WO2023224636A1 - Dispositifs de traitement de stress et d'amélioration de vigilance à l'aide d'une stimulation électrique - Google Patents
Dispositifs de traitement de stress et d'amélioration de vigilance à l'aide d'une stimulation électrique Download PDFInfo
- Publication number
- WO2023224636A1 WO2023224636A1 PCT/US2022/030386 US2022030386W WO2023224636A1 WO 2023224636 A1 WO2023224636 A1 WO 2023224636A1 US 2022030386 W US2022030386 W US 2022030386W WO 2023224636 A1 WO2023224636 A1 WO 2023224636A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- stimulation pulses
- electrode
- series
- stimulation
- delivering
- Prior art date
Links
- 230000000638 stimulation Effects 0.000 title claims abstract description 250
- 230000036626 alertness Effects 0.000 title claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 64
- 230000000694 effects Effects 0.000 claims abstract description 62
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 61
- 230000001537 neural effect Effects 0.000 claims abstract description 46
- 210000005036 nerve Anatomy 0.000 claims abstract description 40
- 210000001186 vagus nerve Anatomy 0.000 claims abstract description 21
- 230000035882 stress Effects 0.000 claims description 80
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 claims description 44
- 238000004891 communication Methods 0.000 claims description 42
- 230000001965 increasing effect Effects 0.000 claims description 28
- 230000000116 mitigating effect Effects 0.000 claims description 26
- 230000000740 bleeding effect Effects 0.000 claims description 20
- 102100025257 Neuropeptide S Human genes 0.000 claims description 19
- 101710100554 Neuropeptide S Proteins 0.000 claims description 19
- ZRCUKBVXFDZBKP-XJEBPGRNSA-N neuropepetide s Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(O)=O)[C@@H](C)O)C(C)C)NC(=O)[C@@H](N)CO)C1=CC=CC=C1 ZRCUKBVXFDZBKP-XJEBPGRNSA-N 0.000 claims description 19
- 230000000770 proinflammatory effect Effects 0.000 claims description 17
- 238000012545 processing Methods 0.000 claims description 15
- 230000003247 decreasing effect Effects 0.000 claims description 14
- 206010062519 Poor quality sleep Diseases 0.000 claims description 12
- 230000009467 reduction Effects 0.000 claims description 12
- 210000000056 organ Anatomy 0.000 claims description 11
- 230000001734 parasympathetic effect Effects 0.000 claims description 9
- 230000001737 promoting effect Effects 0.000 claims description 8
- 230000003213 activating effect Effects 0.000 claims description 6
- 229940076279 serotonin Drugs 0.000 claims description 6
- 230000037326 chronic stress Effects 0.000 claims description 4
- 210000000192 parasympathetic ganglia Anatomy 0.000 claims description 4
- 210000000331 sympathetic ganglia Anatomy 0.000 claims description 4
- 210000003901 trigeminal nerve Anatomy 0.000 claims description 4
- 206010045178 Tunnel vision Diseases 0.000 claims description 3
- 230000037328 acute stress Effects 0.000 claims description 3
- 241000746998 Tragus Species 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 15
- 230000000386 athletic effect Effects 0.000 claims 7
- 230000010004 neural pathway Effects 0.000 claims 3
- 210000000118 neural pathway Anatomy 0.000 claims 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 47
- 230000037361 pathway Effects 0.000 description 53
- 238000011282 treatment Methods 0.000 description 51
- 230000002093 peripheral effect Effects 0.000 description 36
- 210000000627 locus coeruleus Anatomy 0.000 description 28
- 210000001519 tissue Anatomy 0.000 description 24
- 230000001515 vagal effect Effects 0.000 description 24
- 210000004940 nucleus Anatomy 0.000 description 22
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 21
- 229960002748 norepinephrine Drugs 0.000 description 21
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 21
- 230000004044 response Effects 0.000 description 21
- 238000010586 diagram Methods 0.000 description 20
- 210000002216 heart Anatomy 0.000 description 20
- 210000001679 solitary nucleus Anatomy 0.000 description 20
- 210000004515 ventral tegmental area Anatomy 0.000 description 19
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 18
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 18
- 229940077737 brain-derived neurotrophic factor Drugs 0.000 description 18
- 208000032843 Hemorrhage Diseases 0.000 description 17
- 208000026345 acute stress disease Diseases 0.000 description 17
- 208000034158 bleeding Diseases 0.000 description 17
- 210000003027 ear inner Anatomy 0.000 description 17
- 230000015654 memory Effects 0.000 description 17
- 230000003110 anti-inflammatory effect Effects 0.000 description 16
- 230000006870 function Effects 0.000 description 16
- 230000037007 arousal Effects 0.000 description 15
- 210000002442 prefrontal cortex Anatomy 0.000 description 15
- 210000001609 raphe nuclei Anatomy 0.000 description 15
- 210000004556 brain Anatomy 0.000 description 14
- 210000003491 skin Anatomy 0.000 description 14
- 108010049140 Endorphins Proteins 0.000 description 13
- 102000009025 Endorphins Human genes 0.000 description 13
- 230000004913 activation Effects 0.000 description 13
- 239000010410 layer Substances 0.000 description 13
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical group NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 12
- 230000003938 response to stress Effects 0.000 description 12
- 210000003403 autonomic nervous system Anatomy 0.000 description 11
- 238000012544 monitoring process Methods 0.000 description 11
- 210000002820 sympathetic nervous system Anatomy 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 10
- 210000001002 parasympathetic nervous system Anatomy 0.000 description 10
- 230000001960 triggered effect Effects 0.000 description 10
- 210000003169 central nervous system Anatomy 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 9
- 230000007423 decrease Effects 0.000 description 9
- 210000001320 hippocampus Anatomy 0.000 description 9
- 230000033001 locomotion Effects 0.000 description 9
- 210000002963 paraventricular hypothalamic nucleus Anatomy 0.000 description 9
- 230000002889 sympathetic effect Effects 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000007246 mechanism Effects 0.000 description 8
- 239000002858 neurotransmitter agent Substances 0.000 description 8
- 210000001009 nucleus accumben Anatomy 0.000 description 8
- 210000002509 periaqueductal gray Anatomy 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 230000004936 stimulating effect Effects 0.000 description 8
- 210000004727 amygdala Anatomy 0.000 description 7
- 239000000017 hydrogel Substances 0.000 description 7
- 208000028173 post-traumatic stress disease Diseases 0.000 description 7
- 230000009885 systemic effect Effects 0.000 description 7
- 239000000853 adhesive Substances 0.000 description 6
- 239000008280 blood Substances 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 6
- 229960003638 dopamine Drugs 0.000 description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 description 6
- 230000036541 health Effects 0.000 description 6
- 210000004072 lung Anatomy 0.000 description 6
- 210000002569 neuron Anatomy 0.000 description 6
- 230000001681 protective effect Effects 0.000 description 6
- 210000000952 spleen Anatomy 0.000 description 6
- 230000001360 synchronised effect Effects 0.000 description 6
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 5
- 229930182837 (R)-adrenaline Natural products 0.000 description 5
- 101800000414 Corticotropin Proteins 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- 206010044565 Tremor Diseases 0.000 description 5
- 230000006399 behavior Effects 0.000 description 5
- 230000019771 cognition Effects 0.000 description 5
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 5
- 229960000258 corticotropin Drugs 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 208000035475 disorder Diseases 0.000 description 5
- 210000002049 efferent pathway Anatomy 0.000 description 5
- 229960005139 epinephrine Drugs 0.000 description 5
- 229960000890 hydrocortisone Drugs 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000013016 learning Effects 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 230000008447 perception Effects 0.000 description 5
- 230000002829 reductive effect Effects 0.000 description 5
- 210000003411 telomere Anatomy 0.000 description 5
- 108091035539 telomere Proteins 0.000 description 5
- 102000055501 telomere Human genes 0.000 description 5
- 239000000275 Adrenocorticotropic Hormone Substances 0.000 description 4
- 102400000739 Corticotropin Human genes 0.000 description 4
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 4
- 229960004373 acetylcholine Drugs 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000002051 biphasic effect Effects 0.000 description 4
- 150000003943 catecholamines Chemical class 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 230000001149 cognitive effect Effects 0.000 description 4
- 238000004590 computer program Methods 0.000 description 4
- 230000002996 emotional effect Effects 0.000 description 4
- 210000003128 head Anatomy 0.000 description 4
- 210000003016 hypothalamus Anatomy 0.000 description 4
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- 208000019901 Anxiety disease Diseases 0.000 description 3
- 206010010144 Completed suicide Diseases 0.000 description 3
- 206010012335 Dependence Diseases 0.000 description 3
- 108010092674 Enkephalins Proteins 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- URLZCHNOLZSCCA-VABKMULXSA-N Leu-enkephalin Chemical class C([C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 URLZCHNOLZSCCA-VABKMULXSA-N 0.000 description 3
- 208000002193 Pain Diseases 0.000 description 3
- 210000003626 afferent pathway Anatomy 0.000 description 3
- 230000000454 anti-cipatory effect Effects 0.000 description 3
- 239000000935 antidepressant agent Substances 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 210000003295 arcuate nucleus Anatomy 0.000 description 3
- 230000001174 ascending effect Effects 0.000 description 3
- 230000002567 autonomic effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 3
- 210000000133 brain stem Anatomy 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 208000010877 cognitive disease Diseases 0.000 description 3
- 230000000875 corresponding effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000006735 deficit Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 230000005684 electric field Effects 0.000 description 3
- 230000020764 fibrinolysis Effects 0.000 description 3
- 230000003371 gabaergic effect Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 238000002847 impedance measurement Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000012806 monitoring device Methods 0.000 description 3
- 230000009958 parasympathetic pathway Effects 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 208000011117 substance-related disease Diseases 0.000 description 3
- 208000007848 Alcoholism Diseases 0.000 description 2
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- 102000012289 Corticotropin-Releasing Hormone Human genes 0.000 description 2
- 108010022152 Corticotropin-Releasing Hormone Proteins 0.000 description 2
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 206010011953 Decreased activity Diseases 0.000 description 2
- 208000009292 Hemophilia A Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010062767 Hypophysitis Diseases 0.000 description 2
- 108090000189 Neuropeptides Proteins 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 229940121954 Opioid receptor agonist Drugs 0.000 description 2
- 208000026251 Opioid-Related disease Diseases 0.000 description 2
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 2
- 108010017842 Telomerase Proteins 0.000 description 2
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 2
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 2
- 208000031674 Traumatic Acute Stress disease Diseases 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 210000001943 adrenal medulla Anatomy 0.000 description 2
- 230000004075 alteration Effects 0.000 description 2
- 230000036592 analgesia Effects 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 230000036506 anxiety Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 description 2
- 230000003416 augmentation Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000003292 diminished effect Effects 0.000 description 2
- 210000005064 dopaminergic neuron Anatomy 0.000 description 2
- 230000008482 dysregulation Effects 0.000 description 2
- 210000000883 ear external Anatomy 0.000 description 2
- 230000002500 effect on skin Effects 0.000 description 2
- 238000005538 encapsulation Methods 0.000 description 2
- 239000000835 fiber Substances 0.000 description 2
- 230000003862 health status Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 210000001153 interneuron Anatomy 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 230000007257 malfunction Effects 0.000 description 2
- 108020004999 messenger RNA Proteins 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 2
- 230000007383 nerve stimulation Effects 0.000 description 2
- 230000004766 neurogenesis Effects 0.000 description 2
- 239000003402 opiate agonist Substances 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 210000003635 pituitary gland Anatomy 0.000 description 2
- 239000011241 protective layer Substances 0.000 description 2
- 230000001179 pupillary effect Effects 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000000717 retained effect Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 230000001953 sensory effect Effects 0.000 description 2
- 230000020341 sensory perception of pain Effects 0.000 description 2
- 238000004513 sizing Methods 0.000 description 2
- 208000019116 sleep disease Diseases 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 210000002538 spinal trigeminal nucleus Anatomy 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 210000000225 synapse Anatomy 0.000 description 2
- 229960000187 tissue plasminogen activator Drugs 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- 210000000836 trigeminal nuclei Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010001488 Aggression Diseases 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- 206010003840 Autonomic nervous system imbalance Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 208000028698 Cognitive impairment Diseases 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 108010065372 Dynorphins Proteins 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 201000003542 Factor VIII deficiency Diseases 0.000 description 1
- 206010016754 Flashback Diseases 0.000 description 1
- BXNJHAXVSOCGBA-UHFFFAOYSA-N Harmine Chemical compound N1=CC=C2C3=CC=C(OC)C=C3NC2=C1C BXNJHAXVSOCGBA-UHFFFAOYSA-N 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000031220 Hemophilia Diseases 0.000 description 1
- 208000024659 Hemostatic disease Diseases 0.000 description 1
- 206010020710 Hyperphagia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- ZEXLJFNSKAHNFH-SYKYGTKKSA-N L-Phenylalaninamide, L-tyrosyl-L-prolyl-L-tryptophyl- Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)C1=CC=C(O)C=C1 ZEXLJFNSKAHNFH-SYKYGTKKSA-N 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010029412 Nightmare Diseases 0.000 description 1
