Showing papers in "Frontiers in Integrative Neuroscience in 2011"

Altered Auditory and Multisensory Temporal Processing in Autism Spectrum Disorders

Abstract: Autism spectrum disorders (ASD) are characterized by deficits in social reciprocity and communication, as well as by repetitive behaviors and restricted interests. Unusual responses to sensory input and disruptions in the processing of both unisensory and multisensory stimuli also have been reported frequently. However, the specific aspects of sensory processing that are disrupted in ASD have yet to be fully elucidated. Recent published work has shown that children with ASD can integrate low-level audiovisual stimuli, but do so over an extended range of time when compared with typically developing (TD) children. However, the possible contributions of altered unisensory temporal processes to the demonstrated changes in multisensory function are yet unknown. In the current study, unisensory temporal acuity was measured by determining individual thresholds on visual and auditory temporal order judgment (TOJ) tasks, and multisensory temporal function was assessed through a cross-modal version of the TOJ task. Whereas no differences in thresholds for the visual TOJ task were seen between children with ASD and TD, thresholds were higher in ASD on the auditory TOJ task, providing preliminary evidence for impairment in auditory temporal processing. On the multisensory TOJ task, children with ASD showed performance improvements over a wider range of temporal intervals than TD children, reinforcing prior work showing an extended temporal window of multisensory integration in ASD. These findings contribute to a better understanding of basic sensory processing differences, which may be critical for understanding more complex social and cognitive deficits in ASD, and ultimately may contribute to more effective diagnostic and interventional strategies.

Anatomical pathways involved in generating and sensing rhythmic whisker movements.

Abstract: The rodent whisker system is widely used as a model system for investigating sensorimotor integration, neural mechanisms of complex cognitive tasks, neural development, and robotics. The whisker pathways to the barrel cortex have received considerable attention. However, many subcortical structures are paramount to the whisker system. They contribute to important processes, like filtering out salient features, integration with other senses, and adaptation of the whisker system to the general behavioral state of the animal. We present here an overview of the brain regions and their connections involved in the whisker system. We do not only describe the anatomy and functional roles of the cerebral cortex, but also those of subcortical structures like the striatum, superior colliculus, cerebellum, pontomedullary reticular formation, zona incerta, and anterior pretectal nucleus as well as those of level setting systems like the cholinergic, histaminergic, serotonergic, and noradrenergic pathways. We conclude by discussing how these brain regions may affect each other and how they together may control the precise timing of whisker movements and coordinate whisker perception.

Contingent negative variation and its relation to time estimation: a theoretical evaluation.

Abstract: The relation between the contingent negative variation (CNV) and time estimation is evaluated in terms of temporal accumulation and preparation processes. The conclusion is that the CNV as measured from the electroencephalogram (EEG) recorded at fronto-central and parietal-central areas is not a direct reflection of the underlying interval timing mechanism(s), but more likely represents a time-based response preparation/decision-making process.

Moments in time

Abstract: It has been suggested that perception and action can be understood as evolving in temporal epochs or sequential processing units. Successive events are fused into units forming a unitary experience or ‘psychological present’. Studies have identified several temporal integration levels on different time scales which are fundamental for our understanding of behaviour and subjective experience. In recent literature concerning the philosophy and neuroscience of consciousness these separate temporal processing levels are not always precisely distinguished. Therefore, empirical evidence from psychophysics and neuropsychology on these distinct temporal processing levels is presented and discussed within philosophical conceptualizations of time experience. On an elementary level, one can identify a functional moment, a basic temporal building block of perception in the range of milliseconds that defines simultaneity and succession. Below a certain threshold temporal order is not perceived, individual events are processed as co-temporal. On a second level, an experienced moment, which is based on temporal integration of up to a few seconds, has been reported in many qualitatively different experiments in perception and action. It has been suggested that this segmental processing mechanism creates temporal windows that provide a logistical basis for conscious representation and the experience of nowness. On a third level of integration, continuity of experience is enabled by working-memory in the range of multiple seconds allowing the maintenance of cognitive operations and emotional feelings, leading to mental presence, a temporal window of an individual’s experienced presence.

Authenticity, depression, and deep brain stimulation.

Abstract: In 2005 the journal Neuron published Mayberg et al.’s (2005) pioneering study on deep brain stimulation (DBS) targeting treatment-refractory major depressive disorder (MDD). Since then a handful of studies, in total encompassing little over 50 patients, have been published (Aouizerate et al., 2005; Jimenez et al., 2005; Mayberg et al., 2005; Kuhn et al., 2007; Lozano et al., 2008; Neimat et al., 2008; Schlaepfer et al., 2008; Malone et al., 2009; Bewernick et al., 2010; Sartorius et al., 2010) and larger trials are underway (Bell et al., 2009). A common ethical concern voiced when DBS is used for a psychiatric disorder such as MDD is that the stimulation specifically targets cognition, mood, and behavior; elements which are closely linked to the patient's personality. Obviously, this holds true also for other antidepressants such as psychotherapy and medication. Apart from that these standard therapies have been of no avail for the patients considered for MDD DBS, one could still ask whether their potential to alter cognition, mood, and behavior, differ - with regard to ethical concerns - from that of DBS. Further, the relevant ethical concern is arguably not what functions the stimulation are intended to alter, as in psychiatric indications, but rather what functions that could be altered by DBS. Unintended alterations of cognition, mood and behaviour could occur as a consequence of both psychiatric and motoric DBS. Thus, potential alterations of personality seem, apart from the historical stigma connected with the former, to be relevant for most DBS indications. A lot of work remains to be done before a comprehensive analysis of these concerns could be presented. Our contribution is to introduce one question relevant to the intersection of DBS, MDD, and the notion(s) of authenticity.

