Publications and Patents about optic nerve treatment
List of publication
1. Fedorov A, Jobke S, Bersnev V, Chibisova A, Chibisova Y, Gall C and Sabel BA Restoration of vision after optic nerve lesions with noninvasive transorbital alternating current stimulation: a clinical observational study Brain Stimul. 2011 Oct;4(4):189-201
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BACKGROUND: Non-invasive current stimulation can induce neuroplastic changes in the normal brain, including visual system structures. Because it is not known if such plasticity is of clinical value, we wished to learn if vision restoration can be induced after optic nerve damage. METHODS: In an open-label, clinical observational study 446 patients with optic nerve lesions were treated with non-invasive repetitive transorbital alternating current stimulation (rtACS). Current bursts (<1000 μA, 5-20 Hz) were applied to induce phosphenes for one or two 10-day stimulation periods. Efficacy was assessed by monocular measurements of visual acuity and visual field (VF) size. EEG recordings at rest (n = 68) were made before and after treatment and global power spectra changes were analyzed. RESULTS: rtACS improved VF size in the right and left eye by 7.1% and 9.3% (p < 0.001), respectively. VF enlargements were present in 40.4% of right and 49.5% of left eyes. Visual acuity (VA) significantly increased in both eyes (right = 0.02, left = 0.015; p < 0.001). A second 10-day course was conducted 6 months in a subset of 62 patients and resulted in additional significant improvements of VA. Analysis of EEG power spectra revealed that VA and VF improvements were associated with increased alpha power. Increased theta power was observed in patients with optic nerve damage that had only VF enlargements but no VA change. In contrast, non-responders had increased delta power spectra in frontal and occipital areas. CONCLUSIONS: rtACS leads to long-lasting improvements in VA and VF size and after-effects in EEG power spectra. Because physiological and clinical parameters are correlated we hypothesize that rtACS enhances plasticity by inducing synchronization in different cortical regions, but the precise mechanisms needs further clarification. These encouraging results require confirmation by controlled clinical trials.
2. Fedorov A, Chibisova Y, Szymaszek A, Alexandrov M, Gall C, Sabel BA. Non-invasive alternating current stimulation induces recovery from stroke. Restor Neurol Neurosci. 2010;28(6):825-33.
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BACKGROUND: Recovery of post-stroke deficits can be achieved by modulating neuroplasticity with non-invasive brain stimulation. To evaluate potential effects of repetitive transorbital alternating current stimulation (rtACS) on stroke recovery we carried out a randomized, drug-controlled clinical trial. METHODS: Ninety-eight patients that had suffered ischemic stroke 21.4 months earlier were randomly assigned to either group D (n=30) receiving conventional drug therapy, group ACS (n=32) treated for 12 days with rtACS, or group D/ACS (n=36) receiving combined drug therapy/rtACS. Stroke severity level (SSL) was assessed by the NIH-NINDS stroke scale before and after treatment and at a 1-month follow-up to evaluate motor impairments (weakness, ataxia), sensory loss, visual field defects, and cortical deficits (aphasia, neglect). At each time point standard EEG recordings (10-20 system) were conducted. RESULTS: Before therapy SSL was moderate (9.18 ± 0.78) without significant group difference (F =0.86, p=0.43). After 12 days of treatment, SSLs of groups ACS and D/ACS significantly improved by 22.5% and 25.1% over baseline, respectively, with no such change in the control group D (+3%). SSL improvements were mainly due to recovery of motor, sensory, and speech functions. After 1-month follow-up, an additional improvement of 9.7% and 9.4% was seen for the group ACS and D/ACS which led to a total change of +32.3% and +34.7% over baseline. EEG recordings revealed greater interhemispheric synchrony between both temporal lobes which were positively correlated with clinical outcome. CONCLUSIONS: Non-invasive rtACS applied to post-stroke patients can modulate brain plasticity and induce recovery from neurological deficits long after the early post lesion recovery is over.
