Enhancing Attentional Performance in Parkinson's Disease: The Impact of Combined Deep Brain Stimulation of the Substantia Nigra Pars Reticulata and the Subthalamic Nucleus.

OBJECTIVE: The concomitant stimulation of the subthalamic nucleus and the substantia nigra pars reticulata is a promising approach to improve treatment of refractory axial symptoms in Parkinson's disease. While dual stimulation of the subthalamic nucleus and the substantia nigra pars reticulata has previously shown beneficial effects on gait, the role of the substantia nigra, a crucial component of the basal ganglia circuitry, in cognitive functions such as attention and executive control remains underexplored. This study aimed to investigate the impact of selective substantia nigra pars reticulata stimulation on attentional performance in patients receiving standard deep brain stimulation of the subthalamic nucleus. METHODS: Twelve patients with bilateral subthalamic nucleus stimulation underwent computerized assessment of attention using a simple reaction time task. Reaction times were assessed under standard stimulation of the subthalamic nucleus versus simultaneous stimulation of the subthalamic nucleus and the substantia nigra pars reticulata. RESULTS: The results revealed a significant improvement in reaction times during the simple reaction time task when patients received dual stimulation compared to standard stimulation. CONCLUSIONS: Our findings provide further evidence for the pivotal role of the substantia nigra pars reticulata in cognitive functions such as attention. Despite the limitations of the study, including a small sample size, our results suggest potential benefits of simultaneous deep brain stimulation of the subthalamic nucleus and the substantia nigra pars reticulata on attentional performance in patients with Parkinson's disease. Further research with larger cohorts is warranted to confirm these findings and better understand the underlying mechanisms.

Effects of repetitive twice-weekly transcranial direct current stimulations on fatigue and fatigability in people with multiple sclerosis.

Fatigue is associated with a dramatically decreased quality of life in people with multiple sclerosis (pwMS). It refers to a constant subjective feeling of exhaustion and performance decline, known as fatigability. However, inconsistency and heterogeneity in defining and assessing fatigue have led to limited advances in understanding and treating MS-associated fatigue. Transcranial direct current stimulation (tDCS) has emerged as a promising, non-pharmaceutical treatment strategy for subjective fatigue. However, whether repetitive tDCS also have long-term effects on time-on-task performance has not yet been investigated. This pseudorandomized, single-blinded, and sham-controlled study investigated tDCS effects on behavioral and electrophysiological parameters. 18 pwMS received eight twice-weekly 30 min stimulations over the left dorsolateral prefrontal cortex. Fatigability was operationalized as time-on-task-related changes in reaction time variability and P300 amplitude. Additionally, subjective trait and state fatigue ratings were assessed. The results revealed an overall decrease in subjective trait fatigue ratings that lasted at least four weeks after the stimulations. However, the ratings declined after both anodal and sham tDCS. No effects were found on subjective state fatigue and objective fatigability parameters. Linear Mixed Models and Bayesian Regression models likewise favored the absence of a tDCS effect on fatigability parameters. The results confirm the complex relationship between MS-associated fatigue and fatigability. Reliable and clinically relevant parameters need to be established to extend the potential of tDCS for treating fatigability. Furthermore, our results indicate that consecutive stimulations rather than twice-weekly stimulations should be the preferred stimulation scheme in future studies.

Cognitive fatigue-related sensory gating deficits in people with multiple sclerosis.

