Linking Pathological Oscillations With Altered Temporal Processing in Parkinsons Disease: Neurophysiological Mechanisms and Implications for Neuromodulation.

Emerging evidence suggests that Parkinson's disease (PD) results from disrupted oscillatory activity in cortico-basal ganglia-thalamo-cortical (CBGTC) and cerebellar networks which can be partially corrected by applying deep brain stimulation (DBS). The inherent dynamic nature of such oscillatory activity might implicate that is represents temporal aspects of motor control. While the timing of muscle activities in CBGTC networks constitute the temporal dimensions of distinct motor acts, these very networks are also involved in somatosensory processing. In this respect, a temporal aspect of somatosensory processing in motor control concerns matching predicted (feedforward) and actual (feedback) sensory consequences of movement which implies a distinct contribution to demarcating the temporal order of events. Emerging evidence shows that such somatosensory processing is altered in movement disorders. This raises the question how disrupted oscillatory activity is related to impaired temporal processing and how/whether DBS can functionally restore this. In this perspective article, the neural underpinnings of temporal processing will be reviewed and translated to the specific alternated oscillatory neural activity specifically found in Parkinson's disease. These findings will be integrated in a neurophysiological framework linking somatosensory and motor processing. Finally, future implications for neuromodulation will be discussed with potential implications for strategy across a range of movement disorders

Consensus paper:Decoding the Contributions of the Cerebellum as a Time Machine. From Neurons to Clinical Applications

Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research. The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson\u2019s disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum. The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders

Temporal Dynamics of Visual Attention Allocation

We often temporally prepare our attention for an upcoming event such as a starter pistol. In such cases, our attention should be properly allocated around the expected moment of the event to process relevant sensory input efficiently. In this study, we examined the dynamic changes of attention levels near the expected moment by measuring contrast sensitivity to a target that was temporally cued by a five-second countdown. We found that the overall attention level decreased rapidly after the expected moment, while it stayed relatively constant before it. Results were not consistent with the predictions of existing explanations of temporal attention such as the hazard rate or the stimulus-driven oscillations. A control experiment ruled out the possibility that the observed pattern was due to biased time perception. In a further experiment with a wider range of cue-stimulus-intervals, we observed that attention level increased until the last 500 ms of the interval range, and thereafter, started to decrease. Based on the performances of a generative computational model, we suggest that our results reflect the nature of temporal attention that takes into account the subjectively estimated hazard rate and the probability of relevant events occurring in the near future

Optimal perceived timing: integrating sensory information with dynamically updated expectations

The environment has a temporal structure, and knowing when a stimulus will appear translates into increased perceptual performance. Here we investigated how the human brain exploits temporal regularity in stimulus sequences for perception. We find that the timing of stimuli that occasionally deviate from a regularly paced sequence is perceptually distorted. Stimuli presented earlier than expected are perceptually delayed, whereas stimuli presented on time and later than expected are perceptually accelerated. This result suggests that the brain regularizes slightly deviant stimuli with an asymmetry that leads to the perceptual acceleration of expected stimuli. We present a Bayesian model for the combination of dynamically-updated expectations, in the form of a priori probability of encountering future stimuli, with incoming sensory information. The asymmetries in the results are accounted for by the asymmetries in the distributions involved in the computational process

Distinct mechanisms of rhythm- and interval-based attention shifting in time

A fundamental principle of brain function is the use of temporal regularities to predict the timing of upcoming events and proactively allocate attention in time accordingly. Historically, predictions in rhythmic streams were explained by oscillatory entrainment models, whereas predictions formed based on associations between cues and isolated interval were explained by dedicated interval timing mechanisms. A fundamental question is whether predictions in these two contexts are indeed mediated by distinct mechanisms, or whether both rely on a single mechanism. I will present a series of studies that combined behavioral, electrophysiological, neuropsychological and computational approached to investigate the cognitive and neural architecture of rhythm- and interval-based predictions. I will first show that temporal predictions in both contexts similarly modulate behavior and anticipatory neural dynamics measured by EEG such as ramping activity, as well as phase-locking of delta-band activity, previously taken as signature of oscillatory entrainment. Second, I will show that cerebellar degeneration patients were impaired in forming temporal predictions based on isolated intervals but not based on rhythms, while Parkinson’s disease patients showed the reverse pattern. Finally, I will demonstrate that cerebellar degeneration patients show impaired temporal adjustment of ramping activity and delta-band phase-locking, as well as timed suppression of beta-band activity during interval-based prediction. Using computational modelling, I will identify the aspects of neural dynamics that prevail in rhythm-based prediction despite impaired interval-based prediction. To conclude, I will discuss implications for rhythmic entrainment and interval timing models, and the role of subcortical structures in temporal prediction and attention

Behavioral and neural dissociations of rhythmic temporal expectations from memory-based expectations

Background Sensory input with predictable dynamics can be used to create temporal expectations. It has been suggested that when the input is rhythmic, temporal expectations are created to in-phase time points due to oscillatory synchronization with the rhythm period. However, they can also be created by intentionally memorizing a fixed interval and applying it recursively. Using performance measures and EEG in 20 subjects, we dissociated these two processes. In one condition, targets appeared in-phase with a rhythmic sequence of stimuli in 80% of the trials. In another condition, they appeared in 80% of the trials at an interval that was recursively presented to allow memorization, but without creating a rhythmic sequence. In both conditions, a cue indicated explicitly that the next stimulus is the target. Results The behavioral validity effect of rhythmic stimulation was stronger than that of interval memorization, suggesting that the former is more temporally accurate. The CNV, an ERP which reflects temporal anticipation to the target, was more negative in the rhythmic condition, suggesting increased expectation. Furthermore, the effect of cue invalidity on the terminal CNV and on the latency of the P3, an ERP reflecting target evaluation, was more evident in the rhythmic condition, suggesting faster evaluation. Finally, in expected target times there was increased alpha desynchronization, previously shown to occur when directing attention. Conclusion Although the amount of temporal information was matched, the expectation created by rhythmic stimulation was superior over interval-based temporal expectation, both in behavior and in expectation-related neural activity. These findings are inconsistent with the idea that rhythmic expectation is no more than recursive applying a memorized interval, and instead suggest involvement of either an additional mechanism or a different one