3. Fedorov A, AN Chibisova, JM Chibisova. Neuropeptide correction of vision loss caused optic nerve damage in case local and multifocal brain lesions. In the monography: Golovkin and Zhulyov Clinical and experimental aspects of neurogerentology. 2009, Sankt-Petersburg, P.98-128.
4. Fedorov A, Bersnev VP, Chibisova AN, Chibisova JM Vision restoration for the patients with traumatic optic nerve damage by therapeutical electrical stimulation. Palliative medicine and Rehabilitation 2009 V.1 P.33-36
5. Fedorov A, Chibisova AN, Tchibissova JM The rehabilitation for the patients with optic nerve lesion. The analysis of efficiency of therapeutic electrical stimulation application // Vestnik Integrative Medicine. – Vol. 1 (14). – 2005. 8-21
6. Fedorov A, Chibisova AN, Tchibissova JM Impulse modulating therapeutic electrical stimulation (IMTES) increases visual field size in patients with optic nerve lesions // International Congress Series. – 2005. – V. 1282. 525-9
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Objective. The restoration of visual functional loss that results from optic nerve lesions is still considered an unsolved problem. Despite the large number of the optic nerve fibers, their capacity of plasticity to achieve recovery is rather limited. In these conditions, it seems appropriate to activate intact visual cortex of blind or partial sight patients to rehabilitate vision. Methods We applied impulse modulating therapeutic electrical stimulation (IMTES) to activate visual pathway structure and striate cortex, where small electrical currents are applied to the eye ball non-invasively. Efficacy of this treatment was studied clinically with perimetry and physiologically using EEG, VEP and PET data. The recordings were compared between different etiologies, degrees of initial vision loss and the type of visual field (VF) defects. Subjects We analyzed the outcomes of 874 patients, which has sustained either severe or partial optic nerve lesion of traumatic, inflammatory and post-tumour origin. Results Before treatment, most patients had severe vision loss ranging from to total blindness to severe or mild VF defects. The best clinical effect was seen in the group of patients with severe visual impairment. Here, 62.6% of the cases responded positively to IMTES as evidence by perimetric and/or physiological recordings. Repeated perimetry revealed enlargement of peripheral visual field (mean 27.5% from background), visible as contraction or decreased absolute scotoma size. Of the patients with legal blindness (visual acuity not exceed sense of light or small remnant of residual vision was still), 16% showed benefits. In groups of the patients with blindness or slight vision, the recovery of visual function was achieved in 49.7% and 58.2% of the cases, respectively. In some cases, striate cortex activation as documented with EEG and PET confirmed these observations. Conclusions We propose that IMTES-induced restoration of vision is not only mediated by improved optic nerve function but it also activates striate and extrastriate cortex in which plasticity is physiologically induced.
7. Fedorov A, GN. Bisaga, AN Chibisova, VI Golovkin The clinico-physiological substantiation of indications to therapeutic electrical stimulation method used for purpose the treatment optic nerve atrophy at multiple sclerosis. Int Medical J 1998. 11-12 P.967-70
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There were studied 43 patients with the definite diagnosis of multiple sclerosis, the average age – 35,4 + 1,5 years, duration of disease 6,5 + 1,1 years, disability on the scale of J.Kurtzke DSS (1961) – 2,4 + 0,4. We find in 73 of the supervisioned eyes a moderately expressed atrophia of visual nerves, in 13 – the more marked atrophia of visual nerves. Initial acuity 0 – 0,09 – at 47 patients (54,6 %) and 0,1 – 1,0 – at 39 (45,4 %).
Treatment by a method of the therapeutic electrical stimulation carried out with the help of specialized electric stimulator Phosphen. Through 10 sessions of treatment the visual acuity increased in 54.1 % of cases, the visual fields have extended in 27.3 %. The total positive changes of acuity, visual fields and subjective visual sensations were fixed at 52 of 84 (61.9 %) eyes or at 32 of 42 (76.2 %) patients. The improvement of acuity during treatment was in inverse proportion to a disability of the patients (r=-0.40; p=0.021). The duration of the disease did not much influence results of the restoration of visual acuity. The rather best acuity improvement is marked at a greater degree of its decrease.
