Transcript Carl L. Faingold, Hal Blumenfeld

Chapter 33
Future Trends in Neuronal Networks—
Selective and Combined Targeting of
Network Hubs
Carl L. Faingold, Hal Blumenfeld
Copyright © 2014 Elsevier Inc. All rights reserved.
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FIGURE 33.1 Prototypical network that subserves a CNS disorder that consists of an input, several network nuclei (Sites 1–
4) with pathways between the sites, and output symptoms. The diagram also illustrates potential targets for therapy,
including an emergent property (EP) of neurons in each brain site. In “gain-of-function” CNS disorders, such as many cases
of epilepsy, after repeated episodes of the disorder the network may expand to additional nuclei (Site Ω) carried by
enhanced projections via Path 2, which may result in increased severity of the disorder and/or additional symptoms due to
increased output via Path 3. Potential specific drug therapies of this CNS disorder can act at the EP of one or more specific
network sites to reduce or block neuronal firing there, reduce activity of the network, and reduce or prevent symptoms of the
disorder. Stimulation therapy in the periphery or within the brain can inactivate one or more of the network sites or activate a
dormant pathway that competes with the CNS disorder network for control of one or more of the network sites, diminishing
its involvement in the CNS disorder. Combined drug and stimulation therapies can potentially exert additive or even
superadditive effects. In “loss-of-function” CNS disorders, as seen in neurodegenerative disorders, the pathway (Path 1)
between Site 2 and Site 4 may degenerate, causing a loss of normal function and symptoms of the disorder. Drug and/or
therapeutic stimulation paradigms can be directed at specific nuclei or pathways to activate a dormant pathway via Site Δ to
bypass the damaged pathway and restore normal function. In loss-of-function disorders, a therapeutically useful drug could
act on the EP of a network site to increase neuronal firing activity or in a dormant site to restore the normal function of the
network, which may also be induced by a therapeutic stimulation paradigm. Again, combined drug and stimulation therapies
may exert additive or superadditive effects.
Copyright © 2014 Elsevier Inc. All rights reserved.
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FIGURE 33.2 The effects of a GABAA antagonist on brainstem reticular formation (BRF) neurons, using systemic
administration or iontophoretic application. (A) The poststimulus time histogram (PSTH) of the responses of a BRF
(mesencephalon) in the predrug control period shows no evidence of sensory responsiveness to visual stimuli (light flashes)
and minimal firing. (B) The responses of the same neuron are shown after administration of the GABA A antagonist
pentylenetetrazol (PTZ; 10 mg/kg i.v.), and they show extensive firing and considerable responsiveness to the same stimuli, as
indicated by the time-locked peaks in the PSTH. (C) During the 1 min application of GABA (185 nA) directly onto this neuron,
the effect of PTZ was almost completely reversed, and complete recovery from the PTZ occurred rapidly thereafter (not
shown). Another BRF neuron showed some response to auditory stimuli, as shown in (D). (E) Iontophoretic application of PTZ
(175 nA) greatly enhanced the responsiveness of this neuron; and (F) partial recovery from the effect. The insets above (D–F)
are three superimposed oscilloscope trace examples for each PSTH. Data were obtained from unanesthetized cats.
(Source: Modified from Ref. 53 with permission.)
Copyright © 2014 Elsevier Inc. All rights reserved.
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FIGURE 33.3 The network inhibition hypothesis for impaired consciousness in temporal lobe complex partial seizures. (A)
Under normal conditions, the upper brainstem–diencephalic activating systems interact with the cerebral cortex to maintain
normal consciousness. (B) A focal seizure involving the mesial temporal lobe. If the seizure remains confined, then a simplepartial seizure will occur without impairment of consciousness. (C) Spread of seizure activity from the temporal lobe to
midline subcortical structures. Propagation often occurs to the contralateral mesial temporal lobe as well (not shown). (D)
Inhibition of subcortical activating systems leads to depressed activity in the bilateral fronto-parietal association cortex, and
to loss of consciousness.
(Source: Modified with permission from Ref. 74.)
Copyright © 2014 Elsevier Inc. All rights reserved.
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FIGURE 33.4 Effects of combined stimulation and drug therapies on a chronic pain syndrome. Electroacupuncture
(Acup) stimulation in patients with glossopharyngeal neuralgia showed great improvement in pain in a limited number of
patients, but with the addition of phenytoin (PHT), a significantly greater incidence of great improvement was seen (∗p <
0.05, Mann–Whitney U test).
(Source: Based on data from Ref. 22 with permission.)
Copyright © 2014 Elsevier Inc. All rights reserved.
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