Michał Bola

Brain functional connectivity network breakdown and restoration in blindness

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.

The Second Face of Blindness: Processing Speed Deficits in the Intact Visual Field after Pre- and Post-Chiasmatic Lesions

Purpose Damage along the visual pathway results in a visual field defect (scotoma), which retinotopically corresponds to the damaged neural tissue. Other parts of the visual field, processed by the uninjured tissue, are considered to be intact. However, perceptual deficits have been observed in the “intact” visual field, but these functional impairments are poorly understood. We now studied temporal processing deficits in the intact visual field of patients with either pre- or post-chiasmatic lesions to better understand the functional consequences of partial blindness. Methods Patients with pre- (n = 53) or post- chiasmatic lesions (n = 98) were tested with high resolution perimetry – a method used to map visual fields with supra-threshold light stimuli. Reaction time of detections in the intact visual field was then analyzed as an indicator of processing speed and correlated with features of the visual field defect. Results Patients from both groups exhibited processing speed deficits in their presumably “intact” field as indicated by comparison to a normative sample. Further, in both groups processing speed was found to be a function of two factors. Firstly, a spatially restricted (retinotopic) influence of the scotoma was seen in longer reaction times when stimuli were presented in intact field sectors close to the defect. Secondly, patients with larger scotomata had on average longer reaction times in their intact field indicating a more general (non-retinotopic) influence of the scotoma. Conclusions Processing speed deficits in the “intact” visual field of patients with visual system damage demonstrate that visual system lesions have more widespread consequences on perception than previously thought. Because dysfunctions of the seeing field are expected to contribute to subjective vision, including visual tests of the presumed “intact” field may help to better understand vision loss and to improve methods of vision restoration and rehabilitation.

“Sightblind”: Perceptual Deficits in the “Intact” Visual Field

Unilateral visual cortex lesions caused by stroke or trauma lead to blindness in contralateral visual field – a condition called homonymous hemianopia. Although the visual field area processed by the uninjured hemisphere is thought to be “intact,” it also exhibits marked perceptual deficits in contrast sensitivity, processing speed, and contour integration. Such patients are “sightblind” – their blindness reaches far beyond the primary scotoma. Studies showing perceptual deficits in patients’ intact fields are reviewed and implications of these findings are discussed. It is concluded that consequences of partial blindness are greater than previously thought, since perceptual deficits in the “intact” field likely contribute to subjective vision loss in patients with visual field defect. This has important implications for vision diagnosis and rehabilitation.

Alternating Current Stimulation for Vision Restoration after Optic Nerve Damage: A Randomized Clinical Trial

Background Vision loss after optic neuropathy is considered irreversible. Here, repetitive transorbital alternating current stimulation (rtACS) was applied in partially blind patients with the goal of activating their residual vision. Methods We conducted a multicenter, prospective, randomized, double-blind, sham-controlled trial in an ambulatory setting with daily application of rtACS (n = 45) or sham-stimulation (n = 37) for 50 min for a duration of 10 week days. A volunteer sample of patients with optic nerve damage (mean age 59.1 yrs) was recruited. The primary outcome measure for efficacy was super-threshold visual fields with 48 hrs after the last treatment day and at 2-months follow-up. Secondary outcome measures were near-threshold visual fields, reaction time, visual acuity, and resting-state EEGs to assess changes in brain physiology. Results The rtACS-treated group had a mean improvement in visual field of 24.0% which was significantly greater than after sham-stimulation (2.5%). This improvement persisted for at least 2 months in terms of both within- and between-group comparisons. Secondary analyses revealed improvements of near-threshold visual fields in the central 5° and increased thresholds in static perimetry after rtACS and improved reaction times, but visual acuity did not change compared to shams. Visual field improvement induced by rtACS was associated with EEG power-spectra and coherence alterations in visual cortical networks which are interpreted as signs of neuromodulation. Current flow simulation indicates current in the frontal cortex, eye, and optic nerve and in the subcortical but not in the cortical regions. Conclusion rtACS treatment is a safe and effective means to partially restore vision after optic nerve damage probably by modulating brain plasticity. This class 1 evidence suggests that visual fields can be improved in a clinically meaningful way. Trial Registration ClinicalTrials.gov NCT01280877