- 102100028646 Nociceptin receptor Human genes 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 241000282376 Panthera tigris Species 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 206010038743 Restlessness Diseases 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 208000009205 Tinnitus Diseases 0.000 description 1
- 208000027276 Von Willebrand disease Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002390 adhesive tape Substances 0.000 description 1
- 210000004404 adrenal cortex Anatomy 0.000 description 1
- 210000004100 adrenal gland Anatomy 0.000 description 1
- 230000001155 adrenomedullary effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 208000012761 aggressive behavior Diseases 0.000 description 1
- 230000016571 aggressive behavior Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 206010001584 alcohol abuse Diseases 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 208000025746 alcohol use disease Diseases 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000009016 anticipatory response Effects 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 230000003190 augmentative effect Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000006736 behavioral deficit Effects 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000002612 cardiopulmonary effect Effects 0.000 description 1
- 210000001715 carotid artery Anatomy 0.000 description 1
- 230000032677 cell aging Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 210000004889 cervical nerve Anatomy 0.000 description 1
- 210000003737 chromaffin cell Anatomy 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 210000003109 clavicle Anatomy 0.000 description 1
- 230000006999 cognitive decline Effects 0.000 description 1
- 230000037410 cognitive enhancement Effects 0.000 description 1
- 230000007370 cognitive improvement Effects 0.000 description 1
- 231100000870 cognitive problem Toxicity 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000001054 cortical effect Effects 0.000 description 1
- 210000003792 cranial nerve Anatomy 0.000 description 1
- 238000013500 data storage Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000003001 depressive effect Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 230000003205 diastolic effect Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- JMNJYGMAUMANNW-FIXZTSJVSA-N dynorphin a Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 JMNJYGMAUMANNW-FIXZTSJVSA-N 0.000 description 1
- 210000000613 ear canal Anatomy 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- 108010015205 endomorphin 1 Proteins 0.000 description 1
- 108010015198 endomorphin 2 Proteins 0.000 description 1
- XIJHWXXXIMEHKW-LJWNLINESA-N endomorphin-2 Chemical compound C([C@H](N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)C1=CC=C(O)C=C1 XIJHWXXXIMEHKW-LJWNLINESA-N 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000002599 functional magnetic resonance imaging Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 230000004116 glycogenolysis Effects 0.000 description 1
- 230000010243 gut motility Effects 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000008801 hippocampal function Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000006387 hyperactive stress response Effects 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 230000004179 hypothalamic–pituitary–adrenal axis Effects 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000003116 impacting effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000010365 information processing Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000002197 limbic effect Effects 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 238000002595 magnetic resonance imaging Methods 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 206010025482 malaise Diseases 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000001767 medulla oblongata Anatomy 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
- 230000005486 microgravity Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000000955 neuroendocrine Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000006576 neuronal survival Effects 0.000 description 1
- 108010020615 nociceptin receptor Proteins 0.000 description 1
- 201000000988 opioid abuse Diseases 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 235000020830 overeating Nutrition 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000000803 paradoxical effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 208000019899 phobic disease Diseases 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 230000006461 physiological response Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 230000010346 psychosocial stress Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 239000003488 releasing hormone Substances 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 231100000812 repeated exposure Toxicity 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000008672 reprogramming Effects 0.000 description 1
- 230000004043 responsiveness Effects 0.000 description 1
- 230000022676 rumination Effects 0.000 description 1
- 208000015212 rumination disease Diseases 0.000 description 1
- 230000035807 sensation Effects 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 208000022925 sleep disturbance Diseases 0.000 description 1
- 239000004984 smart glass Substances 0.000 description 1
- 238000005476 soldering Methods 0.000 description 1
- 210000005250 spinal neuron Anatomy 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 210000004243 sweat Anatomy 0.000 description 1
- 230000035900 sweating Effects 0.000 description 1
- 230000005062 synaptic transmission Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 231100000886 tinnitus Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 208000012137 von Willebrand disease (hereditary or acquired) Diseases 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/0404—Electrodes for external use
- A61N1/0408—Use-related aspects
- A61N1/0456—Specially adapted for transcutaneous electrical nerve stimulation [TENS]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/36014—External stimulators, e.g. with patch electrodes
- A61N1/36025—External stimulators, e.g. with patch electrodes for treating a mental or cerebral condition
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/36036—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation of the outer, middle or inner ear
Definitions
- Stressors Events that trigger stress are generally called stressors; individuals react differently to similar as well as to dissimilar stressors.
- stressors can be divided into two main categories or types: physical and psychological.
- Physical stressors include a physical threat to bodily homeostasis; for example, bleeding profusely or having an infection.
- Psychological stressors include a perceived threat, which, as such, needs to be interpreted; for example, being in front of a hungry tiger, running late for a meeting, or feeling pressure to properly perform a task. Stress is part of normal life, and a healthy response to a stressor may be demonstrated by an anticipatory phase, a peak response during the event, and a return to baseline.
- Pressure-induced stress in some examples, may be experienced by professional athletes during competition, including those performing electronic sports (Esports), or by military operators, including those operating unmanned vehicles.
- ASR Acute Stress Reaction
- ASD Acute Stress Disorder
- ASR symptoms may also include fatigue, restlessness, panic, irritability, rage, flashbacks, nightmares, intrusive memories, confusion, avoidance of reminders of the event (e.g., avoiding people, conversations, places, etc.), difficulty remembering the event, reckless or aggressive behavior (which may be self-destructive), feeling emotionally numb and detached from others, an inability to experience positive emotions, anxiety, sleep disturbances, and difficulty concentrating.
- some of the physical symptoms of an ASR may include chest pain, pounding heart or palpitations, feeling sick (e.g., nausea), abdominal pain, loss of appetite, headaches, and/or difficulty breathing.
- ASR may lead to performance issues, however, ASR can also manifest into a serious medical problem.
- ASR is a risk factor for completed suicide. In one study, for example, it was found that individuals diagnosed with ASR followed through with complete suicide at a rate of 10 times of those who were not diagnosed with ASR. See Gradus et al. 2010. “Acute Stress Reaction and Completed Suicide.” International Journal of Epidemiology 39 (6): 1478-84.
- ASRs are more common (or at least more commonly diagnosed) in some situations than in others.
- ASR diagnoses are common in the military and can be life threatening to the individual experiencing it as well as to the team working with the individual.
- ASRs may also be referred to as Combat Stress Reaction (CSR) and Operational Stress Reaction (OSR) or together as Combat and Operational Stress Reactions (COSRs).
- CSR Combat Stress Reaction
- OSR Operational Stress Reaction
- COSRs Combat and Operational Stress Reactions
- Burnout manifests as emotional exhaustion, physical fatigue, diminished professional efficacy, cognitive impairments, feelings of ineffectiveness, detachment, and cyngraphy. Burnout is generally the result of a sustained or prolonged psychosocial stress exposure in which a mismatch between demands and resources exists or it is believed by the sufferer to exist. For example, when the personal emotional, cognitive, and physical resources are not, or are perceived to not be sufficient to overcome the demands of a situation or an environment. Available data regarding development of burnout supports an initial hyperactive stress response (in both the Hypothalamic-Pituitary-Adrenal (HP A) axis and the sympathetic system) followed by physiological exhaustion resulting in an impaired physiological response (hyporeactivity of the HPA axis).
- HP A Hypothalamic-Pituitary-Adrenal
- telomere attrition telomeres are the last portion of the chromosomes and protect the DNA. With each cell replication/ division, the telomere length (TL) tends to decrease. TL has been linked to lifespan and has been used as a biomarker of cellular aging.
- An unhealthy response to acute stress e.g., an exaggerated response, such as a very long anticipatory response or a long return to baseline, may result in detrimental changes in telomere regulation, including problems with telomerase activity (TA).
- Telomerase is an enzyme which activity counteracts telomere shortening. For instance, an autonomic overreaction has been correlated with an increased cortisol reactivity to stressors, with diminished immune cell function, and shorter TL. Perseverative cognition (e.g., rumination and concernedness), which can increase the stress reaction and prolong the recovery time to baseline has also been associated with shorter TL. An overreaction in the form of longer, or stronger/exaggerated anticipatory threat appraisals to acute stressors is one example of perseverance cognition.
- the profile of an acute stress reaction is mainly affected by allostatic cases, for example, basal levels of inflammation and hormones as well as baseline autonomic and neuroendocrine activity.
- a prolonged stress reaction and/or repeated exposures to a particular stressor may lead to disturbed allostatic states.
- Shorter TL as well as lower TA have been linked to a decreased vagal tone, increased basal levels of cortisol, oxidative stress, and inflammation.
- the two branches of the autonomic nervous system i.e., the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS) are in a dynamic balance.
- SNS sympathetic nervous system
- PNS parasympathetic nervous system
- SNS sympathetic nervous system
- PNS parasympathetic nervous system
- This stress-related autonomic imbalance is the result of a hyperactive SNS and a hypoactive PNS.
- the general response to both physical and psychological stress is activation of the sympathetic nervous system with inhibition of the parasympathetic nervous system.
- vagal tone e.g., increasing vagal activity
- the present disclosure relates to addressing stress through affecting the balance of the ANS by modulating the activity ratio between the SNS and the PSN.
- modulating the activity ration between the SNS and PSN involves activating vagal and/or auriculotemporal nerve structures, leading to an increase in vagal activity and thus vagal tone. This may be achieved not only by directly stimulating the above-mentioned nerve structures but also as a consequence of the activation of efferent descending pathways from the NTS and the NA.
- Fatigue can be said to be or to manifest as a lack of alertness.
- Wakefulness is a state in which an individual can perceive external stimuli and interact with their surroundings and their environment. The degree of vigilance and alertness during wakefulness is called arousal, and it corresponds to the level of: (a) responsiveness to sensory inputs, (b) emotional reactivity, and (c) cognitive processing.
- the present disclosure relates to increasing both NE and NPS as it activates the LC, trigeminal areas and the PbN. NPS activity is paradoxical as it acts as an anxiolytic and yet increases arousal.
- the present disclosure relates to increased activity in neural medullary structures such as, amongst others, the NTS.
- This activity increase in neural medullary structures triggers a cascade of neural activity in other brain areas which have direct and indirect connections to these neural medullary structures.
- increasing activity in the neural medullary structures may result in increasing the availability of monoamine neurotransmitters such as Serotonin (5-HT) as well as endogenous release of neuropeptides such as endorphins.
- This increase in endorphins triggers further activity in neuronal populations in yet other brain regions, for example, in populations of GABAergic interneurons in the VTA, which are inhibited by the endorphins.
- This inhibition of GABAergic intremeurons leads to an increase in the release of dopamine form dopaminergic neurons also located at the VTA.
- An increasing activity in the TCC may result not only in an activity increase in some medullary neural structures but also in an increase in the availability of a Norepinephrine (NE) and in an improve in BDNF availability.
- NE Norepinephrine
- the bleeding control method is described, for example, in U.S. Patent No. 8,729,129 to Tracey et al.; U.S. Patent No. 10,912,712 to Tracey et al.; U.S. Patent Application Publication No. 2020/0094055 to Manogue; and U.S. Patent Application Publication No. 2019/0321623 to Huston et al., hereby incorporated by reference in their entireties.
- the present disclosure relates to reducing likelihood of bleeding under stressful situations and/or speeding the stoppage of bleeding through vagal and/or trigeminal stimulation in combination with neurostimulation treatment to reduce stress reaction.
