Authors: A.A. PYATKOV, A.V. SERGEEV, E.A. SOKOLOV, A.R. NURMEEVA, A.A. KONONIROVA, S.A. MAKAROV
Note: This research is from Sechenov University in Moscow, Russia. The original paper was written in Russian and has been translated into English.
Abstract
Visual snow syndrome (VSS) is one of the diseases related to visual perception disorder, which was first included in the International Classification of Headache Disorders (3rd edition, 2018) as a possible complication of migraine with aura. Despite the awareness among specialists regarding transcranial magnetic stimulation (TMS) for migraine, its application in VSS remains insufficiently studied and understood. At the same time, TMS as a therapeutic and diagnostic tool aimed at modulating the bioelectrical activity of the cortical brain can both improve the understanding of the pathophysiological mechanisms of VSS and help address the task of correcting symptoms of VSS. This article discusses the potential of TMS as a research and therapeutic method for visual perception disorders.
Introduction
Visual snow syndrome (VSS) is one of the functional disorders of visual perception, which manifests as persistent visual phenomena that significantly reduce the patient’s quality of life. A mandatory clinical manifestation of visual snow syndrome is the appearance of small dots (“static,” “television snow,” “pixelation”) filling the entire visual field bilaterally. The most common additional visual symptoms include palinopsia, intensification of entoptic phenomena, night blindness, and photophobia. Other effects may include halos, floating spots (floaters), impaired twilight vision, “blue field phenomena,” flashes in the visual field with both open and closed eyes, and “floating bright or colored clouds.” Meanwhile, phenomena typical for migraine aura (scintillating scotoma and photopsia) are much less common.
The phenomenon of visual snow was first described in 1995 by a research group led by G.T. Liu in four patients with migraine with aura. Further studies have shown that VSS may not only occur in migraine: 28% of patients with VSS have no history of clinical migraine manifestations. At the same time, the most common comorbid disorders in VSS are perception spectrum disorders: fibromyalgia (75%), somatosensory tinnitus (52%), migraine (72%), postural perceptual dizziness (7.1%), anxiety disorders, and depression (13.3%). Due to the high prevalence of VSS in the migraine patient group, the first diagnostic criteria were developed within the framework of the International Classification of Headache Disorders, 3rd edition (ICHD-3) (2018), in the section “Complications of Migraine” (Table 1).
Currently, visual snow syndrome is diagnosed when it fully meets the diagnostic criteria, and an incomplete phenomenon of visual snow is diagnosed when only criterion A is met, without additional manifestations.
Initially, VSS was thought to be rare; however, data from an online survey of 1,100 patients led by Professor Peter J. Goadsby indicates the widespread prevalence of the syndrome: up to 2.2% of the population may experience symptoms of visual snow.
Transcranial Magnetic Stimulation
Among the non-pharmacological methods being considered for treating visual perception disorders, transcranial magnetic stimulation (TMS) holds a special place, as it can not only have a symptomatic effect but also, possibly, influence the pathophysiological mechanisms of functional visual disorders. In general, TMS is a method of applying a focused magnetic field to specific areas of the cerebral cortex, leading to depolarization of the axons of neurons and the spread of excitation along afferent pathways and/or neural network connections in the brain (depending on the technical parameters of the stimulation). The equipment for performing TMS includes a capacitor block for generating electric current, which is passed through a special inducer (coil) and converted into a magnetic field. It is through the coil that stimulation of the cerebral cortex occurs.
The basis of diagnostic TMS is the application of single or paired (double) stimuli followed by the registration of evoked motor responses from the muscles of the limbs using standard electromyographic electrodes. Therapeutic TMS uses what is known as rhythmic TMS (rTMS), a course of stimulation consisting of discrete series of stimuli of varying intensity and frequency (a total of several hundred to several thousand magnetic stimuli per session) over a defined period of time to cause long-term changes in the brain’s functional state by selectively increasing or decreasing neuronal activity.
Traditional clinical use of rTMS in psychoneurological practice and rehabilitation involves either low-frequency stimulation (usually 1 Hz) or high-frequency stimulation (usually 10 Hz and above). For example, based on a strong evidence base, high-frequency stimulation is used in the treatment of neuropathic pain, while low-frequency stimulation may be used in rehabilitation for post-stroke disorders or auditory hallucinations.
