Browsing by Subject "Thalamus"
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Item Open Access Advances in understanding mechanisms of thalamic relays in cognition and behavior.(J Neurosci, 2014-11-12) Mitchell, Anna S; Sherman, S Murray; Sommer, Marc A; Mair, Robert G; Vertes, Robert P; Chudasama, YogitaThe main impetus for a mini-symposium on corticothalamic interrelationships was the recent number of studies highlighting the role of the thalamus in aspects of cognition beyond sensory processing. The thalamus contributes to a range of basic cognitive behaviors that include learning and memory, inhibitory control, decision-making, and the control of visual orienting responses. Its functions are deeply intertwined with those of the better studied cortex, although the principles governing its coordination with the cortex remain opaque, particularly in higher-level aspects of cognition. How should the thalamus be viewed in the context of the rest of the brain? Although its role extends well beyond relaying of sensory information from the periphery, the main function of many of its subdivisions does appear to be that of a relay station, transmitting neural signals primarily to the cerebral cortex from a number of brain areas. In cognition, its main contribution may thus be to coordinate signals between diverse regions of the telencephalon, including the neocortex, hippocampus, amygdala, and striatum. This central coordination is further subject to considerable extrinsic control, for example, inhibition from the basal ganglia, zona incerta, and pretectal regions, and chemical modulation from ascending neurotransmitter systems. What follows is a brief review on the role of the thalamus in aspects of cognition and behavior, focusing on a summary of the topics covered in a mini-symposium held at the Society for Neuroscience meeting, 2014.Item Open Access Analyzing the Mechanisms of Action of Thalamic Deep Brain Stimulation: Computational and Clinical Studies(2009) Birdno, Merrill JayDeep brain stimulation (DBS) is an established treatment for movement disorders that has been implanted in more than 40,000 patients worldwide. Despite the successes of DBS, its mechanisms of action are not well understood. Early descriptions of the mechanisms of DBS focused on whether DBS excited or inhibited neurons in the stimulated nucleus. However, changes in the patterns of neuronal activity, and not just changes in the rate of neuronal activity, play a major role in the pathology of movement disorders. Therefore, we hypothesized that the temporal pattern of stimulation might be an important factor in determining the effectiveness of DBS. The purpose of this dissertation was to use temporally irregular patterns of stimulation (non-regular interpulse intervals) to probe the mechanisms of thalamic DBS in suppressing tremor. The clinical tremor measurements reported in this dissertation represent the first tremor data published during stimulation with temporally irregular stimulus trains in human subjects. First, we tested the effects of paired-pulse DBS on tremor suppression in human subjects with essential tremor and on the responses of a computational model of thalamic neurons. DBS was more effective at reducing tremor when pulses were evenly spaced than when there were large differences between intrapair and interpair pulse intervals, suggesting that tremor suppression is dependent on the pattern of DBS and not just the average rate of stimulation. Increasing the difference between the intrapair and interpair intervals in the computational model rendered model neurons more likely to fire synchronous bursts. Second, we quantified the effects of the degree of regularity of temporally random stimulus trains in human subjects with tremor. We pioneered an innovative preparation to conduct these experiments--during surgery to replace the implantable pulse generator--which allowed us to establish a direct connection to implanted DBS leads under stable conditions. Stimulus trains were less effective at relieving tremor as the temporal spacing between stimulus pulses in DBS trains became more irregular. However, the reasons for the decreased efficacy of the temporally irregular stimulus trains was not clear. Third, we evaluated the contributions of `pauses,' `bursts,' and `irregularity, per se' to the inability of irregular stimulus trains to suppress tremor. Stimulus trains with pauses were significantly less effective at suppressing tremor than stimulus trains without pauses, while there were no significant changes in tremor suppression between trains with bursts and those without bursts, or between trains that were irregular and those that were periodic. We also developed a computer-based biophysical model of a thalamic network to simulate the response of thalamic neurons to the same temporal patterns of DBS. Trains that effectively suppressed tremor in human subjects also suppressed fluctuations in transmembrane potential at the frequency associated with burst-driven cerebellar inputs to the thalamus. Both clinical and computational findings indicate that DBS suppresses tremor by masking cerebellar burst-driven input to the thalamus.