Non-invasive electric current stimulation for restoration of vision after unilateral occipital stroke

Occipital stroke often leads to visual field loss, for which no effective treatment exists. Little is known about the potential of non-invasive electric current stimulation to ameliorate visual functions in patients suffering from unilateral occipital stroke. One reason is the traditional thinking that visual field loss after brain lesions is permanent. Since evidence is available documenting vision restoration by means of vision training or non-invasive electric current stimulation future studies should also consider investigating recovery processes after visual cortical strokes. Here, protocols of repetitive transorbital alternating current stimulation (rtACS) and transcranial direct current stimulation (tDCS) are presented and the European consortium for restoration of vision (REVIS) is introduced. Within the consortium different stimulation approaches will be applied to patients with unilateral occipital strokes resulting in homonymous hemianopic visual field defects. The aim of the study is to evaluate effects of current stimulation of the brain on vision parameters, vision-related quality of life, and physiological parameters that allow concluding about the mechanisms of vision restoration. These include EEG-spectra and coherence measures, and visual evoked potentials. The design of stimulation protocols involves an appropriate sham-stimulation condition and sufficient follow-up periods to test whether the effects are stable. This is the first application of non-invasive current stimulation for vision rehabilitation in stroke-related visual field deficits. Positive results of the trials could have far-reaching implications for clinical practice. The ability of non-invasive electrical current brain stimulation to modulate the activity of neuronal networks may have implications for stroke rehabilitation also in the visual domain.

Brain-state-dependent non-invasive brain stimulation and functional priming: a hypothesis