Neurophysiological and neurochemical mechanisms underlying the therapeutic effects of rTMS are not precisely defined and are likely to be diverse. However, they can generally be divided into two types. In some cases, rTMS promotes the activation of a function or process (for example, high-frequency stimulation for the treatment of neuropathic pain, fibromyalgia, or migraine stimulates antinociceptive effects and the secretion of β-endorphins). In other cases, rTMS may inhibit a function or process (for example, low-frequency stimulation for visual and auditory hallucinations in schizophrenia enhances GABAergic inhibitory neurotransmission).
It is believed that the mechanism causing more persistent changes (excitement or inhibition) in neuronal activity is related to changes in synaptic connections and synaptic plasticity following repeated sessions of rTMS—remodeling of neuroplasticity from pathological (resulting from prolonged dysregulation) to physiological (adaptive) states. These changes at the synaptic level are likely similar to neurophysiological phenomena such as long-term depression (LTD) or long-term potentiation (LTP).
Pilot Studies on the Use of rTMS for VSS
Another pilot study from Colorado (USA), announced in 2020, provided a detailed description of its methodology. The study will recruit 10 patients with confirmed VSS, aged 19 to 65 years. Stimulation will be performed at a frequency of 1 Hz on the lingual gyrus bilaterally using a special 8-shaped angular coil. The choice of stimulation site was based on the results of preliminary fMRI, conducted for the participants of the study, which showed the greatest reduction in activity in the lingual gyrus bilaterally. A total of 10 daily sessions will be conducted (5 sessions each week), with each session involving the application of 1800 stimuli. The effectiveness of stimulation in correcting the clinical symptoms of VSS will be assessed immediately after the course, and again after 1 month and 3 months, using the Colorado Visual Snow Scale (CVSS), the National Eye Institute Visual Function Questionnaire (VFQ-25), the Generalized Anxiety Disorder Scale (GAD-7), and other functional tests. The only limitation of this pilot study is the absence of a control group with sham stimulation. However, the authors state that they plan to use a sham control in subsequent, larger studies. Unfortunately, the results of this study have not yet been published.
Regardless of the authors of the Colorado study, other well-known specialists in the field of VSS (C. Schankin and F. Puledda) have also confirmed, based on fMRI data, the significant reduction of activity in the lingual gyrus. This supports the potential role of these areas as candidates for rTMS. At the same time, it is emphasized that these are just some of the areas among many other important cortical regions involved in altered processing of visual information. Disruption in connectivity and interaction between several brain networks is considered key in the development and maintenance of visual snow symptoms.
One potential solution to the issue of selecting the area and frequency of stimulation could be the evaluation of alpha rhythms using electroencephalography (EEG), as alpha rhythms are considered correlates of inhibitory modulation in the brain’s visual network in the context of impaired visual perception. A 2024 study analyzing EEG in patients with VSS revealed a reduction in the spectral density of the alpha range over parietal and temporal electrodes, which led the authors to recommend these areas as targets for non-invasive brain stimulation in VSS, with the goal of enhancing alpha rhythm power, i.e., to strengthen the inhibitory mechanisms of visual afferentation.
Experience of Using rTMS in Related Visual Perception Disorders
rTMS has been used not only in patients with VSS but also in other disorders with pathophysiological similarities in visual perception, such as derealization and depersonalization syndrome (DPD) and Hallucinogen Persisting Perception Disorder (HPPD) Type II. For example, in 2024, the first clinical case of successful treatment of a patient with HPPD Type II using rTMS to stimulate the right temporo-parietal junction was published. The authors report a clinically significant reduction in not only visual disturbances (visual snow, photophobia, palinopsia) but also symptoms of derealization, anxiety, and depression. However, the study does not disclose details about the frequency of stimulation, the total number of stimuli applied, or the number of rTMS sessions. The choice of the temporo-parietal junction for stimulation was not accidental, as the authors relied on previous studies involving rTMS in patients with DPD, given the phenotypic similarities between visual perception disturbances in DPD, HPPD Type II, and VSS. Stimulation of the temporo-parietal junction (on one or both sides) in such patients significantly and persistently reduces visual symptoms: visual snow, nyctalopia, palinopsia, photophobia, floaters, and more. In most studies, effective stimulation of the multisensory hub—the temporo-parietal junction—was low-frequency (1 Hz). However, in other studies of patients with DPD, high-frequency stimulation of the left dorsolateral prefrontal cortex at 10 Hz has proven effective for correcting both visual and non-visual symptoms. This protocol is a classic stimulation method whose effectiveness has been proven in many mental disorders and pain syndromes.
