Caitlin Ravichandran - Academia.edu (original) (raw)

Papers by Caitlin Ravichandran

Sleep, Apr 1, 2013

Study Objectives: Primary insomnia (PI) is a sleep disorder characterized by difficulty with slee... more Study Objectives: Primary insomnia (PI) is a sleep disorder characterized by difficulty with sleep initiation, maintenance, and/or the experience of nonrestorative sleep combined with a subsequent impairment of daytime functioning. The hyperarousal hypothesis has emerged as the leading candidate to explain insomnia symptoms in the absence of specific mental, physical, or substance-related causes. We hypothesized that the cellular energetic metabolites, including beta nucleoside triphosphate, which in magnetic resonance spectroscopy approximates adenosine triphosphate (ATP), and phosphocreatine (PCr), would show changes in PI reflecting increased energy demand. Design and Setting: Matched-groups, cross-sectional study performed at two university-based hospitals. Patients: Sixteen medication-free individuals (eight males, eight females; mean ± standard deviation (SD) age = 37.2 ± 8.4 y) with PI and 16 good sleepers (nine males, seven females; mean ± SD age = 37.6 ± 4.7 y). Measurements: Diagnosis was established for all individuals by unstructured clinical interview, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID), sleep diary, and actigraphy. Polysomnography was collected in individuals with PI. Phosphorous magnetic resonance spectroscopy (31P MRS) data were collected on all individuals at 4 Tesla. We assessed cell membrane (anabolic precursors and catabolic metabolites) and bioenergetic (ATP, phosphocreatine) metabolites in gray matter and white matter to determine their relationship to the presence and severity of PI. Results: Individuals with PI showed lower phosphocreatine in gray matter and an unexpected decrease of phosphocholine, a precursor of the cell membrane compound phosphatidylcholine, in white matter. In addition, there was a trend toward a negative association between polysomnographically determined wake after sleep onset and gray matter beta-nucleoside triphosphate and white matter phosphocholine in the primary insomnia group. Conclusions: These results support the hyperarousal hypothesis in PI based on lower phosphocreatine in gray matter in the PI group.

Neuropsychopharmacology, Sep 2, 2016

Brain bioenergetic abnormalities have been observed frequently in adults with major depressive di... more Brain bioenergetic abnormalities have been observed frequently in adults with major depressive disorder (MDD); however, results have been inconsistent regarding whether decreased or increased metabolism was observed. Phosphorus-31 magnetic resonance spectroscopy (31P MRS) allows for the quantification of bioenergetic molecules, containing high-energy phosphates, over the whole brain as well as measuring the differences between gray matter and white matter. We recruited 50 subjects with a current diagnosis of MDD, not currently treated with psychotropic medication, between ages of 18 and 65 (mean ± SD age: 43.4 ± 13.6; 46% female) and 30 healthy volunteers, matched for age and gender (39.0 ± 12.5 years of age; 36.6% female). All subjects received a T1 MP-FLASH scan for tissue segmentation followed by 31P MRS, chemical shift imaging scan with 84 voxels of data collected over the entire brain utilizing a dual-tuned, protonphosphorus coil to minimize subject movement. Phosphocreatine and inorganic phosphate (Pi) varied in opposite directions across gray matter and white matter when MDD subjects were compared with controls. This finding suggests alterations in high-energy phosphate metabolism and regulation of oxidative phosphorylation in MDD patients. In addition, within the MDD group, gray matter Pi, a regulator of oxidative phosphorylation, correlated positively with severity of depression. These data support a model that includes changes in brain bioenergetic function in subjects with major depression.

Journal Of Public Health, Oct 25, 2022

Aim The purpose of the present study was to establish and validate the Survey for Trauma-Informed... more Aim The purpose of the present study was to establish and validate the Survey for Trauma-Informed Systems Change (STISC), a measure of culturally responsive trauma-informed care (TIC) and services that can be administered to professionals in any field or industry. Subject/methods The current study with 262 respondents from judicial, healthcare, political, non-profit, and for-profit settings examined the internal consistency reliability and factor structure of the STISC. Results A total of 262 respondents from various industries accessed the pre-training survey. Seven of the 59 items were reassigned to alternate subscales and three subscales were merged following correlation analysis. Internal consistency reliability for subscales based on the final item assignments was good or excellent (lower 95% confidence limits for hierarchical omega ≥ 0.85). The root mean square error of approximation estimate for the confirmatory factor analysis based on final item assignments was acceptable (0.073; 90% CI 0.71, 0.76). Neither the comparative fit index value of 0.76 nor the Tucker-Lewis fit index value of 0.75 approached conventional thresholds for acceptable fit. Conclusion Given the absence of a validated alternative, this study supports use of the STISC tool to measure the degree of an individual's trauma-informed knowledge and positive attitudes toward trauma-informed systems change, as well as trauma-informed practices in the workplace. Further study and refinement will aim to determine whether the STISC survey is sensitive to change, which will provide stronger support for the survey's potential usefulness as a cost-effective method of standardizing trauma-informed systems change programs across multiple fields and industries.