- FIG. 1A and IB are drawings identifying example neural structures and pathways for delivering therapeutic treatment using an auricular therapeutic device
- FIG. 2A illustrates example connections of the Sympathetic-Adrenomedullary (SMA) Axis pathway
- FIG. 2B illustrates example connections of the Hypothalamic-Pituitary -Adrenal (HP A) Axis pathway
- FIG. 3A illustrates example connections of the main parasympathetic pathway
- FIG. 3B illustrates example connections of the central endorphin pathway
- FIG. 4A illustrates example connections of a stress reduction pathway
- FIG. 4B illustrates example connections of an arousal and alertness control pathway
- FIG. 4C illustrates example connections of an anti-inflammatory pathway
- FIG. 5 A illustrates example mechanisms for using electrical stimulation to control and/or decrease stress
- FIG. 5B illustrates example mechanisms for using electrical stimulation to promote wakefulness, increase arousal/alertness, and counteract fatigue
- FIG. 5C illustrates example mechanisms for using electrical stimulation to for decrease pro-inflammatory processes
- FIG. 6A and FIG. 6B illustrate an example electrode configuration and equivalent circuits for providing therapy
- FIG. 7 illustrates an example timing diagram for supplying stimulation pulses a an auricular therapeutic device
- FIGs. 8A-8B illustrate a first example auricular therapeutic device
- FIGs. 9A-9C illustrate a second example auricular therapeutic device
- FIGs. 10A-10C are drawings of example systems including an example treatment device in communication with remote systems through a computing cloud and/or a peripheral device;
- FIG. 11 is a block diagram of components of an example pulse generator in communication with an example auricular therapy device.
- the terms “approximately,” “about,” “proximate,” “minor variation,” and similar terms generally refer to ranges that include the identified value within a margin of 20%, 10% or preferably 5% in certain embodiments, and any values therebetween.
- treatment systems, devices, and methods for stimulation of neural structures on and surrounding a patient’s ear are designed for providing stimulation without piercing the dermal layers on or surrounding the ear (e.g., transcutaneous stimulation).
- Electrodes may be frictionally and/or adhesively retained against the skin on and surrounding the patient’s ear to target various nerve structures.
- the electrodes may have a substantial surface area in comparison to prior art systems relying upon dermal-piercing electrodes, such that multiple nerve terminals are stimulated by a single electrode during therapy.
- a number of nerve terminals may be situated directly beneath and/or beneath and closely adjacent to the skin upon which the electrode is positioned.
- each electrode does not necessarily need to be precise. Therefore, for example, a patient or caregiver may be able to apply and remove the device as desired / needed (e.g., for sleeping, showering, etc.). Further, targeting multiple nerve terminals is advantageous since stimulating multiple branches of a nerve elicits a stronger response than stimulating a single branch, which is the case when using pinpoint electrodes such as needle electrodes.
- example implementations described herein relate to auricular transcutaneous stimulation, transcutaneous access to target nerve structures, such as vagal and trigeminal nerves and/or nerve branches, is not limited to the auricular branch of the vagus nerve (ABVN) and the auriculotemporal nerve.
- the vagus nerve as it ascends inside the carotid sheath along the neck, approaches the subcutaneous region.
- Trigeminal nerves approach the subcutaneous region at several locations in the face; for example, the supraorbital nerve, supratrochlear nerve, infratrochlear nerve, the palpebral branch of the lacrimal nerve, the external nasal nerve, the infraorbital nerve, the zygomaticofacial nerve, the zygomaticotemporal nerve, the mental nerve, and the buccal nerve are potential trigeminal targets to deliver transcutaneous stimulation.
- a device enabling positioning of electrodes against a subject’s skin such that any of these branches is stimulated, for example, may trigger responses related to trigeminal stimulation described below.
- a device enabling stimulation of one or more of the above-noted branches may be used to reduce bleed time and/or bleed volume when stimulating in a prophylactic fashion and/or after an injury that has caused bleeding to occur.
- a device such as the one described by Simon, et al, in U.S. Patent No. US 10,207, 106 could be utilized to trigger a vagal response.
- the device such as that described by Rigaux in U.S. Patent No. 8,914,123 can be used to trigger such responses.
- both devices could be used simultaneously or in an alternative manner to elicit a vagal, a trigeminal, or a trigeminal-vagal response.
- methods described herein for stimulation of neural structures on and surrounding a patient’s ear may be applied using devices designed for providing percutaneous stimulation.
- electrodes having tissue-penetrating portions and/or electrodes designed to penetrate tissue e.g., needle electrodes
- a minimally invasive manner e.g., through at least a top dermal layer of a patient’s skin.
- An example percutaneous auricular stimulation device is the P-STIM® device by Biegler GmbH, described, for example, in U.S. Patent No. 10,058,478 to Schnetz et al., incorporated herein by reference in its entirety.
- Percutaneous stimulation in other embodiments, may be performed at other locations on a subject’s skin, for example including the regions described above in relation to transcutaneous stimulation.
- FIG. 1A and IB illustrate example neural structures and pathways useful in embodiments disclosed herein for deriving benefits through nerve stimulation.
- the Nucleus Tractus Solitarius (NTS) 104 receives afferent connections from many areas including the Trigeminocervical Complex (TCC) 102, the cervical vagus nerve 128, as well as from the auricular branch of the vagus nerve (ABVN) 118.
- TCC Trigeminocervical Complex
- the TCC 102 is a region in the cervical spinal cord in which spinal cervical nerves from Cl, C2, and C3 converge with sensory trigeminal fibers.
- the trigeminal and occipital fibers synapse, including the Auriculotemporal Nerve 130, the lesser occipital nerve 152, and the greater auricular nerve 154 (e.g., Cervical Spinal 148).
- the TCC 102 projects to multiple areas in the brain stem including, but not limited to parts of the Raphe nuclei (hereafter Raphe Nucleus (RN) 106), the Locus Coeruleus (LC) 108, Periaqueductal Gray (PAG) 110, Nucleus Basalis (NBM) 120, the Nucleus Ambiguus (NA) 122, the Ventral Tegmental Area (VTA) 124, the Nucleus Accumbens (NAc) 126, and Parabrachial nucleus (PbN) 114.
- Raphe Nucleus hereafter Raphe Nucleus (RN) 106
- LC Locus Coeruleus
- PEG Periaqueductal Gray
- NBM Nucleus Basalis
- NA Nucleus Ambiguus
- VTA Ventral Tegmental Area
- NAc Nucleus Accumbens
- PbN Parabrachial nucleus
- the NTS 104 among others, also projects to the RN 106 the LC 108, and the PAG 110 as well as to higher centers like the hypothalamus 132, including into the Arcuate Nucleus (ARC) 112 which receives its majority of non-intrahypothalamic afferents from the NTS 104.
- Cells in the ARC 112 are the main source of endorphins in the Central Nervous System (CNS).
- CNS Central Nervous System
- the medulla oblongata is the lower region of the brainstem containing important neuronal structures (nuclei) modulating, for example, several important involuntary actions such as respiration, heart rate, and blood pressure.
- the medulla contains several important nuclei (medullary nuclei) such as the NTS 104, the spinal trigeminal nucleus, the NA 122, and at least some of the RN 106.
- LC 108, PAG 110, and RN 106 project to the NA 122
- PPN 116 projects into the VTA 124
- the VTA 124 projects to the Prefrontal Cortex 136, being interconnected with the hypothalamus 132 and the hippocampus 138.
- the VTA 124 projects directly to the Hippocampus 138 as well.
- the Hippocampus 138 projects to the NAc 126 and interconnects with the hypothalamus 132.
- MOR/KOR/DOR p/K/6-opioid receptor
- NOP nociception/orphanin FQ receptor
- NAc nucleus accumbens
- PFC prefrontal cortex
- VTA ventral tegmental area. Affinity is presented in parenthesis.
- this neural circuit is crucial for learning and memory as well as for arousal and wakefulness.
- norepinephrine produced by activity in the Locus Coeruleus (LC) 108
- Serotonin (5-HT) produced by activity in the RN
- Acetylcholine (ACh) produced by activity in the Pedunculopontine Nucleus (PPN) 116 or NBM 120 is extremely important for memory and learning.
- Arousal and wakefulness are modulated, amongst others, by catecholamines in the brain, such as norepinephrine and dopamine.
- Indirect connections include connections where there is at least one synapse elsewhere before reaching the target. This means that modulating the activity of these neural circuits can affect the respective organs.
- heart rate can be modulated (e.g., heart rate can be decreased and heart rate variability can be increased); oxygen absorption can be increased at the lungs 142 by increasing the compliance of the bronchi tissue and thus increasing the oxygen transport availability therefore increasing the potential for more oxygen to be absorbed into the blood; gut motility can be increased by descending pathways originating in the dorsal motor nucleus of the vagus nerve (DMV) 304 of FIG. 3B; since DMV activity is modulated by NTS activity, motility in the gut 144 can be affected by modulating the activity in the NTS 104; and a decrease in circulating pro- inflammatory cytokines can be achieved by modulating spleen 146 activity via NTS 104 descending pathways.
- DMV dorsal motor nucleus of the vagus nerve
- the vagus nerve 156 is a cranial nerve that which on its path can be located adjacent to the carotid artery in the neck.
- Direct stimulation of the vagus nerve 156 activates the nucleus tractus solitarius (NTS) 104, which has projections to nucleus basalis (NBM) 120 and locus coeruleus (LC) 108.
- NBM 120 and LC 108 are deep brain structures that release acetylcholine and norepinephrine, respectively, which are pro-plasticity neurotransmitters important for learning and memory.
- Stimulation of the vagus nerve 156 using a chronically implanted electrode cuff is safely used in humans to treat epilepsy and depression and has shown success in clinical trials for tinnitus and motor impairments after stroke.
- the auricular branch of the vagus nerve 158 innervates the dermatome region of outer ear, being the region known as the cymba conchae one of the areas innervated by it.
- Non-invasive stimulation of the auricular branch of the vagus nerve 158 may drive activity in similar brain regions as invasive vagus nerve stimulation.
- Auricular neurostimulation has proven beneficial in treating a number of human disorders.
- the response to a stressor is carried out via two main pathways: the Sympathetic- Adrenomedullary (SMA) Axis 202 and the Hypothalamic-Pituitary-Adrenal (HP A) Axis 204.
- SMA Sympathetic- Adrenomedullary
- HP A Hypothalamic-Pituitary-Adrenal
- LC Locus Coeruleus
- PVN Paraventricular Hypothalamic Nucleus
- the LC 108 is the main producer of Norepinephrine (NE) in the Central Nervous System (CNS) and is one of the main drivers of the SNS. In response to a stressor, the LC 108 releases NE.
- NE Norepinephrine
- CNS Central Nervous System
- the PVN 206 In responding to a stressor, the PVN 206 produces, amongst others, Corticotropin (also written as Corticotrophin) Releasing Hormone (CRH), also known as Corticotropin Releasing Factor (CRF).
- Corticotropin also written as Corticotrophin
- CRF Corticotropin Releasing Factor
- CRH is delivered to several brain nuclei, including the LC 108, as well as to the pituitary gland 208 which consequently releases, amongst others, [3-endorphins 210 and adrenocorticotropic hormone (ACTH) 212 into the blood steam.
- Corticotropin also written as Corticotrophin
- CRF Corticotropin Releasing Factor
- the circulating ACTH 212 reaches the adrenal gland (adrenal cortex) 214 and triggers the release of Epinephrine (Epi), NE, and glucocorticoids into the blood stream, in particular cortisol 216 in humans.
- Epinephrine Epinephrine
- NE Epinephrine
- glucocorticoids glucocorticoids into the blood stream, in particular cortisol 216 in humans.
- the Epi/NE ratio released by the adrenals is 80/20.
- Epi and NE primarily elicit a sympathetic response (e.g., increase heart rate).
- Cortisol 216 has various physiologic effects, including catecholamine release (e.g., Epi, NE, etc.), suppression of insulin, mobilization of energy stores through gluconeogenesis and glycogenolysis, as well as the suppression of the immune-inflammatory response.
- cortisol 216 serves as a feedback molecule-signal to limit the further release of CRH, thus slowing down the stress response.
- the P-endorphins 210 are released from the pituitary gland 208 to opioid receptors primarily in the peripheral nervous system (but also to immune cells), where, amongst other effects, they produce analgesia.
- This analgesia is the result of a cascade of interactions resulting in inhibition of the release of tachykinins, particularly of substance P, which is involved in the transmission of pain.
- the PVN 206 receives stress-related ascending monosynaptic afferent signals from several areas/nuclei. These nuclei include the Nucleus of the Solitary Track (NTS) 104, the LC 108, the parabrachial nuclei (PbN) 114, the Periaqueductal Grey Area (PAG) 110, and the Raphe Nucleus (RN) 106. These ascending pathways carry information regarding the stressor or stressors encountered. In addition to these ascending afferent signals, intrahypothalamic as well as descending afferent signals modulate the PVN 206 response to stressors.
- NTS Nucleus of the Solitary Track
- PbN parabrachial nuclei
- PEG Periaqueductal Grey Area
- RN Raphe Nucleus
- signals from the Prefrontal cortex (PFC) 218, the Hippocampus (Hipp) 138, and the Amygdala 149 reach the PVN 206; in some cases, these signals are further integrated at the Bed Nucleus of the Stria Terminalis (BNST) before reaching the PVN 206. Together, these signals incorporate cognitive and memory information into the stress response.
