Background: Hyposmia is an early symptom of Parkinson's Disease (PD) that often predates motor sy... more Background: Hyposmia is an early symptom of Parkinson's Disease (PD) that often predates motor symptoms by years. Hyposmia has been shown to have a more consistent link to idiopathic PD than to other movement disorders. Olfaction has the potential to be used as a biomarker for PD, either through clinical evaluation or imaging. Objectives: This study uses functional magnetic resonance imaging (fMRI) to assess differences in olfaction pathways between anosmic early PD patients and age and gendermatched controls.
The original version of this article unfortunately contained a mistake specifically in the HTML v... more The original version of this article unfortunately contained a mistake specifically in the HTML version. Ana A. Liso Navarro's given name and family name were incorrectly assigned. The correct given name should be "Ana A." and her family name "Liso Navarro". The update is also given here.
In addition, we examined the effects of the treatments on myogenic differentiation of FSHD myobla... more In addition, we examined the effects of the treatments on myogenic differentiation of FSHD myoblasts. Multiple 3GA compounds (3GA1-5) showed significant knock-down of DUX4 in the FSHD myoblasts, as examined by quantitative RT-PCR. We evaluated two 3GA candidates (3GA3 and 3GA5) at 4 different concentrations, 2.5 nM, 5nM, 25nM, and 50nM, and observed dose-response effects. One of the 3GA compounds completely knocked-down DUX4 expression at 50nM. The effects of 3GAs at25nM on cell differentiation were determined by fusion index, myotube size and number of atrophic myotubes after 7 days of muscle differentiation in culture. Our results showed that the treatments increased fusion index and reduced the number of atrophic myotubes. The studies showed that 3GAs successfully knocked-down DUX4, which improved the myogenic capacity of FSHD myoblasts. The findings demonstrated that the 3GAs are promising therapeutic molecules to be further developed for FSHD treatment.
Mindfulness is paying attention, non-judgmentally, to experience in the moment. Mindfulness train... more Mindfulness is paying attention, non-judgmentally, to experience in the moment. Mindfulness training reduces depression and anxiety and influences neural processes in midline self-referential and lateralized somatosensory and executive networks. Although mindfulness benefits emotion regulation, less is known about its relationship to anger and the corresponding neural correlates. This study examined the relationship of mindful awareness and brain hemodynamics of angry face processing, and the impact of mindfulness training. Eighteen healthy volunteers completed an angry face processing fMRI paradigm and measurement of mindfulness and anger traits. Ten of these participants were recruited from a Mindfulness-Based Stress Reduction (MBSR) class and also completed imaging and other assessments post-training. Self-reported mindful awareness increased after MBSR, but trait anger did not change. Baseline mindful awareness was negatively related to left inferior parietal lobule activation to angry faces; trait anger was positively related to right middle frontal gyrus and bilateral angular gyrus. No significant pre-post changes in angry face processing were found, but changes in trait mindful awareness and anger were associated with sub-threshold differences in paralimbic activation. These preliminary and hypothesis-generating findings, suggest the analysis of possible impact of mindfulness training on anger may begin with individual differences in angry face processing.
Substantial evidence has suggested that the brain structures of the medial prefrontal cortex (mPF... more Substantial evidence has suggested that the brain structures of the medial prefrontal cortex (mPFC) and amygdala (AMYG) are implicated in the pathophysiology of stress-related disorders. However, little is known with respect to the system-level adaptation of their neural circuitries to the perturbations of traumatic stressors. By utilizing behavioral tests and an awake animal imaging approach, in the present study we non-invasively investigated the impact of single-episode predator odor exposure in an inescapable environment on behaviors and neural circuits in rodents. We found that predator odor exposure significantly increased the freezing behavior. In addition, animals exhibited heightened anxiety levels seven days after the exposure. Intriguingly, we also found that the intrinsic functional connectivity within the AMYG-mPFC circuit was considerably compromised seven days after the traumatic event. Our data provide neuroimaging evidence suggesting that prolonged neuroadaptation induced by a single episode of traumatic stress can be non-invasively detected in rodents. These results also support the face validity and construction validity of using the paradigm of single trauma exposure in an inescapable environment as an animal model for post-traumatic stress disorder. Taken together, the present study has opened a new avenue to investigating animal models of stress-related mental disorders by going beyond static neuroanatomy, and ultimately bridging the gap between basic biomedical and human imaging research.
