Optical coherence tomography as a potential surrogate marker of dopaminergic modulation across the life span.

The retina has been considered a "window to the brain" and shares similar innervation by the dopaminergic system with the cortex in terms of an unequal distribution of D1 and D2 receptors. Here, we provide a comprehensive overview that Optical Coherence Tomography (OCT), a non-invasive imaging technique, which provides an "in vivo" representation of the retina, shows promise to be used as a surrogate marker of dopaminergic neuromodulation in cognition. Overall, most evidence supports reduced retinal thickness in individuals with dopaminergic dysregulation (e.g., patients with Parkinson's Disease, non-demented older adults) and with poor cognitive functioning. By using the theoretical framework of metacontrol, we derive hypotheses that retinal thinning associated to decreased dopamine (DA) levels affecting D1 families, might lead to a decrease in the signal-to-noise ratio (SNR) affecting cognitive persistence (depending on D1-modulated DA activity) but not cognitive flexibility (depending on D2-modulated DA activity). We argue that the use of OCT parameters might not only be an insightful for cognitive neuroscience research, but also a potentially effective tool for individualized medicine with a focus on cognition. As our society progressively ages in the forthcoming years and decades, the preservation of cognitive abilities and promoting healthy aging will hold of crucial significance. OCT has the potential to function as a swift, non-invasive, and economical method for promptly recognizing individuals with a heightened vulnerability to cognitive deterioration throughout all stages of life.

Neurofilaments - Small proteins of physiological significance and predictive power for future neurodegeneration and cognitive decline across the life span.

Neurofilaments (NFs) are not only important for axonal integrity and nerve conduction in large myelinated axons but they are also thought to be crucial for receptor and synaptic functioning. Therefore, NFs may play a critical role in cognitive functions, as cognitive processes are known to depend on synaptic integrity and are modulated by dopaminergic signaling. Here, we present a theory-driven interdisciplinary approach that NFs may link inflammation, neurodegeneration, and cognitive functions. We base our hypothesis on a wealth of evidence suggesting a causal link between inflammation and neurodegeneration and between these two and cognitive decline (see Fig. 1), also taking dopaminergic signaling into account. We conclude that NFs may not only serve as biomarkers for inflammatory, neurodegenerative, and cognitive processes but also represent a potential mechanical hinge between them, moreover, they may even have predictive power regarding future cognitive decline. In addition, we advocate the use of both NFs and MRI parameters, as their synthesis offers the opportunity to individualize medical treatment by providing a comprehensive view of underlying disease activity in neurological diseases. Since our society will become significantly older in the upcoming years and decades, maintaining cognitive functions and healthy aging will play an important role. Thanks to technological advances in recent decades, NFs could serve as a rapid, noninvasive, and relatively inexpensive early warning system to identify individuals at increased risk for cognitive decline and could facilitate the management of cognitive dysfunctions across the lifespan.

A Prospect to Ameliorate Affective Symptoms and to Enhance Cognition in Long COVID Using Auricular Transcutaneous Vagus Nerve Stimulation.

Long COVID, the postviral disorder caused by COVID-19, is expected to become one of the leading causes of disability in Europe. The cognitive consequences of long COVID have been described as "brain fog" and characterized by anxiety and depression, and by cognitive deficits. Long COVID is assumed to be a complex condition arising from multiple causes, including persistent brainstem dysfunction and disrupted vagal signaling. We recommend the potential application of auricular transcutaneous vagus nerve stimulation (atVNS) as an ADD-ON instrument to compensate for the cognitive decline and to ameliorate affective symptoms caused by long COVID. This technique enhances vagal signaling by directly activating the nuclei in the brainstem, which are hypoactive in long COVID to enhance mood and to promote attention, memory, and cognitive control-factors affected by long COVID. Considering that atVNS is a non-pharmacological intervention, its ADD-ON to standard pharmaceutical agents will be useful for non-responders, making of this method a suitable tool. Given that atVNS can be employed as an ecological momentary intervention (EMI), we outline the translational advantages of atVNS in the context of accelerating the cognitive and affective recovery from long COVID.

A Metacontrol Perspective on Neurocognitive Atypicality: From Unipolar to Bipolar Accounts.