- PFC Prefrontal cortex
- Hipp Hippocampus
- BNST Bed Nucleus of the Stria Terminalis
- FIG. 3A and FIG. 3B psychological stressors are perceived and interpreted in an anticipatory fashion, and the response can be heavily modulated by the reward circuit, which includes the PFC 218, the Amygdala 149, the Ventral Tegmental Area (VTA) 306, as well as the Nucleus Accumbens (NAc) 126 (dopaminergic pathways, which are highly modulated by the central endorphin pathway 302).
- the reward circuit which includes the PFC 218, the Amygdala 149, the Ventral Tegmental Area (VTA) 306, as well as the Nucleus Accumbens (NAc) 126 (dopaminergic pathways, which are highly modulated by the central endorphin pathway 302).
- the Pre- Limbic (PL) and Infra-Limbic (IL) areas of the PFC 218 coordinate a top-bottom control over the stress response to psychological stressors.
- the brain areas or nuclei forming the neural circuitry involved in the stress response are not only involved in depression but also are integral components of the Endogenous Opioid Circuit (EOC), which includes the Central Endorphin Pathway (FIG. 3B) as well as the secondary connections arising from it.
- EOC Endogenous Opioid Circuit
- FIG. 3B together with Figs 2A and 2B, the NTS 104, LC 108, PbN 114, PAG 110, RN 106, PFC 218, VTA 306, NAc 126 (as it receives afferents from the VTA 306), the Amygdala 149 are part of the EOC.
- the central endorphin pathway 302 interacts with several other brain regions or nuclei including with other hypothalamic areas such as the PVN 206. Stimulating afferent pathways to the central endorphin pathway 302 such as vagal and/or trigeminal structures activates this circuit and connected regions, including the VTA 306, which is one of the main producers of dopamine in the CNS. By activating the central endorphin pathway 302 and connected regions, systems and methods described herein are able to modulate stress and alertness levels.
- one of the characteristics of stress is a hyperactive SNS, and hypoactive PNS, or both; resulting in a high SNS/PNS activity ratio.
- An increase in the activity of the PNS leads to a faster return to baseline after a response to a stressor.
- One way to increase PNS activity is to increase vagal tone which can be achieved by increasing the activity of the Vagus nerve 156.
- Activation of The Main Parasympathetic Pathway 300 of FIG. 3A results in an increase in vagal tone and thus a better stress response.
- the main vagus nerve afferent pathways are those originating in the NTS 104, the NA 122, and the DMV 304. Activity in these regions generally results in an increase in vagal tone.
- Activation of the ABVN 118 and the ATN 130 directly and indirectly lead to increase activity in all three above mentioned pathways going from the NTS 104, the DMV 304, and the NA 122, to the Vagus nerve 156. As seen in FIG. 3A these pathways also involve other nuclei or regions such as LC 108, PAG 110, RN 106, and TCC 102.
- stimulation e.g., of the ABVN 118 and/or ATN 130
- NPS Neuropeptide S
- NE is primarily produced in the LC 108.
- NPS is produced in the LC 108, the trigeminal nucleus, and the Parabrachial Nucleus (PbN) 114.
- the NPS release 404 includes release via the TCC 102, the PbN 114, and the LC 108.
- LC 108 activity is key for arousal.
- Norepinephrine 408 and NPS which are produced in and around the LC 108, promote arousal and wakefulness.
- interventions that increase NE and NPS in the CNS 404 also increase arousal, mitigating the effects of fatigue.
- Descending pathways from the LC 108 directly activate sympathetic preganglionic neurons in the spinal cord (e.g., Coeruleo-Spinal Pathway). Activation of these sympathetic spinal neurons has a net sympathetic effect, such as for example an increase in heart rate. Many of the generalized sympathetic effects are a direct effect of the higher amount of circulating catecholamines, in particular epinephrine and norepinephrine.
- the main source of these catecholamines is the adrenal medulla 412, which is innervated by preganglionic sympathetic nerves 410.
- the adrenal medulla 412 releases a mix of approximately 80% epinephrine and 20% norepinephrine 408 into the blood stream when stimulated.
- Heart rate variability is a reflection of the state of the autonomic nervous system (ANS).
- the sympathetic branch of the ANS which is more active during stress situations tends to increase heart rate (HR) and decrease HRV; the opposite is true for the parasympathetic branch of the ANS, which tend to decrease HR and increase HRV.
- HRV heart rate variability
- an anti-inflammatory effect is provided via activation of an anti-inflammatory pathway 420 (e.g., the cholinergic anti-inflammatory pathway), as illustrated in FIG. 4C.
- the methods and devices described herein may activate the anti-inflammatory pathway by stimulating the ABVN 118 and/or the ATN 130 which, as stated before, have projections to the NTS 104. These projections elicit cholinergic antiinflammatory effects via efferent pathways, mostly via the vagus nerve 156. Systemic antiinflammatory effects occur when the vagus nerve 156 mediates spleen 146 function, thereby reducing the amount of circulating pro-inflammatory cytokines.
- a local anti- inflammatory effect occurs at organs reached by the efferent pathways; for example at the lungs
- Decreasing systemic pro-inflammatory processes and/or pro-inflammatory processes in one or more target organs 140, 142, 144, and/or 146 involves modulating at least a portion of the anti-inflammatory pathway 420 such that activity at the NTS 104 is modulated affecting activity in efferent pathways through the celiac ganglion 422 and/or the parasympathetic ganglion 424, which in turn modulate activity in the spleen 146, lungs 142, gut 144, and/or heart 140 such that an anti-inflammatory response is elicited.
- the anti-inflammatory pathway 420 may be activated to reduce bleeding.
- activation of a portion of the anti-inflammatory pathway 420, via stimulation of the vagus nerve 156, is discussed in U.S. Patent No. 8,729,129 to Tracey et al., incorporated by reference herein in its entirety.
- a stimulation flow diagram 500 illustrates stimulation mechanisms for controlling and/or decreasing stress 510 using a treatment device such as a treatment device 800 of FIG. 8A or a treatment device 900 of FIG. 9A.
- the stimulation mechanisms are produced by a first stimulation 502a and a second stimulation 502b.
- the first and second stimulations in some embodiments, are temporally separated (e.g., in overlapping or nonoverlapping stimulations). In some embodiments, the first and second stimulations are physically separated (e.g., using a different electrode or set of electrodes contacting a different location on the patient).
- the first and second stimulations for example, may be provided via the stress reduction pathways 400 discussed in relation to FIG. 4A.
- the first stimulation 502a and/or the second stimulation 502b may be configured to stimulate the AB VN 118 which projects to the prefrontal cortex and/or the ATN 130 which has a pathway to the prefrontal cortex 136 via the TCC 102.
- parasympathetic activity and/or vagal tone is increased (504).
- Enkephalins may increase BDNF mRNA expression in the hippocampus mediated by DOR and MOR mechanisms while [3-Endorphin, endomorphin- 1 and endomorphin-2 upregulate BDNF mRNA in the prefrontal cortex, hippocampus and amygdala.
- DA dopamine
- VTA Ventral Tegmental Area
- MOR agonist e.g., endorphins and enkephalins
- GABAergic interneurons which in turn inhibit dopaminergic neurons in the VTA.
- these DAergic VTA neurons project to Nucleus Accumbens (NAc) 126, the Prefrontal Cortex (PFC) 136, the Hippocampus (Hipp) 138, and the Amygdala (Amyg) 149.
- NAc Nucleus Accumbens
- PFC Prefrontal Cortex
- Hipp Hippocampus
- Amygdala Amygdala
- ADD attention deficit disorder
- ADHD attention deficit hyper-activity deficit disorder
- the first stimulation 502a increases activity in one or more neural medullary structures 506a, such as the NTS 104, the spinal trigeminal nucleus, the NA 122, and at least some of the RN 106.
- the first stimulation 502a may increase 5-HT availability 506b, leading to an increase in BDNF expression.
- the BDNF may function to protect monoamine neurotransmitter neurons and assist the monoamine neurotransmitter neurons to differentiate.
- the second stimulation 502b also increases 5-HT availability.
- NPS is mainly produced in three areas in the brain: LC 108, PbN 404b, and the trigeminal nucleus, the latter being the target of the ATN 130 and at least partially included in the TCC 102. Activity in any of these three areas is necessary for NPS expression 404.
- the second stimulation 502b increases activity in neural structures in the TCC 508a.
- the second stimulation 502b may increases NPS release 508b via the activation cascade that follows the stimulation of the ATN 130.
- providing the first stimulation 502a and providing the second stimulation 502b involves providing a series of simultaneous and/or synchronized stimulation pulses.
- the parameters may include pulse frequency (e.g., low, mid-range, or high) and/or pulse width. Further, the parameters may indicate electrode pairs for producing biphasic pulses.
- the first stimulation may be applied using a low frequency, while the second stimulation is applied using a mid-range frequency. Conversely, in a second illustrative example, the first stimulation may be applied using a mid-range frequency, while the second stimulation is applied using a low frequency.
- Other combinations of low, mid-range, and high frequency stimulations are possible depending upon the patient and the disorder being treated. Therapy may be optimized according to the needs of individual patients including custom stimulation frequency, custom pulse width, custom stimulation intensity (amplitude), and/or independently controlled stimulation channels.
- a stimulation flow diagram 520 illustrates stimulation mechanisms for promoting wakefulness and increasing arousal/alertness to counteract fatigue 528 using a treatment device such as a treatment device 800 of FIG. 8A or a treatment device 900 of FIG. 9 A.
- the stimulation mechanisms are produced by a first stimulation 522a and a second stimulation 522b.
- the first and second stimulations in some embodiments, are temporally separated (e.g., in overlapping or non-overlapping stimulations). In some embodiments, the first and second stimulations are physically separated (e.g., using a different electrode or set of electrodes contacting a different location on the patient).
- the first and second stimulations may be provided via the arousal alertness/control pathways 402 discussed in relation to FIG. 4B.
- the first stimulation 522a and/or the second stimulation 522b may be configured to stimulate the ABVN 118 which projects to the prefrontal cortex and/or the ATN 130 which has a pathway to the prefrontal cortex via the TCC 102.
- 5-HT and NE availability are increased (524), leading to an increase in BDNF expression.
- the BDNF may function to protect monoamine neurotransmitter neurons and assist the monoamine neurotransmitter neurons to differentiate.
- the second stimulation 522b also increases 5-HT and NE availability.
- NE and 5-HT are respectively produced in the Locus Coeruleus (LC) 108 and in the Raphe Nucleus (RN) 106.
- LC Locus Coeruleus
- RN Raphe Nucleus
- BDNF Brain-Derived Neurotrophic- Factor
- PFC prefrontal cortex
- vagal afferents through the synergetic action of ACh, 5-HT and BDNF.
- acute vagal stimulation has been shown to increase NE and 5-HT release in the PFC 136 and the amygdala 149 as well as to enhance synaptic transmission in the hippocampus 138.
- the cognitive improvement due to the increase in BDNF which leads to a faster reorganization of neural circuits, can be leveraged not only to learn new things faster, but also to eliminate/extinguish undesirable and/or maladaptive behavior such as, in some examples, PTSD, phobias, and addictive behavior such as drug-seeking or overeating.
- vagal activation produces pairing-specific plasticity, thus stimulation of vagal afferents, irrespective of what neuromodulator is produced, can be used to eliminate and/or extinguish undesirable and/or maladaptive behavior such as those described above.
- the cognitive enhancement provided by the systems and methods described herein can be used to overcome the cognitive problems that have been described to occur in people exposed to microgravity environments such as astronauts in the space station or on a long space travel such as visiting Mars.
- BDNF levels have been shown to have an inverse correlation with factors associated with cognitive decline and/or impediments, such as in Alzheimer’s patients.
- the second stimulation 522b increases NPS release 526. As discussed above, this increase in NPS production or expression is the result of the activation cascade that follows the stimulation of the ATN 130.
- providing the first stimulation 522a and providing the second stimulation 522b involves providing a series of simultaneous and/or synchronized stimulation pulses.
- the parameters may include pulse frequency (e.g., low, mid-range, or high) and/or pulse width. Further, the parameters may indicate electrode pairs for producing biphasic pulses.
- the first stimulation may be applied using a low frequency, while the second stimulation is applied using a mid-range frequency. Conversely, in a second illustrative example, the first stimulation may be applied using a mid-range frequency, while the second stimulation is applied using a low frequency.
