A cortical substrate for the long-term memory of saccadic eye movements calibration.

How movements are continuously adapted to physiological and environmental changes is a fundamental question in systems neuroscience. While many studies have elucidated the mechanisms which underlie short-term sensorimotor adaptation (∼10-30 min), how these motor memories are maintained over longer-term (>3-5 days) -and thanks to which neural systems-is virtually unknown. Here, we examine in healthy human participants whether the temporo-parietal junction (TPJ) is causally involved in the induction and/or the retention of saccadic eye movements' adaptation. Single-pulse transcranial magnetic stimulation (spTMS) was applied while subjects performed a ∼15min size-decrease adaptation task of leftward reactive saccades. A TMS pulse was delivered over the TPJ in the right hemisphere (rTPJ) in each trial either 30, 60, 90 or 120 msec (in 4 separate adaptation sessions) after the saccade onset. In two control groups of subjects, the same adaptation procedure was achieved either alone (No-TMS) or combined with spTMS applied over the vertex (SHAM-TMS). While the timing of spTMS over the rTPJ did not significantly affect the speed and immediate after-effect of adaptation, we found that the amount of adaptation retention measured 10 days later was markedly larger (42%) than in both the No-TMS (21%) and the SHAM-TMS (11%) control groups. These results demonstrate for the first time that the cerebral cortex is causally involved in maintaining long-term oculomotor memories.

The role of the posterior cerebellum in saccadic adaptation: a transcranial direct current stimulation study.

The posterior vermis of the cerebellum is considered to be critically involved in saccadic adaptation. However, recent evidence suggests that the adaptive decrease (backward adaptation) and the adaptive increase (forward adaptation) of saccade amplitude rely on partially separate neural substrates. We investigated whether the posterior cerebellum could be differentially involved in backward and forward adaptation by using transcranial direct current stimulation (TDCS). To do so, participants' saccades were adapted backward or forward while they received anodal, cathodal, or sham TDCS. In two extra groups, subjects underwent a nonadaptation session while receiving anodal or cathodal TDCS to control for the direct effects of TDCS on saccadic execution. Surprisingly, cathodal stimulation tended to increase the extent of both forward and backward adaptations, while anodal TDCS strongly impaired forward adaptation and, to a smaller extent, backward adaptation. Forward adaptation was accompanied by a greater increase in velocity with cathodal stimulation, and reduced duration of change for anodal stimulation. In contrast, the expected velocity decrease in backward adaptation was noticeably weaker with anodal stimulation. Stimulation applied during nonadaptation sessions did not affect saccadic gain, velocity, or duration, demonstrating that the reported effects are not due to direct effects of the stimulation on the generation of eye movements. Our results demonstrate that cerebellar excitability is critical for saccadic adaptation. Based on our results and the growing evidence from studies of vestibulo-ocular reflex and saccadic adaptation, we conclude that the plasticity at the level of the oculomotor vermis is more fundamentally important for forward adaptation than for backward adaptation.

Reversing motor adaptation deficits in the ageing brain using non-invasive stimulation.

KEY POINTS: Healthy ageing in man is associated with a decline in motor adaptation. Transcranial direct current stimulation (TDCS) over the primary motor cortex (M1) or the lateral cerebellum can improve motor adaptation in young and older adults, but as yet no direct comparisons of TDCS effects exist between the two age groups and the two stimulation sites. TDCS over M1 enhanced the motor adaptation in both age groups by ∼30% relative to their respective non-stimulated groups and improved the performance of older adults to the extent that it compared with that of young adults without stimulation. The study suggests that the plastic mechanisms activated by TDCS that underpin improvements in motor behaviour in young adults remain available in older adults. The results indicate that TDCS may be a useful tool to help combat the normal decline in motor performance seen in normal healthy ageing. ABSTRACT: Healthy ageing is characterised by deterioration of motor performance. In normal circumstances motor adaptation corrects for movements' inaccuracies and as such, it is critical in maintaining optimal motor control. However, motor adaptation performance is also known to decline with age. Anodal transcranial direct current stimulation (TDCS) of the cerebellum and the primary motor cortex (M1) have been found to improve visuomotor adaptation in healthy young and older adults. However, no study has directly compared the effect of TDCS on motor adaptation between the two age populations. The aim of our study was to investigate whether the application of anodal TDCS over the lateral cerebellum and M1 affected motor adaptation in young and older adults similarly. Young and older participants performed a visuomotor rotation task and concurrently received TDCS over the left M1, the right cerebellum or received sham stimulation. Our results replicated the finding that older adults are impaired compared to the young adults in visuomotor adaptation. At the end of the adaptation session, older adults displayed a larger error (-17 deg) than the young adults (-10 deg). The stimulation of the lateral cerebellum did not change the adaptation in both age groups. In contrast, anodal TDCS over M1 improved initial adaptation in both age groups by around 30% compared to sham and this improvement lasted up to 40 min after the end of the stimulation. These results demonstrate that TDCS of M1 can enhance visuomotor adaptation, via mechanisms that remain available in the ageing population.