Male or Female? Brains are Intersex

Abstract: The underlying assumption in popular and scientific publications on sex differences in the brain is that human brains can take one of two forms “male” or “female”, and that the differences between these two forms underlie differences between men and women in personality, cognition, emotion and behavior. Documented sex differences in brain structure are typically taken to support this dimorphic view of the brain. However, neuroanatomical data reveal that sex interacts with other factors in utero and throughout life to determine the structure of the brain, and that because these interactions are complex, the result is a multi-morphic, rather than a dimorphic, brain. More specifically, here I argue that human brains are composed of an ever-changing heterogeneous mosaic of “male” and “female” brain characteristics (rather than being all “male” or all “female”) that cannot be aligned on a continuum between a “male brain” and a “female brain”. I further suggest that sex differences in the direction of change in the brain mosaic following specific environmental events lead to sex differences in neuropsychiatric disorders.

Ethical issues in deep brain stimulation

Abstract: Deep brain stimulation (DBS) is currently used to treat neurological disorders like Parkinson’s disease (PD), essential tremor and dystonia, and is explored as an experimental treatment for psychiatric disorders like Major Depression (MD) and Obsessive Compulsive Disorder (OCD). This mini review discusses ethical issues in DBS treatment and research, as they have been discussed in the medical and ethical literature. With regard to DBS treatment, the most important issues are balancing risks and benefits and ensuring respect for the autonomous wish of the patient. This implies special attention to patient selection, psycho-social impact of treatment, effects on personal identity, and treatment of children. Moreover, it implies a careful informed consent process in which unrealistic expectations of patients and their families are addressed and in which special attention is given to competence. In the context of research, the fundamental ethical challenge is to promote high-quality scientific research in the interest of future patients, while at the same time safeguarding the rights and interests of vulnerable research subjects. Several guidelines have been proposed to ensure this. One of the preconditions to further development of responsible and transparent research practices is the establishment of a comprehensive registry.

Emotion and time perception: effects of film-induced mood.

Abstract: Previous research into emotion and time perception has been designed to study the time perception of emotional events themselves (e.g., facial expression). Our aim was to investigate the effect of emotions per se on the subsequent time judgment of a neutral, non-affective event. In the present study, the participants were presented with films inducing a specific mood and were subsequently given a temporal bisection task. More precisely, the participants were given two temporal bisection tasks, one before and the other after viewing the emotional film. Three emotional films were tested: one eliciting fear, another sadness, and a neutral control film. In addition, the direct mood experience was assessed using the Brief Mood Introspective Scale that was administered to the participants at the beginning and the end of the session. The results showed that the perception of time did not change after viewing either the neutral control films or the sad films although the participants reported being sadder and less aroused after than before watching the sad film clips. In contrast, the stimulus durations were judged longer after than before viewing the frightening films that were judged to increase the emotion of fear and arousal level. In combination with findings from previous studies, our data suggest that the selective lengthening effect after watching frightening films was mediated by an effect of arousal on the speed of the internal clock system.

Origin and Evolution of Deep Brain Stimulation

Abstract: This paper briefly describes how the electrical stimulation, used since antiquity to modulate the nervous system, has been a fundamental tool of neurophysiologic investigation in the second half of the 18th century and was subsequently used by the early 20th century, even for therapeutic purposes. In mid-20th century the advent of stereotactic procedures has allowed the drift from lesional to stimulating technique of deep nuclei of the brain for therapeutic purposes. In this way, DBS was born, that, over the last two decades, has led to positive results for the treatment of medically refractory Parkinson's disease, essential tremor and dystonia. In recent years, the indications for therapeutic use of DBS have been extended to epilepsy, Tourette's syndrome, psychiatric diseases (depression, obsessive-compulsive disorder), some kinds of headache, eating disorders and the minimally conscious state. The potentials of the DBS for therapeutic use are fascinating, but there are still many unresolved technical and ethical problems, concerning the identification of the targets for each disease, the selection of the patients and the evaluation of the results.

Modeling pharmacological clock and memory patterns of interval timing in a striatal beat-frequency model with realistic, noisy neurons.

Abstract: In most species, the capability of perceiving and using the passage of time in the seconds-to-minutes range (interval timing) is not only accurate but also scalar: errors in time estimation are linearly related to the estimated duration. The ubiquity of scalar timing extends over behavioral, lesion, and pharmacological manipulations. For example, in mammals, dopaminergic drugs induce an immediate, scalar change in the perceived time (clock pattern), whereas cholinergic drugs induce a gradual, scalar change in perceived time (memory pattern). How do these properties emerge from unreliable, noisy neurons firing in the milliseconds range? Neurobiological information relative to the brain circuits involved in interval timing provide support for an striatal beat frequency (SBF) model, in which time is coded by the coincidental activation of striatal spiny neurons by cortical neural oscillators. While biologically plausible, the impracticality of perfect oscillators, or their lack thereof, questions this mechanism in a brain with noisy neurons. We explored the computational mechanisms required for the clock and memory patterns in an SBF model with biophysically realistic and noisy Morris-Lecar neurons (SBF-ML). Under the assumption that dopaminergic drugs modulate the firing frequency of cortical oscillators, and that cholinergic drugs modulate the memory representation of the criterion time, we show that our SBF-ML model can reproduce the pharmacological clock and memory patterns observed in the literature. Numerical results also indicate that parameter variability (noise) - which is ubiquitous in the form of small fluctuations in the intrinsic frequencies of neural oscillators within and between trials, and in the errors in recording/retrieving stored information related to criterion time - seems to be critical for the time-scale invariance of the clock and memory patterns.

