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Ten to 15% of the population is temperamentally shy and have elevated physiological stress responses to novel social situations. Yet, the neural mechanisms underlying this personality trait are not fully understood (Beaton et al., 2009; Schmidt et al., 1997). Efficiently attending to, acting on, and remembering relevant stimuli and filtering out less important information is critical given the sheer volume of sensory and perceptual stimuli the brain is exposed to. Relevant stimuli that garner attention are remembered and consolidated with existing memories. Stimuli that do not warrant extended attention are ignored or habituated to in a process underpinned by cortical and subcortical inhibitory brain networks that reduce processing load on finite attentional resources (Freedman et al., 1991; Adler et al., 1998). Inefficient filtering of irrelevant stimuli could underpin anxiety in those with temperamental shyness and anxiety (Aron, Aron, & Davies, 2005). We measured the P50 auditory event-related potential (ERP) using a paired auditory click paradigm, as well as self-reported social anxiety and shyness, and salivary cortisol in two groups of healthy young adults selected for being very shy or very gregarious. While shy and gregarious groups demonstrated a similar P50 ERP to sound one (S1), the shy group showed elevated P50 amplitudes in response to the second sound (S2) compared to the gregarious group. Participants categorized as being lower or higher on social anxiety displayed a reverse pattern: those higher in social anxiety had a reduced response to S1 compared to those lower in social anxiety, yet a similar response to S2. Further, higher salivary cortisol predicted smaller differences and larger ratios in the P50 ERP from S1 to S2.

The present dissertation evaluated the P50 component of the event-related brain potential (ERP), an index of sensory gating measured during a paired-stimulus paradigm, as an intermediate phenotype between clinical symptoms and neuronal mechanisms that might also contribute to higher-order cognitive dysfunction in schizophrenia. Despite considerable evidence that schizophrenia patients exhibit impaired suppression of the P50 to the second of two identical stimuli, the clinical significance and neural mechanisms associated with the P50 gating deficit remain poorly understood. A series of three related studies sought to more fully define the clinical and neurobiological correlates of P50 suppression deficits in schizophrenia. In Study 1, comparison of 52 schizophrenia patients and 41 healthy participants confirmed a P50 suppression deficit in patients, replicating prior research. Investigation of the clinical correlates of the P50 deficit in patients revealed associations between impaired suppression and clinician ratings of attentional difficulties as well as poor working memory performance. In examining the neural substrates of P50 gating with diffusion tensor imaging, Study 2 found associations between P50 deficits and compromised structural integrity of white matter tracts connecting brain regions previously implicated in the generation of P50 suppression in schizophrenia. Study 3 examined whether P50 impairments are amenable to cognitive training and predictive of treatment outcome. Compared to a control intervention without cognitive targets, patients who completed cognitive remediation demonstrated significant improvements in P50 suppression. Baseline P50 ratios were also predictive of improvement as evidenced by post-treatment clinician ratings and performance on an attention task, thereby indicating that patients with stronger P50 suppression are likely to receive the most benefit from cognitive remediation. All relationships observed in the present set of studies were specific to P50 and did not extend to the N100 component of the ERP. By characterizing the relationship of P50 to clinical symptoms and cognitive dysfunction in schizophrenia, isolating biological mechanisms that might be involved in P50 suppression, and evaluating its amenability to cognitive training, the present dissertation provided support for P50 as a viable biomarker for guiding the development of interventions that target cognitive impairments in this chronic and debilitating mental illness.

