The pathophysiology of visual snow is still under investigation. Given that VSS typically affects the entire visual field in both eyes, it is unlikely to be arising in the anterior visual pathways. Rather, it is likely to be a disorder of visual information processing. It has been hypothesised that similar pathophysiological mechanisms may account for both migraine and VSS and furthermore extend to other disorders of sensory processing such as tinnitus [
42]. Achieving an improved understanding of the neurobiology of VSS will aid clinicians as they discuss the condition with their patients and will direct future research to targeted treatment options.
Cortical Hyperexcitability
One theory to explain the neurobiological mechanism of VSS is that it is a purely cortical phenomenon. Visual disorders due to localised deficit or a region of hyperfunction in the V1/V2 areas of the occipital cortex can present with hallucinations with similarities to visual snow [
43]. A lower threshold for occipital cortex excitability and a loss of habituation to transcranial magnetic stimulation phosphenes was seen in VSS patients compared to controls [
44].
More recent studies have shown that patients with VSS have subtle, but widespread neuro-anatomical differences with an increase in grey matter volume in the left primary and secondary visual cortices and V5 visual motion area [
45]. White matter abnormalities as detected with diffusion tensor imaging are also seen in dorsal and ventral streams in VSS patients [
46]. On functional studies, patients also demonstrate higher regional cerebral blood flow over an extensive brain network when compared to controls [
47]. In addition, fMRI of the resting-state functional connectivity found alterations in the brain regions involved in visual processing, memory, spatial attention and cognitive control in VSS patients [
48]. These papers all suggest a more generalised neurobiological basis for VSS, rather than being purely occipital cortex involved.
Authors agree that there is a widespread dysfunction of higher-order visual processing areas, particularly the extrastriate cortex [
29••]. One potential theory to explain the wider spread cortical mechanism suggests that stochastic resonance, a nonlinear phenomenon in which the addition of noise improves signal-to-noise ratio, improves the ability to detect a weak stimulus [
49]. For example, it may be that coexisting tinnitus enhances the detection of visual stimuli in patients with visual snow syndrome, with one sensory system “priming” another [
49]. Another possibility is that increased cortical neural excitability or visual pathway hypersensitivity leads in turn to perception of otherwise sub-threshold stimuli. In support of this, behavioural studies have demonstrated abnormal contrast and brightness processing in patients with visual snow syndrome [
50].
Direct evidence for altered visual cortex excitability was shown by single case study using EEG [
51]. Visual evoked potentials have shown prolonged latency and reduced amplitudes, which might suggest involvement of pre-striate pathways or the striate cortex itself [
52]. PET scanning has demonstrated increased metabolism at the junction of the right lingual and fusiform gyrus [
41], pointing to extrastriate cortical dysfunction. Other studies have shown that the lingual gyrus is involved in the perception of photophobia in migraine, consistent with the association between visual snow syndrome and migraine [
53]. Using a combination of functional neuroimaging and magnetic resonance spectroscopy, differences were reported in the bilateral insular responses in VSS patients compared to controls, suggesting a localised disturbance in extrastriate anaerobic metabolism. It was hypothesised that this may in turn cause a decrease in the metabolic reserve for the regular processing visual stimuli [
39]. Single-photon emission computed tomography (SPECT) in 3 VSS patients showed abnormal processing within the ventral visual stream in 2 of the patients [
54].
Another area involved in the widespread dysfunction is likely to be the dorsal visual network or motion network which reaches from V1 dorsally to the parietal lobe and involves the motion area V5 in the temporo-parietal-occipital junction. Given the involvement in processing of visual motion, it is likely to play a role in the perception that the static dots are seen to be constantly moving. This region may also play a role in the trail phenomenon seen behind moving objects [
55]. In the visually active state, the dorsal visual network and V5 showed hyper-integration to other brain areas in VSS patients [
56••].
It is also hypothesised that VSS may result from general altered excitability and connectivity due to changes and altered connection in the brain networks involved in cognitive function. Heightened saccade-related activity in visual regions has been seen in VSS patients and may provide an objective clinical measure of this dysfunction [
57]. In particular the salience network (SN) is thought to be responsible for detecting and filtering information necessary to maintain goal-directed behaviour. The SN increases activity in tasks requiring attention to external stimuli. This network refers to a group of brain regions located in the anterior cingulate and ventral anterior insular cortices and includes the thalamus [
58]. The anterior insular cortex is critically involved in visual awareness [
59] as well as emotional processing including anxiety [
60]. Anxiety, depression and depersonalisation are frequent comorbid in a cohort of VSS patients [
61].