Long-Lasting Effects of Human Mesenchymal Stem Cell Systemic Administration on Pain-Like Behaviors, Cellular, and Biomolecular Modifications in Neuropathic Mice

Abstract: Background. Neuropathic pain (NP) is an incurable disease caused by a primary lesion in the nervous system. NP is a progressive nervous system disease that results from poorly defined neurophysiological and neurochemical changes. Its treatment is very difficult. Current available therapeutic drugs have a generalized nature, sometime acting only on the temporal pain properties rather than targeting the several mechanisms underlying the generation and propagation of pain. Methods. Using biomolecular and immunohistochemical methods, we investigated the effect of the systemic injection of human mesenchymal stem cells (hMSCs) on neuropathic pain relief. We used the spared nerve injury (SNI) model of neuropathic pain in the mouse. Human MSCs were injected into the tail vein of the mouse. Stem cell injection was performed 4 days after sciatic nerve surgery. Neuropathic mice were monitored every 10 days starting from day 11 until 90 days after surgery. Results. Human MSCs were able to reduce pain-like behaviours, such as mechanical allodynia and thermal hyperalgesia, once injected into the tail vein. An anti-nociceptive effect was detectable from day 11 post surgery (7 days post cell injection). Human MSCs were mainly able to home in the spinal cord and pre-frontal cortex of neuropathic mice. Injected hMSCs reduced the protein levels of the mouse pro-inflammatory interleukin IL-1s and IL-17 and increased protein levels of the mouse anti-inflammatory interleukin IL-10, and the marker of alternatively activated macrophages CD106 in the spinal cord of SNI mice. Conclusions. As a potential mechanism of action of hMSCs in reducing pain, we suggest that they could exert their beneficial action through a restorative mechanism involving: i) a cell-to-cell contact activation mechanism, through which spinal cord homed hMSCs are responsible for switching pro-inflammatory macrophages to anti-inflammatory macrophages; ii) secretion of a broad spectrum of molecules to communicate with

Identifying a Network of Brain Regions Involved in Aversion-Related Processing: A Cross-Species Translational Investigation

Abstract: The ability to detect and respond appropriately to aversive stimuli is essential for all organisms, from fruit flies to humans. This suggests the existence of a core neural network which mediates aversion-related processing. Human imaging studies on aversion have highlighted the involvement of various cortical regions, such as the prefrontal cortex, while animal studies have focused largely on subcortical regions like the periaqueductal gray and hypothalamus. However, whether and how these regions form a core neural network of aversion remains unclear. To help determine this, a translational cross-species investigation in humans (i.e., meta-analysis) and other animals (i.e., systematic review of functional neuroanatomy) was performed. Our results highlighted the recruitment of the anterior cingulate cortex, the anterior insula, and the amygdala as well as other subcortical (e.g., thalamus, midbrain) and cortical (e.g., orbitofrontal) regions in both animals and humans. Importantly, involvement of these regions remained independent of sensory modality. This study provides evidence for a core neural network mediating aversion in both animals and humans. This not only contributes to our understanding of the trans-species neural correlates of aversion but may also carry important implications for psychiatric disorders where abnormal aversive behavior can often be observed.

Temporal accumulation and decision processes in the duration bisection task revealed by contingent negative variation.

Abstract: The duration bisection paradigm is a classic task used to examine how humans and other animals perceive time. Typically, participants first learn short and long anchor durations and are subsequently asked to classify probe durations as closer to the short or long anchor duration. However, the specific representations of time and the decision rules applied in this task remain the subject of debate. For example, researchers have questioned whether participants actually use representations of the short and long anchor durations in the decision process rather than merely a response threshold that is derived from those anchor durations. Electroencephalographic (EEG) measures, like the Contingent Negative Variation (CNV), can provide information about the perceptual and cognitive processes that occur between the onset of the timing stimulus and the motor response. The CNV has been implicated as an electrophysiological marker of interval timing processes such as temporal accumulation, representation of the target duration, and the decision that the target duration has been attained. Hence, we used the CNV to investigate which durations are involved in the bisection categorization decision. The CNV increased in amplitude up to the value of the short anchor, remained at a constant level until about the geometric mean of the short and long anchors, when it began to resolve. These results suggest that the short anchor and the geometric mean of the short and long anchors are critical target durations used in the bisection categorization decision process. In addition, larger mean N1-P2 amplitude differences were associated with larger amplitude CNVs, which may reflect how precisely a participant is able to initiate timing on each trial across a test session. Overall, the results demonstrate the value of using scalp-recorded EEG to address basic questions about interval timing.

