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acase@tulane.edu / 1 / Jeremiah Hartner

Direct cortico-motoneuronal (CM) connections of corticospinal tract neurons are a distinctive feature of the primate motor system which are known to be important for the capacity to perform independent finger movements. However, it is still unclear how the appropriate combinations of CM cells are recruited to produce the selective (fractionated) control over muscles of the upper limb that is necessary for independent finger movements. I have investigated whether GABAergic intracortical inhibitory (ICI) circuits in human motor cortex contribute to the selection of the appropriate CM cells during a motor task requiring selective activation of one of several intrinsic hand muscles. Behaviour of ICI circuits during voluntary contraction was compared for the dominant and non-dominant hemisphere of right-handed subjects, as hemispheric differences in ICI may contribute to preferential use of the right hand for fine motor tasks. Finally, I investigated the range of forces over which ICI contributes to selective activation of a hand muscle. Neurologically normal adult human subjects were recruited for all experiments. Surface electrodes recorded electromyographic activity of abductor pollicis brevis (APB), first dorsal interosseous and abductor digiti minimi muscles during controlled isometric contractions of APB at different force levels while subjects attempted to keep the other two muscles relaxed using visual feedback of EMG. Paired-pulse transcranial magnetic stimulation (TMS) was used to assess ICI at rest and during selective activation of a hand muscle. TMS intensity and interstimulus interval were varied in different trials. Data were compared for two different directions of induced current in the brain; posteriorly directed current (PA stimulation) and anteriorly directed current (AP stimulation). ICI is suppressed for corticospinal neurons controlling the muscle targeted for selective activation; no change in ICI was seen for corticospinal neurons controlling the muscles required to be relaxed. This indicates that differential modulation of ICI in human motor cortex contributes to selective activation of a hand muscle. The direction of current flow induced in the brain proved to be critical for demonstrating this effect. It was observed with AP stimulation but not PA stimulation. I argue that this is due to preferential activation by PA stimulation of interneurons producing I1 waves in corticospinal neurons. These interneurons are not acted upon by ICI circuits. This problem makes the conventional PA paired-pulse TMS technique unreliable for the assessment of ICI during voluntary contraction. With AP stimulation it was demonstrated that ICI is not modulated during weak selective activation of a hand muscle (&lt5percent of maximal voluntary contraction), but ICI effects on CM cells controlling the target muscle are progressively suppressed at higher levels of activation. The present study is the first to examine hemispheric differences in ICI during selective isometric contraction of an intrinsic hand muscle. No hemispheric differences were observed. These studies have demonstrated a functional role for ICI in fractionation of hand muscle activity in normal subjects. It also provides an improved basis for investigating the changes in ICI with TMS in various neurological conditions in which it has been reported that GABAergic inhibition is abnormal. / Thesis (Ph.D.)--School of Molecular and Biochemical Science, 2004.

Thesis (Ph. D. in Biomedical Engineering)--Vanderbilt University, Dec. 2007. / Title from title screen. Includes bibliographical references.

The work of this thesis concerns how cortical memories are stored and retrieved. In particular, large-scale simulations are used to investigate the extent to which associative attractor theory is compliant with known physiology and in vivo dynamics. The first question we ask is whether dynamical attractors can be stored in a network with realistic connectivity and activity levels. Using estimates of biological connectivity we demonstrated that attractor memories can be stored and retrieved in biologically realistic networks, operating on psychophysical timescales and displaying firing rate patterns similar to in vivo layer 2/3 cells. This was achieved in the presence of additional complexity such as synaptic depression and cellular adaptation. Fast transitions into attractor memory states were related to the self-balancing inhibitory and excitatory currents in the network. In order to obtain realistic firing rates in the network, strong feedback inhibition was used, dynamically maintaining balance for a wide range of excitation levels. The balanced currents also led to high spike train variability commonly observed in vivo. The feedback inhibition in addition resulted in emergent gamma oscillations associated with attractor retrieval. This is congruent with the view of gamma as accompanying active cortical processing. While dynamics during retrieval of attractor memories did not depend on the size of the simulated network, above a certain size the model displayed the presence of an emergent attractor state, not coding for any memory but active as a default state of the network. This default state was accompanied by oscillations in the alpha frequency band. Such alpha oscillations are correlated with idling and cortical inhibition in vivo and have similar functional correlates in the model. Both inhibitory and excitatory, as well as phase effects of ongoing alpha observed in vivo was reproduced in the model in a simulated threshold-stimulus detection task. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper8: In press.</p>

