Electrical stimulation entrainment of targeted neuronal cell types
Electrostimulating waveforms offering simultaneous and controllable cell-type-specific entrainment are described. The waveforms selectively entrain excitatory versus inhibitory cortical and hippocampal neurons including pyramidal neurons, parvalbumin neurons, and somatostatin neurons. The embodiment provides targeted electrical stimulation (ES) entrainment of excitatory versus inhibitory neurons. For example, the current disclosure provides methods of selectively entraining excitatory neurons with ES frequencies below 30 Hertz (Hz) and in particular embodiments to frequencies below 15 Hz, such as 8 Hz and 4 Hz. The current disclosure also provides methods of selectively entraining inhibitory neurons to ES frequencies of at least 30 Hz and depending on the type of inhibitory neuron, utilizing a frequency that is 30-60 Hz or a frequency that is greater than 100 Hz.
1 . A method comprising delivering electrical stimulation(ES) at a first frequency and a second frequency to a brain of a subject wherein the ES having the first frequency entrains a first selected cell type and the ES having the second frequency entrain a second selected cell type, and wherein the first frequency is greater than zero and less than 30 Hertz (Hz) and the first selected cell type is an excitatory neuron, and the second frequency is 30 Hz or greater and the second selected cell type is an inhibitory neuron.
2 . The method of claim 1 , wherein the first frequency is less than 12 Hz, and the excitatory neuron is an excitatory cortical neuron or an excitatory hippocampal neuron.
3 . The method of claim 2 , wherein the excitatory cortical neuron is within a primary visual cortex or the excitatory hippocampal neuron is within a CA1 region of a hippocampus.
4 . The method of claim 1 , wherein:
the first frequency is 8 Hz, and the excitatory neuron is a pyramidal neuron within the primary visual cortex, or
the first frequency is 4 Hz and the excitatory neuron is a pyramidal neuron within the hippocampus.
5 . The method of claim 1 , wherein the subject is performing a task during the delivering.
6 . The method of claim 1 , wherein the delivering is through an implantable device comprising an ES generator or a non-invasive device comprising an ES generator.
7 . The method of claim 1 , wherein the delivering utilizes a sinusoidal waveform.
8 . The method of claim 1 , wherein the delivering utilizes a composite waveform carrying the first frequency and the second frequency.
9 . The method of claim 8 , wherein the delivering comprises producing a first signal having the first frequency and a second signal having the second frequency; and superimposing the first and second signals upon the brain of the subject in a manner that is not phase locked, wherein the superimposing entrains the first selected cell type and the second selected cell type within the brain of the subject.
10 . The method of claim 9 , wherein the first and second selected cell types include excitatory neurons and inhibitory neurons; cortical neurons and hippocampal neurons; pyramidal neurons and Pvalb neurons; pyramidal neurons and Sst neurons; and/or Pvalb neurons and Sst neurons.
11 . The method of claim 9 , wherein:
the first frequency is from greater than 0 to 12 Hz and the second frequency is from 30 to 60 Hz;
the first frequency is from greater than 0 to 12 Hz and the second frequency is from 100 Hz to 160 Hz;
the first frequency is from greater than 0 to 12 Hz and the second frequency is 30 Hz;
the first frequency is from greater than 0 to 12 Hz and the second frequency is 50 Hz;
the first frequency is from greater than 0 to 12 Hz and the second frequency is 60 Hz;
the first frequency is from greater than 0 to 12 Hz and the second frequency is 100 Hz;
the first frequency is from greater than 0 to 12 Hz and the second frequency is 120 Hz;
the first frequency is from greater than 0 to 12 Hz and the second frequency is 140 Hz;
the first frequency is 4 Hz and the second frequency is 30 or greater;
the first frequency is 4 Hz and the second frequency is 30 Hz;
the first frequency is 4 Hz and the second frequency is 50 Hz;
the first frequency is 4 Hz and the second frequency is 60 Hz;
the first frequency is 4 Hz and the second frequency is 100 Hz;
the first frequency is 4 Hz and the second frequency is 120 Hz;
the first frequency is 4 Hz and the second frequency is 140 Hz;
the first frequency is 8 Hz and the second frequency is 30 or greater;
the first frequency is 8 Hz and the second frequency is 30 Hz;
the first frequency is 8 Hz and the second frequency is 50 Hz;
the first frequency is 8 Hz and the second frequency is 60 Hz;
the first frequency is 8 Hz and the second frequency is 100 Hz;
the first frequency is 8 Hz and the second frequency is 120 Hz; or
the first frequency is 8 Hz and the second frequency is 140 Hz.
12 . The method of claim 8 , wherein the delivering comprises (a) creating a first electric field between electrodes in a first pair of electrodes; and (b) creating a second electric field between electrodes in a second pair of electrodes, such that (i) the first and second electric fields constructively and destructively interfere with each other to create an amplitude-modulated waveform and (ii) a largest envelope amplitude of the amplitude-modulated waveform occurs in a cortical region and/or a hippocampal region of the brain of the subject; wherein, during steps (a) and (b), the first and second electrode pairs are electrically coupled to the brain.
13 . The method of claim 12 , wherein the amplitude-modulated waveform entrains selected neurons in the cortical region and/or the hippocampal region of the brain of the subject.
14 . The method of claim 12 , wherein the first and second electric fields are temporally asymmetric.
15 . The method of claim 7 , wherein the second frequency is greater than 100 Hz and the inhibitory neuron is a parvalbumin (Pvalb) neuron, or the second frequency is in a range of 30 Hz-60 Hz and the inhibitory neuron is a somatostatin (Sst) neuron.
16 . The method of claim 15 , wherein the inhibitory neuron is an inhibitory cortical neuron or an inhibitory hippocampal neuron.
17 . The method of claim 16 , wherein the inhibitory cortical neuron is within a primary visual cortex or the inhibitory hippocampal neuron is within a CA1 region of a hippocampus.
18 . The method of claim 15 , wherein the inhibitory neuron is a parvalbumin (Pvalb) neuron.
19 . The method of claim 15 , wherein the second frequency is 140 Hz and the inhibitory neuron is a Pvalb neuron within a primary visual cortex, or
the second frequency is 120 Hz and the inhibitory neuron is a Pvalb neuron within a hippocampus.
20 . A method comprising entraining excitatory pyramidal cortical neurons within a primary visual cortex while simultaneously entraining inhibitory cortical neurons within the primary visual cortex in a brain of a subject, the method comprising:
delivering electrical stimulation(ES) to the brain of the subject, wherein the ES comprises a first frequency and a second frequency, wherein the first frequency is greater than 0 Hz to 12 Hz and the second frequency is from 100-160 Hz,
thereby entraining excitatory pyramidal cortical neurons within the primary visual cortex while simultaneously entraining inhibitory cortical neurons within the primary visual cortex in the subject.