Introduction: Individuals with attention deficit/hyperactivity disorder (ADHD) are susceptible to... more Introduction: Individuals with attention deficit/hyperactivity disorder (ADHD) are susceptible to earlier and more severe nicotine addiction. To shed light on the relationship between nicotine and ADHD, we examined nicotine's effects on functional brain networks in an animal model of ADHD. Methods: Awake magnetic resonance imaging was used to compare functional connectivity in adolescent (post-natal day 44 ± 2) males of the spontaneously hypertensive rat (SHR) strain and two control strains, Wistar-Kyoto and Sprague-Dawley (n = 16 each). We analyzed functional connectivity immediately before and after nicotine exposure (0.4 mg/kg base) in naïve animals, using a region-of-interest approach focussing on 16 regions previously implicated in reward and addiction. Results: Relative to the control groups, the SHR strain demonstrated increased functional connectivity between the ventral tegmental area (VTA) and retrosplenial cortex in response to nicotine, suggesting an aberrant response to nicotine. In contrast, increased VTA-substantia nigra connectivity in response to a saline injection in the SHR was absent following a nicotine injection, suggesting that nicotine normalized function in this circuit. Conclusions: In the SHR, nicotine triggered an atypical response in one VTA circuit while normalizing activity in another. The VTA has been widely implicated in drug reward. Our data suggest that increased susceptibility to nicotine addiction in individuals with ADHD may involve altered responses to nicotine involving VTA circuits. Implications: Nicotine addiction is more common among individuals with ADHD. We found that two circuits involving the VTA responded differently to nicotine in animals that model ADHD in comparison to two control strains. In one circuit, nicotine normalized activity that was abnormal in the ADHD animals, while in the other circuit nicotine caused an atypical brain response in the ADHD animals. The VTA has been implicated in drug reward. Our results would be consistent with an interpretation that nicotine may normalize abnormal brain activity in ADHD, and that nicotine may be more rewarding for individuals with ADHD.
It is unknown how the timing between doses might affect nicotine's impact on neural activity. Our... more It is unknown how the timing between doses might affect nicotine's impact on neural activity. Our objective was to examine how the interdose interval affects nicotine's impact on resting-state functional connectivity (rsFC). Materials and Methods: Adult male Sprague-Dawley rats were administered nicotine daily (0.4 mg/ kg) over 6 days while control animals received saline vehicle. Functional magnetic resonance imaging was used to measure rsFC before and after a challenge dose of nicotine (0.4 mg/kg) delivered for the first time and 3, 6, 12, or 24 hr after the previous dose. Results: As the interval between nicotine doses increased from 3 to 24 hr, the strength of rsFC increased in some circuits, particularly the nucleus accumbens and prefrontal circuits, and decreased in others, namely the interpeduncular nucleus, hippocampus, caudoputamen, retrosplenial cortex, ventral tegmental, and the insular circuits. Conclusions: These data indicate that the effect that nicotine has on the brain is affected by the amount of time that has passed since the previous dose. The effect on rsFC of cumulative doses is not additive. This may have important implications for the study of nicotine addiction as it implies that the same dose of nicotine might have a different impact on the brain depending on the time elapsed from the previous exposure.
This study used Magnetic Resonance Spectroscopy (MRS) to identify potential neurometabolitic mark... more This study used Magnetic Resonance Spectroscopy (MRS) to identify potential neurometabolitic markers of cognitive performance in male (n = 7) and female (n = 8) middle-aged (∼5 years old) common marmosets (Callithrix jacchus). Anesthetized marmosets were scanned with a 4.7 T/40 cm horizontal magnet equipped with 450 mT/m magnetic field gradients and a 20 G/cm magnetic field gradient insert, within 3 months of completing the CANTAB serial Reversal Learning task. Neurometabolite concentrations of N-Acetyl Asparate, Myo-Inositol, Choline, Phosphocreatine + creatine, Glutamate and Glutamine were acquired from a 3 mm 3 voxel positioned in the Prefrontal Cortex (PFC). Males acquired the reversals (but not simple discriminations) faster than the females. Higher PFC Glx (glutamate + glutamine) concentration was associated with faster acquisition of the reversals. Interestingly, the correlation between cognitive performance and Glx was significant in males, but not in females. These results suggest that MRS is a useful tool to identify biochemical markers of cognitive performance in the healthy nonhuman primate brain and that biological sex modulates the relationship between neurochemical composition and cognition.