BACKGROUND: Cognitive fatigue is highly prevalent in people with multiple sclerosis (pwMS) and significantly limits their quality of life. Fatigue can be subdivided into a subjective feeling of constant (trait) or current (state) exhaustion, as well as an objective performance decline, also known as fatigability. However, the current fatigue diagnosis in pwMS is purely subjective, leaving fatigability mostly unattended. Sensorimotor and sensory gating deficits have recently been described as possible objective markers for fatigability in healthy subjects. Thus, this study aimed to investigate the potential of prepulse inhibition (PPI) ratios and the P50 sensory gating suppression as surrogate markers for cognitive fatigue in pwMS. METHODS: PPI and P50 sensory gating ratios were assessed before and after a 30-min fatigability-inducing AX- continuous performance task. Subjective trait fatigue was operationalized via self-report questionnaires, subjective state fatigue via visual analog scales (VAS), and fatigability via the change in both gating ratios. The data were analyzed using Linear Mixed Models and Pearson correlations. RESULTS: We included 18 pwMS and 20 healthy controls (HC) in the final analyses. The task-induced fatigability was more pronounced in pwMS. While the initial PPI and P50 ratios were similar in both groups, P50 sensory gating was significantly disrupted after fatigability induction in pwMS. PPI, on the other hand, decreased in both groups. Moreover, initial P50 sensory gating ratios were negatively associated with subjective trait fatigue in pwMS, indicating that higher trait fatigue is associated with disrupted sensory gating. Finally, fatigability-related changes in P50 sensory gating were associated with the changes in VAS ratings, but only in HC. CONCLUSIONS: This study demonstrated that P50 sensory gating is a promising objective fatigue and fatigability parameter. Importantly, P50 sensory gating correlated with subjective trait and state fatigue ratings. Our results extend the subjective fatigue diagnosis and broaden the understanding of pathophysiological neuronal mechanisms in MS-related fatigue. This is the first study to present fatigue-related disruption of sensory gating in pwMS.

Fatigability-related oscillatory brain activity changes in people with MS.

BACKGROUND: Fatigue, a multidimensional and challenging symptom associated with various underlying conditions, can manifest as a subjective feeling and a performance fatigability. The latter is often defined as an objectively measurable performance decline with time on task. Both syndromes are highly prevalent in people with multiple sclerosis (pwMS) and are often resistant to medical therapy. In the absence of valid and reliable objective parameters, the current cognitive fatigue diagnosis remains purely subjective. Assessing brain wave activity changes has repeatedly been a viable strategy for monitoring cognitive fatigue in healthy subjects. In this study, we aimed to investigate oscillatory brain activity changes and their associations with subjective fatigue in pwMS. METHODS: We enrolled 21 pwMS and 21 healthy controls (HC) in this study. Subjects performed a sustained attention task divided into six blocks over the course of 30 minutes, and underwent resting state EEGs before and after the task. During the task, subjects were repeatedly asked to rate their subjective levels of mental fitness, mental exhaustion, and mind wandering. Using Linear Mixed Models, we explored fatigability-related changes by focusing on the time course of changes in reaction time variability, subjective ratings of fatigability, as well as frontomedial theta, and occipital alpha power. We further investigated initial and fatigability-induced differences between pwMS and HC at rest. Finally, Pearson correlations were used to examine the relationship between subjective fatigue and objective fatigability parameters. RESULTS: Our results revealed a systematically stronger fatigability development in pwMS that was objectively measurable. PwMS reported lower mental fitness levels and demonstrated greater variability in reaction times with time on task. Occipital alpha power significantly increased during the task. Especially for upper alpha power, this increase was significantly more prominent in pwMS compared to HC. However, the time-on-task-induced changes in our study were not associated with the subjective fatigue ratings. CONCLUSIONS: The results of this study expand the understanding of the neural mechanisms underlining cognitive fatigability and may complement the fatigue diagnosis and therapy monitoring with quantitative objective methods.

The therapeutic potential of non-invasive brain stimulation for the treatment of Long-COVID-related cognitive fatigue.

Following an acute COVID-19 infection, a large number of patients experience persisting symptoms for more than four weeks, a condition now classified as Long-COVID syndrome. Interestingly, the likelihood and severity of Long-COVID symptoms do not appear to be related to the severity of the acute COVID-19 infection. Fatigue is amongst the most common and debilitating symptoms of Long-COVID. Other symptomes include dyspnoea, chest pain, olfactory disturbances, and brain fog. Fatigue is also frequently reported in many other neurological diseases, affecting a broad range of everyday activities. However, despite its clinical significance, limited progress has been made in understanding its causes and developing effective treatment options. Non-invasive brain stimulation (NIBS) methods offer the unique opportunity to modulate fatigue-related maladaptive neuronal activity. Recent data show promising results of NIBS applications over frontoparietal regions to reduce fatigue symptoms. In this current paper, we review recent data on Long-COVID and Long-COVID-related fatigue (LCOF), with a special focus on cognitive fatigue. We further present widely used NIBS methods, such as transcranial direct current stimulation, transcranial alternating current stimulation, and transcutaneous vagus nerve stimulation and propose their use as possible therapeutic strategies to alleviate individual pathomechanisms of LCOF. Since NIBS methods are safe and well-tolerated, they have the potential to enhance the quality of life in a broad group of patients.