The treatment of the visual nerves atrophia with the help of the therapeutic electrical stimulation is the most adequate method, as the electrical pulses are capable to remove from a parabiosis morphologicalli unchanged fibres. The efficiency of the therapeutic electrical stimulation is maximum at an easy or moderate degree of multiple sclerosis disability, especially in the remission. However, even at deep atrophia of visual nerves, the realization therapeutic electrical stimulation also is possible to consider justified.
8. Bola M, Gall C, Moewes C, Fedorov A, Hinrichs H, Sabel BA. Brain functional connectivity network breakdown and restoration in blindness. Neurology. 2014 Aug 5;83(6):542-51
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OBJECTIVE: To characterize brain functional connectivity in subjects with prechiasmatic visual system damage and relate functional connectivity features to
extent of vision loss. METHODS: In this case-control study, resting-state, eyes-closed EEG activity was
recorded in patients with partial optic nerve damage (n = 15) and uninjured controls (n = 13). We analyzed power density and functional connectivity (coherence, Granger causality), the latter as (1) between-areal coupling strength
and (2) individually thresholded binary graphs. Functional connectivity was then modulated by noninvasive repetitive transorbital alternating current stimulation (rtACS; 10 days, 40 minutes daily; n = 7; sham, n = 8) to study how this would affect connectivity networks and perception. RESULTS: Patients exhibited lower spectral power (p = 0.005), decreased short- (p= 0.015) and long-range (p = 0.033) coherence, and less densely clustered coherence networks (p = 0.025) in the high-alpha frequency band (11-13 Hz). rtACS strengthened short- (p = 0.003) and long-range (p = 0.032) alpha coherence and this was correlated with improved detection abilities (r = 0.57, p = 0.035) and processing speed (r = 0.56, p = 0.049), respectively. CONCLUSION: Vision loss in the blind is caused not only by primary tissue damage but also by a breakdown of synchronization in brain networks. Because visual field improvements are associated with resynchronization of alpha band coherence, brain connectivity is a key component in partial blindness and in restoration of vision.
9. Henrich-Noack P, Voigt N, Prilloff S, Fedorov A, Sabel BA. Transcorneal electrical stimulation alters morphology and survival of retinal ganglion cells after optic nerve damage. Neurosci Lett. 2013 May 24;543:1-6.
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Traumatic optic nerve injury leads to retrograde death of retinal ganglion cells (RGCs), but transcorneal electrical stimulation (TES) can increase the cell survival rate. To understand the mechanisms and to further define the THERAPEUTICAL ELECTRICAL STIMULATION-induced effects we monitored in living animals RGC morphology and survival after optic nerve crush (ONC) in real time by using in vivo confocal neuroimaging (ICON) of the retina. optic nerve crush was performed in rats and ICON was performed before crush and on post-lesion days 3, 7 and 15 which allowed us to repeatedly record RGC number and size. TES or sham-stimulation were performed immediately after the crush and on post-injury day 11. Three days after optic nerve crush we detected a higher percentage of surviving RGCs in the TES group as compared to sham-treated controls. However, the difference was below significance level on day 7 and disappeared completely by day 15. The death rate was more variable amongst the TES-treated rats than in the control group. Morphological analysis revealed that average cell size changed significantly in the control group but not in stimulated animals and the morphological alterations of surviving neurons were smaller in THERAPEUTICAL ELECTRICAL STIMULATION-treated compared to control cells. In conclusion, TES delays post-traumatic cell death significantly. Moreover, we found “responder animals” which also benefited in the long-term from the treatment. Our in vivo cellular imaging results provide evidence that TES reduces optic nerve crush-associated neuronal swelling and shrinkage especially in RGCs which survived long-term. Further studies are now needed to determine the differences of responders vs. non-responders.
