Active sensing, which incorporates closed-loop behavioral selection of information during sensory acquisition, is an important feature of many sensory modalities. We used the rodent whisker tactile system as a platform for studying the role cortical sensory areas play in coordinating active sensing motions. We examined head and whisker motions of freely moving mice performing a tactile search for a randomly located reward, and found that mice select from a diverse range of available active sensing strategies. In particular, mice selectively employed a strategy we term contact maintenance, where whisking is modulated to counteract head motion and sustain repeated contacts, but only when doing so is likely to be useful for obtaining reward. The context dependent selection of sensing strategies, along with the observation of whisker repositioning prior to head motion, suggests the possibility of higher level control, beyond simple reflexive mechanisms. In order to further investigate a possible role for primary somatosensory cortex (SI) in coordinating whisk-by-whisk motion, we delivered closed-loop optogenetic feedback to SI, time locked to whisker motions estimated through facial electromyography. We found that stimulation regularized whisking (increasing overall periodicity), and shifted whisking frequency, changes that emulate behaviors of rodents actively contacting objects. Importantly, we observed changes to whisk timing only for stimulation locked to whisker protractions, possibly encoding that natural contacts are more likely during forward motion of the whiskers. Simultaneous neural recordings from SI show cyclic changes in excitability, specifically that responses to excitatory stimulation locked to whisker retractions appeared suppressed in contrast to stimulation during protractions that resulted in changes to whisk timing. Both effects are evident within single whisks. These findings support a role for sensory cortex in guiding whisk-by-whisk motor outputs, but suggest a coupling that depends on behavioral context, occurring on multiple timescales. Elucidating a role for sensory cortex in motor outputs is important to understanding active sensing, and may further provide novel insights to guide the design of sensory neuroprostheses that exploit active sensing context.

In this study, 24 adults without any psychological or neurological disorders participated either in 10 neurofeedback training sessions to increase the amplitude of a frequency band between 12 and 15 Hz (sensorimotor rhythm - SMR) or in ten mock neurofeedback sessions. Pre and post training measures of memory and executive functions were completed, along with quantitative electroencephalography (QEEG) measurements in order to detect changes after the training course. Furthermore, measures of SMR amplitude were taken within and across sessions to determine whether self-regulation of SMR had been achieved. The data analysis performed shows no significant differences in cognitive performance between the group who underwent neurofeedback training and the group who underwent mock neurofeedback training. The groups did not show electrophysiological changes after the training. Additionally, no significant changes in SMR amplitude or percent time above threshold across or within the 10 sessions were found in the experimental group. Moreover, the data showed a tendency, which indicates that the higher the baseline amplitude and absolute power of SMR the less time was spent above threshold during the training and the less increase in SMR amplitude between baseline and training periods. The findings obtained indicate that neurofeedback training did not affect memory, executive functions or the QEEG. The absence of significant changes in SMR amplitude across sessions might reflect failure in learning the neurofeedback task and may account for the lack of cognitive improvement and QEEG changes. The fact that the ability to self-regulate SMR might be dependent on baseline amplitude has important implications in setting thresholds. Setting thresholds according to baseline levels might increase the difficulty in maintaining SMR above threshold when the baseline is higher. Future research should also address whether baseline amplitude has a predictive value in determining successful self-regulation of brain activity.