Standard clinical and psychiatric thinking follows a unipolar logic that is centered at "normal" conditions characterized by optimal performance in everyday life, with more atypical conditions being defined by the (degree of) absence of "normality." A similar logic has been used to describe cognitive control, assuming that optimal control abilities are characterized by a strong focus on the current goal and ignorance of goal-irrelevant information (the concept of willpower), while difficulties in focusing and ignoring are considered indications of the absence of control abilities. However, there is increasing evidence that willpower represents only one side of the control coin. While a strong focus on the current goal can be beneficial under some conditions, other conditions would benefit from a more open mind, from flexibility to consider alternative goals and information related to them. According to the metacontrol model, people can vary in their cognitive processing style, on a dimension with the extreme poles of "persistence" on the one hand and "flexibility" on the other. Whereas a high degree of persistence corresponds to the original idea of cognitive control as willpower, with a strong focus on one goal and the information related to it, a high degree of flexibility is characterized by a more integrative, less selective and exclusive processing style, which facilitates switching between tasks, ideas, and actions, and taking into consideration a broader range of possibilities. We argue that this approach calls for a more bipolar account in the clinical sciences as well. Rather than considering individuals as typical or atypical, it would theoretically and practically make more sense to characterize their cognitive abilities in terms of underlying dimensions, such as the persistence/flexibility dimension. This would reveal that possible weaknesses with respect to one pole, such as persistence, and tasks relying thereupon, may come with corresponding strengths with respect to the other pole, such as flexibility, and respective tasks. We bolster our claim by discussing available evidence suggesting that neurodevelopmental atypicality often comes with weaknesses in tasks related to one pole but strengths in tasks related to the other.

The metacontrol hypothesis as diagnostic framework of OCD and ADHD: A dimensional approach based on shared neurobiological vulnerability.

Obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD) are multi-faceted neuropsychiatric conditions that in many aspects appear to be each other's antipodes. We suggest a dimensional approach, according to which these partially opposing disorders fall onto a continuum that reflects variability regarding alterations of cortico-striato-thalamo-cortical (CSTC) circuits and of the processing of neural noise during cognition. By using theoretical accounts of human cognitive metacontrol, we develop a framework according to which OCD can be characterized by a chronic bias towards exaggerated cognitive persistence, equivalent to a high signal-to-noise ratio (SNR)-which facilitates perseverative behaviour but impairs mental flexibility. In contrast, ADHD is characterized by a chronic bias towards inflated cognitive flexibility, equivalent to a low SNR-which increases behavioural variability but impairs the focusing on one goal and on relevant information. We argue that, when pharmacology is not feasible, novel treatments of these disorders may involve methods to manipulate the signal-to-noise ratio via non-invasive brain stimulation techniques, in order to normalize the situational imbalance between cognitive persistence and cognitive flexibility.

Focusing on cognitive potential as the bright side of mental atypicality.

Standard accounts of mental health are based on a "deficit view" solely focusing on cognitive impairments associated with psychiatric conditions. Based on the principle of neural competition, we suggest an alternative. Rather than focusing on deficits, we should focus on the cognitive potential that selective dysfunctions might bring with them. Our approach is based on two steps: the identification of the potential (i.e., of neural systems that might have benefited from reduced competition) and the development of corresponding training methods, using the testing-the-limits approach. Counterintuitively, we suggest to train not only the impaired function but on the function that might have benefitted or that may benefit from the lesser neural competition of the dysfunctional system.

Recognizing emotions in bodies: Vagus nerve stimulation enhances recognition of anger while impairing sadness.

According to the Polyvagal theory, the vagus nerve is the key phylogenetic substrate that supports efficient emotion recognition for promoting safety and survival. Previous studies showed that the vagus nerve affects people's ability to recognize emotions based on eye regions and whole facial images, but not static bodies. The purpose of this study was to verify whether the previously suggested causal link between vagal activity and emotion recognition can be generalized to situations in which emotions must be inferred from images of whole moving bodies. We employed transcutaneous vagus nerve stimulation (tVNS), a noninvasive brain stimulation technique that stimulates the vagus nerve by a mild electrical stimulation to the auricular branch of the vagus, located in the anterior protuberance of the outer ear. In two sessions, participants received active or sham tVNS before and while performing three emotion recognition tasks, aimed at indexing their ability to recognize emotions from static or moving bodily expressions by actors. Active tVNS, compared to sham stimulation, enhanced the recognition of anger but reduced the ability to recognize sadness, regardless of the type of stimulus (static vs. moving). Convergent with the idea of hierarchical involvement of the vagus in establishing safety, as put forward by the Polyvagal theory, we argue that our findings may be explained by vagus-evoked differential adjustment strategies to emotional expressions. Taken together, our findings fit with an evolutionary perspective on the vagus nerve and its involvement in emotion recognition for the benefit of survival.