- Other combinations of low, mid-range, and high frequency stimulations are possible depending upon the patient and the disorder being treated. Therapy may be optimized according to the needs of individual patients including custom stimulation frequency, custom pulse width, custom stimulation intensity (amplitude), and/or independently controlled stimulation channels.
- a stimulation flow diagram 530 is illustrated for providing therapy to decrease systemic pro-inflammatory processes and/or pro-inflammatory processes in one or more target organs.
- the target organs may include the spleen, lungs, gut, and heart.
- the stimulations of flow diagram 530 in some examples, may be applied in mitigating bleeding, reducing volume of bleeding, and/or reducing a time period of blood loss.
- the stimulations of flow diagram 530 for example, may be performed at least in part by a pulse generator.
- a first stimulation 532 is provided at a first tissue location configured to stimulate the anti-inflammatory pathway 420 for decreasing systemic pro- inflammatory processes and/or pro-inflammatory processes in one or more target organs 536.
- the pathways may include a portion of the pathways illustrated in FIG. 4C.
- the first tissue location for example, may include a surface of an ear structure contacted by an in- ear component of an auricular stimulation device.
- the first stimulation 532 is supplied to multiple tissue locations.
- the first stimulation 532 may be applied to a first tissue location including a surface of an ear structure contacted by an in-ear component of an auricular stimulation device as well as to a second tissue location on the tragus of the ear.
- Decreasing systemic pro-inflammatory processes and/or pro-inflammatory processes in one or more target organs 536 involves modulating at least a portion of the anti-inflammatory pathway of FIG. 4C such that activity at the NTS 104 is modulated affecting activity in efferent pathways through the celiac ganglion 422 and/or the parasympathetic ganglion 424, which in turn modulate activity in the spleen 146, lungs 142, gut 144, and/or heart 140 such that an anti-inflammatory response is elicited.
- a second stimulation 534 is provided at a second tissue location configured to stimulate the anti-inflammatory pathway 420 for decreasing systemic pro-inflammatory processes and/or pro-inflammatory processes in one or more target organs 536.
- target pathways and structures for stimulation of the second tissue location include those modulating activity at and/or on the auriculotemporal nerve 130, the lesser occipital nerve 152, and/or the great auricular nerve 154.
- the pathways for example, may include a portion of the pathways illustrated in FIG. 5C.
- providing the first stimulation 532 and providing the second stimulation 534 involves providing a series of simultaneous and/or synchronized stimulation pulses to both the first tissue location and the second tissue location.
- Each of the first stimulation 532 and the second stimulation 534 may be applied using the same or different parameters.
- the parameters may include pulse frequency (e.g., low, midrange, or high) or pulse width. Further, the parameters may indicate electrode pairs for producing biphasic pulses. In a first illustrative example, the first stimulation may be applied using a low frequency, while the second stimulation is applied using a mid-range frequency.
- the first stimulation may be applied using a midrange frequency, while the second stimulation is applied using a low frequency.
- Other combinations of low, mid-range, and high frequency stimulations are possible depending upon the patient and the disorder being treated.
- the therapy provided by the stimulation 532 and/or the stimulation 534 of the stimulation flow diagram 530 includes automatically adjusting delivery of the therapy (e.g., adjusting one or more parameters) based on feedback received from the pulse generator or another computing device in communication with the pulse generator.
- the feedback may include a blood oxygen concentration, a breathing rate, a breathing variation, tidal volume, skin conductance, blood pressure, heart rate, heart rate variability, and/or EEG signal.
- combinations of the stimulations described in stimulation flow diagrams 500 and/or 520 with the stimulations described in stimulation flow diagram 530 may be used to enhance stress reduction through reducing the time and/or volume of the physical stressor of bleeding.
- activation of the anti-inflammatory pathway 420 in combination with activation of the stress reduction pathway 400 of FIG. 4A may mitigate stress reactions in subjects experiencing physical stress at least partially induced by bleeding.
- activating the anti-inflammatory pathway 420 prior to initiation of bleeding may decrease or minimize bleeding if it occurs and may be used in combination with activation of the arousal/alertness control pathway 402 to improve performance, reduce tunnel vision, and maintain focus of the subject during the activity.
- the first stimulation 532 of the stimulation flow diagram 530 may be delivered synchronously or simultaneously with the second stimulation 502b of the stimulation flow diagram 500 of FIG. 5 A for controlling and/or decreasing stress 510 or vice-versa.
- the first stimulation 532 of the stimulation flow diagram 530 may be delivered synchronously or simultaneously with the second stimulation 522b of the stimulation flow diagram 520 of FIG. 5B for promoting wakefulness, increasing arousal/alertness, and counteracting fatigue 528 or vice-versa.
- the therapy of the stimulation flow diagram 500 including both the first stimulation 502a and the second stimulation 502b may be delivered for a first period of time
- the therapy of the stimulation flow diagram 530 including both the first stimulation 532 and the second stimulation 534 may be delivered for a second period of time
- the therapy of the stimulation flow diagram 510 including both the first stimulation 522a and the second stimulation 522b may be delivered for a first period of time
- the therapy of the stimulation flow diagram 530, including both the first stimulation 532 and the second stimulation 534 may be delivered for a second period of time.
- the combined therapies in some embodiments, may be repeated for a number of cycles of the first period of time and the second period of time.
- the length of one or both of the first period of time and the second period of time may be adjusted to control/decrease stress 510 or promote wakefulness, increase arousal/alertness, and counteract fatigue 528 while decreasing systemic pro-inflammatory processes and/or pro-inflammatory processes in one or more target organs 536 in an efficient manner.
- FIG. 6A and FIG. 6B an example electrode configuration of an earpiece device 600 and example equivalent circuits 610a-b for providing therapy are shown.
- the earpiece device 600 in some implementations, includes inner ear component electrode 602, and auricular component electrodes 604, 606, and 608. Circuitry connecting between the electrodes 602, 604, 606, and 608 may be configured to form corresponding circuits 610a and 610b, as illustrated in FIG. 6B.
- an equivalent circuit 610a is formed by electrode 602 and electrode 606 which are configured to stimulate tissue portions 620.
- the inner ear component electrode 602 is configured to contact a tissue portion 620 in the cymba conchae region which is enervated by branches of the auricular branch of the vagus nerve.
- the auricular component electrode 606, in some implementations, is configured to contact a tissue portion 620 in the region behind the ear which is enervated by branches of the great auricular nerve and/or branches of the lesser occipital nerve.
- An equivalent circuit 610b is formed by electrode 604 and electrode 608 of the auricular component of the device 600 and configured to stimulate tissue portions 622.
- the tissue portions 622 are in the region rostral to the ear which is enervated by the auriculotemporal nerve as well as the region behind the ear which is enervated by branches of the great auricular nerve and branches of the lesser occipital nerve.
- the tissue portions include the concha which may be stimulated, for example, at approximately 5Hz or at approximately 15 Hz.
- the tissue portions include tissue enervated by the trigeminal nerve which may be stimulated, for example, at approximately 100Hz.
- the equivalent circuit 1210a is stimulated by a first channel and equivalent circuit 1210b is stimulated by a second channel.
- FIG. 7 pictures a timing diagram 700 illustrating the triggering of multiple channels 704 and 706 using a master clock 702 according to an example.
- the clock 702 triggers pulses 708 at a predetermined clock frequency.
- a first channel 704 can be configured to trigger stimulation of equivalent circuit 610a and a second channel 706 can be configured to trigger stimulation of equivalent circuit 610b of FIG. 6B.
- the triggering can be reversed, for example, where equivalent circuit 610b is triggered before equivalent circuit 610a.
- stimulation is configured to be triggered by every pulse of the master clock 702; i.e., at a 1-to-l ratio.
- stimulation by one channel 704, 706 is configured to be triggered following a specific time interval after the pulse triggered by the other channel 704, 706 ends.
- one of the channels 704, 706 is be configured to be triggered based on every other pulse of the master clock; i.e., at a 2-to-l ratio with the master clock. For example, the triggering by the second channel 706, as shown occurs every other clock cycle and after a specific time delay 714 from the master clock pulse 708.
- stimulation by the second channel 706 may be configured to be triggered following a specific time interval after the pulse triggered by the first channel 704 ends.
- stimulation from one channel 704, 706 is offset from stimulation by the other channel 704, 706 by a synchronous delay.
- the synchronous delay 714 is 2ms and can be as little as zero (making both channels to trigger simultaneously depending on the master clock ratio for each channel) and as much as the master clock period less the combined duration of the stimulations provided by channel 704 and 706 plus the time interval between them. In some embodiments, this delay can be about 10ms.
- the equivalent circuits 610a, 610b are synchronized using a master clock counter and a register per channel.
- each register By setting each register to a number of master clock pulses to trigger the respective channel, each channel may be configured to be triggered when the channel register value equals the master clock pulses. Subsequently, the counter for each channel may be reset after the channel is triggered.
- the trigger frequency can be as high as the master clock frequency (1:1) and as low as 1/64 of the clock frequency (64:1).
- Stimulation delivery may vary based upon the therapy provided by the treatment device.
- Frequency and/or pulse width parameters may be adjusted for one or more if not all electrodes delivering stimulation.
- frequency and/or pulse width parameters are adjusted during therapy, for example responsive to feedback received from monitoring the patient (e.g., using one or more sensors or other devices).
- the stimulation frequencies may include a first or low frequency within a range of about 1 to 30 Hz, a second or mid-range frequency within a range of about 30 to 70 Hz, and/or a third or high frequency within a range of about 70 to 150 Hz.
- Stimulation pulses in some embodiments, are delivered in patterns. Individual pulses in the pattern may vary in frequency and/or pulse width. Patterns may be repeated in stimulation cycles.
- the stimulation patterns are such that stimulating frequencies are not the same in all electrodes.
- a stimulation frequency is varied between 2 Hz and 100 Hz such that different endogenously produced opioid receptor agonist are released (e.g., Mu, Delta, Kappa, nociception opioid receptor agonist).
- the pulse width can be adjusted from between 20 and 1000 microseconds to further allow therapy customization.
- different stimulation frequencies are used at the different electrodes.
- different combinations of high, mid-range and low frequencies can be used at a cymba electrode (602), an auriculotemporal electrode (604), and/or a great auricular nerve and lesser occipital nerve electrode (606, 608).
- a first or low frequency of between 1 to 30 Hz, or in particular one or more of 1 to 5 Hz, 5 to 10 Hz, 10 to 15 Hz, 15 to 20 Hz, 20 to 25 Hz, 25 to 30 Hz may be used at an in-ear electrode
- a third or mid-range frequency of between 30 to 70 Hz, or in particular one or more of 30 to 35 Hz, 35 to 40 Hz, 40 to 45 Hz, 45 to 50 Hz, 50 to 55 Hz, or 55 to 60 Hz or 60 to 65 Hz or 65 to 70 Hz can be used at one or more of the electrodes.
- one or more low or mid-range frequencies can be used at an in-ear electrode such as the cymba electrode 602, while one or more high frequencies is used at an electrode contacting tissue surrounding the ear, such as the auriculotemporal electrode 604.
- a high frequency can be use at an in-ear electrode such as the cymba electrode 602 while a low frequency can be used at an electrode contacting tissue surrounding the ear, such as the auriculotemporal electrode 604.
- Pulse widths may range from one or more of the following: first or short pulse widths within a range of about 10 to 50 microseconds, or more particularly between 10 to 20 microseconds, 20 to 30 microseconds, 30 to 40 microseconds, 40 to 50 microseconds; second or low midrange pulse widths within a range of about 50 to 250 microseconds, or more particularly between 50 to 70 microseconds, 70 to 90 microseconds, 90 to 110 microseconds, 110 to 130 microseconds, 130 to 150 microseconds, 150 to 170 microseconds, 170 to 190 microseconds, 190 to 210 microseconds, 210 to 230 microseconds, or 230 to 250 microseconds; third or high mid-range pulse widths within a range of about 250 to 550 microseconds, or more particularly between 250 to 270 microseconds, 270 to 290 microseconds, 290 to 310 microseconds, 310 to 330 microseconds,
- a variable frequency i.e., stimulating a non-constant frequency
- the variable frequency can be a sweep, and/or a random/pseudo-random frequency variability around a central frequency (e.g., 5 Hz +/- 1.5 Hz, or 100 Hz +/- 10Hz).
- treatment devices may be designed for positioning against various surfaces on or surrounding a patient’s ear.
- an example treatment device 800 is shown including an auricular component 802 configured to contact skin behind and around a patient’s ear.
- the auricular component 802 may wrap around a back of an ear and include electrodes 804 for contacting skin surfaces in front of and behind the ear.