10. Henrich-Noack P, Lazik S, Sergeeva E, Wagner S, Voigt N, Prilloff S, Fedorov A, Sabel BA. Transcorneal alternating current stimulation after severe axon damage in rats results in “long-term silent survivor” neurons. Brain Res Bull. 2013 Jun;95:7-14
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Transcorneal alternating current stimulation (tACS) was proposed to decrease acute death of retinal ganglion cells after optic nerve transection in rats, but it is not known if cell survival is long-term and associated with functional restoration. We therefore evaluated the effects of transcorneal alternating current stimulation in a rat model of optic nerve crush using anatomical, electrophysiological and behavioural measures. Rats were trained in a brightness discrimination visual task and the retinal ganglion cell number was quantified with in vivo confocal neuroimaging. Thereafter, severe optic nerve crush or sham crush was performed and rats were treated under
anaesthesia either with transcorneal alternating current stimulation or sham stimulation immediately after the lesion and on day 3, 7, 11, 15, 19 and 23. Brightness discrimination was evaluated for 6 weeks and retinal ganglion cells were counted in vivo on post-crush days 7 and 28. In additional rats we studied the influence of transcorneal alternating current stimulation on bioelectrical activity. On post-lesion day 28, the tACS-treated group showed a neuronal survival of 28.2% which was significantly greater than in sham operates (8.6%). All animals with optic nerve crush were significantly impaired in brightness discrimination and did not recover performance, irrespective to which group they belonged. In accordance with this, there was no significant influence of the stimulation on EEG power spectra. In conclusion, transcorneal alternating current stimulation induced long-term neuronal protection from delayed retrograde cell death, but in this case of severe axonal damage transcorneal alternating current stimulation did not influence functional restoration and EEG signals recorded over the visual cortex
11. Sergeeva EG, Fedorov A, Henrich-Noack P, Sabel BA. Transcorneal alternating current stimulation induces EEG “aftereffects” only in rats with an intact visual system but not after severe optic nerve damage. J Neurophysiol. 2012 Nov;108(9):2494-500
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Noninvasive alternating current stimulation can induce vision restoration in patients with chronic optic nerve damage and results in electroencephalogram (EEG) aftereffects. To better understand the mechanisms of action, we studied such EEG “aftereffects” of transcorneal alternating current stimulation (tACS) at the chronic posttraumatic state in rats. EEG baseline was recorded from visual cortex under ketamine/xylazine narcosis of healthy rats and rats with chronic severe optic nerve crush. One week later, both groups were again anesthetized and stimulated transcorneally twice for 12 min each time. tACS-induced changes were compared with baseline EEG. Over the course of 65 min narcosis baseline EEG revealed a shift from a dominant delta power to theta. This shift was significantly delayed in lesioned animals compared with healthy controls. transcorneal alternating current stimulation applied during the late narcosis stage in normal rats led to significantly increased theta power with a parallel shift of the dominating peak to higher frequency which outlasted the stimulation period by 15 min (aftereffects). EEG in lesioned rats was not significantly changed. In rodents, tACS can induce neuroplasticity as shown by EEG aftereffects that outlast the stimulation period. But this requires a minimal level of brain activation because aftereffects are not seen when transcorneal alternating current stimulation is applied during deep anesthesia and not when applied to animals after severe optic nerve damage.
We conclude that tACS is only effective to induce cortical plasticity when the the retina can be excited.
12. Sabel BA, Fedorov A, Naue N, Borrmann A, Herrmann C, Gall C. Non-invasive alternating current stimulation improves vision in optic nerve damage. Restor Neurol Neurosci. 2011;29(6):493-505
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PURPOSE: Partial blindness after visual system damage is considered irreversible, yet the brain has residual visual capacities and considerable plasticity potential. We now applied non-invasive alternating current stimulation (ACS) to the visual system of patients with optic nerve damage with the aim to induce recovery of visual functions. METHODS: In a prospective, double-blind, randomized, placebo-controlled clinical trial patients with several year old partial optic nerve lesions were treated with ACS (n = 12) or placebo-stimulation (n = 10). ACS was delivered transorbitally for 40 minutes on 10 days. Visual outcome measures and EEG were measured before and after treatment. RESULTS: ACS, but not placebo, led to significant improvement of a visual field detection deficit by 69%, and also significantly improved temporal processing of visual stimuli, detection performance in static perimetry, and visual acuity. These changes were associated with alpha-band changes in the EEG power spectra. Visual improvements were stable for at least 2-months. CONCLUSIONS: ACS can induce vision restoration many years after optic neuropathy. Though the mechanism is still unclear, EEG changes indicate increased synchronization in posterior brain regions. The present study provides Class Ib evidence that non-invasive transorbital ACS is well tolerated and improves visual function in optic neuropathy.