Detecting Abnormal Eye Movements in Patients with Neurodegenerative Diseases - Current Insights.

This review delineates the ocular motor disturbances across a spectrum of neurodegenerative disorders, including Alzheimer's Disease (AD) and related disorders (ADRD), Parkinson's Disease (PD), atypical parkinsonism, and others, leveraging advancements in eye-tracking technology for enhanced diagnostic precision. We delve into the different classes of eye movements, their clinical assessment, and specific abnormalities manifesting in these diseases, highlighting the nuanced differences and shared patterns. For instance, AD and ADRD are characterized by increased saccadic latencies and instability in fixation, while PD features saccadic hypometria and mild smooth pursuit impairments. Atypical parkinsonism, notably Progressive Supranuclear Palsy (PSP) and Corticobasal Syndrome (CBS), presents with distinct ocular motor signatures such as vertical supranuclear gaze palsy and saccadic apraxia, respectively. Our review underscores the diagnostic value of eye movement analysis in differentiating between these disorders and also posits the existence of underlying common pathological mechanisms. We discuss how eye movements have potential as biomarkers for neurodegenerative diseases but also some of the existing limitations.

Investigating the effects of cerebellar transcranial direct current stimulation on saccadic adaptation and cortisol response.

BACKGROUND: Transcranial Direct Current Stimulation (tDCS) over the prefrontal cortex has been shown to modulate subjective, neuronal and neuroendocrine responses, particularly in the context of stress processing. However, it is currently unknown whether tDCS stimulation over other brain regions, such as the cerebellum, can similarly affect the stress response. Despite increasing evidence linking the cerebellum to stress-related processing, no studies have investigated the hormonal and behavioural effects of cerebellar tDCS. METHODS: This study tested the hypothesis of a cerebellar tDCS effect on mood, behaviour and cortisol. To do this we employed a single-blind, sham-controlled design to measure performance on a cerebellar-dependent saccadic adaptation task, together with changes in cortisol output and mood, during online anodal and cathodal stimulation. Forty-five participants were included in the analysis. Stimulation groups were matched on demographic variables, potential confounding factors known to affect cortisol levels, mood and a number of personality characteristics. RESULTS: Results showed that tDCS polarity did not affect cortisol levels or subjective mood, but did affect behaviour. Participants receiving anodal stimulation showed an 8.4% increase in saccadic adaptation, which was significantly larger compared to the cathodal group (1.6%). CONCLUSION: The stimulation effect on saccadic adaptation contributes to the current body of literature examining the mechanisms of cerebellar stimulation on associated function. We conclude that further studies are needed to understand whether and how cerebellar tDCS may module stress reactivity under challenge conditions.

Decline of auditory-motor speech processing in older adults with hearing loss.