Slow Potentials in Time Estimation: The Role of Temporal Accumulation and Habituation

Abstract: Numerous studies have shown that contingent negative variation (CNV) measured at fronto-central and parietal-central areas is closely related to interval timing. However, the exact nature of the relation between CNV and the underlying timing mechanisms is still a topic of discussion. On the one hand, it has been proposed that the CNV measured at supplementary motor area (SMA) is a direct reflection of the unfolding of time since a perceived onset, whereas other work has suggested that the increased amplitude reflects decision processes involved in interval timing. Strong evidence for the first view has been reported by Macar, Vidal and Casini (1999), who showed that variations in temporal performance were reflected in the measured CNV amplitude. If the CNV measured at SMA is a direct function of the passing of time, habituation effects are not expected. Here we report two replication studies, which both failed to replicate the expected performance-dependent variations. Even more powerful linear-mixed effect analyses failed to find any performance related effects on the CNV amplitude, whereas habituation effects were found. These studies therefore suggest that the CNV amplitude does not directly reflect the unfolding of time

Optimal temporal risk assessment

Abstract: Time is an essential feature of most decisions. Keeping track of time is adaptive because the reward earned from decisions frequently depends on the temporal statistics of the environment. Accordingly, evolution appears to have favored a mechanism that predicts intervals in the seconds-to-minutes range with high accuracy on average, but significant variability from trial to trial. Importantly, the subjective sense of time that results is sufficiently imprecise that maximizing rewards can require substantial behavioral adjustments in response to this temporal uncertainty. Reward-maximization in many daily decisions therefore requires optimal temporal risk assessment. Using tasks that entail different decisions and that impose different time constraints on the reward function, we examine temporal risk assessment ability in terms of the degree to which it approaches optimality. We review recent literature and present human and rodent data that strongly support the hypothesis that these animals take normative account of their endogenous timing uncertainty. By incorporating the psychophysics of interval timing into the study of reward maximization, our approach bridges empirical and theoretical gaps between the interval timing and decision making literatures.

Deep brain stimulation in the media: over-optimistic portrayals call for a new strategy involving journalists and scientists in ethical debates.

Abstract: Deep brain stimulation (DBS) is optimistically portrayed in contemporary media This already happened with psychosurgery during the first half of the twentieth century The tendency of popular media to hype the benefits of DBS therapies, without equally highlighting risks, fosters public expectations also due to the lack of ethical analysis in the scientific literature Media are not expected (and often not prepared) to raise the ethical issues which remain unaddressed by the scientific community To obtain a more objective portrayal of DBS in the media, a deeper collaboration between the science community and journalists, and particularly specialized ones, must be promoted Access to databases and articles, directly or through science media centers, has also been proven effective in increasing the quality of reporting This article has three main objectives Firstly, to explore the past media coverage of leukotomy, and to examine its widespread acceptance and the neglect of ethical issues in its depiction Secondly, to describe how current enthusiastic coverage of DBS causes excessive optimism and neglect of ethical issues in patients Thirdly, to discuss communication models and strategies to enhance media and science responsibility

Differential input of the supplementary motor area to a dedicated temporal processing network: functional and clinical implications.

Abstract: The ability to track the temporal structure of events in a dynamic environment is crucial to cognition and action alike. In order to guide timely reactive and proactive behavior the individual has to draw upon some internal representation of temporal relations or temporal structure. Here an event may be defined as a perceived change in the formal structure of the environment, i.e., the identity (“what”) or the position (“where”) of an object. In turn, the temporal relation between events may be defined as the temporal structure (“when”) of the environment.

Unwinding the Molecular Basis of Interval and Circadian Timing

Abstract: Neural timing mechanisms range from the millisecond to diurnal, and possibly annual, frequencies. Two of the main processes under study are the interval timer (seconds-to-minute range) and the circadian clock. The molecular basis of these two mechanisms is the subject of intense research, as well as their possible relationship. This article summarizes data from studies investigating a possible interaction between interval and circadian timing and reviews the molecular basis of both mechanisms, including the discussion of the contribution from studies of genetically modified animal models. While there is currently no common neurochemical substrate for timing mechanisms in the brain, circadian modulation of interval timing suggests an interaction of different frequencies in cerebral temporal processes.

Balancing the brain: resting state networks and deep brain stimulation.

Abstract: Over the last three decades, large numbers of patients with otherwise treatment-resistant disorders have been helped by deep brain stimulation (DBS), yet a full scientific understanding of the underlying neural mechanisms is still missing. We have previously proposed that efficacious DBS works by restoring the balance of the brain's resting state networks. Here, we extend this proposal by reviewing how detailed investigations of the highly coherent functional and structural brain networks in health and disease (such as Parkinson's) have the potential not only to increase our understanding of fundamental brain function but of how best to modulate the balance. In particular, some of the newly identified hubs and connectors within and between resting state networks could become important new targets for DBS, including potentially in neuropsychiatric disorders. At the same time, it is of essence to consider the ethical implications of this perspective.

Multiple mechanisms for temporal processing.