Psychiatry Research: Neuroimaging, Dec 1, 2010

Benzodiazepines (BZs), which are typically used as anxiolytics, act by modulating inhibitory sign... more Benzodiazepines (BZs), which are typically used as anxiolytics, act by modulating inhibitory signaling through gamma-aminobutyric acid A (GABA)(A) receptors. Functionally, the inhibitory effects of GABA may be counterbalanced by the excitatory effects of glutamate (Glu) as the two neurotransmitter systems are metabolically linked through their synthetic intermediate glutamine (Gln). The primary aim of this study was to determine whether the effects of different BZs on the GABA and Glu/Gln systems would vary according to the pharmacokinetics of the different drugs. Proton magnetic resonance spectroscopy ((1)H MRS) was used to measure GABA, Glu, and Gln levels in six healthy adult volunteers 1h and 10 h following immediate release alprazolam, extended release alprazolam, clonazepam, or placebo. Although there were no differences between 1 and 10 h when the drugs were examined individually, there was a trend level difference between the 1- and 10-h effects of BZs on Gln when the BZs were combined. In post-hoc comparisons, the difference in the Gln to creatine (Cr) ratio was 0.04 for the BZs versus placebo at 1h and 0.01 at 10h following the administration of drug (t(11)=2.49, P=0.03 1 h; t(10)=0.65, P=0.53 10 h; no correction for multiple comparisons). An increase in Gln/Cr at 1 h post-BZ is consistent with a functionally synergistic relationship between Glu/Gln and GABA in the brain. It also suggests that MRS may have sufficient sensitivity to detect acute drug effects.

Journal of Autism and Developmental Disorders, Aug 16, 2023

Journal of the American Academy of Child and Adolescent Psychiatry, Oct 1, 2022

Journal of the American Academy of Child and Adolescent Psychiatry, Oct 1, 2016

The majority of children and adolescents with psychiatric disorders are treated at the primary ca... more The majority of children and adolescents with psychiatric disorders are treated at the primary care office. To identify potential barriers to diagnosis and treatment of mental health disorders, primary outpatient family medicine and pediatric providers completed a survey that characterized their experiences with screening, diagnosis, and treatment of mental illness in their practice. Methods: An anonymous and voluntary investigator-designed online survey was hosted and distributed by the secure web application REDCap (Research Electronic Data Capture). Of the total number of contacted providers (N ¼ 83), 34 percent of providers responded, including 52 percent from the general pediatric clinic and 45 percent from the family medicine clinic. Providers (57 percent) reported that the majority (90 percent) of their patient population was composed of children. Results: Primary care providers (74 percent) reported using evidence-based screening instruments in their practice, such as the Patient Health Questionnaire (PHQ-9) to assess depression, which was the most commonly used screening tool (63 percent); the Vanderbilt Rating Scale for ADHD (19 percent); and the Screen for Child Anxiety Related Disorders (SCARED) (19 percent). A majority of providers (76 percent) reported that they do not treat or routinely screen for anxiety disorders. Providers (84 percent) reported that ADHD was the most commonly diagnosed and treated mental health disorder compared with 4 percent for anxiety disorders. Furthermore, 88 percent reported stimulants as the most commonly prescribed psychotropic medication, whereas 8 percent reported the use of SSRIs. Conclusions: Although anxiety disorders are the most common mental health diagnoses in children and adolescents, with the lifetime prevalence of 25.1 percent in those aged between 13 and 18 years, this study indicates that primary care providers treating children are not screening adequately for anxiety disorders. The most challenging aspects of pediatric mental health reported by providers included the following: difficulty with management of mental health disorders, lack of confidence in managing behavioral and emotional problems, and lack of time required to administer diagnostic screens and managing cases. Future work should focus on interventions to address this lack of screening.

bioRxiv (Cold Spring Harbor Laboratory), Mar 24, 2023

Stress produces profound effects on behavior, including persistent alterations in sleep patterns.... more Stress produces profound effects on behavior, including persistent alterations in sleep patterns. Here we examined the effects of two prototypical stress peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing factor (CRF), on sleep architecture and other translationally-relevant endpoints. Male and female mice were implanted with subcutaneous transmitters enabling continuous measurement of electroencephalography (EEG) and electromyography (EMG), as well as body temperature and locomotor activity, without tethering that restricts free movement, body posture, or head orientation during sleep. At baseline, females spent more time awake (AW) and less time in slow wave sleep (SWS) than males. Mice then received intracerebral infusions of PACAP or CRF at doses producing equivalent increases in anxiety-like behavior. The effects of PACAP on sleep architecture were similar in both sexes and resembled those reported in male mice after chronic stress exposure. Compared to vehicle infusions, PACAP infusions decreased time in AW, increased time in SWS, and increased rapid eye movement sleep (REM) time and bouts on the day following treatment. In addition, PACAP effects on REM time remained detectable a week after treatment. PACAP infusions also reduced body temperature and locomotor activity. Under the same experimental conditions, CRF infusions had minimal effects on sleep architecture in either sex, causing only transient increases in SWS during the dark phase, with no effects on temperature or activity. These findings suggest that PACAP and CRF have fundamentally different effects on sleep-related metrics, and provide new insights into the mechanisms by which stress disrupts sleep. .