A study of cortical functional connectivity has shown that VSS patients have a decreased connectivity during external sensory input within the salience network [
56••]. This paper demonstrated widespread alteration in functional connectivity in VSS in both the resting and stimulated states. Regions within the visual network showed altered internal connectivity, as well as with basal ganglia and frontal eye fields. This dysfunctional salience may cause the brain to misattribute salience to internal stimuli that would otherwise be considered irrelevant causing the “noise-like” perception [
56••].
Thalamic Dysfunction
The thalamus is classically known for its role as a sensory relay in visual, auditory and somatosensory systems, as well as playing a role in consciousness and alertness. It is the lateral geniculate nucleus (LGN) that receives the visual sensory information from the retina to route to the visual cortex. The thalamic nuclei (excitatory and inhibitory) integrate these inputs and then present selected information to the cerebral cortex via thalamocortical radiations for interpretation [
62].
The thalamus could be responsible for VSS symptoms through a localised increase in activity in the LGN or the pulvinar [
29••]. The pulvinar has diffuse projections to the supragranular layers of the cortex and plays a role in attention and stimulus processing by aligning internal excitability patterns to the timing of relevant sensory inputs [
63]. Reduced pulvinar connectivity to the visual cortico-striatal loop at rest has been found in VSS patients [
56••]. Increased diffusivity on MRI has been reported in the thalamic radiations of VSS patients compared to controls [
46]. During a visual task, heightened connectivity between the pulvinar and the lingual gyrus was reported which could explain a sensation of photophobia some patients describe, as well as causing a reduction in the filtering of incoming visual information [
56••].
Oscillatory network activity is a characteristic property of that thalamocortical system and is central to cognitive processes such as attention and perception. An alteration of these oscillations, in particular an increase in the low-frequency delta and theta rhythms during states of wakefulness, is commonly termed thalamocortical dysrhythmia (TCD) [
64]. When hyperexcitability affects cortical networks, as described in the section above, it can lead to TCD. Conversely, neuromodulatory processes involving the thalamus play a central role in how the brain modulates neural excitability [
65]. This common underlying mechanism can produce a range of symptoms depending on the localization of the dysfunction in the thalamocortical network and may account for the spectrum of diseases associated with defaults in sensory processing [
32]. Several apparently unrelated neurological conditions are thought to be a consequence of TCD, including migraine and tinnitus [
66]. Thalamocortical dysrhythmia may therefore account for many of the comorbidities seen in visual snow syndrome such as tinnitus, impaired concentration, lethargy, anxiety, depression, tremor and balance disorders. All of these suggest that the underlying pathophysiology could represent a disorder of simultaneous processing of afferent information arriving at the cortex, not just in the visual domain [
67]. Accordingly, the visual symptoms might simply represent a misperception rather than primary cortical hyperactivity [
1].
Potentially, an underlying homeostatic imbalance of the visual pathways, from altered retinal activity, could cause a disinhibition of projections from the posterior thalamus to primary and secondary visual cortices [
29••]. Imbalances between konio- and parvo/magnocellular pathway processing have previously been reported to underlie thalamocortical dysrhythmia in tinnitus and Parkinsonian tremor [
68]. It is therefore hypothesised that koniocellular yellow-blue processing pathways [
49] are also involved in VSS. The koniocellular pathway contains diffuse cortical connections via the LGN that modulate high-frequency cortical oscillations, thereby influencing sensory excitability [
49]. The koniocellular pathways control slow cortical frequencies, in contrast to the parvo and magnocellular pathways which project to the primary visual cortex and are linked to fast cortical frequencies [
69]. In support of this concept, wearing coloured visual filters helps some patients with visual snow syndrome, particularly those transmitting predominantly short (blue) wavelengths [
7•]. Furthermore, VSS patients show a strong aversion to violet hues near the tritanopic confusion line, or S-cone axis, which increase S-cone excitation. Viewing a visual stimulus through this violet hue filter significantly exacerbated VSS symptoms. It is hypothesised that S-cone signals travelling in the koniocellular pathways contribute to dysregulation of the visual cortex via thalamo-cortical pathways [
70].
Magnetoencephalography (MEG) is a non-invasive tool that is aimed at determining areas of metabolic activity and changes to cortical information spreading. MEG has been shown to identify and localise thalamocortical dysrhythmias in other disorders [
68]. Alterations in the thalamic power-amplitude coupling to the visual cortex have been shown in visual snow patients compared to controls [
71].