Abstract: Many models suggest that time perception is mediated by a unitary mechanism. For example, scalar expectancy theory (SET), the dominant model of timing for the past 30 years, suggests that temporal processing is mediated by a centralized clock-counter module in which elapsed time is measured by the summation of pacemaker pulses (Gibbon et al., 1984). A number of alternative, neurally plausible models have been proposed with clock processes that incorporate either the pacemaker-counter elements of SET, or other neural dynamics such as decay processes or state-dependent network activity (Staddon and Higa, 1999; Karmarkar and Buonomano, 2007; Simen et al., 2011a,b). While these models differ in the mechanisms utilized for the temporal control of behavior, they all suggest that timing is accomplished by a single, amodal process. Support for the hypothesis that timing is mediated by a single mechanism comes from several sources. A number of studies demonstrate that performance is independent of whether the task utilizes motor or “perceptual” temporal representations (Ivry and Hazeltine, 1995; Meegan et al., 2000). Additionally, although an effect of interval duration has been postulated for over a hundred years, such an effect has not been consistently identified; Lewis and Miall (2009), for example, failed to identify a fundamental change in timing performance or “break-point” using stimuli ranging from 68 ms to 16.7 min. We suggest the alternative hypothesis that timing functions are mediated by multiple, overlapping neural systems, which may be flexibly engaged depending on the task requirements. These systems may function independently of one another and may be adaptively engaged pro re nata, such that single or multiple systems may be active during any one timing task, depending on environmental conditions and behavioral requirements. One line of support for this hypothesis comes from a quantitative meta-analysis of 41 neuroimaging studies of time perception in which we found that different neural structures were engaged depending on stimulus duration and the “motor” or “perceptual” nature of the task (Wiener et al., 2010a). Of particular interest in this context, however, is the fact that the meta-analysis also demonstrated two areas engaged across all tasks: supplementary motor area (SMA) and right inferior frontal gyrus (rIFG). In subsequent analyses of this dataset, however, we found that even in regions active across several conditions there is evidence of multiple timing mechanisms at work. Consider the SMA for example. Recent observations suggest that the SMA is a heterogeneous structure that may be functionally divided into the SMA “proper” and pre-SMA (Nachev et al., 2008). A rostro-caudal gradient in the SMA has been proposed according to which SMA and pre-SMA subserve motor and cognitive processes, respectively. Consistent with this finding, we found evidence for a functional gradient in the SMA, wherein perceptual timing tasks are more likely to activate voxels within the pre-SMA while motor timing tasks are associated with SMA proper activation-likelihood (Figure ​(Figure11A). Figure 1 A subset of the results from our previous meta-analysis of neuroimaging timing studies. (A) Sagittal section of a rendered brain including SMA voxels from perceptual or motor timing tasks (regardless of duration length) and their overlap. Crosshairs are ... Fractionation of temporal processing may also be evident in the basal ganglia, a brain region often implicated in studies of time perception and with high connectivity to the SMA. Figure ​Figure1B1B depicts voxels from SMA and basal ganglia regions with significant activation-likelihood. Once again, different patterns of activation-likelihood were noted as a function of the duration of the stimulus and nature of the task. For example, there was a greater propensity for the basal ganglia to be activated during sub-second timing tasks. However, it is crucial to note that the basal ganglia interact with numerous other regions, and so these activation patterns must be considered in the larger context of interactive networks. Additional work beyond neuroimaging also argues for multiple timing systems. For example, we recently adopted a behavioral genetics paradigm to look at single-nucleotide polymorphisms in genes associated with different aspects of the dopamine system (Wiener et al., 2011). We found that a polymorphism affecting the expression of striatal D2 receptors was associated with poorer performance on a perceptual timing task, but only when the intervals tested were below 1 s. In contrast, subjects with a polymorphism affecting the expression of the enzyme catechol-O-methyltransferase (COMT), which is known to regulate prefrontal dopamine tone, were impaired during supra-second, but not sub-second timing. This work suggests that different dopaminergic systems may underlie distinct timing procedures. Another line of data supporting the claim that multiple mechanisms mediate timing comes from the fact that at least under some circumstances timing mechanisms appear to be both modality-specific and mediated by local neural structures. For example, adaptation to focal regions of the visual field produces duration distortions that are localized to that spatial region (Burr et al., 2007). Interestingly, modality-specific regions appear to be invoked for temporal expectations even in the absence of the stimuli themselves (Bueti and Macaluso, 2010), suggesting that the process may be mediated by simulation. The fact that subject strategies influence the neural circuits recruited for timing is also consistent with the hypothesis that multiple distinct procedures underlie timing. For example, a recent study demonstrated that subjects recruited different neural networks depending on whether they implicitly used a beat-based or duration-based strategy (Grahn and McAuley, 2009). Similarly, recordings from rodent striatum demonstrate that patterns of temporally varying neural activity may reflect an integration of the passage of time with its associated action (Portugal et al., 2011), further suggesting that the computations contributing to temporal control may critically depend on both environmental and behavioral context. The hypothesis that timing may be mediated by multiple distinct procedures also accounts for the puzzling lack of neurologic disorders characterized by a profound and selective impairment in temporal processing. Although syndromes characterized by selective deficits in vision, audition, language, attention, and multiple other faculties have been identified, we are unaware of a similar disorder involving temporal processing. Additionally, studies of patients and animals with brain lesions often demonstrate relatively mild deficits in temporal processing. The above discussion is not intended to be exhaustive. Differences in performance on tasks assessing timing for synchronized or syncopated beat timing (Jantzen et al., 2004), as well as explicit or implicit timing to temporal intervals (Coull and Nobre, 2008; Wiener et al., 2010b) have also been identified. A challenge for future research will be to identify these different timing networks and to clarify the functional relationship between them.

Effects of accuracy feedback on fractal characteristics of time estimation.

Abstract: The current experiment investigated the effect of visual accuracy feedback on the structure of variability of time interval estimates in the continuation tapping paradigm. Participants were asked to repeatedly estimate a 1-second interval for a prolonged period of time by tapping their index finger. In some conditions, participants received accuracy feedback after every estimate, whereas in other conditions, no feedback was given. Also, the likelihood of receiving visual feedback was manipulated by adjusting the tolerance band around the 1-second target interval so that feedback was displayed only if the temporal estimate deviated from the target interval by more than 50, 100, or 200 ms respectively. We analyzed the structure of variability of the inter-tap intervals with fractal and multifractal methods that allow for a quantification of complex long-range correlation patterns in the timing performance. Our results indicate that feedback changes the long-range correlation structure of time estimates: Increased amounts of feedback lead to a decrease in fractal long-range correlations, as well to a decrease in the magnitude of local fluctuations in the performance. The multifractal characteristics of the time estimates were not impacted by the presence of absence of feedback. Nevertheless, most of the data sets show significant multifractal signatures. We interpret these findings as showing that feedback acts to constrain and possibly reorganize timing performance. Implications for mechanistic and complex systems-based theories of timing behavior are discussed.