Scientific Reports, Jun 13, 2022

Adults with autism spectrum disorder (ASD) are at risk for excess bodyweight and hypertension, ye... more Adults with autism spectrum disorder (ASD) are at risk for excess bodyweight and hypertension, yet the prevalence of and clinical predictors for these health conditions remain unknown. The objective of this study was to assess the prevalence of overweight, obesity, and hypertension in a large clinical sample of adults with a confirmed diagnosis of ASD and to examine potential clinical predictors. This retrospective chart review study included adult subjects (≥ 20 years) with ASD who had been seen within the past 5 years at a multidisciplinary developmental disorders clinic. Data collected from the electronic health record included age, sex, race and ethnicity, cognitive ability, language ability, body mass index (BMI), hypertension, and use of second generation antipsychotic medications (SGAs). Of 622 adults with a confirmed diagnosis of ASD potentially eligible for the study, 483 (78%) had one or more notes in their records from the past 5 years. Those with recent notes were 23% female, 89% White, and had a mean (SD) age of 28.1 (7.1) years. Overall prevalence estimates for adults represented by this predominantly male, White, and young clinical sample were 28% (95% CI 24%, 32%) for overweight (BMI 25-29.9 kg/m 2), 35% (95% CI 31%, 40%) for obesity (≥ 30 kg/m 2), and 11% (95% CI 9%, 15%) for hypertension. Controlling for age and sex, intellectual disability (ID) was significantly associated with BMI (p = 0.003) but not hypertension (p = 0.69); those with moderate or more severe ID had a mean BMI that was 2.26 kg/m 2 (95% CI 0.96, 3.57) lower than those with no ID. Controlling for age and sex, neither language ability, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) subtype of autism, nor past or current use of SGAs were significantly associated with BMI or hypertension. The study identified a high prevalence of overweight and obesity in adults with ASD consistent with the prevalence of these medical comorbidities in the U.S. population. Overweight and obesity, abnormal or excessive fat accumulation that may impair health, are major public health concerns. Excess bodyweight (overweight and obesity) is a significant and preventable risk factor for several other chronic diseases affecting virtually all major organ systems 1,2. Obesity is associated with decreased life expectancy by 5-20 years 1. Adults with autism spectrum disorder (ASD) may be at increased risk for overweight and obesity for several reasons. First, excess bodyweight is known to be of significant concern in children with ASD. A recent metaanalysis demonstrated that children with ASD are 1.84 times more likely to experience obesity 3 and childhood obesity is known to increase the risk of adult obesity by about five times in the general population 4. Second, the core and associated symptoms of ASD leading to restricted food preferences, decreased physical activity, and use of food as a reward in some behavioral therapies, likely also contribute to excess bodyweight. Finally, the use of

Psychiatric research and clinical practice, Oct 9, 2020

Despite research demonstrating the value of dimensional approaches, standard systems for classify... more Despite research demonstrating the value of dimensional approaches, standard systems for classifying psychotic disorders rely primarily on categorization of patients into distinct diagnoses. We present the first study comparing analyses of dimensional features, categories, and standard diagnoses, all derived from the same sample. Methods: Using symptom ratings from 934 patients hospitalized for psychosis, we examined dimensional models, fit using factor analysis, categorical models, fit to factor-based scores from the dimensional model, and their correspondence with DSM-defined diagnoses. We compared the ability of each model to discriminate patients' assignment to medication regimen as a clinical validator. Results: Dimensional modeling identified four factors (manic, depressive, negative symptoms, and positive symptoms), which corresponded to factors in prior studies and appeared robust to statistical approach. Scores based on these factors overlapped substantially among DSM diagnoses. Patients assigned to clusters had less overlap in factor-based scores. However, categorical models were sensitive to statistical approach. The addition of DSM diagnoses, but not cluster assignments, improved the fits of models with dimensional scores alone as the clinical predictors for some medication classes. Conclusions: The results highlight the variability of symptom presentation within DSM-defined diagnostic categories, the utility of symptom dimensions or factors, and a potential lack of robustness of data-driven categorical approaches. Findings support initiatives to develop updated diagnostic systems that complement categorical classification of psychotic illness with factors representing dimensional ratings of symptoms.

World Psychiatry, Sep 9, 2021

447 is training. Again, training has from the start been foundational to values-based practice. A... more 447 is training. Again, training has from the start been foundational to values-based practice. Among new training initiatives is an international web-based masters-level programme in Phenomenology and Values-based Clinical Care (PVbCC). Jointly sponsored by the Collaborating Centre for Values-based Practice in Oxford and the Santa Casa de São Paulo School of Medical Sciences in Brazil, with international partners (including the WPA Section on Philosophy and Humanities), the programme offers a series of master classes delivered by experts from different parts of the world (see https://metamastersonline.com). Participating students will thereby gain an additional international level of experience over and above their respective national home study programmes. As such, the PVbCC programme will help to build what, many years ago, and anticipating contemporary developments, a former President of the Royal College of Psychiatrists, J. Birley, called an international “open society” of mental health stakeholders underpinning best practice in personalized mental health care. Kenneth W.M. Fulford, Ashok Handa St. Catherine’s College, Oxford, UK; Faculty of Philosophy, University of Oxford, Oxford, UK; Nuffield Department of Surgical Sciences, J. Radcliffe Hospital, Oxford, UK

American Journal of Geriatric Psychiatry, Aug 1, 2019

This study compared brain energy metabolism, as measured by cerebral concentrations of glutamate ... more This study compared brain energy metabolism, as measured by cerebral concentrations of glutamate (Glu), glutamine (Gln), and N-acetyl aspartate (NAA), in older age bipolar depression (OABD) to that of psychiatrically healthy comparison subjects using proton (1 H) magnetic resonance spectroscopy imaging at 4-Tesla. Metabolite levels were assessed in OABD subjects before and after 8 weeks of lamotrigine therapy with the goal of determining relationships between cerebral energy metabolism, depression symptom severity, and changes in depression symptom response. Methods: Individuals (n = 21, mean age: 62.0 § 5.9 years) with bipolar disorder, current episode depressed, and a healthy comparison group (n = 14, mean age: 67.5 § 8.8 years) were selected. Participants with bipolar disorder, current episode depressed, were treated in open label fashion with lamotrigine monotherapy for 8 weeks. All subjects were scanned with 1 H magnetic resonance spectroscopy at 4T at baseline and again after 8 weeks to assess levels of cerebral metabolites in the anterior cingulate cortex and parieto-occipital cortex. Metabolite levels were examined as ratios relative to creatine (Cr). Response to 8 weeks of lamotrigine treatment in the bipolar disorder, current episode depressed group, was assessed as a continuous measure on the Montgomery-Asberg Depression Rating Scale. Results: NAA/Cr ratio in OABD was significantly lower by 14% (95% confidence interval: [1%, 26%]) than in comparison subjects at baseline. However, there were no associations between NAA/Cr, Glu/Cr, or Gln/Cr and either depression severity or lamotrigine treatment. Conclusion: Group differences in NAA suggest evidence for a deficit in cerebral energy metabolism in OABD.