Older adults often experience difficulties in understanding speech, partly because of age-related hearing loss (HL). In young adults, activity of the left articulatory motor cortex is enhanced and it interacts with the auditory cortex via the left-hemispheric dorsal stream during speech processing. Little is known about the effect of aging and age-related HL on this auditory-motor interaction and speech processing in the articulatory motor cortex. It has been proposed that upregulation of the motor system during speech processing could compensate for HL and auditory processing deficits in older adults. Alternatively, age-related auditory deficits could reduce and distort the input from the auditory cortex to the articulatory motor cortex, suppressing recruitment of the motor system during listening to speech. The aim of the present study was to investigate the effects of aging and age-related HL on the excitability of the tongue motor cortex during listening to spoken sentences using transcranial magnetic stimulation and electromyography. Our results show that the excitability of the tongue motor cortex was facilitated during listening to speech in young and older adults with normal hearing. This facilitation was significantly reduced in older adults with HL. These findings suggest a decline of auditory-motor processing of speech in adults with age-related HL.

Facilitation of motor excitability during listening to spoken sentences is not modulated by noise or semantic coherence.

Comprehending speech can be particularly challenging in a noisy environment and in the absence of semantic context. It has been proposed that the articulatory motor system would be recruited especially in difficult listening conditions. However, it remains unknown how signal-to-noise ratio (SNR) and semantic context affect the recruitment of the articulatory motor system when listening to continuous speech. The aim of the present study was to address the hypothesis that involvement of the articulatory motor cortex increases when the intelligibility and clarity of the spoken sentences decreases, because of noise and the lack of semantic context. We applied Transcranial Magnetic Stimulation (TMS) to the lip and hand representations in the primary motor cortex and measured motor evoked potentials from the lip and hand muscles, respectively, to evaluate motor excitability when young adults listened to sentences. In Experiment 1, we found that the excitability of the lip motor cortex was facilitated during listening to both semantically anomalous and coherent sentences in noise relative to non-speech baselines, but neither SNR nor semantic context modulated the facilitation. In Experiment 2, we replicated these findings and found no difference in the excitability of the lip motor cortex between sentences in noise and clear sentences without noise. Thus, our results show that the articulatory motor cortex is involved in speech processing even in optimal and ecologically valid listening conditions and that its involvement is not modulated by the intelligibility and clarity of speech.

Psychosocial stress affects the acquisition of cerebellar-dependent sensorimotor adaptation.

Despite being overlooked in theoretical models of stress-related disorders, differences in cerebellar structure and function are consistently reported in studies of individuals exposed to current and early-life stressors. However, the mediating processes through which stress impacts upon cerebellar function are currently unknown. The aim of the current experiment was to test the effects of experimentally-induced acute stress on cerebellar functioning, using a classic, forward saccadic adaptation paradigm in healthy, young men and women. Stress induction was achieved by employing the Montreal Imaging Stress Task (MIST), a task employing mental arithmetic and negative social feedback to generate significant physiological and endocrine stress responses. Saccadic adaptation was elicited using the double-step target paradigm. In the experiment, 48 participants matched for gender and age were exposed to either a stress (n = 25) or a control (n = 23) condition. Saliva for cortisol analysis was collected before, immediately after, and 10, and 30 min after the MIST. Saccadic adaptation was assessed approximately 10 min after stress induction, when cortisol levels peaked. Participants in the stress group reported significantly more stress symptoms and exhibited greater total cortisol output compared to controls. The stress manipulation was associated with slower learning rates in the stress group, while control participants acquired adaptation faster. Learning rates were negatively associated with cortisol output and mood disturbance. Results suggest that experimentally-induced stress slowed acquisition of cerebellar-dependent saccadic adaptation, related to increases in cortisol output. These 'proof-of-principle' data demonstrate that stress modulates cerebellar-related functions.

Author Correction: Sensorimotor adaptation as a behavioural biomarker of early spinocerebellar ataxia type 6.

A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has been fixed in the paper.

Sensorimotor adaptation as a behavioural biomarker of early spinocerebellar ataxia type 6.

