Backwards is the way forward: feedback in the cortical hierarchy predicts the expected future

Clark offers a powerful description of the brain as a prediction machine, which offers progress on two distinct levels. First, on an abstract conceptual level, it provides a unifying framework for perception, action, and cognition (including subdivisions such as attention, expectation, and imagination). Second, hierarchical prediction offers progress on a concrete descriptive level for testing and constraining conceptual elements and mechanisms of predictive coding models (estimation of predictions, prediction errors, and internal models)

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

The Representation of Multimodal Tactile Sensations in the Human Somatosensory System

The sense of touch is critical to executing basic motor tasks and generating a feeling of embodiment. To construct touch percepts, the brain integrates information from tactile mechanoreceptors with inputs from other senses and top-down variables such as attention and task context. In this thesis, we investigate how these factors influence neural activity within the somatosensory system at different stages of tactile processing, using electrophysiological and behavioral data from a human tetraplegic participant implanted with microelectrode arrays. First, we find that neural responses to imagined touches of different types are decodable in the primary somatosensory cortex, ventral premotor cortex, and the supra-marginal gyrus, and these responses remain stable over many months. Following this analysis, the primary somatosensory cortex is explored in greater depth to better characterize early-stage cortical tactile processing. Touches to the arm and finger are examined during a passive task, in a variety of conditions including visually observed physical touches, physical touches without vision, and visual touches without physical contact. Analysis of the two touch locations suggests that touch encoding in primary somatosensory cortex may be less rigid than in the classical topographic view. Additionally, this experiment uncovers a modulatory effect of vision in the primary somatosensory cortex when it is paired with a physical touch, but no effect of vision alone. Finally, we investigate how visual information impacts artificial tactile sensations, which can be elicited using intra-cortical microstimulation to the primary somatosensory cortex. The ability to elicit reliable, naturalistic artificial touch sensations is vital to the implementation of a tactile brain-machine interface, which would benefit patients with spinal cord injury and others with somatosensory impairments. We find that visual information biases the qualitative percept of artificial stimulation towards an interpretation that is visually plausible. The temporal binding window between vision and stimulation is found to be larger when visual information is biologically relevant, suggesting that the brain’s ability to causally relate artificial stimulation to visual cues depends on visual context. Additionally, recordings from the primary somatosensory cortex indicate that visual information relevant to artificial stimulation is represented across contexts, during an active task. The effect of task on the responsiveness of the primary somatosensory cortex to visual information points to a role of attention in mediating early cortical tactile processing. In combination, the findings presented in this thesis provide insight into the basic neuroscience of how tactile experiences are constructed by the brain, suggesting that early tactile processing is influenced by multisensory, contextual factors. These findings also have clinical applications to developing a brain-machine interface capable of providing naturalistic sensations within a complex real world environment

Attention is more than prediction precision [Commentary on target article]

A cornerstone of the target article is that, in a predictive coding framework, attention can be modelled by weighting prediction error with a measure of precision. We argue that this is not a complete explanation, especially in the light of ERP (event-related potentials) data showing large evoked responses for frequently presented target stimuli, which thus are predicted

Neural dynamics of selective attention to speech in noise

This thesis investigates how the neural system instantiates selective attention to speech in challenging acoustic conditions, such as spectral degradation and the presence of background noise. Four studies using behavioural measures, magneto- and electroencephalography (M/EEG) recordings were conducted in younger (20–30 years) and older participants (60–80 years). The overall results can be summarized as follows. An EEG experiment demonstrated that slow negative potentials reflect participants’ enhanced allocation of attention when they are faced with more degraded acoustics. This basic mechanism of attention allocation was preserved at an older age. A follow-up experiment in younger listeners indicated that attention allocation can be further enhanced in a context of increased task-relevance through monetary incentives. A subsequent study focused on brain oscillatory dynamics in a demanding speech comprehension task. The power of neural alpha oscillations (~10 Hz) reflected a decrease in demands on attention with increasing acoustic detail and critically also with increasing predictiveness of the upcoming speech content. Older listeners’ behavioural responses and alpha power dynamics were stronger affected by acoustic detail compared with younger listeners, indicating that selective attention at an older age is particularly dependent on the sensory input signal. An additional analysis of listeners’ neural phase-locking to the temporal envelopes of attended speech and unattended background speech revealed that younger and older listeners show a similar segregation of attended and unattended speech on a neural level. A dichotic listening experiment in the MEG aimed at investigating how neural alpha oscillations support selective attention to speech. Lateralized alpha power modulations in parietal and auditory cortex regions predicted listeners’ focus of attention (i.e., left vs right). This suggests that alpha oscillations implement an attentional filter mechanism to enhance the signal and to suppress noise. A final behavioural study asked whether acoustic and semantic aspects of task-irrelevant speech determine how much it interferes with attention to task-relevant speech. Results demonstrated that younger and older adults were more distracted when acoustic detail of irrelevant speech was enhanced, whereas predictiveness of irrelevant speech had no effect. All findings of this thesis are integrated in an initial framework for the role of attention for speech comprehension under demanding acoustic conditions

Recursive Behavior Recording: Complex Motor Stereotypies and Anatomical Behavior Descriptions