International Journal of Geriatric Psychiatry, Aug 1, 2009

IntroductionWe investigated tissue specific differences in markers of energy metabolism, includin... more IntroductionWe investigated tissue specific differences in markers of energy metabolism, including high energy phosphate compounds (beta and total NTP, PCr) and pH, in older adults with depression compared with healthy controls, before and after a 12‐week treatment trial of sertraline.MethodsThirteen older adults, age ≥55, with Major Depressive Disorder (HAMD17 score of ≥18) were recruited along with ten age‐matched controls. The depression subjects had a pre‐ and post‐treatment 4T 31P‐MRS scan using a three‐dimensional chemical shift imaging sequence. The extracted brain images were segmented into white matter (WM), gray matter (GM) and CSF. A linear mixed effects model analyzed the effects of pre‐treatment and post‐treatment depression on phosphorus metabolite concentration estimates (including calculated pH and Mg++).ResultsTotal tissue beta‐NTP (−8%, t(18.66) = 3.50; p = 0.0024) and total tissue total NTP (−6%, t(17.41) = 2.68; p = 0.0156) were lower in subjects with geriatric depression compared with healthy controls. Total tissue levels of total‐NTP changed significantly with treatment (−2%, t(14.84) = −2.47; p = 0.0259). Total NTP was reduced in the WM, but not the GM, in the pre‐treatment depression group (t(51.65) = 4.02; p = 0.0002). Intracellular pH was higher in the GM of subjects with pre‐treatment depression (t(1133.84) = −2.10; p = 0.0353) and decreased to approximate control levels after treatment (t(648.86) = −2.53; p = 0.0115).DiscussionThese findings demonstrate bioenergetic changes including tissue specific differences in 31P‐MRS metabolites in geriatric depression. Decreased white matter total NTP may reflect alterations in white matter function. Copyright © 2009 John Wiley & Sons, Ltd.

NMR in Biomedicine, Nov 11, 2009

Evidence suggests that mitochondria undergo functional and morphological changes with age. This s... more Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus (31 P) MRS. 31 P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21-84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (S0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p ¼ 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using 31 P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non-demented and psychiatrically stable older adults and specifically analyzed gray-white matter differences in brain metabolism.

Expert Review of Clinical Pharmacology

American Journal of Psychiatry

Journal of Autism and Developmental Disorders, 2021

The purpose of the study was to characterize repetitive phenomena in Williams syndrome (WS). The ... more The purpose of the study was to characterize repetitive phenomena in Williams syndrome (WS). The parents of 60 subjects with WS completed the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) or Children’s Y-BOCS, the Yale Global Tic Severity Scale, the Stereotyped Behavior Scale, and the Spence Children’s Anxiety Scale–Parent Version. Nineteen males and 41 females participated in the study. Six subjects (10%) had obsessions only, six (10%) had compulsions only, and eleven (18%) had at least one obsession and at least one compulsion. None of the subjects had tics. Fifty subjects (83.3%) endorsed at least one stereotypy. Increased anxiety was associated with increased severity of obsessions, but not severity of compulsions or stereotypies.

Journal of Autism and Developmental Disorders, 2021

Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and qua... more Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and quantitative assessments were used to evaluate for anxiety in 50 subjects with AS. In-person evaluations assessed behaviors concerning for anxiety and circumstances wherein they occurred. Caregivers completed anxiety and other behavioral rating scales. Caregiver responses were categorized and compared to items from anxiety rating scales. The most common behavioral manifestation of anxiety was "aggression." The most common circumstance was "separation from caregiver/parent." Subjects had elevated scores on anxiety, irritability and hyperactivity scales with lower mean scores among subjects with a maternal deletion. The Pediatric Anxiety Rating Scale best captured behaviors described by caregivers. Existing anxiety scales should be adapted for use in AS.

American Journal of Medical Genetics Part A, 2020

The objectives of this study were to characterize the sleep habits of 50 clinically referred indi... more The objectives of this study were to characterize the sleep habits of 50 clinically referred individuals with Angelman syndrome (AS) and to retrospectively compare the effectiveness/tolerability of the three most commonly prescribed sleep medications in the sample. An experienced physician assigned a Clinical Global Impressions‐Severity scale (CGI‐S) score for each subject's AS‐specific symptoms. Caregivers completed the Child Sleep Habits Questionnaire (CSHQ; screen for sleep problems in school‐aged [4–10 years] children), a screening assessment for sleep problems. Caregivers provided information about medication trials targeting disturbed sleep, with the physician assigning a CGI‐Improvement scale (CGI‐I) score for each trial. Linear regression showed significant negative association between age and CSHQ score. In their lifetime, 72% of participants had taken a medication for sleep, most commonly melatonin, clonidine and trazodone. The majority continued these for 6 months or ...