The work in this dissertation bridges an important gap between the hypothesis that high-frequency DBS masks pathological activity in the cerebello-thalamo-cortical circuit and the experimentally observed finding that DBS in the subthalamic area suppresses tremor more effectively than DBS in the Vim thalamus proper. We provided experimental and computational evidence that the mechanism of DBS is to mask the burst-driven cerebellar inputs to the thalamus. Hence, the most relevant neuronal targets for effective tremor suppression are the afferent cerebellar fibers that terminate in the thalamus.
Item Open Access Cocaine dependence does not contribute substantially to white matter abnormalities in HIV infection.(Journal of neurovirology, 2017-06) Cordero, Daniella M; Towe, Sheri L; Chen, Nan-Kuei; Robertson, Kevin R; Madden, David J; Huettel, Scott A; Meade, Christina SThis study investigated the association of HIV infection and cocaine dependence with cerebral white matter integrity using diffusion tensor imaging (DTI). One hundred thirty-five participants stratified by HIV and cocaine status (26 HIV+/COC+, 37 HIV+/COC-, 37 HIV-/COC+, and 35 HIV-/COC-) completed a comprehensive substance abuse assessment, neuropsychological testing, and MRI with DTI. Among HIV+ participants, all were receiving HIV care and 46% had an AIDS diagnosis. All COC+ participants were current users and met criteria for cocaine use disorder. We used tract-based spatial statistics (TBSS) to assess the relation of HIV and cocaine to fractional anisotropy (FA) and mean diffusivity (MD). In whole-brain analyses, HIV+ participants had significantly reduced FA and increased MD compared to HIV- participants. The relation of HIV and FA was widespread throughout the brain, whereas the HIV-related MD effects were restricted to the corpus callosum and thalamus. There were no significant cocaine or HIV-by-cocaine effects. These DTI metrics correlated significantly with duration of HIV disease, nadir CD4+ cell count, and AIDS diagnosis, as well as some measures of neuropsychological functioning. These results suggest that HIV is related to white matter integrity throughout the brain, and that HIV-related effects are more pronounced with increasing duration of infection and greater immune compromise. We found no evidence for independent effects of cocaine dependence on white matter integrity, and cocaine dependence did not appear to exacerbate the effects of HIV.Item Open Access Cortical and Thalamic Representations of Artificial Sensation Projected onto Primary Somatosensory Cortex(2020) Khani, Joshua MSensory neuroprosthetics offer a revolutionary approach to studying as well as treating patients suffering from sensory dysfunction resulting from neurological impairments. Devices, such as cochlear implants, which restore the functionality of defective peripheral sensory organs, have become increasingly more prevalent and provide greater autonomy and independence to patients. For those with damage to the sensory neural circuits themselves as a result of disease or injury, alternative treatment options must be implemented. Cortical prostheses that bypass the damaged circuitry and deliver sensory information directly to the brain offer an alternative option for these patients. This approach could be used to provide tactile sensation for a prosthetic limb, restore a sense of sight in those with cortical visual impairment, or recruit intact cortex to take on the lost functionality of damaged regions of the brain. Importantly, developing devices that best serve these patient populations requires deepening our understanding of the mechanisms underlying the brain’s ability to incorporate information from a sensory prosthesis. Much of the current literature, however, focuses on behavioral and perceptual endpoints rather than changes in the brain at the mesoscopic level.
To that end, this dissertation aims to address that gap by characterizing the emergence of distributed representations of artificial sensation following the use of a cortical sensory prosthesis. Prior research has shown that adult rats could use a microstimulation-based sensory neuroprosthesis that projected information about the infrared (IR) environment onto the barrel fields of primary somatosensory cortex (S1). Equipped with this prosthesis, rats quickly learned to perform a four-choice IR discrimination task with proficiency comparable to that attained in an analogous visual discrimination task. This research established a useful paradigm for studying how the brain adapts to incorporate new sensory information projected directly onto cortex. The original research presented in this dissertation thus utilizes this paradigm for investigating how brain regions distal to the site of stimulation represent the stimulation patterns delivered by the prosthesis.