The aim of using non-invasive brain stimulation techniques in neurorehabilitation is to improve neurological function by modulating brain plasticity in the specific areas of the brain. The fundamental idea of current stimulation treatment is that it alters cortical excitability so as to enhance plasticity in subsequent perceptual or motor training. Another goal is to achieve an entrainment of brain oscillations with external currents, which are delivered at certain frequencies to improve the functions by altering physiological activity that outlasts the stimulation period [see for review, Nitsche and Paulus, 2011; Antal and Paulus, 2013]. However, such approaches often do not consider that the brain is a dynamical system with activity levels and connectivity patterns constantly changing in a highly variable, and so far non-predictable, manner. But it has been known that processing of external (e.g., visual) stimuli depends to some extent on the instantaneous state of brain networks at stimulus onset. Similarly, the effects of the stimulation depend not only on the predefined parameters but also on the state of the brain before and during the stimulation (Silvanto et al., 2007, 2008; Herrmann et al., 2013; Neuling et al., 2013). However, the translation of these findings into clinical practice was so far not realized. In this respect a recent study by Gharabaghi et al. (2014) is of particular interest. These authors explored the possibility of using a brain-state-dependent stimulation (BSDS) approach in post-stroke patients. Here, the subjects were instructed to imagine opening a hand (without actually doing so, moreover, the patient was not capable of hand opening) in order to achieve desynchronization of beta band oscillations within the motor neural circuits. To facilitate the execution of EEG desynchronization, a contingent haptic biofeedback to the hand was provided. Transcranial magnetic pulses were then applied to the motor cortex but only if such desynchronization was achieved, as shown by concurrently recorded EEG. Both in a healthy control volunteer and in a patient with severe hemiparesis, BSDS induced a significant increase in excitability of the motor cortex as measured by motor evoked potentials (MEP). Notably, that only BSDS evoked substantial increase of MEP amplitude, while the stimulation pulses applied without the motor-related EEG desynchronization evoked MEP amplitude decrease, though different TMS stimulation paradigms applied independent of the brain state are currently explored to improve motor function after stroke. An important aspect of the Gharabaghi et al. study (Gharabaghi et al., 2014) is the fact that the brain stimulation was not applied prior to or alternating with motor exercise, but during the neurohabilitation training. This suggests that not “simple” excitability changes were involved here (when excitability is modified by TMS through the whole stimulated area independent on specific functional activity), but that additional mechanisms were involved that altered the brain’s response to the external manipulation. The authors propose that volitional modulation of brain activity with motor imagery improved susceptibility of inherent motor circuits to TMS pulses, perhaps due to voluntary depolarization of intracortical connections targeting pyramidal tract neurons and decrease of the motor cortical excitability as did motor imagery with haptic feedback alone. Though this experiment involved only one healthy subject and one stroke patient, this finding nevertheless is novel because it may lead to new concepts of how brain stimulation may act: in order for plastic changes to emerge in a certain brain area, the central network, and external stimulation drive should be temporally and spatially related. In line with the study from Gharabaghi et al. (2014) is the finding that the endogenous power of brain oscillations (changing with anesthesia stages) has a huge impact on the “aftereffects” of alternating current stimulation (ACS) (Sergeeva et al., 2012). Moreover, Neuling et al. (2013) demonstrated that when the timing was just right, the phase alignment of intrinsic oscillators with the external stimulation lead to an increased amplitude of the response. The importance of the actual brain state to determine behavioral and perceptual effects of TMS and TDS was already addressed by Silvanto et al. (2008). They showed that prior manipulation of neural activation enabled TMS to selectively target populations of neurons to increase functional resolution and achieve a selective excitation of task-related areas (Silvanto et al., 2007). Therefore, the BSDS as described by Gharabaghi et al. (2014) may permit to accurately stimulate the brain, thereby improving task performance as a function of altered excitability in the areas, which were functionally primed. This consideration of state-dependent stimulation is novel in the context of brain current stimulation, though it follows the early theory by Sherrington (1965), and implies that the arousal of brain structures by natural tasks leads to a certain neural constellations of excitation and inhibition, which may serve as an immanent substrate for external stimuli. Since the processing of these stimuli is dependent not only on their physical properties but also on the intrinsic constitution of the stimulated system, we hypothesize that a pre-set task-primed system may show greater responsiveness in terms of better functional output to neuromodulation by brain stimulation. The modulation of brain activity with non-invasive current stimulation has become tremendously popular. But the major concern is how to improve their precision and effectiveness. We therefore expect that future neuromodulation approaches use increasingly more fine-tuned BSDS similar to those we have witnessed most recently with optogenetic approaches (Zemelman et al., 2002): just like the light can specifically activate cells that have optogenetic sensors, the current injection patterns could be controlled to just activate or inhibit particular (primed) neuronal populations. In this manner, functional priming of certain brain areas and even groups of neurons prior or during the current/magnetic stimulation would be a possible solution to better control efficacy and safety of non-invasive brain current stimulation. Because the state of brain networks in patients is likely to be altered, as it was observed in our laboratory in patients with visual system damage (Bola et al., 2014), the stimulation protocols known to exert certain effects in healthy subjects might not work in the same way in patients. Therefore, while it is desirable to discover general principles of priming-dependent stimulation effects in normal subjects, it might be difficult to define protocols optimal for all patients suffering from a certain condition. Rather, stimulation methods should be used in combination with neuroimaging (Fox et al., 2012), e.g., EEG or fMRI, to probe the brain state. These efforts should ultimately lead to closed-loop devices adjusting stimulation parameters automatically based on patient’s brain activity patterns. The BSDS approach provides a basis for a novel restoration strategy. Further exploration of the mechanisms underlying BSDS, i.e., Hebbian plasticity or homeostatic metaplasticity and gating (Ziemann and Siebner, 2008) and how to prime different modes of stimulation in functional domains beyond the motor system will help to advance the field and help us pinpoint the most effective non-invasive brain stimulation protocols for neurorehabilitation and restoration.

Brain restoration as an emerging field in neurology and neuroscience.