Early sensory experiences play a critical role in the activity-dependent development of the sensorimotor system. The sources of sensory input to the neonatal nervous system involve external stimulation (exafference) and sensory feedback arising from self-generated movements (reafference). In the perinatal period, reafference from twitches of the limbs and facial muscles during active (REM) sleep is a powerful driver of neural activity across the entire neuraxis. Thus, sleep-related twitches are thought to contribute to the activity-dependent development of sensorimotor networks. In this dissertation, we first aimed to identify a motor pathway for the generation of twitching. Using newborn rats at postnatal day (P) 8, we provide evidence that the red nucleus (RN; source of the rubrospinal tract) is involved in the production of twitching. In addition, we show that reafference from twitches drives neural activity in the RN, therefore suggesting that the RN is an important site for sensorimotor integration. Also, in the RN of P8 rats, twitch-related reafference triggers theta (4–7 Hz) oscillations. By P12, theta oscillations are expressed continuously and exclusively across bouts of active sleep. Synchronized neuronal oscillations comprise a fundamental mechanism by which distant neural structures establish and express functional connectivity. Thus, we next hypothesized that sleep-dependent theta oscillatory activity enables the expression of network connectivity between the RN and associated neural networks, such as the hippocampus. Simultaneous recordings from the hippocampus and RN at P12 show that theta oscillations in both structures are synchronized, co-modulated, and mutually interactive exclusively during active sleep. Lastly, we test the hypothesis that twitches drive synchronized oscillatory activity across functionally related sensory structures at early ages when the occurrence of oscillations largely depends on sensory input. Focusing on the cortico-hippocampal network at P8, we demonstrate that, unlike periods of wake-related movements or behavioral quiescence, twitching promotes coupled oscillatory activity at Beta2 frequency (~20-30 Hz). Altogether, the findings in this dissertation suggest that one of the functions of active sleep in early infancy is to provide a context for sensorimotor processing and for synchronizing activity within and between forebrain and brainstem structures. Consequently, any condition or manipulation that restricts active sleep can deprive the infant animal of substantial sensory experience, potentially resulting in atypical developmental trajectories.

Nervous systems distinguish between self- and other-generated movements by monitoring discrepancies between planned and performed actions. To do so, when motor systems transmit motor commands to muscles, they simultaneously transmit motor copies, or corollary discharges, to sensory areas. There, corollary discharge signals are compared to sensory feedback arising from movements (reafference), which can result in gating of expected feedback. Curiously, in infant rats, twitches—which are self-generated movements produced exclusively and abundantly during active sleep (AS)—differ from wake-movements in that they trigger robust neural activity. Accordingly, we hypothesized that the gating actions of corollary discharge that predict wake reafference are suspended during twitching. In this dissertation, we first demonstrate that twitches, but not wake movements, robustly activate sensorimotor cortex as they do other brain areas. Next, we demonstrate that wake movements can activate the sensorimotor cortex under conditions involving presumed discrepancies between corollary discharge and reafference signals. Lastly, we reveal a neural mechanism in the brainstem that inhibits reafference, but only during wakefulness; this inhibitory mechanism is suppressed during active sleep. All together, our findings provide the first demonstration of a state-dependent neural comparator of planned and performed actions, one that permits the transmission of sensory feedback from self-generated twitches to the developing nervous system.

