Personality and stress influence vision restoration and recovery in glaucoma and optic neuropathy following alternating current stimulation: implications for personalized neuromodulation and rehabilitation.

PURPOSE: Identifying factors that affect recovery or restoration of neurological function is a key goal of rehabilitation in neurology and ophthalmology. One such factor can be prolonged mental stress, which may be not only the consequence of nervous system damage but also a major risk factor, or cause, of neural inactivation. Using the visual system as a model of neural injury, we wished to study how patients' stress and personality profiles correlate with vision recovery as induced by therapy with alternating current stimulation (ACS) in patients with optic nerve damage. METHODS: Personality and stress questionnaires were sent retrospectively to a clinical convenience sample of patients who suffer low vision due to optic nerve damage, which had previously been treated with ACS. The questionnaires included the NEO Five-Factor Inventory (NEO-FFI), the Trier Inventory of Chronic Stress (TICS), and the Flammer syndrome (FS) checklist, which probes signs of vascular dysregulation (VD). These scores were then correlated with the extent of ACS-induced vision restoration as recorded 1-3 years earlier by perimetric visual field tests. RESULTS: Two NEO-FFI personality factors (lower neuroticism, higher conscientiousness) and the presence of physiological Flammer signs were associated with greater recovery as were individual items of the factors openness and agreeableness. Single NEO-FFI item analysis revealed that recovery relates to greater extraversion (optimistic and happy), openness (less guided by authorities for decisions on moral issues), and agreeableness (argue less, like working with others, thoughtful, considerate) as well as the presence of FS signs (cold hands/feet, hypotension, slim body shapes, tinnitus). This suggests that patients with better recovery were more calm, peaceful and secure, hard-working, and reliable, and with high organizational skills. In contrast, patients with poor recovery had a tendency to be emotionally unstable, anxious, unhappy and prone to negative emotions, impulsive, careless, and unorganized. Chronic stress assessed with TICS did not correlate with recovery. CONCLUSION: Vision restoration induced by ACS is greater in patients with less stress-prone personality traits and those who show signs of VD. Prospective studies are now needed to determine if personality has (i) a causal influence, i.e., patients with less stress-prone personalities and greater VD signs recover better, and/or (ii) if personality changes are an effect of the treatment, i.e., successful recovery induces personality changes. Though the cause-effect relationship is still open, we nevertheless propose that psychosocial factors and VD contribute to the highly variable outcome of vision restoration treatments in low vision rehabilitation. This has implications for preventive and personalized vision restoration and is of general value for our understanding of outcome variability in neuromodulation and neurological rehabilitation.

[Are Visual Field Defects Reversible? - Visual Rehabilitation with Brains]. / Sind Gesichtsfelddefekte doch reversibel? ­ Visuelle Rehabilitation mit Gehirn.

Visual field defects are considered irreversible because the retina and optic nerve do not regenerate. Nevertheless, there is some potential for recovery of the visual fields. This can be accomplished by the brain, which analyses and interprets visual information and is able to amplify residual signals through neuroplasticity. Neuroplasticity refers to the ability of the brain to change its own functional architecture by modulating synaptic efficacy. This is actually the neurobiological basis of normal learning. Plasticity is maintained throughout life and can be induced by repetitively stimulating (training) brain circuits. The question now arises as to how plasticity can be utilised to activate residual vision for the treatment of visual field loss. Just as in neurorehabilitation, visual field defects can be modulated by post-lesion plasticity to improve vision in glaucoma, diabetic retinopathy or optic neuropathy. Because almost all patients have some residual vision, the goal is to strengthen residual capacities by enhancing synaptic efficacy. New treatment paradigms have been tested in clinical studies, including vision restoration training and non-invasive alternating current stimulation. While vision training is a behavioural task to selectively stimulate "relative defects" with daily vision exercises for the duration of 6 months, treatment with alternating current stimulation (30 min. daily for 10 days) activates and synchronises the entire retina and brain. Though full restoration of vision is not possible, such treatments improve vision, both subjectively and objectively. This includes visual field enlargements, improved acuity and reaction time, improved orientation and vision related quality of life. About 70 % of the patients respond to the therapies and there are no serious adverse events. Physiological studies of the effect of alternating current stimulation using EEG and fMRI reveal massive local and global changes in the brain. These include local activation of the visual cortex and global reorganisation of neuronal brain networks. Because modulation of neuroplasticity can strengthen residual vision, the brain deserves a better reputation in ophthalmology for its role in visual rehabilitation. For patients, there is now more light at the end of the tunnel, because vision loss in some areas of the visual field defect is indeed reversible.