A neural noise account of Gilles de la Tourette syndrome.

Tics, often preceded by premonitory urges, are the clinical hallmark of Tourette syndrome. They resemble spontaneous movements, but are exaggerated, repetitive and appear misplaced in a given communication context. Given that tics often go unnoticed, it has been suggested that they represent a surplus of action, or motor noise. In this conceptual position paper, we propose that tics and urges, but also patterns of the cognitive profile in Tourette syndrome might be explained by the principle of processing of neural noise and adaptation to it during information processing. We review evidence for this notion in the light of Tourette pathophysiology and outline why neurophysiological and imaging approaches are central to examine a possibly novel view on Tourette syndrome. We discuss how neurophysiological data at multiple levels of inspections, i.e., from local field potentials using intra-cranial recording to scalp-measured EEG data, in combination with imaging approaches, can be used to examine the neural noise account in Tourette syndrome. We outline what signal processing methods may be suitable for that. We argue that, as a starting point, the analysis of 1/f neural noise or scale-free activity may be suitable to investigate the role of neural noise and its adaptation during information processing in Tourette syndrome. We outline, how the neural noise perspective, if substantiated by further neurophysiological studies and re-analyses of existing data, may pave the way to novel interventions directly targeting neural noise levels and patterns in Tourette syndrome.

Cognitive profile in Restless Legs Syndrome: A signal-to-noise ratio account.

Restless legs syndrome (RLS) is a common neurological disorder characterized by a sensorimotor condition, where patients feel an uncontrollable urge to move the lower limbs in the evening and/or during the night. RLS does not only have a profound impact on quality of life due to the disturbed night-time sleep, but there is growing evidence that untreated or insufficiently managed RLS might also cause cognitive changes in patients affected by this syndrome. It has been proposed that RLS is caused by alterations in the signal-to-noise ratio (SNR) and in dopamine (DA) neurotransmission in the nervous system. Based on this evidence, we propose the "SNR-DA hypothesis" as an explanation of how RLS could affect cognitive performance. According to this hypothesis, variations/reductions in the SNR underlie RLS-associated cognitive deficits, which follow an inverted U-shaped function: In unmedicated patients, low dopamine levels worsen the SNR, which eventually impairs cognition. Pharmacological treatment enhances DA levels in medicated patients, which likely improves/normalizes the SNR in case of optimal doses, thus restoring cognition to a normal level. However, overmedication might push patients past the optimal point on the inverted U-shaped curve, where an exaggerated SNR potentially impairs cognitive performance relying on cortical noise such as cognitive flexibility. Based on these assumptions of SNR alterations, we propose to directly measure neural noise via "1/f noise" and related metrics to use transcranial random noise stimulation (tRNS), a noninvasive brain stimulation method which manipulates the SNR, as a research tool and potential treatment option for RLS.

The Downsides of Cognitive Enhancement.

Cognitive enhancement is becoming progressively popular as a subject of scientific investigation and by the public, although possible adverse effects are not sufficiently understood. We call for cognitive enhancement to build on more specific, mechanistic theories given that a-theoretical approaches to cognitive enhancement are both a cause and a consequence of a strong, if not exclusive focus on the benefits of procedures suited to enhance human cognition. We focus on downsides of cognitive enhancement and suggest that every attempt to enhance human cognition needs to deal with two basic principles: the neuro-competition principle and the nonlinearity principle. We discuss the possibility of both principles in light of recent attempts to improve human cognition by means of transcranial direct current stimulation, a well-established brain stimulation method, and clinically relevant nootropic drugs. We propose that much stronger emphasis on mechanistic theorizing is necessary in guiding future research on both the upsides and the downsides of cognitive enhancement.