- the auricular component 802 is connected to an inner ear component 806 by a connector 808.
- a proximal (auricular component 802 side) end or at distal (inner ear component 806) end of the connector 808 may be designed for releasable connection.
- the connector 808 is integrated with the auricular component 802 and inner ear component 806, behaving as a conduit for bridging an electrical connection between the auricular component 802 and the inner ear component 806.
- the auricular component 802 includes a number of electrodes 804 that are configured to be in contact with the dermis on and around the outer ear.
- the auricular component 802 may include an electrode positioned for proximity to vagal-related neural structures, an electrode positioned for proximity to a neural structure related to the auriculotemporal nerve, an electrode positioned for proximity to neural structures related to the great auricular nerve or its branches, and/or an electrode positioned for proximity to the lesser occipital nerve or its branches.
- the treatment device 800 includes a pulse generator or controller (not illustrated) for delivering a series of therapeutic electrodes to the treatment device 800.
- the pulse generator may include management software for controlling therapy delivery.
- the management software in some examples, may include adjustment functionality for customizing the therapeutic output, input/output (I/O) functionality (e.g., for confirmation of therapeutic delivery), and/or metrics collection functionality for generating and retaining data such as stimulation logs, diagnostic data, and/or event data.
- I/O input/output
- metrics collection functionality for generating and retaining data such as stimulation logs, diagnostic data, and/or event data.
- the controller records overall therapeutic delivery so the caregiver/clinician can measure compliance.
- the management software may notify the wearer, caregiver, clinician if the device has stopped delivering therapy.
- the device may provide an indication of health status, such as reporting on the condition of the electrodes, the conductive hydrogel, and/or the analgesic.
- the management software may report data related to use, events, logs, errors, and device health status.
- the controller may collect information for presentation in usage reports (e.g., generated by a separate portable device app or computer program).
- the treatment device 800 includes a unique identifier that can be used in identifying users and reported data so that multiple devices can be monitored using a single software application (e.g., patients at a certain facility and/or under supervision of a certain doctor).
- a pulse generator is connected to the auricular component 802 by a second connector.
- the second connector may be releasably connected between the auricular component 802 and the pulse generator.
- at least one of a proximal (auricular component 802) end or a distal (pulse generator) end of the second connector may be designed for releasable connection.
- the second connector is integrated with the auricular component 802 and the pulse generator, behaving as a conduit for bridging an electrical connection between the auricular component 802 and the pulse generator.
- a pulse generator is built into the auricular component 802.
- the first connector 808 and/or the second connector in some embodiments, includes a keyed releasable connection with a corresponding port of the treatment device 800 for snug (e.g., non-spinning) connection or for assuring electrical alignment.
- the first connector 808 and/or the second connector is designed for locking connection with the treatment device 800.
- the locking connection for example, may be a water-resistant locking connection to protect against shorting due to moisture from sweat, rain, etc.
- the auricular component 802 and/or the inner ear component 806 are designed from inexpensive materials, allowing the apparatus to be disposable, thereby lowering the cost per treatment and eliminating the need for maintenance. Disposable apparatus also provides for greater hygienics.
- a treatment device such as the device 800 of FIGs. 8A and 8B may be donned as follows.
- Electrodes can be made larger or combined such that, for example, multiple electrodes are combined into one large contact, such as the contact pads 804a, 804b, and 804c.
- a treatment device in some embodiments, includes a set of electrodes configured to be virtually grouped together to form one or more effective electrodes. For example, a first grouping of electrodes can be equivalent to electrode 804a, a second grouping of electrodes can be equivalent to electrode 804b, and a third grouping of electrodes can be equivalent to electrode 804c. Grouping smaller electrodes provides the ability to have multiple electrodes each with its own independently controlled current source, allowing for current steering, thereby providing better spatial resolution and targeting capabilities. Electrodes may be virtually grouped by processing circuitry.
- a treatment device includes one or more haptic feedback actuators between electrode pairs.
- the haptic feedback actuator(s) may move from a first position to a second position in repetitive patterns to mask sensations felt by stimulation of the electrodes.
- the haptic feedback actuator(s) may be configured to isolate or electrically separate conductive shunting pathways between electrodes, for example between portions of conductive gel.
- an earpiece assembly 900 includes a printed circuit board (PCB) layer having electrodes.
- a flexible PCB can include electronic components to suppress electrical spikes as well as a component to identify and/or uniquely identify the PCB. Exposed conductive surfaces on the PCB can serve as contact point to connect hydrogels to the PCB.
- the PCB extends forming a cable-like structure (connector) 904 to integrate an inner ear component 906 and an auricular component 902 without the need for soldering and/or connecting during assembly.
- the earpiece assembly 900 in some embodiments, is extremely flexible, allowing it to easily conform to different shapes presented by the anatomic variability of users.
- the earpiece assembly 900 is at least partially custom printed to provide a fitted shape for the user.
- the flexible PCB is encapsulated in a protective covering.
- the protective covering can be made from a flexible material such as silicone.
- the protective covering may be applied in varying thickness and/or densities, for example to improve comfort during wear, to increase retention strength of the device during wear, and to protect the circuitry from damage.
- the encapsulation is done with at least one material. In some embodiments, the encapsulation is done at least in using one mold and at least one molding step.
- PCB may be at least partially covered with a closed cell foam.
- the auricular component 902 includes a set of electrode contacts 908a, 908b, and 908c. More or fewer electrode contacts may be included, and each electrode contact may be in electrical contact with one or more electrodes of the PCB layer.
- the protective covering includes openings to expose contacts to electrodes. For example, electrode contact pads 908a-c may be added to exposed regions. In other implementations, the entire earpiece assembly 900 is printed, including the protective layer and the contact pads 908a-c.
- the skin-contacting electrodes of the earpiece assembly 900 are formed in layers.
- a first layer may include a medical-grade double-sided conducting adhesive tape
- the second layer may include a conductive flexible metallic and/or fabric mesh for mechanical robustness and homogenic electrical field distribution
- a third layer may include a self-adhesive hydrogel.
- a two-layer version may be provided having a first layer configured for mechanical robustness and homogenic electrical field distribution and a second layer including a self-adhesive hydrogel.
- the PCB electrodes may be formed such that they cover a similar surface area as the skin-contacting hydrogel electrodes. In this manner, homogenic electrical field distribution may be achieved at the hydrogels without the need of any additional conductive layer.
- a first portion 906a of the inner ear component 906 and/or a second portion 906b of the inner ear component 906 includes one or more stimulation electrodes.
- the electrodes may be exposed (e.g., no protective layer covering) and/or one or more contact pads may be applied to the first portion 906a and/or the second portion 906b.
- the connector 904 in some implementations, is designed to curve up to allow for insertion of the inner ear component 906, as illustrated in FIG. 9C.
- the connector 904 is printed as a spring (e.g., telephone cord) to provide mobility of the inner ear component 906.
- the earpiece assembly 900 connects to a pulse generator via a slim keyed connector.
- the PCB layer includes controller circuitry for generating pulses.
- a pulse generator for use with an earpiece device includes a battery and circuitry configured to produce therapy stimulation in communication with the electrodes of the earpiece device.
- the pulse generator includes at least one antenna configured to receive programming instructions encoding stimulation parameters.
- the system may be rechargeable to allow for long-term use.
- the auricular component of the earpiece device is connected to an electrical pulse generator which produces the therapy stimulation going to the electrodes on the auricular component and the inner ear component.
- the pulse generator is located in close proximity with the auricle of the patient.
- the pulse generator may be designed into or releasably connected to a head apparatus similar an over the head or back of the head headphones band or earmuffs band.
- the pulse generator may be releasably retained in a pocket of a cap or head wrap donned by a patient.
- the pulse generator is placed on the body of the user, for example on the pectoral region just below the clavicle.
- the pulse generator can be clipped to the user’s clothing or carried in the user’s trousers pocket or in a specially designed pouch.
- the pulse generator is built into the auricular component of the earpiece device.
- the pulse generator includes an input/output (I/O) interface for user control of the therapy.
- the I/O interface may include a number of controls, such as buttons, dials, or a touch pad, for adjusting therapy.
- the I/O interface may include one or more of a mode selection, a length of time selection, or a stimulation strength control. Separate controls, in a further example, may be provided for the adjustment of the electrodes of the concha apparatus and for the electrodes of the earpiece.
- the pulse generator is remotely configurable via wireless communication.
- the wireless remote device may periodically request therapy status and in some embodiments the status, including any changes, may be communicated to a 3rd party such as a healthcare provider who is monitoring the therapy being applied to the user.
- therapy provided via the pulse generator may be controlled or adjusted at least in part using a peripheral device such as a mobile device, a tablet, or a personal computer.
- a mode and/or stimulation strength may be adjusted by a clinical user (e.g., doctor, nurse, occupational therapist, etc.), while the timing (e.g., powering on and off and/or length of time setting) of the stimulation may be user-controlled via the I/O interface of the pulse generator.
- a software update to the pulse generator may be delivered via wireless communication.
- the wireless communication in some examples, can include radio frequency (RF) communication (e.g., Bluetooth) or near-field communication (NFC).
- RF radio frequency
- NFC near-field communication
- the wireless communication may be enabled via an application installed on the peripheral device.
- other components of the treatment device are configurable by or capable of communication with a peripheral device.
- data collected by the treatment device may be transferred to the peripheral device and thereby exchanged via a computing cloud with third parties such as healthcare professionals and/or healthcare providers.
- a therapeutic auricular device is designed for continuous use for, in some examples, at least thirty minutes, between a half hour and an hour, between one hour and five hours, or for a complete workday (e.g., approximately 8 to 10 hours).
- a device designed for continuous use can be utilized intermitently for short time intervals, or specific duty cycles.
- a device could be active for one 5-to-10 minute period or for several of such periods with an off time between the active periods.
- soldiers may be provided with continuous or intermitent therapy for a number of hours.
- a power pack may be tethered to the therapeutic auricular device and atached to / integrated into a variety of standard equipment, such as a military helmet or air traffic controller headset, to provide adequate power for longer term use.
- the power pack may include additional circuitry, such as controller circuitry for delivering stimulations.
- control circuitry and/or a power unit may be releasably atachable to a therapeutic auricular device.
- a controller component may snap onto or otherwise engage with the auricular component of a therapeutic auricular device to provide stimulation therapy.
- the therapeutic auricular device may be disposable, and the releasable control circuitry and/or power unit may be re-usable.
- a therapeutic auricular device in some implementations, is designed for durability and retention throughout strenuous activities such as, in some examples, military training and/or military operations, police operations, and/or sports competitions (including e-sports).
- the therapeutic auricular device may include water resistance features, impact resistance features, adhesive features and/or anti-slippage features.
- a therapeutic auricular device includes few or no inputs accessible to the wearer.
- the therapeutic auricular device may include a power control buton or switch.
- a disposable therapeutic auricular device may include a removable batery tab that, when removed, engages power to the device and initiates therapeutic delivery.
- a therapeutic auricular device includes circuitry and/or other components to integrate the therapeutic auricular device with other devices, such as communications devices.
- the therapeutic auricular device may include a wireless speaker component, wireless signal reception, and/or wireless signal transmission.
- a therapeutic auricular device may include a Bluetooth or other limited range wireless communication module for remote therapy initiation.
- the therapeutic auricular devices of a group of individuals may be triggered to initiate therapy via a wireless command or signal issued by a single master controller.
- the signal may be a radio frequency (RF) signal issued to a passive or active RF component of the therapeutic auricular device.
- RF radio frequency
- a treatment system can include atreatment device 1000 in communication with anetwork 1020 and/or one or more peripheral devices 1010.
- Certain peripheral devices 1010 may enable communication between the treatment device 1000 and one or more third parties.
- peripheral devices 1010 include a personal computer, a tablet, or phone.
- the peripheral device(s) 1010 include a fitness-monitoring device, such as a Fitbit, Apple Watch, or Garmin Smartwatch.
- the peripheral device (s) 1010 include a healthmonitoring device, such as a glucose meter, a holter monitor, an electrocardiogram (EKG) monitor, or an electroencephalogram (EEG) monitor.
- EKG electrocardiogram
- EEG electroencephalogram
- peripheral devices 1010 include a remote server, server farm, or cloud service accessible via the network 1020.
- Certain peripheral device(s) 1010 may communicate directly with the treatment device 1000 using short-range wireless communications, such as a radio frequency (RF) (e.g., Bluetooth, Wi-Fi, Zigbee, etc.) or near-field communication (NFC).