Estudos demonstram que um toque efetuado pela ponta do dedo indicador sobre uma superfície externa rígida (a força exercida é mínima, não configurando um apoio mecânico) diminui consideravelmente a oscilação postural, o que indica que as informações sensoriais adquiridas pelos receptores táteis da ponta do dedo (i.e. relacionadas com as forças de contato entre o dedo e a superfície de apoio) fornecem ao sistema nervoso central informações relevantes que ajudam a manter a estabilidade postural. Esse efeito estabilizador proveniente do toque também tem sido associado a mecanismos supraposturais, como requisitos de precisão manual e demandas de atenção. A demanda atencional investida durante uma dada tarefa postural tem sido associada à regularidade das oscilações posturais, estimada pela entropia da amostra (SaEn) dos sinais do centro de pressão (CoP) (SaEnCoP). No entanto, nenhuma investigação anterior abordou se a regularidade das trajetórias do CoP é influenciada pelo toque suave do dedo (em inglês light touch LT) durante as tarefas posturais. Com base nos achados de estudos anteriores que sugeriram aumento da demanda atencional associada ao toque suave dos dedos (em comparação às condições de controle sem toque), a hipótese abordada foi de que a realização de tarefas posturais ao tocar levemente uma superfície externa rígida, além de atenuar a magnitude das oscilações posturais, estaria associada a níveis mais altos de regularidade do CoP (isto é, medidas baixas do SaEnCoP) em comparação com as condições de controle sem toque. Neste sentido, o objetivo do presente projeto foi investigar o efeito do toque suave do dedo sobre a regularidade das flutuações do CoP durante a manutenção da postura quieta bipedal e em uma tarefa de equilíbrio unipedal, de modo a analisar duas tarefas de controle postural com diferentes níveis de complexidade, associadas a diferentes níveis de demanda atencional. Sendo assim, 8 voluntários participaram dos experimentos na tarefa em postura quieta bipedal e 14 na tarefa de equilíbrio unipedal, ambas com e sem informação tátil adicional. Foram obtidos maiores valores de SaEnCoP na condição LT, tanto na tarefa de postura bipedal quanto em unipedal, sendo as diferenças significativas em relação a condição NT. Os resultados indicam que a presença de informações táteis adicionais levou a redução da instabilidade postural, mas não aumentou o grau de demanda de atenção na postura pelas flutuações do CoP mais irregulares (maiores valores de SaEnCoP), mesmo na tarefa mais complexa (equilíbrio unipedal). Isso sugere que, a automaticidade do controle postural foi maior, o que significa que a presença do toque tornou o controle postural mais efetivo (reduzindo as oscilações posturais), mas não o tornou mais cognitivamente dependente / Studies have been demonstrated that lightly touching an external rigid (the force exerted is minimal not setting a mechanical support) surface reduce the magnitude of postural oscillation. This decrease of postural sway indicates that the sensory information acquired by fingertip tactile receptors provides the central nervous system relevant information that aid to maintain postural stability. The stabilizing effect of light finger touch has been associated with sensory mechanisms involving enhanced proprioceptive feedback (e.g., from finger and hand muscles as well as from joint and cutaneous mechanoreceptors) and also with suprapostural mechanisms such as manual precision requirements and attentional demand. The attentional demand invested during a postural task has been associated with the regularity of the postural oscillations, as estimated by the sample entropy (SaEn) of center of pressure (CoP) signals (SaEnCoP). However, no previous investigation has addressed whether the regularity of CoP trajectories is influenced by light finger touch during postural tasks. Based on the previous findings that suggested an increased attentional demand associated with light finger touch (as compared to control conditions with no touch), the hypothesis addressed in the present study was that postural tasks performed when lightly touching an external rigid surface, besides attenuating the magnitude of postural oscillations, would be associated with higher levels of CoP regularity (i.e. lower measurements of SaEnCoP) as compared to control conditions with no touch. Therefore, the aim of this study was to investigate the effect of light finger touch on CoP regularity during two postural control tasks, quiet bipedal and single leg stance to investigate postural control tasks with different levels of complexity, which has been associated with different levels of attentional demand. We evaluated the CoP fluctuations in 8 volunteers during quiet bipedal posture and in 14 volunteers during single leg postural task, both with and without light finger touch. We obtained greater values os SaEnCoP in the LT condition in both bipedal and single leg posture tasks with significant differents compared to the NT condition. The findings indicate that light finger touch producing additional tactile informations that reduced postural instability did not increase the degree of attention demand in posture with the more irregular CoP fluctuations, even in the more complex task (single-leg stance). This suggests that the automaticity of postural control was greater which means that the presence of touch made postural control more effective (reducing postural oscillations), but did not made it more cognitively dependent

Chronic neck pain, including subclinical neck pain (SCNP), is a significant problem that places a burden on the healthcare system. Chiropractic manipulation has shown not only to be effective in treating symptoms of neck pain, but also in providing a neuromodulatory effect on the central nervous system. The motor cortex and cerebellum are thought to be important neural structures involved in motor learning and sensorimotor integration (SMI), and are therefore key structures to investigate how SMI is changed in a SCNP group following chiropractic care. Motor sequence learning (MSL) has also been shown to provide alterations in cerebellar projections to the motor cortex. Therefore, the studies in this thesis set out to determine if it was possible to induce both cortical and cerebellar learning, and if chiropractic care could alter motor output via transcranial magnetic stimulation measures to facilitate this learning. The study‟s results suggest that in a healthy group of subjects there is alteration in the intracortical inhibition of the motor cortex and no significant change in the cerebellum, following MSL. However, the results also suggest that in a SCNP group, there is a modulation of the cerebellar connections to the motor cortex but no effect specific to the motor cortex following both MSL and chiropractic manipulation. Therefore, these findings suggest that people with intermittent neck pain have concomitant changes in SMI and could manifest as clinical symptomology. / UOIT