Early detection of the behavioural deficits of neurodegenerative diseases may help to describe the pathogenesis of such diseases and establish important biomarkers of disease progression. The aim of this study was to identify how sensorimotor adaptation of the upper limb, a cerebellar-dependent process restoring movement accuracy after introduction of a perturbation, is affected at the pre-clinical and clinical stages of spinocerebellar ataxia type 6 (SCA6), an inherited neurodegenerative disease. We demonstrate that initial adaptation to the perturbation was significantly impaired in the eighteen individuals with clinical motor symptoms but mostly preserved in the five pre-clinical individuals. Moreover, the amount of error reduction correlated with the clinical symptoms, with the most symptomatic patients adapting the least. Finally both pre-clinical and clinical individuals showed significantly reduced de-adaptation performance after the perturbation was removed in comparison to the control participants. Thus, in this large study of motor features in SCA6, we provide novel evidence for the existence of subclinical motor dysfunction at a pre-clinical stage of SCA6. Our findings show that testing sensorimotor de-adaptation could provide a potential predictor of future motor deficits in SCA6.

Intact Acquisition and Short-Term Retention of Non-Motor Procedural Learning in Parkinson's Disease.

Procedural learning is a form of memory where people implicitly acquire a skill through repeated practice. People with Parkinson's disease (PD) have been found to acquire motor adaptation, a form of motor procedural learning, similarly to healthy older adults but they have deficits in long-term retention. A similar pattern of normal learning on initial exposure with a deficit in retention seen on subsequent days has also been seen in mirror-reading, a form of non-motor procedural learning. It is a well-studied fact that disrupting sleep will impair the consolidation of procedural memories. Given the prevalence of sleep disturbances in PD, the lack of retention on following days seen in these studies could simply be a side effect of this well-known symptom of PD. Because of this, we wondered whether people with PD would present with deficits in the short-term retention of a non-motor procedural learning task, when the test of retention was done the same day as the initial exposure. The aim of the present study was then to investigate acquisition and retention in the immediate short term of cognitive procedural learning using the mirror-reading task in people with PD. This task involved two conditions: one where triads of mirror-inverted words were always new that allowed assessing the learning of mirror-reading skill and another one where some of the triads were presented repeatedly during the experiment that allowed assessing the word-specific learning. People with PD both ON and OFF their normal medication were compared to healthy older adults and young adults. Participants were re-tested 50 minutes break after initial exposure to probe for short-term retention. The results of this study show that all groups of participants acquired and retained the two skills (mirror-reading and word-specific) similarly. These results suggest that neither healthy ageing nor the degeneration within the basal ganglia that occurs in PD does affect the mechanisms that underpin the acquisition of these new non-motor procedural learning skills and their short-term memories.

Oculomotor Adaptation Elicited By Intra-Saccadic Visual Stimulation: Time-Course of Efficient Visual Target Perturbation.

Perception of our visual environment strongly depends on saccadic eye movements, which in turn are calibrated by saccadic adaptation mechanisms elicited by systematic movement errors. Current models of saccadic adaptation assume that visual error signals are acquired only after saccade completion, because the high speed of saccade execution disturbs visual processing (saccadic "suppression" and "mislocalization"). Complementing a previous study from our group, here we report that visual information presented during saccades can drive adaptation mechanisms and we further determine the critical time window of such error processing. In 15 healthy volunteers, shortening adaptation of reactive saccades toward a ±8° visual target was induced by flashing the target for 2 ms less eccentrically than its initial location either near saccade peak velocity ("PV" condition) or peak deceleration ("PD") or saccade termination ("END"). Results showed that, as compared to the "CONTROL" condition (target flashed at its initial location upon saccade termination), saccade amplitude decreased all throughout the "PD" and "END" conditions, reaching significant levels in the second adaptation and post-adaptation blocks. The results of nine other subjects tested in a saccade lengthening adaptation paradigm with the target flashing near peak deceleration ("PD" and "CONTROL" conditions) revealed no significant change of gain, confirming that saccade shortening adaptation is easier to elicit. Also, together with this last result, the stable gain observed in the "CONTROL" conditions of both experiments suggests that mislocalization of the target flash is not responsible for the saccade shortening adaptation demonstrated in the first group. Altogether, these findings reveal that the visual "suppression" and "mislocalization" phenomena related to saccade execution do not prevent brief visual information delivered "in-flight" from being processed to elicit oculomotor adaptation.