For this dissertation, I first discuss the response of two areas directly coupled to S1: the ventral posteromedial nucleus of the thalamus (VPM) - the main input nucleus to S1 and recipient of extensive corticothalamic feedback from S1 - and the posteromedial nucleus of the thalamus (POm) - a modulatory nucleus in the paralemniscal whisker pathway. Specifically, I quantify the stimulation induced response in S1, VPM, and POm. Using recordings from hundreds of multi-units from each region, the proportion of units found to have post-stimulus responses statistically distinguishable from their corresponding baseline activities was 97%, 97%, and 99% for POm, VPM, and S1, respectively. This indicates that the region of the brain affected by electrical stimulation is not constrained to the site of stimulation, but in fact downstream correlates interconnected to the stimulated region of cortex show significant responses as well.
Next I compare the presence of IR receptive field maps and the relative distribution of preferred stimulus orientations. Previously, it has been demonstrated that S1 units develop preferred stimulation patterns. That is, individual units showed variable firing rates depending on the direction to the IR source. This work replicated that finding, but more importantly I found that emergent IR receptive field maps are found in VPM and POm as well. This shows that not only do the thalamic units respond to ICMS, but undergo experience-dependent plasticity that allows the thalamic nuclei to encode the stimulus and participate in the sensory processing of the artificial sensation. A mutual information analysis was preformed to quantify the degree to which these subcortical regions represent the pattern of stimulation delivered to the cortex. The proportion of units found to have significant mutual information values was 57%, 74%, and 69% for POm, VPM, and S1, respectively. These results indicate that the artificial sensory information is readily encoded in native sensory processing circuits. Furthermore it suggests that the cortex can impose significant influence over the receptive field characteristics of thalamic nuclei even in the adult rodent brain.
Finally, I discuss the implementation of graph convolutional neural network (GCN) models to decode the stimulus features from the neural activity recorded during prosthetic use. The best performing GCN model was able to achieve a peak classification performance of 73.5% on a modified ordinal regression performance metric. Additionally, by allowing the model to learn the adjacency matrix for the neural graph data, the adjacency matrix inferred was found to provide a better representation of the underlying neural circuitry encoding the artificial sensation compared to standard techniques (i.e. cross correlation and mutual information). This further demonstrated the observation that thalamic units participated in the processing of the new sense. Because the adjacency matrix derived from training the GCNs reflects the nodes that best improve the predictions of the stimulation patterns, the adjacency matrix also serves as a method of deriving connectivity measures for the recorded units. The interpretation of these results represents a novel approach to determining functional interactions and the effective circuits involved in processing a new sensory modality.
Item Open Access Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy.(Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2021-05) Lee, Hedok; Xu, Feng; Liu, Xiaodan; Koundal, Sunil; Zhu, Xiaoyue; Davis, Judianne; Yanez, David; Schrader, Joseph; Stanisavljevic, Aleksandra; Rothman, Douglas L; Wardlaw, Joanna; Van Nostrand, William E; Benveniste, HeleneDiffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aβ deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.Item Open Access Drivers from the deep: the contribution of collicular input to thalamocortical processing.(Prog Brain Res, 2005) Wurtz, Robert H; Sommer, Marc A; Cavanaugh, JamesA traditional view of the thalamus is that it is a relay station which receives sensory input and conveys this information to cortex. This sensory input determines most of the properties of first order thalamic neurons, and so is said to drive, rather than modulate, these neurons. This holds as a rule for first order thalamic nuclei, but in contrast, higher order thalamic nuclei receive much of their driver input back from cerebral cortex. In addition, higher order thalamic neurons receive inputs from subcortical movement-related centers. In the terminology popularized from studies of the sensory system, can we consider these ascending motor inputs to thalamus from subcortical structures to be modulators, subtly influencing the activity of their target neurons, or drivers, dictating the activity of their target neurons? This chapter summarizes relevant evidence from