Overcoming distracting temporal regularities: preparatory and stimulus-evoked mechanisms of attentional shifting in time away from rhythmic input

Background: To survive in a dynamically changing world, our brain constantly predicts the timing of future events. Rhythmic temporal structure is a potent cue for temporal predictions, such that processing of events is facilitated when they coincide with rhythmic input (i.e. appear on-beat), even for task-irrelevant rhythms. Mechanistically, the CNV, a slow premotor preparatory brain potential, is incidentally driven by rhythms such that it peaks at on-beat times. We tested the potency of rhythms as temporal cues by presenting targets with high probability between visual rhythmic stimuli (i.e. off-beat). This made off-beat moments task-relevant and encouraged observers to intentionally shift attention to them, while ignoring on-beat moments. In another condition, on-beat moments were task-relevant and off-beat moments were irrelevant. Results: When the time of the off-beat targets was jittered, the CNV peaked at on-beat times, which also showed behavioral benefit. However, when the time of the off-beat targets was fixed relative to rhythmic stimuli, responses were faster to off-beat targets compared to on-beat. Crucially, this was accompanied by modulation of the CNV trajectory such that it peaked at the task-relevant times and not at on-beat times. Finally, post-target brain activity demonstrated a sustained positivity for on-beat relative to off-beat targets, starting from 100 ms after target onset, while task-relevance only affected the later N2 ERP. Conclusions: Our findings imply that what seems to be an automatic effect of rhythms can be overcome given sufficient temporal information. This stands in contrast to prevalent entrainment models of temporal predictions, which explain rhythmic temporal predictions by synchronization of slow brain activity to the rhythmicity. Further, the dissociation we find in post-target responses extends the understanding of the unintentional and intentional components of temporal expectation formation in rhythmic environments

Context-specific control over the neural dynamics of temporal attention by the human cerebellum

Physiological methods have identified a number of signatures of temporal prediction, a core component of attention. While the underlying neural dynamics have been linked to activity within cortico-striatal networks, recent work has shown that the behavioral benefits of temporal prediction rely on the cerebellum. Here, we examine the involvement of the human cerebellum in the generation and/or temporal adjustment of anticipatory neural dynamics, measuring scalp electroencephalography in individuals with cerebellar degeneration. When the temporal prediction relied on an interval representation, duration-dependent adjustments were impaired in the cerebellar group compared to matched controls. This impairment was evident in ramping activity, beta-band power, and phase locking of delta-band activity. These same neural adjustments were preserved when the prediction relied on a rhythmic stream. Thus, the cerebellum has a context-specific causal role in the adjustment of anticipatory neural dynamics of temporal prediction, providing the requisite modulation to optimize behavior

Double dissociation of single-interval and rhythmic temporal prediction in cerebellar degeneration and Parkinson's disease

Predicting the timing of upcoming events is critical for successful interaction in a dynamic world, and is recognized as a key computation for attentional orienting. Temporal predictions can be formed when recent events define a rhythmic structure, as well as in aperiodic streams or even in isolation, when a specified interval is known from previous exposure. However, whether predictions in these two contexts are mediated by a common mechanism, or by distinct, context-dependent mechanisms, is highly controversial. Moreover, although the basal ganglia and cerebellum have been linked to temporal processing, the role of these subcortical structures in temporal orienting of attention is unclear. To address these issues, we tested individuals with cerebellar degeneration or Parkinson's disease, with the latter serving as a model of basal ganglia dysfunction, on temporal prediction tasks in the subsecond range. The participants performed a visual detection task in which the onset of the target was predictable, based on either a rhythmic stream of stimuli, or a single interval, specified by two events that occurred within an aperiodic stream. Patients with cerebellar degeneration showed no benefit from single-interval cuing but preserved benefit from rhythm cuing, whereas patients with Parkinson's disease showed no benefit from rhythm cuing but preserved benefit from single-interval cuing. This double dissociation provides causal evidence for functionally nonoverlapping mechanisms of rhythm- and interval-based temporal prediction for attentional orienting, and establishes the separable contributions of the cerebellum and basal ganglia to these functions, suggesting a mechanistic specialization across timing domains

The human cerebellum is essential for modulating perceptual sensitivity based on temporal expectations

A functional benefit of attention is to proactively enhance perceptual sensitivity in space and time. Although attentional orienting has traditionally been associated with cortico-thalamic networks, recent evidence has shown that individuals with cerebellar degeneration (CD) show a reduced reaction time benefit from cues that enable temporal anticipation. The present study examined whether the cerebellum contributes to the proactive attentional modulation in time of perceptual sensitivity. We tested CD participants on a non-speeded, challenging perceptual discrimination task, asking if they benefit from temporal cues. Strikingly, the CD group showed no duration-specific perceptual sensitivity benefit when cued by repeated but aperiodic presentation of the target interval. In contrast, they performed similar to controls when cued by a rhythmic stream. This dissociation further specifies the functional domain of the cerebellum and establishes its role in the attentional adjustment of perceptual sensitivity in time in addition to its well-documented role in motor timing