Sleep, Apr 1, 2013

Study Objectives: Primary insomnia (PI) is a sleep disorder characterized by difficulty with slee... more Study Objectives: Primary insomnia (PI) is a sleep disorder characterized by difficulty with sleep initiation, maintenance, and/or the experience of nonrestorative sleep combined with a subsequent impairment of daytime functioning. The hyperarousal hypothesis has emerged as the leading candidate to explain insomnia symptoms in the absence of specific mental, physical, or substance-related causes. We hypothesized that the cellular energetic metabolites, including beta nucleoside triphosphate, which in magnetic resonance spectroscopy approximates adenosine triphosphate (ATP), and phosphocreatine (PCr), would show changes in PI reflecting increased energy demand. Design and Setting: Matched-groups, cross-sectional study performed at two university-based hospitals. Patients: Sixteen medication-free individuals (eight males, eight females; mean ± standard deviation (SD) age = 37.2 ± 8.4 y) with PI and 16 good sleepers (nine males, seven females; mean ± SD age = 37.6 ± 4.7 y). Measurements: Diagnosis was established for all individuals by unstructured clinical interview, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (SCID), sleep diary, and actigraphy. Polysomnography was collected in individuals with PI. Phosphorous magnetic resonance spectroscopy (31P MRS) data were collected on all individuals at 4 Tesla. We assessed cell membrane (anabolic precursors and catabolic metabolites) and bioenergetic (ATP, phosphocreatine) metabolites in gray matter and white matter to determine their relationship to the presence and severity of PI. Results: Individuals with PI showed lower phosphocreatine in gray matter and an unexpected decrease of phosphocholine, a precursor of the cell membrane compound phosphatidylcholine, in white matter. In addition, there was a trend toward a negative association between polysomnographically determined wake after sleep onset and gray matter beta-nucleoside triphosphate and white matter phosphocholine in the primary insomnia group. Conclusions: These results support the hyperarousal hypothesis in PI based on lower phosphocreatine in gray matter in the PI group.

Neuropsychopharmacology, Sep 2, 2016

Brain bioenergetic abnormalities have been observed frequently in adults with major depressive di... more Brain bioenergetic abnormalities have been observed frequently in adults with major depressive disorder (MDD); however, results have been inconsistent regarding whether decreased or increased metabolism was observed. Phosphorus-31 magnetic resonance spectroscopy (31P MRS) allows for the quantification of bioenergetic molecules, containing high-energy phosphates, over the whole brain as well as measuring the differences between gray matter and white matter. We recruited 50 subjects with a current diagnosis of MDD, not currently treated with psychotropic medication, between ages of 18 and 65 (mean ± SD age: 43.4 ± 13.6; 46% female) and 30 healthy volunteers, matched for age and gender (39.0 ± 12.5 years of age; 36.6% female). All subjects received a T1 MP-FLASH scan for tissue segmentation followed by 31P MRS, chemical shift imaging scan with 84 voxels of data collected over the entire brain utilizing a dual-tuned, protonphosphorus coil to minimize subject movement. Phosphocreatine and inorganic phosphate (Pi) varied in opposite directions across gray matter and white matter when MDD subjects were compared with controls. This finding suggests alterations in high-energy phosphate metabolism and regulation of oxidative phosphorylation in MDD patients. In addition, within the MDD group, gray matter Pi, a regulator of oxidative phosphorylation, correlated positively with severity of depression. These data support a model that includes changes in brain bioenergetic function in subjects with major depression.

Journal Of Public Health, Oct 25, 2022

Aim The purpose of the present study was to establish and validate the Survey for Trauma-Informed... more Aim The purpose of the present study was to establish and validate the Survey for Trauma-Informed Systems Change (STISC), a measure of culturally responsive trauma-informed care (TIC) and services that can be administered to professionals in any field or industry. Subject/methods The current study with 262 respondents from judicial, healthcare, political, non-profit, and for-profit settings examined the internal consistency reliability and factor structure of the STISC. Results A total of 262 respondents from various industries accessed the pre-training survey. Seven of the 59 items were reassigned to alternate subscales and three subscales were merged following correlation analysis. Internal consistency reliability for subscales based on the final item assignments was good or excellent (lower 95% confidence limits for hierarchical omega ≥ 0.85). The root mean square error of approximation estimate for the confirmatory factor analysis based on final item assignments was acceptable (0.073; 90% CI 0.71, 0.76). Neither the comparative fit index value of 0.76 nor the Tucker-Lewis fit index value of 0.75 approached conventional thresholds for acceptable fit. Conclusion Given the absence of a validated alternative, this study supports use of the STISC tool to measure the degree of an individual's trauma-informed knowledge and positive attitudes toward trauma-informed systems change, as well as trauma-informed practices in the workplace. Further study and refinement will aim to determine whether the STISC survey is sensitive to change, which will provide stronger support for the survey's potential usefulness as a cost-effective method of standardizing trauma-informed systems change programs across multiple fields and industries.

Psychiatry Research: Neuroimaging, Dec 1, 2010

Benzodiazepines (BZs), which are typically used as anxiolytics, act by modulating inhibitory sign... more Benzodiazepines (BZs), which are typically used as anxiolytics, act by modulating inhibitory signaling through gamma-aminobutyric acid A (GABA)(A) receptors. Functionally, the inhibitory effects of GABA may be counterbalanced by the excitatory effects of glutamate (Glu) as the two neurotransmitter systems are metabolically linked through their synthetic intermediate glutamine (Gln). The primary aim of this study was to determine whether the effects of different BZs on the GABA and Glu/Gln systems would vary according to the pharmacokinetics of the different drugs. Proton magnetic resonance spectroscopy ((1)H MRS) was used to measure GABA, Glu, and Gln levels in six healthy adult volunteers 1h and 10 h following immediate release alprazolam, extended release alprazolam, clonazepam, or placebo. Although there were no differences between 1 and 10 h when the drugs were examined individually, there was a trend level difference between the 1- and 10-h effects of BZs on Gln when the BZs were combined. In post-hoc comparisons, the difference in the Gln to creatine (Cr) ratio was 0.04 for the BZs versus placebo at 1h and 0.01 at 10h following the administration of drug (t(11)=2.49, P=0.03 1 h; t(10)=0.65, P=0.53 10 h; no correction for multiple comparisons). An increase in Gln/Cr at 1 h post-BZ is consistent with a functionally synergistic relationship between Glu/Gln and GABA in the brain. It also suggests that MRS may have sufficient sensitivity to detect acute drug effects.