A novel anatomical behavioral descriptive taxonomy improves motion capture in complex motor stereotypies (CMS) by indexing precise time data without degradation in the complexity of whole body movement in CMS. The absence of etiological explanation of complex motor stereotypies warrants the aggregation of a core CMS dataset to compare regulation of repetitive behaviors in the time domain. A set of visual formalisms trap configurations of behavioral markers (lateralized movements) for behavioral phenotype discovery as paired transitions (from, to) and asymmetries within repetitive restrictive behaviors. This translational project integrates NIH MeSH (medical subject headings) taxonomy with direct biological interface (wearable sensors and nanoscience in vitro assays) to design the architecture for exploratory diagnostic instruments. Motion capture technology when calibrated to multi-resolution indexing system (MeSH based) quantifies potential diagnostic criteria for comparing severity of CMS within behavioral plasticity and switching (sustained repetition or cyclic repetition) time-signatures. Diagnostic instruments sensitive to high behavioral resolution promote measurement to maximize behavioral activity while minimizing biological uncertainty. A novel protocol advances CMS research through instruments with recursive design

How sleep deprivation degrades task performance: combining experimental analysis with simulations of adenosinergic effects of basal ganglia and cortical circuits

Thesis (Ph.D.)--Boston UniversityHumans configure themselves into "neural machines" to perform optimally on distinct tasks, and they excel at maintaining such configurations for brief episodes. The neural configuration needed for peak performance, however, is subject to perturbations on multiple time scales. This thesis reports new empirical analyses and computational modeling to advance understanding of the variations in reaction time (RT) on simple RT tasks that are associated with the duration of the preceding inter-stimulus interval (order of seconds); the time-on-task duration (order of minutes); and sleep deprivation duration (order of hours to days). Responses from the psychomotor vigilance task (PVT), including anticipations (false alarms), normal RTs, and very long RTs (lapses in attention), were analyzed to discover the effects of: the 1 - 9 second inter-stimulus interval (ISI); the 10-minute task session; up to 50 hours of sleep deprivation (SD); and wake-promoting agents, caffeine and modafinil. Normal RTs and lapses in attention were negatively correlated with ISI length, whereas anticipations were positively correlated. Anticipations, normal RTs, and lapses increased as time-on-task increased, and during SD. Both caffeine and modafinil reduced lapses and anticipations during SD and decreased RT variability. A simple neural network model incorporating both a time-dependent inhibitory process and a time-dependent excitatory process was developed. The model robustly simulated the ISI effect on behavior. The SD effects were reproducible with two parameter adjustments. Informed modeling of drug effects required greater neurobiological detail. In the basal ganglia (BG), adenosine accumulation during SD has two notable effects: it antagonizes dopamine to reduce BG responsiveness to incoming cortical signals, and it reduces cholinergic transmission to parietal and prefrontal cortices, thus reducing attention to visual signals. A detailed computational model of interactions between BG and cortex during PVT was developed to simulate effects of adenosine and their amelioration by caffeine. The model simulates drug, ISI and SD effects on anticipations, RTs, and lapses. This model can be used to describe the effects of SD over a wide range of tasks requiring planned and reactive movements, and can predict and model effects of pharmacological agents acting on the adenosinergic, cholinergic and dopaminergic systems

Interrogating the Role of Cocaine-Generated Silent Synapses in the Regulation of Cocaine-Associated Memory Dynamics

Drug addiction is an acquired behavioral state that develops progressively through repeated drug experience and is characterized by maladaptive and compulsive behavior associated with drug seeking and taking. Cravings and subsequent drug seeking are often precipitated by the reactivation of memories associated with drug use, which are formed between various external stimuli, or cues, and the rewarding and pleasurable experience of taking the drug. As such, drug addiction is often conceptualized as a pathological form of memory that drives maladaptive behavior. This has spurred intensive investigation into the neural substrates underlying drug-associated memories, with the ultimate goal of targeting these substrates to disrupt drug seeking behaviors. To explore the synaptic underpinnings of cocaine-associated memories, we studied AMPA receptor (AMPAR)-silent excitatory synapses, which are generated in the nucleus accumbens (NAc) by cocaine experience. These synapses functionally mature during withdrawal through the recruitment of AMPARs and contribute to subsequent cocaine seeking behavior, indicating these synapses contribute to the encoding of cocaine-associated memories and behaviors. In this dissertation, we have further investigated the role of cocaine-generated silent synapses in the encoding of cocaine-associated memories by examining their role in regulating the natural dynamics of cocaine-associated memories. Our results demonstrate that dynamic changes in the functional state of cocaine-generated synapses contributes to the natural destabilization and reconsolidation of cocaine-associated memories following memory retrieval, and that disrupting these synaptic dynamics impairs subsequent cocaine seeking behaviors. In addition, we also demonstrate that cocaine-generated synapses contribute to the recruitment and activation of neurons within the NAc associated with cocaine seeking behavior during withdrawal, suggesting they may contribute to the encoding of cocaine-associated memories at the circuit level. Collectively, these findings provide further support to the hypothesis that cocaine-generated synapses serve as discrete synaptic substrates underlying aspects of cocaine-associated memories and behaviors