Prostate cancer is the second leading cause of all male cancer deaths. One of the factors present... more Prostate cancer is the second leading cause of all male cancer deaths. One of the factors present in malignant prostate cells and shown to support its metastatic growth is the neuropeptide neurotensin (NT). The primary goal of the present study was to establish the feasibility of using a newly developed paramagnetic receptor ligand for NT and noninvasive ultrahigh-field magnetic resonance (MR) imaging to visualize prostate cancer in rodents. Orthotropic xenografts were initiated in six-week old male BALB/c nu/nu athymic mice (n = 28) by intra-prostatic (ventral lobe) inoculation of human prostate cancer cells (10µL of PC3 cells (10 6 /100l)). Palpable tumors developed within 30-60 days. A microimager utilized in these studies was an actively shielded 9.4T, 89 mm bore, Oxford superconducting magnet with a 100 gauss/cm gradient system. Prior to contrast injection, T2 weighted anatomy scans were done to localize the tumor with a spin-echo multi-slice sequence with TR: 2000 TE: 40 and NEX: 1 in both coronal and axial planes. The paramagnetic ligand data sets were collected with a spin-echo, T1 weighted pulse sequence (MSME): TR 300 msec; TE 5 msec; NEX 4 in both axial and coronal planes. The data sets were taken initially at 5-min intervals post contrast injection for the first half hour and then at 15 min intervals for the next 1.5-2 hours for a time series analyses. The temporal distribution of MR signal intensity in various regions were determined in the absence and presence of NT. Our results confirm that the novel NT molecule was protected from enzymatic degradation and capable of forming a high affinity paramagnetic NT ligand with an extended half-life. During the imaging studies, the signal intensity increased by 200 % in the region of the tumor. This increase in signal intensity approached maximum binding within 30 minutes and remained visible for 1 hour post-injection of the contrast agent. Taken together, these findings suggest that it is feasible to detect and image prostate cancer using a paramagnetic NT ligand and the emergence of the NT receptor ligand that may be used as a diagnostic marker for prostate cancer in humans. .
Previous human imaging studies used facial stimuli to explore the potential association between d... more Previous human imaging studies used facial stimuli to explore the potential association between depression and fear. This study aimed at investigating brain alterations in a rodent model of depression when innate fear was induced in the form of the predator odor trimethylthiazoline (TMT). Flinders sensitive line rats (FSL), a genetic animal model of depression, and their control counterpart Flinders resistant line (FRL), were used in this functional magnetic resonance imaging (fMRI) assessment. Compared to FRL, FSL rats exhibited greater BOLD activation in the cortical amygdala and hypoactivation in the prefrontal cortex in response to TMT, suggesting corticoamygdalar dysfunction in the depressed strain. In addition, the hyperactivation in the insular cortex in FSL rats may be the basis for enhanced neuronal responses to fear and aversion in depression. These results are evidence for the value of translational models of depression in expanding understanding of the neural circuitries sub-serving common human co-morbidities like depression and fear.
Thalamocortical connectivity plays a vital role in brain function. The anatomy and function of th... more Thalamocortical connectivity plays a vital role in brain function. The anatomy and function of thalamocortical networks have been extensively studied in animals by numerous invasive techniques. Non-invasively mapping thalamocortical networks in humans has also been demonstrated by utilizing resting-state functional magnetic resonance imaging (rsfMRI). However, success in simultaneously imaging multiple thalamocortical networks in animals is rather limited. This is largely due to the profound impact of anesthesia used in most animal experiments on functional connectivity measurement. Here we have employed an awake animal imaging approach to systematically map thalamocortical connectivity for multiple thalamic nuclei in rats. Seed-based correlational analysis demonstrated robust functional connectivity for each thalamic nucleus in the cortex, and the cortical connectivity profiles revealed were in excellent accordance with the known thalamocortical anatomical connections. In addition, partial correlation analysis was utilized to further improve the spatial specificity of thalamocortical connectivity. Taken together, these findings have provided important evidence supporting the validity of rsfMRI measurement in awake animals. More importantly, the present study has made it possible to non-invasively investigate the function, neuroplasticity and mutual interactions of thalamocortical networks in animal models.