Non-invasive Brain Stimulation for the Treatment of Gilles de la Tourette Syndrome.

Gilles de la Tourette Syndrome is a multifaceted neuropsychiatric disorder typically commencing in childhood and characterized by motor and phonic tics. Its pathophysiology is still incompletely understood. However, there is convincing evidence that structural and functional abnormalities in the basal ganglia, in cortico-striato-thalamo-cortical circuits, and some cortical areas including medial frontal regions and the prefrontal cortex as well as hyperactivity of the dopaminergic system are key findings. Conventional therapeutic approaches in addition to counseling comprise behavioral treatment, particularly habit reversal therapy, oral pharmacotherapy (antipsychotic medication, alpha-2-agonists) and botulinum toxin injections. In treatment-refractory Tourette syndrome, deep brain stimulation, particularly of the internal segment of the globus pallidus, is an option for a small minority of patients. Based on pathophysiological considerations, non-invasive brain stimulation might be a suitable alternative. Repetitive transcranial magnetic stimulation appears particularly attractive. It can lead to longer-lasting alterations of excitability and connectivity in cortical networks and inter-connected regions including the basal ganglia through the induction of neural plasticity. Stimulation of the primary motor and premotor cortex has so far not been shown to be clinically effective. Some studies, though, suggest that the supplementary motor area or the temporo-parietal junction might be more appropriate targets. In this manuscript, we will review the evidence for the usefulness of repetitive transcranial magnetic stimulation and transcranial electric stimulation as treatment options in Tourette syndrome. Based on pathophysiological considerations we will discuss the rational for other approaches of non-invasive brain stimulation including state informed repetitive transcranial magnetic stimulation.

Transcutaneous vagus nerve stimulation modulates attentional resource deployment towards social cues.

Transcutaneous vagus nerve stimulation (tVNS) has been shown to promote inferences of emotional states based on eye-related information provided by facial expressions of emotions. Eye gaze direction can influence the allocation of attentional sources when processing facial emotional stimuli. Here we sought for further evidence indicating whether tVNS effects would be specific to emotional expressions or to gaze - both socially relevant stimuli - and whether they reflect the enhancement of attention. In two separate sessions receiving either active or sham tVNS, forty-three healthy young volunteers completed a Rapid Serial Visual Presentation task in which participants identified the gender of a target face (T1) with direct (salient social cue) or averted gaze (subtler social cue) with different emotional expressions or a neutral expression, and then judged the orientation of a landscape (T2) that appeared at different temporal lags after T1. Active tVNS, compared to sham stimulation, enhanced conditional T2 accuracy for both neutral and emotional faces and independently of the temporal lag, but only when gaze was directed at the participant. This suggests that tVNS modulates attention to a direct gaze (salient social cue) irrespective of the expressed emotion. We interpret that the effects of tVNS seem to reflect enhanced perception of gaze direction, which in turn attracts attention, making the observer more sensitive and increasing the impact of the socially relevant facial cue. We conclude that tVNS is a promising technique for enhancing social information processing in healthy humans.

Vagal signaling and the somatic marker hypothesis: The effect of transcutaneous vagal nerve stimulation on delay discounting is modulated by positive mood.

Controlling impulsivity and delaying gratifications are key features of effective self-control. Delay Discounting (DD) indexes the ability to delay rewards and previous research has shown that discounting is influenced by affective states such as mood. According to the Somatic Marker Hypothesis (SMH), afferent somatic signals, such as mood, are carried by the vagus and can influence decision making. In the current study, we employed transcutaneous vagus nerve stimulation (tVNS), a novel non-invasive brain stimulation technique that stimulates the auricular branch of the afferent vagus nerve (located in the outer ear), to assess its effects on decision impulsivity, while taking into account individuals' mood and resting-state HRV as a possible confounding factor. Employing a within-subjects cross-over design, 94 participants received active or sham tVNS while performing delay discounting in two separate sessions. As compared to sham, active tVNS increased discounting, but only for individuals reporting lower positive mood, regardless of the level of negative mood reported. We evidence that the effect of tVNS on reward discounting depends on the level of positive mood. This result suggests that positive mood state might be a proxy of task-relevant arousal, likely influencing the effectiveness of afferent vagal stimulation on self-control processes, as temporal discounting.