13. Gall C, Sgorzaly S, Schmidt S, Brandt S, Fedorov A, Sabel BA. Noninvasive transorbital alternating current stimulation improves subjective visual functioning and vision-related quality of life in optic nerve damage. Brain Stimul. 2011 Oct;4(4):175-88. doi: 10.1016/j.brs.2011.07.003. Epub 2011 Oct 6
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BACKGROUND: Noninvasive repetitive transorbital alternating current stimulation (rtACS) can improve visual field size in patients with optic nerve damage, but it is not known if this is of subjective relevance. We now assessed patient reported outcomes to determine the association between visual field changes and vision-related quality of life (QoL). METHODS: Patients having visual field impairments long after optic nerve damage (mean lesion age 5.5 years) were randomly assigned to a rtACS (n = 24) or sham stimulation group (n = 18). Visual fields and patient reported outcome measures (vision-related QoL: National Eye Institute Visual Function Questionnaire, NEI-VFQ and health-related QoL: Short Form Health Survey, SF-36) were collected before and after a 10-day treatment course with daily sessions of 20 to 40 minutes. The primary outcome measure was the percent change from baseline of detection ability (DA) in defective visual field sectors as defined by computer-based high resolution perimetry (HRP). Secondary outcome parameters included further HRP parameters as well as static and kinetic perimetry results. Changes in QoL measures were correlated with changes in primary and secondary outcome measures in both groups. RESULTS: DA increase in the defective visual field was significantly larger after rtACS (41.1 ± 78.9%, M ± SD) than after sham stimulation (13.6 ± 26.3%), P < 0.05. While there was a significant increase of DA in the whole tested HRP visual field after rtACS (26.8 ± 76.7%, P < 0.05), DA in sham-stimulation patients remained largely unchanged (2.7 ± 20.2%, ns). Results of secondary outcome measures (static and kinetic perimetry) provided further evidence of rtACS efficacy. Improvements in NEI-VFQ subscale “general vision” were observed in both groups but were larger in the rtACS group (11.3 ± 13.5, Z = -3.21, P < 0.001) than in the sham group (4.2 ± 9.4, Z = -1.73, P < 0.05) with a significant difference between groups (Z = -1.71, P < 0.05). DA change and some NEI-VFQ domains were correlated (r = 0.29, P < 0.05), but no significant correlations were observed between DA and SF-36 results. CONCLUSIONS: rtACS facilitates vision restoration after unilateral, long-term optic nerve lesion as assessed both by objective DA changes and improvements in some NEI-VFQ subscales. Both were positively but low correlated, which suggests that factors other than visual field size also contribute to improved vision-related QoL.