The sensory representation of time.

Abstract: Time is embedded in many aspects of our sensory experience; sensory events unfold in time and often acquire particular meaning because of their specific temporal structure. The speed of a moving object, the words pronounced by a speaker and the tactile exploration of a texture, are all examples of temporally structured sensory experiences. Despite the ubiquitousness of the temporal dimension of our sensory experience, the understanding of the neural mechanisms underlying the temporal representation of sensory events, that is the capacity to estimate duration in milliseconds/seconds range, remains a controversial and complex issue. The controversy relates to the effective involvement of sensory-specific brain regions in the processing of temporal information. The complexity arises from the neurophysiological mechanisms underlying the representation of time in these areas and the functional interplay between sensory-specific and amodal temporal mechanisms (Harrington et al., 2011). The idea that we time sensory signals via a single “centralized” and “amodal” clock dominated the field of temporal cognition over the last 30 years. More recently the universality of timing mechanisms has been challenged by new theoretical positions and a growing body of empirical data (Buhusi and Meck, 2005). From a theoretical perspective the challenge comes from “distributed” timing models. This is a broad class of models, which – although different regarding the neurophysiological mechanisms proposed for time processing – collectively share the idea that we have multiple timing mechanisms “distributed” across brain areas or circuits; and that the engagement of each single mechanism depends on the psychophysical task, sensory modality, and lengths of temporal intervals (Ivry and Richardson, 2002; Durstewitz, 2003; Matell and Meck, 2004; Buonomano and Maass, 2009). The idea that sensory-specific timing mechanisms exist is supported by studies showing that the ability to discriminate temporal information depends on the modality of the signals. For example, temporal discrimination thresholds are lower for auditory compared to visual signal durations (Grondin, 1993; Grondin et al., 2005; Merchant et al., 2008); and the capacity to keep in memory multiple intervals improves if the temporal signals belong to different modalities and therefore rely on different memory resources (Gamache and Grondin, 2010). The existence of independent sensory-specific clocks is also suggested by the observation that the perceived duration of a sensory event can be distorted by modality-specific properties of the stimuli such as visual adaptation (Johnston et al., 2006; Ayhan et al., 2009), spatial, and temporal frequency (Kanai et al., 2006; Kaneko and Murakami, 2009); or by the observation that such distortions are limited to a single sensory domain, like in case of saccadic eye movements causing compression of the perceived duration of visual but not of auditory stimuli (Morrone et al., 2005; Burr et al., 2011). From the neurophysiological point of view, electrophysiological recordings in animals as well as neuroimaging and magnetic stimulation studies in humans suggest that both modality-specific and supramodal mechanisms underlie the estimation of temporal intervals (Ghose and Maunsell, 2002; Shuler and Bear, 2006; Bosco et al., 2008; Bueti et al., 2008b; Sadeghi et al., 2011). For example, it has been demonstrated that the extrastriate visual area MT/V5 is necessary for temporal discrimination of visual, but not of auditory durations (Bueti et al., 2008a) and that duration estimation to predict expected visual and auditory events involves secondary as well as primary visual and auditory cortices (Ghose and Maunsell, 2002; Shuler and Bear, 2006; Bueti and Macaluso, 2010; Bueti et al., 2010). Taken together these behavioral and neurophysiological data highlight the functional contribution of sensory-specific cortices and support the existence of modality-specific timing mechanisms. However, how temporal information is actually represented in these cortices and what is the neurophysiological mechanism behind it, remain unclear. A few interesting theoretical hypotheses have been advanced. “Intrinsic” timing models for example, describe time as a general and inherent property of neural dynamics. A consequence of this assumption is that any area of the brain is in principle able to encode time. Temporal computations according to these models rely on inherent temporal properties of neural networks like short-term synaptic plasticity [i.e., state-dependent networks (SDNs) model; Buonomano and Maass, 2009] or arise either from the overall magnitude of neural activity (Eagleman, 2008) or from the linear ramping of neuronal firing rate (Durstewitz, 2003; Reutimann et al., 2004). “Intrinsic models” of temporal coding are particularly suitable to describe the functional organization of sensory timing mechanisms because they assume that time is encoded by the same circuits encoding other stimulus properties such as color or motion in the visual modality. However the explanatory power of some of these models, like for example the SDNs model, is constrained to durations of a few hundred milliseconds (i.e., <500 ms; Buonomano et al., 2009; Spencer et al., 2009); this is indeed a strong limitation, given that most of the neurophysiological evidence in favor of modality-specific timing mechanisms deal with durations from hundreds of milliseconds to a few seconds. An alternative possibility is that temporal computations in sensory cortices engage wider and specialized temporal circuit (s), where time signals from sensory cortex are sent to “dedicated” timing areas where these signals are integrated and used to guide action for example (Coull et al., 2011). In this latter case the relationship between sensory-specific and sensory independent timing areas need to be elucidated. Many cortical (parietal, premotor, prefrontal, and insular cortices) and subcortical (basal ganglia and cerebellum) brain structures have indeed been implicated in the processing of temporal information independently from the sensory modality of the stimuli (see Spencer et al., 2003; Coull et al., 2004; Koch et al., 2008; Wiener et al., 2010 for a review; Wittmann et al., 2010). Although there is only a partial agreement regarding the relevance of all these structures to time processing, the challenge is now to explore whether these areas have dissociable or interchangeable/overlapping functional roles and therefore whether these areas support the same or different temporal mechanisms compared to sensory-specific areas. A very special case of multimodal timing area is represented by the auditory cortex, a sensory-specific area. It has been recently demonstrated indeed that the auditory cortex is important for temporal discrimination not only of auditory but also of somatosensory and visual stimuli (Bolognini et al., 2009; Kanai et al., 2011). The supramodal involvement of auditory areas in temporal tasks has been associated with a strategic use of auditory-based mental representations for time estimation (Franssen et al., 2006). An interesting hypothesis, suggested by Kanai and colleagues, is that given the dominance of the auditory system over vision in temporal tasks (Walker and Scott, 1981; Burr et al., 2009), visual information is converted into an auditory code for temporal computation(Kanai et al., 2011). This hypothesis is interesting because offers new insight into the relationship between visual and auditory timing systems and highlights a possible link between modality independent and modality-specific temporal mechanisms. It is therefore clear that the study of the functional architecture of sensory timing mechanisms poses a few more theoretical and experimental challenges. A few important questions are still open. It is, for example, unclear whether the organizational principles that apply to space also apply to time and whether the temporal dimension of visual stimuli is processed by the same or distinct networks compared to those for space. Is time coding in visual cortex retinotopic specific? Do we encode all possible temporal intervals at each retinotopic position? In which context do sensory-specific temporal mechanisms work? Is temporal information encoded in sensory cortices automatically or does it require explicit attention? Are sensory areas engaged only during duration encoding or are also active during working memory maintenance? The already complex scenario of the neural representation of time is getting even more intricate. From the idea of a single “amodal” mechanism we moved into the idea of multiple “modality-specific” and “modality independent” temporal mechanisms (Wiener et al., 2011). The challenge is now to find out the functional architecture of these mechanisms as well as the interaction between them. As a concluding remark, I would like to emphasize that the focus of the majority of studies exploring the neural correlates of temporal processing has been so far to identifying the key components of internal timing networks (i.e., the “where” of timing mechanisms). The result of this approach has been, for example, an exponential increase of the number of neuroimaging studies on this topic that has lead to a substantial disagreement regarding the structures that are relevant to time processing (Wiener et al., 2010 for a review). It is time to adopt new experimental approaches that pose more mechanistically oriented questions about the underlying timing mechanisms while at the same time attempting to link computational models and neurophysiology (Portugal et al., 2011).