neuronal recording, inactivation, and stimulation of pathways projecting from the superior colliculus through thalamus to cerebral cortex. The study concludes that many inputs to the higher order nuclei of the thalamus from subcortical oculomotor areas - from the superior colliculus and probably other midbrain and pontine regions - should be regarded as motor drivers analogous to the sensory drivers at the first order thalamic nuclei. These motor drivers at the thalamus are viewed as being at the top of a series of feedback loops that provide information on impending actions, just as sensory drivers provide information about the external environment.Item Open Access Evidence of transcranial direct current stimulation-generated electric fields at subthalamic level in human brain in vivo.(Brain stimulation, 2018-07) Chhatbar, Pratik Y; Kautz, Steven A; Takacs, Istvan; Rowland, Nathan C; Revuelta, Gonzalo J; George, Mark S; Bikson, Marom; Feng, WuweiBACKGROUND:Transcranial direct current stimulation (tDCS) is a promising brain modulation technique for several disease conditions. With this technique, some portion of the current penetrates through the scalp to the cortex and modulates cortical excitability, but a recent human cadaver study questions the amount. This insufficient intracerebral penetration of currents may partially explain the inconsistent and mixed results in tDCS studies to date. Experimental validation of a transcranial alternating current stimulation-generated electric field (EF) in vivo has been performed on the cortical (using electrocorticography, ECoG, electrodes), subcortical (using stereo electroencephalography, SEEG, electrodes) and deeper thalamic/subthalamic levels (using DBS electrodes). However, tDCS-generated EF measurements have never been attempted. OBJECTIVE:We aimed to demonstrate that tDCS generates biologically relevant EF as deep as the subthalamic level in vivo. METHODS:Patients with movement disorders who have implanted deep brain stimulation (DBS) electrodes serve as a natural experimental model for thalamic/subthalamic recordings of tDCS-generated EF. We measured voltage changes from DBS electrodes and body resistance from tDCS electrodes in three subjects while applying direct current to the scalp at 2 mA and 4 mA over two tDCS montages. RESULTS:Voltage changes at the level of deep nuclei changed proportionally with the level of applied current and varied with different tDCS montages. CONCLUSIONS:Our findings suggest that scalp-applied tDCS generates biologically relevant EF. Incorporation of these experimental results may improve finite element analysis (FEA)-based models.Item Open Access Influence of the thalamus on spatial visual processing in frontal cortex.(Nature, 2006-11-16) Sommer, Marc A; Wurtz, Robert HEach of our movements activates our own sensory receptors, and therefore keeping track of self-movement is a necessary part of analysing sensory input. One way in which the brain keeps track of self-movement is by monitoring an internal copy, or corollary discharge, of motor commands. This concept could explain why we perceive a stable visual world despite our frequent quick, or saccadic, eye movements: corollary discharge about each saccade would permit the visual system to ignore saccade-induced visual changes. The critical missing link has been the connection between corollary discharge and visual processing. Here we show that such a link is formed by a corollary discharge from the thalamus that targets the frontal cortex. In the thalamus, neurons in the mediodorsal nucleus relay a corollary discharge of saccades from the midbrain superior colliculus to the cortical frontal eye field. In the frontal eye field, neurons use corollary discharge to shift their visual receptive fields spatially before saccades. We tested the hypothesis that these two components-a pathway for corollary discharge and neurons with shifting receptive fields-form a circuit in which the corollary discharge drives the shift. First we showed that the known spatial and temporal properties of the corollary discharge predict the dynamic changes in spatial visual processing of cortical neurons when saccades are made. Then we moved from this correlation to causation by isolating single cortical neurons and showing that their spatial visual processing is impaired when corollary discharge from the thalamus is interrupted. Thus the visual processing of frontal neurons is spatiotemporally matched with, and functionally dependent on, corollary discharge input from the thalamus. These experiments establish the first link between corollary discharge and visual processing, delineate a brain circuit that is well suited for mediating visual stability, and provide a framework for studying corollary discharge in other sensory systems.Item Open Access The dusp1 immediate early gene is regulated by natural stimuli predominantly in sensory input neurons.