Acetylcholine is involved in many aspects of auditory function, including plasticity, arousal, and sensory gating. While there have been many studies of acetylcholine in the ear and in the auditory cortex, there is a lack of data on cholinergic innervation of many of the auditory centers that form the ascending auditory pathways. This lack of data has hindered interpretation of physiological studies, especially those in the auditory midbrain. The experiments in this dissertation address questions about cholinergic innervation of the inferior colliculus (IC) and the medial geniculate body (MG), the major auditory centers of the midbrain and thalamus. We combined immunohistochemistry for choline acetyltransferase (ChAT), a marker of cholinergic cells, with retrograde tracers to address questions about cholinergic circuitry in guinea pigs. We found that the pontomesencephalic tegmentum (PMT) is the source of cholinergic input to the IC. The PMT comprises two cholinergic nuclei: the pedunculopontine tegmental nucleus and the laterodorsal tegmental nucleus. The PMT is best known as part of the ascending reticular activating system, which affects activation of the cerebral cortex and behavioral arousal via projections to thalamus. We demonstrated that the PMT projections to the MG are similar to PMT projections to other thalamic nuclei, both in the patterns of projections and the involvement of cholinergic and non-cholinergic projecting neurons. In addition, we found that individual PMT cholinergic cells can innervate multiple auditory nuclei, including both ICs, both MGs, or an IC and an MG. Thus, the cholinergic projections are in a position to modulate auditory functions bilaterally and at multiple levels of the auditory system (i.e. auditory midbrain and thalamus).The results reveal a much broader cholinergic innervation of auditory structures from the PMT than was previously known. This broad innervation is consistent with functions previously associated with the PMT (e.g., modulation of sensory responses during the sleep-wake cycle) as well as other functions only recently related to cholinergic systems, e.g., an essential role in some forms of neuronal plasticity.

Medial prefrontal cortex (mPFC) is a crucial region involved in inhibitory processes. Damage to mPFC leads to loss of normal inhibitory control over motor, sensory, emotional and cognitive functions. The present study was designed to examine basic properties, influence of aversive conditioning, and neuropharmacology of inhibitory gating in mPFC. Inhibitory gating is a neurophysiological assay for sensory filters in higher brain regions that potentially enable or disable information throughput. This perspective has important clinical relevance due to findings that gating is dramatically impaired in individuals with emotional and cognitive impairments (i.e., in schizophrenia, PTSD, and drug abuse). In the present research, single-units and local field potentials (LFPs) were measured using chronic microwire arrays implanted in rat mPFC. The stability of gating was first examined using paired tone tests in short-term (within session) and long-term (between session) analyses of auditory gating. LFPs displayed reduction in amplitudes of tone responses and increase of gating over both short and long-term time windows. A variety of single-unit responses retained similar levels of auditory responsiveness and inhibition in both short and long-term analysis. Next, altering the interval between tones in each tone-pair influenced the potency of inhibition. Neural inhibition decreased monotonically related to the increase in intertone interval for both LFPs and single-units. The influence of fear conditioning was investigated by administering 30 footshock pairings with tones similar to those normally used to test gating. Inhibitory gating of LFPs weakened, and animals’ orienting behavior to tones increased after, compared to before, the session of footshock and tone pairings. Systemic neuropharmacological manipulations were used to investigate effects of dopamine and GABA neurotransmitter systems on inhibitory gating of LFPs in mPFC. For effects of dopaminergic manipulations, the drugs haloperidol and apomorphine respectively strengthened and nearly eliminated inhibitory gating, and the drugs had completely opposite effects of respectively decreasing and increasing evoked response to the first tone. For effects of GABA manipulations, the drugs baclofen and pentobarbital strengthened gating to varying degrees. This set of experiments lays essential framework for investigation of inhibitory gating in mPFC and the network of connected brain structures that also display inhibitory gating.