Temporal and Spatial Categorization in Human and Non-Human Primates

Abstract: It has been proposed that a functional overlap exists in the brain for temporal and spatial information processing. To test this, we designed two relative categorization tasks in which human subjects and a Rhesus monkey had to assign time intervals or distances to a ‘short’ or ‘long’ category according to varying prototypes. The performance of both species was analyzed using psychometric techniques that showed that they may have similar perceptual, memory and/or decision mechanisms, specially for the estimation of time intervals. We also did a correlation analysis with human subjects’ psychometric thresholds and the results imply that indeed, temporal and spatial information categorization share neural substrates. However, not all of the tested distances and intervals correlated with each other, suggesting the existence of sub-circuits that process restricted ranges of distances and intervals. A different analysis was done on the monkey data, in which the influence of the previous categorical prototypes was measured on the task currently being performed. Again, we found a significant interaction between previous and current interval and distance categorization. Overall, the present paper points towards common or at least partially overlapped neural circuits for temporal and spatial categorization in primates.

Adaptive timing of motor output in the mouse: the role of movement oscillations in eyelid conditioning.

Abstract: To survive, animals must learn to control their movements with millisecond-level precision, and adjust the kinematics if conditions, or task requirements, change. Here, we examine adaptive timing of motor output in mice, using a simple eyelid conditioning task. Mice were trained to blink in response to a light stimulus that was always followed by a corneal air-puff at a constant time interval. Different mice were trained with different intervals of time separating the onset of the light and the air-puff. As in previous work in other animal species, mice learned to control the speed of the blink, such that maximum eyelid closure occurred at the interval used during training. Despite this, we found that maximum eyelid speed always occurred in the first 100 ms of the movement, indicating that speed is not uniformly adjusted throughout the duration of the blink. A new analysis, specifically designed to examine the kinematics of blinks in single trials, revealed the nature of the underlying control signal: the learned blinks are made up of oscillatory eyelid movements that are time-locked to the light stimulus at the beginning of the blink, becoming desynchronized later on. Furthermore, mice learn to blink at different speeds and time the movement appropriately by adjusting the amplitude, but not the frequency of the underlying eyelid oscillation.

Exploring the 4th dimension: hippocampus, time, and memory revisited.

Abstract: Accurate and reliable timing is an essential component of nearly every purposeful behavior. Just as the brain contains mechanisms to track and orient the body in space, so too must it be able to orient itself in time. Coincidence detection – the integration of simultaneous activation of multiple inputs – is a proposed solution to the question of how the brain tracks the duration of events in the seconds-to-minutes range using millisecond-scale neural processes (Matell and Meck, 2000). The striatal beat-frequency (SBF) model is one of the most successful attempts at explaining the neural basis of interval timing in terms of coincidence detection of oscillatory processes (Matell and Meck, 2004; Lustig et al., 2005; Harrington et al., 2010; Oprisan and Buhusi, 2011, submitted). The SBF model involves a set of cortical timekeeper neurons that oscillate at regular, but distinct frequencies, allowing a unique pattern of activation to occur at each point in time. These activation patterns project onto striatal integrators that combine their information with feedback (e.g., reward input) and form the basis of interval timing.

Perceived duration of Visual and Tactile Stimuli Depends on Perceived Speed.