- RF radio frequency
- NFC near-field communication
- Certain peripheral device(s) 1010 may communicate with the treatment device 1000 through another peripheral device 1010. For example, using Bluetooth communications, information from the treatment device 1000 may be forwarded to a cloud service via the network 1020 (e.g., using a Wi-Fi, Ethernet, or cellular connection).
- the network 1020 can include a local area network (LAN), wide area network (WAN), metro area network (MAN) or the Internet.
- LAN local area network
- WAN wide area network
- MAN metro area network
- the network is a clinical LAN used for communicating information in a medical environment, such as a hospital, in a secure (e.g., HIPAA-compliant) manner.
- the treatment device 1000 is shown including an auricular component 1002 connected via a connector to a pulse generator 1004, and the pulse generator 1004 is wirelessly connected to the peripheral device(s) 1010 and/or the network 1020.
- This configuration may enable a patient, caregiver, or clinical user to adjust settings and/or monitor treatment controlled by the pulse generator 1004.
- an application running on a peripheral device 1010 may provide one or more adjustable controls to the user for adjusting the delivery of therapy by the pulse generator 1004 to the patient via the auricular component 1002.
- feedback data gathered by the auricular component 1002 and/or the pulse generator 1004 may be supplied by the pulse generator 1004 to one or more of the peripheral devices 1010.
- the feedback may include sensor signals related to symptoms of the patient being treated by the treatment device 1000.
- a clinical user monitoring sensor metrics related to these signals may manually adjust the delivery of therapy accordingly using the one or more adjustable controls provided by the application.
- the feedback may be used by one of the peripheral devices 1010 to generate a notification for review by the patient, a caregiver, or a clinician.
- the notification for example, may include a low power notification, a device removed notification, or a malfunction notification.
- the treatment device 1000 may monitor impedance measurements allowing closed-loop neurostimulation.
- the notifications regarding removal or malfunction may be issued upon determining that the impedance measurements are indicative of lack of a proper contact between one or more electrodes of the treatment device 1000 and tissue on or surrounding the patient’s ear.
- the notifications may be delivered to the patient and/or one or more third parties via an application executing on one of the peripheral devices 1010.
- the application may issue an audible alarm, present a visual notification, or generate a haptic output on the peripheral device 1010.
- the application may issue a notification via a communication means, such as sending an email, text message, or other electronic message to one or more authorized users, such as a patient, caregiver, and/or clinician.
- the configuration illustrated in FIG. 10A enables automatic adjustment of therapy delivery by reviewing feedback provided by the treatment device and/or one or more peripheral devices 1010 (e.g., fitness monitors and/or health monitors used by the patient).
- a cloud platform accessible via the network 1020 may receive the feedback, review present metrics, and relay instructions to the pulse generator 1004 (e.g., via a Wi-Fi network or indirectly via a local portable device belonging to the patient such as a smart phone app in communication with the treatment device 1000).
- the pulse generator 1004 in a further example, may gather feedback from the one or more fitness monitor and/or health monitor devices 1010, analyze the feedback, and determine whether to adjust treatment accordingly.
- the auricular component 1002 of the treatment device 1000 may further be enabled for wireless transmission of information with one or more peripheral devices 1010.
- the auricular component 1002 may include a short-range radio frequency transmitter for sharing sensor data, alerts, error conditions, or other information with one or more peripheral devices 1010.
- the data for example, may be collected in a small non-transitory (e.g., non-volatile) memory region built into the auricular component 1002.
- the pulse generator 1004 is included in the auricular component 1002 that is, they are co-located thus the need for an extension cable to connect them is not necessary.
- the auricular component 1002 and pulse generator 1004 may be wirelessly connected to an electronic device (for example a personal computer, a tablet or a phone) 1010 and/or to a remote server 1010 via the network 1020.
- an electronic device for example a personal computer, a tablet or a phone
- the electronic device 1010 is also wirelessly connected to a remote server via the network 1020.
- the treatment device 1000 can be in communication with the peripheral device(s) 1010 or network 1020.
- the treatment device 1000 includes at least one isolated port 1032 for wired communication with the peripheral device 1010.
- the isolated port 1032 may be a universal serial bus (USB) connection (e.g., a mini-USB connection, a micro-USB connection, a USB-C port, etc.), an Ethernet port, or a Serial ATA (SATA) connector.
- USB universal serial bus
- SATA Serial ATA
- the isolated port 1032 for example, may be included in the pulse generator 1004 for updating a software version running on the pulse generator 1004 or for reprogramming treatment settings of the pulse generator 1004.
- the isolated port(s) 1032 may be connected to a communications port engine 1034 for enabling communications between a peripheral device 1010 and the treatment device 1000 via the isolated port 1032.
- the communications port engine 1034 may couple the isolated port 1032 to one or more microprocessors 1036.
- the communications port engine 1034 may establish a direct (e.g., wired) communication link with one of the peripheral devices 1010 to transfer data 120 from a memory 1038 to the peripheral device 1010.
- a wireless radio frequency (RF) antenna (e.g., transmitter or transmitter/receiver) 1040, in some implementations, is included in the treatment device 1000.
- the RF antenna 1040 can be in wireless communication with the peripheral device(s) 1010 directly or via the network 1020.
- the RF antenna 1040 in combination with processing circuitry for generating wireless communications (e.g., another communication port engine 1034 or a portion of the microprocessor(s) 1036) may function as a broadcast antenna, providing information to any RF receiver in a receiving region of the treatment device 1000.
- the RF antenna 1040 may broadcast sensor data, sensor metrics, alerts, alarms, or other operating information for receipt by one or more peripheral devices 1010.
- the RF antenna 1040 in combination with additional processing circuitry, may establish a wireless communication link with a particular peripheral device 1010.
- the wireless communication link in some embodiments, is a secure wireless communication link (e.g., HIPAA-compliant) for sharing patient data with the peripheral device(s) 1010.
- the wireless communication link may be used to receive control settings from a peripheral device 1010 for controlling the functionality of the pulse generator 1004, for example.
- FIG. 11 a schematic 1100 of components of a pulse generator 1150 in communication with components of the flexible PCB 1160 of the auricular component is shown according to an example.
- the multichannel pulse generator circuit 1150 has at least one microcontroller or a microprocessor 1110 with at least one core. When multiple microcontrollers or multiple cores are present, for example one controls the radio 1120 and other core(s) are dedicated to control the therapy.
- a low power programmable logic circuitry (e.g., FPGA or PLD) 1112 is also available such that the microcontroller 1110 goes into a low power mode as much as possible while the programmable logic circuitry 1112 controls therapy delivery.
- an inverter circuit 1140 is used to generate biphasic/bipolar pulses.
- one inverter circuit is use per channel, while in other embodiment, a single inverter is used for multiple channels.
- each channel targets a different anatomical area 1148.
- a high voltage compliance e.g., >50V, in other embodiments >70V, and yet in others >90V
- an over current detection circuit 1144 is present.
- an impedance measuring circuit is present 1146, such that impedance can be tracked over time and to identify when the electrodes are not in contact or in good contact with the skin or if the cable is disconnected, or if the electrodes have deteriorated or are defective.
- Monitoring impedance over time provides the added advantage that the condition of the contact electrode can be followed; thus allowing the circuit to alert the user when the contact electrodes are close to their end of life or no longer viable.
- an isolated port 1118 such as a USB is used to charge the battery, and to communicate with the microcontroller(s) 1110.
- the communication can be both ways, such that instructions or entire new code can be uploaded to the microcontroller(s) 1110 and to download information stored in the memory 1122.
- memory 1122 can be added to the circuit as an external CHIP, while in other embodiments, the memory 1122 can be internal to the microcontroller(s) 1110.
- the FPGA 1112 may also have internal memory.
- an external trigger circuit 1124 is included, such that the stimulation can be started and/or stopped via an external signal.
- the external trigger signal can be passed through the isolated port 1118; in yet other embodiments a modified USB configuration (i.e., not using the standard USB pin configuration) can be used to pass the trigger signal.
- a modified USB configuration i.e., not using the standard USB pin configuration
- Using a modified USB configuration will force a custom USB cable to be used, thus ensuring that an external trigger cannot be provided by mistake using an off-the-shelf USB cable.
- a hardware user interface is used to interact with the circuit 1126.
- the user interface can comprise of buttons, LEDs, haptic (e.g., piezoelectric) devices such as buzzers, and/or a display, or a combination of any of them.
- an external master clock 1128 is used to drive the microcontroller(s) 1110 and/or the FPGA 1112, in other embodiments the clock(s) can be internal or integrated or co-packaged with the microcontroller(s) 1110 and/or the FPGA 1112.
- one or more oscillators, including in some cases adjustable oscillators 1114 are used to set pulse parameters such as for example, frequency and/or pulse width.
- the auricular component 1160 is made from a thin flex PCB or printed electronics, such that it is light weight and can be easily bent to accommodate different anatomies.
- the auricular circuit 1160 has more than one channel.
- each channel includes a peak suppressing circuit 1147 and electrodes 1148 to contact the skin at the location of the target tissue.
- the auricular circuit 1160 includes a unique chip identifier or unique ID chip 1149. The unique ID chip can be used to track usage as well as to prevent other no authorized circuits to be connected to the multichannel pulse generator 1150. At least one auricular circuit 1160 is connected to the multichannel pulse generator 1150.
- the system utilizes feedback to monitor and/or modify the therapy.
- the feedback may be obtained from one or more sensors capable of monitoring one or more symptoms being treated by the therapy. For example, upon reduction or removal of one or more symptoms, a therapeutic output may be similarly reduced or ceased. Conversely, upon increase or addition of one or more symptoms, the therapeutic output may be similarly activated or adjusted (increased, expanded upon, etc.).
- the sensors may monitor one or more of electrodermal activity (e.g., sweating), movement activity (e.g., tremors, physiologic movement), glucose level, neurological activity (e.g., via EEG), and/or cardio-pulmonary activity (e.g., EKG, heart rate, blood pressure (systolic, diastolic and mean)).
- electrodermal activity e.g., sweating
- movement activity e.g., tremors, physiologic movement
- glucose level e.g., neurological activity
- cardio-pulmonary activity e.g., EKG, heart rate, blood pressure (systolic, diastolic and mean)
- imaging techniques such as MRI and fMRI could be used to adjust the therapy in a clinical setting for a given user.
- imaging of pupillary changes e.g., pupillary dilation
- a common cellular phone and/or smart-glass glasses could be used to provide feedback to make therapy adjustments.
- one or more sensors are integrated into the earpiece and/or concha apparatus.
- One or more sensors are integrated into the pulse generator. For example, periodic monitoring may be achieved through prompting the wearer to touch one or more electrodes on the system (e.g., electrodes built into a surface of the pulse generator) or otherwise interact with the pulse generator (e.g., hold the pulse generator extended away from the body to monitor tremors using a motion detector in the pulse generator).
- one or more sensor outputs may be obtained from external devices, such as a fitness computer, smart watch, or wearable health monitor.
- the monitoring used may be based, in part, on a treatment setting.
- EEG monitoring is easier in a hospital setting
- heart rate monitoring may be achieved by a sensor such as a pulsometer built into the earpiece or another sensor built into a low budget health monitoring device such as a fitness monitoring device or smart watch.
- feedback related to electrodermal activity could be used to monitor and detect a speed or timing of a symptom and/or therapeutic outcome.
- the electrodermal activity could be sensed by electrodes on the therapeutic earpiece device.
- the electrodermal activity could be detected by electrodes on another portion of the body and communicated to the system.
- the system can further include one or more motion detectors, such as accelerometers or gyroscopes, that can be used gather information to modulate the therapy.
- the one or more motion detectors are configured to detect a tremor and/or physiologic movement.
- the tremor and/or the physiologic movement can be indicative of the underlying condition and/or the treatment to the underlying condition.
- the tremor and/or physiologic movement can be indicative of symptoms associated with substance withdrawal.
- feedback from glucose monitoring can be used to modulate the therapy.
- EKG can be used to assess heart rate and heart rate variability, to determine the activity of the autonomic nervous system in general and/or the relative activity of the sympathetic and parasympathetic branches of the autonomic nervous system, and to modulate the therapy.
- Autonomic nervous activity can be indicative of symptoms associated with substance withdrawal.
- the treatment device can be used to provide therapy for treating cardiac conditions such as atrial fibrillation and heart failure.
- therapy can be provided for modulation of the autonomic nervous system.
- the treatment device can be used to provide therapy to balance a ratio between any combinations of the autonomic nervous system, the parasympathetic nervous system, and the sympathetic nervous system.
- the system can monitor impedance measurements allowing closed-loop neurostimulation.