(J Comp Neurol, 2010-07-15) Horita, Haruhito; Wada, Kazuhiro; Rivas, Miriam V; Hara, Erina; Jarvis, Erich DMany immediate early genes (IEGs) have activity-dependent induction in a subset of brain subdivisions or neuron types. However, none have been reported yet with regulation specific to thalamic-recipient sensory neurons of the telencephalon or in the thalamic sensory input neurons themselves. Here, we report the first such gene, dual specificity phosphatase 1 (dusp1). Dusp1 is an inactivator of mitogen-activated protein kinase (MAPK), and MAPK activates expression of egr1, one of the most commonly studied IEGs, as determined in cultured cells. We found that in the brain of naturally behaving songbirds and other avian species, hearing song, seeing visual stimuli, or performing motor behavior caused high dusp1 upregulation, respectively, in auditory, visual, and somatosensory input cell populations of the thalamus and thalamic-recipient sensory neurons of the telencephalic pallium, whereas high egr1 upregulation occurred only in subsequently connected secondary and tertiary sensory neuronal populations of these same pathways. Motor behavior did not induce high levels of dusp1 expression in the motor-associated areas adjacent to song nuclei, where egr1 is upregulated in response to movement. Our analysis of dusp1 expression in mouse brain suggests similar regulation in the sensory input neurons of the thalamus and thalamic-recipient layer IV and VI neurons of the cortex. These findings suggest that dusp1 has specialized regulation to sensory input neurons of the thalamus and telencephalon; they further suggest that this regulation may serve to attenuate stimulus-induced expression of egr1 and other IEGs, leading to unique molecular properties of forebrain sensory input neurons.Item Unknown The role of the thalamus in motor control.(Curr Opin Neurobiol, 2003-12) Sommer, Marc ATwo characteristics of the thalamus--its apparently simple relay function and its daunting multinuclear structure--have been customarily viewed as good reasons to study something else. Yet, now that many other brain regions have been explored and neurophysiologists are turning to questions of how larger circuits operate, these two characteristics are starting to seem more attractive. First, the relay nature of thalamic neurons means that recording from them, like tapping into a wire, can reveal the signals carried by specific circuits. Second, the concentration of like relay neurons into nuclei means that inactivating or stimulating them can efficiently test the functions of the circuits. Recent studies implementing these principles have revealed pathways through the thalamus that contribute to generating movements and to monitoring one's own actions (corollary discharge).Item Unknown Visual perception and corollary discharge.(Perception, 2008) Sommer, Marc A; Wurtz, Robert HPerception depends not only on sensory input but also on the state of the brain receiving that input. A classic example is perception of a stable visual world in spite of the saccadic eye movements that shift the images on the retina. A long-standing hypothesis is that the brain compensates for the disruption of visual input by using advance knowledge of the impending saccade, an internally generated corollary discharge. One possible neuronal mechanism for this compensation has been previously identified in parietal and frontal cortex of monkeys, but the origin of the necessary corollary discharge remained unknown. Here, we consider recent experiments that identified a pathway for a corollary discharge for saccades that extends from the superior colliculus in the midbrain to the frontal eye fields in the cerebral cortex with a relay in the medial dorsal nucleus of the thalamus. We first review the nature of the evidence used to identify a corollary discharge signal in the complexity of the primate brain and show its use for guiding a rapid sequence of eye movements. We then consider two experiments that show this same corollary signal may provide the input to the frontal cortex neurons that alters their activity with saccades in ways that could compensate for the displacements in the visual input produced by saccadic eye movements. The first experiment shows that the corollary discharge signal is spatially and temporally appropriate to produce the alterations in the frontal-cortex neurons. The second shows that this signal is necessary for this alteration because inactivation of the corollary reduces the compensation by frontal-cortex neurons. The identification of this relatively simple circuit specifies the organization of a corollary discharge in the primate brain for the first time and provides a specific example upon which consideration of the roles of corollary activity in other systems and for other functions can be evaluated.