Journal of Autism and Developmental Disorders, Aug 16, 2023

Journal of the American Academy of Child and Adolescent Psychiatry, Oct 1, 2022

Journal of the American Academy of Child and Adolescent Psychiatry, Oct 1, 2016

The majority of children and adolescents with psychiatric disorders are treated at the primary ca... more The majority of children and adolescents with psychiatric disorders are treated at the primary care office. To identify potential barriers to diagnosis and treatment of mental health disorders, primary outpatient family medicine and pediatric providers completed a survey that characterized their experiences with screening, diagnosis, and treatment of mental illness in their practice. Methods: An anonymous and voluntary investigator-designed online survey was hosted and distributed by the secure web application REDCap (Research Electronic Data Capture). Of the total number of contacted providers (N ¼ 83), 34 percent of providers responded, including 52 percent from the general pediatric clinic and 45 percent from the family medicine clinic. Providers (57 percent) reported that the majority (90 percent) of their patient population was composed of children. Results: Primary care providers (74 percent) reported using evidence-based screening instruments in their practice, such as the Patient Health Questionnaire (PHQ-9) to assess depression, which was the most commonly used screening tool (63 percent); the Vanderbilt Rating Scale for ADHD (19 percent); and the Screen for Child Anxiety Related Disorders (SCARED) (19 percent). A majority of providers (76 percent) reported that they do not treat or routinely screen for anxiety disorders. Providers (84 percent) reported that ADHD was the most commonly diagnosed and treated mental health disorder compared with 4 percent for anxiety disorders. Furthermore, 88 percent reported stimulants as the most commonly prescribed psychotropic medication, whereas 8 percent reported the use of SSRIs. Conclusions: Although anxiety disorders are the most common mental health diagnoses in children and adolescents, with the lifetime prevalence of 25.1 percent in those aged between 13 and 18 years, this study indicates that primary care providers treating children are not screening adequately for anxiety disorders. The most challenging aspects of pediatric mental health reported by providers included the following: difficulty with management of mental health disorders, lack of confidence in managing behavioral and emotional problems, and lack of time required to administer diagnostic screens and managing cases. Future work should focus on interventions to address this lack of screening.

bioRxiv (Cold Spring Harbor Laboratory), Mar 24, 2023

Stress produces profound effects on behavior, including persistent alterations in sleep patterns.... more Stress produces profound effects on behavior, including persistent alterations in sleep patterns. Here we examined the effects of two prototypical stress peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing factor (CRF), on sleep architecture and other translationally-relevant endpoints. Male and female mice were implanted with subcutaneous transmitters enabling continuous measurement of electroencephalography (EEG) and electromyography (EMG), as well as body temperature and locomotor activity, without tethering that restricts free movement, body posture, or head orientation during sleep. At baseline, females spent more time awake (AW) and less time in slow wave sleep (SWS) than males. Mice then received intracerebral infusions of PACAP or CRF at doses producing equivalent increases in anxiety-like behavior. The effects of PACAP on sleep architecture were similar in both sexes and resembled those reported in male mice after chronic stress exposure. Compared to vehicle infusions, PACAP infusions decreased time in AW, increased time in SWS, and increased rapid eye movement sleep (REM) time and bouts on the day following treatment. In addition, PACAP effects on REM time remained detectable a week after treatment. PACAP infusions also reduced body temperature and locomotor activity. Under the same experimental conditions, CRF infusions had minimal effects on sleep architecture in either sex, causing only transient increases in SWS during the dark phase, with no effects on temperature or activity. These findings suggest that PACAP and CRF have fundamentally different effects on sleep-related metrics, and provide new insights into the mechanisms by which stress disrupts sleep. .

Scientific Reports, Jun 13, 2022

Adults with autism spectrum disorder (ASD) are at risk for excess bodyweight and hypertension, ye... more Adults with autism spectrum disorder (ASD) are at risk for excess bodyweight and hypertension, yet the prevalence of and clinical predictors for these health conditions remain unknown. The objective of this study was to assess the prevalence of overweight, obesity, and hypertension in a large clinical sample of adults with a confirmed diagnosis of ASD and to examine potential clinical predictors. This retrospective chart review study included adult subjects (≥ 20 years) with ASD who had been seen within the past 5 years at a multidisciplinary developmental disorders clinic. Data collected from the electronic health record included age, sex, race and ethnicity, cognitive ability, language ability, body mass index (BMI), hypertension, and use of second generation antipsychotic medications (SGAs). Of 622 adults with a confirmed diagnosis of ASD potentially eligible for the study, 483 (78%) had one or more notes in their records from the past 5 years. Those with recent notes were 23% female, 89% White, and had a mean (SD) age of 28.1 (7.1) years. Overall prevalence estimates for adults represented by this predominantly male, White, and young clinical sample were 28% (95% CI 24%, 32%) for overweight (BMI 25-29.9 kg/m 2), 35% (95% CI 31%, 40%) for obesity (≥ 30 kg/m 2), and 11% (95% CI 9%, 15%) for hypertension. Controlling for age and sex, intellectual disability (ID) was significantly associated with BMI (p = 0.003) but not hypertension (p = 0.69); those with moderate or more severe ID had a mean BMI that was 2.26 kg/m 2 (95% CI 0.96, 3.57) lower than those with no ID. Controlling for age and sex, neither language ability, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) subtype of autism, nor past or current use of SGAs were significantly associated with BMI or hypertension. The study identified a high prevalence of overweight and obesity in adults with ASD consistent with the prevalence of these medical comorbidities in the U.S. population. Overweight and obesity, abnormal or excessive fat accumulation that may impair health, are major public health concerns. Excess bodyweight (overweight and obesity) is a significant and preventable risk factor for several other chronic diseases affecting virtually all major organ systems 1,2. Obesity is associated with decreased life expectancy by 5-20 years 1. Adults with autism spectrum disorder (ASD) may be at increased risk for overweight and obesity for several reasons. First, excess bodyweight is known to be of significant concern in children with ASD. A recent metaanalysis demonstrated that children with ASD are 1.84 times more likely to experience obesity 3 and childhood obesity is known to increase the risk of adult obesity by about five times in the general population 4. Second, the core and associated symptoms of ASD leading to restricted food preferences, decreased physical activity, and use of food as a reward in some behavioral therapies, likely also contribute to excess bodyweight. Finally, the use of