Abstract: It is known that the perceived duration of visual stimuli is strongly influenced by speed: faster moving stimuli appear to last longer. To test whether this is a general property of sensory systems we asked participants to reproduce the duration of visual and tactile gratings, and visuo-tactile gratings moving at a variable speed (3.5 – 15 cm/s) for three different durations (400, 600 and 800 ms). For both modalities, the apparent duration of the stimulus increased strongly with stimulus speed, more so for tactile than for visual stimuli. In addition, visual stimuli were perceived to last approximately 200 ms longer than tactile stimuli. The apparent duration of visuo-tactile stimuli lay between the unimodal estimates, as the Bayesian account predicts, but the bimodal precision of the reproduction did not show the theoretical improvement. A cross-modal speed-matching task revealed that visual stimuli were perceived to move faster than tactile stimuli. To test whether the large difference in the perceived duration of visual and tactile stimuli resulted from the difference in their perceived speed, we repeated the time reproduction task with visual and tactile stimuli matched in apparent speed. This reduced, but did not completely eliminate the difference in apparent duration. These results show that for both vision and touch, perceived duration depends on speed, pointing to common strategies of time perception.

Computational characterization of visually induced auditory spatial adaptation.

Abstract: Recent research investigating the principles governing human perception has provided increasing evidence for probabilistic inference in human perception. For example, human auditory and visual localization judgments closely resemble that of a Bayesian causal inference observer, where the underlying causal structure of the stimuli are inferred based on both the available sensory evidence and prior knowledge. However, most previous studies have focused on characterization of perceptual inference within a static environment, and therefore, little is known about how this inference process changes when observers are exposed to a new environment. In this study we aimed to computationally characterize the change in auditory spatial perception induced by repeated auditory-visual spatial conflict, known as the ventriloquist aftereffect. In theory, this change could reflect a shift in the auditory sensory representations (i.e., shift in auditory likelihood distribution), a decrease in the precision of the auditory estimates (i.e., increase in spread of likelihood distribution), a shift in the auditory bias (i.e., shift in prior distribution), or an increase/decrease in strength of the auditory bias (i.e., the spread of prior distribution), or a combination of these. By quantitatively estimating the parameters of the perceptual process for each individual observer using a Bayesian causal inference model, we found that the shift in the perceived locations after exposure was associated with a shift in the mean of the auditory likelihood functions in the direction of the experienced visual offset. The results suggest that repeated exposure to a fixed auditory-visual discrepancy is attributed by the nervous system to sensory representation error and as a result, the sensory map of space is recalibrated to correct the error.

The SMAs: Neural Substrate of the Temporal Accumulator?

Abstract: One of the most widely cited models in time estimation is the “pacemaker-counter clock” which consists of a pacemaker gen-erating pulses and an accumulator in which pulses are stored. The level reached in this accumulator at the end of an interval to be estimated sets the subjective elapsed time. Although this model is able to accurately describe temporal performance, it can nevertheless be considered no more than a good metaphor of actual temporal pro-cessing mechanisms. Finding specific brain areas behaving as a pacemaker and/or as an accumulator would provide additional sup-port for this model. Evidence has now been amassed suggesting that the SMAs could be a neural substrate of the accumulator.

How emotions change time.

Abstract: Experimental evidence suggests that emotions can both speed-up and slow-down the internal clock. Speeding up has been observed for to-be-timed emotional stimuli that have the capacity to sustain attention, whereas slowing down has been observed for to-be-timed neutral stimuli that are presented in the context of emotional distractors. These effects have been explained by mechanisms that involve changes in bodily arousal, attention, or sentience. A review of these mechanisms suggests both merits and difficulties in the explanation of the emotion-timing link. Therefore, a hybrid mechanism involving stimulus-specific sentient representations is proposed as a candidate for mediating emotional influences on time. According to this proposal, emotional events enhance sentient representations, which in turn support temporal estimates. Emotional stimuli with a larger share in ones sentience are then perceived as longer than neutral stimuli with a smaller share.

Neural Underpinnings of Distortions in the Experience of Time Across Senses

Abstract: Auditory signals (A) are perceived as lasting longer than visual signals (V) of the same physical duration when they are compared together. Despite considerable debate about how this illusion arises psychologically, the neural underpinnings have not been studied. We used functional magnetic resonance imaging (fMRI) to investigate the neural bases of audiovisual temporal distortions and more generally, intersensory timing. Adults underwent fMRI while judging the relative duration of successively presented standard interval (SI)-comparison interval (CI) pairs, which were unimodal (A-A, V-V) or crossmodal (V-A, A-V). Mechanisms of time dilation and compression were identified by comparing the two crossmodal pairs. Mechanisms of intersensory timing were identified by comparing the unimodal and crossmodal conditions. The behavioral results showed that auditory CIs were perceived as lasting longer than visual CIs. There were three novel fMRI results. First, time dilation and compression were distinguished by differential activation of higher sensory areas (superior temporal, posterior insula, middle occipital), which typically showed stronger effective connectivity when time was dilated (V-A). Second, when time was compressed (A-V) activation was greater in frontal cognitive-control centers, which guide decision making. These areas did not exhibit effective connectivity. Third, intrasensory timing was distinguished from intersensory timing partly by decreased striatal and increased superior parietal activation. These regions showed stronger connectivity with visual, memory, and cognitive-control centers during intersensory timing. Altogether, the results indicate that time dilation and compression arise from the connectivity strength of higher sensory systems with other areas. Conversely, more extensive network interactions are needed with core timing (striatum) and attention (superior parietal) centers to integrate time codes for intersensory signals.