Restoration of brain function was long thought to be impossible. However, as the publications in the journal Restorative Neurology and Neuroscience (RNN) for more than 20 years attest, clinically useful improvement can be achieved after damage or diseases of the brain, the retina, and the peripheral nervous system. By reviewing both pre-clinical studies and clinical work, we explore what advancements can be made today and what to expect going forward. For example, in the last few years we have seen a clinical focus in the area of non-invasive brain stimulations and rehabilitation training trials. In basic animal research multi-modal approaches have been presented to restore brain function with a combination of different treatments. We think that this is an exciting time in the area of restoration of brain function with many new strategies aimed at helping recovering their impaired neurological functions.

The impact of self-esteem on the preferential processing of self-related information: Electrophysiological correlates of explicit self vs. other evaluation

Preferential processing of self-related information is a well-documented phenomenon on both the behavioral and neural levels. However, the impact of self-esteem on this self-preference has not been studied in a systematic way. Here, the electrophysiological correlates of explicit self-reflection were investigated in individuals with low (LSE) and high self-esteem (HSE). Participants evaluated trait adjectives in reference to the self or to an “other” person (close-other, famous) while EEG was recorded. The analysis of event-related potentials focused on the late positive component (LPC), which exhibits a fronto-central distribution and latency over 500 ms. In both LSE and HSE groups, the amplitudes of LPC were enhanced in the self condition when compared to control conditions (both close-other and famous). Crucially, LPC amplitudes in the HSE group were significantly higher than in the LSE group. Moreover, the self-preference effect, defined as the difference between amplitudes of LPC associated with the evaluation of words in relation to oneself vs. other people, was significantly higher in the HSE group than in the LSE group. Overall, our findings indicate that people with high self-esteem tend to engage in self-referential processing to a higher extent.

Rapid, transient, and frequency-specific topological reorganization of cognitive networks

Cognition emerges from interactions within spatially distributed but synchronized brain networks. Such networks are transient and dynamic, established on the timescale of milliseconds in order to perform specific cognitive operations. But it is not known whether topological features of transient cognitive networks contribute to cognitive processing. Cognition might merely change weights of intrinsic functional networks or, conversely, cognitive processing might require qualitatively new topological arrangements. To address this question, we recorded high-density EEG when subjects performed a visual discrimination task and characterized source-space weighted functional networks with graph measures. We revealed rapid, transient, and frequency-specific reorganization of the network’s topology during cognition. Specifically, cognitive networks were characterized by strong clustering, low modularity, and strong interactions between hub-nodes. Our findings suggest that dense and clustered connectivity between the hub nodes belonging to different modules is the “network fingerprint” of cognition. Such reorganization patterns might facilitate global integration of information and provide a substrate for a “global workspace” necessary for cognition and consciousness to occur. Thus, characterizing topology of the event-related networks opens new vistas to interpret cognitive dynamics in the broader conceptual framework of graph theory.How cognition emerges from neural dynamics? The dominant hypothesis states that interactions among distributed brain regions through phase synchronization give basis for cognitive processing. Such phase-synchronized networks are transient and dynamic, established on the timescale of milliseconds in order to perform specific cognitive operations. But unlike resting-state networks, the complex organization of transient cognitive networks is typically not characterized within the graph theory framework. Thus, it is not known whether cognitive processing merely changes strength of functional connections or, conversely, requires qualitatively new topological arrangements of functional networks. To address this question, we recorded high-density EEG when subjects performed a visual discrimination task and conducted and event-related network analysis (ERNA) where source-space weighted functional networks were characterized with graph measures. We revealed rapid, transient, and frequency-specific reorganization of the network?s topology during cognition. Specifically, cognitive networks were characterized by strong clustering, low modularity, and strong interactions between hub-nodes. Our findings suggest that dense and clustered connectivity between the hub nodes belonging to different modules is the ?network fingerprint? of cognition. Such reorganization patterns might facilitate global integration of information and provide a substrate for a ?global workspace? necessary for cognition and consciousness to occur. Thus, characterizing topology of the event-related networks opens new vistas to interpret cognitive dynamics in the broader conceptual framework of graph theory.