Transcranial Magnetic Stimulation as a Diagnostic and Research Tool
The role of TMS in the research diagnosis of VSS and other visual perception disorders is even more modest than its use for the treatment of these conditions. There are only a few studies where TMS was used as a tool to apply single or paired magnetic stimuli to assess processes of excitation and inhibition in the brain.
One of the interesting studies, which provides new data on the neurophysiological differences between VSS and migraine with aura, was conducted in 2021. The authors used TMS as a tool to suppress the primary visual (occipital) cortex in patients with VSS and migraine with aura by applying single subthreshold magnetic stimuli while participants performed a cognitive visual task (reproducing various sequences of numbers), assessing the accuracy of perception during such suppression. The main result of this study was that the suppression of accuracy did not decrease in VSS patients compared to the migraine with aura group. The results suggest that the presumed hyperexcitability in VSS does not originate from the primary visual cortex but is likely explained by dysfunction in the higher-order visual cortex (secondary and tertiary visual centers—parietal, temporal cortex, and temporo-parietal junction).
An equally promising approach for evaluating the pathophysiological aspects of VSS and other visual perception disorders may be the analysis of the so-called short-interval intracortical inhibition (SICI) phenomenon using TMS. The methodology involves applying sequential paired (double) magnetic stimuli to motor cortex areas with an interval between the stimuli of 1 to 6 ms (the first stimulus is a conditioning subthreshold stimulus, and the second is a test suprathreshold stimulus) and registering evoked motor responses from hand muscles using surface electrodes. Under normal conditions, the application of a conditioning stimulus causes the test stimulus to result in a motor response with reduced amplitude compared to when the test stimulus is applied in isolation. The SICI phenomenon reflects the physiological principles of inhibitory processes in the cerebral cortex. A decrease in SICI means that the expected reduction in the amplitude of the motor response due to the conditioning stimulus does not occur when the test stimulus is applied. Evaluation of the SICI phenomenon has become a well-established method for assessing deficits in intracortical inhibition processes, and therefore, a decrease in SICI is considered a marker of cortical hyperexcitability (not only in the motor cortex, as it is commonly assumed, since the identified hyperexcitability of the motor cortex can be extrapolated to other cortical areas).
The registration of the SICI phenomenon has proven to be very useful not only in diagnosing cortical hyperexcitability in motor cortex disorders (e.g., in upper motor neuron damage such as amyotrophic lateral sclerosis) but also in non-motor disorders that are pathophysiologically related to VSS, such as neuropathic pain and migraine with aura. In particular, a decrease in SICI in neuropathic pain is a parameter that objectively reflects a reduction in inhibitory antinociceptive mechanisms and is a marker determining the effectiveness of pain treatment. The more pronounced the decrease in SICI, the higher the expected effectiveness of standard pain treatment methods (drug therapy, rTMS, psychotherapy). In migraine with aura, the SICI phenomenon depends on various factors: the frequency of attacks, whether it is ictal or interictal, the background use of preventive medications (topiramate, β-blockers), etc. Most studies have shown that during the interictal phase in patients with episodic migraine with aura, SICI is reduced, indicating background cortical hyperexcitability. SICI potentially also serves as an objective marker of the neurophysiological dynamics of treatment efficacy. In patients with migraine with aura and neuropathic pain, successful therapy and symptom reduction lead to the return of SICI to normal values, which also confirms the normalization of the balance between activating and inhibiting mechanisms in the brain’s cortex.
Studies directly evaluating SICI in patients with VSS and other visual perception disorders have not yet been conducted. Given the proposed pathogenesis of VSS, research in this area should be initiated to add clarity to the neurophysiological course of visual perception disorders and improve treatment algorithms.