Pro-opiomelanocortin (POMC) is the precursor of many neuropeptides which includ adrenocorticotropin (ACTH). ACTH has a biological activity in regulating adrenocortical function. In the present study, we will investigate the effect of POMC gene transfer on adrenal cortex cells in cell cultures and animal models. The study included adrenal cortical H295R cells for adenovirus-mediated gene delivery. The effects of POMC gene on H295R cell steroidogenesis and cell proliferation were investigated. In addition, there were 32 SD rats dividing into three groups. 1) Control, injected with normal saline via tail vein (n = 8); 2) Ad-GFP, injected with adenovirus containing GFP (n=12); 3) Ad-POMC, injected with adenovirus containing recombinant POMC gene (n=12). Body weight (BW) was measured. Adrenals were collected, fixed and a series of sections were cut for stains for PCNA and MC2-R. The plasma cortisol and VEGF levels of rats were measured. The results showed that Ad-POMC delivery significantly increased the ACTH and cortisol levels by 50-100 fold and 20-100% in H295R cells, respectively. In addition, Ad-POMC delivery significantly inhibited the cell proliferation and increased the apoptotic cells. The expression of MC2-R protein of H295R cells was also suppressed after Ad-POMC delivery. In the study of SD rats, the Ad-POMC-treated rats exhibited reduced weight gain compared with other groups in the first 2 weeks; however, there was no significant change in BW between Ad-POMC and Ad-GFP groups during the experimental period. The weight of adrenal in Ad-POMC-treated rats was significantly higher than Ad-GFP group in the 8th week. Comparing the sequential adrenal weights in Ad-POMC group, those in 6th week were significantly higher than in 2nd and 4th weeks. The plasma VEFG levels of Ad-POMC-treated rats were higher than Ad-GFP group in the 8th week. The adrenal sections showed that Ad-POMC treated rats had moreanti-PCNA stained cells than Ad-GFP treated rats in 8th week. However, less anti-MC2R stained cells were found in Ad-POMC treated rats in 8th week. Ad-POMC treated rats had higher plasma cortisol levels than those in Ad-GFP treated rats, however, there were no statistical significances. In conclusion, POMC gene transfer modulates the morphology and function of the adrenal cortex. POMC gene inhibits the H295R cells proliferation by inducing MC2-R down-regulation and cells apoptosis. In SD rat adrenal, however, it stimulates adrenal cortex in biphasic pattern. The rapid growing pattern noted in the later phase may be due to the effect of VEGF. Besides, the physical regulation of cortisol synthesis is much stricter than that of ACTH.

The overall goals of this dissertation were 1) to understand the role that neurons in primate primary visual cortex (V1) play in the detection of small visual stimuli, and 2) to understand the quantitative relationship between the responses of individual neurons and neural population responses in V1. These goals were addressed in experiments with awake, behaving macaque monkeys using electrophysiological and imaging techniques. Initially, I employed ideal observer models to assess V1 neural detection sensitivity in a reaction-time visual detection task and found it to be comparable to the monkey's detection sensitivity. Using the same detection task, I found weak, but significant, correlations between V1 neural activity and the trial-by-trial behavior of monkeys (choice and reaction time). The conclusion of these studies is that the monkey's behavior in the detection task was likely mediated by large neural populations. Voltage-sensitive dye imaging (VSDI) is a powerful imaging technique that is well suited for assessing the link between the activity of large neural populations and behavior. VSDI measures changes in membrane potential over a cortical area of 1-2 cm² with high spatial and temporal resolutions. Using position tuning experiments with VSDI and electrophysiology, I described the relatively unknown quantitative relationships between spiking activity, the local field potential, and VSDI. These relationships were well captured by non-linear transfer functions. Lastly, these experiments also revealed important new findings about the representation of visual space by populations of neurons in V1. In particular, we resolved a long standing debate regarding the size of the cortical point image (CPI), the area of cortex activated by a single point stimulus. We found that the CPI is constant across eccentricity in parafoveal V1, suggesting that each point in space activates an approximately equivalent amount of cortical tissue. In conclusion, the results and analyses described in this dissertation contribute to our understanding of the role that neural populations in V1 play in mediating visual detection, reveal important properties of the representation of visual space by populations of neurons in V1, and provide the first analysis of the quantitative relationship between VSDI and electrophysiological signals. / text

Previous studies have shown that analogy instruction can be applied effectively in science education and motor skill acquisition; however, little is known about the application of analogy in speech motor performance. In four experiments, analogy instructions were tested in the speech domain. The first experiment (Chapter 2) used focus group methodology to establish a set of analogies that related pitch variation during speech production to a ‘waves at sea’ metaphor. The analogies were then used to elicit speech with different pitch variations. Analogy instructions were more effective than explicit instructions for eliciting speech with minimum pitch variation (i.e., monotonous speech). In the second experiment (Chapter 3), the influence of both analogy and explicit instructions on the perception of speech parameters invoked by maximum pitch variation was examined. Pitch variation in analogy instructed speech was perceived to be greater and more natural than when explicit instructions were provided. In the third experiment (Chapter 4), stress resistance in analogy instructed speech performance was evaluated. Analogy instructed speech performance was demonstrated to be significantly more stable under a psychologically stressful condition than explicitly instructed speech. The last experiment (Chapter 5), investigated the cognitive load of analogy on different components of the working memory system during speech performance. It was found that analogy instructions tended to place more cognitive load on the visual component of working memory than explicit instructions. The findings of the four experiments inform the application of analogy in speech motor skill performance in general, and contribute to understanding the mechanisms that underpin analogy within a working memory framework. The work also has significant potential for application in speech-language pathology treatment. / published_or_final_version / Human Performance / Doctoral / Doctor of Philosophy

Our sensory experiences are encoded in the patterns of activity of the neurons in our brain. While we know we are capable of sensing and responding to a constantly changing sensory environment, we often study neural activity by repeatedly presenting the same stimulus and analyzing the average neural response. It is not understood how the average neural response represents the dynamic neural activity that produces our perceptions. In this work, we use functional imaging of the rodent primary somatosensory cortex, specifically the whisker representations, and apply classic signal-detection methods to test the predictive power of the average neural response. Stimulus features such as intensity are thought to be perceptually separable from the average representation; however, we show that stimulus intensity cannot be reliably decoded from neural activity from only a single experience. Instead, stimulus intensity was encoded only across many experiences. We observed this probabilistic neural code in multiple classic sensory paradigms including complex temporal stimuli (pairs of whisker deflections) and multi-whisker stimuli. These data suggest a novel framework for the encoding of stimulus features in the presence of high-neural variability. Specifically we suggest that our brains can compensate for unreliability by encoding information redundantly across cortical space. This thesis predicts that a somatosensory stimulus is not encoded identically each time it is experienced; instead, our brains use multiple redundant pathways to create a reliable sensory percept.

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