic and dopaminergic activities during development of anxious depression: experimental study

Chronic psychoemotional stress of social defeats produces development of experimental anxious depression in male mice similar to this disorder in humans. 5-HT and 5-HIAA levels, TPH and MAO A activities, 5-HT1A-receptors in different brain areas were investigated at different stages of development of experimental disorder. It has been shown that initial stage (3 days of social stress) is accompanied by increase of 5-HT level in some brain areas. Decreased 5-HIAA levels in the hippocampus, amygdala and nucleus accumbens were discovered at the stage of forming depression (10 days of social stress). Pharmacological desensitisation and decreased number of 5-HT1A-receptors were shown in frontal cortex and amygdala. At the stage of pronounced depression (20 days of stress), there were no differences in 5-HT and 5-HIAA levels in all brain areas (excluding hypothalamus) of depressive animals. However increased number of 5-HT1A-receptors and decreased affinity in amygdala and decreased TPH and MAOA activities in hippocampus were found in depressive mice. Hypofunction of serotonergic system is suggested at the stage of pronounced depression state in animals. Similar processes had place in brain dopaminergic systems. It is concluded that dynamic changes of brain monoaminergic activities accompany the development of anxious depression in animals. Various parameters of monoaminergic systems are differently changed depending on brain area, mediator system and stage of disorder.