The p38 mitogen-activated protein kinase [p38(MAPK)] mediates responses to extracellular stressors. An increase in the phosphorylated form of p38(MAPK) [p-p38(MAPK)] has been associated with early events in Alzheimer disease (AD). Although most often associated with processes including apoptosis, inflammation and oxidative stress, p-p38(MAPK) also mediates beneficial physiological functions, such as cell growth, survival and phagocytosis of cellular pathogens. Amyloid plaques [β-amyloid aggregates] are a hallmark of AD-related pathology. As p38(MAPK) has been detected in the vicinity of senile plaques, we combined immunohistochemistry and stereological sampling to quantify the distribution of plaques and p-p38(MAPK)-immunoreactive (IR) cells in the sensorimotor cortex of 3-, 6- and 10-month-old TgCRND8 mice. This animal model expresses an aggressive nature of the AD-related human amyloid-β protein precursor (APP). It was confirmed by the appearance of both dense-core (thioflavin-S-positive) and diffuse plaques, even in the youngest mice. p-p38(MAPK)-IR cells were associated with both dense-core and diffuse plaques, but the expected age-dependent increase in the density of plaque-associated p-p38(MAPK)-IR cells was restricted to dense-core plaques. Furthermore, the density of dense-core plaque-associated p-p38(MAPK)-IR cells was inversely correlated with the size of the core within the given plaque, which supports a role for these microglia in restricting core growth. p-p38(MAPK)-IR cells were also observed throughout wildtype and TgCRND8 mouse cortical parenchyma, but the density of these non-plaque-associated cells remained constant, regardless of age or genotype. We conclude that the constitutive presence of p-p38(MAPK)-IR microglia in aging mouse brain is indicative of a longitudinal role for this kinase in normal brain physiology. Additionally, the majority of p-p38(MAPK)-IR cells were predominantly co-immunoreactive for the Macrophage-1 (CD11b/CD18) microglial marker, regardless of whether they were associated with plaques or localized to the parenchyma. We suggest that the facts that a pool of p-p38(MAPK)-IR microglia appears to restrict b-amyloid plaque core development and the non-pathological role of p-p38(MAPK) in parenchyma, needs to be considered when anticipating targeted p38(MAPK) therapeutics in the context of clinical AD.

The p38 mitogen-activated protein kinase [p38(MAPK)] mediates responses to extracellular stressors. An increase in the phosphorylated form of p38(MAPK) [p-p38(MAPK)] has been associated with early events in Alzheimer disease (AD). Although most often associated with processes including apoptosis, inflammation and oxidative stress, p-p38(MAPK) also mediates beneficial physiological functions, such as cell growth, survival and phagocytosis of cellular pathogens. Amyloid plaques [β-amyloid aggregates] are a hallmark of AD-related pathology. As p38(MAPK) has been detected in the vicinity of senile plaques, we combined immunohistochemistry and stereological sampling to quantify the distribution of plaques and p-p38(MAPK)-immunoreactive (IR) cells in the sensorimotor cortex of 3-, 6- and 10-month-old TgCRND8 mice. This animal model expresses an aggressive nature of the AD-related human amyloid-β protein precursor (APP). It was confirmed by the appearance of both dense-core (thioflavin-S-positive) and diffuse plaques, even in the youngest mice. p-p38(MAPK)-IR cells were associated with both dense-core and diffuse plaques, but the expected age-dependent increase in the density of plaque-associated p-p38(MAPK)-IR cells was restricted to dense-core plaques. Furthermore, the density of dense-core plaque-associated p-p38(MAPK)-IR cells was inversely correlated with the size of the core within the given plaque, which supports a role for these microglia in restricting core growth. p-p38(MAPK)-IR cells were also observed throughout wildtype and TgCRND8 mouse cortical parenchyma, but the density of these non-plaque-associated cells remained constant, regardless of age or genotype. We conclude that the constitutive presence of p-p38(MAPK)-IR microglia in aging mouse brain is indicative of a longitudinal role for this kinase in normal brain physiology. Additionally, the majority of p-p38(MAPK)-IR cells were predominantly co-immunoreactive for the Macrophage-1 (CD11b/CD18) microglial marker, regardless of whether they were associated with plaques or localized to the parenchyma. We suggest that the facts that a pool of p-p38(MAPK)-IR microglia appears to restrict b-amyloid plaque core development and the non-pathological role of p-p38(MAPK) in parenchyma, needs to be considered when anticipating targeted p38(MAPK) therapeutics in the context of clinical AD.