Sports-related concussions are currently diagnosed through multi-domain assessment by a medical p... more Sports-related concussions are currently diagnosed through multi-domain assessment by a medical professional and may utilize neurocognitive testing as an aide. However, these tests have only been able to detect differences in the days to week post-concussion. Here, we investigate a measure of brain function, namely resting state functional connectivity, which may detect residual brain differences in the weeks to months after concussion.
Journal of Cerebral Blood Flow and Metabolism, Apr 1, 2003
Anesthetics, widely used in magnetic resonance imaging (MRI) studies to avoid movement artifacts,... more Anesthetics, widely used in magnetic resonance imaging (MRI) studies to avoid movement artifacts, could have profound effects on cerebral blood flow (CBF) and cerebrovascular coupling relative to the awake condition. Quantitative CBF and tissue oxygenation (blood oxygen level-dependent [BOLD]) were measured, using the continuous arterial-spin-labeling technique with echo-planarimaging acquisition, in awake and anesthetized (2% isoflurane) rats under basal and hypercapnic conditions. All basal blood gases were within physiologic ranges. Blood pressure, respiration, and heart rates were within physiologic ranges in the awake condition but were depressed under anesthesia (P < 0.05). Regional CBF was heterogeneous with whole-brain CBF values of 0.86 ± 0.25 and 1.27 ± 0.29 mL • g -1 • min -1 under awake and anesthetized conditions, respectively. Surprisingly, CBF was markedly higher (20% to 70% across different brain conditions) under isofluraneanesthetized condition compared with the awake state (P < 0.01). Hypercapnia decreased pH, and increased PCO 2 and PO 2 . During 5% CO 2 challenge, under awake and anesthetized conditions, respectively, CBF increased 51 ± 11% and 25 ± 4%, and BOLD increased 7.3 ± 0.7% and 5.4 ± 0.4%. During 10% CO 2 challenge, CBF increased 158 ± 28% and 47 ± 11%, and BOLD increased 12.5 ± 0.9% and 7.2 ± 0.5%. Since CBF and BOLD responses were substantially higher under awake condition whereas blood gases were not statistically different, it was concluded that cerebrovascular reactivity was suppressed by anesthetics. This study also shows that perfusion and perfusion-based functional MRI can be performed in awake animals.
Joint pain is a prominent symptom of Hip and Knee Osteoarthritis (OA), impairing patients’ moveme... more Joint pain is a prominent symptom of Hip and Knee Osteoarthritis (OA), impairing patients’ movements and affecting the joint mechanics of walking. Self-report questionnaires are currently the gold standard for Hip OA and Knee OA pain assessment, presenting several problems, including the fact that older individuals often fail to provide accurate self-pain reports. Passive methods to assess pain are desirable. This study aims to explore the feasibility of OA-Pain-Sense, a passive, automatic Machine Learning-based approach that predicts patients’ self-reported pain levels using SpatioTemporal Gait features extracted from the accelerometer signal gathered from an anterior-posterior wearable sensor. To mitigate inter-subject variability, we investigated two types of data rescaling: subject-level and dataset-level. We explored six different binary machine learning classification models for discriminating pain in patients with Hip OA or Knee OA from healthy controls. In rigorous evaluatio...
Adults with psychopathy have a high propensity for substance abuse, generally starting from a you... more Adults with psychopathy have a high propensity for substance abuse, generally starting from a young age. This investigation tested hypotheses about differences in the neural responses associated with drug craving among high-risk young offenders with histories of abuse of stimulants and other drugs as a function of psychopathic traits. Fifty-four male adolescents (44 with a history of stimulant abuse and 10 controls) incarcerated at a maximum-security facility (M age = 17.08 years) completed a drug-cue exposure task while brain hemodynamic activity was monitored using functional magnetic resonance imaging (fMRI) with a mobile MRI scanner stationed at the facility. Psychopathic traits were assessed using the Hare Psychopathy Checklist: Youth Version (PCL:YV). In the stimulant abuser group, drug cues elicited activity in classic reward circuitry. Consistent with studies of adult psychopathic traits and substance abuse, there was a negative association between PCL-YV scores and hemodynamic response related to drug craving in the amygdala and ACC in youth with a history of stimulant abuse. However, there were considerably more negative associations between the PCL:YV and hemodynamic response among youth than adults and this was primarily due to callous-unemotional traits rather than interpersonal or behavioral traits. The implications for how personality traits modulate motivations for drugseeking behavior among adolescent offenders are discussed.
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