Repetitive Transcorneal Alternating Current Stimulation Reduces Brain Idling State After Long-term Vision Loss.

BACKGROUND: Deafferentation of visual system structures following brain or optic nerve injury leaves cortical areas deprived of visual input. Deprived cortical areas have a reduced sensory information processing and are characterized with localized enhanced or synchronized rhythms believed to represent an "idling state". OBJECTIVE/HYPOTHESIS: We hypothesized that cortical idling can be modified with transcorneal alternating current stimulation (tACS) known to modulate cortical oscillations and thus change the functional state of the deafferented areas. METHODS: tACS was applied in rat model of severe optic nerve crush using a protocol similar to our clinical studies (200 µA, 2-8 Hz) for 5 treatment days right after the lesion and at the chronic stage (3 months later). EEG and VEP were recorded over the visual cortices. In vivo confocal neuroimaging of the retina and histology of the optic nerves were performed. RESULTS: Morphological investigations showed massive retinal ganglion cells death and degeneration of the optic nerves after crush. Visual loss was associated with increased EEG spectral power and lower coherence, indicating an "idling state". Stimulation induced a significant decrease of EEG power towards normal values. These effects were especially pronounced in the chronic stage. CONCLUSION: Our results suggest that alternating current injected via the eye is able to modulate visually deprived brain areas and thus reduce cortical idling.

Restoration of vision after optic nerve lesions with noninvasive transorbital alternating current stimulation: a clinical observational study.

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 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.

Deficits of respiratory-cardiac coupling in heavy drinkers.

1. Physiological evidence of chronic alcohol abuse prior to the onset of clinical signs of alcohol dependence is difficult to obtain The purpose of this study was to search for possible non-invasive indicators for chronic alcohol consumption yielding information in addition to conventional biological markers. 2. The authors investigated the relationship between respiratory-cardiac coupling and blood alcohol concentration (BAC) in male subjects who lost their driver's license from drunk driving. 3. We found that subjects who had a high BAC level (0.16-0.31% at the time of offense) show altered respiratory sinus arrhythmia (RSA) and, in particular, an altered heart-rate response to auditory stimulation and compared them to a control group of social drinkers. Normal subjects showed a pronounced acoustic heart-rate response, i.e., particularly during expiration there was a difference between the interbeat-interval (IBI) traces with and without auditory stimulation. Subjects who had lost their driver's license from drunk driving had an overall severely reduced heart-rate response, that was even absent particularly in the subgroup having high BAC values (0.21-0.31%). The authors also found some evidence that in the latter subgroup IBI, RSA, and acoustic heart-rate responses partially recover after a six-month period of abstinence. 4. Specific parameters of the acoustic heart-rate response are changed in our group of alcohol abusers presumably, due to impairment of vagal function. These parameters may therefore be useful to serve as a non-invasive measure of alcohol abuse.

Subchronically applied phencyclidine fails to disrupt prepulse inhibition in rats.

To simulate psychosis in rats, the psychotomimetic agent phencyclidine (PCP, 5.0 mg/kg) was administered either by daily pulsatile injections or by continuous delivery with subcutaneously implanted, PCP-loaded controlled release polymers for a 5 day period. The acoustic startle response (ASR) and the prepulse inhibition (PPI) were then assessed 15 and 60 min as well as 24 h after the PCP application was discontinued. An impaired PPI occurred only under the acute influence of the last PCP injection, i.e. 15 and 60 min after last PCP treatment when it had previously been given in a pulsatile manner but not when it was administered continuously. The ASR to unpaired stimuli after PCP was not modified. These findings suggest that disruption of PPI occurs only under the acute influence of PCP and that PPI deficits are not primarily the consequence of structural brain damage which PCP produces.