Illusions such as the McGurk (McGurk and MacDonald, 1976) and ventriloquist (Radeau and Bertelson, 1974) effects or visual capture sensorimotor deficits (Holmes et al., 2004) demonstrate that our perception of and interaction with our environment is shaped by our ability to extract and integrate relevant sensory inputs across multiple modalities. Physiologically extraction occurs through a mechanism that facilitates relevant sensory representations and/or suppresses irrelevant ones within secondary sensory cortices, areas traditionally viewed as “modality-specific” cortex. This mechanism is commonly called “attention”. The purpose of the current thesis is to investigate the influence of motor requirements upon attentional modulation of sensory processing. It was hypothesized that different task demands associated with sensory processing for continuous movement rather than perception would result in earlier loci and/or different mechanisms of attentional modulation. Two studies used functional magnetic resonance imaging (fMRI) to investigate intermodal influences between a vibrotactile and visuospatial stimulus during a continuous sensorimotor task. These studies revealed that attention to vibrotactile stimulation guiding a continuous movement resulted in decreased activation in primary somatosensory cortex (S1) relative to when the same stimulus was an irrelevant distracter. This was regardless of the spatial or temporal properties of the two modalities. In a third study, somatosensory evoked potentials (SEPs) demonstrated that somatosensory processing is influenced as early as arrival to S1 from thalamic-cortical projections, however, SEPs did not demonstrate decreased activation during vibrotactile tracking. A fourth study using transcranial magnetic stimulation (TMS) confirmed differential excitability of S1 dependent upon whether the same sensory stimulus was used for perception or to guide a continuous sensorimotor transformation. Finally, a fifth study using behavioral measures demonstrated that the intramodal signal to noise ratio is an important factor in determining intermodal influence. This thesis provides insight into the influence of motor requirements upon sensory processing and demonstrates its importance in understanding how information is extracted from our environment. Understanding this has important implications for the interpretation/development of future work investigating intermodal influences upon sensory-processing.

Illusions such as the McGurk (McGurk and MacDonald, 1976) and ventriloquist (Radeau and Bertelson, 1974) effects or visual capture sensorimotor deficits (Holmes et al., 2004) demonstrate that our perception of and interaction with our environment is shaped by our ability to extract and integrate relevant sensory inputs across multiple modalities. Physiologically extraction occurs through a mechanism that facilitates relevant sensory representations and/or suppresses irrelevant ones within secondary sensory cortices, areas traditionally viewed as “modality-specific” cortex. This mechanism is commonly called “attention”. The purpose of the current thesis is to investigate the influence of motor requirements upon attentional modulation of sensory processing. It was hypothesized that different task demands associated with sensory processing for continuous movement rather than perception would result in earlier loci and/or different mechanisms of attentional modulation. Two studies used functional magnetic resonance imaging (fMRI) to investigate intermodal influences between a vibrotactile and visuospatial stimulus during a continuous sensorimotor task. These studies revealed that attention to vibrotactile stimulation guiding a continuous movement resulted in decreased activation in primary somatosensory cortex (S1) relative to when the same stimulus was an irrelevant distracter. This was regardless of the spatial or temporal properties of the two modalities. In a third study, somatosensory evoked potentials (SEPs) demonstrated that somatosensory processing is influenced as early as arrival to S1 from thalamic-cortical projections, however, SEPs did not demonstrate decreased activation during vibrotactile tracking. A fourth study using transcranial magnetic stimulation (TMS) confirmed differential excitability of S1 dependent upon whether the same sensory stimulus was used for perception or to guide a continuous sensorimotor transformation. Finally, a fifth study using behavioral measures demonstrated that the intramodal signal to noise ratio is an important factor in determining intermodal influence. This thesis provides insight into the influence of motor requirements upon sensory processing and demonstrates its importance in understanding how information is extracted from our environment. Understanding this has important implications for the interpretation/development of future work investigating intermodal influences upon sensory-processing.