Objective electrophysiological fatigability markers and their modulation through tDCS.

OBJECTIVE: Cognitive fatigability is a frequent symptom after sustained performance. Fatigability is evident in healthy subjects but is also often comorbid in several neuropsychiatric diseases. However, to date, clinical diagnostic almost solely relies on the self-reported subjective experience of fatigue. The goals of this present study were i) to complement the purely subjective fatigue diagnostic with objective electrophysiological fatigability parameters and ii) to prove the potential therapeutic application of transcranial direct current stimulation (tDCS) as a fatigability intervention. METHODS: We performed a pseudo-randomized, sham-controlled, parallel-group trial. Forty healthy participants received either anodal or sham tDCS over the left dorsolateral prefrontal cortex (DLPFC) while they performed an exhaustive cognitive task to induce cognitive fatigability. To assess fatigability changes, we analyzed variations of prepulse inhibition (PPI) and P50 suppression as well as frontomedial theta and occipital alpha power with time-on-task. RESULTS: The task reliably induced subjective exhaustion in all participants. Furthermore, we confirmed fatigability-related increases in frontomedial theta and occipital alpha power throughout the task. Additionally, fatigability significantly reduced PPI as well as P50 sensory gating. Anodal tDCS over the left DLPFC successfully counteracted fatigability and reduced the fatigability-related increase in alpha power as well as the decline in both gating parameters. CONCLUSION: Occipital alpha and sensorimotor/sensory gating are suitable parameters to assess the severity of fatigability objectively. Anodal tDCS can counteract fatigability and has therapeutic potential for the treatment of fatigability in neuropsychiatric diseases. SIGNIFICANCE: Fatigability can be objectively assessed by electrophysiological measures and attenuated by tDCS.

Preserved Contextual Cueing in Realistic Scenes in Patients with Age-Related Macular Degeneration.

Foveal vision loss has been shown to reduce efficient visual search guidance due to contextual cueing by incidentally learned contexts. However, previous studies used artificial (T- among L-shape) search paradigms that prevent the memorization of a target in a semantically meaningful scene. Here, we investigated contextual cueing in real-life scenes that allow explicit memory of target locations in semantically rich scenes. In contrast to the contextual cueing deficits in artificial scenes, contextual cueing in patients with age-related macular degeneration (AMD) did not differ from age-matched normal-sighted controls. We discuss this in the context of visuospatial working-memory demands for which both eye movement control in the presence of central vision loss and memory-guided search may compete. Memory-guided search in semantically rich scenes may depend less on visuospatial working memory than search in abstract displays, potentially explaining intact contextual cueing in the former but not the latter. In a practical sense, our findings may indicate that patients with AMD are less deficient than expected after previous lab experiments. This shows the usefulness of realistic stimuli in experimental clinical research.

Cognitive Fatigue in Multiple Sclerosis: An Objective Approach to Diagnosis and Treatment by Transcranial Electrical Stimulation.

Cognitive fatigue is one of the most frequent symptoms in multiple sclerosis (MS), associated with significant impairment in daily functioning and quality of life. Despite its clinical significance, progress in understanding and treating fatigue is still limited. This limitation is already caused by an inconsistent and heterogeneous terminology and assessment of fatigue. In this review, we integrate previous literature on fatigue and propose a unified schema aiming to clarify the fatigue taxonomy. With special focus on cognitive fatigue, we survey the significance of objective behavioral and electrophysiological fatigue parameters and discuss the controversial literature on the relationship between subjective and objective fatigue assessment. As MS-related cognitive fatigue drastically affects quality of life, the development of efficient therapeutic approaches for overcoming cognitive fatigue is of high clinical relevance. In this regard, the reliable and valid assessment of the individual fatigue level by objective parameters is essential for systematic treatment evaluation and optimization. Transcranial electrical stimulation (tES) may offer a unique opportunity to manipulate maladaptive neural activity underlying MS fatigue. Therefore, we discuss evidence for the therapeutic potential of tES on cognitive fatigue in people with MS.