Smoking is one of the leading causes of death in the world. About 80% of smokers start smoking before the age of 18. In the Appalachian area and the South in the United States, smoking percentages among adults and adolescents are higher than in other regions. Female smoking shows a variety of different trends from male smoking, and smoking brings particular health problems related to production to female smokers. These findings highlighted the importance of studying female teenage smokers in southwest Virginia. The initial project aimed to identify risk factors that might prevent smoking in an early stage. Dr. Helen Crawford led the Cognitive Neuroscience Lab at Virginia Tech in discovering the psychophysiological vulnerabilities of female teenage smokers. Toward this end, event-related potential (ERP), personality, and behavioral data were collected in teenage female smokers and non-smokers. These data were analyzed to examine possible psychophysiological vulnerabilities in female teenage smokers such as deficits in brain and cognitive function, personality traits, and environment influences. The purpose of this dissertation is to further analyze these data to elaborate and clarify the relationships among these vulnerabilities toward understanding teenage smoking behavior. Participants were 49 teenage girls (smokers and non-smokers) with age from 14 to 18. The measures included sensory gating, platelet MAO-B activity, attention, memory, temperament, schizotypal personality, recognition of facial expressions, taste and smell. The initial set of analyses compared smokers and non-smokers, including those classified as high and low dependent, on all dependent measures. The results suggested some psychophysiological vulnerabilities in female teenage smokers, which have been used as support for the self-medication and the orbito-frontal dysfunction models of why teenagers smoke (Crawford et al., 2004). Further examination of these factors may help teenagers to reduce the smoking dependency and possibly improve cognitive function. Specifically, this dissertation focused on the role of the variable of monoamine oxidase-B (MAO-B) in the correlations among sensory gating, MAO and other cognitive and personality measures. All smokers were divided into high and low MAO groups first. Comparison analyses were conducted between them. The high MAO group showed better sensory gating function than the low MAO group. Correlation analyses were conducted among all of the measures. The significant linear relationships between MAO and sensory gating, MAO and CO level and MAO and temperament were demonstrated. MAO activity positively correlated with the sensory gating function and negatively correlated with CO level and temperament characteristics. Finally, to explore the mechanisms of the relationship between MAO and sensory gating, the neurotransmitter systems related to MAO and sensory gating were discussed.

Pain is a complex, ubiquitous phenomenon that can be debilitating and costly. Although it is well known that some individuals can easily tolerate pain while others are more intolerant to pain, little is known of the neurophysiological bases of these differences. Because differences in sensory information processing may underlie variability in tolerance to pain and because measures of sensory gating are used to explore differences in sensory information processing, sensory gating among college students (N = 14) who are tolerant or intolerant to pain was investigated. This investigation explored the hypothesis that those who were more tolerant to pain would evidence greater sensory gating. Pain tolerance was first determined using a cold pressor task. Sensory gating was then determined by the amount of attenuation of the amplitude of a second painful, electrical, somatosensory stimulus (S2) in relation to the amplitude of an identical first stimulus (S1) in a paired-stimulus evoked potential (EP ) paradigm. The results obtained showed the intolerant group exhibiting greater physiological reactivity than the tolerant group, indicating that the tolerant group attained greater sensory gating than the intolerant group.