Caldendrin, a novel neuronal calcium-binding protein confined to the somato-dendritic compartment.

Using antibodies against synaptic protein preparations, we cloned the cDNA of a new Ca2+-binding protein. Its C-terminal portion displays significant similarity with calmodulin and contains two EF-hand motifs. The corresponding mRNA is highly expressed in rat brain, primarily in cerebral cortex, hippocampus, and cerebellum; its expression appears to be restricted to neurons. Transcript levels increase during postnatal development. A recombinant C-terminal protein fragment binds Ca2+ as indicated by a Ca2+-induced mobility shift in SDS-polyacrylamide gel electrophoresis. Antisera generated against the bacterial fusion protein recognize a brain-specific protein doublet with apparent molecular masses of 33 and 36 kDa. These data are confirmed by in vitro translation, which generates a single 36-kDa polypeptide, and by the heterologous expression in 293 cells, which yields a 33/36-kDa doublet comparable to that found in brain. On two-dimensional gels, the 33-kDa band separates into a chain of spots plausibly due to differential phosphorylation. This view is supported by in situ phosphorylation studies in hippocampal slices. Most of the immunoreactivity is detectable in cytoskeletal preparations with a further enrichment in the synapse-associated cytomatrix. These biochemical data, together with the ultra-structural localization in dendrites and the postsynaptic density, strongly suggest an association with the somato-dendritic cytoskeleton. Therefore, this novel Ca2+-binding protein was named caldendrin.

Changes in rapidly transported proteins associated with development of abnormal projections in the diencephalon.

The development of the hamster visual system is accompanied by striking changes in the pattern of proteins that are synthesized in retinal ganglion cells and rapidly transported to their nerve terminals. To determine whether any of these protein changes are regulated by interactions between the developing nerve endings and the cells with which they form synapses, we induced retinofugal axons to form abnormal projections in the lateral posterior (LP) nucleus of the thalamus and dense patches of hyperinnervation in the lateral geniculate nucleus (LGN) by removing their principal target, the superior colliculus (SC), the day after birth. Under these experimental conditions, two rapidly transported proteins, including the neural cell adhesion molecule, NCAM, showed significant changes in their time course of expression. NCAM, identified here using a monospecific antibody, is normally synthesized and transported at high levels at early stages of development and then declines during the second and third postnatal weeks. However, this decline was delayed when optic fibers were re-routed. A second rapidly transported protein, M(r) = 67 kDa, pI = 4.7, normally shows a rise in its synthesis and transport during terminal arbor formation and a subsequent decline, but it also remained elevated for a prolonged period when the SC was absent. These findings cannot be accounted for by a simple delay in the retinal ganglion cells' program of axonal growth, since other rapidly transported proteins, including the growth-associated protein GAP-43, showed a normal developmental time-course when the SC was removed. Target interactions therefore appear to influence the retinal ganglion cells' expression of different proteins in a specific fashion.

Interhemispheric nigrothalamic projections and behavioral recovery following turning behavior induced by unilateral peripheral sensory and motor restriction.

We investigated the relationship between unilateral peripheral lesions plus partial sensory deprivation and interhemispheric nigrothalamic projections. Sensory-motor asymmetries were induced in rats by unilateral ligature of sensory and motor nerves of the forelimbs and hind limbs and partial sensory deprivation (cutting the vibrissae unilaterally and suturing one eyelid). This operation resulted in spontaneous turning which was partially compensated for within the first 5 postoperative days. Sixteen days after the surgery, animals were implanted with horseradish peroxidase in the ventrobasal thalamus of one hemisphere. Brains were processed by the tetramethylbenzidine procedure. Microscopical analysis revealed interhemispheric nigrothalamic projections from the substantia nigra situated ipsilateral but not contralateral to the denervated limbs. The results are interpreted in terms of a reorganization (sprouting) of interhemispheric nigrothalamic projections in response to unilateral peripheral lesions. The lesion-induced behavioral asymmetry and its partial compensation may be one of the determinants of the observed neuronal plasticity.