Psychiatric research and clinical practice, Oct 9, 2020

Despite research demonstrating the value of dimensional approaches, standard systems for classify... more Despite research demonstrating the value of dimensional approaches, standard systems for classifying psychotic disorders rely primarily on categorization of patients into distinct diagnoses. We present the first study comparing analyses of dimensional features, categories, and standard diagnoses, all derived from the same sample. Methods: Using symptom ratings from 934 patients hospitalized for psychosis, we examined dimensional models, fit using factor analysis, categorical models, fit to factor-based scores from the dimensional model, and their correspondence with DSM-defined diagnoses. We compared the ability of each model to discriminate patients' assignment to medication regimen as a clinical validator. Results: Dimensional modeling identified four factors (manic, depressive, negative symptoms, and positive symptoms), which corresponded to factors in prior studies and appeared robust to statistical approach. Scores based on these factors overlapped substantially among DSM diagnoses. Patients assigned to clusters had less overlap in factor-based scores. However, categorical models were sensitive to statistical approach. The addition of DSM diagnoses, but not cluster assignments, improved the fits of models with dimensional scores alone as the clinical predictors for some medication classes. Conclusions: The results highlight the variability of symptom presentation within DSM-defined diagnostic categories, the utility of symptom dimensions or factors, and a potential lack of robustness of data-driven categorical approaches. Findings support initiatives to develop updated diagnostic systems that complement categorical classification of psychotic illness with factors representing dimensional ratings of symptoms.

World Psychiatry, Sep 9, 2021

447 is training. Again, training has from the start been foundational to values-based practice. A... more 447 is training. Again, training has from the start been foundational to values-based practice. Among new training initiatives is an international web-based masters-level programme in Phenomenology and Values-based Clinical Care (PVbCC). Jointly sponsored by the Collaborating Centre for Values-based Practice in Oxford and the Santa Casa de São Paulo School of Medical Sciences in Brazil, with international partners (including the WPA Section on Philosophy and Humanities), the programme offers a series of master classes delivered by experts from different parts of the world (see https://metamastersonline.com). Participating students will thereby gain an additional international level of experience over and above their respective national home study programmes. As such, the PVbCC programme will help to build what, many years ago, and anticipating contemporary developments, a former President of the Royal College of Psychiatrists, J. Birley, called an international “open society” of mental health stakeholders underpinning best practice in personalized mental health care. Kenneth W.M. Fulford, Ashok Handa St. Catherine’s College, Oxford, UK; Faculty of Philosophy, University of Oxford, Oxford, UK; Nuffield Department of Surgical Sciences, J. Radcliffe Hospital, Oxford, UK

American Journal of Geriatric Psychiatry, Aug 1, 2019

This study compared brain energy metabolism, as measured by cerebral concentrations of glutamate ... more This study compared brain energy metabolism, as measured by cerebral concentrations of glutamate (Glu), glutamine (Gln), and N-acetyl aspartate (NAA), in older age bipolar depression (OABD) to that of psychiatrically healthy comparison subjects using proton (1 H) magnetic resonance spectroscopy imaging at 4-Tesla. Metabolite levels were assessed in OABD subjects before and after 8 weeks of lamotrigine therapy with the goal of determining relationships between cerebral energy metabolism, depression symptom severity, and changes in depression symptom response. Methods: Individuals (n = 21, mean age: 62.0 § 5.9 years) with bipolar disorder, current episode depressed, and a healthy comparison group (n = 14, mean age: 67.5 § 8.8 years) were selected. Participants with bipolar disorder, current episode depressed, were treated in open label fashion with lamotrigine monotherapy for 8 weeks. All subjects were scanned with 1 H magnetic resonance spectroscopy at 4T at baseline and again after 8 weeks to assess levels of cerebral metabolites in the anterior cingulate cortex and parieto-occipital cortex. Metabolite levels were examined as ratios relative to creatine (Cr). Response to 8 weeks of lamotrigine treatment in the bipolar disorder, current episode depressed group, was assessed as a continuous measure on the Montgomery-Asberg Depression Rating Scale. Results: NAA/Cr ratio in OABD was significantly lower by 14% (95% confidence interval: [1%, 26%]) than in comparison subjects at baseline. However, there were no associations between NAA/Cr, Glu/Cr, or Gln/Cr and either depression severity or lamotrigine treatment. Conclusion: Group differences in NAA suggest evidence for a deficit in cerebral energy metabolism in OABD.