Sensory gating helps prevent incoming irrelevant sensory information from entering into the higher cortex and ensures normal information processing. Sensory gating is seen as the ability of the nervous system to modulate its sensitivity to incoming stimuli (Braff & Geyer, 1990; Adler, Olincy, Waldo, Harris & Griffith, et al., 1998). Smoking tobacco can facilitate early sensory gating in schizophrenics, and enhance prepulse inhibition asymmetry (right greater than left) in individuals with schizotypal personality. The purpose of this study was to test the following hypotheses: 1) Individuals with schizotypal personalities have poorer sensory gating than those without them. 2) Among individuals with schizotypy (high schizotypy), those who smoke have better sensory gating than those who do not smoke; among those without schizotypy (low schizotypy), smokers will demonstrate better sensory gating. 3) After abstaining, schizotypal smokers will show increased sensory gating due to smoking. 4) Individuals with schizotypy will show greater P50 deficits in the left hemisphere, and smoking can enhance this asymmetry (left greater than right). From 613 online-surveyed participants, 39 (18 men) right-handed undergraduates (Mean age = 18.87) were selected to represent four groups: High and Low Schizotypy, half of which were smokers, and half were non-smokers. Smokers were tested while abstaining and after smoking. Non-smokers were tested twice in the same manner without smoking. P50 sensory gating, P50 amplitude and P50 latency were analyzed separately at frontal (F3, F4, Fz), fronto-central (FC3, FC4, FCz), central (C3, C4, Cz), centro-parietal (CP3, CP4, Cpz) and parietal (P3, P4, Pz) regions. With respect to the hypotheses of the study, it was found that: 1) Sensory gating, as assessed by S2 (P50-N40)/S1 (P50-N40), was greater at frontal-central and central regions in comparison to mid-frontal and parietal regions. 2) Furthermore, sensory gating was significantly greater at midline than left or right hemispheres. 3) Condition 1 showed better sensory gating than Condition 2. 4) The High Schizotypy group showed poorer sensory gating than the Low Schizotypy group among non-smokers. 5) Smokers showed poorer sensory gating than non-smokers in the Low Schizotypy group. In terms of P50 amplitude, it was found that: 1) FCz and Cz showed the highest P50 amplitude, greater than all other sites. 2) S1 had higher P50 amplitude than S2. 3) The low schizotypy individuals had significantly greater P50 amplitude in the left than in the right fronto-central region, but the high schizotypy individuals showed more P50 amplitude in the right hemisphere than did the low schizotypy individuals. 4) Smokers showed a greater left than right P50 amplitude in centro-parietal region, whereas the non-smokers showed the opposite asymmetry with a greater right than left P50 amplitude in central, centro-parietal and parietal regions. In terms of P50 latency, it was found that: 1) The P50 latency became significantly slower from posterior to anterior sites. 2) In HiS/S and LoS/NS groups, Condition1 was faster than Condition 2. In LoS/S and HiS/NS groups, Condition1 was slower than Condition 2. 3) Among smokers, left hemisphere latency was shorter than right hemisphere for S1, but for S2, left hemisphere was slower than right hemisphere. Among non-smokers, left and right hemisphere latencies were almost the same for S1 and S2.

The effects of smoking cigarettes on sensory gating, P50 and stimulus-bound gamma band (32-48 Hz) oscillations were examined in two paradigms: paired-tone and oddball. During a paired-tone paradigm, our previous work (Crawford, McClain-Furmanski, Castagnoli, & Castagnoli, Neuroscience Letters 317(2002) 151-155) found heavy smokers exhibited chronic (rather than acute) effects in the frontal region: (1) larger P50 and GBO responses; (2) greater P50 and GBO sensory gating suppression, as well as earlier GBO sensory gating suppression. During an oddball paradigm, we (McClain-Furmanski, Crawford, Castagnoli & Castagnoli, in prep.) found an acute effect between 0 and 20 ms post-stimulus in the GBO, however we were unable to determine whether this effect was due to nicotine or the act of smoking. In the present study, participants were 24 heavy cigarette (20+/day) right-handed, non-depressed smokers with no known medical or psychiatric problems, and no known familial history of psychiatric problems. In the morning, they were tested after abstaining overnight and after smoking a cigarette containing either 1.1 mg of nicotine, or a denicotinized cigarette (< 0.04 mg). In study 1 (oddball paradigm), although some effects were found related to nicotine and/or smoking, observed as condition by group interactions with the groups changing differently across conditions, they differed in temporal and spatial localization from those hypothesized. Thus, the present study was unable to differentiate between nicotine effects and effects due to the act of smoking. In study 2 (paired-pulse paradigm), in traditional evoked potential analysis, we observed signficant chronic sensory gating, as measured by the ratio of N40-P50 amplitude in response to the second tone (S2) as compared to the response to the first tone (S1). The effect was greatest at the hypothesized location (FCZ). In time series analysis of the underlying GBO, we replicated our earlier findings in that S2/S1 effects could be detected across 60 msec of the response. These results are discussed in relation to the neurochemistry and neural processes underlying sensory gating at GBO production, as well as in relation to the known and hypothesized psychpharmacological effects of smoking tobacco. Furthermore, these results are related to the theorized basis of addiction.