14. Sabel BA, Henrich-Noack P, Fedorov A, Gall C. Vision restoration after brain and retina damage: the “residual vision activation theory”. Prog Brain Res. 2011;192:199-262
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Vision loss after retinal or cerebral visual injury (CVI) was long considered to be irreversible. However, there is considerable potential for vision restoration and recovery even in adulthood. Here, we propose the “residual vision activation theory” of how visual functions can be reactivated and restored. CVI is usually not complete, but some structures are typically spared by the damage. They include (i) areas of partial damage at the visual field border, (ii) “islands” of surviving tissue inside the blind field, (iii) extrastriate pathways unaffected by the damage, and (iv) downstream, higher-level neuronal networks. However, residual structures have a triple handicap to be fully functional: (i) fewer neurons, (ii) lack of sufficient attentional resources because of the dominant intact hemisphere caused by excitation/inhibition dysbalance, and (iii) disturbance in their temporal processing. Because of this resulting activation loss, residual structures are unable to contribute much to everyday vision, and their “non-use” further impairs synaptic strength. However, residual structures can be reactivated by engaging them in repetitive stimulation by different means: (i) visual experience, (ii) visual training, or (iii) noninvasive electrical brain current stimulation. These methods lead to strengthening of synaptic transmission and synchronization of partially damaged structures (within-systems plasticity) and downstream neuronal networks (network plasticity). Just as in normal perceptual learning, synaptic plasticity can improve vision and lead to vision restoration. This can be induced at any time after the lesion, at all ages and in all types of visual field impairments after retinal or brain damage (stroke, neurotrauma, glaucoma, amblyopia, age-related macular degeneration). If and to what extent vision restoration can be achieved is a function of the amount of residual tissue and its activation state. However, sustained improvements require repetitive stimulation which, depending on the method, may take days (noninvasive brain stimulation) or months (behavioral training). By becoming again engaged in everyday vision, (re)activation of areas of residual vision outlasts the stimulation period, thus contributing to lasting vision restoration and improvements in quality of life
15. Gall C, Fedorov AB, Ernst L, Borrmann A, Sabel BA. Repetitive transorbital alternating current stimulation in optic nerve damage. NeuroRehabilitation. 2010;27(4):335-41
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BACKGROUND: Visual field defects after optic nerve damage typically show a limited capacity for spontaneous and treatment-induced recovery. OBJECTIVE: Repetitive transorbital alternating current stimulation (rtACS) was applied to the damaged optic nerve to evaluate visual functions after stimulation. METHODS: A 27-years-old male patient suffering left optic nerve atrophy with nearly complete loss of vision 11 years after atypical traumatic damage was treated transorbitally with biphasic 10-15 pulse trains of rtACS (10-30 Hz, < 600 μA, 30-40 min daily for 10 days) which produced phosphenes. RESULTS: After rtACS treatment detection ability of super-threshold stimuli increased from 3.44% to 17.75% and mean perimetric threshold from 0 dB to 2.21 dB at final diagnostics. CONCLUSION: This improvement of vision may be due to increased neuronal synchronization, possibly involving strengthening of synaptic transmission along the central visual pathway.
16. Chibisova AN, Bersnev VP, Fedorov A, Chibisova JM Neurophysiologic mechanisms of restoration process for patients with optic nerve damage by the method of impulsive modulating electric influences. Kazan neurologic journal 2008 V.4. P. 678-68
17. A Chibisova, A Fedorov, N Fedorov Neurophysiologic features of compensatory brain process at the rehabilitation of sensoneural disturbances of visual and hearing system. J Hum Physiol. 2001, V.3 14-21
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Compensatory rehabilitative reorganization of brain functions upon medical modulating electric treatment directed at afferent inputs of the impaired visual or acoustic systems is considered. General and specific characteristics of the reorganization of brain functioning aimed at compensating visual or hearing defects were revealed by estimating the electroencephalogram (EEG) dynamics and evoked potentials (EP). Electrographic correlates of the transitory and compensated states of the brain in rehabilitation of the disturbed sensory functions were established. Short-term functional structures sharing Δ, α, and θ synchronization patterns were revealed. These structures reflect sequential participation of specific and nonspecific brain systems in the reorganization of brain functioning. Specific interactions between the damaged and the intact sensory systems were found, which indicated common nonspecific mechanisms for processing acoustic and visual afference. The existence of a programmed central mechanism that compensates the disturbed functions of the sensory systems is suggested.
18. AN Chibisova, Fedorov A, J.G.Chastova Neurophysiological aspects of compensatory processes at cerebrospinal fluid therapy of central vision alterations. J Hum Physiol. 1999. Т. 25. 3. P.41-7
19. AS Kiselev, Fedorov A, YeM Tsirulnikov, AN Shandurina Comparative analysis of electrostimulation data and elecrtode localization in sensorineural hypoacusis // Journal Ear, Nose and Gullet Illness. 1995. V 4/5. P. 11-6
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