- monitoring feedback can be used to alert patient/ caregiver if therapy is not being adequately delivered and if the treatment device is removed.
- processors can be utilized to implement various functions and/or algorithms described herein. Additionally, any functions and/or algorithms described herein can be performed upon one or more virtual processors, for example on one or more physical computing systems such as a computer farm or a cloud drive.
- aspects of the present disclosure may be implemented by hardware logic (where hardware logic naturally also includes any necessary signal wiring, memory elements and such), with such hardware logic able to operate without active software involvement beyond initial system configuration and any subsequent system reconfigurations.
- the hardware logic may be synthesized on a reprogrammable computing chip such as a field programmable gate array (FPGA), programmable logic device (PLD), or other reconfigurable logic device.
- FPGA field programmable gate array
- PLD programmable logic device
- the hardware logic may be hard coded onto a custom microchip, such as an application-specific integrated circuit (ASIC).
- software stored as instructions to a non-transitory computer-readable medium such as a memory device, on-chip integrated memory unit, or other non-transitory computer-readable storage, may be used to perform at least portions of the herein described functionality.
- computing devices such as a laptop computer, tablet computer, mobile phone or other handheld computing device, or one or more servers.
- Such computing devices include processing circuitry embodied in one or more processors or logic chips, such as a central processing unit (CPU), graphics processing unit (GPU), field programmable gate array (FPGA), application-specific integrated circuit (ASIC), or programmable logic device (PLD).
- processors or logic chips such as a central processing unit (CPU), graphics processing unit (GPU), field programmable gate array (FPGA), application-specific integrated circuit (ASIC), or programmable logic device (PLD).
- the processing circuitry may be implemented as multiple processors cooperatively working in concert (e.g., in parallel) to perform the instructions of the inventive processes described above
- the process data and instructions used to perform various methods and algorithms derived herein may be stored in non-transitory (i.e., non-volatile) computer-readable medium or memory.
- the claimed advancements are not limited by the form of the computer-readable media on which the instructions of the inventive processes are stored.
- the instructions may be stored on CDs, DVDs, in FLASH memory, RAM, ROM, PROM, EPROM, EEPROM, hard disk or any other information processing device with which the computing device communicates, such as a server or computer.
- the processing circuitry and stored instructions may enable the pulse generator 1004 of FIG. 10A through FIG. 10C or the pulse generator 1150 of FIG. 11 to perform various methods and algorithms described above. Further, the processing circuitry and stored instructions may enable the peripheral device(s) 1010 of FIG. 10A through FIG. 10C to perform various methods and algorithms described above.
- These computer program instructions can direct a computing device or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable medium produce an article of manufacture including instruction means which implement the function/ operation specified in the illustrated process flows.
- the network can be a public network, such as the Internet, or a private network such as a local area network (LAN) or wide area network (WAN) network, or any combination thereof and can also include PSTN or ISDN sub-networks.
- the network can also be wired, such as an Ethernet network, and/or can be wireless such as a cellular network including EDGE, 3G, 4G, and 5G wireless cellular systems.
- the wireless network can also include Wi-Fi, Bluetooth, Zigbee, or another wireless form of communication.
- the network for example, may be the network 1020 as described in relation to FIG. 10A through FIG. 10C.
- the computing device such as the peripheral device(s) 1010 of FIG. 10 A- 10C, in some embodiments, further includes a display controller for interfacing with a display, such as a built-in display or LCD monitor.
- a display such as a built-in display or LCD monitor.
- a general purpose I/O interface of the computing device may interface with a keyboard, a hand-manipulated movement tracked I/O device (e.g., mouse, virtual reality glove, trackball, joystick, etc.), and/or touch screen panel or touch pad on or separate from the display.
- a sound controller in some embodiments, is also provided in the computing device, such as the peripheral device(s) 1010 of FIG. 10A through FIG. 10C, to interface with speakers/mi crophone thereby providing audio input and output.
- circuitry described herein may be adapted based on changes on battery sizing and chemistry or based on the requirements of the intended back-up load to be powered.
- Certain functions and features described herein may also be executed by various distributed components of a system.
- one or more processors may execute these system functions, where the processors are distributed across multiple components communicating in a network such as the network 1020 of FIG. 10A through FIG. 10C.
- the distributed components may include one or more client and server machines, which may share processing, in addition to various human interface and communication devices (e.g., display monitors, smart phones, tablets, personal digital assistants (PDAs)).
- the network may be a private network, such as a LAN or WAN, or may be a public network, such as the Internet. Input to the system may be received via direct user input and received remotely either in realtime or as a batch process.
- a cloud computing environment such as Google Cloud PlatformTM
- Google Cloud PlatformTM may be used perform at least portions of methods or algorithms detailed above.
- the processes associated with the methods described herein can be executed on a computation processor of a data center.
- the data center for example, can also include an application processor that can be used as the interface with the systems described herein to receive data and output corresponding information.
- the cloud computing environment may also include one or more databases or other data storage, such as cloud storage and a query database.
- the cloud storage database such as the Google Cloud Storage, may store processed and unprocessed data supplied by systems described herein.
- the systems described herein may communicate with the cloud computing environment through a secure gateway.
- the secure gateway includes a database querying interface, such as the Google BigQuery platform.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Child & Adolescent Psychology (AREA)
- Developmental Disabilities (AREA)
- Hospice & Palliative Care (AREA)
- Neurology (AREA)
- Psychiatry (AREA)
- Psychology (AREA)
- Social Psychology (AREA)
- Biophysics (AREA)
- Heart & Thoracic Surgery (AREA)
- Otolaryngology (AREA)
- Electrotherapy Devices (AREA)
Abstract
Dans un mode de réalisation illustratif, des systèmes et des procédés de traitement de stress et/ou d'amélioration de vigilance chez un sujet à l'aide d'une thérapie de neurostimulation consistent à mettre en place une ou des premières électrodes sur, au-dessus de, ou adjacentes à un rameau auriculaire du nerf vague, à mettre en place une ou des secondes électrodes sur, au-dessus de, ou adjacentes à un nerf auriculotemporal, et à administrer des impulsions de stimulation thérapeutiques par l'intermédiaire de la ou des premières électrodes et de la ou des secondes électrodes en administrant une première série d'impulsions de stimulation à la ou aux premières électrodes, la première série étant configurée pour accroître l'activité dans une ou des structures médullaires neurales, et en administrant une seconde série d'impulsions de stimulation à la ou aux secondes électrodes, la seconde série étant configurée pour accroître l'activité dans des structures neurales à l'intérieur du complexe trigémino-cervical.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2022/030386 WO2023224636A1 (fr) | 2022-05-20 | 2022-05-20 | Dispositifs de traitement de stress et d'amélioration de vigilance à l'aide d'une stimulation électrique |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/US2022/030386 WO2023224636A1 (fr) | 2022-05-20 | 2022-05-20 | Dispositifs de traitement de stress et d'amélioration de vigilance à l'aide d'une stimulation électrique |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2023224636A1 true WO2023224636A1 (fr) | 2023-11-23 |
Family
ID=82100287
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2022/030386 WO2023224636A1 (fr) | 2022-05-20 | 2022-05-20 | Dispositifs de traitement de stress et d'amélioration de vigilance à l'aide d'une stimulation électrique |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2023224636A1 (fr) |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8729129B2 (en) | 2004-03-25 | 2014-05-20 | The Feinstein Institute For Medical Research | Neural tourniquet |
US8914123B2 (en) | 2004-12-14 | 2014-12-16 | Cefaly Technology Sprl | Apparatus for electro-inhibition of facial muscles |
US10058478B2 (en) | 2012-12-20 | 2018-08-28 | Biegler Gmbh | Electrical stimulation device |
WO2019014250A1 (fr) * | 2017-07-11 | 2019-01-17 | The General Hospital Corporation | Systèmes et procédés de stimulation nerveuse à synchronisation respiratoire |
US10207106B2 (en) | 2009-03-20 | 2019-02-19 | ElectroCore, LLC | Non-invasive magnetic or electrical nerve stimulation to treat gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders |
US20190321623A1 (en) | 2018-04-20 | 2019-10-24 | The Feinstein Institute For Medical Research | Methods and apparatuses for reducing bleeding via electrical trigeminal nerve stimulation |
US20200094055A1 (en) | 2018-09-25 | 2020-03-26 | The Feinstein Institutes For Medical Research | Methods and apparatuses for reducing bleeding via coordinated trigeminal and vagal nerve stimulation |
US10912712B2 (en) | 2004-03-25 | 2021-02-09 | The Feinstein Institutes For Medical Research | Treatment of bleeding by non-invasive stimulation |
US20210213286A1 (en) * | 2018-12-10 | 2021-07-15 | Spark Biomedical, Inc. | Devices and methods for treating cognitive dysfunction and depression using electrical stimulation |
-
2022
- 2022-05-20 WO PCT/US2022/030386 patent/WO2023224636A1/fr unknown
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8729129B2 (en) | 2004-03-25 | 2014-05-20 | The Feinstein Institute For Medical Research | Neural tourniquet |
US10912712B2 (en) | 2004-03-25 | 2021-02-09 | The Feinstein Institutes For Medical Research | Treatment of bleeding by non-invasive stimulation |
US8914123B2 (en) | 2004-12-14 | 2014-12-16 | Cefaly Technology Sprl | Apparatus for electro-inhibition of facial muscles |
US10207106B2 (en) | 2009-03-20 | 2019-02-19 | ElectroCore, LLC | Non-invasive magnetic or electrical nerve stimulation to treat gastroparesis, functional dyspepsia, and other functional gastrointestinal disorders |
US10058478B2 (en) | 2012-12-20 | 2018-08-28 | Biegler Gmbh | Electrical stimulation device |
WO2019014250A1 (fr) * | 2017-07-11 | 2019-01-17 | The General Hospital Corporation | Systèmes et procédés de stimulation nerveuse à synchronisation respiratoire |
US20190321623A1 (en) | 2018-04-20 | 2019-10-24 | The Feinstein Institute For Medical Research | Methods and apparatuses for reducing bleeding via electrical trigeminal nerve stimulation |
US20200094055A1 (en) | 2018-09-25 | 2020-03-26 | The Feinstein Institutes For Medical Research | Methods and apparatuses for reducing bleeding via coordinated trigeminal and vagal nerve stimulation |
US20210213286A1 (en) * | 2018-12-10 | 2021-07-15 | Spark Biomedical, Inc. | Devices and methods for treating cognitive dysfunction and depression using electrical stimulation |
Non-Patent Citations (2)
Title |
---|
BILEVICIUS, ELENA: "Posttraumatic Stress Disorder and Chronic Pain Are Associated with Opioid Use Disorder: Results from a 2012-2013 American Nationally Representative Survey", DRUG AND ALCOHOL DEPENDENCE, July 2018 (2018-07-01), pages 119 - 25 |
GRADUS ET AL.: "Acute Stress Reaction and Completed Suicide", INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, vol. 39, no. 6, 2010, pages 1478 - 84 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7470160B2 (ja) | 末梢神経刺激による心機能不全の治療のためのシステムおよび方法 | |
US10695568B1 (en) | Device and method for the treatment of substance use disorders | |
EP3463550B1 (fr) | Appareil et méthode de stimulation du nerf | |
US10967182B2 (en) | Devices and methods for reducing inflammation using electrical stimulation | |
US20200297999A1 (en) | Systems and methods for applying electrical energy to treat psoriasis | |
EP3996807B1 (fr) | Systèmes d'administration d'une thérapie utilisant un dispositif de stimulation auriculaire | |
US20190001129A1 (en) | Multi-modal stimulation for treating tremor | |
CN112601488A (zh) | 用于治疗震颤的多模态刺激 | |
US20210379374A1 (en) | Nerve stimulation for treating migraine and other headache conditions | |
CN113784748A (zh) | 利用节律生物过程治疗疾病的可穿戴周围神经刺激 | |
US11351370B2 (en) | Devices and methods for treating cognitive dysfunction and depression using electrical stimulation | |
US20240181243A1 (en) | Controlling or reducing stress using auricular neurostimulation | |
WO2019082180A1 (fr) | Dispositif de stimulation électrique et procédés d'utilisation du dispositif | |
US20230149703A1 (en) | Devices and methods for treating stress and improving alertness using electrical stimulation | |
US11623088B2 (en) | Devices and methods for the treatment of substance use disorders | |
WO2023224636A1 (fr) | Dispositifs de traitement de stress et d'amélioration de vigilance à l'aide d'une stimulation électrique | |
US12017068B2 (en) | Devices and methods for treating motion sickness using electrical stimulation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22731397 Country of ref document: EP Kind code of ref document: A1 |