International Journal of Geriatric Psychiatry, Aug 1, 2009

IntroductionWe investigated tissue specific differences in markers of energy metabolism, includin... more IntroductionWe investigated tissue specific differences in markers of energy metabolism, including high energy phosphate compounds (beta and total NTP, PCr) and pH, in older adults with depression compared with healthy controls, before and after a 12‐week treatment trial of sertraline.MethodsThirteen older adults, age ≥55, with Major Depressive Disorder (HAMD17 score of ≥18) were recruited along with ten age‐matched controls. The depression subjects had a pre‐ and post‐treatment 4T 31P‐MRS scan using a three‐dimensional chemical shift imaging sequence. The extracted brain images were segmented into white matter (WM), gray matter (GM) and CSF. A linear mixed effects model analyzed the effects of pre‐treatment and post‐treatment depression on phosphorus metabolite concentration estimates (including calculated pH and Mg++).ResultsTotal tissue beta‐NTP (−8%, t(18.66) = 3.50; p = 0.0024) and total tissue total NTP (−6%, t(17.41) = 2.68; p = 0.0156) were lower in subjects with geriatric depression compared with healthy controls. Total tissue levels of total‐NTP changed significantly with treatment (−2%, t(14.84) = −2.47; p = 0.0259). Total NTP was reduced in the WM, but not the GM, in the pre‐treatment depression group (t(51.65) = 4.02; p = 0.0002). Intracellular pH was higher in the GM of subjects with pre‐treatment depression (t(1133.84) = −2.10; p = 0.0353) and decreased to approximate control levels after treatment (t(648.86) = −2.53; p = 0.0115).DiscussionThese findings demonstrate bioenergetic changes including tissue specific differences in 31P‐MRS metabolites in geriatric depression. Decreased white matter total NTP may reflect alterations in white matter function. Copyright © 2009 John Wiley & Sons, Ltd.

NMR in Biomedicine, Nov 11, 2009

Evidence suggests that mitochondria undergo functional and morphological changes with age. This s... more Evidence suggests that mitochondria undergo functional and morphological changes with age. This study aimed to investigate the relationship of brain energy metabolism to healthy aging by assessing tissue specific differences in metabolites observable by phosphorus (31 P) MRS. 31 P MRSI at 4 Tesla (T) was performed on 34 volunteers, aged 21-84, screened to exclude serious medical and psychiatric diagnoses. Linear mixed effects models were used to analyze the effects of age on phosphorus metabolite concentrations, intracellular magnesium and pH estimates in brain tissue. A significant age associated decrease in brain pH (S0.53% per decade), increase in PCr (1.1% per decade) and decrease in PME (1.7% per decade) were found in total tissue, with PCr effects localized to the gray matter. An increase in beta NTP as a function of age (1% per decade) approached significance (p ¼ 0.052). There were no effects demonstrated with increasing age for intracellular magnesium, PDE or inorganic phosphate. This study reports the effects of healthy aging on brain chemistry in the gray matter versus white matter using 31 P MRS measures of high energy phosphates, pH and membrane metabolism. Increased PCr, increased beta NTP (reflecting ATP) and reduced pH may reflect altered energy production with healthy aging. Unlike some previous studies of aging and brain chemistry, this study examined healthy, non-demented and psychiatrically stable older adults and specifically analyzed gray-white matter differences in brain metabolism.

Expert Review of Clinical Pharmacology

American Journal of Psychiatry

Journal of Autism and Developmental Disorders, 2021

The purpose of the study was to characterize repetitive phenomena in Williams syndrome (WS). The ... more The purpose of the study was to characterize repetitive phenomena in Williams syndrome (WS). The parents of 60 subjects with WS completed the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) or Children’s Y-BOCS, the Yale Global Tic Severity Scale, the Stereotyped Behavior Scale, and the Spence Children’s Anxiety Scale–Parent Version. Nineteen males and 41 females participated in the study. Six subjects (10%) had obsessions only, six (10%) had compulsions only, and eleven (18%) had at least one obsession and at least one compulsion. None of the subjects had tics. Fifty subjects (83.3%) endorsed at least one stereotypy. Increased anxiety was associated with increased severity of obsessions, but not severity of compulsions or stereotypies.

Journal of Autism and Developmental Disorders, 2021

Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and qua... more Anxiety is being increasingly identified in Angelman syndrome (AS). Qualitative questions and quantitative assessments were used to evaluate for anxiety in 50 subjects with AS. In-person evaluations assessed behaviors concerning for anxiety and circumstances wherein they occurred. Caregivers completed anxiety and other behavioral rating scales. Caregiver responses were categorized and compared to items from anxiety rating scales. The most common behavioral manifestation of anxiety was "aggression." The most common circumstance was "separation from caregiver/parent." Subjects had elevated scores on anxiety, irritability and hyperactivity scales with lower mean scores among subjects with a maternal deletion. The Pediatric Anxiety Rating Scale best captured behaviors described by caregivers. Existing anxiety scales should be adapted for use in AS.

American Journal of Medical Genetics Part A, 2020

The objectives of this study were to characterize the sleep habits of 50 clinically referred indi... more The objectives of this study were to characterize the sleep habits of 50 clinically referred individuals with Angelman syndrome (AS) and to retrospectively compare the effectiveness/tolerability of the three most commonly prescribed sleep medications in the sample. An experienced physician assigned a Clinical Global Impressions‐Severity scale (CGI‐S) score for each subject's AS‐specific symptoms. Caregivers completed the Child Sleep Habits Questionnaire (CSHQ; screen for sleep problems in school‐aged [4–10 years] children), a screening assessment for sleep problems. Caregivers provided information about medication trials targeting disturbed sleep, with the physician assigning a CGI‐Improvement scale (CGI‐I) score for each trial. Linear regression showed significant negative association between age and CSHQ score. In their lifetime, 72% of participants had taken a medication for sleep, most commonly melatonin, clonidine and trazodone. The majority continued these for 6 months or ...